Hemodynamic effects of treatment with the ketone body 3-hydroxybutyrate in cardiogenic shock - a randomized, controlled, assessor-blinded porcine trial

Abstract

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Independent Research Fund DK. Background Cardiogenic shock (CS) is a life-threatening disease with limited evidence-based treatment options. Treatment with the ketone body 3-hydroxybutyrate (3-OHB) induces favorable hemodynamic effects in patients with heart failure and CS. It increases cardiac output (CO) and left ventricular (LV) ejection fraction (LVEF) while reducing cardiac filling pressures. Yet, whether treatment with 3-OHB demonstrates beneficial hemodynamic effects during acute ischemic LV stunning in CS must be fully elucidated. This study aimed to examine the acute hemodynamic effects and underlying cardiovascular mechanisms of 3-OHB infusion in the acute phase of LV stunning in a porcine model of ischemic CS. Methods Sixteen 60-kg-pigs were included in a randomised, controlled, assessor-blinded crossover study. CS was achieved by repeated, slow injections of microspheres into the left main coronary artery. CS was defined as ≥30% reduction in CO and/or mixed venous saturation (SVO2). Upon the onset of CS, following a one-hour no-touch period, the pigs received an infusion with 3-OHB and isoosmolar, isovolumic saline (control) for two hours each in random order. Infusion periods were separated by a one-hour washout period. CO (primary endpoint), SVO2, and pulmonary pressures were measured by right heart catheterization. A pressure-volume admittance catheter was placed in the LV to measure LVEF, contractility (the slope of end systolic pressure-volume relationship, denoded as Ees), afterload (arterial elastance, Ea, and end-systolic pressure, ESP), preload (end-diastolic volume, EDV), and work-related parameters. Results CS was successfully achieved in all randomized animals. CO decreased by 36% from 4.5±1.0 L/min to 2.9±0.5 L/min (p<0.001) and SVO2 decreased by 31% from 55.0±8.1% to 37.7±5.8% (p<0.001). During 3-OHB infusion, CO increased by 0.9 L/min (95% CI: 0.4 to 1.3 L/min) compared with the control infusion. In parallel, Ees increased by 0.22 mmHg/mL (95% CI: 0.08 to 0.37 mmHg/mL), LVEF improved by 7 percentage points (95%CI: 1 to 13 percentage points) and cardiac efficiency increased by 6 percentage points (95%CI: 1 to 11 percentage points). Systemic vascular resistance was decreased by 479 dyn*cm5 (95% CI: 736 to 221 dyn*cm5); Ea and ESP remained similar. Heart rate was increased during 3-OHB infusion by 21 bpm (95% CI: 11 to 32 bpm) while no significant change was observed in stroke volume (p=0.6). Conclusion Treatment with 3-OHB improved CO, LVEF, and cardiac efficiency in CS. The increase was mediated through increased ventricular contractility and decreased peripheral resistance accompanied by increased heart rate.CO, Ees and cardiac efficiencyEndpoint parameters during 3-OHB