Cardiac mass and cardiomyocyte size are governed by different genetic loci on either autosomes or chromosome Y in recombinant inbred mice.

Left ventricular hypertrophy is one of the main risk factors for cardiovascular mortality and morbidity. It has been proposed that hypertrophic stimuli act in great part by increasing the size of cardiomyocytes, and that the latter characteristic is a necessary condition to differentiate left ventricular hypertrophy from other benign forms of cardiac enlargement. To test whether the same genetic loci control the size of cardiomyocytes and left ventricular mass, we performed whole genome linkage analyses in a panel of 24 recombinant inbred AXB/BXA mouse strains. Whereas one major locus was linked to left ventricular mass in both males and females, loci linked to the size of cardiomyocytes were clearly distinct and showed sex-specific linkage. Moreover, the parental origin of chromosome Y had strong effects on the size of cardiomyocytes in male mice but did not affect left ventricular mass. In addition to showing that genetic loci that increase the size of cardiomyocytes are not necessarily linked to increased left ventricular mass, our findings have important consequences in evaluating cardiac phenotypes when performing genetic manipulations in mice, and in determining the cause of sex-specific differences when using models derived from C57BL/6J mice.

Compensated volume overload increases the vulnerability of heart mitochondria without affecting their functions in the absence of stress.

Although mitochondrial dysfunction has often been associated to heart failure, it has been suggested that it may represent only a late phenomenon in the disease process. We hypothesized that mitochondrial vulnerability to stress could be impaired in hypertrophied but non-decompensated hearts at a time when overt mitochondrial defects are not yet apparent. In the present study, hypertrophic remodeling was induced by means of an aorto-caval fistula (ACF) in WKHA rats and experiments were performed 12 weeks post surgery. At this time, ACF animals displayed normal contractile function, tissue oxidative capacity as well as mitochondrial membrane potential and respiratory function. However, compared to sham, mitochondria from ACF animals were more vulnerable to anoxia-reoxygenation injury in vitro as indicated by a greater impairment of oxidative phosphorylation and a greater dependence of respiration on exogenous NADH. Addition of the PTP inhibitor CsA restored respiratory function to the level observed in mitochondria from sham animals. Likewise, mitochondria from ACF displayed a greater sensitivity to Ca(2+)-induced PTP opening in vitro compared to their sham counterparts. In addition to the greater vulnerability of mitochondria in vitro, mitochondrial PTP opening measured in situ in perfused hearts was greater following ischemia-reperfusion in ACF animals than in their sham counterparts. This was associated with a more impaired functional recovery and greater tissue damage during reperfusion in hearts from ACF vs sham. Taken together, these results indicate that, in response to volume overload, mitochondria may display increased vulnerability in the absence of any sign of dysfunction under baseline unstressed conditions, at a time when adverse ventricular remodelling is observed but systolic dysfunction and decompensation have not occurred yet.

A genetic locus accentuates the effect of volume overload on adverse left ventricular remodeling in male and female rats.

Although increased left ventricular (LV) mass is highly predictive of cardiovascular morbidity and mortality in humans, it has never been verified in an experimental model that naturally occurring alleles linked to increased LV mass under basal conditions also associate with worsened cardiovascular prognosis. Because we have shown previously that locus Cm24 on chromosome 5 was responsible for differences in LV mass between WKY and WKHA rats, we used WKY.WKHA-(D5Rat45-D5Rat245) congenic rats (where locus Cm24 has been transferred from WKHA into WKY rats) to test how naturally occurring gene variants present in Cm24 would, in addition to their effects under basal conditions, affect LV mass remodeling and/or function in the context of overload. Volume overload was induced in WKY, WKHA, and WKY.WKHA congenic rats by surgical creation of an aorto-caval fistula. In females, the fistula had no effect on the hearts of WKY rats, yet it induced dilated eccentric hypertrophy and isolated diastolic dysfunction in WKHA and WKY.WKHA congenic rats, along with signs of congestive heart failure. In males, the surgical maneuver induced only mild or inconsistent responses in WKY rats but had much more pronounced effects in WKHA and WKY.WKHA congenic rats. Altogether, our data show that a genetic locus that induces, under basal conditions, either mild or no concentric LV remodeling in either male or female rats, respectively, associates with LV dilatation and dysfunction in both sexes when the hearts are additionally challenged.

Dietary isoflavones during pregnancy and lactation provide cardioprotection to offspring rats in adulthood.

In adult rats, elongation of cardiac myocytes (CMs) correlates with dilatation (and sometimes dysfunction) of cardiac ventricles. Although sex steroids may constitute one possible factor that affects the dimensions of CMs, studies on their effects in rodents is complicated by the fact that most commercial soy-based diets also contain abundant phytoestrogens. We report that feeding Wistar-Kyoto rat dams during gestation and lactation with a phytoestrogen-rich soy-based diet caused the CMs of their adult offspring to be shorter than in counterparts originating from mothers fed with a phytoestrogen-free casein-based diet. The soy-based diet had no such effects when given to rats after 6 wk of age, and its effects were replicated when supplementing the maternal casein-based diet with the isoflavones daidzein and genistein (the most abundant phytoestrogens in soy-based diets). In contrast to rats whose mothers had been fed with a soy-based diet, the hearts of adult rats raised with a casein-based diet only featured dilated eccentric hypertrophy and progressed toward congestive heart failure when further challenged. Thus the presence of isoflavones in the maternal diet provides cardioprotection to the hearts of their offspring during adulthood.