An uncommon but lethal cause of right heart failure
While not as common as left heart failure, right heart failure, too, is a major contributor to cardiovascular morbidity and mortality. Pulmonary arterial hypertension (PAH), while a relatively uncommon disease, carries a poor prognosis even today as patients succumb to right heart failure.
In recent decades, the epidemiology of PAH has altered noticeably. Early episodes of PAH were mostly reported at younger ages and predominantly in women with the survival rates of 1-3 years. However, the most current registry data demonstrates the patients affected by PAH are older and have better survival rates with new and combination therapies. Mean age at the diagnosis presently has been estimated to be 50 years, and recent longitudinal data from patients receiving combination therapy show that the 3-year survival rate in PAH may be as high as 84 percent compared with 48 percent from the original National Institutes of Health registry on idiopathic PAH (1980-1985). Overall prevalence based on a variety of registries ranges from 5-52 per million adults.
The symptoms PAH patients experience are dyspnea on exertion, exercise intolerance, fatigue and syncope. Although these symptoms are not unique to PAH, they can help support the diagnosis. Upon physical examination, abnormal pulse oximetry, tricuspid regurgitation, lower-extremity edema and signs of right-heart failure can be a few of the signs suggestive of PAH.
Initially, a noninvasive test such as an echocardiogram can be performed in patients presenting with any of these signs and symptoms. This should always be performed when PAH is suspected.
An estimated systolic pulmonary arterial pressure of 35 to 40 mmHg is suggestive of PAH and may prompt further testing, most importantly a right heart catheterization. Unfortunately in the modern era, the diagnosis of PAH remains delayed as evidenced by data from the REVEAL registry, where 20 percent of patients had symptoms for >2 years before diagnosis. Mean interval between onset of symptoms and diagnosis of PAH in other contemporary registries in Western Europe ranged from 18-32 months.
Clinical manifestations of PAH result from a reduction in the cross-sectional area of the pulmonary arteries driven by a combination of vasoconstriction, thrombosis, inflammation and remodeling of the pulmonary artery wall. In turn, this results in a progressive elevation in pulmonary vascular resistance and chronic elevation in right ventricular afterload. This induces right ventricular enlargement and subsequent failure.
Until the 1990s, PAH was managed with supportive treatments directed against symptoms, which included anticoagulation therapy, diuretics, oxygen and digoxin The first medical therapy, epoprostenol, was commercially available in 1996; however it could only be delivered by continuous infusion.
However, over the past 20 years, advances in our understanding of the pathogenesis of the disease have led to development of targeted therapeutics for PAH. Currently, there are 12 PAH medications approved by the FDA, including oral, inhaled and infused options.
The therapies include a soluble guanylate cyclase stimulator (riociguat); endothelin receptor antagonists (e.g., ambrisentan, bosentan and macitentan); phosphodiesterase-5 inhibitors (e.g., sildenafil and tadalafil); and prostacyclin analogs (e.g., epoprostenol, treprostinil, iloprost, and selexipag).
Combining drugs from different classes is now considered the standard of care and has been demonstrated to improve outcomes. Furthermore, the current treatment paradigm is the early use of combination therapy, often at the time of diagnosis, particularly in patients with severe disease.
Treatment goals for patients with PAH are to improve functional class, improve 6-minute walk distance to > 440 meters, achieve normalization of right ventricular size and function on an echocardiograph, achieve a decrease or normalization of B-type natriuretic peptide and improve hemodynamics. Additional treatment goals include preventing disease progression, increasing patient survival and improving health-related quality of life.
Despite the relative “golden era” for PAH given the improvements in survival and therapeutic options, PAH remains a deadly cause of right heart failure that continues to present diagnostic delays and challenges. Efforts to improve healthcare provider and patient awareness remain paramount as is getting PAH patients to expert referral centers for optimal treatment and diagnosis.
Chad E. Miller, M.D., earned undergraduate degrees in biology and philosophy from the University of Alabama at Birmingham. He completed his medical degree at the University of Alabama School of Medicine in Birmingham, where he also completed his internal medicine residency and his pulmonary and critical care fellowship training, during which he also did additional subspecialty training in pulmonary hypertension and echocardiography. Dr. Miller is the Director of the Pulmonary Hypertension program at Piedmont Physicians Georgia Lung.