Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function

Abstract

Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model. NEW & NOTEWORTHY In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.

Animal models of pulmonary hypertension: Getting to the heart of the problem

“…Interstitial and perivascular RV fibrosis are commonly observed in SuHx and MCT rats and to a lesser extent in PAB rats with adaptive RVH (Bogaard et al, 2009b;De Man et al, 2012a;Borgdorff et al, 2013b), suggesting that fibrotic remodelling is associated with decompensation of RV function. In support of this notion, RV fibrosis was absent in a mouse model of LHD-PH and adaptive RVH (Philip et al, 2019), This article is protected by copyright. All rights reserved.…”

“…Left anterior coronary artery ligation, a common method of inducing myocardial infarction (MI), has been widely used to study PH-HFrEF in rats (Jasmin et al, 2003;Rossoni et al, 2007;Jiang et al, 2010;Yin et al, 2011;Kemi et al, 2013 (Philip et al, 2019). The Fulton index was unchanged in infarcted mice, indicating that RVH developed in proportion to LV remodelling.…”

Reply to Tello et al.: Pending Right Heart Failure in Healthy Preterm-Born Subjects?

“…As elegantly demonstrated decades ago (6, 7), although LV pump function is largely insensitive to RV pump function, the reverse is not true. As we recently showed in a mouse model of pulmonary hypertension secondary to left heart failure, impaired LV function depresses RV-PA Ees/Ea even if the right ventricle itself is in an adaptive, not maladaptive, state of remodeling (8). We anticipate that this is the case in our cohort of preterm-born subjects but must await invasive LV hemodynamic data to prove the point.…”

Current Understanding of the Right Ventricle Structure and Function in Pulmonary Arterial Hypertension

“…The world health organization (WHO) classifies PH into 5 different groups (Simonneau et al, 2019): Group I: PH due to pulmonary arterial hypertension (PAH) or pre-capillary PH, Group II: PH due to left heart disease (PH-LHD), Group III: PH due to underlying lung disease/hypoxia, Group IV: Chronic thromboembolic PH, Group V: PH with multifactorial underlying cause or unclear mechanism. While PH-LHD remains the most common type of PH (Guazzi and Borlaug, 2012), limited data exists on RV biomechanics in the setting of PH-LHD (Simon et al, 2016;Zou et al, 2018;Philip et al, 2019;Bashline et al, 2020), while several biomechanical studies have evaluated RV function in PAH. Hence, the current review focuses on biomechanics of the RV in PAH -the precapillary phenotype of PH (Group I).…”