Of Mouse and Man: Cross-Species Characterization of Hypertensive Cardiac Remodeling

Abstract

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering.

Crosstalk between oxidative stress and epigenetic marks: New roles and therapeutic implications in cardiac fibrosis

“…Replacement or scar fibrosis, which involves the formation of fibrotic tissue to replace damaged or necrotic cardiomyocytes [ 71 ], is a common occurrence in CHD models. In hypertension, fibrosis is initiated in the perivascular space [ 72 ], and it has been demonstrated that hypertensive heart disease is characterized by predominant perivascular fibrosis in both human and murine models [ 73 ].…”

Farrerol prevents Angiotensin II-induced cardiac remodeling in vivo and in vitro

“…Studies have shown that the increased expression of proinflammatory factors promotes cardiac remodeling. The initiation of the inflammatory response causes the accumulation of extracellular matrix and accelerates the process of myocardial fibrosis ( Cooper et al, 2022 ). Oxidative stress is a key element that affects cardiac remodeling ( Mahmoudi et al, 2008 ).…”

Semiautomated pipeline for quantitative analysis of heart histopathology

“…Interestingly, HeartJ analysis revealed that human and murine cardiomyocytes are approximately equal in diameter and hypertrophy within a similar range. So far, there is only one publication that directly compares human and murine cardiac hypertrophy, describing different cross sectional areas of cardiomyocytes and degrees of hypertrophy, however, only quantifying cross sections of cardiomyocytes with nuclei [ 15 ]. In general, the relationship between body size and cell size is controversial and complicated by the different use of cell volume, cell cross sectional area, or cell diameter [ 16 , 17 ].…”