Abstract
Nicotinic acid receptor agonists have previously been shown to cause acute reductions in cardiac contractility. We sought to uncover the changes in cardiac metabolism underlying these alterations in function. In nine humans, we recorded cardiac energetics and function before and after a single oral dose of nicotinic acid using cardiac MRI to demonstrate contractile function and Phosphorus-31 (31 P) magnetic resonance spectroscopy to demonstrate myocardial energetics. Nicotinic Acid 400mg lowered ejection fraction by 4% (64±8% to 60±7%, P=.03), and was accompanied by a fall in phosphocreatine/ATP ratio by 0.4 (2.2±0.4 to 1.8±0.1, P=.04). In four groups of eight Wistar rats, we used pyruvate dehydrogenase (PDH) flux studies to demonstrate changes in carbohydrate metabolism induced by the nicotinic acid receptor agonist, Acipimox, using hyperpolarized Carbon-13 (13 C) magnetic resonance spectroscopy. In rats which had been starved overnight, Acipimox caused a fall in ejection fraction by 7.8% (67.5±8.9 to 60±3.1, P=.03) and a nearly threefold rise in flux through PDH (from 0.182±0.114 to 0.486±0.139, P=.002), though this rise did not match pyruvate dehydrogenase flux observed in rats fed carbohydrate rich chow (0.726±0.201). In fed rats, Acipimox decreased pyruvate dehydrogenase flux (to 0.512±0.13, P=.04). Concentration of plasma insulin fell by two-thirds in fed rats administered Acipimox (from 1695±891ng/L to 550±222ng/L, P=.005) in spite of glucose concentrations remaining the same. In conclusion, we demonstrate that nicotinic acid receptor agonists impair cardiac contractility associated with a decline in cardiac energetics and show that the mechanism is likely a combination of reduced fatty acid availability and a failure to upregulate carbohydrate metabolism, essentially starving the heart of fuel.
Highlights
In the normal adult heart, most (60%-90%) of myocardial adenosine triphosphate (ATP) is generated by mitochondrial β-oxidation of free fatty acids, with a smaller (10%-40%) contribution from glucose oxidation.[1]
Nicotinic acid caused a significant decrease in systolic function, Figure 2 and table 2
Blood glucose was higher in fed than unfed animals and there was a statistically significant increase in blood glucose in the unfed animals injected with Acipimox, which was not seen in the saline injected animals, nor the fed animals injected with Acipimox
Summary
In the normal adult heart, most (60%-90%) of myocardial ATP is generated by mitochondrial β-oxidation of free fatty acids, with a smaller (10%-40%) contribution from glucose oxidation.[1]. Nicotinic acid (and its derivative, Acipimox) act on the GPR109a receptor, blocking lipolysis in adipocytes via adenylyl cyclase inhibition,[6] causing a fall in circulating fatty acids. This has been shown to increase glucose metabolism via the Randle cycle, where low levels of fat metabolism activate glucose metabolism via increasing glucose uptake, phosphofructokinase, and pyruvate dehydrogenase (and vice-versa, where excess beta oxidation causes acetyl-CoA accumulation, inhibiting pyruvate dehydrogenase).[7,8] This stimulation of myocardial glucose uptake has led to their use in FDG-PET, where Acipimox has been shown to increase glucose uptake to a similar extent as a euglycemic insulin clamp.[9,10]
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