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

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 pathophysiological insight back to the growing number of asymptomatic individuals at increased risk for HF development, who may benefit most from early therapeutic interventions.