Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease

Abstract

The development of pulmonary hypertension (PH) is common and has adverse prognostic implications in patients with heart failure due to left heart disease (LHD), and thus far, there are no known treatments specifically for PH-LHD, also known as group 2 PH. Diagnostic thresholds for PH-LHD, and clinical classification of PH-LHD phenotypes, continue to evolve and, therefore, present a challenge for basic and translational scientists actively investigating PH-LHD in the preclinical setting. Furthermore, the pathobiology of PH-LHD is not well understood, although pulmonary vascular remodeling is thought to result from (1) increased wall stress due to increased left atrial pressures; (2) hemodynamic congestion-induced decreased shear stress in the pulmonary vascular bed; (3) comorbidity-induced endothelial dysfunction with direct injury to the pulmonary microvasculature; and (4) superimposed pulmonary arterial hypertension risk factors. To ultimately be able to modify disease, either by prevention or treatment, a better understanding of the various drivers of PH-LHD, including endothelial dysfunction, abnormalities in vascular tone, platelet aggregation, inflammation, adipocytokines, and systemic complications (including splanchnic congestion and lymphatic dysfunction) must be further investigated. Here, we review the diagnostic criteria and various hemodynamic phenotypes of PH-LHD, the potential biological mechanisms underlying this disorder, and pressing questions yet to be answered about the pathobiology of PH-LHD.

A Novel Rat Model of Mild Pulmonary Hypertension Associated with Pulmonary Venous Congestion Induced by Left Pulmonary Vein Banding

“…PH-LHD is thought to occur as a result of increased back pressure due to left heart pathology [ 9 ]. In congestive HF, pulmonary congestion due to increased left atrial pressure results in blood accumulation and pressure elevation in pulmonary veins.…”

“…Despite this unmet medical need in this large group of PH patients, the limited number of animal models of PH-LHD has hampered advancing the understanding of its pathophysiology and development of new therapies [ 7 ]. While no model perfectly recapitulates the heterogeneity of PH-LHD in humans, a number of models have recently been proposed that provide mechanistic insight into how comorbidities known to associate with LHD may contribute to pulmonary vascular remodeling [ 8 , 9 ]. However, given the potent prognostic impact of PH in LHD patients, we sought to establish a novel model of PH-LHD in which the pulmonary vasculature is the main site of changes due to pulmonary congestion.…”

Pulmonary Hypertension Association's 2022 International Conference Scientific Sessions Overview

“…Group 2 PH is the most common type of PH, making up about 2/3rd of prevalent cases with evidence of increasing incidence. 72,73 Group 2 PH can result from elevations in LV filling pressures due to LV systolic or diastolic dysfunction, mitral valve disease, or left atrial dysfunction/stiffness, 74 which can all contribute to elevations of PAWP. 75 Cases of Group 2 PH can be further phenotyped to isolated postcapillary or combined pre-and postcapillary (Cpc-PH) based on whether the PVR is elevated to >3 WU, indicating the presence of concurrent vascular remodeling.…”

Group 2 pulmonary hypertension: from diagnosis to treatment

“…Pulmonary hypertension frequently accompanies left heart disease (PHLHD) and is associated with worse prognosis than left heart disease without pulmonary hypertension [1][2][3]. Because of its frequency, prognostic implications, diagnostic challenges, and evolving treatment strategies, PHLHD is a frequent subject of publications [4 && , [5][6][7][8][9][10][11][12][13][14]. Diagnosis of PHLHD (group 2) requires recognition of patient characteristics that pose risk for having left heart disease.…”