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Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction

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Abstract

To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-β (TGF-β) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-β, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.

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Acknowledgments

A grant to B. Jugdutt from the Canadian Institutes of Health Research, Ottawa, ON supported this work. We thank AstraZeneca and Merck-Frosst for gifts of candesartan and enalapril, respectively, technicians with data collection, and Catherine Graham with manuscript preparation.

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Authors and Affiliations

  1. 2C2 Walter Mackenzie Health Sciences Centre, Division of Cardiology, Department of Medicine, University of Alberta and Hospitals, 8440-112 Street, Edmonton, Alberta, Canada, T6G 2R7

    Bodh I. Jugdutt

  2. Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Alberta, Edmonton, Canada

    Halliday Idikio

  3. Health Sciences Laboratory Animal Services, Faculty of Medicine, University of Alberta, Edmonton, Canada

    Richard R. E. Uwiera

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  1. Bodh I. Jugdutt
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  2. Halliday Idikio
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  3. Richard R. E. Uwiera
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Correspondence to Bodh I. Jugdutt.

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Jugdutt, B.I., Idikio, H. & Uwiera, R.R.E. Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction. Mol Cell Biochem 303, 27–38 (2007). https://doi.org/10.1007/s11010-007-9452-3

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