Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults

INTRODUCTION — 

In patients with a disease that causes left-sided heart failure (left heart disease [LHD]), high left atrial pressure can be transmitted to the pulmonary vessels and cause pulmonary hypertension (PH). This form of PH (henceforth described as PH due to left heart disease [PH-LHD]) can occur in patients with any disease that causes heart failure (HF) including left ventricular systolic dysfunction and any of the left-sided valvular diseases (eg, mitral regurgitation). As such, PH-LHD is typically a marker of the severity of left-sided heart disease and not a specific target for therapy. Rarely, PH-LHD may be a sign of an additional disease that causes PH (eg, venous thromboembolic disease). The recognition of PH-LHD may alter management in patients under evaluation for heart transplantation and has prognostic implications in other groups of patients [1-7].

The prevalence, pathogenesis, evaluation, prognosis, and treatment of PH-LHD are discussed here.

The evaluation and management of patients with HF are discussed separately. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Determining the etiology and severity of heart failure or cardiomyopathy" and "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Treatment and prognosis of heart failure with mildly reduced ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

DEFINITIONS AND CLASSIFICATION

●Pulmonary hypertension – PH is the presence of elevated pulmonary artery pressures and is defined as a resting mean pulmonary arterial pressure (mPAP) >20 mmHg on right heart catheterization. Some experts use an mPAP cutoff of ≥25 mmHg. The reasons for varying cutoffs are described elsewhere in this topic. (See 'Diagnostic criteria' below.)

●Pulmonary hypertension with left heart disease – PH-LHD is PH in the presence of left-sided heart disease, typically a disease causing HF. PH-LHD is classified by the World Health Organization as group 2 PH [3]. A more detailed description of the classification of PH is discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

●Subtypes of PH-LHD – There are two subtypes of PH-LHD [8]:

•Isolated postcapillary PH – In patients with isolated postcapillary PH (Ipc-PH), PH is caused by passive transmission of increased left-sided filling pressure to the pulmonary circulation.

•Combined post- and precapillary PH – In patients with combined post- and precapillary PH (Cpc-PH), PH is caused by passive transmission of increased left-sided filling pressures with superimposed pulmonary vascular disease.

The hemodynamic criteria for PH-LHD, Ipc-PH, and Cpc-PH are described below. (See 'Subtypes of PH in LHD' below.)

EPIDEMIOLOGY — 

The exact prevalence of PH-LHD is not well defined due to variations in study design, PH definitions, and diagnostic modalities employed. Most echo-based series suggest that approximately 70 percent of all PH is caused by LHD [9]. The prevalence of PH in common forms of LHD include:

●Heart failure – The estimated prevalence for combined post- and pre-capillary PH (Cpc-PH) may be as high as 47 percent in patients with HF with reduced ejection fraction (HFrEF) with an acute decompensation and 69 percent in patients with HF with preserved ejection fraction (HFpEF) [10,11].

●Valve disease – Estimates of PH in valvular heart disease vary significantly. In one study of 317 patients with severe mitral stenosis undergoing percutaneous balloon valvuloplasty, 73 percent had a mean pulmonary arterial pressure ≥25 mmHg, but only 19 percent had a TPG >15 mmHg [12]. The importance of mitral regurgitation as a cause of PH was shown in a study of 41 patients with isolated severe mitral regurgitation [13]. PH was identified in 76 percent of patients, of which 17 percent had a pulmonary artery systolic pressure >70 mmHg on RHC.

PATHOGENESIS

●General pathologic findings – There are scant histopathologic data in patients with PH-LHD compared with those with group 1 PH. Small, qualitative studies describe medial hypertrophy, intimal fibrosis, and in-situ thrombosis involving pulmonary arteries, though plexiform lesions, a hallmark of idiopathic pulmonary arterial hypertension (PAH), are rarely seen [14]. In a histologic analysis of 108 patients with PH-LHD, intimal thickening in the pulmonary veins was more prominent than in the arteries, which more closely resembled a pattern seen in patients with pulmonary veno-occlusive disease than that seen in patients with PAH (see 'Differential diagnosis' below) [15]. The extent of pulmonary venous remodeling also correlated with the severity of PH as measured by the transpulmonary gradient and pulmonary vascular resistance.

●Isolated post-capillary PH – The primary hemodynamic insult that leads to isolated postcapillary PH (Ipc-PH) is an elevation in left atrial or ventricular filling pressures. Thus, for the majority of patients with PH-LHD, PH can be considered a manifestation of HF. However, remodeling of the pulmonary arterioles and veins can still be present [16].

Increased left heart filling pressures reduce pulmonary arterial compliance, which promotes "stiff" pulmonary vasculature. This can lead to enhanced pulmonary wave reflections during systole and an elevated pulsatile load on the right ventricle (RV) [17]. Functional mitral regurgitation and loss of left atrial compliance are additional factors that can promote left atrial hypertension and subsequently, PH. [18].

●Combined post- and precapillary PH – Patients with PH-LHD who have combined post- and precapillary PH (Cpc-PH) develop pulmonary vascular disease secondary to vasoconstriction and pathologic remodeling of the pulmonary vasculature. In patients with Cpc-PH, the elevation in mean pulmonary arterial pressure is "disproportionate" to that generated by the transmission of increased left-sided filling pressures alone. Chronic contraction of the right heart against this increased resistive afterload can ultimately lead to maladaptive hypertrophy, dilatation, and subsequent contractile failure [19,20].

Cpc-PH patients may have a genetic predisposition to pulmonary vasculopathy in concert with LHD. In a study of 1456 patients with Ipc-PH, 312 patients with Cpc-PH, and 564 patients with PAH, Cpc-PH and Ipc-PH patients had similar clinical characteristics and similar chronicity and severity of left ventricular dysfunction. However, 141 relevant genes were differentially expressed among PAH and Cpc-PH patients compared with controls with Ipc-PH. These genes were expressed at higher levels in lung tissue and were enriched for biologic processes relevant to vascular remodeling [21,22].

CLINICAL MANIFESTATIONS AND INITIAL WORKUP

Symptoms and signs — Patients with PH-LHD typically present after a diagnosis of one of many forms of left-sided heart disease. Clues to the presence of PH associated with LHD include:

●HF symptoms such as dyspnea, fatigue, or peripheral edema. (See "Heart failure: Clinical manifestations and diagnosis in adults".)

●Physical examination findings such as an accentuated pulmonic component (P2) of the second heart sound, parasternal RV heave, tricuspid regurgitation murmur, hepatomegaly, ascites, and peripheral edema.

●Arrhythmias, such as atrial fibrillation.

Patients with severe LHD and concomitant PH may manifest:

●Dyspnea on minimal exertion.

●Anorexia and early satiety with unintentional weight loss (cardiac cachexia).

●Substernal chest pressure as a result of RV subendocardial ischemia.

●Exertional hypoxemia that may be detected with bedside oximetry.

A comprehensive discussion of findings consistent with advanced right HF and PH are discussed separately. (See "Right heart failure: Clinical manifestations and diagnosis" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

ECG, chest radiography, and transthoracic echocardiogram — In some patients with PH, electrocardiography (ECG), chest radiography, and, more commonly, transthoracic echocardiogram (TTE) suggest the presence of PH:

●ECG – An ECG is commonly obtained in patients with HF to evaluate for potential causes of HF (eg, myocardial infarction) and to detect associated abnormalities, such as arrhythmias. ECG findings in patients with PH-LHD are often nonspecific, but some patients may show findings suggestive of right HF, such as RV hypertrophy, right bundle branch block, or a rightward axis deviation. Presence of atrial fibrillation should also raise suspicion of right HF [7].

●Chest radiograph – A chest radiograph is commonly obtained in patients with PH-LHD to evaluate the cause of dyspnea. Patients with PH-LHD may have findings suggestive of HF, such as cardiomegaly (cardiac-to-thoracic width ratio above 50 percent), cephalization of the pulmonary vessels, Kerley B-lines, and pleural effusions; some may have findings consistent with RV enlargement.

●Transthoracic echocardiogram – For many patients, routine echocardiography obtained during evaluation of LHD (eg, valve disease, HF) suggests the presence of PH. Elevated pulmonary artery systolic pressure or abnormal RV structure and function suggest the presence of PH. The assessment of pulmonary pressures and right heart structure and function are discussed separately. (See "Echocardiographic assessment of the right heart".)

EVALUATION IN SPECIFIC SCENARIOS

Assessment for heart transplantation — In patients under assessment for heart transplantation, evaluation for PH with right heart catheterization (RHC) is required to determine whether transplantation is feasible. The approach to such patients is discussed separately. (See "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance'.)

Testing in confirmed left heart disease — In patients with established LHD, the need for RHC is determined by the clinical scenario:

●Suspicion for another cause of PH – In some patients with PH-LHD, the degree of PH may be significantly out of proportion to that expected for the severity of LHD. PH out of proportion to LHD should be suspected in patients with left-sided heart disease of only mild severity and who have either estimated pulmonary artery systolic pressure (PASP) >35 mmHg or echocardiographic parameters suggestive of RV dysfunction or RV pressure overload (RV dilation, RV free wall hypokinesis, RV outflow tract doppler notching, or interventricular septal flattening). In such patients, RHC may be performed to assess for the presence of findings that suggest that presence of another form of PH (eg, group 1 PH). The decision to proceed with RHC in this setting typically requires assessment by a cardiologist experienced with the patient's left-sided heart disease.

In addition, select patients should be assessed for chronic thromboembolic disease, which is discussed separately. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

●Assessment for reversibility of PH – In patients with PH-LHD who are not undergoing transplant evaluation, the role of vasoreactivity testing to determine the degree of PH reversibility is controversial. While some expert centers may perform tests for reversibility with vasodilators (eg, nitroprusside, inhaled nitric oxide) to determine the reversibility of PH, the value of such maneuvers to guide therapy is not well established in patients with PH-LHD. (See 'Targeted therapy for pulmonary hypertension' below.)

●No suspicion for severe PH – In patients with LHD who have no signs of pulmonary hypertension (eg, normal RV function and size, PASP ≤35 mmHg), evaluation for the severity or type of PH is not required. However, such patients should have periodic echocardiography appropriate for the specific form of LHD that includes estimates of pulmonary pressures, right-sided chamber sizes, and tricuspid valve function.

Aspects of right heart catheterization — In select patients, as described above, RHC should be performed to confirm the presence of PH and further characterize the type of PH. If RHC is performed to assess for PH, a comprehensive hemodynamic profile should be obtained that includes right atrial, RV, pulmonary artery, and pulmonary capillary wedge pressures (PCWP), cardiac output, and mixed venous oxygen saturation measurement. An accurate PCWP is necessary for accurate diagnosis and requires confirmation of catheter position and proper function of equipment. (See "Pulmonary artery catheters: Insertion technique in adults" and "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults" and "Cardiac catheterization techniques: Normal hemodynamics".)

The diagnostic criteria for PH are described elsewhere. (See 'Diagnostic criteria' below.)

For most patients with PH-LHD, provocative testing (eg, exercise, fluid bolus) and vasoreactivity testing (eg, nitroprusside challenge) are not indicated. In patients with suspected HF with preserved ejection fraction (HFpEF) and PCWP <15 mmHg at rest, provocative testing (eg, fluid challenge, exercise) may help identify HFpEF. The diagnostic approach in patients with HFpEF is discussed separately. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis", section on 'Approach to additional testing'.)

DIAGNOSTIC CRITERIA

Left heart disease — A pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or >18 mmHg immediately after fluid challenge is considered diagnostic of LHD [8]. Though various criteria have been used for a pathologic exercise response, the most commonly used criterion for LHD is a PCWP >25 mmHg for supine exercise and PCWP >20 mmHg for upright exercise.

Pulmonary hypertension — PH-LHD is defined hemodynamically on right heart catheterization (RHC) as a mean pulmonary arterial pressure (mPAP) >20 mmHg and a PCWP ≥15 mmHg. However, some contributors to this topic question the specificity of this definition and still consider an mPAP ≥25 mmHg to be a more reliable threshold.

An mPAP >20 mmHg was established by the 6^th World Symposium on Pulmonary Hypertension (table 1) [8].

Subtypes of PH in LHD — Subtypes of PH include isolated postcapillary PH (Ipc-PH), which is defined by a low pulmonary vascular resistance (PVR; eg, PVR <2 to 3 Wood units [WU]), and combined post- and precapillary PH (Cpc-PH), which is defined by a higher PVR (PVR ≥2 to 3 WU). Guidelines recommend a PVR cutoff of 2 WU, while some contributors to this topic use a cutoff of 3 WU [23].

The European Society of Cardiology and European Respiratory Society changed the threshold for an abnormal PVR in 2022, which altered the definition of a precapillary component of PH from 3 to 2 WU across all World Symposium on Pulmonary Hypertension (WSPH) groups [23]. While this definition is reasonable for patients with WSPH group 1 PH, its accuracy and utility for PH-LHD is less clear. The PVR threshold of 2 WU is based on measurements of PVR at rest and with exercise in healthy adults; an analysis of a large database of patients referred for RHC found that a PVR ≥2.2 WU was associated with worse outcomes [24]. Some of the contributors to this topic continue to identify Cpc-PH based on a PVR of 3 WU but recognize that the best variable to describe Cpc-PH remains controversial.

DIFFERENTIAL DIAGNOSIS

●Group 3, 4, or 5 PH and left heart disease – The differential diagnosis of PH-LHD includes concomitant left HF and another cause of PH (such as underlying lung disease, chronic thromboembolic disease, and portopulmonary hypertension). Thus, in patients with combined post- and precapillary PH, additional testing is recommended to exclude causes of PH other than LHD. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

●Group 1 PH – Group 1 PH (ie, pulmonary arterial hypertension [PAH]) and PH from HF with preserved ejection fraction (HFpEF) are frequently confused and can lead to the inappropriate use of targeted PAH therapies for patients with left HF. Advanced age, hypertension, diabetes, obesity, coronary disease, and sleep-disordered breathing are all factors that are more commonly associated with HFpEF than PAH [11,25].

Features on TTE such as left atrial enlargement, left ventricular hypertrophy, and advanced diastolic dysfunction with absence of RV dilation, RV dysfunction, and septal flattening also favor a diagnosis of HFpEF over PAH [26]. The H₂FPEF score is a convenient risk stratification tool for discriminating HFpEF from other causes of dyspnea [25]. When noninvasive evaluation is inconclusive, right heart catheterization with meticulous assessment of pulmonary capillary wedge pressure (PCWP) remains the clinical gold standard to clearly differentiate the two conditions. Provocative testing may also be helpful. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)

●Pulmonary veno-occlusive disease – Pulmonary veno-occlusive disease (PVOD) is a rare and unusual cause of PH. The pathologic hallmark of the disease is diffuse occlusion of the pulmonary veins by fibrous tissue. The triad of PH, pulmonary edema or effusions, and normal or near-normal PCWP, although not pathognomonic, is certainly suggestive of PVOD [27]. By contrast, patients with PH-LHD have a PCWP ≥15 mmHg. The diagnosis of PVOD is discussed in more detail separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

●High-output HF – High-output HF is frequently accompanied by PH and may present similarly to PH-LHD (particularly HFpEF) [28]. The diagnosis is suspected in patients with conditions associated with high-output states, such as obesity or systemic arteriovenous fistula, and is hemodynamically confirmed by identification of a high-output state. (See "Causes and pathophysiology of high-output heart failure".)

MANAGEMENT

Heart transplant candidates — The management of PH in patients under evaluation for heart transplantation is discussed separately. (See "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance'.)

Treatment of underlying left heart disease — The mainstay of treatment for PH-LHD is optimal management of the underlying LHD (eg, valve surgery, medical therapy for HF with reduced ejection fraction [HFrEF]). These treatments are discussed in relevant topics.

There is a clear rationale for this approach, as treatment for LHD should reduce left-sided filling pressures. In patients with combined post- and precapillary PH, successful unloading of the left heart reduces the excess pulsatile and resistive afterload on the RV and may allow the pulmonary vasculature to reverse remodel over time. For example, in a study of 559 patients with rheumatic mitral stenosis undergoing percutaneous valvuloplasty, there was normalization of mean pulmonary arterial pressure (mPAP) at six months regardless of baseline PH severity [29]. Left ventricular assist device therapy may gradually improve mPAP in patients with HFrEF and a high pulmonary vascular resistance [30,31].

Targeted therapy for pulmonary hypertension — PH-targeted therapy is not indicated for routine use in PH-LHD.

This approach agrees with the proceedings of the 6^th World Symposium on Pulmonary Hypertension, which included a strong recommendation against use of PH-targeted therapies in this clinical setting [8].

Multiple pulmonary arterial hypertension medications have been studied in patients with HF and PH-LHD, but none have shown a clear clinical benefit:

●Epoprostenol – A randomized controlled trial of the intravenous prostacyclin epoprostenol in 471 patients with HFrEF was terminated early because of a strong trend towards decreased survival in the treatment group [32].

●Endothelin antagonists – Clinical trials with the agents bosentan and macitentan have not shown evidence of clinical benefit and have raised concern for possible harm in patients with PH-LHD [33-35].

●PDE-5 inhibitor – In randomized trials, there was no clear hemodynamic or clinical benefit of treatment with sildenafil [36-38].

●Soluble guanylate cyclase stimulators – Randomized trials of soluble guanylate cyclase stimulators in patients with HF have not shown a clear benefit [36,37].

PROGNOSIS — 

PH-LHD is associated with increased morbidity and mortality compared with LHD without PH, which appears to be related to the development of RV failure:

●In a study of 1384 HF patients, a pulmonary artery systolic pressure >45 mmHg derived from TTE was associated with increased five-year mortality, independent of the severity of diastolic and systolic dysfunction, mitral regurgitation, or cardiovascular comorbidities [38].

●In a study of 379 patients with HF with reduced ejection fraction who underwent right heart catheterization, patients with PH and reduced RV systolic function had the worst prognosis [2].

●Similarly, in a community-based study of 562 patients with HF with preserved ejection fraction (HFpEF), RV dysfunction was common and was independently associated with all-cause mortality. A low diffusion capacity of the lung for carbon monoxide also suggests a worse prognosis in patients with PH-HFpEF [39].

●Combined post- and precapillary PH in general and, more specifically, pulmonary arterial compliance and pulmonary vascular resistance, have consistently been shown to correlate with increased mortality [7,40].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults" and "Society guideline links: Heart failure in adults".)

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Patients with pulmonary hypertension due to left heart disease (PH-LHD) typically present after a diagnosis of one of many forms of left-sided heart disease. Clues to the presence of PH associated with LHD include heart failure (HF) symptoms, physical examination findings (eg, sternal heave), ECG evidence of right ventricular (RV) hypertrophy, or radiographic evidence of right atrial or RV enlargement. (See 'Clinical manifestations and initial workup' above.)

●When to suspect PH-LHD – PH-LHD should be suspected in patients who have a disease that causes left-sided HF and who have evidence of RV dysfunction. In general, PH should be suspected if estimated pulmonary artery systolic pressure (PASP) is >35 mmHg by echocardiography or there is evidence of RV dysfunction (eg, RV enlargement, RV systolic dysfunction, interventricular septal flattening). (See 'ECG, chest radiography, and transthoracic echocardiogram' above.)

●Evaluation in specific scenarios

•Assessment for heart transplantation – In patients under assessment for heart transplantation, evaluation for PH with right heart catheterization (RHC) is required to determine whether transplantation is feasible. The approach to such patients is discussed separately. (See "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance'.)

•Testing in confirmed left heart disease – PH-LHD is typically a marker of the severity of left-sided heart disease and may prompt the need for additional therapy of left-sided heart disease (eg, valve surgery). Rarely, PH-LHD may be a sign of another disease that causes PH (eg, venous thromboembolic disease).

-Suspicion for another cause of PH – PH out of proportion to LHD should be suspected in patients with left-sided heart disease of only mild severity and who have either estimated PASP >35 mmHg or echocardiographic parameters suggestive of RV dysfunction or RV pressure overload (RV dilation, RV free wall hypokinesis, RV outflow tract doppler notching, or interventricular septal flattening). In such patients, RHC may be performed to assess for the presence of findings that suggest that presence of another form of PH (eg, group 1 PH). The decision to proceed with RHC in this setting typically requires assessment by a cardiologist experienced with the patient's left-sided heart disease.

-Assessment for reversibility of PH – In patients with PH-LHD, the role of vasoreactivity testing to determine the degree of PH reversibility is controversial. While some expert centers may perform tests for reversibility with vasodilators (eg, nitroprusside, inhaled nitric oxide) to determine the reversibility of PH, the value of such maneuvers to guide therapy is not well established in patients with PH-LHD. (See 'Targeted therapy for pulmonary hypertension' above.)

●Diagnostic criteria – PH-LHD is defined hemodynamically as a mean pulmonary arterial pressure (mPAP) ≥20 mmHg and a pulmonary capillary wedge pressure (PCWP) ≥15 mmHg.

Subtypes of PH include isolated postcapillary-PH (Ipc-PH), which is defined by a low pulmonary vascular resistance (PVR; eg, PVR <2 to 3 Wood units [WU]), and combined post- and precapillary PH (Cpc-PH), which is defined by a higher PVR (PVR ≥2 to 3 WU). Guidelines recommend a PVR cutoff of 2 WU, while some experts use a cutoff of 3 WU.

●Differential diagnosis – The differential diagnosis of PH-LHD includes concomitant left HF and another cause of PH. PH from HF with preserved ejection fraction (HFpEF) is frequently misdiagnosed as pulmonary arterial hypertension (PAH) and can lead to inappropriate use of PAH-specific therapies. (See 'Differential diagnosis' above.)

●Management

•Heart transplantation assessment – The management of PH in patients under evaluation for heart transplantation is discussed separately. (See "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance'.)

•Optimal treatment of left heart disease – The mainstay of treatment for PH-LHD is optimized management of the underlying LHD with a focus on use of evidence-based drug therapies (chiefly for HF with reduced ejection fraction [HFrEF]) titrated to target doses, decongestion with diuretics as needed, device therapies including cardiac resynchronization therapy, and surgical or transcatheter interventions as appropriate to treat ischemic heart disease and valvular heart disease. Advanced therapies for refractory HF include mechanical circulatory support (eg, left ventricular assist device) and cardiac transplantation in appropriate candidates. (See 'Treatment of underlying left heart disease' above.)

•Targeted therapy – Based on the available evidence, PH-targeted therapy is not indicated for routine use in PH-LHD and may cause harm. (See 'Targeted therapy for pulmonary hypertension' above.)

●Prognosis – PH-LHD is associated with increased morbidity and mortality, which appear to be related to the development of RV failure. (See 'Prognosis' above.)