The Cardiac and Hemodynamic Effects of Ketone Bodies Are Abnormal in Patients With Type 1 Diabetes: A Randomized Controlled Trial

Abstract

Impaired cardiac ketone oxidative capacity is a possible disease mechanism in the development of diabetic cardiomyopathy. We examined whether the cardiovascular effects of ketone bodies are different in patients with type 1 diabetes (T1D) compared with healthy control individuals. In a single-blind study with a crossover design, nine patients with T1D and eight age-matched, healthy control study participants were randomized to receive a 3-h infusion of 3-hydroxybutyrate (3-OHB) or tonicity-matched saline in random order, separated by a 1-h washout period. Assessor-blinded echocardiographic evaluation of cardiovascular function was performed at baseline and after 150 min of each intervention. Circulating 3-OHB increased during 3-OHB infusion versus placebo in healthy control participants, with a similar increase in patients with T1D. In the control group, 3-OHB infusion increased cardiac output by 1.9 ± 0.4 L/min but only by 0.5 ± 0.1 L/min in patients with T1D. Stroke volume increased by 14 ± 5 mL and left ventricular (LV) ejection fraction by 3 ± 1 percentage points in healthy control participants; there was no change in these parameters in patients with T1D. During 3-OHB infusion in patients with T1D, LV global wasted work increased and LV global work efficiency decreased. In conclusion, patients with T1D had an abnormal cardiovascular response to 3-OHB infusion. Diabetic cardiomyopathy in patients may involve impaired cardiac ketone metabolism. Article Highlights The diabetic heart has reduced ketone utilization due to impaired ketolytic enzyme activity. In a randomized, controlled, crossover trial, we investigated whether the cardiac response to 3-hydroxybutyrate infusion is impaired in type 1 diabetes. The response on cardiac output was blunted by 80% in type 1 diabetes, with no improvement in systolic function and left ventricular work efficiency was reduced. These findings suggest impaired cardiac ketone metabolism may have clinical significance and could contribute to diabetic cardiomyopathy.