UC San Diego

Differential alterations in cardiac mechanical function have been associated with different mechanisms of heart failure (HF). The origins of altered ventricular mechanical function are many, with various mechanisms acting at different scales with respect to the contractile unit of muscle. At the tissue scale, dyssynchronous activation has been shown to alter mechanical synchrony, which can lead to pump dysfunction and heart failure. At the cellular scale, genetic mutations or viral infection can cause cytoskeletal changes that impair resting function, contractile function, or mechanical signaling and can lead to heart failure. At the molecular scale, altered expression of kinases with phosphorylation targets in calcium handling or contractile proteins have been associated with heart failure and are thought to contribute to contractile dysfunction. These mechanisms vary in their contribution to heart failure, but they all contribute to mechanical dysfunction. Mechanical function is disrupted in dyssynchronous heart failure, as the timing of contraction is altered in different regions of the heart, preventing a uniform contraction. This dyssynchrony can be simulated using regional ventricular pacing, which also alters mechanical function. One purpose of the work presented here was to determine the effects of the altered cardiac muscle mechanics that arise due to regional ventricular pacing. It was found that a systolic stretch associated with dyssynchronous contraction can affect tension and work production in isolated cardiac muscle. The timing and magnitude of this stretch was also found to be of importance. Ultimately, the results could mostly be explained by a few well known muscle mechanics mechanisms: time-varying stiffness, the force-velocity relation, and shortening deactivation. This was then taken a step further to see how altering the levels of CaMKII affected tension and work development. CaMKII has phosphorylation targets on both contractile and calcium handling proteins and its over-expression has been shown to lead to HF, while its deletion has been shown to be protective against heart failure in pressure overload studies. It was shown that over-expression of CaMKII led to decreased tension but preserved work development, while deletion led to increased work and tension values. Dilated cardiomyopathy (DCM) is another cause of heart failure, which can be brought about by mechanical dysfunction. The work presented here proposes a novel mechanism for contractile dysfunction associated with cardiac vinculin deletion, which is a precursor to dilated cardiomyopathy. It was shown that an increase in lattice spacing due to vinculin deletion increased transverse systolic stiffness and explains the altered systolic wall strains associated with vinculin deficiency. A combination of experiments, model development, and model simulation was used to uncover how changes in mechanical function associated with heart failure can alter cardiac muscle mechanics