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Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats
Jacob Joseph1, Lija Joseph, Nawal S Shekhawat
1Department of Internal Medicine, Division of Cardiovascular Medicine, Slot 532, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA. josephjacob@uams.edu
Insights
High homocysteine levels directly cause heart muscle thickening and diastolic dysfunction in rats, independent of other heart disease risk factors. This finding links hyperhomocysteinemia to cardiovascular problems.
Area of Science:
- Cardiovascular Science
- Pathology
- Biochemistry
Background:
- Hyperhomocysteinemia (Hhe) is known to worsen cardiac remodeling in hypertension.
- The direct impact of Hhe on cardiac structure and function, without other stimuli, is not well understood.
Purpose of the Study:
- To investigate the direct effects of Hhe on ventricular remodeling and cardiac function.
- To determine if Hhe causes pathological cardiac changes independently of other risk factors.
Main Methods:
- Male Wistar-Kyoto rats were fed control or Hhe-inducing diets for 10 weeks.
- Echocardiography assessed cardiac dimensions and function.
- Histomorphometric and biochemical analyses evaluated cardiac remodeling.
- In vitro studies assessed cardiac function.
Main Results:
- Hhe induced significant left ventricular (LV) and right ventricular (RV) hypertrophy and increased myocyte size.
- Cardiac remodeling included increased collagen, arteriolar thickening, and mast cell infiltration.
- LV diastolic dysfunction was observed due to decreased compliance, while systolic function remained unchanged.
Conclusions:
- Short-term Hhe directly causes pathological cardiac hypertrophy and remodeling in both ventricles.
- Hhe leads to LV diastolic dysfunction.
- These findings suggest a direct link between Hhe and cardiovascular morbidity/mortality, separate from other risk factors.
Abstract:
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.