Targeted deep sequencing analyses of long QT syndrome in a Japanese population.

Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment.

Sheath shape pattern during leadless pacemaker implantation.

PURPOSE: Options for shaping the delivery sheath of leadless pacemakers (LPs) based on the cardiac anatomy of patients are limited. We predicted the shape of the LP sheath during implantation using preoperative computed tomography (CT) and intraoperative fluoroscopy. METHODS: Forty-eight patients with implanted LPs due to symptomatic bradyarrhythmia were divided into two groups, α-loop and non-α-loop, based on the shape of the LP delivery sheath head at implantation. Angles between the inferior vena cava (IVC) and the interventricular septum (IVST), and the IVC and right ventricular apex (RVA) were measured by CT. The relationship between the final sheath shape and position of the IVC and the right or left side of the line drawn vertically from the deflection point of the sheath in the LAO view on fluoroscopy was assessed. RESULTS: Angles between the IVC and IVST (44.4 ± 5.9° vs. 50.2 ± 6.8°) and IVC and RVA (52.5 ± 5.3° vs. 58.8 ± 7.8°) on CT were significantly (p < 0.01) smaller in the α-loop group. To predict the α-loop shape, a combined IVC-IVST angle < 50° and IVC-RVA angle < 55° revealed higher sensitivity (81.8%). The delivery sheath positioned right of the vertical line was more frequent in the α-loop group (90.9% vs. 23.1%, p < 0.01). CONCLUSIONS: When the preoperatively calculated angles of IVC to IVST and RVA on CT were narrow, the right side of the sheath in the IVC from the vertical line drawn from the deflection point in the LAO view indicated the need to shape the delivery sheath head into an α-loop during LP implantation.

Proper use of fentanyl facilitates anesthesia during pulmonary vein isolation.

Although intraoperative anesthetic management of extensive encircling pulmonary vein isolation (PVI) is essential for the safe performance of this procedure, there is no standardized approach for the use of sedation and analgesia. Therefore, the present study aimed to clarify the optimal fentanyl dosage and timing of administration for the anesthetic management during PVI. A total of 364 patients with atrial fibrillation (AF) who underwent PVI at our institution between June 2017 and October 2020 were recruited. All patients were anesthetized with propofol for induction and maintenance under controlled ventilation via the supraglottic airway without neuromuscular blocking drugs. Among them, 234 patients received less frequent injections (Group 1) and 130 received a scheduled injection of 50 mg of fentanyl (Group 2) in addition to propofol during PVI. We compared the total and additional propofol doses, frequency of additional propofol, and procedure time between the two groups. The mean patient age was 67.2 years, and 69% were male. The total propofol dose was significantly lower in Group 2 than in Group 1 (17.0 ± 5.2 mg/kg vs. 19.0 ± 5.5 mg/kg, p < 0.01). The loading dose and frequency of additional propofol were also significantly lower in Group 2 than in Group 1. The procedure time was significantly shorter in Group 2 than in Group 1 (119 ± 36 min vs. 132 ± 31 min, p < 0.01). During PVI, proper use of fentanyl decreased the propofol dose, additional propofol frequency, and procedure time.

Effectiveness of a 3D mapping benchmark for ablation in patients with atrioventricular nodal reentrant tachycardia.

BACKGROUND: Avoiding excessively fast junctional rhythm (JR) during slow pathway (SP) modification for atrioventricular nodal reentrant tachycardia (AVNRT) helps prevent serious atrioventricular block. This study investigated the usefulness of a predictive ablation point that lies near the boundary line between appropriate and excessively fast JRs with three-dimensional (3D) electroanatomical mapping in AVNRT patients. METHODS: Participants were 141 consecutive patients with common AVNRT who received anatomical ablation to an antegrade SP at our institution between August 2013 and December 2019. Patients were divided into two groups: Group A, treated using a location marker that predicts successful ablation sites in a 3D mapping system, and Group B, treated prior to the development of this marker and therefore without it. RESULTS: The average age was 61.9 ± 16.9 years, and 41.1% of patients were male. Excessively fast JRs appeared less frequently in Group A than in Group B, though this difference did not reach significance. The distance from the His bundle to the successful ablation point was significantly longer in Group A than in Group B (13.4 ± 4.5 vs 10.8 ± 4.4 mm, P < .01). The number of ablations near the successful ablation point was significantly lower in Group A (6.5 ± 5.2 vs 11.4 ± 9.9, P < .01), and a greater number of accelerated JRs at the successful ablation point were observed in Group A (46.9 ± 29.2 vs 32.8 ± 19.2, P < .01). CONCLUSION: Using our benchmark for a predictive successful ablation point in 3D mapping simplifies and improves common AVNRT ablation procedures.

The feasibility of leadless pacemaker implantation for superelderly patients.

BACKGROUND: The safety and efficacy of the leadless pacemaker (LP) have been confirmed in previous reports, yet studies on LPs in superelderly patients are limited. METHODS AND RESULTS: A total of 62 patients aged over 85 years old were implanted with single-chamber pacemakers due to symptomatic bradyarrhythmia at Sakakibara Heart Institute from May 2014 through July 2019. We divided them into two groups, a transvenous (TV) single-chamber pacemaker group (35 patients) and an LP group (27 patients), and compared the groups. Mean participant age was 90.3 ± 3.8 y.o., 41.9% were male, and mean participant body mass index (BMI) was 21.3 kg/m2 . The LP group contained a significantly larger proportion of patients with dementia than the TV group did (63% vs. 37.1%, P = .04). The complication-free rate tended to be lower in the LP group in spite of the higher frequency of dementia (88.6% vs. 92.6%, P = .68). At implantation, the pacing threshold was significantly higher in the LP group than in the TV group (1.30 ± 0.91 V vs. 0.71 ± 0.23 V, P < .01), but over the first 3 months after the operation the pacing threshold in the LP group gradually improved (0.82 ± 0.2 V vs. 1.05 ± 1.02 V, P = .16). The procedure time and time from operation to discharge were also shorter in the LP group. CONCLUSIONS: LP implantation appears to be safe and is accordingly becoming the cornerstone for Japanese superelderly patients indicated for single-chamber pacemakers, even for those with small bodies and dementia. However, careful procedures and long follow-ups are needed until a greater volume of data is reported.

Risk stratification for cardiac mortality using electrocardiographic markers based on 24-hour Holter recordings: the JANIES-SHD study.

BACKGROUND: Recent guidelines have stated that left ventricular ejection fraction (LVEF) is the gold standard marker for identifying patients at risk for cardiac mortality. However, little information is present regarding electrocardiographic (ECG) markers. This study aimed to assess ECG markers for predicting mortality or serious arrhythmia in patients with structural heart disease (SHD). METHODS: In total, 1829 patients were enrolled into the Japanese Multicenter Observational Prospective Study (JANIES study). In this study, we analyzed data of 719 patients (569 men, age 64 ± 13 years) with SHD including mainly ischemic heart disease (65.8%). As ECG markers based on 24-hour Holter recordings, nonsustained ventricular tachycardia (NSVT), ventricular late potentials, and heart rate turbulence (HRT) were assessed. The primary endpoint was all-cause mortality, and the secondary endpoint was fatal arrhythmic events. RESULTS: During a mean follow-up of 21 ± 11 months, all-cause mortality was eventually observed in 39 patients (5.4%). Among those patients, 32 patients (82%) suffered from cardiac causes such as heart failure and arrhythmia. Multivariate Cox regression analysis showed that after adjustment for age and LVEF, documented NSVT [hazard ratio = 2.46, 95% confidence interval (CI): 1.16-5.18, p = 0.02] and abnormal HRT (hazard ratio = 2.40, 95% CI: 1.16-4.93, p = 0.02) were significantly associated with the primary endpoint. These two ECG markers also had significant predictive values with the secondary endpoint. The combined assessment of two ECG markers improved predictive accuracy. CONCLUSION: This study demonstrated that combined assessment of documented NSVT and abnormal HRT based on 24-hour Holter ECG recordings are recommended for predicting future serious events in this population.

A safe and simple approach to avoid fast junctional rhythm during ablation in patients with atrioventricular nodal reentrant tachycardia.

INTRODUCTION: Fast junctional rhythm (JR) during slow pathway modification for atrioventricular nodal reentrant tachycardia (AVNRT) is a predictor of serious atrioventricular block. This study investigated the boundary to avoid fast JR during ablation with three-dimensional (3D) electroanatomical mapping in AVNRT patients. METHODS AND RESULTS: Participants were 129 consecutive patients with common AVNRT who received anatomical ablation to an antegrade slow pathway at our institution between August 2013 and March 2019. Successfully ablated sites with JR were evaluated in terms of distances and angles in the left and right anterior oblique views (LAO and RAO, respectively) to the proximal His bundle (His) site using 3D mapping. We divided JR by heart rate: JR1 ≥150 bpm and JR2 <150 bpm. Average age was 61 ± 16 years; 41.1% of patients were male. The distance from the most proximal His to the JR1 and JR2 site was not significantly different (11.9 ± 4.4 vs 10.7 ± 4.5 mm, P = .24). JR1 predominantly appeared closer to the left ventricle than JR2 in LAO (110.5 ± 19.1° vs 77.5 ± 18.6°, P < .01), and was more posterior from the proximal His in RAO (30.8% vs 6.8%, P < .01). The vertical line drawn down from the proximal His in the LAO view was a good indicator of JR1 appearance (sensitivity and specificity 84.6% and 81.6%, respectively). CONCLUSION: The vertical line drawn down from the proximal His in the LAO view can be employed as a boundary to avoid fast JR during ablation in AVNRT.

SMART pass will prevent inappropriate operation of S-ICD.

BACKGROUND: Compared to screening ECG before implantation of a subcutaneous implantable cardioverter-defibrillator (S-ICD), selectable vectors without T-wave oversensing increase after S-ICD implantation. Newer algorithms have recently become available to reduce T-wave oversensing, such as SMART pass (SP). With this function, more selectable vectors are identified after S-ICD implantation. However, this improvement in eligibility utilizing SP has not yet been well validated. We aimed to clarify S-ICD eligibility before and after S-ICD implantation with and without SP. METHODS: Participants comprised 34 patients implanted with an S-ICD at Okayama University Hospital and its affiliated hospitals between February 2016 and August 2017. A total of 102 S-ICD vectors were assessed for eligibility before and after S-ICD implantation, at rest and during exercise testing. Vector availability was evaluated in the presence and absence of SP after S-ICD implantation. RESULTS: Subcutaneous implantable cardioverter-defibrillator eligibility was significantly better after implantation even without SP than S-ICD screening before S-ICD implantation, both at rest (before 65.7% vs after 95.1%, P < 0.01) and during exercise (before 59.3% vs after 90.6%, P < 0.01). SP improved S-ICD eligibility during exercise (SP on 97.9% vs off 90.6%, P = 0.03). Multivariate analysis showed the prevalence of S-ICD eligibility increased significantly after S-ICD implantation compared to screening before implantation. SP further increased selectable vectors in multivariate analysis. CONCLUSION: Available vectors increased significantly after S-ICD implantation compared to preoperative vectors as assessed by S-ICD screening ECG. T-wave oversensing during exercise has been an unresolved issue for S-ICD, but SP will help prevent inappropriate operation with S-ICD.

Prognostic Significance of the Sodium Channel Blocker Test in Patients With Brugada Syndrome.

BACKGROUND: A drug provocation test using a sodium channel blocker (SCB) can unmask a type 1 ECG pattern in patients with Brugada syndrome. However, the prognostic value of the results of an SCB challenge is limited in patients with non-type 1 ECG. We investigated the associations of future risk for ventricular fibrillation with SCB-induced ECG changes and ventricular tachyarrhythmias (VTAs). METHODS AND RESULTS: We administered intravenous pilsicainide to 245 consecutive patients with Brugada syndrome (181 patients with spontaneous type 1 ECG, 64 patients with non-type 1 ECG). ECG parameters before and after the test and occurrence of drug-induced VTAs were evaluated. During a mean follow-up period of 113±57 months, fatal VTA events occurred in 31 patients (sudden death: n=3, ventricular tachycardia/ventricular fibrillation: n=28). Symptomatic patients and spontaneous type 1 ECG were associated with future fatal arrhythmic events. Univariable analysis of ECG parameters after the test showed that long PQ and QRS intervals, high ST level, and SCB-induced VTAs were associated with later VTA events during follow-up. Multivariable analysis showed that symptomatic patients, high ST level (V1) ≥0.3 mV after the test, and SCB-induced VTAs were independent predictors for future fatal arrhythmic events (hazard ratios: 3.28, 2.80, and 3.62, 95% confidence intervals: 1.54-7.47, 1.32-6.35, and 1.64-7.75, respectively; P<0.05). CONCLUSIONS: SCB-induced VTAs and ST-segment augmentation are associated with an increased risk of the development of ventricular tachycardia/ventricular fibrillation events during follow-up in patients with Brugada syndrome.

Exercise stress test reveals ineligibility for subcutaneous implantable cardioverter defibrillator in patients with Brugada syndrome.

BACKGROUND: The eligibility of patients with Brugada syndrome (BrS) for implantation of a subcutaneous implantable cardioverter defibrillator (S-ICD) is not well known. This study aimed to clarify the eligibility of BrS patients for S-ICD using electrocardiography (ECG) at rest and during exercise testing. We also analyzed factors associated with ineligibility for S-ICD from standard 12-lead ECG at rest. METHODS: We enrolled 110 consecutive BrS patients who visited Okayama university hospital from December 2015 to December 2016. All patients were assessed for S-ICD eligibility, which required one lead to satisfy the S-ICD screening template. We assessed standard 12-lead ECG parameters in all participants. Of those who passed S-ICD screening, 45 patients were assessed for S-ICD eligibility during treadmill stress test. RESULTS: Mean age of study patients was 54 ± 13 years and 108 (98%) were men. In total, 89 patients (81%) satisfied S-ICD indications at rest. Existence of complete right bundle branch block (CRBBB) on standard 12-lead ECG was a significant predictor of ineligibility for S-ICD (odds ratio, 5.00; P = 0.03; 95%CI, 1.14-21.98). Of the 45 patients who underwent treadmill stress testing, 11 patients (24%) showed ineligibility for S-ICD during the test. CONCLUSION: CRBBB was a predictor of ineligibility for S-ICD in patients with BrS. Sinus tachycardia changes ECG morphology in some patients and stress testing should be considered before S-ICD implantation.

Initial experience with the subcutaneous implantable cardioverter-defibrillator in a single Japanese center.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is recognized as a viable alternative to the transvenous ICD. The safety and efficacy of this device has been demonstrated in Western countries, but studies with S-ICD implantation in Japanese patients have not been reported. METHODS AND RESULTS: Twelve patients received an S-ICD implant in our institute between February and September 2016. All S-ICDs were successfully implanted without complications. One appropriate and one inappropriate therapy was identified. CONCLUSIONS: S-ICD implantation appears to provide a viable alternative to transvenous ICD implantation for some Japanese patients. However, we should perform careful follow-up of patients to eliminate inappropriate therapy.

Epicardially placed implantable cardioverter-defibrillator for a child with congenital long QT syndrome.

A 7-year-old boy presented at our hospital with syncope. At birth, electrocardiography had shown a long QT interval with torsade de pointes (TdP). Congenital long QT syndrome (LQTS) had been diagnosed by genetic testing, and was successfully controlled with oral propranolol. At age 7, TdP had recurred with syncope. Electrocardiography revealed a prominent long QT interval with T-wave alternans. The propranolol dose was increased, but TdP remained uncontrolled. A cardioverter-defibrillator (ICD) was implanted epicardially, and TdP completely resolved with atrial pacing. We report this rare case of ICD implantation in a child with LQTS.

Comparison of longevity and clinical outcomes of implantable cardioverter-defibrillator leads among manufacturers.

BACKGROUND: An early failure of the Biotronik Linox S/SD implantable cardioverter-defibrillator (ICD) lead has been reported. We have also experienced several cases with early failure of Linox leads. OBJECTIVE: Our aim was to assess the longevity of Linox S/SD (Biotronik, Berlin, Germany) compared with Sprint Fidelis (Medtronic, Minneapolis, MN), Sprint Quattro (Medtronic), and Endotak Reliance (Boston Scientific, Natick, Massachusetts) leads. METHODS: We retrospectively reviewed patients who had undergone implantation of Linox S/SD (n = 90), Sprint Fidelis (n = 37), Sprint Quattro (n = 27), or Endotak Reliance (n = 50) leads between June 2000 and December 2013 at our hospital. Variables associated with lead failure were assessed by the Kaplan-Meier method and Cox survival modeling. RESULTS: Failure rates of Linox, Sprint Fidelis, and Endotak leads were 3.2%/year (7-year survival rate, 81.0%), 3.4%/year (7-year survival rate, 77.2%), and 0.61%/year (7-year survival rate, 95.8%), respectively. No lead failure was found with Sprint Quattro leads. The survival probability of Linox leads was significantly lower than that of Endotak leads (P = .049) and comparable to that of Sprint Fidelis leads (P = .69). In univariate analysis, age was the only predictor of Linox lead failure. Patients <58 years old were at significantly increased risk of lead failure compared with patients ≥58 years old (hazard ratio, 9.0; 95% confidence interval, 1.13-71.3; P = .037). CONCLUSION: In our single-center experience, the survival rate of Linox leads was unacceptably low. The only predictor of Linox lead failure was age at implantation. This is the first description of a lower survival rate for Linox leads in an Asian population.

Two cases of inappropriate implantable cardioverter-defibrillator therapies due to T wave oversensing induced by body twisting.

T wave oversensing (TWOS) is a common cause of inappropriate implantable cardioverter-defibrillator (ICD) therapies. Various algorithms to avoid inappropriate ICD therapy are available; however, they are not helpful to avoid TWOS. Although the reproduction of TWOS is useful to resolve the problem of TWOS, it is sometimes difficult to reproduce TWOS. We report two cases of inappropriate ICD therapy due to TWOS, which were induced only by body twisting. We can successfully manage the device based on the evidence of reproduced TWOS.

Distribution and Prognostic Significance of Fragmented QRS in Patients With Brugada Syndrome.

BACKGROUND: Fragmented QRS complexes (fQRS) in the right precordial leads are associated with occurrence of ventricular fibrillation (VF) in Brugada syndrome. Recently, epicardial mapping has revealed abnormal electrograms at the right ventricular (RV) outflow tract and inferior region of the right ventricle. fQRS may reflect the extent of the area of abnormal potentials, but whether the distribution of fQRS has prognostic value is not known. METHODS AND RESULTS: We evaluated the existence of fQRS in 456 patients with Brugada syndrome, including 117 patients with syncope and 23 patients with VF. The region of fQRS was defined as inferior (II, III, and aVF), lateral (I, aVL, and V5 and V6), anterior (V3 and V4), RV (V1 and V2), and RV outflow tract (V1 and V2 at the third intercostal space). fQRS were present in 229 patients (RV outflow tract in 175, inferior in 135, RV in 90, and lateral in 16 patients). During follow-up (mean 91 months), 39 patients experienced VF. In univariable analyses, fQRS in any distribution and fQRS in each region excluding the RV were associated with VF. Multivariable analysis showed that fQRS in the inferior (hazard ratio, 3.9; confidence interval, 1.9-8.5), lateral (hazard ratio, 3.5; confidence interval, 1.2-8.2), and RV outflow tract (hazard ratio, 2.5; confidence interval, 1.2-5.6) were associated with VF events. The presence of multiple regions of fQRS was associated with worse prognosis. CONCLUSIONS: The distribution of fQRS is associated with prognosis in Brugada syndrome, further supporting the association of fQRS and arrhythmia substrate.

Complete right bundle branch block and QRS-T discordance can be the initial clue to detect S-ICD ineligibility.

BACKGROUND: In order to minimize inappropriate shocks of subcutaneous implantable cardioverter-defibrillators (S-ICD), it is important to recognize who is suitable for S-ICD indication. This study aimed to clarify what types of cardiac disease are likely to fulfill the S-ICD screening criteria and ineligible factors for S-ICD in the standard 12-lead electrocardiogram (ECG). METHODS: A total of 348 patients with heart disease were enrolled. They were assessed by supine and standing ECG recording to simulate the 3 S-ICD sensing vectors and standard 12-lead ECG, simultaneously. Clinical and ECG characteristics were analyzed to compare the patients who are eligible and ineligible with S-ICD screening ECG indication. RESULTS: The mean age of study patients was 49±21 years and 244 (70%) were men. Nineteen percent of patients were unsuitable for S-ICD. There was no significant difference in ineligibility for S-ICD among cardiac diseases (p=0.48). Univariate analysis showed complete right bundle branch block (CRBBB), QRS-T discordance in lead II, and QRS-T discordance in 3 leads (I, II, and aVF) were more frequent in patients who were ineligible for S-ICD than in the eligible group. Multivariate regression analysis showed CRBBB and QRS-T discordance in 3 leads were independent predictors for ineligibility of S-ICD. CONCLUSION: There are no differences in eligibility of S-ICD among types of cardiac diseases. CRBBB and QRS-T discordance were independent predictors for ineligibility.

Measurement of epicardial fat thickness by transthoracic echocardiography for predicting high-risk coronary artery plaques.

Epicardial adipose tissue (EAT) volume is reported to be associated with coronary plaques. We evaluated whether non-invasive measurement of EAT thickness by echocardiography can predict high-risk coronary plaque characteristics determined independently by coronary computed tomography (CT) angiography. We enrolled 406 patients (mean age 63 years, 57 % male) referred for 64-slice CT. EAT was measured on the right ventricle free wall from a parasternal long-axis view at the end of systole. High-risk coronary plaques were defined as low-density plaques (<30 Hounsfield units) with positive remodeling (remodeling index >1.05). Patients were divided into thin or thick EAT groups using a cutoff value derived from receiver operator characteristic curve analysis for discriminating high-risk plaques. The receiver operator characteristic cutoff value was 5.8 mm with a sensitivity of 83 % and specificity of 64 % (area under the curve 0.77, 95 % confidence interval 0.70-0.83, p < 0.01). Compared with the thin EAT group, the thick EAT group had a high prevalence of low-density plaques (4 vs. 24 %, p < 0.01), positive remodeling (39 vs. 60 %, p < 0.01), and high-risk plaques (3 vs. 17 %, p < 0.01). Multiple logistic analysis revealed that thick EAT was a significant predictor of high-risk plaques (odds ratio 7.98, 95 % confidence interval 2.77-22.98, p < 0.01) after adjustment for covariates, including conventional risk factors, visceral adipose tissue area, and medications. The measurement of EAT thickness by echocardiography may provide a non-invasive option for predicting high-risk coronary plaques.