Increased Cardiac Uptake of Ketone Bodies and Free Fatty Acids in Human Heart Failure and Hypertrophic Left Ventricular Remodeling

Abstract

Background: Deranged energy metabolism contributes to the pathophysiology of heart failure (HF). Recent studies showed diminished free fatty acid (FFA) oxidation in experimental HF models with a shift towards oxidation of ketone bodies. However, conflicting clinical data on FFA metabolism and limited knowledge on ketone body metabolism in human HF mandate additional metabolic profiling studies. We, therefore, investigated cardiac uptake of FFAs and ketone bodies (β-hydroxybutyrate and acetoacetate) in patients with HF with reduced ejection fraction (HFrEF) or with aortic stenosis (AS)–induced left ventricular hypertrophy. We hypothesized that FFA oxidation is impaired in HFrEF and in AS and results in decreased concentrations of free carnitine, the necessary carrier for mitochondrial entry of activated FFAs, and in accumulation of metabolic intermediates. Methods and Results: We collected arterial and coronary sinus blood samples in patients with HFrEF (n=15), in AS patients with preserved systolic function (n=15), and in control patients (n=15). Plasma concentration gradients across the heart show significantly greater uptake of ketone bodies in patients with HFrEF than in controls. Patients with AS show significantly increased uptake of β-hydroxybutyrate and FFAs. Free carnitine concentration and concentration gradients of intermediates of FFA oxidation were comparable between groups. Conclusions: In conclusion, our results show significantly increased cardiac uptake of ketone bodies in patients with stable HFrEF and AS and increased uptake of FFAs in AS compared with control patients. The lack of myocardial release of acyl-carnitine species or change in free carnitine uptake suggests no impairment of FFA oxidation.

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

“…However, the available evidence does not support the hypothesis that the effect of SGLT2 inhibitors to reduce the progression of heart failure is related to a favourable action of these drugs on cardiac energy supply. Patients with chronic heart failure have increased circulating levels and utilization of ketone bodies — even in the absence of treatment with a SGLT2 inhibitor. Experimentally, despite an increase in circulating ketone bodies, SGLT2 inhibition does not predictably increase ketone body utilization within the myocardium, and SGLT2 inhibitors exert cardioprotective effects that do not depend on enhanced ketone body uptake and metabolism .…”

Metabolic Alterations in Inherited Cardiomyopathies

“…In spontaneous hypertensive rats with LV hypertrophy, which is associated with reduced CD36 and lower FAO, supplementation with caprylic acid, a medium-chain FA that bypasses FA transporters, reduced ventricular hypertrophy and fibrosis, improved myocardial energetics (as measured by phosphocreatine levels) and reduced oxidative stress markers [74]. Recently, three independent studies [75][76][77] proposed that ketone oxidation might become a dominant source of ATP in the failing heart. Ketone molecules are produced from acetyl-CoA in the liver and subsequently released into circulation to provide extrahepatic tissues with a substrate for energy regeneration during conditions of carbohydrate depletion (e.g., prolonged fasting or starvation).…”

Outcome of patients with heart failure after transcatheter aortic valve implantation

“…All of these clinical findings can be subsumed into the diagnosis of heart failure (HF), given that there is an almost complete overlap of functional, echocardiographic, hemodynamic, and biochemical measurements between patients with symptomatic AS or HF. The concept of concomitant HF in patients with AS is supported by findings that patients with HF and AS have a similar shift in myocardial substrate metabolism [9] and that there are parallels in invasive left ventricular (LV) hemodynamics between the two conditions [10]. Furthermore, the LV displays structural and functional impairments after TAVI that persist after correction of afterload: left ventricular hypertrophy (LVH) has been demonstrated to persist above the upper limit of normal after aortic valve replacement and is associated with impaired long-term survival [11].…”