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EXPERIMENTAL STUDY

Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction

An experimental serial cardiac magnetic resonance imaging study

Matthias Nahrendorf, MD^*,*, Kai Hu, MD^*, Karl-Heinz Hiller, PhD, Paolo Galuppo, PhD^*, Daniela Fraccarollo, PhD^*, German Schweizer^*, Axel Haase, PhD, Georg Ertl, MD^*, Wolfgang R. Bauer, MD, PhD^* and Johann Bauersachs, MD^*

^* Medizinische Universitätsklinik Würzburg, Germany
Experimentelle Physik 5, Universität Würzburg, Würzburg, Germany

Manuscript received January 24, 2002; revised manuscript received June 11, 2002, accepted June 26, 2002.

^* Reprint requests and correspondence: Dr. Matthias Nahrendorf, Medizinische Universitätsklinik, Universität Würzburg, Josef Schneider-Strasse 2, 97080 Würzburg, Germany.
M.Nahrendorf{at}medizin.uni-wuerzburg.de

OBJECTIVES: We sought to assess the influence of long-term hydroxymethylglutaryl coenzyme A reductase inhibition (statin) therapy on left ventricular (LV) remodeling after myocardial infarction (MI) by use of serial cardiac magnetic resonance imaging (CMRI) studies.

BACKGROUND: Statin therapy has been shown to reduce cardiac hypertrophy in vitro and in vivo, but the influence on LV post-MI remodeling is largely unknown.

METHODS: The CMRI measurements were taken four and 12 weeks after left coronary artery ligation in a 7.05-tesla Biospec. The MI size, LV mass and volumes, cardiac output (CO), and ejection fraction were determined. Rats were treated for 12 weeks with either placebo (P), cerivastatin (C; 0.6 mg/kg body weight per day) as a dietary supplement, or cerivastatin plus the nitric oxide synthase (NOS) inhibitor N-methyl-L-arginine methyl ester (L-NAME, 76 mg/100 ml) and hydralazine (8 mg/100 ml) in drinking water (CLH) to assess the contribution of endogenous nitric oxide formation.

RESULTS: Administration of cerivastatin attenuated hypertrophy after MI, and this effect was completely abolished by NOS inhibition (increase of LV mass from 4 to 12 weeks after MI: 235.3 ± 33.7 mg with P vs. 59.8 ± 20.5 mg with C vs. 239.5 ± 16.0 mg with CLH; p < 0.05 vs. P and CLH). Left ventricular dilation was not changed (increase of end-diastolic volume from 4 to 12 weeks after MI: 108.7 ± 28.8 with P vs. 126.6 ± 20.5 with C vs. 173.7 ± 25.1 with CLH; p = NS). The CO was higher in the cerivastatin group (12 weeks: 76.1 ± 2.9 ml/min with P vs. 95.8 ± 4.8 ml/min with C; p < 0.05). The effects of cerivastatin were abolished by NOS inhibition in the CLH group (CO at 12 weeks: 69.3 ± 2.8 ml/min, p < 0.05 vs. C).

CONCLUSIONS: Left ventricular remodeling was profoundly changed by statin treatment. Hypertrophy was attenuated, and global function was improved. These positive effects were abolished by NOS inhibition.

Abbreviations and Acronyms   ACE   angiotensin-converting enzyme   CMRI   cardiac magnetic resonance imaging   CO   cardiac output   EF   ejection fraction   eNOS   endogenous nitric oxide synthase   L-NAME   N-methyl-L-arginine methyl ester   LV   left ventricle or ventricular   MI   myocardial infarction   SV   stroke volume

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