Pulmonary Hypertension

The pulmonary vasculature accommodates cardiac output at pressures less than one-quarter of the systemic circulation because it is a low-resistance, high-capacitance system. In pulmonary hypertension (PH), various conditions lead to increased pulmonary arterial pressures, which result in right ventricular dysfunction. Patients develop symptoms of right-sided heart failure because the right ventricle, which is typically thin-walled, needs to exert against the increased pulmonary arterial pressure to maintain cardiac flow. Pulmonary arterial hypertension is defined by increased mean pulmonary arterial pressure (mPAP >20 mm Hg at rest).

A number of conditions can lead to PH, including drug and toxin exposure, infections, congenital heart diseases, genetics, connective tissue disorders, and portal hypertension. The most common causes of PH are left-sided heart failure and hypoxemic lung disease.

Classification

PH is classified into five groups based on etiology, pathophysiology, and treatment as described in the figure below. Differentiating the etiology of PH is key to determining a management approach. Idiopathic pulmonary arterial hypertension (IPAH) is only diagnosed when the other conditions listed below are ruled out.

The PH classification based on the 2018 meeting of the World Symposium on Pulmonary Hypertension is shown in the figure below, along with the clinical characteristics and hemodynamic profile of each group.

Abbreviations: COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; ILD, interstitial lung disease; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary arterial pressure; OSA, obstructive sleep apnea; PAH, pulmonary arterial hypertension; PAWP, pulmonary arterial wedge pressure; PCH, pulmonary capillary hemangiomatosis; PVOD, pulmonary veno-occlusive disease; PVR, pulmonary vascular resistance; RV, right ventricular; WU, Wood units(Source: Pulmonary Arterial Hypertension. N Engl J Med 2021.)

Assessment

History: A careful history of symptoms and medical comorbidities can help guide the diagnosis. Early in the disease, patients are asymptomatic, but as the disease progresses, patients may experience exertional dyspnea, palpitations, chest pain, presyncope/syncope, and fatigue. Given the range of associated comorbidities, patients should be asked about history of chronic cardiac/lung disease or venous thromboembolism, symptoms of connective tissue disease, chronic lung infection, risk factors for HIV infection, and culprit medication use (e.g., fenfluramine, chemotherapy, interferon, or illicit drugs such as cocaine and methamphetamines).

Physical examination: Patients should be evaluated for evidence of right-sided heart failure. In earlyPH, the patient may be relatively asymptomatic. The examination may be notable for the following:

• loud pulmonic valve (P2; the pulmonic valve component of the second heart sound heard over the left upper sternal border, which may become palpable as the disease progresses)

• signs of right ventricular (RV) failure:

  • holosystolic tricuspid regurgitation murmur

  • elevated jugular venous pressure (with prominent A wave)

  • right ventricular parasternal heave

  • right sided S3 or S4

  • lower-extremity edema, ascites, and a pulsatile liver, which may be evident when there is significant tricuspid regurgitation

Investigations

Right-heart catheterization: Definitive diagnosis of PH is made via right-heart catheterization and requires hemodynamic measurements of mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and the pulmonary capillary wedge pressure (PCWP). A diagnosis of idiopathic pulmonary arterial hypertension is supported by a resting mPAP >20 mm Hg with an elevated PVR ≥3 Wood units and a normal PCWP (e.g., ≤15 mm Hg).

Noninvasive tests: In addition to right-heart catheterization, some noninvasive tests may be indicated to determine the etiology of disease as listed in the World Health Organization (WHO) classification system above. In general, most patients suspected of having PH will receive a transthoracic echocardiogram as an initial screen for left ventricular function and an estimate of right-sided cardiac pressure. Other tests that should be considered in the evaluation of all patients for PH include:

Treatment

Therapy for PH is multifactorial, requiring management of the underlying etiology, treatment of the pathophysiology of disease (e.g., PH-specific therapy), and the consequent right-heart dysfunction.

PH group-specific therapy should first be optimized in all patients if possible. For example:

• Group 1 disease: Treatment involves three targets for treatment aimed at vasodilation: stimulating the nitric oxide-cyclic guanosine monophosphate biological pathway, increasing prostacyclin effects on receptors, and antagonizing the endothelin pathway. Results in three large clinical trials and subsequent meta-analysis have demonstrated that initial treatment with combination therapy improved clinical outcomes as compared with initial treatment with a single agent.

  • Phosphodiesterase inhibitors such as sildenafil and tadalafil are phosphodiesterase type 5 inhibitors that exert a vasodilatory effect through the nitric oxide pathway.

  • Endothelin-receptor antagonists such as ambrisentan, bosentan, and macitentan exert their effects by counteracting endothelin-1, a vasoconstrictor and stimulator of smooth-muscle cells.

  • Prostacyclin agonists such as epoprostenol, treprostinil, and selexipag exert their effects by stimulating production of cyclic adenosine monophosphate (cAMP) and inducing endothelial relaxation.

  • Calcium-channel blockers may be used in select patients with Group 1 PH who are deemed “vasoreactive” during testing at the time of right-heart catheterization.

• Groups 2 and 3 disease: The underlying cardiac or pulmonary conditions should be managed to prevent further progression of PH and symptoms of right-sided heart failure. In patients with PH due to interstitial lung disease (ILD), evidence suggests that inhaled treprostinil improves exercise capacity.

• Group 4 disease: Patients should receive anticoagulation and surgical consultation for possible thromboendarterectomy. In patients with more-advanced cardiac dysfunction, careful diuresis is needed to maintain euvolemia and supplemental oxygen is indicated to prevent chronic hypoxemia.

• Group 5 disease: In general, treatment of group 5 PH is directed toward treating the underlying condition. Consideration may be given to pulmonary arterial hypertension therapies on a case-by-case basis and requires specialist consultation.