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

INTRODUCTION — Left-sided heart failure (left heart disease [LHD]) is the most common cause of pulmonary hypertension (PH). This form of PH (henceforth described as PH due to left heart disease [PH-LHD]) can occur in patients with heart failure (HF; including HF with reduced ejection fraction [HFrEF], HF with mid-range ejection fraction [HFmrEF], HF with preserved ejection fraction [HFpEF], and HF caused by left-sided valvular disease). Recognition of PH-LHD is important because it is clearly associated with increased morbidity and mortality [1-7]; however, therapeutic strategies beyond treatment of the underlying LHD have not been well-established.

The prevalence, pathogenesis, evaluation, prognosis, and treatment of PH-LHD are discussed here. 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 — PH-LHD is identified and classified as follows:

Pulmonary hypertension (PH) is defined as a resting mean pulmonary arterial pressure (mPAP) >20 mmHg on right heart catheterization, as described in the proceedings of the 6^th World Symposium on Pulmonary Hypertension [3]. This change in mPAP cutoff (previously ≥25 mmHg) reflects accumulating data that shows an increased risk of disease progression even in patients with a mild elevation in mPAP (21 to 24 mmHg) [3]. Since the threshold of mPAP >20 mmHg is new, it has not yet gained universal clinical acceptance.

The World Health Organization has clinically categorized PH into five groups based on the underlying etiology for the disease (table 1) [3]. When all five groups are described collectively, the term PH is used. The term pulmonary arterial hypertension is used when referring to patients in group 1. 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'.)

Group 2 consists of patients with PH-LHD.

Prior studies of PH-LHD were generally based on the older definition (mPAP ≥25 mmHg), so the prevalence and clinical significance of mild PH identified by the newer definition (mPAP >20 mmHg) has not been fully defined.

PH-LHD encompasses two subgroups (table 2) [8]:

●Isolated post-capillary PH (Ipc-PH) in which mPAP is elevated solely from passive transmission of increased left-sided filling pressure to the pulmonary circulation.

and

●Combined post- and precapillary PH (Cpc-PH) in which mPAP is elevated from passive transmission of increased left-sided filling pressures with superimposed pulmonary vascular disease.

These two subset definitions replace older and potentially confusing terms which have been used to describe PH-LHD such as pulmonary venous hypertension, out-of-proportion PH, mixed PH, and passive versus reactive PH.

Hemodynamic criteria for PH-LHD, Ipc-PH and Cpc-PH are described below. (See 'Diagnostic criteria' below.)

PREVALENCE — The exact prevalence of PH-LHD is not well defined, in part because of variations in study design, PH definitions, and diagnostic modalities employed. Most echo-based series suggest that 70 percent of PH is caused by LHD [9].

Estimated prevalence rates for combined post- and precapillary PH (Cpc-PH) have been as high as 47 percent in patients with HF with reduced ejection fraction (HFrEF) with an acute decompensation and 69 percent in the HF with preserved ejection fraction (HFpEF) population in an outpatient registry [10,11]. In a study of 4406 patients with PH-LHD, including 2587 patients with HFpEF, pulmonary vascular resistance (PVR) ≥3 Wood units, a transpulmonary gradient (TPG) >12 mmHg, and diastolic pressure gradient (DPG) ≥7 mmHg yielded prevalences of 36.2, 45.9, and 11.7 percent, respectively. Corresponding prevalences within the HFpEF subgroup were 34.2, 48.9, and 13.7 percent [12]. As discussed below, PVR is the metric used to identify Cpc-PH in the 6^th World Congress recommendations [8]. (See 'Diagnostic criteria' below.)

While estimates of PH in valvular heart disease also vary significantly, the Cpc-PH phenotype may describe only a minority of patients. In one study of 317 patients with severe mitral stenosis undergoing percutaneous balloon valvuloplasty, 73 percent had a mean pulmonary arterial pressure (mPAP) ≥25 mmHg, but only 19 percent had a TPG >15 mmHg [13]. In a single-center study of older adult patients with severe aortic stenosis, all of whom underwent right heart catheterization (RHC), 78 percent had PH, but only 12 percent had a DPG ≥7 mmHg [14].

The importance of mitral regurgitation (MR) as a cause of PH was shown in a study of 41 patients with isolated severe MR [15]. PH was identified in 76 percent of patients, of which 17 percent had a pulmonary artery systolic pressure >70 mmHg on RHC.

PATHOGENESIS — The primary hemodynamic insult that leads to isolated post-capillary PH (Ipc-PH) is an elevation in left atrial or ventricular filling pressures. Thus, for the majority of patients with PH-LHD, the elevation in mean pulmonary arterial pressure (mPAP) can be considered a manifestation of HF, with a normal pulmonary vascular response, though early remodeling of pulmonary arterioles and veins can still be present [16].

Increased left heart filling pressures can also reduce pulmonary arterial compliance promoting "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 hemodynamic insults that can promote left atrial hypertension that transmits back to the pulmonary vasculature.

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 mPAP 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 [18,19].

There are scant histopathologic data in patients with PH-LHD as 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 [20]. In a contemporary histomorphometric analysis of the pulmonary vasculature in 108 PH-LHD patients, intimal thickening in veins was more prominent than in arteries, and more closely resembled a pattern seen in patients with pulmonary veno-occlusive disease rather than PAH (see 'Differential diagnosis' below). The extent of pulmonary venous remodeling also correlated with the severity of PH, based on the transpulmonary gradient and pulmonary vascular resistance [21].

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 PAH patients, Cpc-PH and Ipc-PH patients had similar clinical characteristics and similar chronicity and severity of left ventricular (LV) dysfunction. However, 141 relevant genes were differentially expressed among PAH and Cpc-PH patients when 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 [22,23].

CLINICAL MANIFESTATIONS

Symptoms and signs — Patients with PH-LHD typically present with symptoms and signs related to HF such as dyspnea, fatigue, and signs of pulmonary and/or peripheral edema. A detailed description of these features is discussed separately. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Initial blood tests'.)

Distinguishing isolated post-capillary PH, combined post- and precapillary PH (Cpc-PH), and LHD without PH is difficult based on history and physical examination alone. Patients who develop Cpc-PH may progress along a clinical spectrum from a syndrome of isolated left HF with normal right ventricular (RV) function into a syndrome of right HF with jugular venous distension, ascites, peripheral edema, and echocardiographic findings that include a dilated and dysfunctional RV, interventricular septal flattening, and tricuspid regurgitation [5].

The following are symptoms and signs suggestive of right HF. Patients will often describe a history of dyspnea on minimal exertion. Anorexia and early satiety may result in unintentional weight loss (cardiac cachexia). Patients may experience substernal chest pressure as a result of RV subendocardial ischemia. Physical examination findings may include an accentuated pulmonic component (P2) of the second heart sound, a parasternal RV heave, a murmur of tricuspid regurgitation, hepatomegaly, ascites, and peripheral edema. Exertional hypoxemia may be detected with bedside oximetry. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

Initial tests — Initial tests such as electrocardiography and chest radiography are not diagnostic of PH-LHD but may suggest RV dysfunction in some patients.

An electrocardiogram (ECG) is commonly obtained in patients with HF to evaluate causes (eg, myocardial infarction) and 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, and/or a rightward axis deviation. Presence of atrial fibrillation should also raise suspicion of right HF [7].

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 suggestive of RV enlargement. In patients with suspected PH-LHD, a chest radiograph may also be part of the initial evaluation to exclude concomitant lung disease. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Chest radiograph' and 'Tests to identify other causes of PH' below.)

DIAGNOSIS AND EVALUATION

When to suspect PH-LHD — PH-LHD should be suspected in patients with left HF (HF with reduced ejection fraction [HFrEF], HF with mid-range ejection fraction [HFmrEF], HF with preserved ejection fraction [HFpEF], or HF secondary to mitral or aortic valve disease) when there is clinical evidence suggesting right HF such as a loud P2 or a parasternal heave, echocardiographically estimated pulmonary artery systolic pressure (PASP) exceeds 35 mmHg, or cardiac imaging (eg, echocardiography) suggests right ventricular (RV) or right atrial dilation, RV dysfunction, moderate to severe tricuspid regurgitation, or interventricular septal flattening.

As discussed separately, a comprehensive transthoracic echocardiogram (TTE) is a key component of the evaluation of all patients with HF. Estimation of PASP to screen for PH is an important component of this assessment. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Echocardiography'.)

Initial diagnostic evaluation — In patients with suspected PH-LHD, the clinical evaluation is integrated with a comprehensive TTE to determine whether right heart catheterization (RHC) is clinically indicated, as follows:

●The presence, type, and severity of left HF is determined based upon clinical assessment including TTE, as discussed in detail separately. Common types of left HF associated with PH include HFpEF, HFrEF and mitral or aortic valve disease. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Determining the etiology and severity of heart failure or cardiomyopathy".)

●PASP is estimated by TTE, as feasible. Experts use a combination of peak tricuspid regurgitation jet velocity, estimated PASP, and other echocardiographic parameters to assess the probability of PH, as discussed separately (table 3). (See "Echocardiographic assessment of the right heart", section on 'Pulmonary artery pressure'.)

In some patients, echocardiographic parameters can also be used to estimate whether or not pulmonary capillary wedge pressure (PCWP) is elevated, but these parameters are frequently indeterminate. (See "Echocardiographic evaluation of left ventricular diastolic function in adults", section on 'Estimation of left atrial pressure'.)

When to perform right heart catheterization — In patients with suspected PH-LHD, the decision on whether RHC is clinically indicated is based upon the following considerations:

●If estimated PASP by echocardiography is >35 mmHg, hemodynamic assessment by RHC is suggested only if one or more of the following conditions is present:

•Evidence of right ventricular (RV) dysfunction. Echocardiographic parameters suggestive of RV dysfunction (with volume and/or pressure overload) include RV dilation, RV free wall hypokinesis, or interventricular septal flattening.

•The cause of PH is unclear or more than one cause is suspected, or

•Advanced HF therapies are being considered.

●If estimated PASP by echocardiography is ≤35 mmHg and the clinical suspicion for Cpc-PH is low, no further evaluation is generally required. However, if CpC-PH or RV dysfunction is suspected or advanced HF therapies are being considered, RHC is suggested, as a normal estimated PASP by echocardiography does not rule out PH. Presence of one or more of the following clinical characteristics of right HF suggests CpC-PH: moderate to severe or greater tricuspid regurgitation, biatrial enlargement, or atrial fibrillation.

Right heart catheterization — When clinically indicated (as described above), RHC is performed to confirm a diagnosis and further categorize PH-LHD. (See 'Initial diagnostic evaluation' above.)

When RHC is performed, a comprehensive hemodynamic profile should be obtained, including right atrial, RV, pulmonary artery and pulmonary capillary wedge pressures, cardiac output, and mixed venous oxygen saturation measurement. An accurate PCWP is necessary, and so proper positioning should be confirmed, and if there is uncertainty, direct measurement of LV diastolic pressures should be obtained. These issues are discussed separately. (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".)

Based on these parameters, the diastolic pulmonary vascular pressure gradient (DPG), transpulmonary gradient (TPG), and pulmonary vascular resistance (PVR) can be calculated and used in concert with the noninvasive evaluation to characterize the subgroup of PH-LHD.

Diagnostic criteria — The following criteria were included in the 6^th World Symposium on Pulmonary Hypertension (table 2) [8]:

●PH-LHD is defined hemodynamically on RHC as a mPAP >20 mmHg and a PCWP ≥15 mmHg. However, some experts question the specificity of this new definition and still consider an mPAP ≥25 mmHg to be a more reliable threshold.

Among patients with PH-LHD:

•Cpc-PH is identified by a PVR ≥3 Wood units

•Ipc-PH is identified by PVR <3 Wood units

The current guidelines from the 6^th World Symposium endorse identification of Cpc-PH using PVR alone. The best variable to describe CpC-PH remains controversial, and all of the proposed metrics have limitations. Other metrics that have been used to identify CpC-PH include the transpulmonary gradient (TPG = mPAP - PCWP; normal ≤12 to 15 mmHg) and the diastolic pressure gradient (DPG= pulmonary artery diastolic pressure [PADP] - PCWP; normal <7 mmHg). Some experts continue to consider a carefully measured DPG to be a powerful metric, as it is less dependent on preload and cardiac output and more specific for pathologic changes in the pulmonary arterioles compared with other indices [16,24].

Provocative testing

Indications and methods — We recommend provocative testing during cardiac catheterization in patients with PCWP of 13 to 15 mmHg with suspected LHD [8], particularly those with HFpEF. In addition, we perform provocative testing in selected patients with PCWP <13 with high index of suspicion of LHD. Because left-sided filling pressures can change with loading conditions, a normal PCWP does not exclude a diagnosis of LHD, especially in patients who have been aggressively diuresed prior to RHC and provocative testing may unmask occult LHD [25,26].

Provocative testing may be performed by either exercise or fluid challenge:

●Where appropriate expertise exists, provocative exercise testing is preferable as it provides a more physiologic load [27]. Provocative exercise testing in the catheterization lab is performed with upright or supine bicycle ergometry; this technique enables controlled increases in workload to evaluate changes in pulmonary pressures, left-sided filling pressures, and cardiac output, and may be more sensitive for the detection of HFpEF compared with saline loading.

●When exercise testing is not feasible, fluid challenge (eg, intravenous administration of 500 cc of saline within 5 to 10 minutes) should be performed with or without arm exercises to raise the heart rate.

Criteria for left heart disease — A PCWP >18 mmHg immediately after fluid challenge is considered diagnostic of LHD [8]. Various criteria have been used for a pathologic exercise response. The most commonly used criteria for LHD is a PCWP >25 mmHg for supine exercise and PCWP >20 mmHg for upright exercise.

Limitations for both saline infusion and exercise testing include the absence of standardized protocols and a lack of uniform definitions regarding what degree of change is physiologic versus pathologic.

Tests to identify other causes of PH — If Cpc-PH is confirmed, we recommend additional testing to identify or exclude other possible etiologies for pulmonary vascular disease. While the World Symposium Classification of PH describes groups that are more "hemodynamically pure" (table 1), there is considerable overlap for individual patients in real world practice [28].

Evaluation for other causes of PH should include the following tests (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.):

●HIV serology (to screen for pulmonary arterial hypertension [PAH] caused by HIV infection).

●Liver function tests (to screen for PAH associated with portal hypertension).

●Antinuclear antibody (to screen for connective tissue disease).

●A ventilation/perfusion scan is suggested to evaluate for chronic thromboembolic disease, as HF confers a hypercoagulable state.

Additional tests that are suggested if underlying lung disease is suspected including pulmonary function tests and high resolution computed tomography scan. Polysomnography is indicated for suspected sleep disordered breathing.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PH-LHD includes concomitant left HF and another cause of PH (such as underlying lung disease, chronic thromboembolic disease, pulmonary arterial hypertension [PAH], 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 'Tests to identify other causes of PH' above.)

Three additional conditions that can be mistakenly identified as PH-LHD are PAH, pulmonary veno-occlusive disease, and high-output HF.

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]. Features on transthoracic echocardiography such as left atrial enlargement, LV hypertrophy, and advanced diastolic dysfunction along with an absence of right ventricular (RV) dilation, RV dysfunction, or septal flattening also favor a diagnosis of HFpEF over PAH [29]. 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" and 'Provocative testing' above.)

Pulmonary veno-occlusive disease 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/effusions, and normal or near normal PCWP, although not pathognomonic for the disease, is certainly suggestive [30]. By contrast, patients with PH-LHD have a PCWP ≥15 mmHg. This condition 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 is frequently accompanied by PH and may present similarly to PH-LHD (particularly PH-HFpEF) [31]. The diagnosis is suspected in patients with conditions associated with high-output states, such as obesity or presence of systemic arteriovenous fistula, and is hemodynamically confirmed by identification of a high-output state. (See "Causes and pathophysiology of high-output heart failure".)

PROGNOSTIC SIGNIFICANCE — PH-LHD is associated with increased morbidity and mortality compared with LHD without PH, which appears to be related to the development of right ventricular (RV) failure [6,7,14,19,30,32-37].

●In a study of 1384 HF patients, a pulmonary artery systolic pressure (PASP) >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 [32].

●In a study of 379 HF patients with reduced ejection fraction, all of whom 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 HF with preserved ejection fraction (HFpEF) patients, 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 [38].

MANAGEMENT

Optimized management 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. These treatments are discussed in detail separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with preserved ejection fraction".)

There is a clear rationale for this approach as treatment for LHD aims to reduce left-sided filling pressures which should subsequently improve pulmonary pressures. Adequate decongestion with diuresis and other pharmacologic therapy is critical to reduce left-sided pressures and reduction of lung water may also improve pulmonary vascular function [39].

In patients with combined post- and precapillary PH (Cpc-PH), successful unloading of the left heart reduces the excess pulsatile and resistive afterload on the right ventricle (RV), suggesting that the pulmonary vasculature can 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 [35]. LVAD therapy has also been shown to gradually improve mPAP in patients with HFrEF and a high pulmonary vascular resistance (PVR) [36,40].

Systemic vasodilator challenge as a guide for therapy — Systemic vasodilator challenge is indicated in selected candidates for heart transplantation to assess the reversibility of PH, and the test has been most studied in this clinical setting. Use of systemic vasodilator challenge in other patients with PH-LHD is controversial. (See 'Management of heart transplant candidates' below and "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance'.)

However, we also often utilize nitroprusside with or without inhaled nitric oxide during right heart catheterization in patients with PH-LHD who are not being evaluated for heart transplantation. We generally avoid a vasodilator challenge in patients with resting systolic blood pressure (SBP) <100 mmHg or with severe aortic stenosis, mitral stenosis, or dynamic outflow tract obstruction given the risk of precipitating hypotension.

Vasodilator challenge tests are performed as follows:

For patients with Cpc-PH, PVR ≥3 Wood units or a transpulmonary gradient (TPG) >15 mmHg, pulmonary capillary wedge pressure (PCWP) >15 mmHg, and SBP >100 mmHg, we will give intravenous nitroprusside at 0.25 to 1 mcg/kg/minute and will then repeat an assessment of pulmonary arterial pressure (PAP), cardiac output, and PCWP.

●Normalization or near normalization of PAPs with decreases in PVR and PCWP, but without a concomitant decrease in SBP to less than 90 mmHg, identifies a cohort of patients with a reversible, precapillary component of PH. The mechanism for precapillary PH in these patients is more likely to be vasoconstriction or decreased compliance of the pulmonary vasculature and less likely to be pulmonary vascular remodeling or fibrosis. In patients with severe valvular regurgitation, this may identify a subset with a lower risk of residual PH or acute RV failure after valvular intervention or surgery. In patients with HFrEF or HFpEF, this can allow for better optimization of antihypertensives and afterload-reducing therapies.

●In patients with persistent PH with nitroprusside alone (mPAP remains approximately >30 mmHg), but with an appropriate reduction in PCWP to <15 mmHg, we will add inhaled nitric oxide at a dose of 20 to 40 ppm on top of continuous nitroprusside for 10 minutes and will then repeat another hemodynamic assessment. This may identify additional patients with a reversible precapillary component of PH. Also, a subsequent rise in PCWP with the addition of inhaled nitric oxide may predict an adverse response to the use of a pulmonary vasodilator.

Notably, the presence of reversibility in Cpc-PH should not be confused with the reversibility that can classically be seen in a small subset of patients with idiopathic pulmonary arterial hypertension (PAH). There is no role for calcium channel blockers as a pulmonary vasodilator in Cpc-PH, and the association of reversibility with a better prognosis has not been clearly established outside of heart transplant.

Targeted therapy for pulmonary hypertension

Indications — Based on the available evidence, PH-targeted therapy is not indicated for routine use in PH-LHD; the proceedings of the 6^th World Symposium on Pulmonary Hypertension include a strong recommendation against use of PH-targeted therapies in this clinical setting [8]. Further study is required to determine the safety and efficacy of these agents in patients with PH-LHD.

Despite the limited available evidence, we suggest use of low doses of phosphodiesterase-5-inhibitor (PDE-5) therapy (eg, sildenafil 20 mg three times daily) in select patients with PH-LHD when all of the following criteria are met:

●Presence of documented Cpc-PH with associated RV dysfunction.

●PCWP is optimized and low enough to ensure a safety margin for use of PDE-5 therapy (ie, risk of pulmonary edema deemed low). While there are no firm hemodynamic thresholds at which the use of pulmonary vasodilators are considered appropriate or safe, the "20/20/10/5" rule (TPG >20 mmHg, PCWP <20 mmHg, diastolic pulmonary vascular pressure gradient [DPG] >10 mmHg, PVR >5 Wood units) can serve as a simple checklist when initially considering the use of these agents.

●Symptoms (eg, dyspnea) persist despite near normalization of the PCWP.

●There is evidence of clinical response to PDE-5 therapy to warrant continued use.

As an example, the above criteria are met in some patients postoperatively following initiation of LVAD support, when the risk for acute RV failure is increased [41]. We will often use inhaled nitric oxide postoperatively and bridge these patients to sildenafil when there is concern for residual PH and/or RV dysfunction, as the risk for inducing significant pulmonary edema is low in the presence of LVAD support.

Evidence — There is no targeted PAH medication with established safety and efficacy in patients with PH-LHD; all of these agents can precipitate acute pulmonary edema from increased pulmonary flow into a noncompliant left atrium and ventricle. Despite this concern, multiple PAH medications across various drug classes have been studied in this population. These studies have not identified a clinical benefit from PAH medications in patients with PH-LHD, though very few were limited to patients with Cpc-PH:

●Epoprostenol - A randomized controlled trial of the intravenous prostacyclin epoprostenol in 471 HFrEF patients was terminated early because of a strong trend towards decreased survival in the treatment group [42].

●Endothelin antagonists - Clinical trials with the agents bosentan and macitentan have not shown evidence of clinical benefit and have raised concern for greater fluid retention, particularly with bosentan therapy.

•Bosentan - The endothelin receptor antagonist bosentan has been investigated in a few randomized studies, with reports of more fluid retention and no clinical improvement [43-45]. In two identical trials enrolling a total of 1613 patients with New York Heart Association (NYHA) functional class IIIb to IV HF and an LV ejection fraction (LVEF) <35 percent, patients were randomly assigned to receive bosentan or placebo for a median of 1.5 years. Bosentan did not improve clinical status at nine months and caused fluid retention within the first two to four weeks (with increased peripheral edema, weight gain, and increased risk of hospitalization for HF, despite diuretic therapy) [45].

•Macitentan – The MELODY-1 trial in 63 patients with PH-LHD with Cpc-PH found no evidence of clinical benefit from 12 weeks of therapy with macitentan 10 mg daily compared with placebo [46]. A composite of significant fluid retention or worsening NYHA functional calls was nominally but not significantly worse in patients treated with macitentan. The macitentan group showed no significant change in PVR or PCWP.

●PDE-5 inhibitor - Although the PDE-5 inhibitor sildenafil had a favorable impact on exercise capacity, RV function, peak oxygen consumption, and hemodynamic variables in small studies [47,48], in larger randomized trials not limited to patients with Cpc-PH, a hemodynamic or clinical benefit was not identified [49-51]. A randomized trial studying 216 HFpEF patients, in which the presence of PH was not a specified inclusion criterion, found no benefit from sildenafil treatment [49]. In a randomized trial of 54 PH-HFpEF patients, sildenafil did not improve PAP, PCWP, cardiac output, or peak oxygen consumption, though this study did not require high PVR or DPG [50]. In a randomized trial of 200 patients with residual PH-LHD after successful correction of valvular heart disease, major clinical outcomes were worse in the sildenafil group compared with placebo [51]. Finally, in a large, multicenter, observational study of LVAD recipients, approximately 10 percent were treated with PDE-5 inhibitors prior to LVAD implantation. Even after propensity matching, preoperative use of PDE-5 inhibitors was associated with an increased incidence of severe, early right HF [52].

●Soluble guanylate cyclase stimulators – Randomized trials of soluble guanylate cyclase stimulators in patients with HF have shown no significant improvement in primary endpoints but have suggested potential beneficial effects that require further study. In a randomized trial of the soluble guanylate cyclase stimulator riociguat in patients with PH-HFrEF, there was no reduction in the primary end point of mPAP or exercise capacity [53]. The SOCRATES-REDUCED trial in patients with HF with LVEF <45 percent and SOCRATES-PRESERVED trial in patients with HF with LVEF ≥45 percent also compared the effects of soluble guanylate cyclase stimulator vericiguat (in varying doses) to placebo [54,55]. In these trials, vericiguat did not have a significant effect on change of NT-proBNP level at 12 weeks. However, secondary analysis of SOCRATES-REDUCED showed a significant dose-response relationship between vericiguat dose and reductions in NT-proBNP [54]. In SOCRATES-PRESERVED, an exploratory analysis revealed significant improvement in quality of life score (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score) compared with placebo [55].

Management of heart transplant candidates — A favorable hemodynamic response to vasodilators such as nitroprusside, characterized by a reduction in PCWP, mPAP, and PVR, without systemic hypotension, is associated with improved mortality following heart transplant in HFrEF [56]. Additionally, the use of mechanical circulatory support may be used to gradually reduce PVR over time. Despite an elevated PVR at baseline, these patients can still be eligible for heart transplant. On the other hand, some patients have irreversibly elevated PVR and thus are not considered candidates for heart transplantation; heart-lung transplantation may be an alternative option in these patients. These issues are discussed in detail separately. (See "Heart transplantation in adults: Indications and contraindications", section on 'Elevated pulmonary vascular resistance'.)

A strategy of postoperative inhaled nitric oxide and subsequent initiation of sildenafil can be used for the treatment of post-transplant patients when there is concern for residual precapillary PH and/or RV dysfunction [57].

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

●Left-sided heart disease is the most common cause of pulmonary hypertension (PH). PH due to left heart disease (PH-LHD) can occur in patients with heart failure (HF; including HF with reduced ejection fraction [HFrEF], HF with mid-range ejection fraction [HFmrEF], HF with preserved ejection fraction [HFpEF], and HF caused by left-sided valvular disease). (See 'Definitions and classification' above.)

●PH-LHD is defined hemodynamically as a mean pulmonary arterial pressure (mPAP) ≥20 mmHg and a pulmonary capillary wedge pressure (PCWP) ≥15 mmHg. PH-LHD encompasses the following two subgroups (table 2) (see 'Definitions and classification' above and 'Diagnostic criteria' above):

•Isolated post-capillary PH (Ipc-PH) in which mPAP is elevated solely from passive transmission of increased left-sided filling pressure to the pulmonary circulation. Ipc-PH is identified by a PVR <3 Wood units.

and

•Combined post- and precapillary PH (Cpc-PH) in which mPAP is elevated from passive transmission of increased left-sided filling pressures with superimposed pulmonary vascular disease. Cpc-PH is identified by a PVR ≥3 Wood units.

●Patients with Cpc-PH develop pulmonary vascular disease secondary to vasoconstriction and pathologic remodeling of the pulmonary vessels. Contraction of the right ventricle (RV) against this increased afterload can lead to maladaptive hypertrophy, dilatation, and subsequent RV failure. (See 'Pathogenesis' above.)

●PH-LHD should be suspected in patients with left HF when there is clinical evidence suggesting right HF, echocardiographically estimated pulmonary artery systolic pressure exceeds 35 mmHg, or cardiac imaging (such as echocardiography) suggests RV dilation, RV dysfunction, or interventricular septal flattening. (See 'When to suspect PH-LHD' above.)

●In patients with suspected PH-LHD, the clinical evaluation is integrated with a comprehensive transthoracic echocardiogram (TTE) to determine the need for right heart catheterization (RHC). RHC is necessary to confirm a diagnosis and further categorize the disease based on the diastolic pulmonary vascular pressure gradient (DPG), transpulmonary gradient (TPG), and pulmonary vascular resistance (PVR). (See 'Initial diagnostic evaluation' above.)

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

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

●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 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 'Management' above.)

●Based on the available evidence, PH-targeted therapy is not indicated for routine use in PH-LHD. For selected patients with PH-LHD meeting all of the following criteria, we suggest phosphodiesterase-5-inhibitor (PDE-5) therapy (eg, sildenafil) (Grade 2C): documented Cpc-PH with associated RV dysfunction, PCWP low enough that risk of pulmonary edema is deemed low, symptoms persist despite near normalization of the PCWP, and there is evidence of a clinical response to PDE-5 therapy to warrant continued use. (See 'Targeted therapy for pulmonary hypertension' above.)