Sudden cardiac death: the lost fatty acid hypothesis

Abstract

Evidence that an excess of plasma free fatty acids (FFA) might lead to primary ventricular fibrillation and sudden cardiac death has hardened over the 36 years since the hypothesis was proposed. When the sympathetic nervous system is stimulated during the onset of an acute coronary syndrome, catecholamine-induced tissue lipolysis occurs, with a surge of plasma FFA. This may overload the acutely ischaemic myocardium and impair glucose utilization. Myocardial oxygen consumption can increase in regional areas of ischaemia, and could lead to abnormal electrophysiological conduction and refractoriness, with irreversible ventricular arrhythmias. Efforts to combat the adverse effects of excess FFA include beta-blockade, increasing glucose availability and extraction, or inhibition of lipolysis. This last approach appears promising, but no method has yet been clearly shown to prevent primary ventricular fibrillation or sudden cardiac death. The hypothesis remains viable. More research is needed to derive treatment that can be applied as soon as the onset of acute myocardial ischaemia is suspected.

Role of adipose tissue in the pathogenesis of cardiac arrhythmias

“…However studies have demonstrated association of ventricular arrhythmias with elevated serum free fatty acids during acute ischemia 36 . In addition to this intramyocardial lipid accumulation has been noted in the early post infarct phase.…”

“…The precise pathophysiology behind the intracellular lipid accumulation is unclear. Plasma norepinephrine concentrations increase almost immediately after the onset of an acute coronary syndrome36 . This results in increased tissue lipolysis and more free fatty acids being presented to the myocardium.…”

Nonesterified Fatty Acids and Cardiovascular Mortality in Elderly Men with CKD

“…Elevated concentrations of NEFA with subsequent increased b-oxidation in the cardiomyocytes can be harmful for the heart via increased oxidative stress (35) and activation of apoptosis of endothelial cells (27). The heart toxicity of NEFA has been demonstrated to cause abnormalities in mitochondrial function (which may further impair myocardial function), and leads to damage in plasma membranes, including disturbances of the cardiomyocytes' ion channels (2), which have been considered to exert proarrhythmic effects (36)(37)(38). Finally, levocarnitine deficiency often appears with progressive kidney dysfunction (39,40) and has been suggested to affect cardiac function in this patient population (41).…”

CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis

“…Accordingly, it is possible that transgenic SHR with wild-type Cd36 are predisposed to arrhythmias due to increased FA uptake. The mechanisms of these FA associated proarrhythmogenic effects are not fully understood but might include an increased requirement of oxygen for FA catabolism (26,36), an accumulation of potentially toxic intermediates of FA metabolism such as long chain acylcarnitine and long chain acyl coenzyme A, or an FA-mediated inhibition of glucose utilization by myocardium (7,9,36,53). On the other hand, SHR rats with mutant Cd36, with reduced FA transport and oxidation in the heart and with increased glucose oxidation for ATP production are relatively protected from adverse metabolic effects of increased FA levels.…”