SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca2+/voltage uncoupling in hypertrophied hearts.

Ventricular arrhythmia (VA) is the major cause of death in patients with left ventricular (LV) hypertrophy and/or acute ischemia. We hypothesized that apamin, a blocker of small-conductance Ca2+-activated K+ (SK) channels, alters Ca2+ handling and exhibits anti-arrhythmic effects in ventricular myocardium. Spontaneous hypertensive rats were used as a model of LV hypertrophy. A dual optical mapping of membrane potential (Vm) and intracellular calcium (Cai) was performed during global hypoxia (GH) on the Langendorff perfusion system. The majority of pacing-induced VAs during GH were initiated by triggered activities. Pretreatment of apamin (100 nmol/L) significantly inhibited the VA inducibility. Compared with SK channel blockers (apamin and NS8593), non-SK channel blockers (glibenclamide and 4-AP) did not exhibit anti-arrhythmic effects. Apamin prevented not only action potential duration (APD80) shortening (-18.7 [95% confidence interval, -35.2 to -6.05] ms vs. -2.75 [95% CI, -10.45 to 12.65] ms, P = 0.04) but also calcium transient duration (CaTD80) prolongation (14.52 [95% CI, 8.8-20.35] ms vs. 3.85 [95% CI, -3.3 to 12.1] ms, P < 0.01), thereby reducing CaTD80 - APD80, which denotes "Cai/Vm uncoupling" (33.22 [95% CI, 22-48.4] ms vs. 6.6 [95% CI, 0-14.85] ms, P < 0.01). The reduction of Cai/Vm uncoupling was attributable to less prolonged Ca2+ decay constant and suppression of diastolic Cai increase by apamin. The inhibition of VA inducibility and changes in APs/CaTs parameters caused by apamin was negated by the addition of ouabain, an inhibitor of Na+/K+ pump. Apamin attenuates APD shortening, Ca2+ handling abnormalities, and Cai/Vm uncoupling, leading to inhibition of VA occurrence in hypoxic hypertrophied hearts.NEW & NOTEWORTHY We demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca2+-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca2+-activated K+ channels, especially "apamin," showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca2+ handling abnormalities, most notably the "Ca2+/voltage uncoupling."

Fast pathway ablation unmasks nodoventricular fibers in a 15-year-old patient with supraventricular tachycardia.

We described a 15-year-old boy who underwent the catheter ablation for the nodoventricular (NV) tachycardia that had difficulty in differentiation from atrioventricular nodal reentrant tachycardia with upper common pathway. The modification of the fast pathway revealed an anterograde conduction of the NV fiber. We successfully performed the catheter ablation targeting for the right ventricular insertion site of the NV fiber.

A single premature stimulation from the para-Hisian region unmasked negative involvement of the left anterior fascicle in the verapamil-sensitive ventricular tachycardia with a right bundle branch block and right-axis deviation.

A 33-year-old man had verapamil-sensitive ventricular tachycardia (VT) with a right bundle branch block (RBBB) and right axis deviation. Programmed stimulation from the para-Hisian region induced ventricular tachycardias (VT1 or VT2). VT1 was entrained during pacing from the para-Hisian region. A single para-Hisian stimulation antidromically captured the proximal portion of the left anterior fascicle (LAF), but the cycle length of VT2 remained unchanged. This observation indicated that the upper limb of the LAF was a bystander of the reentry circuit. We have clarified this mechanism with applying a single premature stimulation from the para-Hisian region.

Electrical Storm as an Independent Mortality Risk in Patients with Preserved or Moderately Reduced Left Ventricular Function.

Electrical storm (ES), defined by 3 or more occurrences of ventricular arrhythmias within 24 hours, has been shown to be associated with an increased risk of mortality; however, detailed information remains lacking. We aimed to examine the incidence and determinants of ES and its impact on mortality in patients enrolled in the nationwide implantable cardioverter-defibrillator (ICD) registry.We studied 1,256 patients (age 65 ± 12 years) who had structural heart disease with an ICD. The patients were classified into reduced ejection fraction (EF < 35%; 657 (52%) patients) and preserved or moderately reduced EF (EF ≥ 35%; 599 (48%) patients).ES occurred in 49 (7%) and 36 (6%) patients in the EF < 35% and EF ≥ 35% groups (log-rank P = 0.297) during the median follow-up of 2.3 years. ICD with resynchronization therapy was associated with a lower incidence of ES in patients with EF < 35%. Non-ischemic heart disease and diuretics were associated with ES in patients with EF ≥ 35%. During the follow-up, 10/49 (20%) patients with ES and 80/608 patients (13%) without ES died in patients with EF < 35%, while 7/36 (19%) patients with ES and 38/563 patients (7%) without ES died in those with EF ≥ 35%. We have created 4 Cox multivariate models. All models showed approximately 2-fold higher hazard ratios in patients with EF ≥ 35% compared to EF < 35%.Our study showed that the determinants of ES differed between EF < 35% and EF ≥ 35%. The impact of ES for mortality was numerically higher in EF ≥ 35% than in EF < 35%, although a significant interaction was not detected.

Rapid-rate nonsustained ventricular tachycardias in high-risk dilated cardiomyopathy patients.

AIMS: Nonsustained ventricular tachycardia (NSVT) occurs frequently in patients with dilated cardiomyopathy (DCM), especially in high-risk patients. The role of rapid-rate NSVT (RR-NSVT) documented by an implantable cardioverter-defibrillator (ICD) in DCM patients has not been fully explored. This study aimed to determine the relationship between RR-NSVT and the occurrence of ventricular tachyarrhythmias (VTAs) in DCM patients with ICD. METHODS: From December 2000 to December 2017, 136 DCM patients received ICD or cardiac resynchronization therapy defibrillator (CRT-D) implantation for primary or secondary prevention of VTAs. Based on the occurrence of documented RR-NSVT, patients were classified into RR-NSVT (-) or RR-NSVT (+) groups. RESULT: During the median follow-up of 4.5 years, 50.0% (68/136) patients experienced ≥1 episode, and 25.0% (34/136) patients experienced ≥3 episodes of RR-NSVT. Event-free survival for VTAs was significantly higher in the RR-NSVT (-) group, whereas those for heart failure admission and cardiovascular mortality were comparable between groups. In the multivariate Cox regression analysis, any RR-NSVT showed a positive association with the occurrence of VTAs (hazard ratio: 5.087; 95% confidence interval: 2.374-10.900; P < .001). In RR-NSVT (+) patients, a cluster (≥3 times/6 months) and frequent pattern (≥3 runs/day) of RR-NSVT were observed in 42.6% (29/68) and 30.9% (21/68) patients, respectively, who showed further increased incidence of VTAs. CONCLUSION: In DCM patients with ICD/CRT-D, 50.0% patients experienced at least one episode of RR-NSVT. RR-NSVT documentation showed a positive association with subsequent occurrence of VTAs, suggesting the importance of constructive arrhythmia management for patients with RR-NSVT.

Retrograde sharp potential resembling the his-bundle electrogram: is this a case of atrioventricular re-entrant tachycardia involving twin atrioventricular nodes with the anterior node exhibiting only retrograde conduction?

A 2-year-old male with right isomerism was referred for supraventricular tachycardias. Atrial pacing study revealed that anterograde conduction was only through the posterior atrioventricular node. During the mapping of ventriculoatrial conduction, we identified a sharp potential resembling a His-bundle electrogram with a decremental property at the anterior wall of the common atrium. Catheter ablation for the potential eliminated the anterior ventriculoatrial conduction, thereby indicating retrograde activation of the possible anterior atrioventricular node.

Higher Pulmonary Arterial Pressure Was Related to Non-Pulmonary Vein Atrial Tachyarrhythmia.

Recurrence of atrial tachyarrhythmias (ATA) following catheter ablation for atrial fibrillation (AF) is often associated with the recovery of conduction into previously isolated pulmonary veins (PVs). Little evidence concerning repeat PV isolation (PVI) and non-PV ATA ablation has been reported. This study aimed to explore the clinical outcome of recurrent ATA ablation after PVI and the difference between patients with and without non-PV ATA.A total of 49 patients without structural heart diseases who received catheter ablation for recurrent AF between January 2014 and December 2018 were recruited (prior ablation with PVI only 71.4% and PVI with cavotricuspid isthmus line ablation 28.6%). Patients were divided into two groups according to the presence or absence of non-PV ATA.Most patients (53.1%) experienced very late recurrence with a median duration of 15 months. A total of 15 patients had non-PV ATA and received non-PV ATA ablation whereas 34 patients received only repeat PVI for reconnected PVs. A higher pulmonary arterial systolic pressure (PASP) was associated with non-PV ATA (odds ratio: 1.161; 95% confidence interval: 1.021-1.321; P = 0.023). During 4.7 ± 1 months, 4/15 (26.7%) and 1/34 (2.9%) patients with and without non-PV ATA, respectively, had ATA recurrence (P = 0.011). The cumulative incidence of ATA recurrence after repeat ablation was significantly lower in patients without non-PV ATA (P = 0.013).In our study, a high PASP was associated with non-PV ATA in patients with recurrent AF. Repeat PVI had a high rate of maintenance of sinus rhythm in patients without non-PV ATA.

Evaluation of the pulmonary artery potential using a 20-polar circumferential catheter and three-dimensional integrated intracardiac echocardiography.

Prolongation of the pulmonary artery potentials (PAPs) in response to short coupling intervals was related to polymorphic QRS configurations during the ventricular tachycardia originating above the pulmonary valve (PA-VT). This prospective study was aimed to investigate the mechanisms of polymorphic changes during the PA-VT. We performed the mapping above the pulmonary valve using a 20-polar circumferential catheter and three-dimensional integrated intracardiac echocardiography in 9 consecutive patients with outflow tract arrhythmias undergoing catheter ablation (UMIN ID: UMIN000021682). The location of successful ablation was right ventricular outflow tract (RVOT) in 6 patients, above the pulmonary valve in 1 patient, left coronary cusp in 1 patient, and unknown in 1 patient. The PAP was detected in six (67%) patients with bipolar voltage of 0.56 ± 0.27 mV. Pacing from bipolar electrodes of the circumferential catheter located above the pulmonary valve captured the PA myocardium only in 1 patient who had the PA-VT (100% in PA-VT vs 0% in non-PA-VT, P = 0.0046), and slight changes of the QRS morphology was observed in accordance with the conduction delay from the stimulus to activation of the RVOT myocardium. The selective PAP capture with conduction delays evoked by bipolar stimulations through a 20-polar circumferential catheter may be a characteristic property of patients with the PA-VT. Conduction delays within the PA and PA-RVOT junction appears to contribute polymorphic QRS changes during the PA-VT.

Small-conductance Ca2+-activated K+ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy.

The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca2+-activated K+ (SK) channels are activated during hypoxia via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K+ channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K+ channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr286 (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca2+-activated K+ channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca2+-activated K+ channels interact with phosphorylated Ca2+/calmodulin-dependent protein kinase II at Thr286 in hypertrophied hearts.

Current Trends in Implantable Cardioverter-Defibrillator Therapy in Children　- Results From the JCDTR Database.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) are being used with increasing frequency in children. Our aim was to examine the current trend of pediatric ICD implantation in Japan. Methods and Results: Data was extracted from the Japanese Cardiac Device Treatment Registry (JCDTR), a nation-wide registry started in 2006. All patients aged less than 18 years who had an ICD implantation registered between 2006 and 2016 were included in the analysis. A total of 201 patients were included, with a median age of 16 years (range 1-18). The underlying cardiac diagnosis was primary electrical disease (67%), cardiomyopathy (26%) and congenital heart disease (4%), with idiopathic ventricular fibrillation (29%) and long QT syndrome (21%) being the 2 most common diagnoses. Implantation indication was primary prevention in only 30 patients (15%). There were 27 patients (13%) aged ≤12 years, with a larger proportion of patients with cardiomyopathy (33%). The indication in younger children was secondary prevention in all cases. Younger children may be under-represented in our study given the nature of the database as it is a predominantly adult cardiology database. CONCLUSIONS: In the past decade, ICD implantation has been performed in approximately 20 children per year in Japan, mostly for secondary prevention. There was no increase in the trend nor a change in age distribution.

Reentrant atrial tachycardia originating from the sinus venosa region.

A 78-year old woman with palpitation exhibited an atrial tachycardia (AT) of variable cycle lengths resembling atrial fibrillation (AF). Vague centrifugal activation was noted at the sinus venosa region where overdrive pacing demonstrated entrainment with concealed fusion and the stimulus to P wave approximated the electrogram to the P wave interval of 125ms. Application of radiofrequency energy to this site resulted in termination of the AT as well as formation of a fixed block line manifested by the presence of discrete double potentials. These observations indicated the reentrant mechanism of AT originating from the sinus venosa region.

Survival and Heart Failure Hospitalization in Patients With Cardiac Resynchronization Therapy With or Without a Defibrillator for Primary Prevention in Japan　- Analysis of the Japan Cardiac Device Treatment Registry Database.

BACKGROUND: Randomized control trials comparing the effectiveness of cardiac resynchronization therapy devices, with (CRT-D) or without (CRT-P) a defibrillator, are scarce in heart failure patients with no prior sustained ventricular tachyarrhythmias.Methods and Results:The Japan Cardiac Device Treatment Registry (JCDTR) has data for 2714 CRT-D and 555 CRT-P recipients for primary prevention with an implantation date between January 2011 and August 2015. Of these patients, follow-up data were available for 717. Over the mean follow-up period of 21 months, Kaplan-Meier curves of survival free of combined events for all-cause death or heart failure hospitalization (whichever came first) diverged between the CRT-D (n=620) and CRT-P (n=97) groups with a rate of 22% vs. 42%, respectively, at 24 months (P=0.0011). However, this apparent benefit of CRT-D over CRT-P was no longer significant after adjustment for covariates. With regard to mortality, including heart failure death or sudden cardiac death, there was no significant difference between the 2 groups. CONCLUSIONS: In patients without sustained ventricular tachyarrhythmias enrolled in the JCDTR, there was no significant difference in mortality between the CRT-D and CRT-P groups, despite a lower trend in CRT-D recipients. This study was limited by large clinical and demographic differences between the 2 groups.

Point catheter ablation of macro-re-entrant ventricular tachycardia in a patient after surgical repair for double-outlet right ventricle.

Catheter ablation of ventricular tachycardia is often difficult in patients after surgery for CHD. In patients with a ventricular septal defect patch, it is necessary to decide which ventricular side is appropriate for catheter ablation. In this article, we report a case of successful point catheter ablation of re-entrant ventricular tachycardia. Identification of the ventricular septal defect patch using intra-cardiac echocardiography was useful.

Characteristics of idiopathic ventricular tachycardia originating above the pulmonary valve.

Panoptic studies of ventricular tachycardia (VT) originating above the pulmonary valve are scarce. The purpose of this study is to clarify the characteristic of idiopathic VT arising above pulmonary valve. We analyzed 15 consecutive patients with idiopathic VT that was successfully abolished by catheter ablation at the right ventricular outflow tract (RVOT-VT, n = 11) and above the pulmonary valve (PA-VT, n = 4). Incidence of syncope was higher in PA-VT than RVOT-VT (100 vs 27 %, P < 0.05) and polymorphic VT was also more prevalent in PA-VT (75 vs 0 %, P < 0.05). The coupling interval (315 ± 29 vs 449 ± 32 ms, mean ± SE) at the onset of VT and minimum cycle length (CL) (192 ± 13 vs 344 ± 37 ms) during VT were shorter in PA-VT (both P < 0.05). Among 12-lead ECG parameters, only R-wave amplitude in lead II was different between groups (2.05 ± 0.17 mV in PA-VT vs 1.44 ± 0.05 mV in RVOT-VT, P < 0.005). At the successful ablation site, the activation time from the onset of QRS complex did not differ between groups (-37 ± 3 vs -31 ± 4, P = 0.405), whereas, the amplitude of intracardiac electrograms was significantly lower in PA-VT (0.83 ± 0.38 mV vs 2.39 ± 0.36 mV, P < 0.05). Although the number of patients in this study is limited, VT originating above the pulmonary valve demonstrated rapid excitation and often degenerated into polymorphic VT, suggesting its malignant electrophysiological characteristics.

Small-conductance Ca2+-activated K+ current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats.

Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca(2+)-activated K(+) (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and apamin-sensitive K(+) current (IKAS), which is inhibited by apamin (100 nM), an SK channel blocker, was evaluated. IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P < 0.05). IKAS was almost completely abolished by 1 µM KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P < 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (phosphorylated CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P < 0.05) despite a comparable total amount of CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.

Predictors of high defibrillation threshold in patients with implantable cardioverter-defibillator using a transvenous dual-coil lead.

BACKGROUND: Defibrillation testing (DT) is considered a standard procedure during implantable cardioverter-defibrillator (ICD) implantation. However, little is known about the factors that are significantly related to patients with high defibrillation threshold (DFT) using the present triad system. METHODS AND RESULTS: We examined 286 consecutive patients who underwent ICD implantation with a transvenous dual-coil lead and DT from December 2000 to December 2011. We defined patients who required 25 J or more by the implanted device as the high DFT group, and those who required less than 25 J as the normal DFT group. For each patient, assessment parameters included underlying disease, comorbidities, NYHA functional class, drugs, and echocardiographic measures. The high DFT group consisted of 12 patients (4.2%). Multivariate analysis identified 3 independent predictors for high DFT: atrial fibrillation (odds ratio (OR) 4.85, 95% confidence interval (CI) 1.24-22.33, P=0.023), hypertension (OR 4.01, 95% CI 1.08-15.96, P=0.039), thickness of interventricular septum (IVS) >12 mm (OR 4.82, 95% CI 1.17-20.31, P=0.030). CONCLUSIONS: Atrial fibrillation, hypertension and IVS hypertrophy were significantly associated with high DFT. Identification of such patients could help to lower the risk of complications with DT.

Predictors and Proarrhythmic Consequences of Inappropriate Implantable Cardioverter-Defibrillator Therapy.

BACKGROUND: Despite the benefits of implantable cardioverter-defibrillator (ICD) therapy, inappropriate shocks can lead to multiple adverse effects. The aim of this study was to clarify the predictors of inappropriate ICD shocks and their proarrhythmic consequences. METHODS AND RESULTS: We retrospectively studied 316 consecutive patients who underwent ICD implantation from December 2000 to December 2011. Of them, 70 (22%) experienced inappropriate ICD shocks without proarrhythmia requiring some intervention; 2 patients (0.6%) had proarrhythmic inappropriate ICD therapy by antitachycardia pacing (ATP), thereby calculated to be 0.18% of patients per year. However, they did not have syncope from this inappropriate ATP. Multivariate analysis identified younger age (≤56 years: hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.02-2.77, P=0.043), paroxysmal atrial fibrillation (HR 3.00, 95% CI 1.64-5.31, P=0.0002), stroke (HR 2.23, 95% CI 1.11-4.47, P=0.024), and no diuretic use (HR 1.72, 95% CI 1.03-2.93, P=0.039) as independent predictors of the occurrence of inappropriate ICD shocks. CONCLUSIONS: Young age, paroxysmal atrial fibrillation, stroke, and no use of diuretics were independently associated with inappropriate ICD shocks. Proarrhythmic inappropriate ICD therapy was observed with an annual incidence of 0.18% by ATP.

Ca2+/calmodulin-dependent protein kinase II increases the susceptibility to the arrhythmogenic action potential alternans in spontaneously hypertensive rats.

Action potential duration alternans (APD-ALT), defined as long-short-long repetitive pattern of APD, potentially leads to lethal ventricular arrhythmia. However, the mechanisms of APD-ALT in the arrhythmogenesis of cardiac hypertrophy remain undetermined. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to modulate the function of cardiac sarcoplasmic reticulum and play an important role in Ca(2+) cycling. We thus aimed to determine the role of CaMKII in the increased susceptibility to APD-ALT and arrhythmogenesis in the hypertrophied heart. APD was measured by high-resolution optical mapping in left ventricular (LV) anterior wall from normotensive Wistar-Kyoto (WKY; n = 10) and spontaneously hypertensive rats (SHR; n = 10) during rapid ventricular pacing. APD-ALT was evoked at significantly lower pacing rate in SHR compared with WKY (382 ± 43 vs. 465 ± 45 beats/min, P < 0.01). These changes in APD-ALT in SHR were completely reversed by KN-93 (1 µmol/l; n = 5), an inhibitor of CaMKII, but not its inactive analog, KN-92 (1 µmol/l; n = 5). The magnitude of APD-ALT was also significantly greater in SHR than WKY and was completely normalized by KN-93. Ventricular fibrillation (VF) was induced by rapid pacing more frequently in SHR than in WKY (60 vs. 10%; P < 0.05), which was also abolished by KN-93 (0%, P < 0.05). Western blot analyses indicated that the CaMKII autophosphorylation at Thr287 was significantly increased in SHR compared with WKY. The increased susceptibility to APD-ALT and VF during rapid pacing in hypertrophied heart was prevented by KN-93. CaMKII could be an important mechanism of arrhythmogenesis in cardiac hypertrophy.