Mechanism of action
Chronic Heart Failure induces mechanical and neuro-hormonal stresses on myocardial cells. The effects of these stresses have a progressive negative impact on left ventricular function, inducing left ventricular remodeling and recapitulation of the fetal gene program.
Studies performed in humans and in dogs with heart failure have established that CCM therapy reverses the left ventricular remodeling characteristic of CHF and improves left ventricular contractile strength. These effects are the result of a chain of intracellular molecular processes, which are apparent just seconds after initiating CCM treatment.
CCM signals normalize the protein function in a dog model of CHF
CCM Signals have been shown to normalize the phosphorylation of regulatory proteins such as Phospholamban (PLB) in-vitro, within seconds of treatment. This rapid effect allows restoration of cellular function and an acute improvement in contractile force.
CCM reverses the fetal gene program to the normal adult gene program
Among the genes whose expression is down-regulated in heart failure are those of key proteins associated with intracellular cycling of calcium. These abnormalities lead to one of the primary cellular defects that underlie myocardial contractile dysfunction in heart failure. Studies in both human subjects and in dogs with heart failure demonstrated improvements in mRNA expression of several of these important calcium handling proteins in response to CCM therapy (figure below), consistent with reversal of the fetal gene program. These changes initially occur in the region near the electrodes and, within months, affect all regions of the heart.
Improved regional cardiac function induces global improvements and reverse remodeling
Over time, local changes result in unloading of stress and normalization of gene expression in remote areas across the entire myocardium. These interrupt the “remodeling cascade” and induce global reverse remodeling and improvement in cardiac function (figure below). 3D Echocardiographic studies in humans and ventriculography studies in animals demonstrate reverse remodeling within 3 months of initiating CCM therapy.
Classic positive ionotropic drug therapies are also known to improve left ventricular systolic function. However, these improvements also result in increased myocardial oxygen consumption (MVO2) which can be detrimental to already over-stressed and failing cardiac tissue. The improvement induced by CCM therapy, on the other hand, does not result in a detectable increase in MVO2. The improvements in left ventricular function with CCM are associated with improved left ventricular efficiency, similar to the effects seen with left ventricular pacing.
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