Heart failure enhances susceptibility to arrhythmogenic cardiac alternans

Wilson, Lance D.; Jeyaraj, Darwin; Wan, Xiaoping; Hoeker, Gregory S.; Said, Tamer; Gittinger, Matthew; Laurita, Kenneth R.; Rosenbaum, David S.

doi:10.1016/j.hrthm.2008.11.008

Cited by 120 publications

(106 citation statements)

References 37 publications

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“…Rapid pacing at a CL of 150 ms decreased calcium transient amplitude in normal and HF preparations by 14% and 6%, respectively, compared with baseline pacing (CL ϭ 600 ms); however, this difference did not reach statistical significance. Rapid pacing also induced calcium transient amplitude alternans, similar to that reported previously in normal and HF canine wedge preparations (41).…”

Section: Resultssupporting

confidence: 87%

Spontaneous calcium release in tissue from the failing canine heart

Hoeker

Katra

Wilson

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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malities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P Ͻ 0.05] and increased duration (252 vs. 229 s, P Ͻ 0.05) compared with those of normal. Under control conditions and during ␤-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P Ͻ 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P Ͻ 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA. heart failure; arrhythmia; delayed afterdepolarization; triggered activity HEART FAILURE (HF) is a serious public health problem that afflicts millions of people in the United States alone (32). HF is associated with impaired cardiac contractility and relaxation, as well as a high incidence of ventricular arrhythmias and sudden death. Abnormal calcium handling has been implicated as a source of both mechanical and electrical dysfunction observed in HF, making it a key target for investigation and clinical therapy.At the myocyte level, impaired ventricular contractility and relaxation in HF have been attributed to decreased calcium transient amplitude due to diastolic sarcoplasmic reticulum (SR) calcium leak (12,13,35) and reduced SR calcium uptake (3,8,22,24). Calcium dysregulation in human HF has been associated with a significant incidence of nonreentrant arrhythmias (28,30,33) that can occur as the result of early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs). At the subcellular level, a DAD is caused by spontaneous calcium release from the SR that activates a transient inward current with a magnitude that depends on the amount of calcium flux (33). While studies in isolated myocytes have provided valuable insight into cellular pathophysiology, the translation of these results to arrhythmogenesis at the tissue level is not straightforward.The fact...

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Section: Resultssupporting

confidence: 87%

Spontaneous calcium release in tissue from the failing canine heart

Hoeker

Katra

Wilson

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…An interesting implication of these results is that RAN could be antiarrhythmic in the settings of ischemia and congestive heart failure where the vulnerability to calcium alternans is also increased (Kapur et al, 2009a;Wasserstrom et al, 2009;Wilson et al, 2009) and where enhanced late I Na has been demonstrated (Maltsev et al, 2001(Maltsev et al, , 2007Undrovinas et al, 2002Undrovinas et al, , 2006Valdivia et al, 2005), although a link between these two effects remains to be investigated. Finally, it is important to note that RAN also blocks human ether a-go-go-related gene channels and thus might induce some of its electrophysiological actions independently from the blockade of I Na,L .…”

Section: Ran Blocks Effects Of Late I Na On Cardiac Calcium Cycling 389mentioning

confidence: 96%

Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart

Wasserstrom

Sharma²,

O'Toole³

et al. 2009

J Pharmacol Exp Ther

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Pathological conditions, including ischemia and heart failure, are associated with altered sodium channel function and increased late sodium current (I Na,L ), leading to prolonged action potential duration, increased intracellular sodium and calcium concentrations, and arrhythmias. We used anemone toxin (ATX)-II to study the effects of increasing I Na,L on intracellular calcium cycling in rat isolated hearts. Cardiac contraction was abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late I Na . Hearts were loaded with fluo-4-acetoxymethyl ester, and myocyte intracellular calcium transients (CaTs) were measured using laser scanning confocal microscopy. ATX (1 nM) prolonged CaT duration at 50% recovery in hearts paced at a basal rate of 2 Hz and increased the sensitivity of the heart to the development of calcium alternans caused by fast pacing.ATX increased the time required for recovery of CaT amplitude following a previous beat, and ATX induced spontaneous calcium release waves during rapid pacing of the heart. ATX prolonged the duration of repolarization from the initiation of the activation to terminal repolarization in the pseudo-electrocardiogram. All actions of ATX were both reversed and prevented by subsequent or prior exposure, respectively, of hearts to RAN (10 M). Most importantly, the increased vulnerability of the heart to the development of calcium alternans during rapid pacing was reversed or prevented by 10 M RAN. These results suggest that enhancement of I Na,L alters calcium cycling. Reduction by RAN of I Na,L -induced dysregulation of calcium cycling could contribute to the antiarrhythmic actions of this agent in both reentrant and triggered arrhythmias.The pathology of calcium overload in the heart includes both mechanical and electrical dysfunction (Vassalle and Lin, 2004). At slow rates of pacing, the reopening of calcium channels late in the action potential plateau may facilitate the occurrence of early afterdepolarizations, whereas at fast rates, abnormalities of calcium handling and intracellular calcium transients become manifest, including spontaneous release of calcium from the sarcoplasmic reticulum (SR), transient inward current, delayed afterdepolarizations and aftercontractions, calcium alternans, and triggered arrhythmic activity. There is growing evidence that rate-dependent alternations in SR calcium release (i.e., calcium alternans) contribute to action potential duration alternans (Walker and Rosenbaum, 2003;Pruvot et al., 2004;Wasserstrom et al., 2008; Kapur et al., 2009a,b), which may be responsible for T-wave alternans, the development of repolarization gradients, and re-entrant arrhythmias.As a consequence of Na,Ca-exchange, an increase of sodium influx can lead to increases of calcium influx and intracellular calcium concentration and calcium overload in the heart (Verdonck et al., 1991;Verdonck et al., 1993). Cardiac sodium channels that fail to inactivate quickly after a brief This work was supported by a grant from Gilead Sciences, Inc. Ar...

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“…In HF, some ionic currents and Ca 2+ transport proteins are remodeled, resulting in a longer APD, lowered Ca 2+ transient, elevated [Na + ], and enhanced propensity to the occurrence of alternans (O'Rourke et al, 1999;Wilson et al, 2009). According to the experimental reports (Wilson et al, 2009), the CL needed to initiate alternans has increased from 240 to 500 ms for canine ventricular cells in HF. They attribute this increased propensity to the reduced expression of SERCA in HF.…”

Section: Heart Failure and Alternansmentioning

confidence: 99%

“…In addition to the usually observed prolonged APD, depressed Ca 2+ transient, and elevated Na + concentration, the heart rate threshold for the onset of APD alternans is observed to be significantly lowered in HF (Wilson et al, 2009). Nevertheless, the governing factors underlying the enhanced susceptibility to alternans in HF are less understood.…”

Section: Introductionmentioning

confidence: 99%

Cellular mechanism of cardiac alternans: an unresolved chicken or egg problem

Zang

Xia

2014

J. Zhejiang Univ. Sci. B

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T-wave alternans, a specific form of cardiac alternans, has been associated with the increased susceptibility to cardiac arrhythmias and sudden cardiac death (SCD). Plenty of evidence has related cardiac alternans at the tissue level to the instability of voltage kinetics or Ca 2+ handling dynamics at the cellular level. However, to date, none of the existing experiments could identify the exact cellular mechanism of cardiac alternans due to the bi-directional coupling between voltage kinetics and Ca 2+ handling dynamics. Either of these systems could be the origin of alternans and the other follows as a secondary change, therefore making the cellular mechanism of alternans a difficult chicken or egg problem. In this context, theoretical analysis combined with experimental techniques provides a possibility to explore this problem. In this review, we will summarize the experimental and theoretical advances in understanding the cellular mechanism of alternans. We focus on the roles of action potential duration (APD) restitution and Ca 2+ handling dynamics in the genesis of alternans and show how the theoretical analysis combined with experimental techniques has provided us a new insight into the cellular mechanism of alternans. We also discuss the possible reasons of increased propensity for alternans in heart failure (HF) and the new possible therapeutic targets. Finally, according to the level of electrophysiological recording techniques and theoretical strategies, we list some critical experimental or theoretical challenges which may help to determine the origin of alternans and to find more effective therapeutic targets in the future.

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Heart failure enhances susceptibility to arrhythmogenic cardiac alternans

Cited by 120 publications

References 37 publications

Spontaneous calcium release in tissue from the failing canine heart

Spontaneous calcium release in tissue from the failing canine heart

Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart

Cellular mechanism of cardiac alternans: an unresolved chicken or egg problem

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