Natural History Of Pulmonary Arterial Hypertension Research Articles

Pulmonary Arterial Hypertension: Advancing Insights into a Historically Neglected Disease

Pulmonary arterial hypertension (PAH) is a rare spectrum of closely related diseases with myriad genetic, infectious, toxic, and immunologic triggers characterized by pathologic pulmonary vascular remodeling. While the natural history of PAH is marked by progressive dyspnea, hypoxia, right ventricular failure, and death, modern insights into disease pathogenesis, combined with breakthroughs in therapeutics, has greatly improved morbidity and time to disease worsening over the past two decades. Traditionally thought of as a disease of imbalance between vasodilators, such as nitric oxide and prostacyclin, and vasoconstrictors such as endothelin-1, more recent investigations have revealed important roles for perturbations in cellular metabolism, fibroblast activity, extracellular matrix maintenance, and apoptosis which contribute to pulmonary artery smooth muscle cell proliferation. Careful history and physical exam, along with echocardiography and right heart catheterization, remain essential for accurate workup and diagnosis. Cardiopulmonary exercise testing, cardiac magnetic resonance, and genetic testing have important ancillary roles. The number of approved pulmonary vasodilator therapies for PAH continues to expand, with evidence demonstrating the survival benefits of up-front combination therapy. Future prospects of next generation therapies that address the molecular origins of disease combined with comprehensive molecular profiling may usher in a new era of precision medicine for PAH. This review contains 7 figures, 5 tables, and 57 references. Keywords: pulmonary hypertension, vascular biology, therapeutics, hemodynamics, epidemiology, exercise physiology, genetic basis of disease, connective tissue disease, cardiac magnetic resonance imagining

Pulmonary Arterial Hypertension: Advancing Insights into a Historically Neglected Disease

Pulmonary arterial hypertension (PAH) is a rare spectrum of closely related diseases with myriad genetic, infectious, toxic, and immunologic triggers characterized by pathologic pulmonary vascular remodeling. While the natural history of PAH is marked by progressive dyspnea, hypoxia, right ventricular failure, and death, modern insights into disease pathogenesis, combined with breakthroughs in therapeutics, has greatly improved morbidity and time to disease worsening over the past two decades. Traditionally thought of as a disease of imbalance between vasodilators, such as nitric oxide and prostacyclin, and vasoconstrictors such as endothelin-1, more recent investigations have revealed important roles for perturbations in cellular metabolism, fibroblast activity, extracellular matrix maintenance, and apoptosis which contribute to pulmonary artery smooth muscle cell proliferation. Careful history and physical exam, along with echocardiography and right heart catheterization, remain essential for accurate workup and diagnosis. Cardiopulmonary exercise testing, cardiac magnetic resonance, and genetic testing have important ancillary roles. The number of approved pulmonary vasodilator therapies for PAH continues to expand, with evidence demonstrating the survival benefits of up-front combination therapy. Future prospects of next generation therapies that address the molecular origins of disease combined with comprehensive molecular profiling may usher in a new era of precision medicine for PAH. This review contains 7 figures, 5 tables, and 57 references. Keywords: pulmonary hypertension, vascular biology, therapeutics, hemodynamics, epidemiology, exercise physiology, genetic basis of disease, connective tissue disease, cardiac magnetic resonance imagining

ATORVASTATIN IN PULMONARY HYPERTENSION (APATH) STUDY

ObjectivesStatins have been shown to both prevent and attenuate pulmonary hypertension in animal models. This study investigates the potential therapeutic benefits of atorvastatin as an affordable treatment for pulmonary hypertension...

Atorvastatin in Pulmonary Arterial Hypertension (APATH) study

Statins have been shown to both prevent and attenuate pulmonary hypertension in animal models. This study investigates the potential therapeutic benefits of atorvastatin as an affordable treatment for pulmonary hypertension patients. 220 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were randomised, double-blind, to receive atrovastatin 10 mg daily or matching placebo in addition to supportive care. At 6 months, 6-min walk distance decreased by 16.6 m in the atorvastatin group and 14.1 m in the placebo group. The mean placebo-corrected treatment effect was -2.5 m (95% CI: -38-33; p=0.96), based on intention to treat. A small nonsignificant increase in pulmonary vascular resistance and fall in cardiac output was seen in both treatment groups. There was no significant difference in the proportion of patients who improved, remained stable or showed a deterioration in World Health Organization functional class between atorvastatin and placebo treatments. Nine patients died in the atorvastatin group and 11 in the placebo group. Serum cholesterol levels fell significantly on atorvastatin treatment. Discontinuation rates were 23.2% and 26.9% on atorvastatin and placebo, respectively. Atorvastatin 10 mg daily has no beneficial effect on the natural history of PAH or CTEPH over 6 months.

Assessment of endpoints in the pediatric population: congenital heart disease and idiopathic pulmonary arterial hypertension

Children with pulmonary arterial hypertension (PAH) are a distinct patient population, requiring a different approach to disease management and treatment. In developed countries, pulmonary hypertension is more common in children than adults. It is frequently associated with congenital heart disease. A smaller number of children have rapidly progressive idiopathic PAH. The natural history of PAH and the response to treatment can differ in children and adults. In idiopathic PAH, for example, infants and younger children may present with fatigue and impaired growth, as well as syncope, whereas teenagers may present with symptoms similar to those seen in adults. Aggressive therapy is usually required early in young children because the disease can progress more rapidly. Thus far, no randomized trial of a pulmonary hypertension-specific drug in pediatric patients has been published. Trial methodology needs refining with selection of the most appropriate endpoints. Recent studies suggest that treatment with the dual endothelin receptor antagonist, bosentan, can benefit children. Treatment response can be difficult to quantitate in children. There are challenges involved in performing and interpreting the traditional treatment endpoints used in adults: primarily exercise capacity, but also functional class and quality of life. It may be possible to overcome these problems in future pediatric trials by using a composite endpoint, time to clinical worsening, as in the adult PAH population. A composite endpoint uses parameters such as symptomatic progression and the need for additional therapy, hospitalization, transplantation, or death.

A MULTIDISCIPLINARY OUT-PATIENT APPROACH TO PULMONARY ARTERIAL HYPERTENSION

PURPOSE: Pulmonary arterial hypertension (PAH) is a clinical syndrome characterized by progressive increases in pulmonary vascular resistance, leading to marked increases in pulmonary artery pressure, exercise intolerance, and ultimately death. The natural history of PAH is heterogeneous, with more rapid clinical deterioration in patients with a greater degree of right ventricular dysfunction (AJRCCM 2006;174:1034–41). Many teams interact with PAH patients, including specialists in pulmonary, cardiology and rheumatology. Hypothesis: We questioned whether formation of a comprehensive PAH Center, with specialists from pulmonary, cardiology and rheumatology, would minimize traditional delays of both scheduling and diagnosing PAH.

Changing the Prognosis of Pulmonary Arterial Hypertension: Impact of Medical Therapy

Pulmonary arterial hypertension (PAH) is a progressive arteriopathy of the pulmonary circulation that can affect a wide group of patients. Presentation and natural history of PAH are intimately linked to progressive right ventricular failure. Historically, survival in PAH has been poor, especially for patients with PAH associated with progressive systemic sclerosis and human immunodeficiency virus. Oral, subcutaneous, and intravenous therapies that have emerged during the last decade can improve symptoms and hemodynamics. This review explores the impact of these therapies on prognosis in PAH, which ultimately rests on the ability to reverse the pulmonary arteriopathy and preserve right ventricular function.

Efficacy and safety of sildenafil citrate in Pulmonary Arterial Hypertension (PAH): Results of a multinational, randomized, double-blind, placebo-controlled trial

The purpose of this study was to evaluate the efficacy and safety of sildenafil, a phosphodiesterase 5 inhibitor, in patients with PAH. In this double-blind, placebo-controlled study, 278 patients with PAH were randomized to oral placebo or sildenafil (20, 40, or 80 mg) 3 times daily. The primary endpoint was change in 6-minute walk distance from baseline to Week 12. Secondary endpoints were change from baseline in mean pulmonary artery pressure (MPAP), time from randomization to clinical worsening, and change from baseline in Borg dyspnea score. The 6-minute walk distance increased in all sildenafil groups compared with placebo; mean placebo-corrected treatment effects were 45 m (99% confidence interval [CI], 21–70; P<0.001), 46 m (99% CI, 20–72; P<0.001), and 50 m (99% CI, 23–77; P<0.001) for 20, 40, and 80 mg sildenafil 3 times daily, respectively. All sildenafil doses reduced MPAP at Week 12; mean placebo-corrected treatment effects were −2.7 mmHg (95% CI, −5.4 to −0.1; P=0.021) for 20 mg, −3.0 mmHg (95% CI, −5.3 to −0.7; P=0.006) for 40 mg, and −5.1 mmHg (95% CI, −7.5 to −2.6; P<0.001) for 80 mg sildenafil. Compared with placebo, there were trends towards reductions in the incidence of clinical worsening events (in particular, hospitalizations) and improvement in the level of dyspnea during exercise in the sildenafil-treated groups. Adverse events were of mild to moderate severity, consistent with the natural history of PAH and the established safety profile of sildenafil administered for erectile dysfunction. This study confirms the efficacy and safety of sildenafil in the treatment of patients with PAH.