Pathophysiological Mapping of Experimental Heart Failure: Left and Right Ventricular Remodeling in Transverse Aortic Constriction Is Temporally, Kinetically and Structurally Distinct

Abstract

A growing proportion of heart failure (HF) patients present with impairments in both ventricles. Experimental pressure-overload (i.e., transverse aortic constriction, TAC) induces left ventricle (LV) hypertrophy and failure, as well as right ventricle (RV) dysfunction. However, little is known about the coordinated progression of biventricular dysfunction that occurs in TAC. Here we investigated the time course of systolic and diastolic function in both the LV and RV concurrently to improve our understanding of the chronology of events in TAC. Hemodynamic, histological, and morphometric assessments were obtained from the LV and RV at 2, 4, 9, and 18 weeks post-surgery.Results: Systolic pressures peaked in both ventricles at 4 weeks, thereafter steadily declining in the LV, while remaining elevated in the RV. The LV and RV followed different structural and functional timelines, suggesting the patterns in one ventricle are independent from the opposing ventricle. RV hypertrophy/fibrosis and pulmonary arterial remodeling confirmed a progressive right-sided pathology. We further identified both compensation and decompensation in the LV with persistent concentric hypertrophy in both phases. Finally, diastolic impairments in both ventricles manifested as an intricate progression of multiple parameters that were not in agreement until overt systolic failure was evident.Conclusion: We establish pulmonary hypertension was secondary to LV dysfunction, confirming TAC is a model of type II pulmonary hypertension. This study also challenges some common assumptions in experimental HF (e.g., the relationship between fibrosis and filling pressure) while addressing a knowledge gap with respect to temporality of RV remodeling in pressure-overload.

Antibody‐mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload

“…The AAC model is a strong stimulus for cardiac fibrosis and triggers rapid and severe pressure overload with early onset LV hypertrophy 8 and fibrosis 11‐13 . In comparison, myocardial fibrosis and cardiac hypertrophy occurs later on in the TAC or ANGII models 14‐16 . We show here in the newly studied AAC model that neutralizing antibodies against IL11 or IL11RA reduces myocardial fibrosis and that this is associated with lesser ERK1/2 activation.…”

Nanoscale reorganization of sarcoplasmic reticulum in pressure-overload cardiac hypertrophy visualized by dSTORM

“…Transverse aortic constriction surgery and time-point analysis was performed as previously described by Platt et al . 12 . Progressive pathological left ventricular hypertrophy was observed at 2 and 4-week post-TAC with peak left ventricular pressure observed at 4-week post-TAC surgery.…”

“…As previously described 12 , TAC was applied to the descending aorta by placing a 7-0 silk suture with the aid of a 27-gauge hypodermic needle on CD1 mice (Charles River Laboratory) at 8 to 10 weeks of age. Sham mice underwent the same surgical procedures except the ligature was not tightened; surgical details have been published previously 12,13 . Hearts were harvested 2 weeks and 4 weeks post TAC or sham surgery and cardiomyocytes were isolated.…”

Effects of combination treatment with alprostadil and statins in patients with refractory heart failure

“…As the heart fails, preload and afterload in ventricles increases, resulting to oxidative damage in cardiac muscle cells (Reboul et al 2017;Ribeiro-Samora et al 2017), excessive oxygen free radicals, increased apoptosis, imbalance in extracellular matrix, thickened and prolonged cardiac muscle cells, spherical changes of heart chambers, and ventricular remodeling (Merlo et al 2018;Platt et al 2018). Oxidative stress damage and imbalance in the extracellular matrix play a vital role in the pathophysiological process of heart failure.…”