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Chronic inhibition of fatty acid oxidation: new model of diastolic dysfunction
S E Litwin1, T E Raya, R G Gay
1Department of Internal Medicine, Veterans Administration Medical Center, Tucson 85723.
Abstract:
This study was designed to determine the changes in the heart that result from inhibition of long-chain fatty acid oxidation with 2-tetradecylglycidic acid (TDGA). Male Sprague-Dawley rats (n = 64) were treated with TDGA (20 mg.kg-1.day-1) or a comparable volume of vehicle by gavage feeding for 7 or 21 days. In conscious rats TDGA produced no changes in heart rate, left ventricular systolic or end-diastolic pressures, left ventricular pressure development (dP/dt), or the time constant of left ventricular relaxation. Left ventricular developed pressure was not changed at 21 days. TDGA increased left ventricular weight, left ventricular weight-to-body weight ratio, and total heart weight-to-body weight ratio. Left ventricular endocardial and epicardial myocyte volumes were increased by 53 and 65%, respectively. Myocardial triglyceride content was increased threefold. Left ventricular chamber stiffness constants between end-diastolic pressures of 0 and 30 mmHg were increased, and left ventricular end-diastolic volumes at operating end-diastolic pressures were decreased at both 7 and 21 days. The myocardial stiffness constant was also increased at 7 and 21 days. Thus inhibition of long-chain fatty acid oxidation with TDGA increased left ventricular mass and altered left ventricular chamber and muscle stiffness without changing left ventricular relaxation or systolic function. We conclude that inhibition of long-chain fatty acid oxidation produced an unusual model of left ventricular hypertrophy and diastolic dysfunction characterized by abnormalities of passive-elastic properties but preserved relaxation.
Insights
Inhibition of long-chain fatty acid oxidation in rats using 2-tetradecylglycidic acid (TDGA) increased heart mass and stiffness. This study reveals TDGA causes left ventricular hypertrophy and diastolic dysfunction without impacting systolic function.
Area of Science:
- Cardiovascular Physiology
- Metabolic Biochemistry
Background:
- Long-chain fatty acid oxidation is crucial for cardiac energy metabolism.
- Inhibition of this pathway may lead to cardiac dysfunction.
Purpose of the Study:
- To investigate the cardiac effects of inhibiting long-chain fatty acid oxidation using 2-tetradecylglycidic acid (TDGA).
Main Methods:
- Male Sprague-Dawley rats were administered TDGA or vehicle for 7 or 21 days.
- Cardiac function, mass, myocyte volume, and myocardial triglyceride content were assessed.
- Left ventricular stiffness and relaxation properties were evaluated.
Main Results:
- TDGA significantly increased left ventricular and heart weight-to-body weight ratios.
- Myocyte volumes and myocardial triglyceride content increased, indicating hypertrophy and lipid accumulation.
- Left ventricular chamber and muscle stiffness increased, while end-diastolic volumes decreased.
- No significant changes were observed in heart rate, systolic pressures, or relaxation time constant.
Conclusions:
- Inhibition of long-chain fatty acid oxidation induces left ventricular hypertrophy and diastolic dysfunction.
- The observed dysfunction is characterized by altered passive-elastic properties with preserved relaxation.
- TDGA provides a model for studying cardiac hypertrophy and diastolic dysfunction.