Overview of WHO Group 2 Pulmonary Hypertension Due to Left Heart Disease

NOMENCLATURE, CLASSIFICATION, AND DEFINITIONS OF PH-LHD

The nomenclature that has emerged to categorize patients with PH-LHD attempts to describe the clinical context, pathophysiology, and hemodynamic features seen in these patients. This has resulted in a wide variety of terms used in an effort to accurately describe patients with PH-LHD. Multiple different terms, sometimes used in combination, may be appropriate to describe the unique characteristics of an individual patient with PH-LHD. Adding to this complexity is changes in terminology that have occurred over time as our understanding of PH-LHD has evolved. Recent guidelines attempted to simplify this language and to classify patients with PH-LHD according to hemodynamic characteristics (Table 1).

Table 1. Nomenclature for Pulmonary Hypertension-Left Heart Disease.

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The hemodynamic definition of PH is a sustained elevation in mean pulmonary artery pressure (mPAP) ≥25 mm Hg. The usual hemodynamic findings in a patient with PH-LHD are mPAP ≥25 mm Hg in combination with elevated left heart filling pressures, defined as a pulmonary artery wedge pressure (PAWP) >15 mm Hg or left ventricular end diastolic pressure (LVEDP) >15 mm Hg. The clinical characteristics (ie, presence of reduced ejection fraction [EF], clinical features of HFpEF, presence of valvular heart disease) are considered together with the hemodynamic features to arrive at a final diagnosis of PH-LHD.

In patients with PH-LHD, it is important to characterize elevated mPAP as resulting only from passive transmission of elevated left heart filling pressures proximally into the pulmonary circulation vs increased pulmonary arteriolar resistance resulting from changes in the function and structure of pulmonary arterioles. The terms used to describe patients in whom PH results from transmission of elevated left heart filling pressures include pulmonary venous hypertension and passive PH. The most recent guidelines recommend using the term isolated postcapillary PH (Ipc-PH) for this group of patients. In these patients, reduction of left heart filling pressures to normal also reduces mPAP to normal.111

In other patients, the elevated mPAP is not fully accounted for by passive, proximal transmission of elevated left heart filling pressures. In these patients, it is believed that long-standing elevations in mPAP result in part from vasoconstriction and remodeling of the pulmonary arterioles so that mPAP is elevated out of proportion to the PAWP. Terms that have been used to describe this hemodynamic profile include mixed and out-of-proportion PH. The most recent guidelines recommend using the simple descriptive term “combined post-capillary and precapillary PH” (Cpc-PH).

Differentiating Ipc-PH from Cpc-PH is important because it has prognostic implications, especially in patients undergoing evaluation for heart transplant (Figure 2). Typically, PH-LHD has been characterized by measures of resistance and pressure difference across the pulmonary vasculature (Table 2). Patients have been considered to have Ipc-PH if the pulmonary vascular resistance (PVR) and transpulmonary gradient (TPG) are normal and Cpc-PH if the PVR and TPG are elevated. Recent guidelines support the use of the diastolic pressure gradient (DPG) to differentiate the hemodynamic subtypes of PH-LHD.11 The rationale for this recommendation is that the DPG is less dependent on stroke volume and left atrial pressure, and it was shown to be predictive of survival and correlated with pathologic changes.1213 However, the DPG is subject to error1415 and the association with survival is inconsistent, a reminder that a single measurement is rarely useful to characterize patients with PH.16–18

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Table 2. Hemodynamic Parameters Used in the Classification of Pulmonary Hypertension-Left Heart Disease.

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EPIDEMIOLOGY

Accurate prevalence estimates for PH-LHD are limited by factors such as reliance on echocardiographic assessments of pulmonary artery pressure (PAP) to identify affected patients,2223 and inconsistent definitions and cutoffs to diagnose PH-LHD. Studies that make use of gold-standard invasive hemodynamics may be affected by referral bias since sicker patients are likely referred for right heart catheterization (RHC). Even well done invasive studies only provide data at a single time point while the patient is at rest, fasting, and possibly sedated—all of which may affect hemodynamic measurements.24

Estimated rates of PH in LHD vary widely. The prevalence of Cpc-PH has ranged from 25% to 47% in hospitalized patients, and was 40% in a recent large ambulatory HFrEF population.102526 Among patients with HFpEF, PH is present in 36% to 83%. A large community study examined echocardiograms from 244 patients with HFpEF and 719 hypertensive controls. Pulmonary hypertension, defined as pulmonary artery systolic pressure (PASP) >35 mm Hg was found in 83% of HFpEF patients compared to only 8% of controls. Using a higher PASP cutoff of 45 mm Hg would have resulted in prevalence of about 50%,727 a rate similar to that found in another study of 299 patients with HFpEF.28 A single-center registry of patients undergoing RHC found PH, defined as PVR >2.5 or TPG >12, in 69% of HFpEF patients evaluated.29

Left-sided valvular heart disease is also commonly associated with PH and is important to recognize because it is an indication for valve replacement or repair. Mitral stenosis is the valvular lesion most often associated with PH, at a rate of up to 73%.30 Pulmonary hypertension occurs at lower rates in patients with mitral regurgitation (23%–44%) and aortic stenosis (29%–47%).31–37

PROGNOSIS

Compared to patients with LHD and no PH, patients with PH-LHD have worse outcomes, including worse survival.42738–41 This is true in both HFpEF and HFrEF and in studies using both echocardiography and invasive hemodynamics to diagnose PH.41 Additionally, survival worsens as PAP increases. A study of patients undergoing endomyocardial biopsy showed a 25% increase in the risk of death for every increase of 5 mm Hg in mPAP.4 Patients with Cpc-PH generally have more severe hemodynamic impairment and worse prognosis compared to Ipc-PH.41026

PATHOBIOLOGY AND PATHOPHYSIOLOGY

Our understanding of the pathophysiology of PH-LHD has improved in recent years; however, significant gaps remain. It is believed that the first event in the development of PH-LHD is increasing left heart filling pressures and pulmonary venous hypertension. Even when left ventricular (LV) systolic function is normal, diastolic filling abnormalities may result in increased PAP.42 Additionally, elevated left heart filling pressures also reduce compliance of the pulmonary vasculature and increase RV afterload by enhancing pulmonary artery wave reflections.43 Next, pulmonary arteriolar vasoconstriction occurs secondary to endothelial dysfunction characterized by decreased production of and/or decreased responsiveness to nitric oxide (NO), as well as overproduction of endothelin-1 (ET-1), activation of the reninangiotensin-aldosterone system (RAAS), and neurogenic activation. Elevated PAPs lead to injury, followed by pathologic remodeling of the pulmonary arterioles including muscularization, medial hypertrophy, and neointimal proliferation.44–49 Ultimately the increased afterload imposed on the RV leads to RV systolic dysfunction and failure.350

ASSESSMENT AND DIAGNOSTIC APPROACH

Making a diagnosis of PH-LHD is challenging because symptoms are nonspecific, diagnostic tests can be difficult to interpret, and PH may be multifactorial. Consequently, PH-LHD is often incorrectly diagnosed and treated as PAH, especially in elderly patients.5152 A thoughtful and comprehensive approach to the evaluation of PH is needed so that appropriate treatment can be chosen.

History and Physical Examination

Information gathered during a comprehensive history and physical examination is important because it is used to prioritize next steps in the diagnostic evaluation and to provide context for the interpretation of diagnostic testing (Table 3). Details about congenital heart disease, murmurs, valvular disease, HFrEF and HFpEF, and coronary artery disease (CAD), as well as an assessment of risk factors for LHD should be ascertained. Special attention should be paid to factors associated with HFpEF29 such as female gender, advanced age, diabetes, hypertension, CAD, arrhythmias, and sleep-disordered breathing. Orthopnea and paroxysmal nocturnal dyspnea in a patient with PH strongly suggest the presence of LHD. Physical examination findings that point toward LHD include pulmonary crackles, left-sided S3 or S4, left-sided murmurs, or irregular heart sounds consistent with arrhythmia.

Table 3. Assessment of Left Heart Disease in Pulmonary Hypertension.

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Echocardiography

Echocardiography is the most useful noninvasive modality for the evaluation of PH. It is easy to obtain and may immediately point to LHD as a cause of PH (Table 4, Figure 3). Echocardiographic findings of diastolic dysfunction are well described,53 but are potentially insensitive for the diagnosis of HFpEF.275455 Therefore, HFpEF should be suspected when findings such as LV hypertrophy and left atrial enlargement are present.29 In a community-based study of 244 HFpEF patients and 719 hypertensive controls, elevated PAP on echocardiography was both sensitive and specific for the diagnosis of HFpEF,27 suggesting that the presence of PH on echocardiography is often itself evidence of HFpEF.

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Table 4. Distinguishing Pulmonary Hypertension-Left Heart Disease From Pulmonary Artery Hypertension Using Echocardiography.

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Echocardiographic estimation of PASP is the most commonly used method to assess for PH. To estimate the PASP, the tricuspid regurgitant (TR) jet is imaged and interrogated with spectral Doppler in multiple echo windows, and the peak TR jet velocity is determined. The PASP is calculated using the modified Bernoulli equation: PASP=4(V2)+right atrial (RA) pressure. This technique is limited because it cannot be utilized in patients without an adequate TR jet and spectral Doppler signal.9 Errors in estimation of PASP may lead to important misclassification of PH.23

The shape of the ventricular outflow tract Doppler signal is useful to differentiate patents with PH-LHD. Transient flow deceleration in the right ventricular outflow tract during systole is caused by early return of reflected pulmonary arterial waves, resulting in notched pattern of the Doppler signal. Early wave reflection occurs in the setting of elevated PVR, and notching occurs earlier in systole as PVR increases. Thus, the presence of PH without notching strongly favors a diagnosis of PH-LHD, specifically Ipc-PH.56

Echocardiography is also useful to assess for RV dysfunction, which is an important marker of increased mortality.357 Abnormalities of RV size, thickness, and function also provide evidence of clinically significant PH when the PASP cannot be estimated, or indicate that the severity of PH is worse than the estimated PASP suggests. Measurements including RV fractional area change, tricuspid annular systolic plane excursion (TAPSE), tissue Doppler imaging of the tricuspid valve annulus, and strain analysis may all be useful to assess RV systolic function and have prognostic value.57–59 These measurements have important limitations so that the overall impression of an experienced echocardiographer is important.

MANAGEMENT OF PH-LHD

With few exceptions, the appropriate therapy for PH-LHD is optimizing treatment of the underlying LHD. In the case of HFrEF and HFpEF, therapy should include guideline-recommended treatments with diuretics, vasodilators, and neurohormonal antagonists, as well as with device and surgical therapies when appropriate.67 The benefits of these therapies were emphasized in a recent study showing that adjustment of diuretics and vasodilator agents in response to data from continuous PAP monitoring devices reduced heart failure hospitalizations.68 Comorbidities that may contribute to PH such as sleep apnea, pulmonary embolism, and chronic obstructive pulmonary disease should also be identified and aggressively treated.

Increased morbidity and mortality associated with PH in patients with LHD makes PH an attractive therapeutic target. However, despite beneficial acute hemodynamic effects and small studies with phosphodiesterase type 5 (PDE5) inhibitors that have shown improvement in exercise capacity, no study has shown PAH therapies to be beneficial in PH-LHD, and some PAH therapies have been associated with significant adverse effects including increased mortality.1869 Most studies of PAH therapies in LHD have not specifically enrolled PH-LHD, so it is possible that undetected benefits will be found in future trials.

Data demonstrating acute hemodynamic improvements including reduced PAWP, PVR, and increased cardiac output provided the rationale for the Flolan International Randomized Survival Trial (FIRST) of epoprostenol in HFrEF. However, the FIRST trial was stopped early when a trend toward increased mortality in the epoprostenol group was identified.70 Multiple trials of endothelin receptor antagonists for the treatment of HFrEF have been performed and shown either no improvement or worsening edema and hospitalization. Several of these negative studies have never been published.71–75

Phosphodiesterase type 5 inhibitors also have been shown to have beneficial acute hemodynamic benefits including improvements in gas exchange, skeletal muscle function, diastolic function, and RV function69; reduced PVR and TPG; increasing cardiac output; improvements in peak oxygen consumption and 6-minute walk; and decreased heart failure hospitalizations.7677 Similar improvements have been shown in patients treated with the soluble guanylate cyclase stimulator riociguat.78 In clinical practice, sildenafil also decreases PVR and improves RV function after heart transplantation and LVAD implantation.7980 Despite these encouraging findings, long-term benefits of treatment with these agents have not yet been demonstrated in a randomized controlled trial so that they should not be routinely prescribed in patients with PH-LHD. Additional trials are now underway.

Prolonged treatment with intravenous vasodilators and mechanical support may restore vasodilator response in patients with HFrEF found to have initially irreversible Cpc-PH during heart transplant evaluation.81 In several reports, LV assist device support has been shown to be effective in reversing PH permitting heart transplant without increased rates of RV failure or death.798283

CONCLUSION

Much remains unknown about PH-LHD. An improved understanding of triggers and development of vascular changes in PH-LHD as well as the relationship between the LV and the pulmonary vasculature is needed. Failure of studies to demonstrate beneficial long-term outcomes in PH-LHD patients treated with pulmonary vasodilators suggests that PH in this setting may be a marker of severe or inadequately treated left heart failure. Studies that are specifically designed to focus on pulmonary vasodilators in PH-LHD patients with optimally managed LHD are needed.