title: The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy.
abstract: 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/dt(max)): 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/dt(max)) 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.
authors.affiliation: Dept. of Physiology, Univ. of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: James R
authors.initials: JR
authors.lastname: Bell
authors.forename: Enzo R
authors.initials: ER
authors.lastname: Porrello
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Huggins
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Harrap
authors.forename: Lea M D
authors.initials: LM
authors.lastname: Delbridge
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011918:Rats, Inbred SHR; D020127:Recovery of Function; D012737:Sex Factors; D015398:Signal Transduction; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D007770:L-Lactate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3