Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats

Departments of 1 Internal Medicine, 2 Pharmaceutical Sciences, 3 Pathology, 4 Pharmacology and Toxicology, and 5 Surgery, Central Arkansas Veterans Healthcare System, and University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 Submitted 19 February 2003 ; accepted in final form 23 April 2003 A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with significantly increased myocyte size in the LV and right ventricle (RV). LV and RV remodeling was characterized by a disproportionate increase in perivascular and interstitial collagen, coronary arteriolar wall thickening, and myocardial mast cell infiltration. In vitro study of LV function demonstrated abnormal diastolic function secondary to decreased compliance because the rate of relaxation did not differ between groups. LV systolic function did not vary between groups in vitro. In summary, in the absence of other hypertrophic stimuli short-term intermediate Hhe caused pathological hypertrophy and remodeling of both ventricles with diastolic dysfunction of the LV. These results demonstrate that Hhe has direct adverse effects on cardiac structure and function, which may represent a novel direct link between Hhe and cardiovascular morbidity and mortality, independent of other risk factors. homocysteine; diastolic dysfunction; cardiac remodeling; collagen; cardiomyocyte Address for reprint requests and other correspondence: J. Joseph, Div. of Cardiovascular Medicine, Slot 532, Univ. of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205 (E-mail: josephjac