Upregulated Na/Ca exchange is involved in both contractile dysfunction and arrhythmogenesis in heart failure.
Systolic heart failure (HF) is characterized by reduced systolic function and often by arrhythmias. We studied a rabbit model of HF (induced by combined aortic insufficiency and stenosis) which shows both contractile dysfunction and arrhythmogenesis. In this model we find an approximately 100% increase in Na/Ca exchange (NaCaX) expression at the level of mRNA, protein and function, but only a modest decrease in SR Ca-ATPase (approximately 24%, only detectable in cellular function). This combination results in a 40% reduction in SR Ca content in HF, which is sufficient to explain the 40% reduction in twitch Ca transients and 30-38% decrease in contractile function in this HF model. When stimulated by isoproterenol the SR Ca load readily reaches the threshold for spontaneous SR Ca release (this threshold Ca load is unchanged in HF). This SR Ca release activates a transient inward current (I(ti)) carried exclusively by NaCaX. For a given SR Ca release there is greater I(ti) in HF (due to higher NaCaX). We also find a 49% decrease in the inward rectifier potassium current (I(K1)), which allows greater depolarization for a given I(ti). Thus, higher NaCaX and lower I(K1) greatly increase the likelihood that an SR Ca release-induced delayed afterdepolarization (DAD) will trigger an arrhythmogenic action potential. We conclude that NaCaX contributes in major ways to both contractile dysfunction (by reducing SR Ca) and increased propensity for triggered arrhythmias (by increasing I(ti) and DADs).
Bers
Donald M
DM
Department of Physiology, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA. dbers@lumc.edu
Pogwizd
Steven M
SM
Schlotthauer
Klaus
K
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002303:Cardiac Output, Low / Q000150:complications* / Q000503:physiopathology*; D006801:Humans; D009200:Myocardial Contraction; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D015854:Up-Regulation
D019831:Sodium-Calcium Exchanger