More than just a small left ventricle: the right ventricular fibroblast and ECM in health and disease

Abstract

Fibroblasts intricately organize and regulate the extracellular matrix (ECM) in cardiac health and disease. Excess deposition of ECM proteins causes fibrosis, resulting in disrupted signaling conduction and contributing to the development of arrhythmias and impaired cardiac function. Fibrosis is causally involved in cardiac failure in the left ventricle (LV). Fibrosis likely occurs in right ventricle (RV) failure yet mechanisms remain unclear. Indeed, RV fibrosis is poorly understood with mechanisms often extrapolated from the LV to the RV. However, emerging data suggests that the LV and RV are distinct cardiac chambers and differ in regulation of the ECM and response to fibrotic stimuli. In the present review, we will discuss differences in ECM regulation in the healthy RV and LV. We will discuss the importance of fibrosis in the development of RV disease in pressure overload, inflammation, and aging. During this discussion, we will highlight mechanisms of fibrosis with respect to the synthesis of ECM proteins while acknowledging the importance of considering collagen breakdown. We will also discuss current knowledge of anti-fibrotic therapies in the RV and the need for additional research to help delineate the shared and distinct mechanisms of RV and LV fibrosis.

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons

“…We speculate that the region-specific response to oxidative stress may be related to stress adaptation in the left side of the heart, possibly influenced by the differential pressure loads between the heart chambers. For example, the LV works against higher pressure to pump oxygenated blood through the peripheral systemic vasculature while the RV works against low pressure to deliver deoxygenated blood to the lungs [35]. The elevated pressure load in the LV is a form of mechanical stress and pressure overload is linked to increased formation of superoxide anions [36].…”

Defining Transcriptomic Heterogeneity between Left and Right Ventricle-Derived Cardiac Fibroblasts

“…The pulsed Doppler sample volume was placed slightly distal to the site of constriction to record the stenotic flow jet during systole. The peak velocity (V max ) of the stenotic jet was measured to calculate the maximal pressure gradient using a simplified Bernoulli equation: maximal pressure gradient (mmHg) = 4(V max ) 2 . Then, the diameter of the pulmonary orifice at peak systole and the Doppler blood flow velocity spectrum at the same level were measured for calculating the right ventricular stroke volume and cardiac output.…”

“…This phenomenon occurs primarily through the actions of resident cardiac fibroblasts (CFs), which become activated following cardiac injury and upregulate the secretion of ECM and other pro-fibrotic proteins [1]. Different pathophysiologic stimuli can trigger CF activation in the left ventricle (LV) and/or right ventricle (RV), creating distinct patterns of fibrosis throughout the myocardium [2].…”