Pulmonary Hypertension PDF

Preface

Pulmonary Hypertension will provide a comprehensive review of clinical and investigative aspects of pulmonary hypertension including idiopathic (primary) and secondary forms. Management of pulmonary arterial hypertension (PAH) is difficult and has generally been managed by a few cardiologists or pulmonologists. Given the rarity of PAH and the need for right-heart catheterization (RHC) to substantiate the diagnosis (i.e., a mean pulmonary artery pressure above 25 mmHg), most practicing clinicians have inadequate personal experience to deal with these diverse disorders. This book enlists internationally recognized experts to discuss controversies and evolving concepts in the diagnosis and management of pulmonary hypertension. The first nine chapters provide an overview of PAH, including classification and epidemiology, pathology, pathogenesis, genetics, and diagnosis. Chapters 10 through 21 discuss the most important causes of pulmonary hypertension, starting with idiopathic pulmonary arterial hypertension (IPAH). Individual chapters review PAH complicating connective tissue diseases (CTD), congenital heart diseases, human immunodeficiency virus (HIV) infection, and a host of other disorders. Chapters 22 through 32 discuss treatment. Separate chapters are included for each of the pharmacological and surgical therapies [including lung transplantation (LT)] for PAH. Importantly, separate chapters are devoted to each of the pharmacological agents (or classes of agents) used to treat PAH. This provides a detailed understanding of mechanisms, toxicities, and efficacy of each of these agents. A separate chapter by Drs. Rubin and Gaine addresses in detail the role of combination therapies, novel agents, and future directions. Additionally, the management of PAH in specific patient populations (e.g., pregnancy, the pediatric population, and critically ill patients in intensive care units) is discussed in chapters 31–33. The final chapter by Dr. Peacock discusses appropriate end points and designs for future therapeutic trials.

PAH is a disease of the small pulmonary arteries characterized by vascular proliferation and remodeling. Progressive increase in pulmonary vascular resistance ultimately leads to right ventricular failure and death. In the 1970s, major causes of pulmonary hypertension are recognized including the so-called "secondary" causes [e.g., congenital heart disease, collagen vascular disease (typically scleroderma), chronic pulmonary thromboembolism, or endstage lung disease] and IPAH. In the 1960s, a link between PAH and the appetite suppressant aminorex fumarate was established in Europe. Subsequent studies implicated other toxic agents (e.g., fenfluramine, toxic rapeseed oil) in some patients with PAH. Within the past two decades, it has increasingly been recognized that PAH may complicate diverse diseases such as HIV infection, hepatic cirrhosis, hemolytic anemia, interstitial lung disorders, etc. In 1998, the World Symposium on Primary Pulmonary Hypertension proposed a classification schema and definition for PAH. Within the past few years, further insights into familial cases of PAH were gained, when mutations in the coding region of the gene for bone morphogenetic protein receptor type 2 (BMPPR2) were discovered.

Most of the data on treatment of PAH has been gleaned from studies in IPAH, a rare disorder (with an incidence of only two cases per million) that predominantly affects women in the prime of life. In the 1980s, median survival after diagnosis was 2.8 years. The use of intravenous (IV) epoprostenol in the mid-1990s led to improvements in clinical outcomes, quality of life (QoL), and survival. Within the past decade, several additional agents have been added to the therapeutic armamentarium for IPAH. However, these therapies are not curative. Further, the relevance and application of these agents for causes of PAH other than IPAH have not been rigorously studied.

Given the devastating nature of the disease, initial treatment in the 1970s and 1980s involved the use of vasodilators, diuretics, and anticoagulants, with limited efficacy. A small subset of patients responded to vasodilators (principally calcium channel blockers), but for most patients, the course was inexorable, leading to death within two to five years of onset. By the 1990s, it was clear that vasoconstriction is only one component of this disease. Vascular remodeling is a cardinal feature and may lead to irreversible destruction and distortion of pulmonary vessels. The pathogenesis of PAH reflects deficiencies of pulmonary vasodilators (particularly nitric oxide and prostacyclin) with overexpression of endothelin-1, a potent vasoconstrictor and mitogen. Novel therapeutic strategies targeting vascular remodeling have improved the prognosis of this once inevitably fatal disorder. IV epoprostenol (prostacyclin) was first used to treat PAH in the early 1980s and approved for use in the United States and several European agencies in the mid-1990s. IV prostacyclin remain the gold standard for severe PAH. However, IV epoprostenol is logistically difficult (requires a central line and continuous infusion) and expensive (>$60,000 annually) and has potentially serious adverse effects. Subsequently, additional agents were developed, including subcutaneous treprostinil, inhaled iloprost, endothelin-1 receptor antagonists (e.g., bosentan, sitaxsentan, and ambrisentan), and phosphodiesterase type 5 inhibitors (e.g., sildenafil, tadalafil). These agents are expensive and are associated with significant adverse effects. Importantly, optimal therapy has not yet been established; randomized studies comparing one agent versus another are lacking. Further, clinical trials comprised primarily patients with IPAH and (in some studies) associated PAH such as patients with systemic sclerosis.

Whether conclusions from these pivotal studies can be extrapolated to PAH from diverse other causes (e.g., HIV infections, congenital heart diseases, portopulmonary hypertension, etc.) has not been well established. Currently, prostacyclin derivatives have a central role in treating patients with severe PAH. Phosphodiesterase type 5 inhibitors and endothelin-1 receptor antagonists may be of value in patients with less severe disease or to augment the effects of prostacyclin. However, responses to these diverse pharmacological agents are incomplete and may not be sustained. Combinations of therapies have been used, with some successes, but are very expensive and require additional studies to demonstrate that they affect mortality. Additionally, each of these agents is expensive (typically >$40,000 annually), so irresponsible or inappropriate use will lead to escalating health care costs. Patients failing medical therapy may be candidates for LT. However, LT has significant morbidity and mortality. Who to list for LT and when to list are difficult decisions. Delays in listing may result in severe, even fatal, right-heart failure. Additional surgical techniques such as pulmonary endarterectomy are curative for the subset of patients with proximal chronic thromboembolic disease.

Given the rarity of IPAH, many physicians have limited experience with this disease, and appropriate management remains controversial. Further, optimal techniques to diagnose PAH have not been clarified. Right-heart catheterization is the "gold standard" but is invasive. Echocardiography is of major interest to screen for pulmonary hypertension. It gives an estimate of pulmonary arterial pressure and assesses right ventricular function, but it has several limitations. Additional diagnostic studies include magnetic resonance imaging, blood tests (e.g., brain natriuretic peptide), and physiological tests (e.g., six-minute walk tests, cardiopulmonary exercise tests, etc.). Further, optimal tests or markers to monitor response to therapy or the course of the disease have not been well defined. Each of these questions and issues will be addressed in this comprehensive book.

This book will provide a global perspective of the current and future management of these diverse pulmonary vascular disorders. The book will be of great interest to pulmonologists, cardiologists, intensivists (physicians and nurses), pathologists, radiologists, and basic scientists with an interest in the pulmonary vasculature and PAH.