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 Cardiac Contractility Modulation 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 the treatment.
The signals have been shown to normalize the phosphorylation of regulatory proteins such as Phospholamban (PLB) in-vitro, within seconds of treatment. Improvement in calcium handling via SERCA2a upregulation and restoration of the sodium/calcium exchanger further increase contractile function in subjects with heart failure.
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 underlies 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 Cardiac Contractility Modulation 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.
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 Cardiac Contractility Modulation 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 Cardiac Contractility Modulation therapy, on the other hand, does not result in a detectable increase in MVO2. The improvements in left ventricular function with Cardiac Contractility Modulation are associated with improved left ventricular efficiency, similar to the effects seen with left ventricular pacing.