Abstract 17878: Calmodulin Mutation (CALM-F90L) Associated With Familial Idiopathic Ventricular Fibrillation Disrupts L-type Ca Channel Inactivation and Activates Sarcoplasmic Reticulum Ca Release in Ventricular Myocytes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Dmytro Kryshtal ◽  
Hyun S Hwang ◽  
Christopher Johnson ◽  
Walter Chazin ◽  
Alfred L George ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Sarcoplasmic Reticulum ◽  
Binding Affinity ◽  
Ventricular Myocytes ◽  
Qt Prolongation ◽  
Polymorphic Ventricular Tachycardia ◽  
Ca Channel ◽  
Idiopathic Ventricular Fibrillation ◽  
Channel Inactivation ◽  
Exercise Induced

Introduction: The F90L mutation in calmodulin (CaM) has been associated with a familial form of autosomal-dominant idiopathic ventricular fibrillation (IVF) with features of exercise-induced QT prolongation, but the underlying arrhythmia mechanism is unknown. We previously found that CaM mutations that cause sudden death due to catecholaminergic polymorphic ventricular tachycardia (CPVT) activate ryanodine receptor (RyR2) Ca release channels; whereas CaM mutations associated with long QT syndrome (LQTS) have no effects on RyR2 channels but prolong the cardiac action potential by impairing L-type Ca current inactivation. Objective: To determine the effect of F90L mutant CaM on Ca binding affinity, L-type Ca currents and Ca handling and compare them to CaM mutants associated with CPVT (CPVT-CaM) and LQTS (LQTS-CaM). Methods and Results: We prepared recombinant wild-type (WT) and mutant CaM proteins associated with CPVT (N54I), LQTS (D96V, D130G, F142L) and IVF (F90L). Similar to LQTS CaMs, the F90L IVF mutation drastically reduced Ca binding affinity of CaM C-lobe (7-fold reduction compared to WT-CaM), whereas CPVT N54I has no effect. In voltage-clamped mouse ventricular myocytes dialyzed either with WT or mutant CaM, IVF-CaM F90L significantly impaired L-type Ca channel inactivation, similar to the effect of LQTS-CaMs, whereas CPVT-CaM had no effect (Fig. A, **p<0.01 vs WT). Next, mutant CaMs effects on sarcoplasmic reticulum Ca release were tested in permeabilized ventricular myocytes. At physiological free CaM [100 nM] and Ca [120 nM], IVF-CaM F90L increased spontaneous Ca wave activity analogous to CPVT-CaM N54I, but of significantly smaller effect size (Fig. B). In contrast, LQTS-CaMs had either no effect or reduced Ca waves (Fig. B). Conclusion: The F90L CaM mutation shares characteristics with both CPVT and LQTS CaMs, which may help explain clinical features of modest exercise-induced QT prolongation and sudden arrhythmic death in patient carriers.

Idiopathic ventricular fibrillation: the ongoing quest for diagnostic refinement

EP Europace ◽  
2020 ◽  
Author(s):  
Giulio Conte ◽  
John R Giudicessi ◽  
Michael J Ackerman
Keyword(s):  
Ventricular Fibrillation ◽  
Heart Diseases ◽  
Sudden Cardiac Arrest ◽  
Polymorphic Ventricular Tachycardia ◽  
Molecular Evidence ◽  
Idiopathic Ventricular Fibrillation ◽  
Diagnostic Approaches ◽  
Exercise Induced ◽  
Definition Of ◽  
Electrocardiogram Ecg

Abstract Prior to the recognition of distinct clinical entities, such as Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome, all sudden cardiac arrest (SCA) survivors with ventricular fibrillation (VF) and apparently structurally normal hearts were labelled as idiopathic ventricular fibrillation (IVF). Over the last three decades, the definition of IVF has changed substantially, mostly as result of the identification of the spectrum of SCA-predisposing genetic heart diseases (GHDs), and the molecular evidence, by post-mortem genetic analysis (aka, the molecular autopsy), of cardiac channelopathies as the pathogenic basis for up to 35% of unexplained cases of sudden cardiac death (SCD) in the young. The evolution of the definition of IVF over time has led to a progressively greater awareness of the need for an extensive diagnostic assessment in unexplained SCA survivors. Nevertheless, GHDs are still underdiagnosed among SCA survivors, due to the underuse of pharmacological challenges (i.e. sodium channel blocker test), misrecognition of electrocardiogram (ECG) abnormalities/patterns (i.e. early repolarization pattern or exercise-induced ventricular bigeminy) or errors in the measurement of ECG parameters (e.g. the heart-rate corrected QT interval). In this review, we discuss the epidemiology, diagnostic approaches, and the controversies related to role of the genetic background in unexplained SCA survivors with a default diagnosis of IVF.

Sodium-calcium exchange-mediated contractions in feline ventricular myocytes

1992 ◽  
Vol 263 (4) ◽  
pp. H1161-H1169 ◽  
Author(s):  
H. B. Nuss ◽  
S. R. Houser
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Membrane Potentials ◽  
Exchange Mechanism ◽  
Ca Channel ◽  
Ca Current ◽  
Voltage Step ◽  
Reverse Mode ◽  
Sodium Calcium ◽  
Calcium Exchange

The hypothesis that Ca entry by the sarcolemmal Na-Ca exchange mechanism induces sarcoplasmic reticulum (SR) Ca release, loads the SR with Ca, and/or directly induces contractions by elevating cytosolic free Ca was tested in voltage-clamped feline ventricular myocytes. Intracellular Na concentration was increased by cellular dialysis to enhance Ca influx via "reverse-mode" Na-Ca exchange at positive membrane potentials, at which the "L-type" Ca current (ICa) should be small. Contractions were induced in the presence of Ca channel antagonists by depolarization to these potentials, suggesting that Ca influx via reverse-mode Na-Ca exchange was involved. These contractions had both phasic (SR related) and tonic components of shortening. They were smaller and began with more delay after depolarization than contractions which involved ICa. The magnitude of shortening was graded by the amount and duration of depolarization, suggesting that Ca influx via reverse-mode Na-Ca exchange has the capacity to induce and grade SR Ca release. Small slow contractions could be evoked in the presence of ryanodine (to impair SR function) and verapamil (to block ICa), supporting the idea that Ca influx via Na-Ca exchange is sufficient to directly activate the contractile proteins. Contractions induced by voltage steps to +10 mV, which were usually small when ICa was blocked, were potentiated if preceded by a voltage step to strongly positive potentials. This potentiation was inhibited by ryanodine, suggesting that Ca entry that occurs by Na-Ca exchange may be important for normal SR Ca loading.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Properties of L-type calcium channel gating current in isolated guinea pig ventricular myocytes.

1991 ◽  
Vol 98 (2) ◽  
pp. 265-285 ◽  
Author(s):  
R W Hadley ◽  
W J Lederer
Keyword(s):  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Channel Gating ◽  
Charge Movement ◽  
Ca Channel ◽  
Dependent Manner ◽  
Gating Current ◽  
Ca Current ◽  
Channel Inactivation ◽  
Time Dependencies

Nonlinear capacitative current (charge movement) was compared to the Ca current (ICa) in single guinea pig ventricular myocytes. It was concluded that the charge movement seen with depolarizing test steps from -50 mV is dominated by L-type Ca channel gating current, because of the following observations. (a) Ca channel inactivation and the immobilization of the gating current had similar voltage and time dependencies. The degree of channel inactivation was directly proportional to the amount of charge immobilization, unlike what has been reported for Na channels. (b) The degree of Ca channel activation was closely correlated with the amount of charge moved at all test potentials between -40 and +60 mV. (c) D600 was found to reduce the gating current in a voltage- and use-dependent manner. D600 was also found to induce "extra" charge movement at negative potentials. (d) Nitrendipine reduced the gating current in a voltage-dependent manner (KD = 200 nM at -40 mV). However, nitrendipine did not increase charge movement at negative test potentials. Although contamination of the Ca channel gating current from other sources cannot be fully excluded, it was not evident in the data and would appear to be small. However, it was noted that the amount of Ca channel gating charge was quite large compared with the magnitude of the Ca current. Indeed, the gating current was found to be a significant contaminant (19 +/- 7%) of the Ca tail currents in these cells. In addition, it was found that Ca channel rundown did not diminish the gating current. These results suggest that Ca channels can be "inactivated" by means that do not affect the voltage sensor.

scholarly journals Phospholamban Knockout Breaks Arrhythmogenic Ca 2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice

2013 ◽  
Vol 113 (5) ◽  
pp. 517-526 ◽  
Author(s):  
Yunlong Bai ◽  
Peter P. Jones ◽  
Jiqing Guo ◽  
Xiaowei Zhong ◽  
Robert B. Clark ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Mouse Model ◽  
Ventricular Myocytes ◽  
Mutant Mice ◽  
Polymorphic Ventricular Tachycardia ◽  
Patch Clamp Recording ◽  
Plasmic Reticulum ◽  
Paradoxical Effects ◽  
Triggered Arrhythmias ◽  
The Impact

Rationale : Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca 2+ ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca 2+ load and Ca 2+ leak. Conversely, PLN-KO accelerates Ca 2+ sequestration and aborts arrhythmogenic spontaneous Ca 2+ waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca 2+ -triggered arrhythmias. Objective : We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT. Methods and Results : We generated a PLN-deficient, RyR2-mutant mouse model (PLN −/− /RyR2-R4496C +/− ) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT–associated RyR2-R4496C mutant mice. Ca 2+ imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C +/− ventricular myocytes during sarcoplasmic reticulum Ca 2+ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca 2+ sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca 2+ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca 2+ ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li + failed to convert mini-waves to cell-wide SCWs in PLN −/− /RyR2-R4496C +/− ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs. Conclusions : Our results demonstrate that despite severe sarcoplasmic reticulum Ca 2+ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca 2+ sequestration represents an effective approach for suppressing Ca 2+ -triggered arrhythmias.

scholarly journals Oral adrenergic agents produced Ventricular fibrillation and QT prolongation in an elderly patient carrying an RYR2 variant.

2021 ◽  
Author(s):  
Kanae Hasegawa ◽  
Kentaro Ishida ◽  
Shinsuke Miyazaki ◽  
Seiko Ohno ◽  
Minoru Horie ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Long Qt Syndrome ◽  
Qt Prolongation ◽  
Polymorphic Ventricular Tachycardia ◽  
Long Qt ◽  
Causative Gene ◽  
Drug Induced ◽  
Adrenergic Agents ◽  
First Case ◽  
Qt Syndrome

Mutant cardiac ryanodine receptor channels (RyR2) are “leaky,” and spontaneous Ca2+ release through these channels causes delayed afterdepolarizations that can deteriorate into ventricular fibrillation (VF). RYR2 is a causative gene of type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT). Some patients carrying RYR2 mutations in CPVT exhibit QT prolongation and are initially diagnosed with long QT syndrome. However, none have been reported to cause drug-induced VF in patients with RYR2 variants. We describe the first case of an elderly woman with drug-induced QT prolongation and VF who carried a novel RYR2variant but no other mutations related to long QT syndrome.

scholarly journals Identification of Loss-of-function RyR2 Mutations Associated with Idiopathic Ventricular Fibrillation and Sudden Death

2021 ◽  
Author(s):  
Xiaowei Zhong ◽  
Wenting Guo ◽  
Jinhong Wei ◽  
Yijun Tang ◽  
Yingjie Liu ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Sudden Death ◽  
Negative Impact ◽  
Deficiency Syndrome ◽  
Dominant Negative ◽  
Exercise Stress ◽  
Hek293 Cells ◽  
Polymorphic Ventricular Tachycardia ◽  
Loss Of Function ◽  
Idiopathic Ventricular Fibrillation

Mutations in cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most CPVT RyR2 mutations characterized are gain-of-function (GOF), indicating enhanced RyR2 function as a major cause of CPVT. Loss-of-function (LOF) RyR2 mutations have also been identified and are linked to a distinct entity of cardiac arrhythmia termed RyR2 Ca2+ release deficiency syndrome (CRDS). Exercise stress testing (EST) is routinely used to diagnose CPVT, but it is ineffective for CRDS. There is currently no effective diagnostic tool for CRDS in humans. An alternative strategy to assess the risk for CRDS is to directly determine the functional impact of the associated RyR2 mutations. To this end, we have functionally screened 18 RyR2 mutations that are associated with idiopathic ventricular fibrillation (IVF) or sudden death. We found two additional RyR2 LOF mutations E4146K and G4935R. The E4146K mutation markedly suppressed caffeine activation of RyR2 and abolished store overload induced Ca2+ release in HEK293 cells. E4146K also severely reduced cytosolic Ca2+ activation and abolished luminal Ca2+ activation of single RyR2 channels. The G4935R mutation completely abolished caffeine activation of and [3H]ryanodine binding to RyR2. Co-expression studies showed that the G4935R mutation exerted dominant negative impact on the RyR2 wildtype channel. Interestingly, the RyR2-G4935R mutant carrier had a negative EST, and the E4146K carrier had a family history of sudden death during sleep, which are different from phenotypes of typical CPVT. Thus, our data further support the link between RyR2 LOF and a new entity of cardiac arrhythmias distinct from CPVT.

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