Ketone Bodies in Cardiovascular Disease: The Vasculature as a Therapeutic Target

Abstract

Evidence for the potential of ketone bodies (KBs) in the treatment of cardiovascular disease is growing rapidly. In addition to serving as sources of myocardial fuel, KBs exert an array of pleiotropic activities via multiple mechanisms. The vasculature is emerging as a key target of KBs. Recent small clinical studies have shown that the administration of exogenous KBs to patients with heart failure is associated with a marked reduction in systemic vascular resistance and improvement in myocardial function. Exogenous KBs have also been shown to increase coronary blood flow; decrease pulmonary vascular resistance; promote endothelial function and angiogenesis; increase skeletal muscle oxygenation and capillarization; and inhibit atherosclerosis, vascular calcification, and senescence. These vasculo-protective properties likely contribute to the beneficial effects of exogenous KBs observed in heart failure, pulmonary hypertension, and myocardial ischemia/infarction, and suggest potential wide applications in several other cardiovascular diseases and related conditions. In this review, we will discuss the salutary vascular effects of KBs and their cardioprotective roles.

Keywords: cardioprotective; exogenous; ketone bodies; pleiotropic; vascular.

Graphical abstract

Figure 1

Ketone Body Oxidation and Energy Generation Following synthesis in the liver, ketone bodies (KBs) are released into the circulation and transported into cells through monocarboxylate transporters (MCTs). KBs enter the mitochondria and undergo oxidative metabolism via beta-hydroxybutyrate dehydrogenase 1 (BDH1) that catalyzes the conversion of beta-hydroxybutyrate (β-OHB) to acetoacetate (AcAc). AcAc is then metabolized into acetoacetyl-CoA by succinyl-CoA:3-oxoacid-CoA transferase (SCOT). Acetoacetyl-CoA is finally converted to acetyl-CoA for entry into the tricarboxylic acid (TCA) cycle. ACTA1 = acetyl-CoA acetyltransferase 1; CoA-SH = coenzyme A; ETC = electron transport chain; NADH = nicotinamide-adenine dinucleotide.

Figure 2

The Beneficial Vascular, Cardiac, and Systemic Effects of Exogenous KBs Vasculoprotective properties of exogenous ketone bodies include vasodilation of systemic, pulmonary, and coronary circulation, enhancing endothelial function; decreasing blood pressure; promoting angiogenesis and lymphangiogenesis; and preventing vascular senescence, calcification, and atherosclerosis. Cardiac effects of KBs include improving cardiac energetics, ameliorating pathological remodeling, and enhancing cardiac function. Systemic metabolic effects of KBs include decreasing glucose and non-esterified fatty acid (NEFA) levels, suppressing appetite, and weight loss. KBs may also improve exercise tolerance and inhibit the sympathetic nervous system. Cellular mechanisms for the above activities include roles as a fuel source, anti-inflammatory, antioxidative stress, and promoter of mitochondrial function.

Central Illustration

The Vascular and Cardiac Effects of Ketones Bodies Ketone bodies (KBs) serve as an alternate fuel source for the myocardium but also possess pleiotropic activities including anti-inflammatory, antioxidative stress, and enhancing mitochondrial function among others. KBs accomplish these functions via several mechanisms, including inhibiting histone deacetylase (HDAC), acting via their G-protein coupled receptors (GPRs), β-hydroxybutyrylation of cellular proteins and histones, and activation of voltage-gated potassium channels (V-gated K+ channels). The vasculature is the main target of the pleiotropic activities of KBs. The effects of KBs on the vasculature include systemic, pulmonary, and coronary vasodilation, enhancing endothelial function, and promoting angiogenesis. The vascular effects of KBs contribute to the beneficial effects of KBs in ischemia-reperfusion injury, pathological cardiac remodeling, heart failure, and pulmonary hypertension.