Mr Papp Zoltan
This symposium analyzed key steps of myofilament remodeling in the transition from early stage compensations to late and end stage decompensation. The central hypothesis was that stress induced and maladaptive modifications of sarcomeric proteins in acquired heart failure are critical and early mechanisms in the transition to decompensation. This hypothesis is supported by the linkage of sarcomeric protein mutations to familial hypertrophic and dilated cardiomyopathies.
When analyzing sarcomeric mechanics in detail, an altered sarcomeric response to calcium emerges as a hallmark of maladaptive myofilament protein modifications in various acquired and genetically determined models of heart failure and in human heart failure as well. A reduction in the calcium regulated maximal force level can be linked to compromised systolic function, while the increase in the calcium sensitivity of force production is associated with impaired cardiac relaxation. Altered intracellular signaling, and a decreased beta-adrenergic responsiveness in particular, appears as a key mechanism in the modulation of myofilament proteins in the remodeled myocardium. A reduction in protein kinase A mediated phosphorylation of the thin filament troponin I molecule has a strict relationship with the increase in the calcium sensitivity of force production. In addition, hypophosphorylation of sarcomeric titin leads to the enhancement of the calcium independent passive stiffness, and hence these molecular changes together may explain large part of left ventricular diastolic dysfunction.
Experimental evidence suggests that restoration of myofilament calcium responsiveness (e.g. by beta-blocker therapy) has the potential to halt the progression of maladaptive myofilament protein changes, and to prevent transition to failure.
Myofilament proteins and heart failure
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