What is Pulmonary Hypertension?

Pulmonary hypertension is a substantial global health issue. All age groups are affected, with growing importance in its effect on the elderly. Present estimates suggest a prevalence of ~1% of the global population, which increases up to 10% in individuals 65 years or older. Delayed, incomplete, and inappropriate diagnoses of pulmonary hypertension are common and reported in as many as 85% of at-risk patients. Sadly, development of pulmonary hypertension is associated with worsening health and increased risk of death.

How do you define and diagnose pulmonary hypertension?

Pulmonary hypertension is defined by either a mean pulmonary artery pressure at rest of 20 mm Hg or more as measured by a right heart catheterization (RHC) or a right ventricular systolic pressure (RVSP) of 30 mm Hg or more as measured by an echocardiogram. An RHC is the diagnostic gold standard and an essential component in the evaluation of pulmonary hypertension. While an echocardiogram can be a useful screening tool for the presence of pulmonary hypertension, it only provides an estimate of RVSP. An RHC is absolutely required to confirm the diagnosis, assess the severity of hemodynamic impairment, provide risk assessment, and guide pulmonary hypertension-specific therapy.

The threshold to perform a left heart catheterization (LHC) in addition to an RHC should be low in patients with risk factors for heart disease and when the measurement of left ventricular end-diastolic pressure (LVEDP) is important to avoid potential misclassification of pulmonary hypertension.

What are the hemodynamic definitions?

There are three major hemodynamic definitions of pulmonary hypertension: 1) pre-capillary, 2) isolated post-capillary, and 3) combined pre- and post-capillary. These hemodynamic definitions are determined according to various combinations of pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), diastolic pressure gradient (DPG), transpulmonary pressure gradient (TPG), cardiac output (CO), and pulmonary vascular resistance (PVR). These hemodynamic definitions can be determined at the time of an RHC, again underscoring the importance of an RHC in the diagnosis and management of pulmonary hypertension, to allow for categorizing into a specific World Health Organization (WHO) group.

What are the clinical classifications or groups (i.e. WHO groups)?

Additional laboratory, diagnostic, and imaging tests are completed to further characterize the possible etiology of pulmonary hypertension. The additional tests include, but are not limited to:

• Blood tests and immunology
• Electrocardiogram
• Chest X-ray
• 6-minute walk test
• Echocardiogram with bubble study
• Abdominal ultrasound
• Pulmonary ventilation/perfusion (V/Q) scan
• High-resolution CT scan without contrast
• Pulmonary function test with arterial blood gases
• Sleep study
• Genetic testing, in select patients

At this point, all the information obtained from the RHC and additional testing listed above allows for categorizing into a specific WHO group. The clinical classification of pulmonary hypertension is intended to categorize multiple clinical conditions into five groups according to their similar clinical presentation, pathological findings, hemodynamic characteristics, and treatment strategy. The classifications or groups are defined by the World Health Organization (WHO) and are referred to as WHO group 1-5:

WHO Group 1 (due to pulmonary arterial hypertension [PAH])

• idiopathic, heritable, drug- or toxin-induced, and associated with connective tissue disease, HIV infection, portal hypertension, congenital heart disease, or schistosomiasis

• pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH)

• diagnosing PAH requires exclusion of comorbid cardiac, lung, thromboembolic, and other diseases that predispose to increasing pulmonary artery pressures

WHO Group 2 (due to left-sided heart disease)

• left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular heart disease, or specific congenital abnormalities

WHO Group 3 (due to lung disease and/or hypoxia)

• chronic obstructive pulmonary disease, interstitial lung disease, other mixed restrictive or obstructive lung disease, sleep-disordered breathing, or chronic exposure to high altitude

WHO Group 4 (due to chronic thromboembolic pulmonary hypertension [CTEPH] and other pulmonary artery obstructions)

• chronic thromboembolic pulmonary hypertension or other pulmonary artery obstructions (e.g., angiosarcoma, other intravascular tumors, arteritis, congenital stenoses, and parasites)

WHO Group 5 (due to unclear and/or multifactorial mechanisms)

• renal disease and various hematological, systemic, or metabolic disorders

Certain WHO groups are more common than others. For example, left-sided heart disease (i.e. WHO group 2), particularly heart failure with preserved ejection fraction (HFpEF), is becoming a leading cause of pulmonary hypertension, probably affecting 5-10% of individuals aged 65 years or older. The bottom line is that determining your WHO group classification is critically important to guide subsequent treatment strategies.

What is exercise-induced pulmonary hypertension?

As stated above, the current definition of pulmonary hypertension is a mean pulmonary artery pressure at rest of 20 mm Hg or more. However, patients with occult or milder forms of pulmonary vascular disease or left-sided heart disease might fail to meet this resting threshold but still develop shortness of breath or dyspnea with exertion and exercise. Exercise-induced changes in mean pulmonary artery pressure and pulmonary capillary wedge pressure may be helpful in certain clinical situations, 1) differentiating WHO group 1 versus WHO group 2, 2) identifying symptomatic left-sided heart disease, and 3) identifying symptomatic exercise-induced WHO group 1. In these situations, an exercise RHC (i.e. a symptom-limited supine or upright bicycle with invasive hemodynamic monitoring) may be required for further evaluation. Here is an example of a typical set-up for a supine bicycle in a heart catheterization laboratory:

How do you risk stratify and provide a risk assessment?

Regular risk assessment of patients with pulmonary hypertension is strongly recommended. A comprehensive risk assessment is required since there is no single determinant that provides enough prognostic information. The most important question to be addressed at every clinic visit, is the patient compatible with a good long-term prognosis (i.e. meet low-risk criteria)? To answer this question, a structured approach is needed, and all pulmonary hypertension specialists should have a checklist (see below) to help provide a comprehensive risk assessment:

Achieving low clinical risk also functions as the primary treatment goal, thus treatment should be tailored to achieve and maintain a low-risk status.

What is the treatment?

There is supportive therapy and specific drug therapy (i.e. pulmonary hypertension-specific therapy) for pulmonary hypertension.

Supportive therapy includes:

• Oral anticoagulants, in select patients
• Diuretics, in patients with fluid overload
• Oxygen, in patients with correctable oxygen desaturation
• Digoxin, in patients with atrial tachyarrhythmias
• Iron substitution, in patients with iron deficiency

Pulmonary hypertension-specific therapy includes:

• Calcium channel blockers (CCBs), only in select patients: nifedipine and amlodipine
• Phosphodiesterase type 5 (PDE-5) inhibitors and soluble guanylate cyclase (sGC) stimulators: sildenafil, tadalafil, and riociguat
• Endothelin receptor antagonists (ERAs): bosentan, ambrisentan, and macitentan
• Prostacyclin analogues and prostacyclin receptor agonists (i.e. prostanoids): epoprostenol, iloprost, treprostinil, and selexipag

Over the past several years, some important trends have appeared in the management of pulmonary hypertension. The phosphodiesterase type 5 (PDE-5) inhibitors or soluble guanylate cyclase (sGC) stimulators, endothelin receptor antagonists (ERAs), and prostaglandin replacement therapies (i.e. prostanoids), administered as monotherapy or in sequential combination, now have proven effectiveness in the treatment of pulmonary hypertension. Also, findings from the AMBITION trial mark an exciting shift in pulmonary hypertension-specific therapy by providing evidence in favor of initial combination therapy over monotherapy for newly diagnosed pulmonary hypertension patients.

What is the prognosis?

Pulmonary hypertension has evolved into a treatable disease with decreased morbidity and improved survival. The REVEAL registry, which tracks patients with PAH in the United States, reported that the 1- and 5-year survival rates of patients were 90% and 65%, respectively. Similar findings were observed in Spain, the United Kingdom, and China that the 1- and 3-year survival rates of patients receiving combination therapy for PAH were 96% and 84%, respectively. The course of pulmonary hypertension is one of gradual decline with sporadic episodes of acute worsening. It is difficult to predict when pulmonary hypertension patients will die, as death may come either suddenly or slowly because of progressive right heart failure.

Pulmonary hypertension has evolved into a modern disease with a high standard for defining the diagnosis and treatment goals. However, unfortunately, there is a lack of awareness among non-pulmonary hypertension specialists regarding the importance of early and accurate diagnosis and treatment.

It is important to know your specific WHO group, as well as the treatment strategy for your pulmonary hypertension, so that you can be a better participant in your health care. Current evidence indicates that pulmonary hypertension management at a specialty care center is associated with improvements in survival and hospitalizations. Thus, finding a pulmonary hypertension specialist in your area is critically important. Take control of your health!

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