sildenafil-citrate and Heart-Failure

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Topics: Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Guanosine Monophosphate; Guanylate Cyclase; Heart Failure; Humans; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Retrospective Studies; Sildenafil Citrate; Soluble Guanylyl Cyclase; Tadalafil; Vasodilator Agents

Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Cardiac Catheterization; Cardiac Surgical Procedures; Echocardiography; Endothelin Receptor Antagonists; Heart Failure; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Magnetic Resonance Imaging; Nitric Oxide; Oxygen Inhalation Therapy; Prostaglandins I; Sildenafil Citrate; Tomography, X-Ray Computed; Tricuspid Valve Insufficiency; Vascular Resistance; Vasodilator Agents

There is no cure for pulmonary hypertension due to left heart disease (PH-LHD), but the rationale for using sildenafil to treat pulmonary arterial hypertension with heart failure with reduced ejection fraction (HFrEF) has been supported by short-term studies. We performed a meta-analysis to evaluate the effectiveness of sildenafil for PH-LHD with HFrEF. A systematic literature search of PubMed, EMBASE and the Cochrane Central Register of Controlled Trials was conducted from inception through October 2014 for randomized trials and for observational studies with control groups, evaluating the effectiveness of sildenafil to treat PH-LHD with HFrEF. Sildenafil therapy decreased pulmonary arterial systolic pressure both at the acute phase and at the 6-month follow-up (weighted mean difference (WMD): -6.03 mm Hg, P=0.02; WMD: -11.47 mm Hg, P<0.00001, respectively). Sildenafil was found to reduce mean pulmonary artery pressure (WMD: -3 mm Hg, P=0.0004) and pulmonary vascular resistance (WMD: -60.0 dynes cm(-5), P=0.01) at the 3-month follow-up. Oxygen consumption at peak significantly increased to 3.66 ml min(-1) kg(-1) (P<0.00001), 3.36 ml min(-1) kg(-1) (P<0.00001) and 2.60 ml min(-1) kg(-1) (P=0.03) at 3, 6 and 12 months, respectively. There were significant reductions in ventilation to CO2 production slope of -2.00, -4.68 and -7.12 at 3, 6 and 12 months, respectively (P<0.00001). Sildenafil was superior to placebo regarding left ventricular ejection fraction at the 6-month follow-up (WMD: 4.35, P<0.00001), and it significantly improved quality of life. Sildenafil therapy could effectively improve pulmonary hemodynamics and cardiopulmonary exercise testing measurements of PH-LHD with HFrEF, regardless of acute or chronic treatment.

Topics: Exercise Test; Heart Failure; Humans; Hypertension, Pulmonary; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Quality of Life; Sildenafil Citrate; Stroke Volume; Ventricular Function, Left

The Fontan operation is the final step of palliation for patients with a functionally single ventricle. Since its introduction in the 1970s, the Fontan surgery has become part of a successful surgical strategy that has improved single ventricle mortality. In recent years, we have become more aware of the limitations and long-term consequences of the Fontan physiology. Pulmonary vascular resistance plays an important role in total cavopulmonary circulation, and has been identified as a potential therapeutic target to mitigate Fontan sequelae. In this review, we will discuss the results of different pulmonary vasodilator trials and the use of pulmonary vasodilators as a treatment strategy for Fontan patients.

Topics: Bosentan; Cardiac Output; Endothelin Receptor Antagonists; Fontan Procedure; Heart Defects, Congenital; Heart Failure; Humans; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Pulmonary Circulation; Pyridazines; Sildenafil Citrate; Sulfonamides; Vascular Resistance; Vasodilator Agents

Clinical trials have evaluated the use of phosphodiesterase (PDE) 5 inhibitors sildenafil as a potential adjunct in the treatment of heart failure (HF) with mixed results. Thus, we undertook a meta-analysis to evaluate the clinical viability of sildenafil in HF.. Relevant studies were searched and identified in the MEDLINE and EMBASE databases. Randomized clinical trials (RCT) comparing sildenafil to placebo, in heart failure patients, reporting at least one outcome of interest were included. Data were extracted regarding the characteristics and clinical outcomes.. We identified 9 RCTs enrolling 612 HF patients. There were no significant differences in adverse events between sildenafil group and placebo group (RR=1.10, 95% CI=0.74 to 1.65, P=0.41), whereas sildenafil therapy was associated with a marked improvement in hemodynamic parameter peak VO2 (MD=3.25, 95% CI=2.07 to 4.42, P<0.00001) in HF with reduced ejection fraction (HFrEF) patients but not in HF with preserved ejection fraction (HFpEF) patients. Also, sildenafil therapy improved VO2 at anaerobic threshold (AT) (MD=3.47, 95% CI=1.68 to 5.27, P=0.0002), VE/VCO2 slope (MD=-7.06, 95% CI=-8.93 to -5.19, P<0.00001) and LV ejection fraction (MD=5.43, 95% CI=3.66 to 7.20, P<0.00001) compared to placebo in HF patients, which had no impact on blood pressure and heart rate. For quality of life (emotional function, fatigue and breathlessness), there was no significant difference between the two groups.. Sildenafil improved hemodynamic parameters particularly in HFrEF patients when compared to placebo, with no increase in adverse events. Sildenafil treatment was well tolerated and had no impact on quality of life.

Topics: Heart Failure; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Ventricular Remodeling

There is no robust evidence that any treatment can modify the natural history of patients with heart failure and preserved left ventricular ejection fraction (HFpEF), although most agree that diuretics can control congestion and improve symptoms. HFpEF is often complicated by systemic and pulmonary hypertension, atrial fibrillation, obesity, chronic lung and kidney disease, lack of physical fitness, and old age that can complicate both diagnosis and management. Further trials should phenotype patients precisely and create better definitions of HFpEF based on biomarkers.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin-Converting Enzyme Inhibitors; Digoxin; Drug Therapy, Combination; Female; Heart Failure; Humans; Male; Middle Aged; Piperazines; Prognosis; Purines; Randomized Controlled Trials as Topic; Reference Values; Risk Assessment; Sildenafil Citrate; Stroke Volume; Sulfonamides; Survival Analysis; Syndrome; Treatment Outcome; Ventricular Function, Left

Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases.

Topics: Animals; Coronary Circulation; Cross-Over Studies; Disease Models, Animal; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Prognosis; Purines; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Analysis; Treatment Outcome

Nitric oxide (NO) is recognized as one of the most important cardiovascular signaling molecules, with multiple regulatory effects on myocardial and vascular tissue as well as on other tissues and organ systems. With the growth in understanding of the range and mechanisms of NO effects on the cardiovascular system, it is now possible to consider pharmaceutical interventions that directly target NO or key steps in NO effector pathways. This article reviews aspects of the cardiovascular effects of NO, abnormalities in NO regulation in heart failure, and clinical trials of drugs that target specific aspects of NO signaling pathways.

Topics: Biological Availability; Cardiovascular System; Endothelium, Vascular; Guanylate Cyclase; Heart Failure; Humans; Nitric Oxide; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Treatment Outcome; Ventricular Dysfunction, Left

Cyclic guanosine monophosphate (cGMP) and its primary signaling kinase, protein kinase G, play an important role in counterbalancing stress remodeling in the heart. Growing evidence supports a positive impact on a variety of cardiac disease conditions from the suppression of cGMP hydrolysis. The latter is regulated by members of the phosphodiesterase (PDE) superfamily, of which cGMP-selective PDE5 has been best studied. Inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischemic injury, and cardiotoxicity. Clinical trials have begun exploring their potential to benefit dilated cardiomyopathy and heart failure with a preserved ejection fraction. This review discusses recent developments in the field, highlighting basic science and clinical studies.

Topics: Carbolines; Cardiomyopathy, Dilated; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Fibrosis; Heart; Heart Failure; Humans; Hypertrophy; Myocardium; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Transforming Growth Factor beta; TRPC Cation Channels; Ventricular Remodeling

Topics: Carbolines; Heart Failure; Humans; Imidazoles; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Tadalafil; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

To review the efficacy and safety of phosphodiesterase-5 (PDE5) inhibitors in the treatment of patients with chronic systolic heart failure (HF).. Literature was retrieved through MEDLINE (1966-September 2011) and EMBASE (1980-September 2011), using the medical subject heading terms heart failure and phosphodiesterase-5 inhibitors, sildenafil, tadalafil, and vardenafil. Focus was placed on multidose trials of patients with systolic HF, because of these trials' greater strength of clinical evidence.. All English-language, peer-reviewed publications were analyzed for relevance. Studies appropriate to the objective were evaluated, including 4 multidose trials investigating the effect of sildenafil on cardiovascular function.. In patients with New York Heart Association class II or III HF, treatment with sildenafil was associated with improvements in cardiac index, right ventricular ejection fraction, and other markers of cardiovascular function, as well as reduced pulmonary arterial pressure. Study durations ranged from 4 weeks to 1 year, and the studies used varying doses of sildenafil, ranging from 75 to 225 mg/day, in divided doses. The most common adverse effects associated with sildenafil therapy were headache and flushing.. Based on current studies, sildenafil appears to be well tolerated and can improve markers of cardiovascular and pulmonary function in patients with HF. PDE5 inhibitors may be a therapeutic option for patients who cannot tolerate standard therapy for HF or who remain symptomatic with standard therapy. Larger long-term trials are necessary to better understand the role of PDE5 inhibitors in HF.

Topics: Chemotherapy, Adjuvant; Clinical Trials as Topic; Heart Failure; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones

Drugs that inhibit cyclic nucleotide phosphodiesterase activity act to increase intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content. In total, 11 families of these enzymes-which differ with respect to affinity for cAMP and cGMP, cellular expression, intracellular localization, and mechanisms of regulation-have been identified. Inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases raise intracellular cAMP content in cardiac and vascular smooth muscle, with inotropic and, to a lesser extent, vasodilatory actions. These drugs have been used for many years in the treatment of patients with heart failure, but their long-term use has generally been shown to increase mortality through mechanisms that remain unclear. More recently, inhibitors of PDE5 cyclic nucleotide phosphodiesterases have been used as cGMP-raising agents in vascular smooth muscle. With respect to cardiovascular disease, there is evidence that these drugs are more efficacious in the pulmonary than in the systemic vasculature, for which reason they are used principally in patients with pulmonary hypertension. Effects attributable to inhibition of myocardial PDE5 activity are less well characterized. New information indicating that enzymes from the PDE1 family of cyclic nucleotide phosphodiesterases constitute the majority of cAMP- and cGMP-hydrolytic activity in human myocardium raises questions as to their role in regulating these signaling pathways in heart failure.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Heart Failure; Hemodynamics; Humans; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Pulmonary hypertension (PH) is a relatively common hemodynamic finding in patients with left-sided heart disease and is usually associated with increased morbidity and mortality. However, so far no study has demonstrated long-term benefit from drugs specifically designed to improve pulmonary hemodynamics. There are currently no consensus recommendations on the management of PH in patients with chronic left heart failure. Most importantly, the underlying cause of left heart disease should be treated first. While previous studies with endothelin receptor antagonists or epoprostenol have been disappointing, initial promising results have been published for the phosphodiesterase-5 inhibitor sildenafil. Following acute administration and with chronic therapy for up to 6 months sildenafil improved hemodynamic parameters and exercise capacity in patients with PH and chronic left heart failure. Until the results from larger randomized controlled trials become available, the treatment of chronic left heart failure should follow the current guidelines.

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Treatment of heart failure (HF) is a challenging task. An impaired nitric oxide pathway contributes to several abnormal cardiac and vascular phenotypes typical of the failing cardiovascular system. Inhibition of phosphodiesterase-5 (PDE5) is a new therapeutic strategy for overexpressing nitric oxide signaling by increasing the availability of cyclic guanosine monophosphate (cGMP). A number of background studies support the use of PDE5 inhibitors in HF. Treatment of pulmonary hypertension secondary to left ventricular dysfunction appears to be a primary target by virtue of the high PDE5 selectivity for the pulmonary circulation. Basic studies suggest that increased cGMP activity by PDE5 inhibition has potentially favorable direct myocardial effects that may block adrenergic, hypertrophic, and proapoptotic signaling. Furthermore, studies in humans have underscored the benefits of acute PDE5 inhibition on lung diffusion capacity, systemic endothelial function, muscle perfusion, and exercise performance. Despite promising initial data, larger controlled trials are necessary to define the safety, tolerability, and potential impact of PDE5 inhibitors on morbidity and mortality across the wide spectrum of patients with HF.

Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Exercise Tolerance; Female; Heart Failure; Heart Function Tests; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Purines; Respiratory Function Tests; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

Modern health care has greatly increased longevity for patients with congenital hemolytic anemias (such as sickle cell disease and thalassemia) and human immunodeficiency virus (HIV) infection. It is estimated that 10% of patients with hemoglobinopathies and 0.5% of patients with HIV infection develop moderate to severe pulmonary hypertension. Pulmonary hypertension is a relentlessly progressive disease leading to right heart failure and death. Worldwide, there are an estimated 30 million patients with sickle cell disease or thalassemia and 40 million patients with HIV disease. Considering the prevalence of pulmonary vascular disease in these populations, sickle cell disease and HIV disease may be the most common causes of pulmonary hypertension worldwide. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for these diseases are summarized. Because therapy is likely to reduce morbidity and prolong survival, efforts to screen, diagnose, and treat these patients represent a global health opportunity.

Topics: Anemia, Hemolytic, Congenital; Anemia, Sickle Cell; Antiretroviral Therapy, Highly Active; Blood Transfusion; Echocardiography, Doppler, Color; Heart Failure; HIV Infections; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive disease marked by vasoconstriction and vascular remodeling within pulmonary arteries leading to right heart failure and death. Significant advances in understanding the pathobiology of the disease have identified three key pathways involved in progression of this disease, which are the endothelin pathway, the prostacyclin pathway, and the nitric oxide/cyclic guanosine monophosphate pathway. Echocardiogram is the best screening tool to obtain an estimation of the pulmonary artery systolic pressure but right heart catheterization remains the standard by which the diagnosis is made. There are currently six FDA approved therapies for PAH. The mechanistic rationale, evidence behind their use and side effect considerations in utilizing these therapies in PAH patients will be the focus of this review.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Disease Progression; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Prognosis; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasoconstriction

Type Sphosphodiesterase inhibitors (FDEI-5) used to be applied as the main drugs for treatment of erectile dysfunction. At present, this pharmacological group is being studied intensively in various fields of clinical medicine, such as pulmonology, cardiology, gastroenterology, gynecology etc. Part II of this system literature review is dedicated to analysis of the results of such application. In many randomized and non-randomized controlled studies sildenafil decreased pulmonary arterial pressure (independently of etiology) and pulmonary vascular resistance; it could be successfully combined with nitric oxide, illoprost, or epoprostenolol. Clinical studies have also demonstrated an increase in physical load tolerance, optimization of PAH studies according to NYHA functional classes, and good tolerance to the drug. In the recent years, antiischaemic effects of FDEI-5 and their ability to inhibit apoptosis have been proved It is possible to draw the conclusion that nature created a universal phosphodiesterase mechanism for the interconnection of biochemical processes that provide the vital activity of the cell and organism. The fact that more than 15 controlled studies of clinical application of sildenafil not for treatment of erectile dysfunction have been planned and commenced confirms the importance of further studies of this mechanism. Further analysis of the results will show how universal this mechanism is.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Bronchodilator Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy; Drug Therapy, Combination; Forecasting; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Myocardial Infarction; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

In less than 20 years, the first selective type 5 phosphodiesterase inhibitor, sildenafil, has evolved from a potential anti-angina drug to an on-demand oral treatment for erectile dysfunction (Viagra), and more recently to a new orally active treatment for pulmonary hypertension (Revatio). Here we describe the key milestones in the development of sildenafil for these diverse medical conditions, discuss the advances in science and clinical medicine that have accompanied this journey and consider possible future indications for this versatile drug.

Topics: Angina Pectoris; Cerebrovascular Circulation; Erectile Dysfunction; Heart Failure; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Patients with heart failure (HF) due to left ventricular (LV) systolic dysfunction have abnormal endothelium-dependent, nitric oxide-cyclic guanosine monophosphate-mediated vasodilation in the pulmonary and skeletal muscle vasculature. Therefore, inhibition of type 5 phosphodiesterase (PDE5), the principle enzyme responsible for cyclic guanosine monophosphate catabolism in the lungs and skeletal muscle, has been targeted in an effort to counteract vasoconstriction that contributes to increased right and LV afterload in HF. The efficacy of PDE5 inhibition in the treatment of pulmonary arterial hypertension has led to the investigation of its potential utility in the treatment of HF patients with secondary pulmonary hypertension. Moreover, recent preclinical studies suggest direct myocardial effects of PDE5 inhibition that may counteract beta-adrenergic, hypertrophic, and pro-apoptotic signaling, three critical pathways in the development of LV dysfunction. This review outlines both the underlying rationale and the results of initial studies of the therapeutic effects of PDE5 inhibition in HF.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise Tolerance; Heart; Heart Failure; Humans; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilation

Chronic heart failure (HF) is an increasingly common cardiovascular disorder. The goal of health-care providers is to optimize quality of life in this population, including sexual health. Up to 75% of patients with HF report erectile dysfunction (ED). As HF is a condition with distinct physiologic sequelae, some unique organic and psychological factors contributing to ED in this patient population have been identified, along with risk factors common to the development of coronary artery disease, HF and ED. This review describes contributing factors to ED in the setting of HF and highlights treatment considerations for this distinct patient population.

Topics: Adrenergic beta-Antagonists; Angioplasty, Balloon; Depression; Digoxin; Diuretics; Endothelium, Vascular; Erectile Dysfunction; Exercise; Heart Failure; Humans; Male; Piperazines; Purines; Sexual Behavior; Sildenafil Citrate; Sulfones

The availability of selective inhibitors of the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase (PDE5) has created increasing interest in unlocking the therapeutic potential of PDE5 inhibition in cardiovascular diseases that are marked by dysfunction of nitric oxide (NO)-cGMP signaling. Pulmonary arterial hypertension (PAH) and heart failure (HF) are characterized by pulmonary arterial vasoconstriction that is thought to be caused by relative deficiencies of vasodilators such as NO and exaggerated production of vasoconstrictors such as endothelin. PDE5 is abundant in the pulmonary vasculature where it catabolizes cGMP, the second messenger of NO. Inhibition of PDE5 has been shown to lower pulmonary vascular resistance in PAH and HF by augmenting local cGMP. This review outlines the therapeutic potential of PDE5 inhibition for the treatment of PAH and HF.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

Vericiguat is approved for the treatment of patients with heart failure with ejection fraction < 45%. Sildenafil, indicated for the treatment of erectile dysfunction, is a potential co-medication in male patients. This study investigated the safety and tolerability of co-administration of vericiguat and sildenafil in healthy volunteers.. This was a single-center, randomized, placebo-controlled, parallel-group study in 32 healthy white male volunteers. Participants received vericiguat 10 mg or placebo once daily for 16 days. Both groups received single doses of sildenafil (25 mg, 50 mg, and 100 mg) on days 13-15. Safety, hemodynamic changes, and pharmacokinetic effects were assessed.. All subjects in the vericiguat group and seven (43.8%) in the placebo group reported one or more treatment-emergent adverse events, all of mild or moderate intensity. Decreases in seated blood pressure (≤ 5.4 mmHg) with the vericiguat-sildenafil combination compared with placebo-sildenafil were small and there was no evidence of a sildenafil dose-related effect. Standing blood pressure and standing and seated heart rate were similar between treatment groups. Co-administration of sildenafil did not affect vericiguat pharmacokinetics. A mild increase in sildenafil exposure (≤ 22%) when co-administered with vericiguat was observed.. Adding single doses of sildenafil to vericiguat 10 mg once daily at steady state was well tolerated and produced a minimal reduction in seated blood pressure (≤ 5.4 mmHg) compared with administration of sildenafil alone. There was no effect of sildenafil on vericiguat pharmacokinetics, and an increase in sildenafil exposure with vericiguat co-administration was not clinically relevant.. EudraCT no. 2015-004997-14.. Vericiguat is approved for the treatment of patients with heart failure with reduced ejection fraction. Sildenafil is a treatment for erectile dysfunction. This study investigated whether sildenafil was safe to use in individuals treated with vericiguat. In total, 32 healthy white male volunteers were randomly allocated to receive either vericiguat 10 mg or placebo once daily for 16 days. Both groups received single doses of sildenafil (25 mg, 50 mg, and 100 mg) on days 13–15. Co-administration of single doses of sildenafil and vericiguat 10 mg was well tolerated. All side effects were of mild or moderate intensity, and the addition of sildenafil to vericiguat had a minimal effect on blood pressure. Giving these drugs together did not alter the way either drug was absorbed, distributed, or eliminated by the body to a clinically relevant extent.

Topics: Adult; Double-Blind Method; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Male; Pyrimidines; Sildenafil Citrate

Long-term benefits of pulmonary artery denervation (PADN) for patients with combined precapillary and postcapillary pulmonary hypertension (CpcPH) secondary to left heart failure are unknown.. The authors sought to report the 3-year clinical results of PADN for patients with CpcPH.. A total of 98 patients with CpcPH, defined as having mean pulmonary arterial pressure of ≥25 mm Hg, pulmonary capillary wedge pressure of >15 mm Hg, and pulmonary vascular resistance of >3.0 WU, were randomly assigned to receive the sham + sildenafil or PADN. The primary endpoint was the occurrence of clinical worsening defined as cardiopulmonary death, rehospitalization or heart/lung transplantation at 3-year follow-up. Changes in the 6-minute walk distance and N-terminal pro-B-type natriuretic peptide served as secondary points.. At the 3-year follow-up, clinical worsening was reported in 49 (50.0%) patients, with 31 (62.0%) in the sham + sildenafil group and 18 (37.5%) in the PADN group (HR: 2.13 [95% CI: 1.19-3.81]; P = 0.011), largely driven by a higher rate of rehospitalization in the sham + sildenafil group (56.2% vs 35.4%; HR: 1.96 [95% CI: 1.07-3.58]; P = 0.029) by Cox proportional hazards regression. At the end of the study, cardiopulmonary-related deaths occurred in 16 (32.0%) patients in the sham and 9 (18.8%) (P = 0.167) patients in the PADN group. PADN also resulted in a more profound increase in the 6-minute walk distance and reduction in N-terminal pro-B-type natriuretic peptide.. PADN is associated with significant improvements in exercise capacity, cardiac function, and clinical outcomes. Further study without approved drugs for pulmonary arterial hypertension is required to confirm the benefits of PADN for patients with CpcPH. (Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure [PADN-5]; NCT02220335).

Topics: Heart Failure; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Pulmonary Artery; Sildenafil Citrate

Pulmonary hypertension (PHT) may complicate heart failure with reduced ejection fraction (HFrEF) and is associated with a substantial symptom burden and poor prognosis. Sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, might have beneficial effects on pulmonary haemodynamics, cardiac function and exercise capacity in HFrEF and PHT. The aim of this study was to determine the safety, tolerability, and efficacy of sildenafil in patients with HFrEF and indirect evidence of PHT.. The Sildenafil in Heart Failure (SilHF) trial was an investigator-led, randomized, multinational trial in which patients with HFrEF and a pulmonary artery systolic pressure (PASP) ≥40 mmHg by echocardiography were randomly assigned in a 2:1 ratio to receive sildenafil (up to 40 mg three times/day) or placebo. The co-primary endpoints were improvement in patient global assessment by visual analogue scale and in the 6-min walk test at 24 weeks. The planned sample size was 210 participants but, due to problems with supplying sildenafil/placebo and recruitment, only 69 patients (11 women, median age 68 (interquartile range [IQR] 62-74) years, median left ventricular ejection fraction 29% (IQR 24-35), median PASP 45 (IQR 42-55) mmHg) were included. Compared to placebo, sildenafil did not improve symptoms, quality of life, PASP or walk test distance. Sildenafil was generally well tolerated, but those assigned to sildenafil had numerically more serious adverse events (33% vs. 21%).. Compared to placebo, sildenafil did not improve symptoms, quality of life or exercise capacity in patients with HFrEF and PHT.

Topics: Aged; Double-Blind Method; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase 5 Inhibitors; Quality of Life; Sildenafil Citrate; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Double-Blind Method; Exercise Tolerance; Heart Failure; Humans; Hypertension, Pulmonary; Sildenafil Citrate; Stroke Volume; Ventricular Dysfunction, Left

We explore the dual benefits of sildenafil on bi-ventricular functions in the form of improvement of ejection fraction, pulmonary vascular resistance and functional capacity of systolic heart failure patients either related to dilated or ischemic cardiomyopathy.. To evaluate the effect of oral sildenafil on biventricular function in patients with left ventricular systolic dysfunction.. The prospective randomised case-control study included 80 patients with left ventricular systolic dysfunction resulting from dilated or ischemic cardiomyopathy were equally randomised to one of the treatment groups in (1:1) who were collected from the outpatient clinic of cardiac care unit (CCU) of Beni-Suef University hospital; each group contained 40 patients: The first group (control group): received the guideline-recommended treatment of heart failure with reduced ejection fraction which consists of [angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonist, digoxin]. The second group (sildenafil group): received the previously mentioned guideline-recommended treatment in the control group plus sildenafil 25 mg three times per day. All patients were subjected to detailed history taking, baseline transthorathic echocardiography and exercise ECG using the Naughton protocol. Follow-up transthorathic echocardiography and exercise ECG was conducted after 3 months.. Sildenafil improves heart failure symptoms such as dyspnea or orthopnea or increasing the functional capacity of myocardium which is measured by estimated metabolic equivalents of task (METS) (P = .017), and exercise duration (P = .013). Sildenafil increased cardiac output (P = .033), which is considered one of the desirable targets in heart failure patients.. In patients with left ventricular systolic dysfunction secondary to dilated or ischemic cardiomyopathy, relatively small doses of sildenafil significantly enhances exercise period and functional ability, with substantial improvement in left ventricular systolic function irrespective of the existence of major pulmonary hypertension.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Heart Failure; Hemodynamics; Humans; Prospective Studies; Sildenafil Citrate; Ventricular Dysfunction, Left; Ventricular Function, Left

We aimed to 1) describe characteristics of patients with heart failure with preserved ejection fraction (HFpEF) enrolled in RELAX stratified by normal or elevated baseline serum uric acid (sUA) level; 2) evaluate the association between sUA level and surrogate clinical measures; and 3) assess associations between changes in sUA level over time and changes in surrogate clinical measures.. We analyzed 212 patients with HFpEF and normal or elevated (>6 mg/dL) baseline sUA measurements from the RELAX trial. Variables examined included clinical characteristics, cardiopulmonary exercise testing, 6-minute walk testing, quality of life, echocardiography, and serum biomarker testing. Baseline characteristics between groups were compared and scatter plots with quadratic regression lines and linear regression modeling were used to assess the relationship between baseline sUA and clinical measures. Kaplan-Meier curves were used to describe composite death or cardiovascular/renal hospitalization.. sUA is an important marker of comorbidities and functional status in patients with HFpEF. Clinical trials of sUA-lowering therapies in patients with HFpEF are promising.

Topics: Aged; Double-Blind Method; Female; Heart Failure; Humans; Male; Middle Aged; Sildenafil Citrate; Uric Acid; Vasodilator Agents

Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH). A pulmonary vascular contribution could be considered as a substantial therapeutic target in HFpEF and PH and combined pre- and postcapillary PH (Cpc-PH).. We enrolled 50 patients with HFpEF and Cpc-PH who were determined by echocardiography to have pulmonary artery systolic pressure (PASP) > 40 mmHg, pulmonary vascular resistance > 3 Wood units, and/or transpulmonary gradient > 15 mmHg.. The patients were assigned to the phosphodiesterase 5 (PDE5) inhibitor sildenafil group (25 mg TID for 3 months followed by 50 mg TID for 3 months; n = 30) or the control group (n = 20). In the sildenafil group after 6 months, the 6-min walk distance increased by 50 m (95% CI, 36 to 64 m); substantial improvement in NYHA functional class and exercise capacity during diastolic stress test were revealed; decreases in early mitral inflow to mitral annulus relaxation velocities ratio by 2.4 (95% CI, - 3.3 to - 1.4) and PASP by 17.0 mmHg (95% CI, 20.4 to 13.5) were observed; right ventricular systolic function (M-mode tricuspid annular plane systolic excursion) increased by 0.42 cm (95% CI, 0.32 to 0.52 cm; P < 0.01 for all). No changes occurred in the control group.. In a subset of patients with HFpEF and Cpc-PH assessed by echocardiography, PDE5 inhibition was associated with an improvement in exercise capacity, pulmonary haemodynamic parameters, and right ventricular function. The role of sildenafil needs to be considered in randomized trials in selected patients with HFpEF with invasively confirmed Cpc-PH.. Russian National Information System of Research, Development and Technology Data of Civilian Usage (NIS, https://rosrid.ru), registration number 01201257849 . Registered 20 April 2012. This manuscript adheres to the CONSORT guidelines.

Topics: Aged; Arterial Pressure; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pilot Projects; Pulmonary Artery; Recovery of Function; Russia; Sildenafil Citrate; Stroke Volume; Time Factors; Treatment Outcome; Vasodilator Agents; Ventricular Function, Right

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

Topics: Aged; Cytochrome P-450 CYP3A; Exercise Tolerance; Female; Genotype; Heart Failure; Humans; Male; Middle Aged; Sildenafil Citrate; Stroke Volume; Vasodilator Agents

We aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD).. The sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure ≥ 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group [odds ratio 0.39; 95% confidence interval (CI) 0.22-0.67; P < 0.001]. The Kaplan-Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0-4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler-derived systolic pulmonary pressure were similar in both groups.. Treatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided. The trial is registered with ClinicalTrials.gov, number NCT00862043.

Topics: Aged; Double-Blind Method; Female; Heart Failure; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Male; Placebos; Pulmonary Wedge Pressure; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Microvascular inflammation may contribute to the pathogenesis of both heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH). We investigated whether the inflammation biomarker C-reactive protein (CRP) was associated with clinical characteristics, disease severity or PH in HFpEF.. Patients in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart failure (RELAX) trial had baseline high-sensitivity CRP levels measured (n = 214). Clinical characteristics, exercise performance, echocardiographic variables and biomarkers of neurohumoral activation, fibrosis and myocardial necrosis were assessed. Patients with normal (≤3mg/L) versus high (>3mg/L) CRP levels were compared.. The median CRP level was 3.69mg/L. CRP was elevated in 57% of patients. High CRP levels were associated with younger age, higher body mass index (BMI), chronic obstructive pulmonary disease (COPD), lower peak oxygen consumption and higher endothelin-1 and aldosterone levels. CRP increased progressively with the number of comorbidities (0.7mg/L per increment in comorbidity number, P = 0.02). Adjusting for age, BMI and statin use, high CRP levels were additionally associated with atrial fibrillation, right ventricular dysfunction, and higher N-terminal pro-B-type natriuretic peptide levels (P<0.05 for all). CRP was not associated with PH or left ventricular function. CRP did not identify responders to sildenafil(P-value for interaction 0.13).. In HFpEF, high CRP is associated with greater comorbidity burden and some markers of disease severity but CRP was normal in 40% of patients. These findings support the presence of comorbidity-driven systemic inflammation in HFpEF but also the need to study other biomarkers which may better reflect the presence of systemic inflammation.

Topics: Aged; Biomarkers; C-Reactive Protein; Comorbidity; Female; Heart Failure; Humans; Male; Middle Aged; Motor Activity; Phosphodiesterase 5 Inhibitors; Severity of Illness Index; Sildenafil Citrate; Stroke Volume

We recently showed that sildenafil did not improve pulmonary pressures and exercise capacity in a cohort of patients with heart failure and preserved ejection fraction (HFpEF) and predominantly postcapillary pulmonary hypertension. Here, we present the effects of sildenafil on cardiac structure and function, cardiopulmonary exercise testing, laboratory parameters and health-related quality of life measures.. Fifty-two HFpEF patients with pulmonary hypertension (mean pulmonary artery pressure >25 mmHg; pulmonary artery wedge pressure >15 mmHg) were randomized to sildenafil 60 mg three times a day or placebo and treated for 12 weeks. Sildenafil neither changed cardiac structure nor function on echocardiography compared with placebo. Considering all patients irrespective of maximal effort, sildenafil reduced peak heart rate by 8 b.p.m. [95% confidence interval (CI) -14.97 to -1.03] and peak blood pressure by 13.8 mmHg (95% CI -22.04 to -5.47)/7.3 mmHg (95% CI -13.60 to -1.07) (both P < 0.05 vs. placebo). The minute ventilation/carbon dioxide production (VE/VCO. Treatment with sildenafil for 12 weeks in patients with HFpEF and predominantly isolated postcapillary pulmonary hypertension did not affect cardiac structure and function, integrative exercise responses, laboratory parameters, and/or quality of life. Clinicaltrials.gov number NCT01726049.

Topics: Aged; Aged, 80 and over; Blood Pressure; Cardiac Catheterization; Echocardiography; Exercise Test; Female; Glycated Hemoglobin; Health Status; Heart Failure; Heart Rate; Hemoglobins; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Pulmonary Wedge Pressure; Quality of Life; Sildenafil Citrate; Stroke Volume; Treatment Outcome

Soluble suppression of tumorigenicity 2 (sST2) receptor is a biomarker that is elevated in certain systemic inflammatory diseases. Comorbidity-driven microvascular inflammation is postulated to play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology, but data on how sST2 relates to clinical characteristics or inflammatory conditions or biomarkers in HFpEF are limited. We sought to determine circulating levels and clinical correlates of sST2 in HFpEF.. At enrollment, patients (n=174) from the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial of sildenafil in HFpEF had sST2 levels measured. Clinical characteristics; cardiac structure and function; exercise performance; and biomarkers of neurohumoral activation, systemic inflammation and fibrosis, and myocardial necrosis were assessed in relation to sST2 levels. Median sST2 levels in male and female HFpEF patients were 36.7 ng/mL (range 30.9-49.2 ng/mL; reference range 4-31 ng/mL) and 30.8 ng/mL (range 25.3-39.3 ng/mL; reference range 2-21 ng/mL), respectively. Among HFpEF patients, higher sST2 levels were associated with the presence of diabetes mellitus; atrial fibrillation; renal dysfunction; right ventricular pressure overload and dysfunction; systemic congestion; exercise intolerance; and biomarkers of systemic inflammation and fibrosis, neurohumoral activation, and myocardial necrosis (. In HFpEF, sST2 levels were associated with proinflammatory comorbidities, right ventricular pressure overload and dysfunction, and systemic congestion but not with left ventricular geometry or function. These data suggest that ST2 may be a marker of systemic inflammation in HFpEF and potentially of extracardiac origin.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.

Topics: Aged; Biomarkers; Diastole; Dose-Response Relationship, Drug; Echocardiography, Doppler; Exercise Test; Exercise Tolerance; Female; Heart Failure; Heart Ventricles; Humans; Interleukin-1 Receptor-Like 1 Protein; Magnetic Resonance Imaging, Cine; Male; Phosphodiesterase 5 Inhibitors; Receptors, Interleukin-1; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure

Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV-pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV-PA coupling may be uniquely sensitive to sildenafil.. In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV-PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO2 slope were unchanged with sildenafil. There was no interaction between RV-PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO2 in patients with pulmonary hypertension and RVD.. HFpEF patients with RVD and impaired RV-PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV-PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.

Topics: Aged; Aged, 80 and over; Diastole; Exercise Tolerance; Female; Heart Failure; Humans; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Circulation; Pulmonary Ventilation; Recovery of Function; Severity of Illness Index; Sildenafil Citrate; Stroke Volume; Time Factors; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Right; Ventricular Function, Left; Ventricular Function, Right

Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity.. Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean±SD, 8.3±2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40±0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92±0.39 and 0.84±0.33% per mm Hg, respectively) compared to the control group (1.39±0.32% per mm Hg, P<0.0001 for all three). PV distensibility was associated with change in right ventricular ejection fraction (RVEF, ρ=0.39, P<0.0001) with exercise and was an independent predictor of peak VO2. PV distensibility also predicted cardiovascular mortality independent of peak VO2 in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10-0.93; P=0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility (P=0.015) in the sildenafil group only.. PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Topics: Adult; Aged; Antihypertensive Agents; Arterial Pressure; Case-Control Studies; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Models, Cardiovascular; Multivariate Analysis; Phosphodiesterase 5 Inhibitors; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Pulmonary Artery; Risk Assessment; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Stroke Volume; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilator Agents; Ventricular Function, Right

How sildenafil acutely provides hemodynamic alterations in patients with decompensated congestive heart failure remains unknown. The aim of this study was to investigate whether myocardial and/or hemodynamic conditions affect hemodynamic response to sildenafil in patients with decompensated heart failure.. Twenty-five consecutive patients with decompensated congestive heart failure were enrolled. The patients underwent echocardiography before and 1 hour after a single oral administration of sildenafil (20 mg). Sildenafil decreased pulmonary vascular resistance by 24% (P < 0.05), and increased left ventricular (LV) time-velocity integral by 17% (P < 0.05). Alteration of the ratio of peak velocity of early LV filling to early diastolic myocardial velocity (E/E'), an indicator of LV filling pressure, following administration of sildenafil, negatively associated with the deceleration time of early filling wave (DcT) at baseline. Patients with baseline DcT ≥ 200 milliseconds (n = 11) exhibited E/E' increase, whereas patients with baseline DcT <200 milliseconds (n = 14) exhibited E/E' decrease.. Administration of sildenafil elevated LV filling pressure in decompensated heart failure patients with shortened deceleration time of early diastolic transmitral flow.

Topics: Aged; Aged, 80 and over; Diastole; Echocardiography; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Vascular Resistance; Vasodilator Agents; Ventricular Function, Left

Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction.. A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus -0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV -52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus -6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure.. In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Topics: Aged; Arterial Pressure; Endothelium, Vascular; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Hyperemia; Male; Middle Aged; Myocardial Contraction; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfonamides; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents; Ventricular Function, Left

Studies have demonstrated that phosphodiesterase 5 (PDE5) inhibition is associated with right ventricle (RV) functional improvement in patients with primary pulmonary hypertension. This study aims to demonstrate the immediate impact of Sildenafil, a PDE5 inhibitor, on RV function, measured by cardiovascular magnetic resonance (CMR), in patients with heart failure (HF).. We conducted a randomized double-blind controlled trial.. diagnosis of HF functional class I-III; left ventricle ejection fraction < 35%. Patients underwent CMR evaluation and were then equally randomly assigned to either 50 mg of Sildenafil or Placebo groups. One hour following drug administration, they were submitted to a second scan examination.. 26 patients were recruited from a tertiary reference center in Brazil and 13 were allocated to each study group. The median age was 61.5 years (50-66.5 years). Except for the increase in RV fractional area change following the administration of sildenafil (Sildenafil [before vs. after]: 34.3 [25.2-43.6]% vs. 42.9 [28.5-46.7]%, p = 0.04; Placebo [before vs. after]: 28.1 [9.2-34.8]% vs. 29.2 [22.5-38.8]%, p = 0.86), there was no statistically significant change in parameters. There was no improvement in left ventricular parameters or in the fractional area change of the pulmonary artery.. This study demonstrated that a single dose of Sildenafil did not significantly improve RV function as measured by the CMR.. ClinicalTrials.gov NCT01936350.

Topics: Adult; Aged; Aged, 80 and over; Female; Heart Failure; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Treatment Outcome; Ventricular Dysfunction, Right; Ventricular Function, Left; Ventricular Function, Right

Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects.. In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (-1 ± 2%; P = 0.043), systemic vascular resistance (-87 ± 156 dyn·s·cm; P = 0.034), and RVTG (-2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil.. Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.

Topics: Chronic Disease; Cross-Over Studies; Double-Blind Method; Echocardiography, Doppler; Exercise; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Oxygen Consumption; Pulmonary Circulation; Sildenafil Citrate; Vasodilator Agents; Ventricular Function, Left; Ventricular Function, Right

Heart failure with preserved ejection fraction (HFpEF), with associated pulmonary hypertension is an increasingly large medical problem. Phosphodiesterase (PDE)-5 inhibition may be of value in this population, but data are scarce and inconclusive.. In this single centre, randomized double-blind, placebo-controlled trial, we included 52 patients with pulmonary hypertension [mean pulmonary artery pressure (PAP) >25 mmHg; pulmonary artery wedge pressure (PAWP) >15 mmHg] due to HFpEF [left ventricular ejection fraction (LVEF) ≥45%]. Patients were randomized to the PDE-5 inhibitor sildenafil, titrated to 60 mg three times a day, or placebo for 12 weeks. The primary endpoint was change in mean PAP after 12 weeks. Secondary endpoints were change in mean PAWP, cardiac output, and peak oxygen consumption (peak VO2). Mean age was 74 ± 10 years, 71% was female, LVEF was 58%, median NT-proBNP level was 1087 (535-1945) ng/L. After 12 weeks, change in mean PAP was -2.4 (95% CI -4.5 to -0.3) mmHg in patients who received sildenafil, vs. -4.7 (95% CI -7.1 to -2.3) mmHg in placebo patients (P = 0.14). Sildenafil did not have a favourable effect on PAWP, cardiac output, and peak VO2. Adverse events were overall comparable between groups.. Treatment with sildenafil did not reduce pulmonary artery pressures and did not improve other invasive haemodynamic or clinical parameters in our study population, characterized by HFpEF patients with predominantly isolated post-capillary pulmonary hypertension. (ClinicalTrials.gov, number NCT01726049).

Topics: Aged; Double-Blind Method; Drug Administration Schedule; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Stroke Volume

Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF.. RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak VO2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and VE/VCO2 was higher.. AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.

Topics: Age Factors; Aged; Atrial Fibrillation; Blood Pressure; Cohort Studies; Comorbidity; Exercise Tolerance; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Treatment Outcome

Sildenafil, a phosphodiesterase-5 inhibitor, has been shown to decrease pulmonary vascular resistance (PVR) in patients with heart failure. The purpose of the study was to evaluate the effect of sildenafil on clinical status and pulmonary vascular reactivity in patients with congestive heart failure.. We enrolled 20 patients (18 men and 2 women, mean age 51 ± 12 years, diagnosed with congestive heart failure and pulmonary hypertension. This was a prospective, single-center study. Patients were treated with sildenafil 25 mg TDS for 12 months. Protocol included NYHA evaluation and repeated echocardiography, cardiac pulmonary stress tests, and right- sided catheterization.. Initially, there were 16 (80%) patients in III NYHA status and 4 (20%) patients in II NYHA. After 12 months, 8 patients were in NYHA III (40%) status and 12 patients in NYHA II (60%). Peak oxygen consumption increased from 12 ± 3 ml/kg/min to 19 ± 4 ml/kg/min after 1-year therapy (p<0.001). The cardiac index increased from 3.1 ± 0.6 L/min/m2 to 3.6 ± 0.4 L/min/m2 (p<0.05). Pulmonary vasculature resistance decreased after 1-year therapy (4.7 ± 1 vs. 1.6 ± 0.5 Woods units (p<0.005) comparing to initials. Mean pulmonary artery pressure decreased to 23 ± 6 mmHg from 42 ± 5 mmHg (p<0.001) after 1-year therapy.. One-year sildenafil therapy effectively improved clinical status and pulmonary vascular resistance in patients diagnosed with congestive heart failure.

Topics: Adult; Cardiac Catheterization; Exercise Test; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prognosis; Prospective Studies; Pulmonary Wedge Pressure; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) study was a multicenter, randomized trial of sildenafil versus placebo in heart failure with preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants.. The aim of this study was to characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiological mechanisms.. The RELAX study enrolled 216 stable outpatients with heart failure, an ejection fraction ≥ 50%, increased natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months.. Compared with nondiabetic patients (n = 123), diabetic HFpEF patients (n = 93) were younger, more obese, and more often male and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p < 0.05 for all). Uric acid, C-reactive protein, galectin-3, carboxy-terminal telopeptide of collagen type I, and endothelin-1 levels were higher in diabetic patients (p < 0.05 for all). Diabetic patients had more ventricular hypertrophy, but systolic and diastolic ventricular function parameters were similar in diabetic and nondiabetic patients except for a trend toward higher filling pressures (E/e') in diabetic patients. Diabetic patients had worse maximal (peak oxygen uptake) and submaximal (6-min walk distance) exercise capacity (p < 0.01 for both). Diabetic patients were more likely to have been hospitalized for heart failure in the year before study entry (47% vs. 28%, p = 0.004) and had a higher incidence of cardiac or renal hospitalization at 6 months after enrollment (23.7% vs. 4.9%, p < 0.001).. HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multimorbidity, impaired chronotropic reserve, left ventricular hypertrophy, and activation of inflammatory, pro-oxidative, vasoconstrictor, and profibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure [The RELAX Study]; NCT00763867).

Topics: Aged; Cohort Studies; Diabetes Mellitus; Female; Heart Failure; Humans; Male; Middle Aged; Phenotype; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Stroke Volume; Sulfones

Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF).. To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF.. Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012.. Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.. Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks.. Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%).. Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.. clinicaltrials.gov Identifier: NCT00763867.

Topics: Aged; Blood Pressure; Double-Blind Method; Exercise Tolerance; Female; Health Status; Heart Failure; Humans; Male; Middle Aged; Outpatients; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Treatment Outcome; Walking

Sildenafil decreases pulmonary vascular resistance index (PVRI), in patients with pulmonary hypertension (PH). We investigated sildenafil's effects on central hemodynamics of mechanically ventilated patients with WHO group-III PH and RV failure necessitating dobutamine administration.. Prospective non-controlled study involving 12 (9 males, 59 ± 4 years old), patients with the above characteristics. All patients in phase-1 (days 1-2) received dobutamine (5 μg/kg/min IV). During phase-2 (days 3-6), sildenafil was started via nasogastric tube (80 mg/day) and dobutamine discontinuation was attempted. Patients were designated responders or non-responders based on whether dobutamine could be stopped or not. Phase-3 lasted from day 7 to day of weaning from mechanical ventilation; or if weaning failed, until day 20 following admission (end-of-study). Invasive and echocardiographic parameters were repeatedly recorded throughout the study.. Significantly changed parameters (P<0.025) from baseline to phase-1, -2 and -3 (%change of mean ratios), in responders (n=7) included among others PVRI (-40%, -51%, -42%), RV stroke work index (RVSWI: 43%, 79%, 41%) and cardiac index (49%, 54%, 48%), which also differed significantly from non-responders (N=5). In phases-1 and -3 non-responders had not significant changes, in phase-2 PVRI (27%) and RVSWI (-22%) changed significantly. In contrast to non-responders, all responders were weaned from mechanical ventilation until the end-of-study (P<0.025).. Sildenafil may improve central hemodynamics and RV function indices in ventilated patients with WHO group-III PH and RV failure requiring dobutamine infusion, when they respond favorably to the latter. Accordingly, an adequate RV systolic reserve may be mandatory for sildenafil to exert its actions.

Topics: Adrenergic beta-1 Receptor Agonists; Dobutamine; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Purines; Respiration, Artificial; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Ventricular Dysfunction, Right

Heart failure (HF) is a major clinical problem and, despite advances in both pharmacological and device therapy, the mortality remains high and quality of life poor. Over the last decade there has been growing interest in using phosphodiesterase-5 (PDE-5) inhibitors in HF associated with group 2 pulmonary hypertension (PH), with benefits reported on pulmonary haemodynamic and functional status in single-centre trials Methods The Sildenafil in Heart Failure (SilHF) trial is a randomized, placebo-controlled multinational trial designed to assess efficacy and tolerability of PDE-5 inhibition with sildenafil (target dose 40 mg three times per day) in 210 patients with HF, New York Heart Association (NYHA) functional class II or III, and evidence of group 2 PH. The co-primary endpoints are patient global assessment and the 6 min walk test. Secondary endpoints include NYHA functional class and the quality of life tools Euro QoL 5D and the Kansas City questionnaire. Patients will be followed up for 6 months.. The authors hypothesize that PDE-5 inhibition can improve exercise capacity and symptoms with acceptable tolerability in patients with HF and group 2 PH.

Topics: Dose-Response Relationship, Drug; Exercise Tolerance; Female; Follow-Up Studies; Heart Failure; Humans; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Stroke Volume; Sulfones; Surveys and Questionnaires; Treatment Outcome

Exercise oscillatory breathing (EOB) is a ventilatory abnormality that occurs in ∼20% of heart failure (HF) patients and carries a very unfavourable prognosis. Pulmonary vasoconstriction has been suggested to be involved in this disorder. We hypothesized that modulation of pulmonary vascular hypertone by oversignalling of the nitric oxide pathway with phosphodiesterase 5 (PDE5) inhibition might be beneficial. Accordingly, we performed a 1-year pilot trial with sildenafil in patients with HF and EOB.. Among 122 HF cases, 32 presented with EOB during cardiopulmonary exercise testing (CPX) and were randomized to receive placebo (n = 16) or sildenafil (n = 16) at the dose of 50 mg three times a day, in addition to their current antifailure treatment. CPX-derived variables and pulmonary haemodynamics were assessed at 6 and 12 months. Sildenafil reversed EOB in 87% of patients at 6 months and 93% at 1 year, respectively (P < 0.01). This effect was accompanied by an improvement in functional performance (peak VO(2); from 9.6 to 12.4 and 13.2 mL/min/kg; P < 0.01) and exercise ventilation efficiency (ventilation to CO(2) production slope; from 41.1 to 32.7 and 31.5; P < 0.01). Chronic treatment with PDE5 inhibition significantly decreased pulmonary capillary wedge pressure (from 21 to 14 and 14 mmHg), mean pulmonary artery pressure (PAP; from 34.8 to 23 and 24 mmHg), and pulmonary vascular resistance (PVR; from 360 to 270 and 266 dyne/s/cm(5)) compared with placebo (P < 0.01 for each comparison). On exploratory analysis, there was a correlation between PAP and PVR and the decrease in EOB in the treatment group. Placebo did not alter any of the aforementioned variables.. PDE5 inhibition in HF patients with EOB offers the dual advantage of improving functional capacity and modulating the EOB pattern. PAP and PVR reduction seem to underlie the correction of the breathing disorder. Whether reversal of this unfavourable prognostic signal can affect survival remains unconfirmed at the moment.

Topics: Aged; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Outcome Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Circulation; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Time; Treatment Outcome; Vascular Resistance; Vasoconstriction; Ventilation-Perfusion Ratio

Topics: Aged; Heart Failure; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil has been demonstrated as effective for the treatment of pulmonary arterial hypertension (PAH). The purpose of this study was to investigate the occurrence of clinical events after sildenafil monotreatment as a first-line therapy in patients with PAH over a long-term observation period.. Sildenafil was administered as a first-line drug to 46 patients with PAH (including 24 patients with idiopathic PAH) during 2003-2010. We investigated subsequent clinical events such as the addition of epoprostenol, hospitalization for right-side heart failure, and death. All the hemodynamic parameters and the 6-min walk distance improved significantly in the enrolled patients as a whole receiving sildenafil treatment; 15 (33%) of the 46 patients required the addition of epoprostenol during follow-up. Kaplan-Meier analysis demonstrated that more than 60% of the patients receiving first-line sildenafil treatment did not require the addition of epoprostenol for a 5-year period. Furthermore, the 5-year survival rate after first-line sildenafil treatment was 81%. Finally, more than 75% of the enrolled patients did not reach the composite endpoint of hospitalization for right-side heart failure and death for a 5-year period.. This study describes the long-term outcome of patients with PAH receiving sildenafil monotreatment as a first-line therapy and suggests that it is a promising therapeutic strategy.

Topics: Adult; Antihypertensive Agents; Disease-Free Survival; Epoprostenol; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Survival Rate

Unresponsive pulmonary hypertension (PH) may contraindicate heart transplant since it implies poor early outcomes. The present study reports the effectiveness of oral perioperative sildenafil in allowing heart transplant candidacy and surgery in a selected group of patients initially deemed ineligible because of PH.. Between May 2005 and December 2009, 31 consecutive patients (5 females, 9 with a history of idiopatic cardiomyopathy and 16 with a history of coronary artery disease, 10 with previous sternotomies, 71.42 ± 27.69 ml/min/m(2) mean preoperative epidermal growth factor receptor) were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-week trial, RHC disclosed PH reversibility (mean pulmonary vascular resistance index: 9.57 ± 4.07 WU, mean transpulmonary gradient 14.47 ± 5.66 mmHg and mean systolic pulmonary artery pressure: 68.96 ± 15.15 mmHg), allowing listing despite a higher risk for early post-transplant RV failure. Transplant protocol included donor/recipient size matching ≥ 0.8 and inhaled nitric oxide in the early postoperative period followed by reinstitution of oral sildenafil.. All patients underwent heart transplantation. Mean overall graft ischaemic time was 179 ± 47 min; mean donor recipient weight ratio was 1.04 ± 0.17. Right ventricular failure developed in three patients (9.6%) and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary haemodynamic profile normalization within the third postoperative month allowing weaning from sildenafil in the 30 hospital survivors. One-year RHC confirmed PH reversal (n = 29 patients, all who survived up to 1 year).. This pilot prospective uncontrolled trial suggests that oral sildenafil is effective in allowing candidacy, safe transplantation and postoperative pulmonary profile normalization in potential recipients initially disqualified because of PH.

Topics: Administration, Oral; Adult; Cardiac Catheterization; Contraindications; Drug Administration Schedule; Female; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pilot Projects; Piperazines; Prospective Studies; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

Nitric oxide (NO) can temporally and spatially match microvascular oxygen (O(2)) delivery (Qo(2mv)) to O(2) uptake (Vo(2)) in the skeletal muscle, a crucial adjustment-to-exercise tolerance that is impaired in chronic heart failure (CHF). To investigate the effects of NO bioavailability induced by sildenafil intake on muscle Qo(2mv)-to-O(2) utilization matching and Vo(2) kinetics, 10 males with CHF (ejection fraction = 27 ± 6%) undertook constant work-rate exercise (70-80% peak). Breath-by-breath Vo(2), fractional O(2)extraction in the vastus lateralis {∼deoxygenated hemoglobin + myoglobin ([deoxy-Hb + Mb]) by near-infrared spectroscopy}, and cardiac output (CO) were evaluated after sildenafil (50 mg) or placebo. Sildenafil increased exercise tolerance compared with placebo by ∼20%, an effect that was related to faster on- and off-exercise Vo(2) kinetics (P < 0.05). Active treatment, however, failed to accelerate CO dynamics (P > 0.05). On-exercise [deoxy-Hb + Mb] kinetics were slowed by sildenafil (∼25%), and a subsequent response "overshoot" (n = 8) was significantly lessened or even abolished. In contrast, [deoxy-Hb + Mb] recovery was faster with sildenafil (∼15%). Improvements in muscle oxygenation with sildenafil were related to faster on-exercise Vo(2) kinetics, blunted oscillations in ventilation (n = 9), and greater exercise capacity (P < 0.05). Sildenafil intake enhanced intramuscular Qo(2mv)-to-Vo(2) matching with beneficial effects on Vo(2) kinetics and exercise tolerance in CHF. The lack of effect on CO suggests that improvement in blood flow to and within skeletal muscles underlies these effects.

Topics: Aged; Cardiac Output; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise; Exercise Tolerance; Heart Failure; Humans; Male; Microcirculation; Middle Aged; Muscle, Skeletal; Nitric Oxide; Oxygen; Oxygen Consumption; Piperazines; Prospective Studies; Purines; Regional Blood Flow; Signal Transduction; Sildenafil Citrate; Sulfones; Vasodilator Agents

In some patients, heart failure (HF) is associated with increased pulmonary vascular resistance (PVR). The magnitude and the reversibility of PVR elevation affect the HF management. Sildenafil has been recently recognized as potent PVR-lowering drug in HF. The aim of the study was to compare hemodynamic effects and pulmonary selectivity of sildenafil to prostaglandin E(1) (PGE(1)). Right-heart catheterization was performed in 13 euvolemic advanced HF patients with elevated PVR (6.3+/-2 Wood's units). Hemodynamic parameters were measured at the baseline, during i.v. infusion of PGE1 (alprostadil 200 ng · kg(-1) · min(-1)) and after 40 mg oral dose of sildenafil. Both drugs similarly reduced systemic vascular resistance (SVR), but sildenafil had higher effect on PVR (-28 % vs. -49 %, p = 0.05) and transpulmonary pressure gradient than PGE(1). The PVR/SVR ratio--an index of pulmonary selectivity, did not change after PGE(1) (p = 0.7) but it decreased by -32 % (p = 0.004) after sildenafil. Both drugs similarly reduced pulmonary artery mean and wedge pressures and increased cardiac index (+27 % and +28 %). Sildenafil led more often to transplant-acceptable PVR while causing smaller drop of mean systemic pressure than PGE(1). In conclusion, vasodilatatory effects of sildenafil in patients with heart failure are more pronounced in pulmonary than in systemic circulation.

Topics: Adult; Alprostadil; Cardiac Catheterization; Cardiac Output; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Artery; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil.. Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (-42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (-54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, -71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, -15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, -13.0±1.9%; isovolumic relaxation time, -14.0±1.7%; septal mitral annulus velocity, -76.4±9.2%). Results were similar at 12 months.. The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy.. URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01156636.

Topics: Aged; Aged, 80 and over; Double-Blind Method; Female; Heart Failure; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prevalence; Purines; Respiratory Function Tests; Sildenafil Citrate; Stroke Volume; Sulfones

Topics: Administration, Oral; Antihypertensive Agents; Blood Pressure; Bosentan; Contraindications; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Piperazines; Prospective Studies; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents

The reversibility of elevated pulmonary vascular resistance in heart failure bears an important relation to outcome after cardiac transplantation. The phosphodiesterase 3 (PDE3) and PDE5 inhibitors both increase levels of cyclic nucleotides in the vascular smooth muscle, causing vasodilatation. PDE3 inhibitors also have direct inotropic effects. We contrasted the acute hemodynamic responses to intravenous PDE3 and PDE5 inhibitors in patients with congestive cardiac failure to assess their relative suitability for reversibility testing in this setting.. Thirty patients undergoing assessment for cardiac transplantation underwent right heart catheterization. Patients were randomized to receive an intravenous bolus of milrinone (0.05 mg/kg) or sildenafil citrate at a high (0.43 mg/kg) or low dose (0.05 mg/kg).. Differences between low- and high-dose sildenafil were not significant. Both agents caused similar reductions in systemic and pulmonary vascular resistance. Milrinone caused significantly greater reductions in pulmonary artery wedge and mean pulmonary artery pressure, and increases in heart rate. In all study groups, greater increases in cardiac index (>25%) were seen in patients with a higher pulmonary artery wedge pressure at baseline (29 +/- 1 vs 20 +/- 2 mm Hg; p < 0.001).. In end-stage congestive cardiac failure, intravenous milrinone and sildenafil both cause similar reductions in systemic and pulmonary vascular resistance; however, milrinone has more cardiac selective effects on left ventricular filling and heart rate. Both agents appear to have a suitable hemodynamic profile for testing of reversibility of secondary pulmonary hypertension in congestive cardiac failure. Larger studies are needed to confirm these results.

Topics: Adult; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Heart Failure; Heart Rate; Heart Transplantation; Humans; Hypertension, Pulmonary; Injections, Intravenous; Male; Middle Aged; Milrinone; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance

Ventilatory efficiency, right ventricular (RV) function, and secondary pulmonary hypertension are each prognostic indicators in patients with heart failure due to left ventricular systolic dysfunction, but the relationships among these variables have not been comprehensively investigated. In this study, we hypothesized that inefficient ventilation during exercise, as defined by an abnormally steep relationship between ventilation and carbon dioxide output (Ve/Vco(2) slope), may be a marker of secondary pulmonary hypertension and RV dysfunction in heart failure.. A cohort of patients with systolic heart failure (mean+/-SD age, 58+/-13 years; left ventricular ejection fraction, 0.27+/-0.05; peak oxygen uptake, 11.2+/-3.2 mL kg(-1) min(-1)) underwent incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring and first-pass radionuclide ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary vasodilator, or placebo. Ve/Vco(2) slope was positively related to rest and exercise pulmonary vascular resistance (R=0.39 and R=0.60, respectively) and rest pulmonary capillary wedge pressure (R=0.49, P<0.005 for all) and weakly indirectly related to peak exercise RV ejection fraction (R=-0.29, P=0.03). Over the 12-week study period, Ve/Vco(2) slope fell 8+/-3% (P=0.02) with sildenafil and was unchanged with placebo. Changes in Ve/Vco(2) slope correlated with changes in exercise pulmonary vascular resistance (R=0.69, P<0.001) and rest and exercise RV ejection fraction (R=-0.58 and -0.40, respectively, both P<0.05).. In patients with systolic heart failure and secondary pulmonary hypertension, ventilatory efficiency is closely related to RV function and pulmonary vascular tone during exercise.

Topics: Aged; Carbon Dioxide; Cohort Studies; Double-Blind Method; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Muscle Tonus; Muscle, Smooth, Vascular; Piperazines; Pulmonary Circulation; Purines; Respiration; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Function, Right; Ventriculography, First-Pass

Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.

Topics: Brachial Artery; Carbon Dioxide; Case-Control Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Exercise; Heart Failure; Humans; Hyperventilation; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Ventilation; Purines; Reflex; Respiratory Function Tests; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation; Vasodilator Agents

The effects of chronic inhibition of 5'-phosphodiesterase with sildenafil on functional capacity, ventilatory efficiency, oxygen uptake, pulmonary hypertension, and endothelial function in chronic heart failure (CHF) are unknown.. We conducted a randomized, double-blind, placebo-controlled trial to assess the acute (1 hour after 50 mg by mouth) and chronic (4 weeks after 50 mg 3 times per day by mouth) effects of sildenafil in outpatients with CHF. The outcomes were cardiopulmonary exercise test parameters (chronic effect), echocardiographic-derived pulmonary artery systolic pressure, and plethysmography-derived forearm blood flow (acute and chronic effects).. Nineteen patients with CHF (48 +/- 12 years) with an ejection fraction of 28% +/- 6% were studied. Patients who received sildenafil (n = 11) showed improved maximal oxygen uptake, ventilatory efficiency, and oxygen uptake kinetics. Sildenafil decreased pulmonary artery systolic pressure levels at 60 minutes and at 4 weeks compared with changes after placebo (P = .004 for group and time interaction). Improvement in ventilatory efficiency was positively associated with reductions in pulmonary artery systolic pressure. Patients allocated to placebo demonstrated a trend toward decreased forearm blood flow after reactive hyperemia, whereas this remained unchanged in patients allocated to sildenafil.. Sildenafil administration for 4 weeks in stable outpatients with CHF improves functional capacity, ventilatory efficiency, oxygen uptake kinetics, and pulmonary hypertension. These effects may be mediated in part by improvements in endothelial function.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Exercise Test; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Multivariate Analysis; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Plethysmography; Probability; Purines; Reference Values; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Rate; Time Factors; Treatment Outcome

Patients with systolic heart failure (HF) who develop secondary pulmonary hypertension (PH) have reduced exercise capacity and increased mortality compared with HF patients without PH. We tested the hypothesis that sildenafil, an effective therapy for pulmonary arterial hypertension, would lower pulmonary vascular resistance and improve exercise capacity in patients with HF complicated by PH.. Thirty-four patients with symptomatic HF and PH were randomized to 12 weeks of treatment with sildenafil (25 to 75 mg orally 3 times daily) or placebo. Patients underwent cardiopulmonary exercise testing before and after treatment. The change in peak VO2 from baseline, the primary end point, was greater in the sildenafil group (1.8+/-0.7 mL x kg(-1) x min(-1)) than in the placebo group (-0.27 mL x kg(-1) x min(-1); P=0.02). Sildenafil reduced pulmonary vascular resistance and increased cardiac output with exercise (P<0.05 versus placebo for both) without altering pulmonary capillary wedge or mean arterial pressure, heart rate, or systemic vascular resistance. The ability of sildenafil treatment to augment peak VO2 correlated directly with baseline resting pulmonary vascular resistance (r=0.74, P=0.002) and indirectly with baseline resting right ventricular ejection fraction (r=-0.64, P=0.01). Sildenafil treatment also was associated with improvement in 6-minute walk distance (29 m versus placebo; P=0.047) and Minnesota Living With Heart Failure score (-14 versus placebo; P=0.01). Subjects in the sildenafil group experienced fewer hospitalizations for HF and a higher incidence of headache than those in the placebo group without incurring excess serious adverse events.. Phosphodiesterase 5 inhibition with sildenafil improves exercise capacity and quality of life in patients with systolic HF with secondary PH.

Topics: Aged; Blood Pressure; Exercise; Female; Follow-Up Studies; Heart Failure; Heart Rate; Humans; Hypertension, Pulmonary; Male; Middle Aged; Motor Activity; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Systole; Treatment Outcome; Vascular Resistance

We performed a short-term outcome analysis of orthotopic heart transplantation (OHT) in patients with pulmonary hypertension (PH) treated perioperatively with oral sildenafil.. PH (pulmonary vascular resistance > 2.5 Wood units, and/or transpulmonary gradient > 12 mmHg) was diagnosed in 6 of 25 (group A) heart transplant recipients operated in 2006. This group of patients underwent a modified medication protocol including perioperative administration of oral sildenafil: 50 mg before followed by 50 or 25 mg TID after heart transplantation. Sildenafil treatment was discontinued 10 to 14 days post OHT, after stepwise dose reduction. During the ICU stay all patients underwent circulatory monitoring of pulmonary and systemic pressures and resistance as well as transthoracic echocardiogram (TTE) evaluation.. Perioperative oral sildenafil administration in PH patients undergoing OHT was associated with good short-term outcomes in the majority of transplanted patients (4/6). Sildenafil treatment reduced pulmonary resistance and pressures with a low rate of hemodynamic instability among OHT patients.. Pharmacologic perioperative reduction of PH improves the short-term prognosis for successful OHT. One may speculate whether sildenafil treatment transplant recipients with PH would be associated with long-term improvement of pulmonary vascular status, therefore leading to extended life-expectancy and improved outcomes.

Topics: Adult; Cardiac Output; Drug Administration Schedule; Echocardiography, Transesophageal; Female; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

This study sought to test the functional exercise capacity and endothelial function in a cohort of chronic heart failure (CHF) patients treated with chronic type 5 phosphodiesterase (PDE5) inhibitor.. In CHF, endothelial dysfunction is involved in muscle underperfusion, ergoreflex oversignaling, and exercise ventilation inefficiency. Inhibition of PDE5 by improving endothelial dysfunction might be beneficial.. Stable CHF patients were randomly assigned to placebo (23 patients) or sildenafil at the dose of 50 mg twice per day (23 patients) in addition to their current drug treatment for 6 months, with assessments (at 3 and 6 months) of endothelial function by brachial artery flow-mediated dilatation (FMD), cardiopulmonary exercise testing, and ergoreflex response.. In the sildenafil group only, at 3 and 6 months we observed reduction of systolic pulmonary artery pressure (from 33.7 to 25.2 mm Hg and 23.9 mm Hg), ergoreflex effect on ventilation (from 6.9 to 2.3 l x min(-1) and 1.9 l x min(-1)), ventilation to CO2 production slope (V(E)/VCO2, from 35.5 to 32.1 and 29.8), and breathlessness (score) (from 23.6 to 16.6 and 17.2), and an increase of FMD (from 8.5% to 13.4% and 14.2%), peak VO2 (from 14.8 to 18.5 ml x min(-1) x kg(-1) and 18.7 ml x min(-1) x kg(-1)), and ratio of VO2 to work rate changes (from 7.7 to 9.3 and 10.1). All changes were significant at p < 0.01. In the sildenafil group, a significant correlation was found at 3 and 6 months between changes in FMD and those in ergoreflex. Changes in ergoreflex correlated with those in peak VO2 and V(E)/VCO2 slope. No adverse effects were noted except for flushing in 3 patients.. In CHF, improvement in exercise ventilation and aerobic efficiency with sildenafil is sustained and is significantly related with an endothelium-mediated attenuation of exercising muscle oversignaling. Chronic sildenafil seems to be a remedy based on CHF pathophysiology and devoid of remarkable adverse effects.

Topics: Aged; Brachial Artery; Chronic Disease; Endothelium, Vascular; Exercise Test; Heart Failure; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation

Erectile dysfunction is common in patients with chronic heart failure and sildenafil is an effective treatment option in this population. Sildenafil has been reported to increase sympathetic outflow in normal volunteers. To date, experience with sildenafil in patients with congestive heart failure is limited and the impact of phosphodiesterase-5 inhibition on sympathetic activity in this population has not been evaluated.. 10 patients with heart failure (ejection fraction 23+/-3%) were studied. Generalized and cardiac sympathetic activity responses to an intravenous infusion of sildenafil were measured by the norepinephrine spillover method. In response to sildenafil, there was a significant reduction in mean pulmonary artery (-26+/-5%, P<0.01) and mean arterial pressures (-8+/-1%, P<0.01). These hemodynamic responses were accompanied by a 22+/-5% reduction in cardiac norepinephrine spillover (P<0.02) but no change in total body norepinephrine spillover.. The acute administration of sildenafil is associated with a modest reduction in systemic arterial blood pressure and a more substantial reduction in pulmonary arterial pressure. These hemodynamic changes are observed in the absence of systemic sympathetic activation and are associated with a reduction in cardiac norepinephrine spillover in patients with chronic heart failure. These observations are relevant given the high prevalence of erectile dysfunction in this patient population.

Topics: Dose-Response Relationship, Drug; Heart Failure; Humans; Infusions, Intravenous; Piperazines; Purines; Sildenafil Citrate; Sulfones; Sympathetic Nervous System

ACE (angiotensin-converting enzyme) inhibitors and PDE5 (phosphodiesterase type 5) inhibitors have each been reported to improve endothelial function in cardiovascular disease patients, but the comparative and combined effects of these two classes have not been studied previously. We sought to characterize the acute effects of ramipril alone, sildenafil alone, or their combination on endothelial function in patients with CHF (chronic heart failure). CHF subjects (n=64) were randomized to receive placebo, 10 mg of ramipril alone, 50 mg of sildenafil alone or a combination of ramipril and sildenafil in a double-blind manner. FMD (flow-mediated dilation) of the brachial artery was determined by high-resolution ultrasound imaging before and at 1, 2 and 4 h after administration of the study drug. Ramipril alone increased FMD at 4 h compared with placebo (+2.3+/-1.3%, P=0.02). Sildenafil alone increased FMD at 1, 2 and 4 h compared with placebo (+3.9+/-1.4, +4.6+/-1.8 and +3.7+/-1.3% respectively, all P<0.02). Sildenafil in combination with ramipril increased FMD at 1, 2 and 4 h when compared with placebo (+3.5+/-1.5, +4.5+/-1.8 and +4.8+/-1.3% respectively, all P<0.03). Ramipril and sildenafil both acutely improved FMD in patients with CHF, with additive effects evident at 4 h during combination therapy. Therefore further work to characterize chronic effects of combined ACE and PDE5 inhibition on endothelial function are warranted.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Brachial Artery; Cyclic Nucleotide Phosphodiesterases, Type 5; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Prospective Studies; Purines; Ramipril; Sildenafil Citrate; Sulfones; Ultrasonography

Chronic heart failure (CHF) is an increasingly common cardiovascular disorder. Many patients who have CHF report moderate to marked decreases in the frequency of sexual activity, and up to 75% of patients report erectile dysfunction (ED). There are few controlled clinical data on the efficacy and safety of sildenafil citrate in men who have ED and CHF; thus, we evaluated these parameters in patients who had stable CHF. This was a double-blind, placebo-controlled, flexible-dose study. Men who had ED and stable CHF were randomized to receive sildenafil or placebo for 12 weeks. Primary outcomes were questions 3 and 4 of the International Index of Erectile Function. Secondary outcomes included the 5 functional domains of the International Index of Erectile Function, 2 global efficacy assessment questions, intercourse success rate, the Erectile Dysfunction Inventory of Treatment Satisfaction, and the Life Satisfaction Checklist. By week 12, patients who received sildenafil (n = 60) showed significant improvements on questions 3 and 4 compared with patients who received placebo (n = 72; p <0.002). Larger percentages of patients who received sildenafil reported improved erections (74%) and improved intercourse (68%) compared with patients who received placebo (18% and 16%, respectively). Intercourse success rates were 53% among patients who received sildenafil and 20% among those who received placebo. Patients who received sildenafil were highly satisfied with treatment and their sexual life compared with patients who received placebo. Sixty percent of patients who received sildenafil and 48% of patients who received placebo developed adverse events, including transient headache, facial flushing, respiratory tract infection, and asthenia. The incidence of events related to cardiovascular effects was low. Sildenafil is an effective and well-tolerated management of ED in men who have mild to moderate CHF.

Topics: Adult; Aged; Aged, 80 and over; Double-Blind Method; Erectile Dysfunction; Heart Failure; Humans; Male; Middle Aged; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil is rarely used in patients with heart failure despite a high prevalence of erectile dysfunction, and the theoretic possibility that by increasing nitric oxide availability, it may improve left ventricular (LV) load and performance. This study aimed to determine the peak effects of sildenafil on LV load and performance in patients with heart failure caused by systolic LV dysfunction. Twenty patients with controlled LV failure and ejection fractions <35% received sildenafil 50 mg or a matching placebo when not receiving regular medication for > or =12 hours, in a randomized, placebo-controlled, double-blind, 2-way crossover fashion. Cardiac output was measured by Doppler echocardiography. The aortic pressure waveform was determined using generalized transfer function from radial artery applanation tonometry. Aortic and femoral arterial stiffness was determined as carotid-femoral and femoral-pedal pulse-wave velocity (PWV); wave reflection was measured as an augmentation index (AIx). Cardiac index increased significantly (by 0.37 L/min.m(2), p <0.0001), with the peak effect 60 minutes after sildenafil administration. Compared with the baseline value, total systemic resistance showed a reduction of 479 dynes.s.cm(-5) (p <0.0001). Aortic and lower limb PWV decreased significantly (by 0.89 and 1.14 m/s, respectively, p <0.0001 for both), as did AIx (by 3.6% absolute, p <0.0001); these remained significant after adjustment for mean pressure and heart rate changes. In conclusion, sildenafil improves cardiac performance because of a decrease in LV load, which is caused by decreases in peripheral resistance, in aortic and large artery stiffness, and in wave reflection from peripheral sites. This can explain the increase in cardiac output and in exercise capacity with sildenafil in patients with heart failure.

Topics: Aged; Aged, 80 and over; Aorta; Blood Flow Velocity; Blood Pressure; Cross-Over Studies; Double-Blind Method; Echocardiography, Doppler; Heart Failure; Heart Rate; Heart Ventricles; Humans; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Left

Erectile dysfunction (ED) is common in patients with congestive heart failure (CHF) and is often associated with symptoms of depression. Although sildenafil citrate, a phosphodiesterase 5 inhibitor, is effective in treating ED, its use is considered a relative contraindication in CHF. We hypothesized that sildenafil is a safe and effective treatment for ED in patients with New York Heart Association classes II and III CHF and that treatment of ED will improve symptoms of depression and enhance perceived of quality of life.. We studied 35 patients in a prospective, placebo-controlled, crossover trial for 12 weeks. Inclusion required a history of chronic ED and absence of ischemia (negative results from exercise stress test or nuclear perfusion scan) or nitrate use. The tolerability of sildenafil citrate was established by monitoring the ambulatory blood pressure for 4 hours after a single 50-mg dose. Improvement in ED, the primary end point, was assessed using the International Index of Erectile Function survey. The effect of improved erectile function on quality of life and mood was assessed using the Minnesota Living With Heart Failure Questionnaire, the Beck Depression Index, and the Center for Epidemiological Studies-Depression Scale.. Sildenafil caused a mean +/- SEM asymptomatic decrease in blood pressure of 6 +/- 3 mm Hg, and no patient experienced symptomatic hypotension or other significant adverse effects. Sildenafil improved the International Index for Erectile Function (P<.001) and both sets of depression scores. The Living With Heart Failure Questionnaire index also improved with sildenafil (P =.02).. Sildenafil is a safe and effective treatment for ED in men with New York Heart Association classes II and III CHF and provides relief of depressive symptoms, explaining an improvement in the perception of quality of life.

Topics: Comorbidity; Cross-Over Studies; Depression; Double-Blind Method; Heart Failure; Humans; Impotence, Vasculogenic; Male; Middle Aged; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Vasodilator Agents

Chronic heart failure (CHF) may be associated with a disordered nitric oxide (NO)-mediated regulation of the pulmonary vessel tone and permeability and of the gas transfer across the alveolar-capillary membrane. Whether enhancement of NO availability is beneficial with regard to these functions has not been explored. Phosphodiesterase 5 inhibitors, such as sildenafil, may provide a tool with which to test this possibility.. In 10 patients with CHF and 10 normal subjects, before and at 60 minutes after sildenafil (50 mg) or placebo, we measured left ventricular ejection fraction, pulmonary hemodynamics, lung diffusion capacity for carbon monoxide and its alveolar-capillary membrane and blood capillary volume subcomponents, and flow-mediated brachial artery dilation (FMD) during reactive hyperemia to distal circulatory arrest (an indirect index of NO-mediated endothelial function).. In patients with CHF, sildenafil caused no variations in ejection fraction, cardiac index, wedge pulmonary pressure, and blood capillary volume; it decreased pulmonary artery systolic (-21.6%) and diastolic (-31.8%) pressure and arteriolar resistance (-36.9%); and it increased lung diffusion capacity for carbon monoxide (+11.2%), diffusing capacity of the alveolar-capillary membrane (+10.6%), and FMD (from +8.3% to +13.4%). All changes were significant at P < .01. None of these effects was observed in healthy subjects. Placebo was ineffective in both patients and control subjects.. This study provides the novel information that, in patients with CHF, phosphodiesterase 5 inhibition with sildenafil ameliorates the pulmonary hemodynamics and reduces the impedance of the alveolar-capillary interface, even if left ventricular filling pressure and function remain steady. The associated improvement in FMD at the periphery substantiates the possibility that an enhancement in NO release may underlie these effects.

Topics: Heart Failure; Hemodynamics; Humans; Lung; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiratory Function Tests; Severity of Illness Index; Sildenafil Citrate; Sulfones

This study sought to evaluate the utility of sildenafil in assessing pulmonary artery reactivity in left-sided cardiac failure and secondary pulmonary hypertension (PH). Fourteen consecutive patients with heart failure were studied, with oral doses of either sildenafil 25 mg (n = 8) or 50 mg (n = 6) every 8 hours for 20% decreases in pulmonary artery pressures. There was also a 20% reduction of the pulmonary vascular resistance/systemic vascular resistance ratio, indicating relative pulmonary artery selectivity. Compared with sildenafil 25 mg, sildenafil 50 mg demonstrated greater reductions of pulmonary pressures. Oral sildenafil is safe and effective for the evaluation of PH reactivity in heart failure.

Topics: Administration, Oral; Adult; Aged; Dose-Response Relationship, Drug; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Left

Erectile dysfunction (ED) is common in patients with congestive heart failure (CHF). ED reduces quality of life, and it may affect compliance, thereby impairing the success of CHF treatment.. In the first phase (fixed-dose double-blind, randomized, placebo-controlled, two-way crossover study), we studied in 23 men with CHF the effects of 50 mg sildenafil on exercise and neurohormonal activation. Patients underwent a treadmill 6-minute cardiopulmonary walking (6'WT) test followed by a maximal cardiopulmonary exercise test (ET). In the second phase, patients received sildenafil, taken as required for ED. Sildenafil reduced the heart rate (HR) (bpm) before the 6'WT (from 75+/-15 to 71+/-14, P=0.02) and ET (from 75+/-15 to 71+/-15, P=0.02); the systolic blood pressure (mm Hg) before the 6'WT (from 116+/-18 to 108+/-18, P=0.004) and ET (from 116+/-15 to 108+/-17, P=0.001); the diastolic blood pressure before the 6'WT (from 69+/-9 to 63+/-11, P=0.01) and ET (from 70+/-8 to 65+/-10, P=0.004); and the Ve/VCO2 slope during the 6'WT (from 32+/-7 to 31+/-6, P=0.04) and ET (from 33+/-8 to 31+/-5, P=0.03). Sildenafil attenuated the HR increment during the 6'WT (P=0.003) and ET (P=0.000). Sildenafil increased the peak *O2 from 16.6+/-3.4 to 17.7+/-3.4 mL/kg per min (P=0.025) and the exercise time from 12.3+/-3.4 to 13.7+/-3.2 minutes (P=0.003). Sildenafil improved most scores of International Index of Erectile Function.. Sildenafil was tolerated and effective for ED treatment in CHF, and improved the exercise capacity. The reduction of HR during exercise with sildenafil could theoretically decrease the myocardial oxygen consumption during sexual activity.

Topics: Administration, Oral; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Erectile Dysfunction; Exercise Test; Exercise Tolerance; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Norepinephrine; Oxygen Consumption; Patient Satisfaction; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling.

Topics: Animals; Familial Primary Pulmonary Hypertension; Heart Failure; Hypertension, Pulmonary; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Vascular Remodeling; Vasodilator Agents

Topics: Heart Failure; Humans; Kidney; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Stroke Volume

Topics: Heart Failure; Humans; Sildenafil Citrate; Stroke Volume; Vasodilator Agents; Ventricular Dysfunction, Left

Phosphodiesterase-5A inhibitors (PDE5i) are sometimes used in patients with advanced heart failure with reduced ejection fraction before heart transplant or left ventricular assist device implantation to decrease right ventricular (RV) afterload and mitigate the risk of right heart failure. Conflicting evidence exists regarding the impact of these drugs on RV contractility. The aim of this study was to explore the acute effects of PDE5i on ventricular-vascular coupling and load-independent RV contractility.. Twenty-two patients underwent right heart catheterization and gated equilibrium blood pool single photon emission computed tomography, before and after 20 mg intravenous sildenafil. Single photon emission computed tomography and right heart catheterization-derived data were used to calculate RV loading and contractility.. PDE5i induced a decrease in the right atrial pressure (-43%), pulmonary artery (PA) mean pressure (-26%), and PA wedge pressure (PAWP; -23%), with favorable reductions in pulmonary vascular resistance (-41%) and PA elastance (-40%), and increased cardiac output (+13%) (all P < 0.01). The RV ejection fraction increased with sildenafil (+20%), with no change of RV contractility (P = 0.74), indicating that the improvement in the RV ejection fraction was related to enhanced RV-PA coupling (r = 0.59, P = 0.004) by a decrease in the ventricular load. RV diastolic compliance increased with sildenafil. The decrease in the PAWP correlated with RV end-diastolic volume decrease; no relationship was observed with the change in LV transmural pressure, suggesting decreased pericardial constraint.. Acute PDE5i administration has profound RV afterload-reducing effects, improves the RVEF, decreases RV volumes, and decreases the PAWP, predominantly through relief of pericardial constraint, without effects on RV chamber contractility. These findings support further study of PDE5i in protection of RV function in advanced heart failure with reduced ejection fraction who are at risk of RV failure.

Topics: Heart Failure; Humans; Pulmonary Artery; Sildenafil Citrate; Ventricular Dysfunction, Right; Ventricular Function, Right

BACKGROUND To explore the efficacy of beraprost sodium combined with sildenafil and its effects on the vascular endothelial function and inflammation in left heart failure patients complicated with pulmonary arterial hypertension. MATERIAL AND METHODS A total of 80 patients with left heart failure complicated with pulmonary arterial hypertension was enrolled as the subjects of this study and assigned into an observation group (n=40) and a control group (n=40) using a random number table. The changes in pulmonary arterial hypertension-associated indicators at 3 months after treatment and the alterations in the levels of cardiac function-associated biochemical indicator brain natriuretic peptide (BNP), inflammatory factor tumor necrosis factor alpha (TNF-alpha), and mean pulmonary arterial pressure during treatment were compared between the 2 groups. RESULTS At 3 months after treatment, the pulmonary arterial hypertension-associated indicators human urotensin II and calcitonin gene-related peptide in the observation group were lower and higher, respectively, than those in control group. Moreover, the observation group had significantly lower BNP and TNF-alpha levels and mean pulmonary arterial pressure than the control group. After intervention, the echocardiographic parameters left ventricular ejection fraction (LVEF), cardiac output (CO), and stroke volume (SV) in both groups were significantly higher than those before intervention, and the observation group had significantly higher LVEF, SV, and CO than the control group after intervention. CONCLUSIONS Beraprost sodium combined with sildenafil for left heart failure complicated with pulmonary arterial hypertension can effectively improve pulmonary arterial hypertension, alleviate left heart failure, and reduce inflammatory responses, thereby achieving better clinical efficacy in patients.

Topics: Aged; Aged, 80 and over; Echocardiography; Endothelial Cells; Epoprostenol; Exercise Tolerance; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Ventricular Function, Right

Topics: Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Sildenafil Citrate

cGMP-dependent protein kinase 1α (PKG1α) promotes left ventricle (LV) compensation after pressure overload. PKG1-activating drugs improve heart failure (HF) outcomes but are limited by vasodilation-induced hypotension. Signaling molecules that mediate PKG1α cardiac therapeutic effects but do not promote PKG1α-induced hypotension could therefore represent improved therapeutic targets. We investigated roles of mixed lineage kinase 3 (MLK3) in mediating PKG1α effects on LV function after pressure overload and in regulating BP. In a transaortic constriction HF model, PKG activation with sildenafil preserved LV function in MLK3+/+ but not MLK3-/- littermates. MLK3 coimmunoprecipitated with PKG1α. MLK3-PKG1α cointeraction decreased in failing LVs. PKG1α phosphorylated MLK3 on Thr277/Ser281 sites required for kinase activation. MLK3-/- mice displayed hypertension and increased arterial stiffness, though PKG stimulation with sildenafil or the soluble guanylate cyclase (sGC) stimulator BAY41-2272 still reduced BP in MLK3-/- mice. MLK3 kinase inhibition with URMC-099 did not affect BP but induced LV dysfunction in mice. These data reveal MLK3 as a PKG1α substrate mediating PKG1α preservation of LV function but not acute PKG1α BP effects. Mechanistically, MLK3 kinase-dependent effects preserved LV function, whereas MLK3 kinase-independent signaling regulated BP. These findings suggest augmenting MLK3 kinase activity could preserve LV function in HF but avoid hypotension from PKG1α activation.

Topics: Animals; Aorta; Blood Pressure; Cyclic GMP-Dependent Protein Kinase Type I; Heart Failure; HEK293 Cells; Humans; Hypertension; Male; MAP Kinase Kinase Kinases; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase Kinase Kinase 11; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrroles; Sildenafil Citrate; Vascular Stiffness; Vasodilator Agents; Ventricular Dysfunction, Left

Although decreased protein kinase G (PKG) activity was proposed as potential therapeutic target in heart failure with preserved ejection fraction (HFpEF), randomized clinical trials (RCTs) with type-5 phosphodiesterase inhibitors (PDE5i) showed neutral results. Whether specific subgroups of HFpEF patients may benefit from PDE5i remains to be defined. Our aim was to test chronic sildenafil therapy in the young male ZSF1 obese rat model of HFpEF with severe hypertension and metabolic syndrome. Sixteen-week-old ZSF1 obese rats were randomly assigned to receive sildenafil 100 mg·Kg

Topics: Animals; Glucose Tolerance Test; Heart; Heart Failure; Male; Metabolic Syndrome; Obesity; Rats; Rats, Inbred WKY; Sildenafil Citrate; Stroke Volume; Vasodilator Agents

Severe pulmonary hypertension is a risk factor for mortality, due to increased postoperative right ventricular failure, in a heart transplant patient. Elevated pulmonary vascular resistance (PVR) in heart transplant candidates can be reduced using a left ventricular assist device or medical therapy. This study analysed the effect of inhaled iloprost and oral sildenafil combination therapy (ilo-sil) on pulmonary haemodynamic parameters in patients with secondary pulmonary hypertension.. Between May 2011 and April 2014, 25 patients who were unresponsive to reversibility test and PVR >3.5 Wood units (WU) during right heart catheterisation were included in this study. After 6 months of oral sildenafil (3 × 20 mg/day) and inhaled iloprost (6 × 5 μg/day) combination therapy, second right heart catheterisations were performed and eligibility for heart transplant was evaluated.. Repeat right heart catheterisation revealed that there was a significant decrease in the PVR from 5.4 ± 1.6 WU to 3.54 ± 2.5 WU (p<0.001), with trans-pulmonary gradient from 13.7 ± 5.6 to 11.46 ± 6.64 (p=0.042), and mean cardiac index (CI) increasing non-significantly from 1.45 ± 0.51 L/min/m2 to 1.82 ± 0.60 (p=0.157). The mean sPAP was initially 57.54 ± 14.79 mmHg and fell to 52.93 ± 16.83 mm Hg (p=0.03). Twenty (20) (80%) patients were enrolled in the waiting list since their PVR values decreased to <3.5 WU. Of these 20 patients, one had undergone heart transplant and four were bridged to transplant with mechanical circulatory support devices.. After a decrease in PVR with ilo-sil combination therapy for patients with severe pulmonary hypertension, these patients may become candidates for heart transplant without bearing additional risk. Ilo-sil combination therapy could be a viable option with which to evaluate the reversibility of PVR.

Topics: Administration, Inhalation; Administration, Oral; Adult; Cardiac Catheterization; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Iloprost; Male; Middle Aged; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Prenatal closure of foramen ovale without CHD is a rarely reported entity. Therefore, clinical and echocardiographic findings are poorly defined in these patients. We report a patient with prenatal closure of foramen ovale that presented with severe pulmonary hypertension of the newborn and left ventricular failure. Judicious management strategies were utilised to successfully treat both life-threatening conditions.

Topics: Bosentan; Echocardiography; Female; Foramen Ovale; Heart Failure; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Pregnancy; Sildenafil Citrate; Treatment Outcome; Ultrasonography, Prenatal

Patients with heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) represent a high-risk phenotype. The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial enrolled a high proportion of CKD participants, allowing investigation into differences in HFpEF by CKD status.. Renal dysfunction in HFpEF is characterized by echocardiographic and biomarker profiles indicative of more advanced disease, and reduced hemoglobin is a strong mediator of the association between renal dysfunction and low exercise capacity. Sildenafil therapy was associated with worsening of renal function in RELAX.

Topics: Diastole; Heart Failure; Humans; Kidney Diseases; Sildenafil Citrate; Stroke Volume

Topics: Antihypertensive Agents; Female; Heart Arrest; Heart Failure; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Artery; Pulmonary Wedge Pressure; Risk Factors; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents; Ventricular Function, Left

Elevated pulmonary vascular resistance (PVR) is a risk factor for early right ventricular failure and poor prognosis after heart transplantation (HT) as well as an indication for treatment with vasodilators. The aim of the study was to determine the relationship between the baseline values of the modified Model for End-Stage Liver Disease (modMELD) score and the presence of elevated PVR in patients with advanced heart failure (HF) after 6 months of sildenafil treatment.. The study was a retrospective review of 86 adult patients with end-stage HF who were evaluated for HT at our institution between 2015 and 2017. All patients had reversible PVR according to right heart catheterization. They all received sildenafil therapy in the maximum tolerated doses. Before the inclusion of sildenafil, the modMELD scores were calculated based on the serum bilirubin, creatinine, and albumin levels. The study's endpoint was PVR >3 Wood units after 6 months of sildenafil therapy.. The median age of the patients was 57 (50-63) years, and 91.9% of them were men. Elevated PVR values (>3 Wood units) after 6 months of sildenafil treatment were found in 36 patients (42%). The area under the ROC curve (AUC) for modMELD was 0.848 (95% CI: 0.768-0.929). The cutoff point for modMELD (>11.1) had a sensitivity of 97% and a specificity of 68%.. The modMELD score may be a useful indicator of the ineffectiveness of sildenafil treatment in patients with advanced HF evaluated for HT.

Topics: Drug Resistance; Female; Heart Failure; Heart Transplantation; Humans; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

The adult worms of Angiostrongylus vasorum reside in the pulmonary artery of dogs and can lead to cardiac, respiratory, and central neurologic signs. Due to luminal obstruction and perivascular inflammation of the pulmonary artery branches, pulmonary hypertension can arise. Pulmonary hypertension, in turn, can lead to severe damage of the right-sided cardiac structures, leading to right ventricular remodeling and tricuspid valve regurgitation.. An 8-year-old neutered female English Cocker Spaniel was presented to the author's institution because of abdominal distention and exercise intolerance. Ascites caused by congestive right-sided heart failure was found to be responsible for these problems. The underlying etiology of the right-sided heart failure was a severe pulmonary hypertension caused by Angiostrongylus vasorum infection. Echocardiography revealed, in addition to a severe concentric and eccentric right ventricular hypertrophy, right atrial and pulmonary trunk dilation, severe tricuspid valve regurgitation, and a systolic flail of the anterior leaflet of the tricuspid valve, resulting from ruptured chordae tendineae. As a coincidental finding, a congenital mitral stenosis was found. Oral therapy was initiated with daily administration of fenbendazole for 2 weeks along with daily administration of oral sildenafil until the re-check examination. At the 6-week re-check the dog showed full clinical and partial echocardiographic recovery, and both the blood antigen test for Angiostrongylus vasorum and the fecal Baermann larva isolation test were negative. When the sildenafil therapy was ceased after tapering the daily dosage, the owner reported recurrence of abdominal distension. Re-starting the sildenafil therapy resulted in resolution of this problem. The dog was reported to be clinically healthy with daily sildenafil administration 7 months after the initial presentation.. The present case report describes a dog where angiostrongylosis led to congestive right-sided heart failure resulting from severe pulmonary hypertension. The secondary right ventricular eccentric hypertrophy together with suspected papillary muscular ischemia were the suspected cause of the ruptured major tricuspid chordae tendineae, which led to a severe tricuspid valve regurgitation. Despite eradication of the worms, the severe pulmonary hypertension persisted. Treatment with daily oral sildenafil, a pulmonary arterial vasodilator, was enough to keep the dog free of clinically apparent ascites.

Topics: Angiostrongylus; Animals; Antinematodal Agents; Dog Diseases; Dogs; Female; Fenbendazole; Heart Failure; Heart Valve Diseases; Hypertension, Pulmonary; Sildenafil Citrate; Strongylida Infections; Tricuspid Valve; Vasodilator Agents

Activation of the atrial natriuretic signaling pathway is intrinsic to the pathological responses associated with a range of cardiovascular diseases that stress the heart, especially those involved in sustained cardiac pressure overload which induces hypertrophy and the pathological remodeling that frequently leads to heart failure. We identify transient receptor potential cation channel, subfamily V, member 1, as a regulated molecular component, and therapeutic target of this signaling system. Data show that TRPV1 is a physical component of the natriuretic peptide A, cGMP, PKG signaling complex, interacting with the Natriuretic Peptide Receptor 1 (NPR1), and upon binding its ligand, Natriuretic Peptide A (NPPA, ANP) TRPV1 activation is subsequently suppressed through production of cGMP and PKG mediated phosphorylation of the TRPV1 channel. Further, inhibition of TRPV1, with orally delivered drugs, suppresses chamber and myocyte hypertrophy, and can longitudinally improve in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction, reversing pre-established hypertrophy induced by pressure load while restoring chamber function. TRPV1 is a physical and regulated component of the natriuretic peptide signaling system, and TRPV1 inhibition may provide a new treatment strategy for treating, and reversing the loss of function associated with cardiac hypertrophy and heart failure.

Topics: Acrylamides; Administration, Oral; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cardiomegaly; Heart Failure; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Signal Transduction; Sildenafil Citrate; TRPV Cation Channels

Systemic artery to pulmonary artery fistulas (SA-PAFs), are extremely rare in people without congenital heart disease. In this group of patients pulmonary arterial hypertension was reported in the single case. Then, we describe a case of multiple SA-PAFs, which were the cause of severe nonreversible arterial pulmonary hypertension in a patient who had a right-sided pneumothorax 35 years earlier.. 52-year-old male Caucasian patient with echocardiographically confirmed pulmonary hypertension (PH) was admitted to cardiology department due to exertional dyspnea and signs of right ventricle failure. Routine screening for causes of secondary PH was negative. Right heart catheterization (RHC) confirmed a high degree arterial PH [mean pulmonary artery pressure (mPAP); 50,6 mmHg, pulmonary wedge pressure (PWP); 11,3 mmHg, pulmonary vascular resistance (PVR); 11,9 Wood's units (WU)] irreversible in the test with inhaled nitric oxide. Oxygen saturation (SaO. Non-congenital SA-PAFs are extremely rare, however, they should be excluded in patients with pulmonary arterial hypertension and history of inflammatory or infectious disease of the lung and pleura, pneumothorax, cancer or Takayashu's disease and after chest trauma.

Topics: Arterio-Arterial Fistula; Cardiac Catheterization; Computed Tomography Angiography; Familial Primary Pulmonary Hypertension; Fatal Outcome; Heart Failure; Humans; Iloprost; Lung; Male; Middle Aged; Pneumothorax; Pulmonary Artery; Pulmonary Wedge Pressure; Sildenafil Citrate; Vascular Resistance

Pulmonary hypertension associated with human immunodeficiency virus infection is an extremely rare disease in pediatrics; it requires a high clinical suspicion to reach a diagnosis. Its appearance poses an unfavorable prognostic, but early diagnosis and specific treatment can improve outcomes. We report the clinical case of a fifteen-year-old patient diagnosed with human immunodeficiency virus infection of vertical transmission, without antiretroviral treatment, with cough and progressive exertional dyspnea, associated with signs of right heart failure in which severe pulmonary hypertension was diagnosed. After discarding other causes, it was assumed pulmonary hypertension associated with human immunodeficiency virus infection. Treatment was performed with sildenafil with good response.. La hipertensión pulmonar asociada a la infección por virus de inmunodeficiencia humana es una enfermedad sumamente infrecuente en pediatría, por lo que requiere alta sospecha clínica para llegar a su diagnóstico. Su aparición es de pronóstico desfavorable, pero el diagnóstico precoz y el tratamiento específico pueden mejorar su evolución. Se presenta el caso clínico de un paciente de 15 años con diagnóstico de infección por virus de inmunodeficiencia humana de transmisión vertical, sin tratamiento antirretroviral, con tos y disnea de esfuerzo progresiva asociadas a signos de falla cardíaca derecha en el cual se diagnosticó hipertensión pulmonar grave. Luego de descartarse otras causas, se asumió la hipertensión pulmonar asociada a la infección por virus de inmunodeficiencia humana. Se realizó el tratamiento con sildenafil y presentó buena respuesta.

Topics: Adolescent; Heart Failure; HIV Infections; Humans; Hypertension, Pulmonary; Infectious Disease Transmission, Vertical; Male; Severity of Illness Index; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Phosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure with Preserved Ejection Fraction (RELAX) clinical trial. Metabolic impairments may explain the neutral results.. To test the hypothesis that profiling metabolites in the RELAX trial would clarify the mechanisms of sildenafil effects and identify metabolites associated with clinical outcomes in HFpEF.. Paired baseline and 24-week plasma samples of 160 stable outpatient individuals with HFpEF enrolled in the RELAX clinical trial were analyzed using flow injection tandem mass spectrometry (60 metabolites) and conventional assays (5 metabolites).. Sildenafil (n = 79) or a placebo (n = 81) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.. The primary measure was metabolite level changes between baseline and 24 weeks stratified by treatments. Secondary measures included correlations between metabolite level changes and clinical biomarkers and associations between baseline metabolite levels and the composite clinical score.. No metabolites changed between baseline and 24 weeks in the group treated with a placebo; however, 7 metabolites changed in the group treated with sildenafil, including decreased amino acids (alanine and proline; median change [25th-75th], -38.26 [-100.3 to 28.19] and -28.24 [-56.29 to 12.08], respectively; false discovery rate-adjusted P = .01 and .03, respectively), and increased short-chain dicarboxylacylcarnitines glutaryl carnitine, octenedioyl carnitine, and adipoyl carnitine (median change, 6.19 [-3.37 to 14.18], 2.72 [-3 to 12.57], and 10.72 [-11.23 to 29.57], respectively; false discovery rate-adjusted P = .01, .04, and .05, respectively), and 1 long-chain acylcarnitine metabolite (palmitoyl carnitine; median change, 7.83 [-5.64 to 26.99]; false discovery rate-adjusted P = .03). The increases in long-chain acylarnitine metabolites and short-chain dicarboxylacylcarnitines correlated with increases in endothelin-1 and creatinine/cystatin C, respectively. Higher baseline levels of short-chain dicarboxylacylcarnitine metabolite 3-hydroxyisovalerylcarnitine/malonylcarnitine and asparagine/aspartic acid were associated with worse clinical rank scores in both treatment groups (β, -96.60, P = .001 and β, -0.02, P = .01; after renal adjustment, P = .09 and .02, respectively).. Our study provides a potential mechanism for the effects of sildenafil that, through adverse effects on mitochondrial function and endoplasmic reticulum stress, could have contributed to the neutral trial results in RELAX. Short-chain dicarboxylacylcarnitine metabolites and asparagine/aspartic acid could serve as biomarkers associated with adverse clinical outcomes in HFpEF.

Topics: Aged; Asparagine; Aspartic Acid; Biomarkers; Carnitine; Female; Heart Failure; Humans; Male; Metabolomics; Middle Aged; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Stroke Volume

Persistent low-level hemolysis (LLH) during continuous-flow mechanical circulatory support is associated with subsequent thrombosis. Free hemoglobin from ongoing hemolysis scavenges nitric oxide (NO) to create an NO deficiency which can augment platelet function leading to a prothrombotic state. The phosphodiesterase-5 inhibitor, sildenafil, potentiates NO signaling to inhibit platelet function. Accordingly, we investigated the association of sildenafil administration and thrombotic events in patients with LLH during Heart Mate II support.. A single-center review of all patients implanted with a Heart Mate II who survived to discharge (n=144). LLH was defined by a discharge lactate dehydrogenase level of 400 to 700 U/L. Patients were categorized as (1) LLH not on sildenafil, (2) LLH on sildenafil, (3) no LLH not on sildenafil, and (4) no LLH on sildenafil. Age, sex, platelet count, and mean platelet volume were similar between groups. Seventeen patients had either device thrombosis or ischemic stroke. Presence of LLH was associated with a greater risk of thrombosis (adjusted hazard ratio, 15; 95% confidence interval, 4.5-50;. Sildenafil is associated with reduced device thrombosis and ischemic stroke during ongoing LLH on Heart Mate II support.

Topics: Brain Ischemia; Chi-Square Distribution; Disease-Free Survival; Heart Failure; Heart-Assist Devices; Hemolysis; Humans; Kaplan-Meier Estimate; Mean Platelet Volume; Phosphodiesterase 5 Inhibitors; Proportional Hazards Models; Prosthesis Design; Protective Factors; Retrospective Studies; Risk Factors; Sildenafil Citrate; Stroke; Time Factors; Treatment Outcome

Topics: Heart Failure; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Sildenafil Citrate; Stroke Volume

Topics: Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Sildenafil Citrate

Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits.. A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg(-1)·d(-1), sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes.. TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R(2)=0.74, P<0.01) and global LV function (R(2)=0.47, P<0.01).. Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure.

Topics: Animals; Cardiomegaly; Heart Failure; Male; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Ventricular Function, Left; Ventricular Remodeling

Heart failure (HF) is one of the main causes for cardiovascular morbidity and mortality. This study was designed to examine the effect of PDE-5 inhibition on cardiac geometry, function and apoptosis in post-infarct HF. Our data revealed that treatment of the PDE-5 inhibitor sildenafil, beginning 3 days after left anterior descending coronary artery ligation, attenuated LV remodeling, cardiac dysfunction, cardiomyocyte apoptosis and mitochondrial anomalies including ATP production, mitochondrial respiratory defects, decline of mitochondrial membrane potential (MMP) and compromised mitochondrial ultrastructure. Sildenafil partially ameliorated the downregulation of Sirt3 protein and acetylation of PGC-1alpha in peri-infarct myocardial regions. In cultured neonatal mouse ventricular myocytes subjected to hypoxia for 24 hrs, sildenafil suppressed apoptosis, promoted ATP production and elevated MMP, along with the increased Sirt3 protein expression and decreased PGC-1alpha acetylation. Interestingly, knock down of Sirt3 attenuated or nullified sildenafil-offered beneficial effects. Our findings demonstrated that sildenafil exerts its cardioprotective effect against post-infarction injury by improving mitochondrial ultrastructure and function via the Sirt3/PGC-1alpha pathway. This observation should shed some lights towards application of sildenafil in energy-related cardiovascular diseases.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Hypoxia; Heart Failure; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Infarction; Myocytes, Cardiac; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphodiesterase 5 Inhibitors; Signal Transduction; Sildenafil Citrate; Sirtuin 1; Sirtuin 3; Ventricular Remodeling

We report a 3-year-old boy weighing 13.5 kg who presented with intractable cardiac failure resulting from myocarditis and was treated by implantation of a HeartWare (HVAD) device. He was discharged home with the device. His cardiac function subsequently recovered, and the device was decommissioned. We believe this to be the youngest HVAD recipient and the only child to have recovered and had the device decommissioned.

Topics: Anticoagulants; Biopsy; Cardiomyopathy, Dilated; Child, Preschool; Combined Modality Therapy; Heart Failure; Heart-Assist Devices; Humans; Imaging, Three-Dimensional; Male; Milrinone; Myocarditis; Myocardium; Recovery of Function; Sildenafil Citrate; Thrombosis; Tomography, X-Ray Computed; Vasodilator Agents

In dogs with canine monocytic ehrlichiosis (CME), respiratory signs are uncommon and clinical and radiographic signs of interstitial pneumonia are poorly described. However, in human monocytic ehrlichiosis, respiratory signs are common and signs of interstitial pneumonia are well known. Pulmonary hypertension (PH) is classified based on the underlying disease and its treatment is aimed at reducing the clinical signs and, if possible, addressing the primary disease process. PH is often irreversible, but can be reversible if it is secondary to a treatable underlying etiology. CME is currently not generally recognized as one of the possible diseases leading to interstitial pneumonia and secondary PH in dogs. Only one case of PH associated with CME has been reported worldwide.. A seven-year-old, male intact, mixed breed dog was presented with 2 weeks history of lethargy and dyspnea. The dog previously lived in the Cape Verdean islands. Physical examination showed signs of right-sided congestive heart failure and poor peripheral perfusion. Thoracic radiography showed moderate right-sided cardiomegaly with dilation of the main pulmonary artery and a mild diffuse interstitial lung pattern with peribronchial cuffing. Echocardiography showed severe pulmonary hypertension with an estimated pressure gradient of 136 mm Hg. On arterial blood gas analysis, severe hypoxemia was found and complete blood count revealed moderate regenerative anemia and severe thrombocytopenia. A severe gamma hyperglobulinemia was also documented. Serology for Ehrlichia canis was highly positive. Treatment with oxygen supplementation, a typed packed red blood cell transfusion and medical therapy with doxycycline, pimobendan and sildenafil was initiated and the dog improved clinically. Approximately 2 weeks later, there was complete resolution of all clinical signs and marked improvement of the PH.. This report illustrates that CME might be associated with significant pulmonary disease and should be considered as a possible differential diagnosis in dogs presenting with dyspnea and secondary pulmonary hypertension, especially in dogs that have been in endemic areas. This is important because CME is a treatable disease and its secondary lung and cardiac manifestations may be completely reversible.

Topics: Animals; Antiparasitic Agents; Dog Diseases; Dogs; Doxycycline; Ehrlichiosis; Heart Failure; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Pyridazines; Radiography, Thoracic; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Topics: Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Sildenafil Citrate; Vasodilator Agents

Topics: Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Right ventricular (RV) function immediately after left ventricular assist device (LVAD) implantation is a crucial prognostic factor. RV failure is linked to increased mortality and worse outcome. A phosphodiesterase 5 inhibitor, sildenafil, was shown to decrease pulmonary vascular resistance and pulmonary artery pressure post-LVAD. We report on a series of heart failure patients, and the effect of sildenafil on the incidence of RV failure after LVAD implantation. We retrospectively analyzed the data of end-stage heart failure patients who underwent LVAD implantation with pulmonary hypertension and RV dysfunction prior to surgery. Patients were divided into two groups; group 1: patients who received sildenafil perioperatively, and group 2: patients who did not receive sildenafil. Hemodynamic and echographic data were collected before and after surgery. Fourteen patients were included, 8 patients in group 1 and 6 in group 2. Sildenafil was administered with a mean dose of 56.2 ± 9.4 mg in group 1 and was able to significantly reduce right heart failure incidence, and to demonstrate a significant reduction in pulmonary vascular resistance, pulmonary artery pressure, transpulmonary gradient, and a significant increase in cardiac output. In conclusion, sildenafil seems to have a promising role perioperatively in preventing acute RV failure postsurgery in patients with RV dysfunction and pulmonary hypertension, requiring LVAD therapy.

Topics: Adult; Cardiac Output; Female; Heart Failure; Heart-Assist Devices; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Ventricular Dysfunction, Right

Topics: Cardiomyopathies; Child; Echocardiography; Heart Failure; Humans; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Unresponsive pulmonary hypertension (PH) implies poor posttransplant outcomes. Data on late adaptation of the right ventricle (RV) are still few. This study evaluated three-yr RV function and remodeling, exercise capacity, and hemodynamic data in a selected group of patients initially disqualified because of PH. Between May 2005 and December 2009, 31 consecutive patients were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-wk trial, RHC disclosed PH reversibility (mean PVR: 5.41 ± 3 Wood units, mean TPG 14.5 ± 5.6 mmHg, and mean systolic PAP 68.9 ± 15.1 mmHg), allowing listing even though as high-risk procedures. All patients underwent heart transplantation. RV failure developed in three patients (9.6%), and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary hemodynamic profile normalization within the third postoperative month, allowing weaning from sildenafil in the 30 hospital survivors. One- and three-yr RHCs confirmed stable PH reversal (n = 26, all three-yr survivors). Parameters of late RV function and remodeling proved satisfactory. Parameters of functional capacity (Vo2 peak 19.7 ± 3.6 mL/kg/min and slope VE/Vco2 34.8 ± 2.7) proved homogeneous to those measured in transplant recipients with normal preoperative pulmonary artery pressure. Oral sildenafil is effective in allowing candidacy, safe transplantation, and long-term survival in PH recipients initially disqualified.

Topics: Administration, Oral; Allografts; Cardiac Catheterization; Exercise Tolerance; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Prognosis; Prospective Studies; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Transplant Recipients; Vasodilator Agents; Ventricular Function, Right

Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Iα (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.

Topics: Animals; Cardiotonic Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Disease Models, Animal; Estradiol; Estrogens; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Guanylate Cyclase; Heart Diseases; Heart Failure; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Ovariectomy; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Receptors, Atrial Natriuretic Factor; Sex Characteristics; Sildenafil Citrate; Sulfones; Treatment Outcome

Study of pulmonary hypertension (PAH) during pregnancy has characteristics of the high risk factors for patient death and its clinical characteristics.. Death in patients with clinical data was collected from January 2006 to October 2013 in Beijing Anzhen Hospital Affiliated to Capital Medical University treated 8 cases of pregnancy complicated with PAH in hospital. According to the mechanism of PAH patients will be divided into two categories, Idiopathic pulmonary arterial hypertension (IPAH) in 4 cases, 4 cases of secondary PAH [are secondary to congenital heart disease, also known as congenital heart disease associated PAH (CHD-PAH)]. Analyze the clinical features of 8 cases of patients and pregnancy outcome.. (1) In 8 patients, 4 cases were IPAH, none of them with primary diseases, and they were complicated with severe tricuspid regurgitation. 4 cases were CHD-PAH, all with Eisenmenger's syndrome. 8 patients were not preconception counseling and regular prenatal examination. (2) The pregestational cardiac function of 8 cases was grade I-II, and it was grade III-IV on admission. The estimation pressure (sPAP) of pulmonary artery systolic by echocardiography was 101 mmHg (1 mmHg = 0.133 kPa). In 8 patients, 7 cases were in pregnancy 27 weeks and beyond for treatment since the clinical symptoms increased, 1 case of pregnant 18 weeks for treatment caused by the increased clinical symptoms. (3) In 8 patients, 1 patient with CHD- PAH secondary to patent ductus arteriosus, its sPAP was 170 mmHg, dead at 12 hours after admission; the remaining 7 cases termination with cesarean section. 4 patients with IPAH were continuous epidural anesthesia, including 1 case for the intraoperative PAH crisis and respiratory and cardiac arrest with general anesthesia, 3 cases of CHD- PAH patients in 1 case with continuous epidural anesthesia, 2 cases of general anesthesia.(4) In 8 patients, 7 cases of median death time were 3 days after delivery, including 4 cases of IPAH patients death for 2.5 days after delivery; the causes of death were PAH crisis and heart failure. Time of death in 4 cases of CHD-PAH, 1 case was dead at 12 hours after admissions, the remaining 3 cases median death time were 13 days after delivery; the death causes for 4 cases of CHD-PAH were PAH crisis and multiple organ failure. (5) In 8 patients, 1 patient with CHD-PAH secondary to patent ductus arteriosus in gestational week 31 stillbirths occur. 1 case of pregnant 19 weeks had treatment of caesarean operation, the remaining 6 cases respectively at 28-30 weeks of gestation live birth, neonatal survival. (6) Before delivery, 4 cases of IPAH and 3 cases of CHD-PAH patients treated with alprostadil, iloprost, sildenafil, reduction of pulmonary artery pressure treatment, 1 case of CHD-PAH patient was dead after 12 hours in hospital, no drug treatment.. (1) PAH in patients need for consultation prior to conception, pregnancy must conduct regular prenatal examination, symptoms occur during pregnancy, the cardiac function was significantly decreased, and no improvement of drug treatment should be early terminated the pregnancy. (2) Compared with the pregnant women with CHD- PAH, faster progress and poor prognosis in patients with IPAH disease. (3)The patients during cesarean operation or intrapartumare easy to cause PAH crisis and heart failure or multiple organ failure. Taking active measures to maintain stability of hemodynamics is the key to prevent the occurrence of death of pregnant women with PAH.

Topics: Anesthesia, General; Cesarean Section; Delivery, Obstetric; Echocardiography; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Heart Defects, Congenital; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Maternal Mortality; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pulmonary Artery; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides

A retrospective analysis of the records of all the patients of pulmonary arterial hypertension with pregnancy at AIIMS, New Delhi, India, to study maternal and perinatal outcome and to compare outcome between severe and mild pulmonary arterial hypertension.. A retrospective analysis was carried out of 30 pregnancies in women with pulmonary arterial hypertension (PAH) who delivered at ≥ 28 weeks of gestation from July 2006 through July 2012 at a tertiary care center in India. Pulmonary artery blood pressure (PABP) during the first trimester of pregnancy or before pregnancy was considered to define PABP as severe or mild, with severe cases having systolic PABP >50 mmHg on echocardiography.. Out of 30 patients, 14 patients had severe PAH and 16 patients had mild PAH. Women with severe PAH had a significantly higher incidence of preterm delivery (11 vs. 3, P < 0.05), small for gestational age infants (10 vs. 2, P < 0.05) and cardiac complications (6 vs. 1, P < 0.05) compared to women with mild PAH. There was maternal mortality in a patient with Eisenmenger syndrome. In women with severe PAH and mild PAH, PABP increased in later pregnancy from 63.14 ± 7.6 to 71.57 ± 7.9 mmHg (P < 0.05) and from 40.37 ± 3.6 to 41.69 ± 4.1 mmHg (P < 0.05), respectively.. Pregnancy in women with severe PAH is associated with higher maternal morbidity and adverse fetal outcome compared to pregnancy in women with mild PAH.

Topics: Adult; Arrhythmias, Cardiac; Arterial Pressure; Birth Weight; Cesarean Section; Echocardiography; Eisenmenger Complex; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Heart Failure; Humans; Hypertension, Pulmonary; India; Infant, Newborn; Infant, Small for Gestational Age; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Third; Premature Birth; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

There has been no established medical therapy to ameliorate pulmonary hypertension (PH) owing to left heart disease (LHD-PH). It has recently been shown that the left ventricular assist device (LVAD) can improve LHD-PH and therefore has the potential to become a major bridge tool for heart transplantation (HTx). However, some patients still have persistent PH even after LVAD treatment. It is essential to demonstrate the reversibility of end-organ dysfunction, including PH, prior to implantable LVAD treatment, especially in Japan, because implantable LVAD treatment is indicated only as bridge to transplantation. Here we report a patient with LHD-PH whose PH was demonstrated to be reversible by the acute pulmonary vasoreactivity test (APVT) with nitrogen monoxide (NO) and the phosphodiesterase-5 inhibitor sildenafil. Both inhaled NO and sildenafil reduced pulmonary vascular resistance, but pulmonary capillary wedge pressure was increased by NO, which was conversely decreased under increased cardiac output by sildenafil. After the patient was listed as an HTx recipient, pulmonary vascular resistance recovered down to an acceptable range with LVAD treatment. Based on these findings, we suggest that the APVT with sildenafil may be a useful and safe tool to predict improvement of PH after LVAD treatment.

Topics: Adult; Cardiomyopathy, Dilated; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Piperazines; Prosthesis Implantation; Purines; Sildenafil Citrate; Sulfones

We investigated if soluble guanylate cyclase stimulation either alone or in combination with phosphodiesterase-5 (PDE5) inhibition could prevent pressure overload-induced right ventricular (RV) hypertrophy and failure.. The soluble guanylate cyclase stimulator BAY 41-2272 (BAY, 10 mg · kg⁻¹ · d⁻¹) either alone or in combination (BAY + SIL) with a PDE5 inhibitor sildenafil (SIL, 100 mg · kg⁻¹ · d⁻¹) was examined for prevention of RV hypertrophy and failure in Wistar rats (n = 73) operated by pulmonary trunk banding.. All treatments failed to inhibit the development of RV hypertrophy and failure. In the BAY and BAY + SIL groups, there was an increased mortality. Mean arterial blood pressure was lowered and cardiac output increased in the BAY + SIL group. Systolic RV pressure was increased in the BAY and BAY + SIL groups possibly because of an inotropic response and/or increased venous return.. Stimulation of soluble guanylate cyclase by BAY 41-2272 alone or in combination with sildenafil failed to prevent the development of RV hypertrophy and failure in rats subjected to pulmonary trunk banding. An increased mortality was observed in animals treated by BAY 41-2272 alone and in combination with sildenafil.

Topics: Animals; Blood Pressure; Cardiac Output; Cyclic GMP; Disease Models, Animal; Disease Progression; Enzyme Activators; Guanylate Cyclase; Heart Failure; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Pyridines; Random Allocation; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfones; Survival Analysis

Inhibition of the cGMP-specific phosphodiesterase 5 (PDE5) exerts profound beneficial effects on failing hearts. However, the mechanisms underlying the therapeutic effects of PDE5 inhibition on heart failure are unclear. The purpose of this study was to investigate whether PDE5 inhibition decreases endoplasmic reticulum (ER) stress, a key event in heart failure.. Heart failure was induced by isoprenaline s.c. injection in Sprague-Dawley rats and transverse aortic constriction (TAC) in mice. PDE5 was inhibited with sildenafil. Heart function was detected by invasive pressure-volume analysis and echocardiography. ER stress markers were analysed by Western blotting. Apoptosis was measured by flow cytometric analysis.. PDE5 inhibition markedly attenuated isoprenaline-induced and TAC-induced cardiac hypertrophy and dysfunction, and reduced ER stress and apoptosis. Further, PDE5 inhibition with sildenafil largely prevented ER stress and reduced apoptosis in isoprenaline- or thapsigargin-treated cardiomyocytes. PKG inhibition markedly prevented the protective effects of sildenafil in vivo and in vitro. To further understand the mechanism of the effect of PDE5 inhibition on ER stress, we demonstrated that PDE5 inhibitor increased sarco-(endo)-plasmic reticulum Ca(2+) -ATPase activity via phosphorylation of phospholamban at Ser(16) . This may contribute to the attenuation of ER stress induced by PDE5 inhibition.. These results suggest that PDE5 inhibition can attenuate ER stress and improve cardiac function in vivo and in vitro. Suppression of ER stress by inhibiting PDE5 may contribute to the therapeutic effects on heart failure.

Topics: Animals; Aorta; Apoptosis; Calcium-Binding Proteins; Cardiomegaly; Constriction; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Heart Failure; Humans; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Sildenafil Citrate; Stroke Volume; Sulfones; Ventricular Function, Left

We report a case of an elderly woman with heart failure with preserved ejection fraction and pulmonary hypertension (HFpEF-PH), refractory to conventional therapy for left heart failure and successfully treated by sildenafil.

Topics: Aged; Female; Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Right ventricular (RV) failure (RVF) is the main cause of death in patients with pulmonary artery hypertension (PAH). Sildenafil, a phosphodiesterase type 5 inhibitor, was approved recently for treatment of PAH patients. However, the mechanisms underlying RV contractile malfunction and the benefits of sildenafil on RV function are not well understood. We aimed to investigate the following: (1) the ultrastructural and excitation-contraction coupling alterations underlying PAH-induced RVF; (2) whether the ultrastructural changes are reversible; and (3) the mechanisms underlying the therapeutic benefits of sildenafil in PAH-RVF. We used a single injection of monocrotaline in Wistar rats to induce pulmonary vascular proliferation, which led to PAH and RVF. RV myocytes displayed severe transverse (T)-tubule loss and disorganization, as well as blunted and dys-synchronous sarcoplasmic reticulum Ca(2+) release. Sildenafil prevented and reversed the monocrotaline-induced PAH and LV filling impairment. Early intervention with sildenafil prevented RV hypertrophy and the development of RVF, T-tubule remodeling, and Ca(2+) handling dysfunction. Although late treatment with sildenafil did not reverse RV hypertrophy in animals with established RVF, RV systolic function was improved. Furthermore, late intervention partially reversed both the impairment of myocyte T-tubule integrity and Ca(2+) handling protein and sarcoplasmic reticulum Ca(2+) release function in monocrotaline-treated rats. In conclusion, PAH-induced increase in RV afterload causes severe T-tubule remodeling and Ca(2+) handling dysfunction in RV myocytes, leading to RV contractile failure. Sildenafil prevents and partially reverses ultrastructural, molecular, and functional remodeling of failing RV myocytes. Reversal of pathological T-tubule remodeling, although incomplete, is achievable without the regression of RV hypertrophy.

Topics: Animals; Calcium; Disease Models, Animal; Excitation Contraction Coupling; Heart Failure; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Microscopy, Confocal; Monocrotaline; Myocardial Contraction; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Treatment Outcome; Ventricular Dysfunction, Right; Ventricular Remodeling

Sildenafil inhibits cyclic GMP-specific phosphodiesterase type-5A (PDE5A) and can prevent cardiac hypertrophy and left ventricular (LV) dysfunction in mice subjected to severe pressure-overload. The pathophysiological role of sildenafil in adverse remodeling in the hypertensive heart after chronic renin-angiotensin aldosterone system stimulation is unknown. Therefore, we studied the efficacy of the PDE5A inhibitor sildenafil for treating advanced cardiac hypertrophy and LV remodeling due to angiotensin (Ang)II-induced heart failure (HF) in vivo. C57BL6/J mice were subjected to AngII-induced cardiac hypertrophy for 3 weeks and cardiac dysfunction, cardiac inflammatory stress response, adverse remodeling as well as apoptosis were documented. Mice were subsequently treated with sildenafil (100 mg/kg/day) or placebo with delay of 5 days for treating AngII infusion-induced adverse events. Compared to controls, AngII infusion resulted in impaired systolic (dP/dt (max) -46 %, SV -16 %, SW -43 %, E (a) +51 %, EF -37 %, CO -36 %; p < 0.05) and diastolic (dP/dt (min) -36 %, LV end diastolic pressure +73 %, Tau +21 %, stiffness constant β +74 %; p < 0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased inflammatory response was also indicated by an increase in immune cell infiltration and apoptosis. Treatment with sildenafil led to a significant improvement in systolic and diastolic LV performance. This effect was associated with less LV hypertrophy, remodeling, cardiac inflammation and apoptosis. PDE5A inhibition with sildenafil may provide a new treatment strategy for cardiac hypertrophy and adverse remodeling in the hypertensive heart.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Apoptosis; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic Nucleotide Phosphodiesterases, Type 5; Cytokines; Extracellular Matrix; Heart Failure; Heart Function Tests; Hydralazine; Male; Mice; Mice, Inbred C57BL; Myocarditis; Myocardium; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Sildenafil Citrate; Sulfones; Vasoconstrictor Agents; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Elevated pulmonary vascular resistance (PVR) in heart transplant (HT) candidates is associated with poor survival after HT. This study assessed the effect of peri-operative sildenafil administration on pulmonary hemodynamics and clinical outcomes in patients with advanced heart failure who were considered high-risk for HT because of elevated PVR and transpulmonary gradient (TPG).. The study included 119 consecutive patients who underwent HT between 2004 and 2011. Fifteen patients (Group A) had severe pulmonary hypertension (PH), defined as mean pulmonary pressure (MPAP)>25 mm Hg and PVR>2.5 Wood units (WU), and/or TPG>12 mm Hg after vasodilator test or the continuous administration of inotropics drugs, and 104 patients (Group B) were without severe PH. Group A received sildenafil therapy. Pulmonary hemodynamics were evaluated before HT with and without sildenafil therapy. Right catheterization was performed early after HT with sildenafil therapy and late after HT without sildenafil. Survival after HT was compared between the groups.. The sildenafil dosage was 109±42 mg/day during 163±116 days before HT. After sildenafil therapy MPAP, PVR, and TPG decreased from 43.9±12.5 to 33.4±5.8 mm Hg, 5.0±1.1 to 3.0±1.6 WU, and 17.3±3.2 to 10.2±4.1 mm Hg, respectively (p<.01). All patients underwent successful HT. Sildenafil dosage was 140±70 mg/day for 43±45 days after HT. There were no differences in PVR and TPG with sildenafil therapy early after HT and without sildenafil 6 months after HT. Survival after HT was similar between the groups.. Sildenafil therapy before and after HT in patients with severe PH is associated with improved pulmonary hemodynamics and successful HT, without an increase in post-HT mortality.

Topics: Female; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Perioperative Period; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Cyclic GMP (cGMP) signaling attenuates cardiac remodeling, but it is unclear which cGMP effectors mediate these effects and thus might serve as novel therapeutic targets. Therefore, we tested whether the cGMP downstream effector, cGMP-dependent protein kinase G Iα (PKGIα), attenuates pressure overload-induced remodeling in vivo.. The effect of transaortic constriction (TAC)-induced left ventricular (LV) pressure overload was examined in mice with selective mutations in the PKGIα leucine zipper interaction domain. Compared with wild-type littermate controls, in response to TAC, these Leucine Zipper Mutant (LZM) mice developed significant LV systolic and diastolic dysfunction by 48 hours (n=6 WT sham, 6 WT TAC, 5 LZM sham, 9 LZM TAC). In response to 7-day TAC, the LZM mice developed increased pathologic hypertrophy compared with controls (n=5 WT sham, 4 LZM sham, 8 WT TAC, 11 LZM TAC). In WT mice, but not in LZM mice, phosphodiesterase 5 (PDE5) inhibition with sildenafil (Sil) significantly inhibited TAC-induced cardiac hypertrophy and LV systolic dysfunction in WT mice, but this was abolished in the LZM mice (n=3 WT sham, 4 LZM sham, 3 WT TAC vehicle, 6 LZM TAC vehicle, 4 WT TAC Sil, 6 LZM TAC Sil). And in response to prolonged, 21-day TAC (n=8 WT sham, 7 LZM sham, 21 WT TAC, 15 LZM TAC), the LZM mice developed markedly accelerated mortality and congestive heart failure. TAC induced activation of JNK, which inhibits cardiac remodeling in vivo, in WT, but not in LZM, hearts, identifying a novel signaling pathway activated by PKGIα in the heart in response to LV pressure overload.. These findings reveal direct roles for PKGIα in attenuating pressure overload-induced remodeling in vivo and as a required effector for the cardioprotective effects of sildenafil.

Topics: Animals; Cardiotonic Agents; Cyclic GMP-Dependent Protein Kinase Type I; Echocardiography; Heart; Heart Failure; Immunoblotting; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase Inhibitors; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Cardiomyopathy, Dilated; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Humans; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Ventricular Remodeling

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.

Topics: Adolescent; Age Factors; Aryl Hydrocarbon Hydroxylases; Asian People; Bayes Theorem; Body Weight; Bosentan; Child; Child, Preschool; Computer Simulation; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Drug Interactions; Familial Primary Pulmonary Hypertension; Female; Genotype; Heart Failure; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Liver-Specific Organic Anion Transporter 1; Male; Models, Biological; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Piperazines; Polymorphism, Single Nucleotide; Purines; Sildenafil Citrate; Solute Carrier Organic Anion Transporter Family Member 1B3; Sulfonamides; Sulfones

Chronic inhibition of phosphodiesterase-5 with sildenafil immediately after permanent occlusion of the left anterior descending coronary artery was shown to limit ischemic heart failure (HF) in mice. To mimic a more clinical scenario, we postulated that treatment with sildenafil beginning at 3 days post-myocardial infarction (MI) would also reduce HF progression through the inhibition of the RhoA/Rho-kinase pathway. Adult male ICR mice with fractional shortening < 25% at day 3 following permanent left anterior descending coronary artery ligation were continuously treated with either saline (volume matched, ip, 2 times/day) or sildenafil (21 mg/kg, ip, 2 times/day) for 25 days. Echocardiography showed fractional shortening preservation and less left ventricular end-diastolic dilatation with sildenafil treatment compared with saline treatment at 7 and 28 days post-MI (P < 0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), respectively, were attenuated in the sildenafil-treated mice (P < 0.05 vs. saline). Western blot analysis showed enchanced Bcl-2-to-Bax ratio with sildenafil treatment (P < 0.05 vs. saline). Activity assay showed sildenafil-mediated PKG activation 1 day after treatment (P < 0.05 vs. sham and saline). PKG activation was associated with sildenafil-mediated inhibition of Rho kinase (P < 0.05) compared with saline treatment, whereas PKG inhibition with KT-5823 abolished this inhibitory effect of sildenafil. In conclusion, for the first time, our findings show that chronic sildenafil treatment, initiated at 3 days post-MI, attenuates left ventricular dysfunction independent of its infarct-sparing effect, and this cardioprotection involves the inhibition of the RhoA/Rho-kinase pathway. Sildenafil may be a promising therapeutic tool for advanced HF in patients.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cardiomegaly; Cyclic GMP-Dependent Protein Kinases; Heart Failure; Hemodynamics; Male; Mice; Mice, Inbred ICR; Models, Animal; Phosphodiesterase 5 Inhibitors; Piperazines; Proto-Oncogene Proteins c-bcl-2; Purines; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

We present a case of a 21 year-old man who has had Fontan type correction 17 years ago with symptoms of severe heart insufficiency (III NYHA class, cahectic, with massive peripheral oedema and ascites) caused by increased pulmonary vascular resistance and increased pulmonary artery pressure. He was treated successfully with long term sildenafil medication.

Topics: Adult; Fontan Procedure; Heart Failure; Humans; Male; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The patency of foramen ovale (FO) in fetal circulation is very important, and premature closure of FO could be associated with several pathological conditions.. We report a patient in whom premature closure of FO in fetal life was associated with late clinical onset of mitral valve stenosis and subsequent development of irreversible pulmonary hypertension (PH).. The patient showed persistent PH after birth, which completely regressed at the age of 8 months. However, the patient developed heart failure due to mitral valve lesions (hammock valve) at the age of 11 months and underwent artificial valve replacement. The patient subsequently developed severe PH, which was refractory to anti-PH therapy with sildenafil and bosentan in addition to home oxygen.. This case illustrates that mitral stenosis can be overlooked during early neonatal life, and thus emphasizes the need for close follow-up for potential existence of mitral stenosis and later clinical manifestation in patients with premature FO closure even when initial careful examination of the mitral valves does not indicate any abnormalities. In addition, premature closure of FO could cause pulmonary vascular disease, which may lead to later development of irreversible PH.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Fetal Diseases; Foramen Ovale; Heart Failure; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Mitral Valve Stenosis; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Failure; Ultrasonography, Doppler, Pulsed; Ultrasonography, Prenatal; Vasodilator Agents

Topics: Altitude; Exercise Tolerance; Heart Failure; Humans; Mountaineering; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tai Ji; Vasodilator Agents

Topics: Aged; Aged, 80 and over; Double-Blind Method; Female; Heart Failure; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prevalence; Purines; Respiratory Function Tests; Sildenafil Citrate; Stroke Volume; Sulfones

Chronic phosphodiesterase-5 inhibition improves peak oxygen consumption, ventilatory efficiency (VE/VCO(2) slope) and pulmonary artery pressure (PAP) in heart failure (HF). In 40 male patients, Sildenafil treatment produced a significant (p<0.001) decrease in dyspnea upon exertion (DOE) at maximal exercise. The correlations between the change in systolic PAP and both the change in the VE/VCO(2) slope (r=0.57, p<0.001) and DOE at maximal exercise (r(s)=0.49, p<0.001) were significant. DOE at maximal exercise is significantly reduced and the degree of improvement in PAP is reflected by the degree of improvement in the VE/VCO(2) slope and DOE following Sildenafil therapy.

Topics: Aged; Dyspnea; Exercise Test; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Physical Exertion; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Work of Breathing

Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF.. Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased approximately equal 4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3'-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF.. Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.

Topics: Animals; Antioxidants; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Heart Failure; Humans; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Nitric Oxide Synthase Type II; Organometallic Compounds; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-akt; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Superoxide Dismutase

Sildenafil is increasingly being used in the management of pulmonary arterial hypertension in the newborn. Its role in patients with congenital cardiac disease is less well defined and as yet has only been reported sporadically.. Present our experience with sildenafil treatment in patients with a failing Fontan circulation.. Retrospective review of 13 symptomatic patients after Fontan palliation who received treatment with sildenafil between January, 2006 and July, 2008.. Three patients suffered from protein-losing enteropathy, four patients presented with bronchial casts, two had severe cyanosis after fenestrated Fontan procedure, two had prolonged chylous effusions, one had a previous failure of Fontan and take-down, and one patient had arrhythmias and end-stage cardiac failure requiring conversion to an extra-cardiac Fontan. Sildenafil was used in the dosage of 1-2 milligrams per kilogram 3-4 times per day. Protein-losing enteropathy and alpha-1-antitrypsin levels improved in all three patients on sildenafil treatment. One of these patients had a concomitant catheter creation of a fenestration, as did two patients presenting with bronchial casts and both patients with persistent chylous effusions. All four patients with bronchial casts and two patients with cyanosis improved significantly on sildenafil treatment. Chylous effusions decreased after sildenafil and stent enlargement of a fenestration. There were no significant side effects requiring sildenafil withdrawal over a treatment period ranging from 2 months to 2 years.. Sildenafil can be used safely and effectively in the treatment of patients with a failing Fontan circulation.

Topics: Child; Child, Preschool; Female; Follow-Up Studies; Fontan Procedure; Heart Failure; Humans; Hypertension, Pulmonary; Male; Piperazines; Postoperative Complications; Protein-Losing Enteropathies; Purines; Retrospective Studies; Shock; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Previous research has demonstrated an increase in large vessel stiffness in patients with heart failure (HF). Furthermore, heart rate recovery (HRR) may be negatively impacted by increased arterial stiffness secondary to altered baroreceptor discharge. The purpose of the present study was to determine if chronic phosphodiesterase 5 (PDE5) inhibition with Sildenafil, previously shown to improve arterial stiffness, favorably impacts HRR in patients with HF. Forty male subjects (age: 65.3+/-7.3 years, baseline ejection fraction: 37.1+/-7.4%, 15 non-ischemic HF/25 ischemic HF) participated in this study. Subjects received Sildenafil (25 mg, 3 times/day) for six months. Symptom-limited exercise testing was performed at baseline and six months with a lower extremity ergometer. Heart rate recovery was defined as HR at maximal exercise minus HR at 1 min recovery. No adverse effects were reported throughout the study period. Paired t-testing revealed that HRR was significantly improved following six months of Sildenafil therapy (baseline: 17.5+/-3.5 bpm vs. Post: 20.6+/-3.2 bpm). The results of the present study indicate that chronic Sildenafil therapy significantly increases HRR, an important prognostic marker, in patients with HF. A plausible mechanism for the improvement of HRR is the previously demonstrated impact Sildenafil has on arterial stiffness and therefore baroreceptor function.

Topics: Aged; Heart Failure; Humans; Male; Middle Aged; Piperazines; Purines; Recovery of Function; Sildenafil Citrate; Sulfones; Vasodilator Agents

Phosphodiesterase-5 (PDE5) inhibitors, which induce relaxation of smooth muscle with some selectivity for the pulmonary vasculature, are used in the treatment of pulmonary hypertension. In some patients, the use of PDE5 inhibitors does not result in the desired magnitude of pulmonary vasodilation. The use of additional vasodilators to further reduce pulmonary vascular resistance is often accompanied by unacceptable reductions in systemic arterial pressure.. In 3 patients with heart failure, pulmonary hypertension and low systemic arterial pressures treated with sildenafil, systemic nitrates were added to reduce pulmonary hypertension further. Hemodynamic measurements were made before and after addition of nitrates. Addition of systemic nitrates to sildenafil led to a reduction in mean pulmonary arterial pressure of 11 mm Hg, from 37 mm Hg to 26 mm Hg (P = .06), whereas mean systemic arterial pressure decreased by only 4 mm Hg, from 77 mm Hg to 73 mm Hg (P = .53). The ratio of pulmonary vascular resistance to systemic vascular resistance was reduced by 45% (P = .1). Treatment with sildenafil and nitrates was continued for two to eight months, with no episodes of marked systemic hypotension, syncope, or lightheadedness.. These results suggest that addition of systemic nitrates to sildenafil results in a potentiation of vasodilation that is relatively selective for the pulmonary vasculature, and that this combination may be safe and effective in the treatment of pulmonary hypertension in patients with low systemic arterial pressures.

Topics: Cyclic GMP; Drug Therapy, Combination; Heart Failure; Humans; Hypertension, Pulmonary; Isosorbide Dinitrate; Male; Middle Aged; Nitro Compounds; Nitroglycerin; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Pulmonary hypertension (PH) is a factor of poor prognosis in the postoperative period of heart transplant (HT) and thus, the study of the degree of reversibility to vasodilators is mandatory during the preoperative assessment.. To evaluate the pulmonary and systemic hemodynamic effects of sildenafil as a vasodilator during the PH reversibility test in patients that are candidates to HT.. Patients awaiting HT were submitted to the measurement of systemic and pulmonary hemodynamic variables before and after the administration of a single sublingual dose of 100 mg of sildenafil during right heart catheterization.. Fourteen patients (age: 47+/-12 years, 71.4% men) with advanced heart failure Ejection Fraction (EF) 25 +/- 7%, Functional Class (FC - NYHA) FC III - 6 and FC IV - 8, were evaluated in this study. The acute administration of sildenafil showed to be effective in decreasing the systolic (62.4 +/- 12.1 vs 51.5 +/- 9.6 mmHg, CI=95%, p<0.05) and mean (40.7 +/- 7.3 vs 33.8 +/- 7.6 mmHg, CI=95%, p <0.05) pressures of the pulmonary artery. There was also a significant decrease in the pulmonary (4.2 +/- 3 vs 2.0 +/- 0.9 uWood, CI=95%, p<0.05) and systemic vascular resistance (22.9 +/- 6.8 vs 18.6 +/- 4.1 Wood, CI=95%, p<0.05), associated to an increase in the cardiac output (3.28 +/- 0.79 vs 4.12 +/-1.12 uWood, CI=95%, p<0.05) without, however, significantly interfering in the systemic arterial pressure (87.8 +/- 8.2 vs 83.6 +/- 9.1 mmHg, CI=95%, p=0.3).. The sublingual administration of sildenafil is an effective and safe alternative as a vasodilator during the PH reversibility test in patients with heart failure and awaiting a HT.

Topics: Administration, Sublingual; Female; Heart Failure; Heart Rate; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

In mouse models of cardiac disease, the type 5 (PDE5)-selective cyclic nucleotide phosphodiesterase inhibitor sildenafil has antihypertrophic and cardioprotective effects attributable to the inhibition of cGMP hydrolysis. To investigate the relevance of these findings to humans, we quantified cGMP-hydrolytic activity and its inhibition by sildenafil in cytosolic and microsomal preparations from the left ventricular myocardium of normal and failing human hearts. The vast majority of cGMP-hydrolytic activity was attributable to PDE1 and PDE3. Sildenafil had no measurable effect on cGMP hydrolysis at 10 nM, at which it is selective for PDE5, but it had a marked effect on cGMP and cAMP hydrolysis at 1 microM, at which it inhibits PDE1. In contrast, in preparations from the left ventricles of normal mice and mice with heart failure resulting from coronary artery ligation, the effects of sildenafil on cGMP hydrolysis were attributable to inhibition of both PDE5 and PDE1; PDE5 comprised approximately 22 and approximately 43% of the cytosolic cGMP-hydrolytic activity in preparations from normal and failing mouse hearts, respectively. These differences in PDE5 activities in human and mouse hearts call into question the extent to which the effects of sildenafil in mouse models are likely to be applicable in humans and raise the possibility of PDE1 as an alternative therapeutic target.

Topics: Animals; Coronary Vessels; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Cytosol; Heart Failure; Humans; Hydrolysis; Male; Mice; Mice, Inbred ICR; Microsomes; Myocardium; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase I; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Subcellular Fractions; Sulfones

We sought to identify factors that discriminate heart failure (HF) patients with normal and elevated pulmonary vascular resistance (PVR) and to elucidate the role of cyclic guanosine monophosphate (cGMP)-dependent vasodilation.. Mechanisms of PVR increase in patients with chronic HF are incompletely understood.. Twenty-two HF patients with high pulmonary vascular resistance (H-PVR) (>200 dyn.s.cm(-5)) were compared with 24 matched low pulmonary vascular resistance (L-PVR) patients of similar age, sex, body size, HF severity, and volume status who were undergoing invasive hemodynamic study. Pulmonary arterial (PA) and venous blood samples from a wedged PA catheter were used to calculate transpulmonary B-type natriuretic peptide (BNP) uptake and cGMP release. The H-PVR patients were re-examined 1 h after a 40-mg oral dose of sildenafil.. Although transpulmonary BNP uptake was similar (p = 0.2), cGMP release was diminished in the H-PVR patients (-1.9 vs. 27.8 nmol.min(-1); p = 0.005). Transpulmonary BNP uptake and cGMP release correlated in the L-PVR patients (R = 0.6, p = 0.004) but not in the H-PVR. The H-PVR patients also had lower PA compliance, systemic arterial compliance (by 47% and 20%, p < 0.001 and p < 0.03), and cardiac index. Sildenafil reduced PVR (-47%), systemic resistance (-24%) and heart rate (-8%), increased cardiac index (+24%), and PA compliance (+87%, all p < 0.001), with a parallel increase of cGMP release (from -5.6 to 16.5 nmol.min(-1), p = 0.047), without affecting BNP uptake or norepinephrine(PA). The PVR response was not dependent on PA wedge pressure or pulmonary hypertension reversibility with prostaglandin E(1).. The H-PVR patients have stiffening of both pulmonary and systemic arteries, preserved transpulmonary BNP uptake, but diminished cGMP release, which is reversible by the administration of sildenafil. This study provides in vivo evidence that phosphodiesterase 5A inhibition restores sensitivity of pulmonary vasculature to endogenous cGMP-dependent vasodilators.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Female; Guanosine Monophosphate; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilation; Vasodilator Agents

Increased pulmonary vascular resistance causing pulmonary artery hypertension is a major problem in the treatment of congenital diaphragmatic hernia with a strong association to mortality. We here report a patient with intractable pulmonary hypertension at 4 weeks of age unresponsive to conventional treatment. After administration of the platelet-derived growth factor (PDGF) receptor antagonist imatinib, pulmonary artery pressure gradually decreased to acceptable levels and the patient's clinical condition gradually improved.

Topics: Benzamides; Bosentan; Combined Modality Therapy; Continuous Positive Airway Pressure; Diuretics; Enteral Nutrition; Extracorporeal Membrane Oxygenation; Heart Failure; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Imatinib Mesylate; Infant, Newborn; Male; Nitric Oxide; Piperazines; Protein Kinase Inhibitors; Purines; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Sildenafil Citrate; Sulfonamides; Sulfones

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5). Its chronic administration has been shown to improve exercise capacity, World Health Organization functional class, and haemodynamics in patients with symptomatic pulmonary arterial hypertension (PAH). There is however, no data describing the clinical consequences of sudden cessation of sildenafil treatment. In this series, 9 patients with NYHA Class II-IV PAH who were stable on 2 months of sildenafil monotherapy, had their sildenafil ceased to accommodate a 2-week washout period, required for enrollment in research involving an endothelin receptor antagonist. Six minute walk distance (SMWD) and clinical assessments were performed before cessation of sildenafil, and again 2 weeks later. Over the course of this 2-week washout period, 6 of the 9 patients reported increased breathlessness and fatigue, 1 of these was hospitalized with worsening right heart failure. The SMWD fell in 6 patients, with falls of greater than 100 m recorded in 4 patients. This was accompanied by a worsening of NYHA Class from 2.5 +/- 0.2 to 3.1 +/- 0.1 (mean +/- SEM, p = 0.01). These data indicate that sudden cessation of sildenafil monotherapy, in patients with PAH, carries with it a significant and unpredictable risk of rapid clinical deterioration. We recommend that if sildenafil needs to be ceased, it would be more prudent to consider concurrent vasodilator therapy before the gradual cessation of sildenafil.

Topics: Adult; Disease Progression; Drug Administration Schedule; Exercise Tolerance; Fatigue; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiration; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Withholding Treatment

Sildenafil is used for pulmonary hypertension treatment and its use is safe in chronic heart failure (HF) patients.. To analyze the effects of sildenafil on lung mechanics, gas diffusion, exhaled nitric oxide (eNO) at rest and during exercise in chronic HF. We did so to evaluate if sildenafil prevents exercise-induced pulmonary edema formation.. We studied 22 chronic HF males. We measured after a single dose of placebo, sildenafil (25 mg) and sildenafil (100 mg), lung diffusion (DLCO), molecular diffusion (DM), pulmonary capillary volume (VC), eNO, all at rest and during exercise, standard pulmonary function, and maximal cardiopulmonary exercise.. At rest sildenafil improved pulmonary mechanics and DLCO from 23.1+/-6.3 ml/mmHg/min to 23.9+/-6.4 (25 mg, p<0.05) and to 25.3+/-6.7 100 mg, p<0.02). Sildenafil (100 mg) prevents edema formation (highest DM/VC during exercise). At rest eNO was low and not affected by tested drugs. With light exercise eNO was higher with sildenafil 100 mg. Peak VO(2) increased with sildenafil from 1376+/-331 ml/min to 1471+/-375 (25 mg, p<0.01) and 1524+/-461 (100 mg, p<0.02). Peak VO(2) increase was related to DLCO improvement.. In chronic HF sildenafil increases exercise performance, improves lung mechanics and gas diffusion and prevents exercise-induced pulmonary edema formation probably by restoring NO pathways.

Topics: Aged; Capillary Permeability; Exercise Test; Forced Expiratory Volume; Heart Failure; Humans; Male; Maximal Voluntary Ventilation; Middle Aged; Piperazines; Pulmonary Alveoli; Pulmonary Diffusing Capacity; Purines; Sildenafil Citrate; Sulfones; Vital Capacity

Heart failure is a condition that affects nearly 5 million people in the United States and costs the nation an estimated $35 billion a year. Although common, the condition presents treating clinicians with real challenges. There currently are few effective therapies for people with acute decompensated disease. As part of the National Heart Lung and Blood Institute-funded Heart Failure Network, Minnesota researchers are attempting to change this. This article describes the work of the Heart Failure Network and several Minnesota-designed protocols that are being tested, including one that's looking at 2 different treatment strategies for patients hospitalized with acute decompensated heart failure who go on to develop poor renal function and another that will evaluate the use of sildenafil (Viagra) for patients with heart failure and preserved left ventricular systolic function.

Topics: Diuretics; Heart Failure; Hemofiltration; Humans; Minnesota; Mitral Valve Insufficiency; National Heart, Lung, and Blood Institute (U.S.); Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; United States; Vasodilator Agents

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antihypertensive Agents; Carbolines; Cardiomyopathies; Cardiovascular Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Doxorubicin; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents; Ventricular Remodeling

The aim of this work was to test whether acute phosphodiesterase 5 (PDE5) inhibition via sildenafil (SIL) mimics and/or potentiates cardiorenal effects of exogenous natriuretic peptide (NP) infusion.. Heart failure (HF) is often accompanied by elevated NP secretion yet blunted responsiveness. Such NP resistance may, in part, relate to increased cyclic guanosine monophosphate (cGMP) catabolism by PDE5.. Dogs (n = 7) were studied before and after tachypacing-induced HF. Animals received 30-min infusion of B-type natriuretic peptide (BNP) (2 mug/kg bolus, 0.02 mug/kg/min), and on a separate day SIL (1 mg/kg, intravenous), followed by BNP (SIL + BNP). Phosphodiesterase 5 activity was measured in lung, vasculature, and kidney.. At baseline (non-failing), BNP lowered central venous, pulmonary capillary wedge, diastolic, mean pulmonary artery, and mean arterial pressure. Sildenafil had no effects, and SIL + BNP was similar to BNP alone. In contrast, SIL lowered these pressures similarly to BNP in dogs with HF, and SIL + BNP was additive in further reducing pulmonary pressures over BNP alone. Plasma cGMP/plasma BNP ratio was markedly reduced with HF, indicating NP resistance. Sildenafil plus BNP increased this ratio in HF, but had no effect in non-failing animals. Sildenafil had no independent diuretic/natriuretic effects nor did it enhance BNP effects under baseline or HF conditions. In HF, PDE5 activity was significantly increased in the systemic and pulmonary vasculature and in the kidney.. The PDE5 activity in systemic and pulmonary vasculature increases in HF rendering hemodynamic responses to PDE5 inhibition identical to those from BNP infusion. Natriuretic peptide desensitization in HF relates, in part, to increased PDE5 activity, supporting a therapeutic role for PDE5 inhibition.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Female; Heart Failure; Infusions, Intravenous; Male; Multivariate Analysis; Natriuretic Peptide, Brain; Piperazines; Probability; Purines; Random Allocation; Reference Values; Risk Factors; Sensitivity and Specificity; Sildenafil Citrate; Sulfones

We report on the management of Candida endocarditis in a 5-month old infant. The orifice of the tricuspid valve was totally obstructed, and the tension apparatus of the valve destroyed. Excision of the valve led to severe failure of the right heart. The combined use of anti-failure treatment, and reduction of right ventricular afterload with oxygen, nitric oxide and sildenafil, proved successful.

Topics: Antifungal Agents; Candidiasis; Endocarditis; Female; Fluconazole; Heart Failure; Humans; Infant; Nitric Oxide; Oxygen Inhalation Therapy; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Tricuspid Valve; Vasodilator Agents

Pulmonary hypertension can complicate the early clinical course in newborn infants with congenital diaphragmatic hernia. We report the successful use of combination therapy with enteral sildenafil and intravenous prostaglandin E1 in a preterm infant with severe pulmonary hypertension and right heart failure early after congenital diaphragmatic hernia repair.

Topics: Alprostadil; Drug Therapy, Combination; Heart Failure; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Piperazines; Postoperative Care; Premature Birth; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n = 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n = 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 microg/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 +/- 2 versus 21 +/- 3 pmol/ml; P < 0.05) and urinary cGMP (4219 +/- 900 versus 1954 +/- 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 +/- 6 to 45 +/- 6 ml/min; P < 0.05) and that was not observed in group 2 (25 +/- 6 to 29 +/- 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 +/- 900 to 8600 +/- 1600 pmol/min; P < 0.05) as compared with group 2 (1954 +/- 300 to 3580 +/- 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Heart Failure; Kidney; Male; Natriuretic Peptide, Brain; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Sildenafil, a phosphodiesterase-5 inhibitor, induces cardioprotection against ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels. It is unclear whether sildenafil would provide similar protection from doxorubicin-induced cardiotoxicity.. Male ICR mice were randomized to 1 of 4 treatments: saline, sildenafil, doxorubicin (5 mg/kg IP), and sildenafil (0.7 mg/kg IP) plus doxorubicin (n=6 per group). Apoptosis was assessed with the use of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and in situ oligo ligation methods. Desmin distribution was determined via immunofluorescence. Bcl-2 expression was analyzed by Western blot. Left ventricular function was assessed by measuring developed pressure and rate pressure product in Langendorff mode. ECG changes indicative of doxorubicin cardiotoxicity were also measured. For in vitro studies, adult ventricular cardiomyocytes were exposed to doxorubicin (1 micromol/L), sildenafil (1 micromol/L) with or without N(G)-nitro-L-arginine methyl ester (L-NAME) (100 micromol/L), or 5-hydroxydecanoate (100 micromol/L) 1 hour before doxorubicin and incubated for 18 hours. Doxorubicin-treated mice demonstrated increased apoptosis and desmin disruption, which was attenuated in the sildenafil+doxorubicin group. Bcl-2 was decreased in the doxorubicin group but was maintained at basal levels in the sildenafil+doxorubicin group. Left ventricular developed pressure and rate pressure product were significantly depressed in the doxorubicin group but were attenuated in the sildenafil+doxorubicin group. ST interval was significantly increased in the doxorubicin group over 8 weeks. In the sildenafil+doxorubicin group, ST interval remained unchanged from baseline. Doxorubicin caused a significant increase in apoptosis, caspase-3 activation, and disruption of mitochondrial membrane potential in vitro. In contrast, sildenafil significantly protected against doxorubicin cardiotoxicity; however, this protection was abolished by both L-NAME and 5-hydroxydecanoate.. Prophylactic treatment with sildenafil prevented apoptosis and left ventricular dysfunction in a chronic model of doxorubicin-induced cardiomyopathy.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Apoptosis; Cardiomyopathies; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Doxorubicin; Drug Therapy, Combination; Heart Failure; Male; Mice; Mice, Inbred ICR; Myocytes, Cardiac; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Premedication; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH.. Single center, case series, pharmacohemodynamic study.. Cardiac catheterization laboratory of a tertiary care academic teaching hospital.. We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH.. We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization.. Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function.. PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.

Topics: Adult; Bronchodilator Agents; Cardiac Output; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Erectile Dysfunction; Heart Failure; Humans; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Erectile Dysfunction; Heart Failure; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Adaptation, Physiological; Age Factors; Blood Circulation; Contraindications; Depression; Heart Failure; Humans; Male; Piperazines; Purines; Respiratory Insufficiency; Risk Assessment; Sildenafil Citrate; Sulfones; Vasodilator Agents

Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition with sildenafil in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/dt(max)) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 +/- 1.4 to 23 +/- 1.4 mmHg. Sildenafil (2 and 10 mg/kg per os) caused a 5- to 6-mmHg decrease of aortic pressure (P < 0.05), with no change of heart rate, LV systolic pressure, or LV dP/dt(max). Sildenafil caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals, sildenafil did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Coronary Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Dose-Response Relationship, Drug; Endothelium, Vascular; Heart Failure; Heart Rate; Myocardium; Oxygen Consumption; Pacemaker, Artificial; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilation

Sildenafil citrate is a potent donor of nitric oxide that has been proved to be effective for the treatment of male erectile dysfunction, but it has been contraindicated in patients with cardiovascular diseases, because of sudden death occurred to some of them. Based on the known vasodilator effect of nitrix oxide, effect that should be beneficial for some cardiomyopathies, this work was carried out in order to prove the cardiovascular effects of sildenafil citrate on: 1) heart rate, rhythm and repolarization changes on the ecg; 2) systolic and diastolic arterial blood pressure; 3) left ventricular systolic function and 4) right and left ventricular diastolic function in 26 patients suffering from the following cardiomyopathies: chronic Chagas's and diabetic cardioneuromyopathies, hypertensive and/or hypertrophic cardiomyopathies with or without chronic congestive heart failure.. sildenafil citrate 50 mgr after a single oral dose: 1) improved the ecg findings in some patients, worsening the basal ecg in none of the studied patients; 2) significantly reduced systolic and diastolic arterial blood pressure being such reduction very strong in those with basal high level 3) significantly improved left ventricular systolic function in those patients with basal reduced function and 4) Right ventricular diastolic function evaluation: Sildenafil citrate 50 mgr significantly modified to normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with restrictive pattern of tricupid diastolic influx to the right ventricle during the echo-duplex interrogation (p < 0.0001) 5) Left ventricular diastolic function evaluation: Sildenafil citrate 50 mgr significantly modified to normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with restrictive pattern of mitral diastolic influx to the left ventricle, during the echo-duplex interrogation (p 0 <.0001).. Based on the above findings it is feasible to propose the use of sildenafil citrate to treat patients with cardiovascular diseases, with exclusion of severe obstructive coronary artery disease, hypertrophic subaortic stenosis and patients with funduscopic alterations that may be affected by a significant and acute increase of flow within the ophthalmic arteries. The right ventricular diastolic changes observed with Sildenafil Citrate may be useful in patients with abnormal right ventricular compliance such as pulmonary stenosis or hypertension.

Topics: Blood Pressure; Cardiovascular Diseases; Chagas Disease; Diabetic Angiopathies; Electrocardiography; Female; Heart Failure; Heart Rate; Humans; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents; Ventricular Function

Pulmonary hypertension (PHT) is mainly explained by four underlying pathophysiological phenomena: 1. Vasoconstriction, 2. reduction of pulmonary vascular bed, 3. reduction in vessel elasticity, and 4. obliteration of the vessel lumen by thrombotic material and subsequent cellular alterations of the vessel wall (vascular remodeling). Chronic right heart load is thus a consequence of increased pulmonary pressure and vascular resistance. Main targets of advanced therapeutic strategies are therefore first: resolution of chronically increased vascular tone by smooth muscle cell relaxation (vasodilators), second: reversal of vascular remodeling and third: prevention from pulmonary embolization and/or in-situ thrombosis (chronic anticoagulation). Long term administration of high dose calcium channel blockers (though operative only in a minority of 10 - 15 % of all patients), prostanoids (eg. prostacyclin, iloprost), and the recently approved unselective oral endothelin antagonist bosentan are regarded as established medical therapies for treatment of chronic PHT. However, applicability of these substances can be limited by potentially serious adverse events and/or necessity for elaborate parenteral application. Recent data are indicative for a strong pulmonary vasodilative potency of the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil. Smaller clinical studies and numerous case reports underline the good tolerability of this orally applied substance in various form of PHT. Based on these encouraging results, the simple availability, and the low costs (in comparison to "established therapies") of the drug, sildenafil is currently widely used in an "off-label" indication for treatment of PHT. Controlled randomized studies have to confirm the current findings, before general recommendations regarding the use of sildenafil for treatment of PHT can be made.

Topics: Clinical Trials as Topic; Heart Failure; Humans; Hypertension, Pulmonary; Models, Cardiovascular; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Alveoli; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Topics: Aged; Coronary Disease; Electrocardiography; Erectile Dysfunction; Exercise Test; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Product Surveillance, Postmarketing; Purines; Risk; Sildenafil Citrate; Sulfones; Vasodilator Agents

Recently, case reports of patients with primary pulmonary hypertension (PPH) treated with sildenafil demonstrated encouraging results. The mechanism proposed is a relatively selective pulmonary vasodilation via increased levels of cGMP because of the inhibition of phosphodiesterase type 5. Two siblings with a similar medical history, severe symptoms and elevated levels of pulmonary artery pressures were diagnosed with PPH after a thorough diagnostic work-up. Both patients were treated with coumadin, sildenafil, furosemide, spironolactone and digoxin. One of the patients had no improvement during the hospital course and died two months after discharge. The other patient improved dramatically during the hospital course, and this improvement was sustained. At the three-month follow-up control, she was much improved in terms of clinical status and echocardiographic findings.

Topics: Adolescent; Adult; Cardiac Catheterization; Echocardiography; Fatal Outcome; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents