The emerging role of sacubitril/valsartan in pulmonary hypertension with heart failure

Abstract

Pulmonary hypertension due to left heart disease (PH-LHD) represents approximately 65%-80% of all patients with PH. The progression, prognosis, and mortality of individuals with left heart failure (LHF) are significantly influenced by PH and right ventricular (RV) dysfunction. Consequently, cardiologists should devote ample attention to the interplay between HF and PH. Patients with PH and HF may not receive optimal benefits from the therapeutic effects of prostaglandins, endothelin receptor antagonists, or phosphodiesterase inhibitors, which are specific drugs for pulmonary arterial hypertension (PAH). Sacubitril/valsartan, the angiotensin receptor II blocker-neprilysin inhibitor (ARNI), was recommended as the first-line therapy for patients with heart failure with reduced ejection fraction (HFrEF) by the 2021 European Society of Cardiology Guidelines. Although ARNI is effective in treating left ventricular (LV) enlargement and lower ejection fraction, its efficacy in treating individuals with PH and HF remains underexplored. Considering its vasodilatory effect at the pre-capillary level and a natriuretic drainage role at the post-capillary level, ARNI is believed to have a broad range of potential applications in treating PH-LHD. This review discusses the fundamental pathophysiological connections between PH and HF, emphasizing the latest research and potential benefits of ARNI in PH with various types of LHF and RV dysfunction.

Keywords: clinical benefits; left heart failure; pharmacological mechanism; pulmonary hypertension; right ventricular dysfunction; sacubitril/valsartan.

Figure 1

RAAS and NP mechanism in PH. In the pulmonary circulation, activated RAAS induce smooth muscle cell contraction. Angiotensin-(1–7) counteracts angiotensin II to produce vasodilatory effects. BNP released from heart ventricle counteracts RAAS to attenuate vasoconstriction, hypertrophy, fibrosis and other deleterious effects. RAAS, renin-angiotensin-aldosterone system; NP, natriuretic peptide; PH, pulmonary hypertension; PAEC, pulmonary artery endothelial cells; PASMC, pulmonary artery smooth muscle cell; Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1–7), angiotensin-(1–7); ACE, angiotensin-converting enzyme; BNP, B-type natriuretic peptide; NPR-A, natriuretic peptide receptor-A; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate.

Figure 2

Interaction and pathogenesis of PH in LV/RV heart failure. Hypoxia, precapillary component and increased PAP may trigger pulmonary arterial vasoconstriction, leading to increased PVR and reduced PA compliance. Functional mitral regurgitation will further result in elevations of LAP and PVR. Elevated filling pressures cause PH, which is a consequence of systolic or diastolic LV dysfunction. The persistent elevations of pulmonary pressures and PVR result in dilatation and maladaptive remodeling of right heart chambers, and ultimately RV failure. PH, pulmonary hypertension; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; PA, pulmonary artery; LAP, left atrial pressure; LV, left ventricular; RV, right ventricular.