In humans, volume overload (VOL) increases the risk of sudden cardiac death, but there is also important inter-individual variability, presumably because of differences in genetic backgrounds. Although VOL has rapid effects on myocardial properties, it is not known to which extent the severity of these early responses correlate with the effect of sustained VOL on mortality. In order to test this question, we induced VOL in male rats from two genetically distinct strains [i.e., Sprague-Dawley (SD) and Wistar Kyoto-derived Hyperactive (WKHA) rats] by creating a surgical aorto-caval fistula (ACF). Only 36% of SD rats remained alive after 39 weeks of ACF, in contrast to 82% of the operated WKHA rats. We also monitored myocardial hemodynamic function, mitochondrial properties, left ventricular (LV) morphology and LV wall diastolic properties at different times ranging from 2 to 12 weeks after either ACF or sham surgery. ACF had a rapid impact on the LV walls of both rat strains, but the only variables that were affected to a greater extent in the mortality-prone SD strain were normalized LV weight, LV cavity area, and myocardial wall stiffness. In contrast, there were only marginal strain-related differences in the way ACF affected hemodynamic and mitochondrial functions. Thus, while early morphologic responses of LV walls to ACF (along with their downstream consequences on myocardial diastolic wall stress) correlated well with strain-dependent differences in late mortality, other functional changes showed no predictive effects. Close monitoring of early changes in cardiac geometry (as well as new methods to analyze myocardial diastolic strain) might, therefore, be helpful to further improve risk stratification in humans with volume overload cardiopathies.

The purpose of this study was to compare two genetically different strains of rats submitted to overload‐induced ventricular remodelling to examine factors that predispose to the progression toward heart failure. Volume overload was induced by an aorto‐caval fistula (ACF) in SD and WKHA male rats, and hearts were studied at 4, 8 and 12 weeks after surgery. Compared to WKHA, ACF‐induced LV hypertrophy and dysfunction progressed more rapidly in SD rats, and functional recovery of SD hearts to I‐R was poorer vs WKHA during the compensated phase of disease. At later times (up to 40 weeks after ACF), SD rats (but not WKHA rats) died progressively of acute cardiac decompensation. Both strains developped a vulnerability to opening of the PTP, as measured in situ (in ischemic‐reperfused hearts using the mitochondrial [3H]DOG entrapment method) or in isolated mitochondria submitted to in vitro stress. Increased vulnerability to PTP opening was observable beginning at 4 weeks but no differences in severity was apparent between strains. The % of collagen‐cross linking increased progressively after ACF in both strains, but to a lower extent in SD vs. WKHA hearts. These results suggest that, while mitochondrial dysfunction may participate to the negative consequences of ACF‐induced LVH in both strains, it is not responsible for the more the rapid progression to decompensation observed in SD rats. Further experiments are underway to test the differences in cardiac outcome may be due to differences in the levels of collagen‐cross linking.Funded by: CIHR, FRSQ