sildenafil-citrate and Ventricular-Dysfunction--Left

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

Topics: Carbolines; Diastole; Drug Resistance; Heart Failure, Diastolic; Humans; Hypertension; Medical Illustration; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome; Ventricular Dysfunction, Left

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

Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

Topics: Adiponectin; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Antioxidants; Carbazoles; Cardiolipins; Cardiotonic Agents; Carvedilol; Doxorubicin; Erythropoietin; Heart; Heart Diseases; Humans; Lipid Peroxidation; Liposomes; Neoplasms; Piperazines; Propanolamines; Purines; Razoxane; Risk Factors; Sildenafil Citrate; Sulfones; Survivors; Ventricular Dysfunction, Left

At least two thirds of patients with chronic severe left heart disease have associated pulmonary hypertension, and mortality associated with biventricular failure is >two-fold higher compared with isolated left ventricular failure. This review considers and discusses emerging concepts and strategies from recent studies of specific treatments in populations with pulmonary hypertension complicating overt left ventricular dysfunction. While the results reported in the studies considered are encouraging, to date there are no large randomised studies of specific treatments in populations with pulmonary hypertension complicating overt left ventricular dysfunction.

Topics: Aged; Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Heart Disease; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

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

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

In heart failure (HF), a defective nitric oxide signaling is involved in left ventricular (LV) diastolic abnormalities and remodeling. PDE5 inhibition, by blocking degradation of nitric oxide second-messenger cyclic guanosine monophosphate, might be beneficial. In a cohort of systolic HF patients, we tested the effects of PDE5 inhibition (sildenafil) on LV ejection fraction, diastolic function, cardiac geometry, and clinical status.. Forty-five HF patients (New York Heart Association class II-III) were randomly assigned to placebo or sildenafil (50 mg three times per day) for 1 year, with assessment (6 months and 1 year) of LV ejection fraction, diastolic function, geometry, cardiopulmonary exercise performance, and quality of life. In the sildenafil group only, at 6 months and 1 year, LV ejection fraction, early diastolic tissue Doppler velocities (E') at the mitral lateral (from 4.62 to 5.20 and 5.19 m/s) and septal (from 4.71 to 5.23 and 5.24 m/s) annuli significantly increased, whereas the ratio of early transmitral (E) to E' lateral decreased (from 13.1 to 9.8 to 9.4) (P<0.01). Changes were accompanied by a reverse remodeling of left atrial volume index (from 32.0 to 29.0 and 29.1 mL/m(2); P<0.01) and LV mass index (from 148.0 to 130.0 and 128.0 g/m(2); P<0.01). Furthermore, sildenafil improved exercise performance (peak Vo(2)), ventilation efficiency (ventilation to CO(2) production slope), and quality of life (P<0.01). Minor adverse effects were noted: flushing in 4 and headache in 2 treated patients.. Findings confirm that in HF, sildenafil improves functional capacity and clinical status and provide the first human evidence that LV diastolic function and cardiac geometry are additional targets of benefits related to chronic PDE5 inhibition.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Diastole; Double-Blind Method; Exercise Test; Heart Failure, Systolic; Humans; Longitudinal Studies; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

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

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

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

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

Myocardial relaxation and stiffness are influenced by fibrillar collagen content. Cyclic nucleotide signaling regulators have been investigated targeting more effective modulation of collagen deposition during myocardial healing process. To assess the effects of phosphodiesterase type 3 and phosphodiesterase type 5 inhibitors on cardiac function and left ventricular myocardial fibrosis in catecholamine-induced myocardial injury, sildenafil and pimobendan were administered to male Wistar rats 24 hours after isoproterenol injection. Echocardiography and electrocardiogram were performed to assess kinetic and rhythm changes during 45 days of drug administration. At the end of study, type I and type III collagen were measured through immunohistochemistry analysis, and left ventricular pressure was assessed through invasive method. Echocardiography assessment showed increased relative wall thickness at 45 days in pimobendan group with significant diastolic dysfunction and increased collagen I deposition compared with nontreated positive group (3.03 ± 0.31 vs. 2.73 ± 0.28%, P < 0.05). Diastolic pressure correlated positively with type I collagen (r = 0.54, P < 0.05). Type III collagen analysis did not demonstrate difference among the groups. Sildenafil administration attenuated type I collagen deposition (2.15 ± 0.51 vs. positive group, P < 0.05) and suggested to be related to arrhythmic events. Arrhythmic events were not related to the quantity of fibrillar collagen deposition. Although negative modulation of collagen synthesis through cyclic nucleotides signaling have shown promising results, in this study, pimobendan postconditioning resulted in increased collagen type I formation and severe diastolic dysfunction while sildenafil postconditioning reduced collagen type I deposition and attenuated diastolic dysfunction.

Topics: Animals; Arrhythmias, Cardiac; Collagen Type I; Collagen Type III; Disease Models, Animal; Fibrosis; Isoproterenol; Male; Myocardium; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Pyridazines; Rats, Wistar; Risk Assessment; Sildenafil Citrate; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Closure of congenital atrial communications in the presence of either severe pulmonary arterial hypertension (PAH) with pulmonary-to-systemic (right-to-left) shunting, or severe left ventricular (LV) non-compliance with left-to-right shunting is often considered prohibitive. Thus, the recognition of durable reversibility of these physiologic conditions is crucial. We describe a hemodynamic conundrum in a patient with five septal communications in whom the coexistence of unmasked bidirectional physiologic shunting, severe PAH, and worsening left-sided overload dissuaded initial closure. We report our strategy for hemodynamic evaluation and successful closure of all defects.

Topics: Balloon Occlusion; Cardiac Catheterization; Dyspnea; Echocardiography, Transesophageal; Heart Septal Defects, Atrial; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Septal Occluder Device; Sildenafil Citrate; Ventricular Dysfunction, Left

We describe the case of a 54-year-old man who presented with exertional dyspnea and fatigue that had worsened over the preceding 2 years, despite a normally functioning bioprosthetic aortic valve and stable, mild left ventricular dysfunction (left ventricular ejection fraction, 0.45). His symptoms could not be explained by physical examination, an extensive biochemical profile, or multiple cardiac and pulmonary investigations. However, abnormal cardiopulmonary exercise test results and a right heart catheterization-combined with the use of a symptom-limited, bedside bicycle ergometer-revealed that the patient's exercise-induced pulmonary artery hypertension was out of proportion to his compensated left heart disease. A trial of sildenafil therapy resulted in objective improvements in hemodynamic values and functional class.

Topics: Antihypertensive Agents; Cardiac Catheterization; Exercise; Exercise Test; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Point-of-Care Testing; Predictive Value of Tests; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Function, Left

To elucidate left ventricular function in pulmonary hypertension, we measured parameters of left ventricular as well as right ventricular function by echocardiography in 11 patients with pulmonary hypertension (idiopathic pulmonary artery hypertension in 4, chronic thromboembolic pulmonary hypertension in 5, and other pulmonary hypertension in 2). The percent change in these parameters 6 months after treatment with pulmonary artery vasodilators (beraprost in 8 and sildenafil in 3) was assessed. There was a correlation between the relative change in right ventricular systolic pressure (RVSP) and the relative changes in left ventricular outflow tract velocity-time integral (r = -0.730, P = 0.011) and mitral valve velocity-time integral (r = -0.621, P = 0.041). However, there was no correlation between the relative change in RVSP and the relative changes in left ventricular ejection fraction, left ventricular diastolic dimension, and systolic blood pressure. The relative change in RVSP was also correlated with the relative change in early diastolic myocardial velocity at the medial mitral annulus (r = -0.675, P = 0.023). Reduction of RVSP by pulmonary artery vasodilators might increase left ventricular preload, leading to an increase in stroke volume. Right ventricular load reduction might improve left ventricular diastolic function in patients with pulmonary hypertension, possibly through altered interventricular septal performance.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Diastole; Echocardiography, Doppler; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Linear Models; Male; Middle Aged; Mitral Valve; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Systole; Time Factors; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure

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

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

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

Topics: Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Edema; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

Sildenafil may be beneficial during myocardial ischaemia/reperfusion, but this effect may be dose-dependent, accounting for previous conflicting results. We have explored the effects of two acute and one chronic administration regimen on left ventricular function.. The study was conducted on 36 Wistar rats (290 +/- 7 g). Sildenafil was administered 30 min before ischaemia at a low (0.7 mg/kg, n= 8) or high (1.4 mg/kg, n= 8)dosage. The chronic treatment arm (n= 8) consisted of two daily injections of sildenafil (0.7 mg/kg) for three weeks. The control group was formed by 12 rats. Ischaemic contracture, post-ischaemic recovery and hypercontracture were measured in isolated, Langendorff-perfused preparations.. Ischaemic contracture tended to be lower after high-dose sildenafil, while remaining unchanged after low-dose or chronic sildenafil administration. Compared with controls (62.9 +/- 2.0% of baseline developed pressure), post-ischaemic recovery was higher (P= 0.0069) after low dose (75.1 +/- 2.4%), unchanged (P= 0.13) after high dose (69.1 +/- 2.1%), but lower (P < 0.001) after chronic (42.9 +/- 4.5%) sildenafil administration. Compared with controls (71.8 +/- 3.9 mmHg), hypercontracture was higher (P= 0.0052) after chronic sildenafil administration (89.5 +/- 4.1 mmHg), but similar after acute low dose (65.7 +/- 3.3 mmHg, P= 0.33) or high dose (67.1 +/- 4.7 mmHg, P= 0.43).. The effects of sildenafil after ischaemia/reperfusion were strongly dose-dependent. Beneficial actions on left ventricular function were evident after acute pretreatment with a low dosage, but were lost after doubling the dose. Chronic sildenafil administration deteriorated left ventricular function during ischaemia and reperfusion.

Topics: Animals; Cardiotonic Agents; Dose-Response Relationship, Drug; Heart; In Vitro Techniques; Ischemic Contracture; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Phosphodiesterase Inhibitors; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

This study sought to test the efficacy of phosphodiesterase type 5A (PDE5A) inhibition for treating advanced hypertrophy/remodeling caused by pressure overload, and to elucidate cellular and molecular mechanisms for this response.. Sildenafil (SIL) inhibits cyclic guanosine monophosphate-specific PDE5A and can blunt the evolution of cardiac hypertrophy and dysfunction in mice subjected to pressure overload. Whether and how it ameliorates more established advanced disease and dysfunction is unknown.. Mice were subjected to transverse aortic constriction (TAC) for 3 weeks to establish hypertrophy/dilation, and subsequently treated with SIL (100 mg/kg/day) or placebo for 6 weeks of additional TAC.. The SIL arrested further progressive chamber dilation, dysfunction, fibrosis, and molecular remodeling, increasing myocardial protein kinase G activity. Isolated myocytes from TAC-SIL hearts showed greater sarcomere shortening and relaxation, and enhanced Ca(2+) transients and decay compared with nontreated TAC hearts. The SIL treatment restored gene and protein expression of sarcoplasmic reticulum Ca(2+) uptake adenosine triphosphatase (SERCA2a), phospholamban (PLB), and increased PLB phosphorylation (S16), consistent with improved calcium handling. The phosphatase calcineurin (Cn) and/or protein kinase C-alpha (PKCalpha) can both lower phosphorylated phospholamban and depress myocyte calcium cycling. The Cn expression and PKCalpha activation (outer membrane translocation) were enhanced by chronic TAC and reduced by SIL treatment. Expression of PKCdelta and PKCepsilon also increased with TAC but were unaltered by SIL treatment.. SIL treatment applied to well-established hypertrophic cardiac disease can prevent further cardiac and myocyte dysfunction and progressive remodeling. This is associated with improved calcium cycling, and reduction of Cn and PKCalpha activation may be important to this improvement.

Topics: Animals; Calcineurin; Calcium; Gene Expression; Heart; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase Inhibitors; Piperazines; Pressure; Protein Kinase C-alpha; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left; Ventricular Remodeling

Heart failure (HF) is frequently associated with dysregulation of nitric oxide-mediated pulmonary vascular tone. Sildenafil, a type 5 phosphodiesterase inhibitor, lowers pulmonary vascular resistance in pulmonary hypertension by augmenting intracellular levels of the nitric oxide second messenger, cyclic GMP. We tested the hypothesis that a single oral dose of sildenafil (50 mg) would improve exercise capacity and exercise hemodynamics in patients with chronic systolic HF through pulmonary vasodilation.. Thirteen patients with New York Heart Association class III HF underwent assessment of right heart hemodynamics, gas exchange, and first-pass radionuclide ventriculography at rest and with cycle ergometry before and 60 minutes after administration of 50 mg of oral sildenafil. Sildenafil reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased resting and exercise cardiac index (P<0.05 for all) without altering mean arterial pressure, heart rate, or pulmonary capillary wedge pressure. Sildenafil reduced exercise pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular resistance/systemic vascular resistance ratio, which indicates a selective pulmonary vasodilator effect with exercise. Peak VO2 increased (15+/-9%) and ventilatory response to CO2 output (VE/VCO2 slope) decreased (16+/-5%) after sildenafil treatment. Improvements in right heart hemodynamics and exercise capacity were confined to patients with secondary pulmonary hypertension (rest pulmonary arterial pressure >25 mm Hg).. The present study shows that in patients with systolic HF, type 5 phosphodiesterase inhibition with sildenafil improves peak VO2, reduces VE/VCO2 slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with HF and pulmonary hypertension.

Topics: Adult; Blood Pressure; Cardiac Output; Cardiac Output, Low; Exercise; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Piperazines; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

Sildenafil, a phosphodiesterase type-5 inhibitor, offers potential to treat pulmonary hypertension associated with a variety of conditions. We assessed the early impact of sildenafil on a cohort of patients referred to our unit who had severe pulmonary hypertension secondary to chronic thromboembolic disease which was not amenable to pulmonary thromboendarterectomy and who also had coexisting left ventricular dysfunction. Six patients were studied. Diagnosis of pulmonary embolic disease was made by ventilation perfusion scanning and/or CT pulmonary angiography. All patients were anticoagulated with oral coumarin derivatives and none were considered suitable for pulmonary thromboendarterectomy. Pulmonary hypertension was diagnosed by right heart catheterisation and each patient had Medical Research Council (MRC) dyspnoea score and New York Heart Association (NYHA) class noted and 2D echocardiography prior to commencement of sildenafil 50 mg three times a day. After 6 weeks of sildenafil therapy, right heart catheterisation and 2D echocardiography were repeated, and MRC dyspnoea score, NYHA class and exercise capacity were recorded. All patients demonstrated an improvement in mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, MRC dyspnoea score, NYHA class and gas transfer. No adverse effects of sildenafil were noted. Our data suggests that sildenafil is an effective and well-tolerated therapy for patients with severe pulmonary hypertension associated with pulmonary thromboembolic disease and impaired left ventricular function, producing beneficial effects as early as 6 weeks.

Topics: Adult; Aged; Cardiac Output; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left

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

Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg(-1)) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140+/-52 vs 437+/-127% and episodes of ventricular tachycardia 4.0+/-3.2 vs 19.3+/-7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST-segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia-induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Dogs; Electrocardiography; Hemodynamics; Myocardial Reperfusion Injury; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Tachycardia, Ventricular; Ventricular Dysfunction, Left; Ventricular Fibrillation; Ventricular Premature Complexes

To determine the acute vasodilator effect of sublingual sildenafil in heart transplant candidates with severe pulmonary hypertension due to severe left ventricular dysfunction (LVD).. Pulmonary hypertension confers an increased risk of early graft failure.. Seven patients, (mean age of 53+/-8) with severe LVD (mean EF: 19+/-1.7%, functional class III-IV) due to coronary artery disease, dilated cardiomyopathy and valvulopathy were evaluated for heart transplant. All patients presented a mean transpulmonary gradient >12 mmHg and pulmonary vascular resistances >2.5 W.U., despite full treatment for advanced heart failure. The following hemodynamic data were obtained at basal state and then 15, 30 and 45 min after administration of 100 mg of sublingual sildenafil: right atrial, mean pulmonary artery pressure (mPAP), mean pulmonary capillary wedge pressures, mean transpulmonary gradient (mTPG), blood pressure, cardiac output, pulmonary vascular resistances (PVR) and systemic vascular resistances. Sublingual sildenafil was given without changing the previous treatment of heart failure.. After 30 min of sublingual sildenafil, mPAP decreased from 37 (28-61) to 30 (16-42) mmHg and PVR decreased from 5.2 (1.9-13.8) to 2.5 (1.4-3.9) W.U. after 45 min. Mean TPG decreased from 19 (16-33) to 12 (8-14) mmHg at 45 min. Mean pulmonary capillary wedge pressure, cardiac output, systemic vascular resistances and mean blood pressure were unchanged. Sublingual sildenafil was well tolerated, with only transient facial flushing in 4 patients and mild headache in 2.. Based on this initial study, sublingual sildenafil may be a useful alternative drug to perform acute vasodilator test in heart transplant candidates with significant pulmonary hypertension due to severe LVD. Nevertheless, further studies are warranted to confirm our results.

Topics: Administration, Sublingual; Blood Pressure; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Left