P499The effects of aging on pathologic left ventricular remodeling and dysfunction depend critically on the underlying pathology

Purpose: The prevalence of heart failure is increasing due to improved survival of cardiovascular disease in an aging population. Interestingly, the normal aging heart already undergoes structural and functional alterations which are reminiscent to the changes observed in the failing heart. These alterations may increase the vulnerability of the aging heart to develop heart failure. Consequently, we studied the effect of aging on left ventricular (LV) remodeling and dysfunction in response to mechanical overload. Methods: Mice were subjected to pressure overload by transverse aortic constriction (TAC) or myocardial infarction (MI) at 3, 12 or 24 months of age. Eight weeks after TAC or MI, LV geometry and function were measured and isometric force determined in single permeabilized cardiomyocytes. Results: Aging mildly affected LV function in sham operated animals, demonstrated by increases in LV weight (26%) and end-diastolic lumen diameter (8%) and by decreases in LV dP/dt at 40 mmHg (dP/dtP40) (19%) and in dP/dtmin (27%) in 24 vs. 3 mo old mice (all p<0.05). TAC and MI produced LV hypertrophy, LV dysfunction and backward failure in all age groups. Interestingly, the % change in LV weight compared to sham during age in both models was diminished (TAC: 90% to 58% MI: 33% to 5%, resp. 3 to 24 mo). The blunted TAC-induced LV hypertrophy was associated with aggravated LV dysfunction, demonstrated by a further decrease in LV dP/dtP40 (33%) and dP/dtmin (32%) and increases in lung fluid and RV weight (28%) in the 24 vs. 3 mo old mice (all p<0.05). In contrast, the blunted MI-induced LV hypertrophy was associated with a trend towards ameliorated LV diastolic dysfunction, demonstrated by decreases in tau (8%) and LV end diastolic pressure (45%) in 24 vs. 3 mo old mice. Furthermore, the survival rate in the 12 and 24 mo old mice was higher compared to the 3 mo old mice. This was contrary to the survival rate in the TAC-operated mice. The TAC-induced LV dysfunction at the age of 3 mo was accompanied by 51% elevated cardiomyocyte maximal force development (Fmax) whereas the MI-induced LV dysfunction was accompanied by 34% reduced Fmax (all p<0.05). Conversely, passive isometric myofilament force (Fpas) was markedly elevated in TAC (157%) but unchanged in MI. Aging resulted in reduction of Fmax and Fpas in TAC to baseline sham levels which were not altered in MI. Conclusion: These observations indicated that the effects of aging on the cardiac response to hemodynamic overload depend critically on the underlying pathology.