Calcium cycling in congestive heart failure

Altered calcium cycling of significant relevance for the pathophysiology of heart failure and may be causally related to the transition to failure. Altered calcium cycling predominantly results from disturbed SR function with impaired SR calcium accumulation. Different molecular alteration seem contribute to disturbed SR function. First, decreased SERCA expression and function seem to be a major defect resulting in reduced SR calcium accumulation with impaired systolic as well as diastolic function. Second, increased forward mode NCX activity due to increased NCX protein levels opposes SR calcium accumulation. and decreases SR calcium content and systolic SR calcium release. However , in patients with increased NCX levels, overall capacity for diastolic calcium removal and diastolic function seem to be preserved. Because forward mode NCX activity creates a net inward current, this may be associated with increased arrhythmias. Third, RYR2 dysfunction, possibly due to hyperphosphorylation and reduced FKBP12 binding, seems to contribute significantly to altered calcium handling. Reduced FKBP12 binding to RyR impairs systolic calcium release by decreasing SR calcium load and RYR gating and conductivity. Moreover, increased calcium leak impairs diastolic function. promotes arrhythmias and increases energy consumption for calcium cycling. Finally, increased diastolic calcium may be a major factor for altered gene expression in hypertrophy and failure. Better understanding of the mechanisms underlying altered expression and function of calcium regulatory proteins should enable us to develop new and more causally oriented strategies for the theraphy of heart failure.