Our cover story this month takes on the daunting task of describing the complexities of pulmonary hypertension (PH). The story emphasizes that patients with PH need early recognition and treatment. It also points out what most of us would agree upon: patients with PH often fall into diagnostic and therapeutic cracks. Patients with PH complain of nonspecific symptoms (fatigue, shortness of breath on exertion, mild edema, dizziness, chronic cough, palpitations) that are often attributed to poor conditioning or aging. Who should take on such patients? Pulmonologists? General cardiologists? Pulmonary surgeons? Cardiac surgeons? Only specialized "centers of excellence"? All five?

PH is indeed like a Gordian knot! Alexander the Great famously cleft the Gordian knot with a single swipe of his sword, making him ruler of Asia and establishing a straightforward strategy for problem solving. Unfortunately, the problem of PH does not lend itself to such an easy dissection. Even the WHO Grouping for PH is not entirely clear: Group 1 refers to pulmonary arteriolar medial and intimal proliferation (PAH); Group 2 is due to left heart disease and/or aortic or mitral valve abnormalities (PH-LHD); Group 3 is due to chronic pulmonary disease and hypoxia (e.g., sleep apnea); Group 4 is due to recurrent (usually small, asymptomatic) pulmonary emboli (chronic thrombo-embolic pulmonary hypertension (CTEPH), and Group 5 is associated with unknown cause(s). Thus, for physicians faced with trying to make an accurate diagnosis, it seems unravelling the cause(s) is a proper strategy.

The trusty echocardiogram provides information as an initial screening tool – it can estimate pulmonary artery pressure and certainly helps to understand structural abnormalities that might be contributors. But the echo, if abnormal, should be followed by a right heart catheterization to confirm the diagnosis. A right heart catheterization can also help determine the important difference between primary pulmonary artery pathology (PAH) and PH that is secondary and associated with left heart diseases (PH-LHD) that can be structural, coronary or myocardial. Once a diagnosis of PH is made, then what?

The cover story further outlines how diverse the therapies are for the various subgroups of patients with PH. And highlights what may be "obvious" first-line therapy, such as pulmonary vasodilators for treatment of PH-LHD, may actually be detrimental. Caveat emptor! What further frustrates clinical cardiologists and/or pulmonologists who choose to take on patients with PH is that aside from complex decisions regarding therapy, the cost of the new therapeutic drugs may be prohibitively expensive. In short, a single, specific therapy simply is not available, is expensive, and the complexity of interventional therapies as well as therapeutic decisions means that patients must often be referred to centers specializing in such treatments.

But there is good news as well. New therapeutic agents have been approved by the U.S. Food and Drug Administration for treatment of PH and its many forms. Even pulmonary artery surgery to relieve clot burden or interventional balloon therapies are making a debut. Sotatercept is the latest drug darling that works! PAH can now be treated with sotatercept, which combats pulmonary artery/arteriole cellular proliferation that is the cause of PAH. Sotatercept improves the balance between pro-proliferative and anti-proliferative signaling in the pulmonary arteries, decreasing pulmonary vascular resistance in patients receiving the drug vs. placebo – so much so that clinical trials were stopped early for demonstrated multiple benefits.

Two important final thoughts. As a bonus to the cover story, this month's Cardiology includes a review of PH and shunting in pregnancy, which describes the pathophysiology and what constitutes best care of such patients, along with a case study. It's a must-read! Finally, remember COVID, and "long" COVID? COVID is associated with a prothrombotic state – specifically venous thromboembolism resulting in PH (CTEPH). "Long" COVID may, in some patients, be due to CTEPH! Now there is riociguat, which activates soluble guanylate cyclase and increases levels of cyclic guanosine monophosphate, leading to an increase in sensitivity to nitrous oxide and relaxation of vascular smooth muscle cells, thus reducing pulmonary artery pressure.

The Gordian knot for PH is far from unravelled – but it seems help is on the way.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Pulmonary Hypertension, Hypertension

Keywords: Cardiology Magazine, ACC Publications, Hypertension, Pulmonary, Pulmonary Artery, Pulmonologists, Cardiac Catheterization, Mitral Valve