CALL FOR PAPERS Sex Steroids and Gender in Cardiovascular-Renal Physiology and Pathophysiology The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy

Bell JR, Porrello ER, Huggins CE, Harrap SB, Delbridge LM. The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy. Am J Physiol Heart Circ Physiol 294: H1514–H1522, 2008. First published February 1, 2008; doi:10.1152/ajpheart.01283.2007.—Important sex differences in cardiovascular disease outcomes exist, including conditions of hypertrophic cardiomyopathy and cardiac ischemia. Studies of sex differences in the extent to which load-independent (primary) hypertrophy modulates the response to ischemia-reperfusion (I/R) damage have not been characterized. We have previously described a model of primary genetic cardiac hypertrophy, the hypertrophic heart rat (HHR). In this study the sex differences in HHR cardiac function and responses to I/R [compared to control normal heart rat (NHR)] were investigated ex vivo. The ventricular weight index was markedly increased in HHR female (7.82 0.49 vs. 4.80 0.10 mg/g; P 0.05) and male (5.76 0.22 vs. 4.62 0.07 mg/g; P 0.05) hearts. Female hearts of both strains exhibited a reduced basal contractility compared with strain-matched males [maximum first derivative of pressure (dP/dtmax): NHR, 4,036 171 vs. 4,258 152 mmHg/s; and HHR, 3,974 160 vs. 4,540 259 mmHg/s; P 0.05]. HHR hearts were more susceptible to I/R (I 25 min, and R 30 min) injury than NHR hearts (decreased functional recovery, and increased lactate dehydrogenase efflux). Female NHR hearts exhibited a significantly greater recovery (dP/dtmax) post-I/R relative to male NHR (95.0 12.2% vs. 60.5 9.4%), a resistance to postischemic dysfunction not evident in female HHR (29.0 5.6% vs. 25.9 6.3%). Ventricular fibrillation was suppressed, and expression levels of Akt and ERK1/2 were selectively elevated in female NHR hearts. Thus the occurrence of load-independent primary cardiac hypertrophy undermines the intrinsic resistance of female hearts to I/R insult, with the observed abrogation of endogenous cardioprotective signaling pathways consistent with a potential mechanistic role in this loss of protection.