Role of Diastolic Properties in the Transition to Failure in a Mouse Model of Cardiac Dilatation Authors

Although the physiological states of hypertrophic remodeling and congestive heart failure have been intensively studied, less is known about the transition from one to the other. The use of genetically engineered murine models of heart failure has proven valuable in characterizing the progression of remodeling and its ultimate decompensation to failure. Mice deficient in the cytoskeletal muscle LIM-only protein are known to present with a clinical picture of dilated cardiomyopathy and transition to failure as adults. Longitudinal high field MR cardiac imaging provided a time course of remodeling where an improvement in ejection fraction and stroke volume (15wk vs. 31wk MLP: P<0.0001) was temporally concurrent with an abrupt phase of enddiastolic chamber dilatation. Hemodynamic analysis conducted throughout that dilatation phase showed improved dP/dtmax/EDP (15wk vs. 31wk MLP : P<0.0005), dP/dtmin/EDP (15wk vs. 31wk MLP: P<0.003) and developed pressure (15wk vs. 31wk MLP: P<0.0001) levels in the MLP. Computational modeling techniques were used to estimate the end diastolic pressure volume relationship revealing that, although MLP hearts possess a stiffer stress-strain relation, chamber compliance increased as a function of dilatation. This detailed physiological characterization during a phase of rapid anatomical remodeling suggests that systolic function in the MLP may temporarily improve as a result of alterations in chamber compliance, which are mediated by dilatation. In turn, a balance may exist between exploiting the Frank Starling mechanism and altering chamber compliance that maintains function in the absence of hypertrophic growth. Though initially compensatory, this process may exhaust itself and consequently transition to a maladaptive course.