Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death

Hong D. Xiao, Sebastien Fuchs, Duncan J. Campbell, William Lewis, Samuel C. Dudley, Vijaykumar S. Kasi, Brian D. Hoit, George Keshelava, Hui Zhao, Mario R. Capecchi, Kenneth E. Bernstein

Research output: Contribution to journalArticlepeer-review

223 Scopus citations

Abstract

To investigate the local effects of angioiensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the α-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death.

Original languageEnglish (US)
Pages (from-to)1019-1032
Number of pages14
JournalAmerican Journal of Pathology
Volume165
Issue number3
DOIs
StatePublished - Sep 2004

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