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PRECLINICAL STUDIES

Left Ventricular Eccentric Remodeling and Matrix Loss Are Mediated by Bradykinin and Precede Cardiomyocyte Elongation in Rats With Volume Overload

Thomas D. Ryan, MD, PhD^_*, Emily C. Rothstein, PhD^_*, Inmaculada Aban, PhD, Jose A. Tallaj, MD^,, Ahsan Husain, PhD^_*,, Pamela A. Lucchesi, PhD^_* and Louis J. Dell'Italia, MD^_*,,,_*

^_* Departments of Physiology and Biophysics
Department of Biostatistics
Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
Birmingham Veteran Affairs Medical Center, Birmingham, Alabama

Manuscript received March 28, 2006; revised manuscript received May 25, 2006, accepted June 19, 2006.

^_* Reprint requests and correspondence: Dr. Louis J. Dell'Italia, Center for Heart Failure Research, University of Alabama at Birmingham, 432 BMR2, 901 19th Street South, Birmingham, Alabama 35294-2180. (Email: loudell{at}uab.edu).

OBJECTIVES: We hypothesized that left ventricular (LV) remodeling and matrix loss in volume overload (VO) are mediated by bradykinin (BK) and exacerbated by chronic angiotensin-converting enzyme (ACE) inhibition.

BACKGROUND: Chronic ACE inhibition increases anti-fibrotic BK and does not attenuate LV remodeling in pure VO. The relative contribution of changes in extracellular matrix versus cardiomyocyte elongation in acute and chronic LV chamber remodeling during VO is unknown.

METHODS: Echocardiography, LV collagen content, and isolated cardiomyocytes were studied in rats after aortocaval fistula (ACF) of 12 h, 2 and 5 days, and 4, 8, and 15 weeks. We also studied ACF rats after BK₂ receptor (BK₂R) blockade (2 days) or ACE inhibition (4 weeks).

RESULTS: At 2 days after ACF, LV end-diastolic dimension (LVEDD)/wall thickness was increased, and LV interstitial collagen was decreased by 50% without cardiomyocyte elongation. The BK₂R blockade prevented collagen loss and normalized LVEDD/wall thickness. From 4 to 15 weeks after ACF, interstitial collagen decreased by 30% and left ventricular end-systolic (LVES) dimension increased despite normal LVES pressure and isolated cardiomyocyte function. The ACE inhibition did not decrease LVEDD/wall thickness, further decreased LV interstitial collagen, and did not improve LV fractional shortening despite decreased LVES pressure.

CONCLUSIONS: Immediately after ACF induction, eccentric LV remodeling is mediated by interstitial collagen loss without cardiomyocyte elongation. Acute BK₂R blockade prevents eccentric LV remodeling and improves function. Chronic ACE inhibition does not prevent eccentric LV remodeling or improve function. These findings suggest that ACE inhibitor-mediated increase in LV BK exacerbates matrix loss and explains why ACE inhibition is ineffective in VO.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ACF = aortocaval fistula   BK = bradykinin   BK2R = BK receptor type 2   LV = left ventricle/ventricular   LVED = left ventricular end-diastolic   LVEDD = left ventricular end-diastolic dimension   LVES = left ventricular end-systolic   LVESD = left ventricular end-systolic dimension   MAP = mean arterial pressure   MMP = matrix metalloproteinase   TIMP = tissue inhibitor of matrix metalloproteinase   VCFr = velocity of circumferential shortening

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