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Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2.

ABSTRACT: Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca(2+)-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias.Optical maps of action potentials and Ca(2+)-transients from Langendorff rabbit hearts were measured at low (150×150 ?m(2)/pixel) and high (1.5×1.5 ?m(2)/pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of IKr (the rapid component of rectifying K+ current), produced spontaneous Ca(2+)-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca(2+-)waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca(2+-)elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca(2+) (40%-60% of peak-Ca(2+)-transients), appeared first in small islands (0.5×0.5 mm(2)) that enlarged and spread throughout the epicardium. Synchronous systolic Ca(2+-)elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca(2+)-transient-durations and action potential-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca(2+)-dynamics (multiple chaotic Ca(2+)-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca(2+)-elevations and arrhythmias.The results indicate that systolic and diastolic Ca(2+)-elevations emanate from sarcoplasmic reticulum Ca(2+)-release and systolic Ca(2+)-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca(2+), which overcomes source-sink mismatch to trigger arrhythmias in intact hearts.

SUBMITTER: Kim JJ

PROVIDER: S-EPMC4472565 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2.

Kim Jong J JJ Němec Jan J Li Qiao Q Salama Guy G

Circulation. Arrhythmia and electrophysiology 20150226 3

<h4>Background</h4>Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca(2+)-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias.<h4>Methods and re ...[more]

PMID: 25722252

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Project description:ObjectivesThis study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS).BackgroundUse of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS.MethodsThis study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study.ResultsThe rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR]: 3.3, 99.95% confidence interval [CI]: 1.0 to 10.8, p = 3.7 × 10(-4)). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10(-4)). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10(-4)). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10(-4)).ConclusionsThese results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.

Project description:For the heart to function as a pump, intracellular calcium concentration ([Ca2+ ]i ) must increase during systole to activate contraction and then fall, during diastole, to allow the myofilaments to relax and the heart to refill with blood. The present study investigates the control of diastolic [Ca2+ ]i in rat ventricular myocytes. We show that diastolic [Ca2+ ]i is increased by manoeuvres that decrease sarcoplasmic reticulum function. This is accompanied by a decrease of systolic [Ca2+ ]i such that the time-averaged [Ca2+ ]i remains constant. We report that diastolic [Ca2+ ]i is controlled by the balance between Ca2+ entry and Ca2+ efflux during systole. The results of the present study identify a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i .The intracellular Ca concentration ([Ca2+ ]i ) must be sufficently low in diastole so that the ventricle is relaxed and can refill with blood. Interference with this will impair relaxation. The factors responsible for regulation of diastolic [Ca2+ ]i , in particular the relative roles of the sarcoplasmic reticulum (SR) and surface membrane, are unclear. We investigated the effects on diastolic [Ca2+ ]i that result from the changes of Ca cycling known to occur in heart failure. Experiments were performed using Fluo-3 in voltage clamped rat ventricular myocytes. Increasing stimulation frequency increased diastolic [Ca2+ ]i . This increase of [Ca2+ ]i was larger when SR function was impaired either by making the ryanodine receptor leaky (with caffeine or ryanodine) or by decreasing sarco/endoplasmic reticulum Ca-ATPase activity with thapsigargin. The increase of diastolic [Ca2+ ]i produced by interfering with the SR was accompanied by a decrease of the amplitude of the systolic Ca transient, such that there was no change of time-averaged [Ca2+ ]i . Time-averaged [Ca2+ ]i was increased by β-adrenergic stimulation with isoprenaline and increased in a saturating manner with increased stimulation frequency; average [Ca2+ ]i was a linear function of Ca entry per unit time. Diastolic and time-averaged [Ca2+ ]i were decreased by decreasing the L-type Ca current (with 50 μm cadmium chloride). We conclude that diastolic [Ca2+ ]i is controlled by the balance between Ca entry and efflux during systole. Furthermore, manoeuvres that decrease the amplitude of the Ca transient (without decreasing Ca influx) will therefore increase diastolic [Ca2+ ]i . This identifies a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i .

Project description:ImportanceTruncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.ObjectiveTo determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv).Design, setting, and participantsThis cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020.Main outcomes and measuresThe primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only.ResultsIn total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03).Conclusions and relevanceThe high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

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Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2.

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Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2.

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