Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is defined as clinical features of heart failure, ideally with biomarker evidence such as elevated plasma natriuretic peptide levels, in the setting of an ejection fraction (EF) greater than 50% and imaging evidence of diastolic left ventricular dysfunction [1,2]. In the absence of cardiac imaging or invasive hemodynamics, this is a clinical syndrome that is often indistinguishable from heart failure with reduced ejection fraction (HFrEF). HFpEF and HFrEF present with a cadre of comparable signs and symptoms including jugular venous distention, pulmonary rales on auscultation, breathlessness, orthopnea, exercise intolerance, exertional dyspnea, fatigue and peripheral edema. HFpEF accounts for at least half of all diagnoses of heart failure [1,2]. Pulmonary hypertension (PH) is a common complication of HFpEF that is linked to worse disease morbidity and mortality. In fact, mortality has been linked to increases in the intrinsic pulmonary vascular resistance in the setting of increased left ventricular end diastolic pressure, characterized hemodynamically by rises in the transpulmonary pressure gradient, pulmonary vascular resistance or diastolic pressure gradient. Despite being the most common form of PH, there are no approved therapies for the treatment of PH secondary to HFpEF. This review will summarize the hemodynamic classifications of PH in the setting of HFpEF, mechanisms of disease, the potential contribution of pulmonary vascular disease to poor outcomes in patients with HFpEF, and new approaches to therapy.

Keywords: HFpEF; PH-HFpEF; Pulmonary Hypertension.

Figure 1:

Subphenotypes of PH-HFpEF. Top Figure: Isolated post-capillary PH (Ipc-PH) refers to an elevated pulmonary arterial pressure (PAP) due to passive transmission of left sided pressures. This subphenotype can be defined by a transpulmonary gradient (TPG) less than or equal to 12, a diastolic pressure gradient (DPG) less than 7, or a pulmonary vascular resistance (PVR) less than or equal to 3 WU. Bottom Figure: Combined pre- and post-capillary PH (Cpc-PH) refers to an out of proportion elevation of PAP due to passive transmission of left sided pressures in addition to pulmonary vascular remodeling. This is defined by a TPG greater than 12, DPG greater than or equal to 7, or a PVR greater than 3.

Figure 2:

Data obtained from the University of Pittsburgh and previously published with permission by Vanderpool et al representing the breakdown of patients with PH secondary to left heart disease (LHD) and PH-HFpEF by transpulmonary gradient (TPG), pulmonary vascular resistance (PVR), and diastolic pulmonary gradient (DPG)⁷.

Figure 3:

Risk factors for the development of PH-HFpEF include female gender, atrial enlargement, coronary artery disease, right ventricular hypertrophy and features of the metabolic syndrome including diabetes, hypertension, and obesity.

Figure 4:

Schematic of the molecular pathways proposed to be aberrant in PH-HFpEF and the drugs which have targeted these pathways. Patients with HFpEF have abnormal nitric oxide (NO) bioavailability which results in an abnormal NO-sGC-CGMP pathway ultimately leading to impaired vascular smooth muscle cell (SMC) and myocardial relaxation which impairs myocardial relaxation and results in myocardial stiffness. Aberrancies in this pathway have been the molecular target of drugs including nitrite, vericiguat, riociguat, and sildenafil. The Endothelin-1 pathway has also been implicated in HFpEF. Endothelin-1, a potent vasoconstrictor, is increased in HFpEF. Via the interaction with the Endothelin receptor a (ET_AR) and endothelin receptor B (ET_BR) this results in a vascular smooth muscle cell proliferation and vasoconstriction which is more profound than the co-occurring ET_BR mediated endothelial cell vasodilation. Vascular smooth muscle cell and fibroblast ET_AR and ET_BR are the targets of ambrisentan, bosentan, and macitentan.