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Animal Model |
From the Department of Pathology and Laboratory Medicine,* Emory University, Atlanta, Georgia; St. Vincent’s Institute of Medical Research and Department of Medicine University of Melbourne, Fitzroy, Victoria, Australia; the Division of Cardiology, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta, Georgia; the Department of Medicine, Case Western Reserve University, Cleveland, Ohio; and Howard Hughes Medical Institute,¶ Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah
To investigate the local effects of angiotensin 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 
-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.
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