Pulmonary Hypertension in Left Heart Diseases: Pathophysiology, Hemodynamic Assessment and Therapeutic Management

Abstract

Pulmonary hypertension (PH) associated with left heart diseases (PH-LHD), also termed group 2 PH, represents the most common form of PH. It develops through the passive backward transmission of elevated left heart pressures in the setting of heart failure, either with preserved (HFpEF) or reduced (HFrEF) ejection fraction, which increases the pulsatile afterload of the right ventricle (RV) by reducing pulmonary artery (PA) compliance. In a subset of patients, progressive remodeling of the pulmonary circulation resulted in a pre-capillary phenotype of PH, with elevated pulmonary vascular resistance (PVR) further increasing the RV afterload, eventually leading to RV-PA uncoupling and RV failure. The primary therapeutic objective in PH-LHD is to reduce left-sided pressures through the appropriate use of diuretics and guideline-directed medical therapies for heart failure. When pulmonary vascular remodeling is established, targeted therapies aiming to reduce PVR are theoretically appealing. So far, such targeted therapies have mostly failed to show significant positive effects in patients with PH-LHD, in contrast to their proven efficacy in other forms of pre-capillary PH. Whether such therapies may benefit some specific subgroups of patients (HFrEF, HFpEF) with specific hemodynamic phenotypes (post- or pre-capillary PH) and various degrees of RV dysfunction still needs to be addressed.

Keywords: left heart disease; pathophysiology; pulmonary hypertension; therapeutics.

Figure 3

Right ventricle afterload, contractility and the concept of right ventricle–pulmonary artery coupling. (A) Pulmonary vascular resistance (PVR) and compliance (PAC) are related according to a hyperbolic relationship, and their product, the pulmonary artery time constant (RC-time), is invariable. In left heart disease, the increased PAWP shifts the relationship to the left, with a reduction in the RC-time, and more reduced PAC at any value of PVR (increased pulsatile afterload). (B) Right ventricle pressure–volume (PV) curves for the determination of end-systolic elastance (Ees). Ees is expressed as the slope of the end-systolic pressure–volume relationship of successive PV loops at rapidly reduced preload. (C) Isolated right ventricle PV curve for the simplified assessment of Ees (end-systolic pressure/end-systolic volume, ESP/ESV) and effective arterial elastance (Ea) as a measure of RV afterload (Ea = ESP/SV). The ratio of Ees to Ea defines RV-PA coupling. (D) Right ventricle PV loops with different Ees/Ea ratios. The blue loop indicates an RV exposed to increased afterload, with adapted contractility through homeometric adaptation and maintenance of RV-PA coupling. The red loop shows an uncoupled RV with increased dimension (heterometric adaptation). Adapted from Refs. [64,75,76].

Figure 1

Schematic representation of the impact of PAWP on dPAP, mPAP, sPAP and TPG at a given stroke volume of 80 mL. Backwards transmission of PAWP to dPAP at a 1:1 mmHg ratio and >1:1 mmHg rise in sPAP and mPAP, resulting in a TPG of 7 mmHg if PAWP is at 10 mmHg (TPG 1) and of 17 mmHg if PAWP is at 30 mmHg (TPG 2). See text for abbreviations. Adapted from Ref. [30].

Figure 2

Algorithm for the hemodynamic diagnosis of pulmonary hypertension associated with left heart disease (PH-LHD). The black squares indicate the hemodynamic variables obtained during right heart catheterization. The red squares indicate the different diagnoses according to the measured hemodynamic values. The dashed lines indicate the procedure to follow in case of normal hemodynamic variables: in the presence of a clinical probability of PH-LHD, provocative tests are warranted, including either exercise testing or fluid challenge. Abbreviations: PH: pulmonary hypertension; mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; CO: cardiac output; Ipc-PH: isolated post-capillary pulmonary hypertension; Cpc-PH: combined pre- and post-capillary pulmonary hypertension.