Understanding the physiology of heart failure through cellular and in vivo models‐towards targeting of complex mechanisms

Abstract

New Findings r What is the topic of this review?Heart failure is a progressive disease syndrome that, in the early stages, involves subtle tissue and cellullar changes. This review highlights novel imaging techniques that allow quantitative investigation of the underlying pathophysiological mechanisms in vivo. r What advances does it highlight?High-content voltage imaging of the left ventricle showed significant conduction slowing in the mdx mouse model of heart failure, corresponding to selective loss of Na + channels and dystrophin in the lateral cardiac myocyte membrane. Super-resolution STED imaging after myocardial infarction uncovered proliferative, differential remodelling of individual T-tubules and network properties leading to intracellular Ca 2+ release heterogeneity. These techniques reveal potential mechanisms of arrhythmia susceptibility, tissue degeneration and contractile dysfunction.Heart failure (HF) is a complex disease syndrome, which affects physiology at all levels, from the molecule to the whole organism. Following a causative insult, a maladaptive response occurs, which sustains cardiac remodelling and leads to a final common pathway of debilitating HF symptoms. In terms of mechanisms, distinct defects of excitation-contraction coupling compartments and organelles have been identified in cardiac samples of patients and animal models, which include changes in Ca 2+ transport proteins and T-tubules. From a physiological standpoint, the source of regulatory intracellular Ca 2+ is defined by ∼20,000 Ca 2+ release units per cardiac myocyte, which jointly modulate contractile force production. We and others have characterized key changes in protein and membrane components of Ca 2+ release units during HF in patient samples and transgenic models to gain insight into complex disease mechanisms. While earlier HF studies identified intracellular Ca 2+ release as a major cause of contractile dysfunction, electrical dysfunction has gained attention as an important mechanism of HF mortality. In parallel, high-resolution imaging techniques have become instrumental to understand HF mechanisms in the intact cell and tissue environment, supporting translation of novel diagnostic strategies. Indeed, the increased spatial and temporal resolution of different experimental imaging techniques addresses the vastly different scales of HF pathophysiology, to correlate experimental with clinical surrogate markers, and to extend mechanisms to early, often subtle changes in HF. This last goal, in particular, will be essential to translate novel

Mitochondrial quality-control dysregulation in conditional HO-1–/– mice

“…Hmox1-deficient mice are highly susceptible to ischemia/reperfusion (I/R) injury and, after hypoxia, show evidence of right ventricular infarction (10,11). This enzyme system has thus been a focus of attention in several cardiovascular diseases, including heart failure (HF) (12,13), which is accompanied by oxidant-mediated hypertrophy, dilation, fibrosis, and metabolic disturbances that reduce contractile function (14,15). The rare human HO-1 deficiency state and certain polymorphisms of the human HO-1 gene promoter are also associated with the development of cardiovascular disease (16,17).…”

Stimulated Emission Depletion Microscopy

“…The pathophysiology of heart failure is known to take place over vastly different spatial scales, and STED imaging has recently been used to resolve its finer details, revealing membrane remodeling in cardiac myocytes from rat and from a postmyocardial infarction mouse model. − The membrane remodeling can be correlated to heterogenic intracellular Ca 2+ release, which in turn can be an underlying mechanism of arythmia susceptibility, tissue degeneration, and contractile dysfunction (i.e., clinical manifestations of heart failure observed at a later stage). Notably, detailed investigations of nanodomains of Ca 2+ release units in live cardiac myocytes, and the changes in underlying membrane structures cannot be resolved by CLSM nor be investigated by EM.…”

Mouse models of arrhythmogenic cardiovascular disease: challenges and opportunities

“…In addition to the cardiac ion channelopathies, the mouse has also proven to be very useful in efforts to develop experimental models of other inherited [37–39], as well as acquired [40–43], arrhythmogenic cardiovascular diseases. Intracellular Ca 2+ plays a pivotal role in electromechanical coupling in the mammalian heart and, as would be expected, derangements in the regulation of Ca 2+ influx and intracellular Ca 2+ are linked to congenital and acquired arrhythmias [4, 6], including congenital catecholaminergic polymorphic ventricular tachycardia (CPVT).…”