Synergistic exacerbation of diastolic stiffness from short-term tachycardia-induced cardiodepression and angiotensin II.
Synergistic interaction between angiotensin II (Ang II) and evolving cardiodepression may play an important role in worsening chamber function, particularly in diastole. To test this hypothesis, Ang II was infused at 10 or 17 ng.kg(-1).min(-1) in 18 conscious dogs 4 days before and during induction of subacute cardiodepression by 48-hour tachypacing. The lower dose yielded negligible systemic pressure changes. Twelve additional animals served as paced-only controls. Pressure-dimension relations were recorded, and serial endocardial biopsies were obtained to assess histological and metalloproteinase (MMP) changes. Forty-eight-hour pacing alone depressed systolic function but had little effect on diastolic stiffness. Ang II alone only modestly raised diastolic stiffness at both doses and enhanced contractility at the higher dose. These changes recovered toward baseline after a 7-day infusion. However, Ang II (at either dose) combined with 48-hour pacing markedly increased ventricular stiffness (110+/-26% over baseline) and end-diastolic pressure (22+/-1.7 mm Hg). In contrast, pacing-induced inotropic and relaxation abnormalities were not exacerbated by Ang II. Zymography revealed MMP activation (72- and 92-kD gelatinases and 52-kDa caseinase) after a 4-day Ang II infusion (at both doses), which persisted during pacing. Tachypacing initiated 24 hours after cessation of a 7-day Ang II infusion also resulted in diastolic stiffening and corresponded with MMP reactivation. Ang II also induced myocyte necrosis, inflammation, and subsequent interstitial fibrosis, but these changes correlated less with chamber mechanics. Thus, Ang II amplifies and accelerates diastolic dysfunction when combined with evolving cardiodepression. This phenomenon may also underlie Ang II influences in late-stage cardiomyopathy, when chamber distensibility declines.
Senzaki
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H
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md 21287, USA.
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Janicki
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D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D003971:Diastole / Q000187:drug effects*; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D013610:Tachycardia / Q000503:physiopathology*; D013997:Time Factors
D000804:Angiotensin II; D000803:Angiotensin I; D008666:Metalloendopeptidases