Progressive Cardiac Metabolic Defects Accompany Diastolic and Severe Systolic Dysfunction in Spontaneously Hypertensive Rat Hearts

Abstract

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose positron emission tomography in vivo in 9‐, 12‐, and 18‐month‐old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9‐month‐old SHR decreasing) 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12‐month‐old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2‐[ 18 F] fluoro‐2‐deoxy‐ d ‐glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.