New perspectives on the key role of calcium in the progression of heart disease.

The heart continuously adapts to adjust its output to a continuum of pathophysiological situations ensuring adequate blood distribution. These situations range from high performance in well-trained athletes to failure in a variety of cardiac syndromes. Changes in the concentration of intracellular Ca2+ ([Ca2+]i) are crucial. They have immediate and late effects that can be oversimplified as follows. Immediate effects result from abrupt and large variations in [Ca2+]i triggering contraction after binding to the contractile proteins. These variations are involved in the process known to as excitation-contraction (EC) coupling. In contrast, the late effects involve a process that is, by analogy, referred to as excitation-transcription (ET) coupling. This process involves activation of gene expression by Ca2+. In this scheme, specific and localised elevations of Ca2+ can be converted into changes in gene expression with long-term effects on the adaptation of the heart to a sustained stimulus. There is emerging evidence of an extraordinary diversity of responses, depending on the location, intensity, and duration of Ca2+ signals that can be activated during pathology. Whereas alterations of cellular and molecular mechanisms underlying chronic pathology are relatively well defined, the initial changes and their hierarchy are unknown. However, the actual picture suggests promising perspectives for new therapeutic interventions on old targets or new strategies. Some of these aspects are reviewed here.