Purpose: To investigate the cardiac and hemodynamic effects of short-term 3-OHB infusion compared to placebo in patients with stable HFrEF. The primary outcome was cardiac output (CO), and secondary outcomes were stroke volume (SV), mixed venous saturation (SVO2), central venous pressure (CVP), left ventricular filling pressure (PCWP), LVEF and strain (GLS).
Methods: We studied 24 stable chronic HFrEF patients (LVEF 36±4%, age 61±11 years) using Swan-Ganz catheterization and echocardiography. Study 1: In a randomized, single blinded cross-over design, 16 patients received 3-OHB (0.18 g/kg/h) or saline (placebo) at an equivalent volume for 3 hours. Study 2: Eight patients were examined in a dose-response study at 3 different rates of 3-OHB infusion for 2 hours consisting of a) saline followed by b) 3-OHB 0.045g/kg/h and c) 3-OHB 0.09g/kg/min.
Results: Study 1: Compared to placebo, 3-OHB infusion increased circulating 3-OHB levels from 0.4 [0.1;0.6]mM to 3.3 [3.1;3.7]mM. (p<0.001). This was associated with an increase in CO of 42% (p<0.001, table 1 and figure 1A) mediated by an increase in SV (p<0.001) and heart rate (p<0.001). During 3-OHB infusion, SVO2 increased (p<0.001) whereas CVP (p=0.04) and PCWP (p=0.04) decreased while mean arterial (p=0.47) and pulmonary pressure (p=0.83) remained unaffected. LVEF (p=0.001) and GLS (p<0.001) improved as compared with placebo. Study 2: 3-OHB increased gradually from a: <0.1mM to b: 0.7±0.1mM and c: 1.6±0.3mM (p<0.001) with an associated increase in CO (a: 5.0±0.9 vs. b: 5.3±1.0 vs. c: 6.2±1.3 L/min; p<0.001), which, however, was lower than in the high-dose study 1 (p=0.007) (figure 1B).
Conclusion: The findings demonstrate dose-dependent beneficial cardiac and hemodynamic effects of 3-OHB in HFrEF patients. Thus, 3-OHB may be used for short-term treatment of heart failure.