Genetic variation in angiotensin-converting enzyme does not prevent development of cardiac hypertrophy or upregulation of angiotensin II in response to aortocaval fistula

Background-Experimental and clinical evidence suggests that angiotensin II may be an important mediator of cardiac hypertrophy in response to hemodyna mic stress. We investigated the effect of genetic variation in angiotensin- converting enzyme (ACE) on the development of cardiac hypertrophy and left ventricular (LV) dysfunction in response to volume overload. Methods and Results--Male heterozygous ACE knockout (1/0) and wild-type (1/ 1) mice were studied 4 weeks after the creation of an aortocaval fistula (A CF), The LV weight/body weight ratio increased 74% in ACF versus sham-opera ted control mice but did not differ between genotypes. Echocardiographic ci rcumferential stress versus rate-corrected velocity of circumferential shor tening curves demonstrated depressed LV function in ACF versus sham-operate d mice but no difference between genotypes, LV ACE activity was higher in 1 /1 versus 1/0 mice and in ACF versus sham-operated mice, and it increased s ignificantly more in the 1/1 versus the 1/0 mice after ACF (P<0.001 for eff ect of genotype, ACF/sham operation, and interaction term). LV angiotensin II was higher in ACF versus sham-operated mice but did not differ between g enotypes, despite 3-fold higher LV ACE activity in ACF 1/1 versus ACF 1/0 m ice. Conclusions--ACE underexpression does not prevent cardiac hypertrophy or LV dysfunction in response to volume overload. LV angiotensin II is unaffecte d by ACE genotype, both at baseline and after volume overload, indicating t hat the heart can maintain angiotensin II levels across a broad range of ge netic ACE variation under both physiological and pathophysiological conditi ons.