Pulmonary hypertension includes conditions that result in elevated pressures in the lung vasculature. Pulmonary hypertension is defined as a mean pulmonary artery pressure of greater than 20 mm Hg at rest found during right heart catheterization.¹ Pulmonary hypertension affects an estimated 1% of the global population and approximately 10% of people older than 65 years.^1,2 Pulmonary arterial hypertension, a subset of pulmonary hypertension, is a relatively rare diagnosis with a high mortality rate if untreated.¹ Family physicians most often encounter pulmonary hypertension as a downstream consequence of cardiac or pulmonary disease.

The pulmonary vascular system comprises many thin-walled vessels that enable efficient gas diffusion with little blood flow resistance, allowing the thin-walled right ventricle to maintain the same cardiac output as the left ventricle. Destruction, remodeling, vasoconstriction, or blockage of the pulmonary vasculature can increase the resistance to blood flow and lead to pulmonary hypertension and increased strain on the right ventricle, causing progressive right-sided heart failure (HF). The pathologic vascular changes can originate in the pulmonary arteries, capillaries, or veins, alone or in combination.³

PRESENTATION

The presentation of pulmonary hypertension is nonspecific and similar to HF or valvular disease (Table 1¹). Symptoms of pulmonary hypertension are chronic, progressive dyspnea with minor exertion (60%), fatigue (19%), and presyncope or syncope (13%).⁴ Patients with advanced disease may have evidence of right-sided HF, including jugular venous distention, ascites, lower extremity edema, and, in very advanced cases, hemoptysis.¹ For most patients, there are no specific examination findings distinct from those of the cause of the pulmonary hypertension. Recognizing undiagnosed pulmonary hypertension is challenging in the primary care setting, with a mean time to diagnosis of 2 years, because insidious symptoms and signs may initially be attributed to underlying chronic heart or lung disease.⁴

The differential diagnosis for pulmonary hypertension is broad and includes HF, coronary artery disease, pulmonary fibrosis, chronic obstructive pulmonary disease, valvular heart disease, pulmonary embolism (PE), liver disease, and Budd-Chiari syndrome. Clinical suspicion for pulmonary hypertension should be increased in younger, symptomatic patients with comorbid diseases such as HIV, sickle cell disease, connective tissue disease, and congenital heart disease or a history of methamphetamine use. Delayed diagnosis of pulmonary arterial hypertension by more than 2 years is associated with an 11% increase in the mortality rate.⁵

DIAGNOSTIC EVALUATION

When a patient’s history suggests possible pulmonary hypertension, electrocardiography, chest radiography, echocardiography, pulmonary function testing, and basic laboratory testing should be performed. Table 2 summarizes suggested tests and findings for pulmonary hypertension.^1,6–8 Although the role of brain natriuretic peptide (BNP) in diagnosis is uncertain, normal BNP results with normal electrocardiography findings suggest that pulmonary hypertension is unlikely. Chest radiography is often the first imaging test performed and has a high sensitivity and specificity for detecting moderate to severe pulmonary hypertension. Findings on chest radiography may include enlargement of the pulmonary artery, right atrium, or right ventricle.⁹

Transthoracic echocardiography is the recommended initial test for patients with suspected pulmonary hypertension.^10,11 Although echocardiography findings cannot confirm the diagnosis, abnormal findings can be categorized as low, intermediate, or high risk^1,6 (Table 3¹). Echocardiography findings suggestive of pulmonary hypertension include the quantitative findings of a peak tricuspid regurgitation velocity of more than 2.8 meters per second or an estimated systolic pulmonary artery pressure greater than 35 mm Hg, with at least two anatomic abnormalities (e.g., abnormal right or left ventricle size, wall thickness, function, increased right atrium size, increased inferior vena cava and pulmonary artery diameter).^1,7,8,11

Pulmonary hypertension found incidentally on echocardiography performed for other reasons should be taken seriously. Even mild elevations in pulmonary pressures increase mortality risk.¹² Patients should be evaluated by the standard clinical pathway. If any combination of the workup suggests pulmonary hypertension, referral to a specialist is indicated. Right heart catheterization is the standard for diagnosing and classifying pulmonary hypertension and informs the treatment of pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Right heart catheterization may not be indicated when left-sided heart disease or lung disease is a sufficient explanation for clinical and echocardiography findings in the absence of suspicion for pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.¹

Current guidelines recommend measuring pulmonary artery wedge pressure and pulmonary vascular resistance (PVR) during catheterization to determine if the source of hypertension is precapillary, postcapillary, or both because this affects the clinical classification group, prognosis, and treatment options.^10,13 Pulmonary arterial wedge pressure is an indirect estimate of the pressure in the left atrium; therefore, it is normal when the source of the pulmonary hypertension originates in the precapillary pulmonary vascular bed, such as in pulmonary arterial hypertension, and is elevated when the source originates in the postcapillary vascular bed such as in left-sided HF. PVR is a calculated value of the difference between the mean pulmonary artery pressure and the left atrial pressure and is elevated in pulmonary arterial hypertension but normal in pulmonary hypertension caused by HF.

TREATMENT

Treatment of pulmonary hypertension focuses on the optimization of cardiopulmonary comorbidities, assessment of the risk of disease progression, and use of combination therapies. Patients are risk-stratified based on World Health Organization functional classification (Table 4¹⁴), a 6-minute walking test, and BNP/N-terminal pro-BNP level, which further guide the treatment strategy.^1,14 Medications targeting pulmonary hypertension are only available for pulmonary arterial hypertension and select patients with chronic thromboembolic pulmonary hypertension; treatment for other types focuses on the underlying etiology.

PROGNOSIS

Pulmonary hypertension is a poor prognostic sign, with a 5-year estimated survival rate of 67% or less. The prognosis is slightly worse when pulmonary hypertension is secondary to lung disease and slightly better in chronic thromboembolic pulmonary hypertension.¹⁵ Although numerous prognostic factors exist for each etiology of pulmonary hypertension, functional capacity measured by a 6-minute walking test has predictive value across all groups.¹⁵ Regardless of the etiology, the development of pulmonary hypertension is associated with worsening symptoms and increased mortality.^1,16

CLINICAL CLASSIFICATION GROUPS

Pulmonary hypertension is divided into five clinical groups based on etiology (Table 5).^1,17

Group 1: Pulmonary Arterial Hypertension

In pulmonary arterial hypertension, the intima, media, and adventitia of small pulmonary arteries and arterioles undergo remodeling, hyperplasia, and vasoconstriction, narrowing the lumen and increasing vascular resistance. Certain conditions increase the risk of pulmonary arterial hypertension; therefore, expert consensus recommends annual screening for pulmonary arterial hypertension with transthoracic echocardiography for patients at high risk^1,11,18 (Table 6^1,18).

Pulmonary arterial hypertension requires right heart catheterization because pulmonary arterial wedge pressure and PVR are essential to a diagnosis. Patients should be referred to a specialized center for targeted treatment because therapy for pulmonary arterial hypertension is complex.¹

Pulmonary arterial hypertension is treated with vasoactive medications that decrease the PVR (Table 7¹). Patients with idiopathic pulmonary arterial hypertension who have positive findings on vasoreactivity testing during right heart catheterization (acute vasodilation in response to short-acting pulmonary vasodilators) benefit from high-dose calcium channel blockers.¹ Long-term oxygen therapy, including in-flight oxygen, is recommended in patients with pulmonary arterial hypertension with arterial blood oxygen pressure less than 60 mm Hg or oxygen saturation less than 90% at sea level.¹ These patients may require an increase in the flow rate of supplemental oxygen if they travel to a high altitude.^1,19,20

Targeted therapies and support strategies for pulmonary arterial hypertension have significantly improved survival for group 1. The 5-year survival rate for pulmonary arterial hypertension is estimated at 59%.¹⁵ Patients who do not respond to optimal medical therapy or have an elevated risk of mortality should be referred for a lung transplant. Patients who survive 1 year after a lung transplant have a median survival of 10 years.^1,19

Group 2: Pulmonary Hypertension Associated With Left-Sided Heart Disease

Heart disease is the most common cause of pulmonary hypertension. Up to 72% of patients who have HF with reduced ejection fraction and 83% of patients who have HF with preserved ejection fraction have pulmonary hypertension.¹⁶ For patients with left-sided heart disease, elevated pressure in the left atrium can cause pulmonary venous congestion, leading to remodeling and vasoconstriction of pulmonary veins and pulmonary hypertension.

Therapy for patients with pulmonary hypertension secondary to cardiac disease emphasizes goal-directed treatment of the underlying disease process.¹ Group 2 pulmonary hypertension has a 5-year survival rate comparable to pulmonary arterial hypertension.¹⁵

Group 3: Pulmonary Hypertension Associated With Lung Disease

The second most common cause of pulmonary hypertension is chronic obstructive lung disease. Group 3 pulmonary hypertension affects up to 5% of patients with severe chronic obstructive lung disease.^1,2 In this group, destruction of lung tissue is accompanied by loss of pulmonary capillaries to increase PVR, while hypoxia causes pulmonary arteriole vasoconstriction.

Therapy for patients with pulmonary hypertension secondary to lung disease emphasizes goal-directed treatment of the underlying disease process.¹ The 5-year survival rate is 38% for this group.¹⁵

Group 4: Pulmonary Hypertension Associated With Pulmonary Artery Obstruction

This is a rare but increasingly recognized cause of pulmonary hypertension in which pulmonary arteries become obstructed by chronic fibrotic clots, usually as a sequela of PE.^1,3 Chronic thromboembolic pulmonary hypertension has a prevalence of 3 per 100,000 and occurs in up to 3% of patients who survive PE.²¹ These patients tend to be older and are more likely to have had recurrent, proximal PE.²¹ Chronic thromboembolic pulmonary hypertension should be suspected in patients with PE who are dyspneic after appropriate treatment. Diagnostic testing should include ventilation-perfusion imaging and pulmonary computed tomography angiography.

Surgical intervention via pulmonary endarterectomy is the treatment of choice for surgical candidates who have chronic thromboembolic pulmonary hypertension and accessible lesions. Balloon angioplasty may be an alternative for patients who cannot have surgery or for those with persistent pulmonary hypertension following pulmonary endarterectomy.²² Lifelong therapeutic anticoagulation is recommended for all patients who have chronic thromboembolic pulmonary hypertension.^1,22

Group 5. Pulmonary Hypertension With Unclear or Multifactorial Etiologies

Group 5 includes pulmonary hypertension with unclear or multiple mechanisms and is related to conditions such as sickle cell anemia, glycogen storage disease, and chronic renal failure.¹

OTHER CONSIDERATIONS

Exercise-Induced Pulmonary Hypertension

Some patients with mild pulmonary vascular disease or left-sided heart disease have normal pulmonary artery pressures at rest but develop pulmonary hypertension and exertional dyspnea with exercise. Although the clinical significance of this condition is unclear, exercise-induced pulmonary hypertension can lead to adverse outcomes and reduced survival in patients with systemic sclerosis or valvular heart disease.^23,24

Exercise Rehabilitation

Patients with pulmonary hypertension who are stable should be referred for a supervised rehabilitation and exercise training program.^1,19 Exercise training programs have demonstrated improvement in exercise capacity as measured by the 6-minute walking test, peak oxygen consumption, functional capacity, and quality-of-life scores, especially for patients in pulmonary hypertension groups 1 and 4.^25,26

Advance Directives and Code Status

Discussions around goals of care are important in chronic diseases. Conversations about advance directive planning for patients with pulmonary hypertension should take place in a sensitive and caring manner, especially for patients with World Health Organization functional status class III or IV. Code status is important because in-hospital cardiopulmonary resuscitation has a low survival rate. Palliative care and hospice can help manage distressing symptoms as functional status worsens toward the end of life.^1,19

Contraception and Pregnancy

Patients of childbearing potential who have pulmonary hypertension should be counseled to avoid pregnancy because of the high risk of worsening disease and maternal or fetal death.¹ A 2020 systematic review demonstrated a 12% risk of maternal mortality and 23% risk of pregnancy loss in patients with pulmonary hypertension.²⁷

There is no strong evidence or consensus to guide the best choice of contraception.²⁸ It is prudent to use two forms of contraception (a primary mode plus a backup barrier of protection) because the implications of pregnancy are serious in patients with pulmonary hypertension. Low-dose combined oral contraceptives and emergency contraceptives are safe; however, bosentan, an endothelin receptor antagonist, reduces the effectiveness of hormonal contraception.¹ Long-acting reversible contraceptives are another option with low failure rates.

If the patient is pregnant, referral to a pulmonary hypertension specialty center is indicated because outcomes are better when pulmonary hypertension is well controlled at pregnancy onset. Endothelin receptor antagonists, one of the primary treatments for pulmonary arterial hypertension, are teratogenic and not recommended.¹

COVID-19

Patients with persistent dyspnea after recovery from COVID-19 are at increased risk of pulmonary hypertension. In one meta-analysis, 22% of patients developed pulmonary hypertension after intensive care unit admission due to COVID-19.²⁹ Persistent pulmonary vasculopathy after COVID-19 may be a long-term sequela, regardless of the severity of the infection, that can lead to pulmonary arterial hypertension. Microthrombi in pulmonary vessels during COVID-19 may cause the development of chronic thromboembolic pulmonary hypertension.

More long-term studies are needed to assess the risk between COVID-19 and pulmonary hypertension. Pulmonary hypertension associated with COVID-19 has not yet been classified into one group, although it appears to be responsive to conventional pulmonary arterial hypertension treatment pathways.³⁰

Immunizations

Patients who have pulmonary hypertension should receive immunizations for influenza, pneumococcus, and COVID-19.^1,19

Mental Health

Patients with pulmonary hypertension often experience frustrating delays in diagnosis, uncomfortable and worsening symptoms that negatively affect lifestyle and income, complicated medical regimens, and the burden of having a serious disease. These factors influence emotional health. In 2021, a study of 217 patients found that 38.2% met the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., criteria for a mental health disorder after receiving a diagnosis of pulmonary arterial hypertension, most commonly major depressive disorder (23%) and panic disorder (15.2%).³¹ Patients with pulmonary hypertension should be screened for depression and anxiety disorders using standard tools and encouraged to engage with support groups and counseling, and consider psychopharmacology.^1,31

Perioperative Assessment

Pulmonary hypertension increases the risk of surgical complications, especially right-sided HF and death.^1,32 The 2023 American Heart Association guideline for managing pulmonary hypertension in noncardiac surgery recommends a preoperative risk assessment to guide decision-making.³² For ideal intraoperative and postoperative management, the preoperative risk assessment and surgery should be performed at a center specializing in pulmonary hypertension. Preoperative evaluation includes repeat echocardiography, electrocardiography, laboratory tests, a 6-minute walking test, possible repeat right heart catheterization, and evaluation by anesthesia, a pulmonary hypertension specialist, or cardiology and pulmonology specialists.³² Pulmonary hypertension should be medically optimized for a minimum of 2 to 4 weeks before a planned surgery.¹⁹

CODING AND BILLING

Hierarchical condition category codes can be used when evaluating and caring for patients with pulmonary hypertension. Individual codes correspond to the clinical classification groups. Physicians should be specific in their documentation to ensure appropriate risk adjustment. Related International Classification of Diseases, Tenth Revision (ICD-10) codes include the following³³:

• Unspecified pulmonary hypertension: I27.20

• Unspecified secondary pulmonary arterial hypertension: I27.21

• Pulmonary hypertension groups 2 to 4: I27.22 to I27.24, respectively

• Pulmonary hypertension group 5: I27.29.

This article updates previous articles on this topic by Dunlap and Weyer³⁴; Stringham and Shah³⁵; and Nauser and Stites.³⁶

Data Sources: A PubMed search was completed using the key terms pulmonary hypertension and pulmonary arterial hypertension with diagnosis, pathophysiology, treatment, contraception, exercise, surgical assessment, COVID, and ESC/ERS. The search included meta-analyses, randomized controlled trials, clinical trials, and expert reviews. Essential Evidence Plus and the Cochrane database were also searched in addition to reference lists in retrieved articles. Also searched were the Library Services at the Naval Medical Center Portsmouth and Eastern Virginia Medical School. We critically reviewed studies that used patient categories such as race and/or gender but did not define how these categories were assigned, stating their limitations in the text. Search dates: June 2023, July 2023, January 2024, and June 2024.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Navy, the U.S. Department of Defense, or the U.S. government.