cardiovascular-agents and Hypertension--Pulmonary

Pulmonary hypertension (PH) due to left ventricular heart failure (LV-HF) is a disabling and life-threatening disease for which there is currently no single marketed pharmacological agent approved. Despite recent advances in the pathophysiological understanding, there is as yet no prospect of cure, and the majority of patients continue to progress to right ventricular failure and die. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent or reverse the increase in pulmonary artery pressures while enhancing cardiac performance in PH due to LV-HF. In the present article, we first focused on the Natriuretic Peptide Receptor type C (NPR-C) based therapeutic strategies aimed at lowering pulmonary artery pressure. Second, we reviewed potential NPR-C therapeutic strategies to reverse or least halt the detrimental effects of diastolic dysfunction and impaired nitic oxide signalling pathways, as well as possibilities for neurohumoral modulation.

Topics: Animals; Cardiovascular Agents; Heart Failure; Humans; Hypertension, Pulmonary; Natriuretic Peptide, C-Type; Treatment Outcome; Ventricular Dysfunction, Left

Cardiovascular disease complicating pregnancy is rising in prevalence secondary to advanced maternal age, cardiovascular risk factors, and the successful management of congenital heart disease conditions. The physiological changes of pregnancy may alter drug properties affecting both mother and fetus. Familiarity with both physiological and pharmacological attributes is key for the successful management of pregnant women with cardiac disease. This review summarizes the published data, available guidelines, and recommendations for use of cardiovascular medications during pregnancy. Care of the pregnant woman with cardiovascular disease requires a multidisciplinary team approach with members from cardiology, maternal fetal medicine, anesthesia, and nursing.

Topics: Breast Feeding; Cardiovascular Agents; Connective Tissue Diseases; Female; Hematologic Agents; Hemodynamics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Pregnancy; Pregnancy Complications, Cardiovascular; Teratogens

The past 2 decades have witnessed a >40% improvement in mortality for patients with heart failure and left ventricular systolic dysfunction.

Topics: Cardiovascular Agents; Disease Progression; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Risk Factors; Stem Cell Transplantation; Treatment Outcome; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

Apelin is a vasoactive peptide and is an endogenous ligand for APJ receptors, which are widely expressed in blood vessels, heart, and cardiovascular regulatory regions of the brain. A growing body of evidence now demonstrates a regulatory role for the apelin/APJ receptor system in cardiovascular physiology and pathophysiology, thus making it a potential target for cardiovascular drug discovery and development. Indeed, ongoing studies are investigating the potential benefits of apelin and apelin-mimetics for disorders such as heart failure and pulmonary arterial hypertension. Apelin causes relaxation of isolated arteries, and systemic administration of apelin typically results in a reduction in systolic and diastolic blood pressure and an increase in blood flow. Nonetheless, vasopressor responses and contraction of vascular smooth muscle in response to apelin have also been observed under certain conditions. The goal of the current review is to summarize major findings regarding the apelin/APJ receptor system in blood vessels, with an emphasis on regulation of vascular tone, and to identify areas of investigation that may provide guidance for the development of novel therapeutic agents that target this system.

Topics: Animals; Apelin; Apelin Receptors; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Drug Discovery; Heart Failure; Humans; Hypertension, Pulmonary; Ligands; Muscle, Smooth, Vascular

Pulmonary hypertension (PH) is a spectrum disorder with multiple causes of the elevation of pressure in the lungs. It often is difficult to diagnose because it mimics many commonly reported symptoms (eg, dyspnea, exercise intolerance, chest pain). Diagnosis is made via right heart catheterization; however, transthoracic echocardiography may show evidence of elevated pulmonary pressure as the first clue to the diagnosis. Diagnostic tests to consider include a liver panel, complete blood count, and thyroid function test; electrocardiogram; chest x-ray; pulmonary function testing; and possibly lung imaging via computed tomography scan or ventilation-perfusion scan. PH is grouped into several broad categories: group 1 is pulmonary artery hypertension, group 2 is PH due to left heart disease, group 3 is PH due to lung disease, group 4 is chronic thromboembolic PH, and group 5 is PH due to unclear or multifactorial mechanisms. Therapy targets the underlying etiology and may include physical activity and pulmonary rehabilitation; drugs such as diuretics, vasodilators, and anticoagulants; oxygen therapy; and lung transplantation. Significant PH can result in increased mortality risk. Because of its complex and heterogeneous nature, PH is best managed by subspecialists with expertise in the condition.

Topics: Cardiac Catheterization; Cardiovascular Agents; Echocardiography; Exercise; Family Practice; Hematologic Tests; Humans; Hypertension, Pulmonary; Lung Transplantation; Oxygen Inhalation Therapy; Radiography, Thoracic; Respiratory Function Tests; Respiratory Therapy

PDE5 inhibitors (PDE5i) are widely known as treatment for erectile dysfunction (ED). This favorable action has emerged as a "side effect" from pioneering studies when PDE5i have been originally proposed as treatment for coronary artery disease (CAD). PDE5i showed marginal benefits for CAD treatment; although disappointing for that indication, they improved systemic and pulmonary vasodilation and ameliorated general endothelial function. Therefore, PDE5i have been approved and licensed also for pulmonary artery hypertension (PAH), besides ED. Nowadays, fine-tuned biomolecular mechanisms of PDE5i are well recognized to be beneficial onto myocardial contractility and geometry, to reduce tissue fibrosis, hypertrophy and apoptosis. PDE5i consistently exert benefits on heart failure, infarct, cardiomyopathy. The concept that PDE5i likely blunt Th1-driven inflammatory processes, which shift the homeostatic balance from health to disease, has emerged; PDE5i seem to decrease the release of active biomolecules from cells to tissues interested by inflammation. In this view, following clinical and basic research progresses, PDE5i can be undoubtedly "re-allocated" for cardiac indications and, hopefully, they could be approved as therapeutic tools to treat and prevent heart disease. This review aims to summarize PDE5i different clinical applications, from past to present and future, focusing on their potential power as treatment for cardiac diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Evidence-Based Medicine; Heart; Humans; Hypertension, Pulmonary; Myocardium; Phosphodiesterase 5 Inhibitors; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a serious life threatening disease that leads to right heart failure and death. Elevated pulmonary vascular resistance (PVR) is the main pathophysiological component that leads to elevated pulmonary arterial pressures and increased right ventricular afterload. Increased PVR is related to different mechanisms that include vasoconstriction, proliferative and obstructive remodeling of the pulmonary vessel wall and in situ thrombosis. Numerous molecular, genetic and humoral abnormalities have been proposed to play an important role in pulmonary vasoconstriction and remodeling. Of those, calcium (Ca(+2)) is a well recognized parameter involved in the pathogenetic mechanisms of PAH, because of its twofold role in both vasoconstriction and pulmonary artery smooth muscle cell (PASMC) proliferation. The aim of this review is to focus on Ca(+2) handling and dysregulation in PASMC of PAH patients.

Topics: Animals; Calcium; Calcium Channels; Cardiovascular Agents; Endoplasmic Reticulum; Extracellular Space; Humans; Hypertension, Pulmonary; Intracellular Space; Pulmonary Artery; Sarcoplasmic Reticulum; Vascular Remodeling; Vasoconstriction

To review the pharmacologic treatment options for pulmonary arterial hypertension in the cardiac intensive care setting and summarize the most-recent literature supporting these therapies.. Literature search for prospective studies, retrospective analyses, and case reports evaluating the safety and efficacy of pulmonary arterial hypertension therapies.. Mechanisms of action and pharmacokinetics, treatment recommendations, safety considerations, and outcomes for specific medical therapies.. Specific targeted therapies developed for the treatment of adult patients with pulmonary arterial hypertension have been applied for the benefit of children with pulmonary arterial hypertension. With the exception of inhaled nitric oxide, there are no pulmonary arterial hypertension medications approved for children in the United States by the Food and Drug Administration. Unfortunately, data on treatment strategies in children with pulmonary arterial hypertension are limited by the small number of randomized controlled clinical trials evaluating the safety and efficacy of specific treatments. The treatment options for pulmonary arterial hypertension in children focus on endothelial-based pathways. Calcium channel blockers are recommended for use in a very small, select group of children who are responsive to vasoreactivity testing at cardiac catheterization. Phosphodiesterase type 5 inhibitor therapy is the most-commonly recommended oral treatment option in children with pulmonary arterial hypertension. Prostacyclins provide adjunctive therapy for the treatment of pulmonary arterial hypertension as infusions (IV and subcutaneous) and inhalation agents. Inhaled nitric oxide is the first-line vasodilator therapy in persistent pulmonary hypertension of the newborn and is commonly used in the treatment of pulmonary arterial hypertension in the ICU. Endothelin receptor antagonists have been shown to improve exercise tolerance and survival in adult patients with pulmonary arterial hypertension. Soluble guanylate cyclase stimulators are the first drug class to be Food and Drug Administration approved for the treatment of chronic thromboembolic pulmonary hypertension.. Literature and data supporting the safe and effective use of pulmonary arterial hypertension therapies in children in the cardiac intensive care are limited. Extrapolation of adult data has afforded safe medical treatment of pulmonary hypertension in children. Large multicenter trials are needed in the search for safe and effective therapy of pulmonary hypertension in children.

Topics: Adult; Calcium Channel Blockers; Cardiovascular Agents; Child; Coronary Care Units; Critical Care; Endothelin Receptor Antagonists; Heart Defects, Congenital; Heart Failure; Humans; Hypertension, Pulmonary; Intensive Care Units, Pediatric; Nitrous Oxide; Vasodilator Agents

The management of pulmonary hypertension is multi-faceted, with therapies directed at supporting cardiovascular and pulmonary function, treating the underlying cause (if feasible), and preventing irreversible remodeling of the pulmonary vasculature. Recently, manipulation of signaling pathways and mediators contained within the pulmonary vascular endothelial cell has become a new target. This article will review the pathophysiology of pulmonary hypertension and the broad principles involved in its management, with specific emphasis on pharmacological therapies directed at the pulmonary vascular endothelium.

Topics: Cardiovascular Agents; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Infant, Newborn; Lung

Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted.

Topics: Animals; Arrhythmias, Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Death, Sudden, Cardiac; Disease Progression; Heart Failure; Humans; Hypertension, Pulmonary; Mineralocorticoid Receptor Antagonists; Models, Biological; Off-Label Use; Receptors, Mineralocorticoid; Severity of Illness Index

Pulmonary arterial hypertension (PAH) is a complex obliterative vascular disease. It remains deadly despite an explosion of basic research over the past 20 years that identified myriads of potential therapeutic targets, few of which have been translated into early phase trials. Despite the agreement over the past decade that its pathogenesis is based on an antiapoptotic and proproliferative environment within the pulmonary arterial wall, and not vasoconstriction, all the currently approved therapies were developed and tested in PAH because of their vasodilatory properties. Numerous potential therapies identified in preclinical research fail to be translated in clinical research. Here we discuss 7 concepts that might help address the "translational gap" in PAH. These include: a need to approach the "pulmonary arteries-right ventricle unit" comprehensively and develop right ventricle-specific therapies for heart failure; the metabolic and inflammatory theories of PAH that put many "diverse" abnormalities under 1 mechanistic roof, allowing the identification of more effective targets and biomarkers; the realization that PAH might be a systemic disease with primary abnormalities in extrapulmonary tissues including the right ventricle, skeletal muscle, immune system, and perhaps bone marrow, shifting our focus toward more systemic targets; the realization that many heritable components of PAH have an epigenetic basis that can be therapeutically targeted; and novel approaches like cell therapy or devices that can potentially improve access to transplanted organs. This progress marks the entrance into a new and exciting stage in our understanding and ability to fight this mysterious deadly disease.

Topics: Animals; Biomedical Research; Cardiovascular Agents; Cell- and Tissue-Based Therapy; Humans; Hypertension, Pulmonary; Practice Guidelines as Topic; Ventricular Function, Right

Pulmonary arterial hypertension (PAH) is a complex disease characterized by elevated pulmonary arterial pressure, pulmonary vascular remodelling and occlusive pulmonary vascular lesions, leading to right heart failure. Evidence from recent epidemiological studies suggests the influence of gender on the development of PAH with an approximate female to male ratio of 4:1, depending on the underlying disease pathology. Overall, the therapeutic strategy for PAH remains suboptimal with poor survival rates observed in both genders. Endogenous sex hormones, in particular 17β oestradiol and its metabolites, have been implicated in the development of the disease; however, the influence of sex hormones on the underlying pathobiology remains controversial. Further understanding of the influence of sex hormones on the normal and diseased pulmonary circulation will be critical to our understanding the pathology of PAH and future therapeutic strategies. In this review, we will discuss the influence of sex hormones on the development of PAH and address recent controversies.

Topics: Androgens; Animals; Cardiovascular Agents; Disease Susceptibility; Drug Resistance; Estrogens; Evidence-Based Medicine; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Incidence; Lung; Male; Models, Biological; Pulmonary Circulation; Receptors, Estrogen; Sex Characteristics; Vascular Resistance

Right ventricular (RV) failure is a complex problem with poor outcomes. Diagnosis requires a high degree of clinical suspicion, because many of the signs and symptoms of this condition are nonspecific and can be acute or chronic. Identification of the underlying aetiology, which can include pulmonary hypertension, cardiomyopathy, myocardial infarction, congenital or valvular heart disease, and sepsis, is essential. Echocardiography is the technique of choice for first-line assessment, but cardiac MRI is the current gold standard for anatomical and functional assessment of the right ventricle. Therapy for RV failure should be directed at the underlying cause, although management of symptoms is also important. Therapeutic options range from pharmacological treatment to mechanical RV support and heart transplantation. The complex 3D geometry of the right ventricle and its intricate interactions with the left ventricle have left many questions about RV failure unanswered. However, promising new targeted therapies are under development and mechanical support is becoming increasingly feasible. The next decade will be an exciting time for advances in our understanding and management of RV failure.

Topics: Cardiovascular Agents; Diagnostic Imaging; Heart Failure; Heart Transplantation; Heart-Assist Devices; Hemodynamics; Humans; Hypertension, Pulmonary; Predictive Value of Tests; Risk Factors; Treatment Outcome; Ventricular Dysfunction, Right; Ventricular Function, Right

This review summarizes the role of soluble guanylate cyclase (sGC)-cyclic guanosine 3', 5'-monophosphate pathways in heart failure and several new drugs that modify guanylate cyclase. The sGC activators and stimulators as modulators of sGC are promising drugs in the therapy for decompensated heart failure and pulmonary hypertension. Cinaciguat is a nitric oxide (NO)-independent direct activator of sGC, which also may be effective under oxidative stress conditions resulting in oxidized or heme-free sGC refractory to organic nitrates. Riociguat is an NO-independent direct stimulator of sGC with beneficial effects in patients with decompensated heart failure and pulmonary hypertension. The sGC modulators play an important role in patients with heart failure and pulmonary hypertension.

Topics: Benzoates; Cardiovascular Agents; Guanylate Cyclase; Heart Failure; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Signal Transduction

Here we give an overview over treatment recommendations propagated by the European League Against Rheumatism (EULAR), EULAR Scleroderma Trials and Research Group, the German Network for Systemic Sclerosis, the European Respiratory Society, and the International Society of Heart and Lung Transplantation. As response to immunosuppressant (IS) therapy is usually weaker in systematic sclerosis (SSc) compared to other connective tissue disorders IS should be considered with caution. To prevent scleroderma renal crisis steroid doses should not exceed 15 mg/d. The definitive role of a number of new immunosuppressant drugs and the effects of autologous stem cell transplantation in systemic clerosis (SSc) have to be elucidated. Prostanoids, especially iloprost, are widely used as intravenous formulas for the treatment of severe Raynaud's phenomenon (RP) and digital ulcers (DU). Calcium antagonists are of limited therapeutic value. Bosentan, an oral endothelin receptor antagonists (ETRA), was shown to prevent new DU, but failed to heal existing DU, while the oral phopshodiesterase inhibitor (PDI) Sildenafil reduces the occurrence of RP and might be effective in ulcer healing. Combination therapies of PDI with ETRA are currently evaluated. Therapy of pulmonary arterial hypertension (PAH) is usually started as oral monotherapy, frequently using an ETRA. When this first-line therapy is not tolerated ETRA is substituted by PDI. If treatment goals are not reached with monotherapy combinationtherapy is started, for example by adding a PDI to an existing ETRA. In general, treatment of PAH in patients with connective tissue disease follows the same algorithms as in idiopathic PAH.

Topics: Antihypertensive Agents; Cardiovascular Agents; Drug Therapy, Combination; Europe; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Practice Guidelines as Topic; Raynaud Disease; Scleroderma, Systemic; Societies, Medical; Stem Cell Transplantation; Treatment Outcome; Ulcer

Pulmonary hypertension (PH) is a sequel of a variety of cardiovascular and systemic diseases. Heterozygous mutation of BMPRII, a member of the TGFβ superfamily is the commonest genetic defect so far identified in PH. Recent advances have contributed a great deal to the understanding of the disease; however, the actual mechanism/s is not yet clear. Endothelial damage is the key underlying feature of PH. The main effects are loss of vascular relaxation response, increased cell proliferation and impaired apoptosis, matrix deposition, obstruction in the small pulmonary arteries, right ventricular hypertrophy; and eventually leading to right heart failure and death. The diagnosis of PH is often made late because of the insidious onset of symptoms, therefore the treatment poses a daunting challenge. Furthermore, depending on the underlying pathology, not all patients respond equally to same therapeutic agents. Current therapy includes a group of drugs mainly involved in improving vascular relaxation (cAMP and cGMP mechanisms) and endothelin receptor blockers alone or in combination. Newer drugs such as guanylate cyclase activators, PDGF blocker, RhoA/Rho kinase blockers have shown encouraging results in animal studies and in a few clinical cases of PH. Other drugs and signaling pathways such as nitrites, PPARγ, ACE2, ghrelin etc. are under investigation. Studies with gene therapy are being actively pursued. This review summarizes the available therapy and the future prospects.

Topics: Animals; Cardiovascular Agents; Genetic Therapy; Humans; Hypertension, Pulmonary; Vascular Resistance

Pressure overload of the right ventricle results in right ventricular failure and death. Identifying right ventricular dysfunction at less severe stages, which would allow for more effective intervention, has been limited largely due to complex three-dimensional geometry, complex left ventricular/septum interactions, and lack of accepted approaches to assess regional and organ-level right ventricular function. There have been several recent approaches to better identifying right ventricular dysfunction. Recent advances, particularly in the field of pulmonary arterial hypertension, have highlighted the importance of the right ventricle and rekindled research interest to better understand its adaptation to pressure overload. This review focuses on advances in our understanding of right ventricular adaptation to pressure overload.. Advances in hemodynamic analysis and imaging the complex three-dimensional right ventricular shape continue to be reported. Additionally, several advances have occurred in our understanding of the pathophysiology of right ventricular adaptation to pressure overload.. Imaging and hemodynamic assessments may lead to better identification of right ventricular dysfunction and tools to follow response to treatment. Advances in pathophysiology are beginning to identify several novel treatments that may be of benefit to the failing right ventricle.

Topics: Acute Disease; Cardiovascular Agents; Chronic Disease; Echocardiography; Hemodynamics; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Tomography, X-Ray Computed; Ventricular Dysfunction, Right

Cardiovascular magnetic imaging is a noninvasive, three dimensional tomographic technique that allows for a detailed morphology of the cardiac chambers, the accurate quantification of right ventricle volumes, myocardial mass, and transvalvular flow. It can also determine whether right ventricular diastolic function is impaired through pulmonary hypertension. The aim of this article is to review the main kinetic, morphological and functional changes of the right ventricle that can occur in patients affected by pulmonary arterial hypertension (PAH) and to assess how the MRI findings can influence the prognosis, and guide the decision-making strategy. In those cases in which MRI shows a significant cardiac diastolic dysfunction, the prognosis is predictive of pharmacological treatment failure, and mortality. This leaves double lung-heart transplantation as the only therapeutic option. The coexistence of PAH and left ventricle impairment causes worse right ventricle function, leads to a poor prognosis, and may change the therapeutic strategies (for example, PAH associated with left ventricle dysfunction may require a double lung-heart transplant).

Topics: Adult; Blood Pressure; Cardiovascular Agents; Contrast Media; Diagnosis, Differential; Female; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Predictive Value of Tests; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; Ventricular Function, Right

Topics: Cardiac Catheterization; Cardiovascular Agents; Diagnostic Imaging; Echocardiography; Electrocardiography; Humans; Hypertension, Pulmonary; Protein-Tyrosine Kinases; Serotonin Antagonists

New treatment options have improved the prognosis of patients with pulmonary arterial hypertension. However, drugs such as prostanoids, PDE5 inhibitors and endothelin receptor antagonists mainly act as vasodilating agents. Recently, it has become clear that pulmonary arterial hypertension is an inflammatory and vasoproliferative disease. Therefore new anti-inflammatory and antiproliferative treatments are needed. This review will focus on the pathogenesis of inflammation and vasoproliferation in pulmonary hypertension. In addition, an overview on possible new antiinflammatory and antiproliferative drugs in pulmonary hypertension (e.g. Rho-kinase inhibitors, imatinib mesylate. HMG-CoA reductase inhibitors) will be given along with recent patents.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cell Proliferation; Endothelial Cells; Endothelium, Vascular; Enzyme Inhibitors; Humans; Hypertension, Pulmonary; Inflammation; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle

Soluble guanylyl cyclase (sGC) is one of the key enzymes of the nitric-oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. Located in virtually all mammalian cells, it controls the vessel tone, smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In vivo sGC activity is mainly regulated by NO which in turn is released from L-arginine by nitric oxide synthases. One of the main diseases of the cardiovascular system, endothelial dysfunction, leads to a diminished NO synthesis and thus increases vessel tone as well as the risk of thrombosis. The predominant therapeutic approach to this condition is a NO replacement therapy, as exemplified by organic nitrates, molsidomin, and other NO releasing substances. Recent advances in drug discovery provided a variety of other approaches to activate sGC, which may help to circumvent both the tolerance problem and some non-specific actions associated with NO donor drugs. Substances like BAY 41-2272 stimulate sGC in a heme-dependent fashion and synergize with NO, allowing to enhance the effects both of endogenous NO and of exogenous NO donors. On the other hand, heme-independent activators like BAY 58-2667 allow to activate sGC even if it is rendered unresponsive to NO due to oxidative stress or heme loss. Furthermore, a few substances have been described as specific inhibitors of sGC that allow to alleviate the effects of excess NO production as seen in shock. This review discusses the cardiovascular effects of heme-dependent and heme-independent activators as well as of inhibitors of sGC.

Topics: Animals; Atherosclerosis; Carbon Monoxide; Cardiovascular Agents; Cyclic GMP; Guanylate Cyclase; Humans; Hypertension; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Donors; Signal Transduction

Systemic sclerosis (SSc) is a complex and heterogeneous chronic illness characterized by substantial patient to patient variability in clinical manifestations, internal organ involvement, and outcome. Genetic factors contribute to disease susceptibility, but environmental influences also play a significant role. The pathogenesis of SSc encompasses vascular, immunological, and fibrotic processes, which contribute to clinical manifestations and morbidity and must be addressed in the treatment plan. Although vascular interventions appear to reduce the frequency and severity of complications, such as scleroderma renal crisis and pulmonary hypertension, current therapies generally target the immune component of SSc in a non-selective fashion and have largely failed as diseases-modifying interventions. Newer insights into the mechanisms underlying autoimmunity, vascular injury and destruction, and particularly tissue fibrosis provide novel potential targets for therapy. Transforming growth factor-ss is a ubiquitous cytokine that appears to contribute to fibroblast activation, collagen overproduction, and pathological tissue fibrosis. Neutralizing antibodies and small molecules that block TGF-beta activation or function are effective in shutting down TGF-beta signaling and selectively inhibit the progression of fibrosis and may be entering clinical trials for the treatment of SSc.

Topics: Blood Vessels; Cardiovascular Agents; Fibrosis; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lung Diseases, Interstitial; Raynaud Disease; Scleroderma, Systemic; Skin; Transforming Growth Factor beta; Treatment Outcome

Erectile dysfunction (ED) is a sensitive indicator of wider arterial insufficiency and an early correlate for the presence of ischemic heart disease. Among patients with coronary artery disease, prevalence reports of ED range from 42% to 75%. The US Food and Drug Administration has approved 3 phosphodiesterase-5 (PDE-5) inhibitors for treatment of male sexual dysfunction: sildenafil, tadalafil, and vardenafil. PDE-5 inhibitors also have cardiovascular effects. They inhibit PDE-5 enzymes in pulmonary vasculature, which causes vasodilation that decreases pulmonary vascular pressure. Sildenafil is approved for treatment of patients with pulmonary hypertension. PDE-5 inhibition with sildenafil improves cardiac output by balancing pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled nitric oxide in patients with chronic congestive heart failure and pulmonary hypertension. In vivo and in vitro studies are examining the possible beneficial effects of PDE-5 inhibitors in conditions such as myocardial infarction and endothelial dysfunction.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Heart Failure; Humans; Hypertension, Pulmonary; Male; Myocardial Ischemia; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Treatment Outcome

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, in situ thrombosis, and vascular remodeling of small pulmonary arteries inducing increased pulmonary arterial resistance. Conventional treatment is based on life style modification and nonspecific treatment (warfarine, diuretics, oxygen). Calcium channel blockers are vasodilatators that have been shown to be of great efficacy in a very specific subpopulation of patients with PAH. For the majority of patients, specific PAH therapies are still lacking. Numerous studies evaluating prostacyclin agonists, endothelin-receptor antagonists, and phosphodiesterase type 5 inhibitors are now available to guide therapeutic choices. Despite those important advances there is still no cure for PAH. Fortunately, research is ongoing and many drugs show promises.

Topics: Algorithms; Altitude; Anticoagulants; Cardiovascular Agents; Contraception; Contraindications; Diuretics; Enzyme Inhibitors; Female; Humans; Hypertension, Pulmonary; Hypnotics and Sedatives; Hypoxia; Lung Transplantation; Pregnancy; Vasoconstrictor Agents

The most important strategies in pharmacogenomics are gene expression profiling and the network analysis of human disease models. We have previously discovered novel drug target candidates in cardiovascular diseases through investigations of these pharmacogenomics. The significant induction of S100C mRNA and protein expression was detected in the rat pulmonary hypertension and myocardial infarction model. We also found increased taurine in hypoxia, a calcium-associated cytoprotective compound, to suppress the hypoxia-induced S100C gene expression and vascular remodeling. These results suggest that S100C may be one of the potential novel drug targets in hypoxic or ischemic diseases. Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage causes cerebral ischemia and infarction. Using a DNA microarray, a prominant upregulation of heme oxygenase-1 (HO-1) and heat shock protein (HSP) 72 mRNAs were observed in the basilar artery of a murine vasospasm model. Antisense HO-1 and HSP 72 oligodeoxynucleotide inhibited HO-1 and HSP 72 induction, respectively, and significantly aggravated cerebral vasospasm. Moreover, we have also developed a unique heart failure model in zebrafish and identified several candidate genes as novel drug targets. These results suggest that pharmacogenomic network analysis has the potential to bridge the gap between in vitro and in vivo studies and could define strategies for identifying novel drug targets in various cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression Profiling; Gene Regulatory Networks; Genetic Therapy; Heart Failure; Heme Oxygenase-1; HSP72 Heat-Shock Proteins; Humans; Hypertension, Pulmonary; Pharmacogenetics; Rats; S100 Proteins; Vasospasm, Intracranial; Zebrafish

The treatment of pulmonary arterial hypertension--once a lethal condition--has evolved considerably over the past few years as the number of therapeutic options available to treat this disease has increased. In this Review we attempt to summarize the current knowledge of the pathogenesis of pulmonary hypertension, in relation to the therapies presently available and those that could become available in the near future. The use of prostacyclin and its analogs, calcium-channel blockers, endothelin-receptor antagonists and phosphodiesterase type 5 inhibitors is reviewed. Newer concepts, such as the use of combination therapy, and the potential for long-term disease amelioration and improvement of outcomes, are also discussed. The role of supportive care and medications not specific to pulmonary hypertension is also examined. In addition, we review the novel emerging therapies, such as imatinib, fasudil, simvastatin, ghrelin and vasoactive intestinal peptide, which hold therapeutic potential for disease modification as well as treatment of symptoms.

Topics: Cardiovascular Agents; Drug Therapy, Combination; Humans; Hypertension, Pulmonary

Pulmonary hypertension (PH) is common in the critical care setting, and may be a target for specific therapy. Moderate degrees of pulmonary hypertension are most often the consequence of acute or chronic heart failure, hypoxemia, or acute pulmonary embolism, and may be relatively rapidly reversible. The consequences of more severe forms of PH, both acute and chronic, can include hypotension; low cardiac output; right heart failure with congestion of the liver, gut, and kidneys; and varying degrees of hypoxemia, each of which can lead to death or severe disability. We review the physiology, definitions, classification, pathogenesis, diagnostic tools, and algorithms for diagnosis and specific treatments for the various causes of PH as seen in the critical care setting.

Topics: Acute Disease; Algorithms; Cardiovascular Agents; Chronic Disease; Critical Care; Humans; Hypertension, Pulmonary; Thromboembolism

Bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs) control the development and homeostasis of multiple tissue types in many organisms, from humans to invertebrates. These morphogens are expressed in a tissue-specific manner and they signal by binding to serine-threonine kinase receptors, resulting in coordinated changes in gene expression that regulate the differentiation and development of multiple tissue types. In addition, these proteins are regulated post-transcriptionally through binding to several soluble proteins. In this review we focus on a subset of BMPs and GDFs that have been implicated in the pathophysiology of type 2 diabetes and cardiovascular disease.

Topics: Animals; Atherosclerosis; Bone Morphogenetic Protein 7; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Proteins; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Growth Differentiation Factor 3; Humans; Hypertension, Pulmonary; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Metabolic Diseases; Signal Transduction; Transforming Growth Factor beta

Pulmonary hypertension (PH), defined as a mean pulmonary arterial (PA) pressure of >25 mmHg at rest or >30 mmHg during exercise, is characterized by a progressive and sustained increase in pulmonary vascular resistance that eventually leads to right ventricular failure. Clinically, PH may result from a variety of underlying diseases (Table 1 and Refs. 50, 113, 124). Pulmonary arterial hypertension (PAH) may be familial (FPAH) or sporadic (idiopathic, IPAH), formerly known as primary pulmonary hypertension, i.e., for which there is no demonstrable cause. More often, PAH is due to a variety of identifiable diseases including scleroderma and other collagen disorders, liver disease, human immunodeficiency virus, and the intake of appetite-suppressant drugs such as phentermine and fenfluramine (72). Other, more common, causes of PAH include left ventricular failure (perhaps the most common cause), valvular lesions, chronic pulmonary diseases, sleep-disordered breathing, and prolonged residence at high altitude. This classification, now widely accepted, was first proposed at a meeting in Evian, France, in 1998, and modified in Venice, Italy, in 2003 (124).

Topics: Animals; Cardiovascular Agents; Cell Proliferation; Disease Models, Animal; Growth Substances; Humans; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Pulmonary Circulation; Vasomotor System

Endothelin (ET) is among the strongest endogenous vasoconstrictors known and a potent mitogen. A rich body of experimental evidence suggests that ET contributes to vascular remodeling and end-organ damage in several cardiovascular conditions. Therefore, blockade of ET receptors has been suggested as an attractive target in a number of acute and chronic cardiovascular indications, including pulmonary arterial hypertension (PAH), systemic hypertension, and heart failure. To date, clinical studies have confirmed expectations in PAH and yielded promising initial results in systemic hypertension, which are currently awaiting confirmation in large-scale trials. In contrast, no added benefit could be demonstrated in large clinical trials on top of current standard treatment in both acute and chronic heart failure. Further clinical development in heart failure has therefore been suspended. Other indications that are currently being studied clinically or would possibly merit clinical trials include acute myocardial ischemia and reperfusion, cerebral vasospasm after intracranial bleeding, glaucoma, acute severe pancreatitis, systemic sclerosis, (diabetic) renal failure, restenosis after angioplasty/stent implantation, and late transplant rejection. This article critically reviews the available clinical data on ET receptor antagonism in cardiovascular indications against the background of the underlying preclinical research.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endothelin Receptor Antagonists; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertension, Pulmonary; Ventricular Remodeling

Primary pulmonary hypertension (PPH) is a rare but life-threatening disease. Median survival, from the time of diagnosis, is considered to be 2.8 years. However, therapeutic medical advances over the past 2 decades have resulted in significant improvements in quality of life and survival in patients with PPH. Because pulmonary vasoconstriction, endothelial cell proliferation, smooth muscle cell proliferation, and in situ thrombosis contribute to the development of this disease, treatment with vasodilators, anti-proliferative agents, and anticoagulants is recommended.Currently, oral administration of calcium channel antagonists and intravenous infusion of epoprostenol (prostacyclin) are established as treatment of PPH. Epoprostenol has vasoprotective effects including vasodilation, anti-platelet aggregation, and inhibition of smooth muscle cell proliferation. Interestingly, prostacyclin synthase deficiency in the lungs, and impaired prostacyclin production, have been linked to the development of pulmonary hypertension in this disease. As a result, continuous intravenous infusion of epoprostenol has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with PPH. The dramatic success of long-term intravenous prostacyclin is now leading to the development of epoprostenol analogs using newer drug delivery systems (oral beraprost, aerosolized iloprost, and subcutaneous treprostinil). In addition, promising drugs including endothelin antagonists and type V phosphodiesterase inhibitors have recently been developed. Furthermore, gene therapy with endothelial nitric oxide synthase gene or prostacyclin synthase gene may hold great promise in the treatment of PPH. Finally, accurate evaluation of disease severity and the efficacy of vasodilator therapy are important in the management of patients with PPH. In addition to invasive assessment by cardiac catheterization, we recommend repeated measurements of plasma brain natriuretic peptide, serum uric acid, and the distance walked in 6 minutes. These noninvasive parameters may be helpful as part of the evaluation of treatment in patients with PPH and, in particular, as a guide to the selection and timing for alternative therapies.

Topics: Anticoagulants; Cardiovascular Agents; Clinical Trials as Topic; Diuretics; Genetic Therapy; Humans; Hypertension, Pulmonary; Oxygen Inhalation Therapy; Vasodilator Agents

Topics: Anesthesia; Anesthetics; Cardiovascular Agents; Humans; Hypertension, Pulmonary; Pulmonary Circulation; Ventricular Function, Right

Pulmonary hypertension (PH) is a rare blood vessel disorder of the lung, in which the pressure in the pulmonary artery rises above normal levels and can become life-threatening. The authors discuss the disease process, symptoms, investigations and patient management.

Topics: Ambulatory Care; Cardiac Catheterization; Cardiovascular Agents; Coronary Circulation; Electrocardiography; Exercise Test; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Nurse's Role; Oxygen Inhalation Therapy; Pulmonary Circulation; Severity of Illness Index

United Therapeutics Corp (UTC) is developing treprostinil sodium (Remodulin, UT-15), a stable structural analog of prostacyclin, for the potential treatment of primary pulmonary (arterial) hypertension (PAH), peripheral vascular disease (PVD) and other cardiovascular conditions [327593], including critical limb ischemia (CLI) [412483]. In August 2000, UTC submitted the initial, non-clinical sections of an NDA for the treatment of pulmonary hypertension [378906]. Treprostinil, which had previously been designated as an Orphan Drug, was also awarded Priority Review status by the US FDA in October 2000 [385864], [386271]. In December 2000, UTC agreed with the FDA that the NDA for treprostinil did not need to be presented to the Cardiovascular and Renal Drugs Advisory Committee, which was expected to allow UTC and the FDA to work towards the 6-month Priority Review timeline [393888]. On August 9, 2001, the advisory committee recommended approval of treprostinil and UTC refiled the NDA on the same day [418682]. In February 2002, the FDA issued an approvable letter for treprostinil injection for the treatment of PAH. The FDA proposed drug labeling for PAH consistent with the treatment of both primary and secondary pulmonary hypertension in patients with New York Heart Association (NYHA) Class II-IV symptoms. The approvable letter also stated that the FDA intended to approve treprostinil with a requirement that UTC subsequently conduct a post-marketing controlled clinical trial to verify and further describe the drug's clinical benefit [439278]. In February 2001, UTC submitted a marketing authorization application (MAA) in France for approval of treprostinil for the treatment of PAH. Upon approval of the MAA, UTC planned to file for Mutual Recognition in other European countries and was also preparing similar submissions to non-European countries [391986], [397958]. By early 2001, phase II trials of treprostinil for the treatment of CLI were underway [412483]. In March 2001, the company was planning a phase III pivotal study in late-stage PVD by the end of 2001 [424180]. In April 2000, UTC was issued US-06054486 for the method of treating PVD with treprostinil [364130]. In February 2000, UTC entered into an agreement with Paladin Labs for the exclusive Canadian distribution of treprostinil for the remainder of clinical trials and after regulatory approvals [357302]. In November 2000, UTC and Antigen Pharmaceuticals entered into a strategic alliance for the distr

Topics: Cardiovascular Agents; Clinical Trials as Topic; Epoprostenol; Extremities; Humans; Hypertension, Pulmonary; Ischemia; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors

Topics: Cardiovascular Agents; Chronic Disease; Combined Modality Therapy; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Pulmonary Heart Disease; Regional Blood Flow

Topics: Acute Disease; Cardiovascular Agents; Combined Modality Therapy; Hemodynamics; Humans; Hypertension, Pulmonary; Oxygen; Pulmonary Embolism; Pulmonary Heart Disease; Vascular Resistance; Ventilation-Perfusion Ratio

Topics: Cardiovascular Agents; Humans; Hypertension, Pulmonary; Prognosis

Disorders of the heart frequently cause pulmonary dysfunction because of the close structural and functional association of the heart and lungs. The pulmonary vasculature is very commonly affected by cardiac pathology. The pulmonary vasculature is normally a low-pressure, low-resistance circuit with high compliance and tremendous vascular reserve. Although resting vascular tone is low, there are many identified mediators of pulmonary arterial tone that may help mediate pulmonary blood flow. Alveolar hypoxia is clearly a stimulus for increasing pulmonary vascular resistance although factors that mediate the response to hypoxia are not fully understood. Patients with left-to-right shunting due to congenital heart disease because of elevations in pulmonary artery flow and pressure tend to develop progressive anatomic changes in the pulmonary vasculature. This leads to an increase in pulmonary vascular resistance, irreversible pulmonary hypertension, right heart failure, reversal of shunt flow, and Eisenmenger's syndrome. The degree of anatomic vascular damage due to left-to-right shunting can be graded histologically. Lesser grades of damage are reversible with corrective surgery, whereas more severe grades show no improvement or progression with operation. Chronic left-sided congestive heart failure seen in rheumatic mitral stenosis can cause secondary changes in the pulmonary vasculature. Pulmonary hypertension and increased pulmonary vascular resistance can increase reflexly and form a "second stenosis" that further limits cardiac output. Unlike congenital heart disease, severe grades of pulmonary arterial damage are not seen in left heart failure from mitral stenosis or other causes, and consequently with surgical correction pulmonary hypertension reverses. Pulmonary function testing is adversely affected by congestive heart failure. Both restrictive (stiff lungs) and obstructive (cardiac asthma) defects are observed in congestive heart failure. DLCO is abnormally decreased. With treatment of heart failure these defects reverse. Both elevated systemic and pulmonary venous pressures affect fluid filtration in the pleural space and cause pleural fluid accumulation. The fluid is transudative with low protein, low lactate dehydrogenase, and low cell counts. Transudative effusions from heart failure resolve with treatment. With large effusions and cardiomegaly, pulmonary dysfunction results because of atelectasis from compression and space-occupying effects o

Topics: Cardiovascular Agents; Heart Defects, Congenital; Heart Diseases; Humans; Hypertension, Pulmonary; Lung Diseases; Pleural Diseases; Pulmonary Circulation; Pulmonary Embolism; Respiratory Function Tests

Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.. We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.. A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.. In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Topics: Adult; Cardiovascular Agents; Double-Blind Method; Exercise Tolerance; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Pulmonary Arterial Hypertension; Recombinant Fusion Proteins; Respiratory System Agents; Treatment Outcome; Vascular Resistance; Walk Test

Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH.. This randomized, placebo-controlled, double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness.. Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness "right now"-morning and evening-measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291).. Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness "right now" was higher on morphine compared with placebo both for morning [mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = -0.22 (-0.6 to 0.2)] and evening [(M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = -0.33 (-0.8 to 0.1)]. All secondary measures of breathlessness were higher with morphine as were nausea and constipation.. This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms.

Topics: Cardiovascular Agents; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Dyspnea; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Morphine; Patient Selection; Quality of Life; Sample Size; Treatment Failure

No previous study has been done on whether systemic lupus erythematosus (SLE) disease activity is related to the hemodynamics and right ventricular (RV) function in patients with SLE-associated pulmonary artery hypertension (SLE-APAH).. This study prospectively recruited 54 patients (mean age, 32.8±8.4 years; 92.6% female) with SLE-APAH, including 34 patients with SLE disease activity index (SLEDAI) <5 (low score) and 20 with SLEDAI ≥5 (high score). All patients underwent right heart catheterization and iloprost inhalation, and echocardiography was performed before and immediately after iloprost inhalation. There was no difference in baseline mean pulmonary artery pressure (mPAP) between the 2 groups; pulmonary vascular resistance (PVR) was significantly higher and cardiac index was significantly lower in the low-SLEDAI group. The patients with low SLEDAI had larger RV size and worse RV systolic function on echocardiography. After iloprost inhalation, the patients with low SLEDAI had a greater decrease in mPAP and PVR than those with high SLEDAI, while significantly increased RV systolic function was found only in the low-SLEDAI group.. SLE activity is related to hemodynamics and RV function in SLE-APAH patients, and those with low SLEDAI might have better acute response to vasodilator inhalation.

Topics: Adult; Cardiac Catheterization; Cardiovascular Agents; Echocardiography; Female; Humans; Hypertension, Pulmonary; Iloprost; Lupus Erythematosus, Systemic; Male; Vascular Resistance; Vasodilation; Ventricular Function, Right

Levosimendan has anti-ischaemic effects, improves myocardial contractility and increases systemic, pulmonary and coronary vasodilatation. These properties suggest potential advantages in high-risk cardiac valve surgery patients where cardioprotection would be valuable. The present study investigated the peri-operative haemodynamic effects of prophylactic levosimendan infusion in cardiac valve surgery patients with low ejection fraction and/or severe pulmonary arterial hypertension.. Between May 2006 and July 2007, 20 consecutive patients with severe pulmonary arterial hypertension (systolic pulmonary artery pressure ≥ 60 mmHg) and/or low ejection fraction (< 50%) who underwent valve surgery in our clinic were included in the study and randomised into two groups. Levosimendan was administered to 10 patients in group I and not to the 10 patients in the control group. Cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (MPAP) were recorded for each patient preoperatively and for 24 hours following the operation.. CO and CI values were higher in the levosimendan group during the study period (p < 0.05). MPAP and PVR values were significantly lower in the levosimendan group for the 24-hour period (p < 0.05) and SVR values were significantly lower after 24 hours in both groups. When clinical results were considered, no difference in favour of levosimendan was detected regarding the mortality and morbidity rates between the groups.. Levosimendan improved the haemodynamics in cardiac valve surgery patients with low ejection fraction and/or severe pulmonary arterial hypertension, and facilitated weaning from cardiopulmonary bypass in such high-risk patients when started as a prophylactic agent.

Topics: Arterial Pressure; Cardiopulmonary Bypass; Cardiovascular Agents; Drug Administration Schedule; Familial Primary Pulmonary Hypertension; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Hemodynamics; Humans; Hydrazones; Hypertension, Pulmonary; Infusions, Parenteral; Pulmonary Artery; Pyridazines; Severity of Illness Index; Simendan; Stroke Volume; Time Factors; Treatment Outcome; Turkey; Vascular Resistance

Pulmonary vein stenosis (PVS) is a growing problem for the pediatric congenital heart population. Sirolimus has previously been shown to improve survival and slow down the progression of in-stent stenosis in patients with PVS. We evaluated patients before and after initiation of sirolimus to evaluate its effects on re-intervention and vessel patency utilizing Optical Coherence Tomography (OCT).. We performed a retrospective study, reviewing the charts of patients with PVS, who had been prescribed sirolimus between October 2020 and December 2021. OCT was performed in the pulmonary vein of interest as per our published protocol. Angiographic and OCT imaging was retrospectively reviewed. Statistical analysis was performed using Chi square and Wilcoxon signed-rank test to compare pre-and post-sirolimus data.. Ten patients had been started and followed on sirolimus. Median age at sirolimus initiation was 25 months with median weight of 10.6 kg and average follow-up of 1 year. Median total catheterizations were 7 for patients prior to starting sirolimus and 2 after starting treatment (p = 0.014). Comparing pre- and post-sirolimus, patients were catheterized every 3 months vs every 11 months (p = 0.011), median procedure time was 203 min vs 145 min (p = 0.036) and fluoroscopy time, 80 min vs 57.2 min (p = 0.036). 23 veins had severe in-stent tissue ingrowth prior to SST (luminal diameter < 30% of stent diameter). Post-sirolimus, 23 pulmonary veins had moderate to severe in-stent tissue ingrowth that responded to non-compliant balloon inflation only with stent luminal improvement of > 75%.. Our study suggests that the addition of sirolimus in patients with moderate-severe PVS helps to decrease disease progression with decrease frequency of interventions. Reaching therapeutic levels for sirolimus is critical and medication interactions and side-effects need careful consideration. OCT continues to be important for evaluation and treatment guidance in this patient population.

Topics: Altitude; Cardiovascular Agents; Child; Coronary Vessels; Humans; Hypertension, Pulmonary; Percutaneous Coronary Intervention; Retrospective Studies; Sirolimus; Stenosis, Pulmonary Vein; Tomography, Optical Coherence; Treatment Outcome

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.

Topics: Animals; Antipsychotic Agents; Cardiovascular Agents; Cell Proliferation; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Repositioning; Female; Forkhead Box Protein O3; Gene Expression Regulation; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Indoles; Monocrotaline; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Pyrroles; Rats; Rats, Sprague-Dawley; Survivin; Trifluoperazine

Despite the progress in the management of patients with adult congenital heart disease (ACHD), a significant proportion of patients still develop pulmonary hypertension (PH). We aimed to highlight the rate of the complications in PH-ACHD and the predicting factors of cumulative mortality risk in this population.. Data were obtained from the cohort of the national registry of ACHD in Greece from February 2012 until January 2018.. Overall, 65 patients receiving PH-specific therapy were included (mean age 46.1±14.4 years, 64.6% females). Heavily symptomatic (New York Heart Association (NYHA) class III/IV) were 53.8% of patients. The majority received monotherapy, while combination therapy was administered in 41.5% of patients. Cardiac arrhythmia was reported in 30.8%, endocarditis in 1.5%, stroke in 4.6%, pulmonary arterial thrombosis in 6.2%, haemoptysis in 3.1% and hospitalisation due to heart failure (HF) in 23.1%. Over a median follow-up of 3 years (range 1-6), 12 (18.5%) patients died. On univariate Cox regression analysis history of HF hospitalisation emerged as a strong predictor of mortality (HR 8.91, 95% CI 2.64 to 30.02, p<0.001), which remained significant after adjustment for age and for NYHA functional class.. Long-term complications are common among patients with PH-ACHD. Hospitalisations for HF predict mortality and should be considered in the risk stratification of this population.

Topics: Adult; Arrhythmias, Cardiac; Cardiovascular Agents; Female; Follow-Up Studies; Greece; Heart Defects, Congenital; Heart Failure; Hospitalization; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mortality; Prognosis; Registries; Risk Assessment; Stroke

Endothelial injury is considered as a trigger of pulmonary vascular lesions in the pathogenesis of hypoxic pulmonary hypertension (HPH). Although endothelial colony-forming cells (ECFCs) have vascular regeneration potential to maintain endothelial integrity, hypoxia-induced precise alteration in ECFCs function remains controversial. This study investigated the impact of hypoxia on human ECFCs function in vitro and the underlying mechanism. We found that hypoxia inhibited ECFCs proliferation, migration and angiogenesis. Compared with no treatment, the expression of hypoxia inducible factor-1α (HIF-1α) in hypoxia-treated ECFCs was increased, with an up-regulation of p27 and a down-regulation of cyclin D1. The over-secreted vascular endothelial growth factor (VEGF) was detected, with the imbalanced expression of fetal liver kinase 1 (flk-1) and fms related tyrosine kinase 1 (flt-1). Hypoxia-induced changes in ECFCs could be reversed by HIF-1α inhibitor KC7F2. These data suggest that HIF-1α holds the key in regulating ECFCs function which may open a new perspective of ECFCs in HPH management.

Topics: Adult; Cardiovascular Agents; Cell Cycle; Cell Movement; Cell Proliferation; Cells, Cultured; Cyclin D1; Disulfides; Endothelial Cells; Humans; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Middle Aged; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sulfonamides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Young Adult

Cardiac air embolism should be suspected in any neonate with acute unexplained cardiovascular collapse or worsening oxygenation. We present here five cases that presented with the above symptoms. A comprehensive evaluation including targeted neonatal echocardiography and near-infrared spectroscopy helped confirm the diagnosis and assess the hemodynamic state. Management was supportive including left lateral positioning, chest compressions, and cardiovascular medications to treat pulmonary hypertension and systemic hypotension.

Topics: Cardiovascular Agents; Echocardiography; Embolism, Air; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Hypotension; Infant, Newborn; Male; Patient Positioning; Respiratory Therapy; Spectroscopy, Near-Infrared

Treprostinil, a potent vasodilator, is the treatment of choice for severe pulmonary arterial hypertension (PAH) during pregnancy. Its inhibition of platelet aggregation increases the risk of hemorrhage. In addition, anticoagulation therapy is widely used in pregnancy with PAH due to the hypercoagulable state. However, very little is known about the complications of anticoagulants' use in pregnancy with PAH.. A 27-year-old pregnant woman was admitted to the hospital at 32weeks with progressive dyspnea.. The pregnant was diagnosed with ventricular septal defect 12 years prior to presentation. Combining clinical manifestation with results of right heart catheterization (RHC) and echocardiography, it was consistent with severe World Health Organization (WHO) group I PAH.. Supportive treatment included supplemental oxygen, intravenous treprostinil, sildenafil and prophylactic anticoagulation.. Gastrointestinal bleeding is occurred in our patient when dalteparin were used in conjunction with treprostinil. Her care was further complicated refractory to usual conservative measures before delivery.. This case report illustrates the complexities that arise when prostacyclin therapies are combined with necessary anticoagulation in patients with PAH during pregnancy. More intention should play to the complications of anticoagulant in pregnancy with PAH during treprostinil therapy.

Topics: Adult; Anticoagulants; Antihypertensive Agents; Cardiovascular Agents; Dalteparin; Epoprostenol; Female; Gastrointestinal Hemorrhage; Humans; Hypertension, Pulmonary; Pregnancy; Pregnancy Complications, Cardiovascular; Sildenafil Citrate; Vasodilator Agents

There is an increase in oxidative stress and apoptosis signaling during the transition from hypertrophy to right ventricular (RV) failure caused by pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). In this study, it was evaluated the action of copaiba oil on the modulation of proteins involved in RV apoptosis signaling in rats with PAH. Male Wistar rats (±170 g, n = 7/group) were divided into 4 groups: control, MCT, copaiba oil, and MCT + copaiba oil. PAH was induced by MCT (60 mg/kg intraperitoneally) and, 7 days later, treatment with copaiba oil (400 mg/kg by gavage) was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and the RV was collected for morphometric evaluations, oxidative stress, apoptosis, and cell survival signaling, and eNOS protein expression. Copaiba oil reduced RV hypertrophy (24%), improved RV systolic function, and reduced RV end-diastolic pressure, increased total sulfhydryl levels and eNOS protein expression, reduced lipid and protein oxidation, and the expression of proteins involved in apoptosis signaling in the RV of MCT + copaiba oil as compared to MCT group. In conclusion, copaiba oil reduced oxidative stress, and apoptosis signaling in RV of rats with PAH, which may be associated with an improvement in cardiac function caused by this compound.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cardiovascular Agents; Disease Models, Animal; Fabaceae; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; JNK Mitogen-Activated Protein Kinases; Male; Monocrotaline; Myocardium; Nitric Oxide Synthase Type III; Oxidative Stress; Plant Oils; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar; Signal Transduction; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH.

Topics: Animals; Arterial Pressure; Cardiovascular Agents; Disease Models, Animal; Fibrosis; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Macrophages, Alveolar; Male; Monocrotaline; Myocytes, Cardiac; Natriuretic Peptide, Brain; Osteopontin; Pioglitazone; PPAR gamma; Pulmonary Artery; Rats, Sprague-Dawley; Thiazolidinediones; Vascular Remodeling; Ventricular Function, Right; Ventricular Remodeling

Topics: Aneurysm; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Combined Modality Therapy; Continuous Positive Airway Pressure; Echocardiography, Transesophageal; Enterobacteriaceae Infections; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Marfan Syndrome; Middle Aged; Mitral Valve Insufficiency; Oxygen Inhalation Therapy; Postoperative Complications; Pulmonary Artery; Pulmonary Valve Insufficiency; Respiratory Insufficiency

Topics: Adult; Angioplasty, Balloon; Cardiovascular Agents; Chronic Disease; Humans; Hypertension, Pulmonary; Male; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Treatment Outcome; Ventricular Function, Right

Topics: Aged; Cardiovascular Agents; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Pilot Projects; Ranolazine; Stroke Volume

Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH.. A single s.c. injection of MCT (50 mg·kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg(-1) C21, 3 mg·kg(-1) PD-123319 or 0.5 mg·kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses.. Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21.. Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH.

Topics: Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Animals; Cardiovascular Agents; Disease Models, Animal; Fibrosis; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Imidazoles; Lung; Male; Monocrotaline; Myocardium; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Fibrosis; Pyridines; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Signal Transduction; Vascular Remodeling; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

Topics: Adult; Calcium Channel Blockers; Cardiac Surgical Procedures; Cardiovascular Agents; Contraindications; Diagnostic Techniques, Cardiovascular; Disease Management; Eisenmenger Complex; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Nitric Oxide; Patient Selection; Practice Guidelines as Topic; Prognosis; Vasodilator Agents

Highly concentrated carbon dioxide (GO2) is useful for treating ischemic diseases. Therefore, we investigated whether treatment with a few micrometers of CO2 molecules, atomized by two fluid nozzles (CO2 mist), could attenuate the development of right ventricular (RV) dysfunction in pulmonary hypertensive rats.. Six-week-old male Wistar rats were divided into three groups: one that received injected saline; a second that received subcutaneous monocrotaline (MCT; 60 mg/kg) without treatment (PH-UT) group; and a third that received MCT with CO2 mist treatment (PH-CM) after MCT administration. The lower body of each rat was encased in a polyethylene bag, filled with the designated gaseous agent via a gas mist generator, for 30 minutes daily. Hemodynamics and cardiac function were measured at 28 days after beginning MCT administration. Protein levels were measured by western blotting.. Rats that received MCT without treatment began to die within 3-4 weeks of the initial administration. However, treatment with CO2 mist extended the survival period of rats in that group. At 28 days after MCT administration, the hemodynamic status, such as the blood pressure and heart rate, involved with left ventricular function, of rats in the PH-UT group were similar to those of rats in the PH-CM group. However, MCT-induced RV weight and RV dysfunction were significantly attenuated by treatment with CO2 mist. Both RV phosphorylated endothelial nitric oxide synthase and heat shock protein 72 levels increased significantly in the PH-CM group, compared to the PH-UT group.. Percutaneous CO2 mist therapy may alleviate RV dysfunction in patients with pulmonary hypertension.

Topics: Aerosols; Animals; Carbon Dioxide; Cardiovascular Agents; Disease Models, Animal; Hemodynamics; HSP72 Heat-Shock Proteins; Hypertension, Pulmonary; Male; Monocrotaline; Myocardium; Nebulizers and Vaporizers; Nitric Oxide Synthase Type III; Phosphorylation; Rats, Wistar; Time Factors; Ventricular Dysfunction, Right; Ventricular Function, Right

Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.

Topics: Cardiovascular Agents; Child; Child, Preschool; Combined Modality Therapy; Diagnostic Imaging; Disease Management; Extracorporeal Membrane Oxygenation; Genetic Counseling; Heart Defects, Congenital; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Lung; Lung Transplantation; Nitric Oxide; Oxygen Inhalation Therapy; Persistent Fetal Circulation Syndrome; Postoperative Complications; Respiration, Artificial; Ventilator-Induced Lung Injury

Heart failure (HF) is a progressive disorder associated with impaired quality of life, high morbidity, mortality and frequent hospitalization and affects millions of people from all around the world. Despite further improvements in HF therapy, mortality and morbidity remains to be very high. The life-long treatment, frequent hospitalization, and sophisticated and very expensive device therapies for HF also leads a substantial economic burden on the health care system. Therefore, implementation of evidence-based guideline-recommended therapy is very important to overcome its worse clinical outcomes. However, HF therapy is a long process that has many drawbacks and sometimes HF guidelines cannot answers to every question which rises in everyday clinical practice. In this paper, commonly encountered questions, overlooked points, controversial issues, management strategies in grey zone and problems arising during follow up of a HF patient in real life clinical practice have been addressed in the form of expert opinions based on the available data in the literature.

Topics: Adrenergic beta-Antagonists; Aged; Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Cardiovascular Agents; Chronic Disease; Diabetes Mellitus; Diuretics; Evidence-Based Medicine; Female; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Disease, Chronic Obstructive; Renal Insufficiency, Chronic; Turkey

Topics: Bosentan; Cardiovascular Agents; Dose-Response Relationship, Drug; Familial Primary Pulmonary Hypertension; Fingers; Humans; Hypertension, Pulmonary; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Treatment Outcome

Topics: Cardiovascular Agents; Humans; Hypertension, Pulmonary; Lung

Pulmonary hypertension (PH) is a group of diseases characterized by progressive increases in pulmonary vascular resistance and pulmonary artery pressure, which results in right ventricular heart failure and sudden death. Based on the current version of the guidelines for PH diagnosis and treatment, adopted by the experts of the European Society of Cardiology and the European Respiratory Society in 2009, and on the data of Russian and foreign clinical trials, the Russian experts elaborated clinical guidelines for PH in 2013. The latter consider the current classifications of PH, the specific features of its pathogenesis, and its diagnostic algorithm. The section dealing with drugs for maintenance therapy discusses data on the use of oral anticoagulants, diuretics, cardiac glycosides, and oxygen therapy. PH-specific therapy includes calcium antagonists, prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Surgical procedures for PH involve atrial septostomy, thromboendartectomy, and lung or heart-lung transplantation. A treatment algorithm is proposed for PH patients. The current medicinal approaches using specific therapy agents and their combinations offer new promises for the effective treatment of patients with PH and improve its prognosis.

Topics: Algorithms; Anticoagulants; Cardiac Surgical Procedures; Cardiovascular Agents; Disease Management; Disease Progression; Humans; Hypertension, Pulmonary; Lung Transplantation; Practice Guidelines as Topic; Prognosis; Prostaglandins; Pulmonary Circulation; Pulmonary Wedge Pressure; Randomized Controlled Trials as Topic; Symptom Assessment; Vascular Resistance

Topics: Cardiovascular Agents; Clinical Trials as Topic; Congresses as Topic; Diagnostic Techniques, Cardiovascular; Disease Management; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Respiratory Function Tests; Sulfonamides; Therapies, Investigational; Ventricular Dysfunction, Right

Haemodynamic changes that occur during pregnancy are maximal between 28 and 34 weeks. In the pregnant woman with several associated diseases, such as hypertensive myocardiopathy and pre-gestational diabetes, these changes can lead to a difficult control of pulmonary hypertension and acute pulmonary oedema. We report the case of a pregnant woman with long term type 1 diabetes mellitus who suffered pre-eclampsia in a previous pregnancy, and since then developed hypertensive cardiomyopathy. She was admitted at 30 week gestation for metabolic and blood pressure control, and developed congestive cardiac failure after the administration of betamethasone for foetal lung maturity. A transthoracic echocardiogram showed a non-dilated hypertrophic left ventricle with good systolic function, restrictive diastolic dysfunction and moderate pulmonary arterial hypertension. When her general condition improved, we performed a caesarean section under regional anaesthesia to prevent the complications of pulmonary and systemic hypertension. We present the anaesthetic management and resolution of complications after oxytocin administration.

Topics: Adult; Anesthesia, Epidural; Anesthesia, Obstetrical; Betamethasone; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Cesarean Section, Repeat; Diabetes Mellitus, Type 1; Diastole; Female; Heart Failure; Humans; Hypertension, Pulmonary; Hypotension; Infant, Newborn; Intraoperative Complications; Norepinephrine; Oxytocin; Phenylephrine; Pre-Eclampsia; Preanesthetic Medication; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Supine Position

Atrial flutter and fibrillation are being increasingly reported in patients with pulmonary hypertension but little is known about their clinical implications. We sought to determine the incidence and clinical impact of these arrhythmias in patients with pulmonary hypertension.. In a 5-year, prospective study, we assessed the incidence of new-onset atrial flutter and fibrillation as well as risk factors, clinical consequences, management, and impact on survival in patients with pulmonary arterial hypertension (PAH, n=157) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH, n=82).. The cumulative 5-year incidence of new-onset atrial flutter and fibrillation was 25.1% (95% confidence interval, 13.8-35.4%). The development of these arrhythmias was frequently accompanied by clinical worsening (80%) and signs of right heart failure (30%). Stable sinus rhythm was successfully re-established in 21/24 (88%) of patients initially presenting with atrial flutter and in 16/24 (67%) of patients initially presenting with atrial fibrillation. New-onset atrial flutter and fibrillation were an independent risk factor of death (p=0.04, simple Cox regression analysis) with a higher mortality in patients with persistent atrial fibrillation when compared to patients in whom sinus rhythm was restored (estimated survival at 1, 2 and 3 years 64%, 55%, and 27% versus 97%, 80%, and 57%, respectively; p=0.01, log rank analysis).. Atrial flutter and fibrillation develop in a sizable number of patients with PAH or inoperable CTEPH and often lead to clinical deterioration and right heart failure. Mortality is high when sinus rhythm cannot be restored.

Topics: Aged; Atrial Fibrillation; Atrial Flutter; Cardiovascular Agents; Cohort Studies; Electric Countershock; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies

Topics: Adult; Age Factors; Biomarkers; Cardiovascular Agents; Child; Clinical Trials as Topic; Forecasting; Humans; Hypertension, Pulmonary; National Heart, Lung, and Blood Institute (U.S.); Phenotype; Prognosis; Research; United States; Vascular Resistance

Topics: Aortic Aneurysm; Aortic Dissection; Cardiomyopathies; Cardiovascular Agents; Cooperative Behavior; Female; Heart Defects, Congenital; Heart Valve Diseases; Heart Valve Prosthesis; Humans; Hypertension, Pulmonary; Infant, Newborn; Interdisciplinary Communication; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Diagnosis; Risk Assessment; Venous Thromboembolism

Topics: Cardiovascular Agents; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Predictive Value of Tests; Raynaud Disease; Scleroderma, Systemic; Treatment Outcome; Ulcer

Intravenous periodic Iloprost is proven effective in the treatment of Raynaud phenomenon (RP) related to connective tissue disorder (CTD). It's well known that synthetic prostaglandins are effective drugs for the treatment of pulmonary arterial hypertension (PAH), and that PAH is frequently associated with CTD.. The aim of the study is to evaluate in the chronic effect of cyclic intravenous Iloprost on pulmonary arterial pressure.. We studied 17 consecutive patients with CTD (14 systemic sclerosis, 3 mixed CTD) and RP, at the entry and after at least 6months of treatment of RP with cyclic Iloprost. On both occasions, in all patients we performed transthoracic Doppler echocardiography and we determined NT-proBNP plasma levels, NYHA functional class, 6 Minute-Walk Distance (6MWD).. At follow-up (8.2±1.9months; range 6-12) mean values of pulmonary arterial systolic pressure (PASP) significantly decreased (from 32.2±9.2 to 29.2±7.6mmHg, p<0.04) and mean values of 6MWD significantly increased (from 407.5±101.5 to 448.3±89.9m, p<0.01). Moreover, we observed a significant direct correlation between PASP and NT-proBNP values and a significant inverse correlation both between NT-proBNP and 6MWD values and between PASP and 6MWD values.. Our results suggest that cyclic intravenous Iloprost may protect against the development or worsening of PAH in patients with CTD and RP.

Topics: Adult; Aged; Cardiovascular Agents; Connective Tissue Diseases; Dose-Response Relationship, Drug; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Pulmonary Wedge Pressure; Retrospective Studies; Time Factors; Treatment Outcome

The prognostic implications and surgical benefit of isolated significant tricuspid regurgitation (TR) and prognostic factors in patients with TR were investigated.. In 870 consecutive patients with significant isolated TR, all-cause mortality was analyzed over 4.9+/-2.9 years. It was found that the survival rate tended to be higher in the 57 patients who underwent tricuspid valve (TV) surgery than the 813 patients who did not by using propensity-score matching (P=0.068), although it was not significant. Of the 813 patients that did not undergo TV surgery, the 5-year survival rate was 74%. According to the Cox proportional hazards model, the initial TR jet area (hazard ratio [HR], 1.044; 95% confidence interval [CI], 1.016-1.073), pulmonary artery systolic pressure (HR, 1.024; 95%CI, 1.017-1.032) and presence of right ventricular (RV) dysfunction (HR, 2.256; 95% CI, 1.329-3.828) were predictors of mortality independent of patient age and presence of diabetes mellitus and renal failure in medically managed patients.. In patients with isolated significant TR, there was a tendency, although not significant, towards a higher survival rate after TV surgery. The severity of TR and pulmonary hypertension, and the presence of RV dysfunction are independent prognostic factors in medically managed patients. Further prospective randomized studies are necessary to demonstrate the benefit of TV surgery in these poor prognostic populations.

Topics: Aged; Cardiac Surgical Procedures; Cardiovascular Agents; Female; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Propensity Score; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome; Tricuspid Valve Insufficiency; Ventricular Dysfunction, Right

Hypoxic pulmonary hypertension is a disease of the lung vasculature that is usually quantified by pulmonary vascular resistance (PVR). However, a more complete description of lung vascular function and right ventricular afterload is provided by pulmonary vascular impedance (PVZ) from spectral analysis of pulsatile pressure-flow relationships. We studied pulsatile pressure-flow relationships in isolated, perfused lungs of mice in normoxia, after induction of hypoxic pulmonary hypertension by 10 days of hypoxic exposure, and after the administration of the vasoactive agents sodium nitroprusside and serotonin in order to gain insight into the effects of disease and vasoactive agents on afterload. Chronic hypoxia exposure increased 0 Hz impedance (Z(0)) from 2.0 +/- 0.2 to 3.3 +/- 0.2 mmHg min/mL but decreased characteristic impedance (Z(C)) from 0.21 +/- 0.02 to 0.18 +/- 0.01 mmHg min/mL (both p < 0.05). Sodium nitroprusside only slightly decreased Z(0) but increased Z(C) in normal lungs (p < 0.05) and did not affect Z(C) and decreased Z(0) in hypertensive lungs (p < 0.05). Serotonin increased Z(C) in normal and hypertensive lungs but decreased Z(0) in hypertensive lungs (p < 0.05). There was an inverse correlation between mean pulmonary artery pressure and Z(C) in all circumstances. These findings demonstrate that vasoactive interventions can have different sites of action (i.e., proximal vs. distal segments) in the normal and chronically hypoxic pulmonary vasculature, and the pressure-dependency of Z(C) and R(W). The measurement of PVZ in isolated lungs allows for an improved understanding of the modes of action of drugs and hypoxia on the pulmonary circulation.

Topics: Animals; Blood Vessels; Cardiovascular Agents; Electric Impedance; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mice; Mice, Inbred C57BL; Nitroprusside; Pulmonary Circulation; Pulsatile Flow; Vascular Resistance

We report here on the successful treatment for right ventricular outflow tract obstruction after bilateral lung transplantation in a patient with primary pulmonary hypertension. A 31-year-old female patient with primary pulmonary hypertension underwent successful bilateral lung transplantation. She had a pressure gradient of 30 mmHg through the right ventricular outflow tract one week after transplantation, but was successfully treated with atelenol and disopyramide. Long-term follow-up cardiac catheterization did not show any significant right ventricular outflow tract obstruction. The actual cause of the right ventricular outflow tract obstruction remained unknown, but longstanding pulmonary hypertension might have induced significant structural changes in the heart, such as right ventricular hypertrophy and enlargement.

Topics: Adult; Atenolol; Cardiac Surgical Procedures; Cardiovascular Agents; Disopyramide; Drug Therapy, Combination; Female; Heart Septal Defects, Atrial; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Transplantation; Radiography; Treatment Outcome; Ventricular Outflow Obstruction

Topics: Algorithms; Biomarkers; Cardiovascular Agents; Diagnostic Techniques, Cardiovascular; Exercise Tolerance; Heart Diseases; Humans; Hypertension, Pulmonary; Hypoxia; Lung Transplantation; Prognosis; Pulmonary Veno-Occlusive Disease; Referral and Consultation; Risk Factors; Terminal Care; Thromboembolism

The increased incidence of pulmonary hypertension and its association with decreased survival is well-recognised in patients with systemic sclerosis. This association is not widely appreciated in patients with polymyositis-dermatomyositis. We report clinical and hemodynamic characteristics and response to vasoactive therapy in three patients with polymyositis-dermatomyositis and pulmonary hypertension and discuss them in light of the available literature.

Topics: Adult; Cardiovascular Agents; Dermatomyositis; Fatal Outcome; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Scleroderma, Systemic; Vasodilator Agents

Appropriate parameters are needed for the monitoring of children with pulmonary arterial hypertension (PAH). Various biologic markers seem to be of use in adults with PAH. No data are available on their value in children with PAH. In this study, the relation between serum markers, functional parameters, and hemodynamic variables in pediatric PAH and their ability to predict survival is determined. Serum N-terminal pro brain natriuretic peptide (NT-proBNP), uric acid, norepinephrine, and epinephrine were measured and correlated with invasive hemodynamics, functional parameters, and outcome in 29 pediatric patients with PAH who visited a tertiary reference center for pediatric PAH between 1997 and 2005. NT-proBNP correlated with functional class (R = 0.36; p = 0.03) and 6-min walking distance (6MWD) (R = -0.53; p < 0.001). Uric acid correlated with mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index (R = 0.63, p = 0.01; R = 0.71, p = 0.03, and R = -0.65, p = 0.007, respectively). After initiation of treatment, NT-proBNP decreased. This decrease correlated with an increased 6MWD. Finally, norepinephrine and NT-proBNP levels were highly predictive for mortality. In this series of children with PAH, biologic markers were correlated with hemodynamics and functional capacity, as parameters of disease severity. The data indicate that these markers can be used to monitor treatment effects and predict mortality in pediatric PAH.

Topics: Adolescent; Biomarkers; Blood Pressure; Cardiac Output; Cardiovascular Agents; Child; Child, Preschool; Drug Monitoring; Epinephrine; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infant; Male; Natriuretic Peptide, Brain; Norepinephrine; Peptide Fragments; Predictive Value of Tests; Pulmonary Artery; Recovery of Function; Reproducibility of Results; Severity of Illness Index; Treatment Outcome; Uric Acid; Vascular Resistance; Walking

Pulmonary arterial compliance (C) is increasingly being recognized as an important contributor to right ventricular afterload, but for monitoring of treatment of pulmonary hypertension (PH) most often still only pulmonary vascular resistance (R) is used. We aimed at testing the hypothesis that R and C are coupled during treatment of PH and that substantial changes in both R and C would result in more haemodynamic improvement than changes in R alone.. Data were analysed of two right-heart catheterizations of 52 patients with pulmonary arterial hypertension and 10 with chronic-thromboembolic PH. The product of R and C (= stroke volume over pulse pressure) did not change during therapy (P = 0.320), implying an inverse relationship. Changes in cardiac index correlated significantly (P < 0.001) with changes in R (R(2) = 0.37), better with changes in C (R(2) = 0.66), and best with changes in both (R(2) = 0.74).. During therapy for PH, R and C remain inversely related. Therefore, changes in both R and C better explain changes in cardiac index than either of them alone. Not only resistance but also compliance plays a prominent role in PH especially in an early stage of the disease.

Topics: Adult; Aged; Cardiac Catheterization; Cardiovascular Agents; Compliance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Vascular Resistance

Fructose-1,6-diphosphate (FDP) is reported to have a salutary effect in endotoxin shock and sepsis. This investigation describes the effect of FDP on pulmonary and systemic hemodynamics, lung lymph protein clearance, and leukocyte count in sheep infused with Escherichia coli endotoxin.. Anesthetized sheep (n = 18), some of which underwent thoracotomy to cannulate lymphatic nodes, were used in this study. After stabilization, all sheep received E. coli endotoxin, 5 microg/kg i.v. infusion over 30 min. Concomitant with the endotoxin infusion, half of the animals were randomly selected to receive an i.v. bolus of FDP (10%), 50 mg/kg, followed by a continuous infusion of 5 mg.kg(-1).min(-1) for 4 h; the rest were treated in the same manner with glucose (10%) in 0.9% NaCl.. Pulmonary artery pressure (PAP) and resistance in the glucose group increased from 20.8 +/- 1.6 to 36.7 +/- 3.2 mmHg (P < 0.007) and from 531 +/- 114 to 1137 +/- 80 dyn.s(-1).cm(-5), respectively (P < 0.005). Despite an increase during endotoxin infusion, these parameters in the FDP group returned to control values. There were no differences in left ventricular pressures, cardiac output, heart rate, and arterial oxygen tension between the groups. In the glucose group, lymph protein clearance was higher (P < 0.01) and blood leukocyte count was lower (P < 0.02). The wet/dry lung weight ratio (g/g) for the glucose group was 5.57 +/- 0.04 and for the FDP-treated group 4.76 +/- 0.06 (P < 0.0005).. FDP treatment attenuated significantly the characteristic pulmonary hypertension, lung lymph protein clearance, and pulmonary vascular leakage seen in sheep infused with endotoxin.

Topics: Animals; Cardiovascular Agents; Endotoxemia; Endotoxins; Extravascular Lung Water; Fructosediphosphates; Hypertension, Pulmonary; Leukocyte Count; Lymph; Pulmonary Wedge Pressure; Respiratory Distress Syndrome; Sheep; Vascular Resistance

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 management of asymptomatic severe mitral regurgitation remains controversial. The aim of this study was to evaluate the outcome of a watchful waiting strategy in which patients are referred to surgery when symptoms occur or when asymptomatic patients develop left ventricular (LV) enlargement, LV dysfunction, pulmonary hypertension, or recurrent atrial fibrillation.. A total of 132 consecutive asymptomatic patients (age 55+/-15 years, 49 female) with severe degenerative mitral regurgitation (flail leaflet or valve prolapse) were prospectively followed up for 62+/-26 months. Patients underwent serial clinical and echocardiographic examinations and were referred for surgery when the criteria mentioned above were fulfilled. Overall survival was not statistically different from expected survival either in the total group or in the subgroup of patients with flail leaflet. Eight deaths were observed. Thirty-eight patients developed criteria for surgery (symptoms, 24; LV criteria, 9; pulmonary hypertension or atrial fibrillation, 5). Survival free of any indication for surgery was 92+/-2% at 2 years, 78+/-4% at 4 years, 65+/-5% at 6 years, and 55+/-6% at 8 years. Patients with flail leaflet tended to develop criteria for surgery slightly but not significantly earlier. There was no operative mortality. Postoperative outcome was good with regard to survival, symptomatic status, and postoperative LV function.. Asymptomatic patients with severe degenerative mitral regurgitation can be safely followed up until either symptoms occur or currently recommended cutoff values for LV size, LV function, or pulmonary hypertension are reached. This management strategy is associated with good perioperative and postoperative outcome but requires careful follow-up.

Topics: Aged; Atrial Fibrillation; Cardiovascular Agents; Case Management; Comorbidity; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Life Tables; Male; Middle Aged; Mitral Valve Insufficiency; Mitral Valve Prolapse; Prospective Studies; Survival Analysis; Time Factors; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Left

Nesiritide is a recombinant brain-type natriuretic peptide (BNP), which decreases pulmonary arterial (PA) pressures and myocardial oxygen consumption while increasing coronary flow and urine output. Mitral valve (MV) surgery in patients with severe mitral regurgitation (MR), impaired left ventricular function, and pulmonary hypertension is associated with a high operative mortality. We hypothesized that the perioperative use of Nesiritide is safe, and may improve surgical outcomes.. From May 2003 to August 2004, 14 patients (11 male, 3 female; mean age, 64 years [23-87 years]; mean systolic PA, 63 mm Hg [48-94 mm Hg]; mean ejection fraction, 36% [10-50%]), undergoing MV surgery (10 repairs, 2 replacements, and 2 rereplacements) for severe MR, were treated for a median of 24 hours (13-55 hours) preoperatively with intravenous Nesiritide. Expected mortality by EuroSCORE was 26% (7.8-59%) (5 reoperations). Concomitant procedures included tricuspid valve repair (n = 7), coronary artery bypass grafting (n = 5), and left atrial maze procedure (n = 3). Eleven patients received Nesiritide postoperatively during a mean duration of 22 hours (2-80 hours).. Operative mortality was 0%. Prior to surgery after BNP treatment, mean systolic PA pressure dropped to 39 mm Hg (p = 0.0003), pulmonary capillary wedge pressure to 15 mm Hg (p = 0.001), central venous pressure to 6 mm Hg (p = 0.002), and weight by 3.7 kg (p = 0.006). Postoperative median ventilation time was 14 hours (4-48 hours). All other major hemodynamic parameters (systemic blood pressure, heart rate, and cardiac output) remained constant. The treatment was well-tolerated in all patients.. Perioperative use of Nesiritide is safe, and may contribute to improved early outcomes in high-risk patients undergoing MV surgery. This may be due to improved ventricular loading conditions (decreased PA pressures, more effective diuresis) and/or a direct myocardial effect of BNP. Further prospective evaluation of the role of BNP in cardiac surgery is warranted.

Topics: Adult; Aged; Aged, 80 and over; Cardiac Surgical Procedures; Cardiovascular Agents; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mitral Valve; Mitral Valve Insufficiency; Natriuretic Peptide, Brain; Prospective Studies; Ventricular Dysfunction, Left

Topics: Arterial Occlusive Diseases; Cardiovascular Agents; Connective Tissue Diseases; Dyspnea; Hemangioma; HIV Infections; Humans; Hypertension, Pulmonary; Risk Factors

The effects of the novel, selective endothelin-A (ETA) receptor antagonist YM598 on both-side heart failure were investigated. Right-side heart failure secondary to pulmonary hypertension was produced by a single subcutaneous injection of 60 mg/kg monocrotaline, and post-ischemic congestive left-side heart failure (CHF) produced by surgical left coronary artery ligation. In right-side heart failure rats, oral YM598 (0.1 and 1 mg/kg for 4 weeks), but not bosentan (30 mg/kg), significantly inhibited the progression of pulmonary hypertension and the development of right ventricular hypertrophy. YM598 also improved hypoxemia and morphological pulmonary lesions in these rats. In CHF rats, moreover, long-term oral administration of YM598 (1 mg/kg/day for approximately 30 weeks) significantly ameliorated their poor survival rate (P < 0.05). In the measurement of cardio-hemodynamic parameters, YM598 improved the contractile/diastolic capacity of the left ventricle and the preload in the right ventricle to the levels seen in sham-operated rats. YM598 also markedly inhibited both ventricular hypertrophy and pulmonary congestion, as well as lowering high plasma brain natriuretic peptide levels in CHF rats. These findings suggest that YM598 may have a clinical benefit with regards to ameliorating the cardiopulmonary changes of right-side heart failure, and the cardiac dysfunction and mortality/morbidity of CHF.

Topics: Administration, Oral; Animals; Cardiovascular Agents; Coronary Vessels; Disease Models, Animal; Disease Progression; Endothelin A Receptor Antagonists; Heart Failure; Hemodynamics; Hypertension, Pulmonary; Ligation; Male; Monocrotaline; Myocardial Infarction; Pulmonary Heart Disease; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Sulfonamides

A rat model of acute pulmonary air embolism (APAE) was developed. These animals had a higher right ventricular systolic pressure (RVSP) (+ 69% at 15-minute peak, and 21-34% at 30-180 minutes), as well as a reduced mean arterial blood pressure (10-20% at 60-180 minutes), heart rate (20-26% at 60-180 minutes) and PaO2 (9-11% at 30-180 minutes) compared with control rats. The role of the endothelin (ET) system, known to be involved in pulmonary hypertension of various etiologies, was investigated by evaluating the effect of the four classes of ET blockers: ET-converting enzyme inhibitor (ECEi) (CGS 35066), selective endothelin-A receptor antagonist (ETA-Ra) (Atrasentan, ABT-627), endothelin-B receptor antagonist (ETB-Ra) (A-192621) or mixed endothelin-A/endothelin-B receptor antagonist (ETA/B-Ra) (A-182086) in this animal model. All four were effective, to various degrees, at reducing the APAE-induced rise in RVSP. The relative efficacy of those compounds in reducing the acute elevation (15 minutes) of RVSP was ECEi >or= ETA/B-Ra >> ETA-Ra = ETB-Ra. The sustained elevation (30-180 minutes) of RVSP was totally abolished by ECEi and attenuated by other ET blockers with a relative efficacy of ETA-Ra > ETA/B-Ra >or= ETB-Ra. ET receptor antagonists did not affect right ventricular basal tone (control rats) whereas ECEi reduced it by up to 12% after 2 hours. The APAE reduction in mean arterial blood pressure was unaffected by ETARa, was completely normalized by ETB-Ra, but was further reduced by either ETA/B-Ra or ECEi. The basal mean arterial blood pressure in control rats was unaffected by ETA-Ra, was elevated by ETB-Ra, but was depressed by ETA/B-Ra and ECEi. All ET blockers maintained normal oxygen saturation in APAE. These results support a role for ETs in rat APAE, since ET blockers can attenuate the cardiopulmonary deterioration and blood gas exchange. However, modulation of the central hemodynamic profile is more complex and may limit the usefulness of some ET blockers.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Atrasentan; Benzofurans; Cardiovascular Agents; Disease Models, Animal; Embolism, Air; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-Converting Enzymes; Endothelins; Hemodynamics; Hypertension, Pulmonary; Male; Metalloendopeptidases; Organophosphonates; Protease Inhibitors; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Time Factors; Ventricular Dysfunction, Right

The effects of long-term administration of YM598, a selective endothelin-A antagonist, on improving the exercise tolerance of chronic heart failure model rats were examined using a treadmill exercise loading test. Rats were acclimatized to the treadmill apparatus and the coronary artery was ligated to prepare a myocardial infarction-induced congestive heart failure (CHF) model. Starting 10 days postoperatively, when the acute phase of infarction was over, YM598 was administered orally once daily for approximately 25 weeks at a dose of 1 mg/kg. At weeks 20 and 24 the treadmill test was performed. YM598 prolonged running time, which had been shortened as a result of heart failure. The weights, relative to the body weight, of the left and right ventricles and lungs of surviving rats with CHF were significantly greater than those of sham-operated rats, suggesting hypertrophy of the ventricles and congestion of the lungs. Administration of YM598 markedly reduced ventricular hypertrophy and pulmonary congestion. Examination of cardiac function revealed that, in surviving CHF rats, the peak positive first derivative of left ventricular pressure was significantly lower, and left ventricular end-diastolic pressure, right ventricular systolic pressure and central venous pressure were significantly higher in comparison to sham-operated rats. These data demonstrate that, in rats with CHF, the contractile and diastolic capacity of the left ventricle decreased and pulmonary hypertension and systemic congestion occurred. Long-term administration of YM598 improved left ventricular function of CHF rats to the level of sham-operated rats, and reduced the workload placed on the right side of the heart. Histological examination revealed that long-term treatment with YM598 prevented fibrosis of the surviving left ventricular myocardium. In conclusion, long-term administration of YM598 to rats with CHF improved exercise tolerance and inhibited remodeling of cardiac muscles, leading to marked improvement of cardiac function.

Topics: Administration, Oral; Animals; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Endothelin A Receptor Antagonists; Exercise Tolerance; Fibrosis; Heart Failure; Hypertension, Pulmonary; Male; Myocardial Contraction; Myocardial Infarction; Myocardium; Physical Exertion; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Preexisting pulmonary hypertension in pediatric patients is associated with poor outcome after cardiac transplantation because of donor right ventricular dysfunction. To avoid a combined heart-lung transplantation in a 17-year-old patient, we used an intensified pretreatment with intravenous prostacyclin and dobutamine combined with an inhalative therapy with the aerosolized prostacyclin-analog Iloprost. With this regimen, the patient was hemodynamically stabilized for the waiting period of 21 days after which an uneventful cardiac transplantation was performed.

Topics: Adolescent; Aerosols; Cardiovascular Agents; Heart Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Male; Preoperative Care; Severity of Illness Index

Angiopeptin is an analog of somatostatin-14, which has been found to inhibit cellular proliferation in several models of systemic vascular injury. As proliferation plays a major role in pulmonary hypertension, we examined the hypothesis that angiopeptin would inhibit the development of chronic hypoxic pulmonary hypertension in the rat. Angiopeptin was infused intravenously (90-100 microg/kg/day) by minipumps in 10 rats during a 3-week exposure to hypobaric hypoxia and in six normoxic rats. Normal saline was infused in six hypoxic control rats and in seven normoxic control rats. Angiopeptin produced no significant difference in mean pulmonary arterial pressure and resistance, right ventricular weight, or medial thickness of small pulmonary vessels. Vasoconstrictor responses of isolated lungs to acute hypoxia were not affected by angiopeptin. We conclude that angiopeptin, at the high intravenous dose used, does not significantly reduce the development of chronic hypoxic pulmonary hypertension in rats.

Topics: Animals; Cardiovascular Agents; Chronic Disease; Heart Ventricles; Hematologic Tests; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Oligopeptides; Organ Size; Peptides, Cyclic; Perfusion; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Somatostatin

Topics: Atrial Fibrillation; Cardiovascular Agents; Humans; Hypertension, Pulmonary; Male; Middle Aged; Survival Analysis; Time Factors

Isoproterenol, dobutamine, dopamine, and nitroprusside are four vasoactive drugs used to decrease pulmonary arterial pressure and increase cardiac output in newborns, infants, and children with sepsis. Thromboxane A2 likely produces some of the hemodynamic changes in sepsis, and U46619, a thromboxane A2 mimetic, produces similar changes in lambs. We studied the hemodynamic effects of these four vasoactive drugs in 10 spontaneously breathing newborn lambs during an infusion of U46619. After baseline hemodynamic measurements, U46619 (1-2 micrograms/kg/min) was infused to increase pulmonary arterial pressure and to decrease cardiac output. Then, either isoproterenol (0.05-1.0 micrograms/kg/min), dobutamine (5-20 micrograms/kg/min), dopamine (3-30 micrograms/kg/min), or nitroprusside (0.5-10.0 micrograms/kg/min) was infused. Every 10 min, measurements were repeated and the dose increased. U46619 significantly increased pulmonary arterial pressure by 182% and decreased cardiac output by 25% (p less than 0.05). Isoproterenol decreased pulmonary arterial pressure by 30% (p less than 0.05) and increased cardiac output by 25% (p less than 0.05) at low doses, and increased cardiac output by 115% at the maximum dose (p less than 0.05). Dobutamine decreased pulmonary arterial pressure by 11% (p less than 0.05) at low doses, and increased cardiac output by 28% (p less than 0.05) at low doses, and increased cardiac output by 71% at the maximum dose (p less than 0.05). Dopamine did not decrease pulmonary arterial pressure or increase cardiac output. Nitroprusside decreased pulmonary arterial pressure by 11% at the maximum dose (p less than 0.05). Isoproterenol and dobutamine may be more useful than dopamine and nitroprusside in the management of pulmonary hypertension and decreased cardiac output during sepsis.

Topics: Animals; Animals, Newborn; Cardiovascular Agents; Dobutamine; Dopamine; Hemodynamics; Hypertension, Pulmonary; Isoproterenol; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Sheep; Thromboxane A2

Vasodilator therapy in pulmonary hypertension is limited by the lack of an agent selective for the pulmonary circulation. The effects of intravenous prostacyclin and two stable prostaglandin analogs, ZK 36-374 and CL 115,347, were assessed on the preconstricted pulmonary vasculature of the anesthetized dog. During hypoxic vasoconstriction ZK 36-374 (0.4 micrograms/kg per min) markedly reduced pulmonary artery pressure (26 +/- 3 to 13 +/- 1 mm Hg) (p less than 0.05) and pulmonary vascular resistance (6.2 +/- 1.1 to 2.8 +/- 0.2 mm Hg/liter per min) (p less than 0.01). There was no significant effect on cardiac output, aortic pressure or arterial blood gases. Pulmonary vasoconstriction induced by prostaglandin F2 alpha was similarly affected by ZK 36-374, and in this instance the aortic pressure was also reduced (158 +/- 11 to 129 +/- 11 mm Hg) (p less than 0.01). ZK 36-374 (0.2 micrograms/kg per min) was more effective in lowering hypoxic pulmonary vascular resistance (from 6.5 +/- 0.6 to 3.0 +/- 0.3 mm Hg/liter per min) than was prostacyclin (0.75 micrograms/kg per min) (from 6.3 +/- 0.6 to 4.2 +/- 0.4 mm Hg/liter per min) (p less than 0.05) and resulted in a smaller fall in aortic pressure (p less than 0.05). CL 115,347 (1.0 micrograms/kg per min) had no effect on the pulmonary vasculature during normoxia or when preconstricted by prostaglandin F2 alpha or hypoxia, but reduced aortic pressure and total systemic resistance (p less than 0.05). It appears to be a selective systemic vasodilator with no pulmonary vascular activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cardiovascular Agents; Dinoprost; Dogs; Drug Evaluation, Preclinical; Epoprostenol; Female; Hypertension, Pulmonary; Hypoxia; Iloprost; Male; Prostaglandins F; Pulmonary Circulation; Vascular Resistance

Topics: Aminorex; Animals; Cardiovascular Agents; Dogs; Dyspnea; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Prognosis; Pyrrolizidine Alkaloids; Rats

Topics: Adolescent; Adult; Blood Pressure; Cardiovascular Agents; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Inhalation Therapy; Pulmonary Circulation; Thromboembolism; Vasoconstriction

Topics: Cardiovascular Agents; Humans; Hypertension; Hypertension, Pulmonary; Mitral Valve Stenosis; Muscle Relaxants, Central