Phospholipid Lysophosphatidylcholine as a Metabolic Trigger and HERG as an Ionic Pathway for Extracellular K⁺ Accumulation and “Short QT Syndrome” in Acute Myocardial Ischemia

Abstract

The most profound abnormalities during acute myocardial ischemia are extracellular K⁺ accumulation ([K⁺]_o–?) and shortening of action potential duration or QT interval (APD–? or QT–?), which are pivotal in the genesis of ischemic arrhythmias and sudden cardiac death. The ionic mechanisms however remained obscured. We performed studies in a rabbit model of acute global myocardial ischemia in order to explore ionic and metabolic mechanisms for ischemic [K⁺]_o–? and QT–?. Exogenous 1-palmitoyl-lysophosphatidylcholine (LPC-16) mimicked the low-perfusion ischemia to produce significant [K⁺]_o–? and QT–?. The [K⁺]_o–? and QT–? induced by either LPC-16 or ischemia were prevented by dofetilide, a blocker of rapid delayed rectifier K⁺ current (I_Kr), but not by blockers for other K⁺ channels. Consistently, dofetilide efficiently abolished the ventricular tachy-arrhythmias induced by ischemia or LPC-16. LPC-16 remarkably shortened APD and enhanced the function of I_Kr and HERG (the pore-forming subunit of I_Kr). The effects of LPC-16 manifested with shorter APD (faster repolarization rate) and at more negative potential (membrane repolarization). Dofetilide abolished the I_Kr/HERG enhancing and APD shortening effects of LPC-16. Our results suggest that LPC-16 accumulation/HERG enhancement may be a link between metabolic trigger and ionic pathway for ischemic [K⁺]_o– ? and QTc– ?. This represents the first documentation of I_Kr/HERG as the ionic mechanism in ischemic [K⁺]_o–? and QTc–?. Inhibition of LPC-16 production and accumulation and/or of I_Kr/HERG may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease.

Onset of decreased heart work is correlated with increased heart rate and shortened QT interval in high-carbohydrate fed overweight rats

“…Another compensation mechanism may be induction of QT shortening during our experiments as initial response, instead of prolonged QT observed in obese patients (Pietrobelli et al 1997). Indeed, this prolongation could be almost normalized when patients had even short-term weight loss (Bai et al 2007;Pietrobelli et al 1997) It is well accepted that MetS is a risk factor for prolonged QT, which may further increase cardiovascular morbidity and mortality in these subjects. A short QT-interval is defined as short QT syndrome, generally a genetic disease of the electrical system of the heart and mutations in the KCNH2, KCNJ2, and KCNQ1 genes.…”

Endogenous red blood cell membrane fatty acids and sudden cardiac arrest

“…23 During ischemia, activation of phospholipase A2 leads to the release of a polyunsaturated fatty acid from the sn2 position and the formation of lysophospholipids with a single fatty acid 24. The levels of polyunsaturated n-3 fatty acids in membrane phospholipids are known to influence the risk of SCA, 2, 5 and DHA or EPA released from the sn2 position during ischemia might protect from the effects of lysophospholipids on arrhythmogenesis 25, 26. It is also possible that the nature of the remaining fatty acid on the lysophospholipids affects the risk of arrhythmia.…”

The genetic basis of long QT and short QT syndromes: A mutation update

“…Interestingly, the sensitivity to I Kr -blocking drugs was much reduced [Brugada et al, 2004]. A metabolic-based gain-offunction of Kv11.1 has been noted in myocardial ischemia and is considered to be the basis of the shortened QT interval and the associated propensity for arrhythmia in ischemic heart disease [Bai et al, 2007].…”