The utility of zebrafish cardiac arrhythmia model to predict the pathogenicity of KCNQ1 variants.

Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.

Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with KCNH2 mutation.

AIMS: Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. CONCLUSION: These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.

Hypertrophic Cardiomyopathy Predicts Thromboembolism and Heart Failure in Patients With Nonvalvular Atrial Fibrillation　- A Prospective Analysis From the Hokuriku-Plus AF Registry.

BACKGROUND: The prognostic effect of concomitant hypertrophic cardiomyopathy (HCM) on adverse events in patients with atrial fibrillation (AF) has not been evaluated in a multicenter prospective cohort study in Japan.Methods and Results: Using the Hokuriku-Plus AF Registry, 1,396 patients with nonvalvular AF (1,018 men, 72.3±9.7 years old) were assessed prospectively; 72 (5.2%) had concomitant HCM. During a median follow-up of 5.0 years (interquartile range 3.5-5.3 years), 79 cases of thromboembolism (1.3 per 100 person-years) and 192 of heart failure (HF) (3.2 per 100 person-years) occurred. Kaplan-Meier analysis revealed that the HCM group had a significantly greater incidence of thromboembolism (P=0.002 by log-rank test) and HF (P<0.0001 by a log-rank test) than the non-HCM group. The Cox proportional hazards model demonstrated that persistent AF (adjusted hazard ratio 2.98, 95% confidence interval 1.56-6.21), the CHA2DS2-VASc score (1.35, 1.18-1.54), and concomitant HCM (2.48, 1.16-4.79) were significantly associated with thromboembolism. Conversely, concomitant HCM (2.81, 1.72-4.43), older age (1.07, 1.05-1.10), lower body mass index (0.95, 0.91-0.99), a history of HF (2.49, 1.77-3.52), and lower left ventricular ejection fraction (0.98, 0.97-0.99) were significantly associated with the development of HF. CONCLUSIONS: Concomitant HCM predicts the incidence of thromboembolism and HF in AF patients.

Effect of Catheter Ablation for Atrial Fibrillation in Heart Failure With Mid-Range or Preserved Ejection Fraction　- Pooled Analysis of the AF Frontier Ablation Registry and Hokuriku-Plus AF Registry.

BACKGROUND: A recent randomized trial demonstrated that catheter ablation for atrial fibrillation (AF) in patients with heart failure with reduced ejection fraction (EF) is associated with a reduction in death or heart failure. However, the effect of catheter ablation for AF in patients with heart failure with mid-range or preserved EF is unclear.Methods and Results: We screened 899 AF patients (72.4% male, mean age 68.4 years) with heart failure and left ventricular EF ≥40% from 2 Japanese multicenter AF registries: the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) as the ablation group (525 patients who underwent ablation) and the Hokuriku-Plus AF Registry as the medical therapy group (374 patients who did not undergo ablation). Propensity score matching was performed in these 2 registries to yield 106 matched patient pairs. The primary endpoint was a composite of cardiovascular death and hospitalization for heart failure. At 24.6 months, the ablation group had a significantly lower incidence of the primary endpoint (hazard ratio 0.32; 95% confidence interval 0.13-0.70; P=0.004) than the medical therapy group. CONCLUSIONS: Compared with medical therapy, catheter ablation for AF in patients with heart failure and mid-range or preserved EF was associated with a significantly lower incidence of cardiovascular death or hospitalization for heart failure.

Ablation index-guided high-power vs. moderate-power cavotricuspid isthmus ablation.

Ablation index (AI)-guided ablation is useful for pulmonary vein isolation (PVI) and cavotricuspid isthmus (CTI) ablation. However, the impact of radiofrequency (RF) application power on CTI ablation with a fixed target AI remains unclear. One-hundred-thirty drug-refractory atrial fibrillation and/or atrial flutter patients who underwent AI-guided CTI ablation with or without PVI between July 2020 and August 2021 were randomly assigned to high-power (45 W) and moderate-power (35 W) groups. We performed CTI ablation with the same target AI value in both groups: 500 for the anterior 1/3 segments and 450 for the posterior 2/3 segments. In total, first-pass conduction block of the CTI was obtained in 111 patients (85.4%), with 7 patients (5.4%) showing CTI reconnection. The rate of first-pass conduction block was significantly higher in the 45 W group (61/65, 93.8%) than in the 35 W group (50/65, 76.9%, P = 0.01). CTI ablation and CTI fluoroscopy time were significantly shorter in the 45 W group than in the 35 W group (CTI ablation time: 192.3 ± 84.8 vs. 319.8 ± 171.4 s, P < 0.0001; CTI fluoroscopy time: 125.2 ± 122.4 vs. 171.2 ± 124.0 s, P = 0.039). Although there was no significant difference, steam pops were identified in two patients from the 45 W group at the anterior segment of the CTI. The 45 W ablation strategy was faster and provided a higher probability of first-pass conduction block than the 35 W ablation strategy for CTI ablation with a fixed AI target.

Characterization of baseline clinical factors associated with incident worsening kidney function in patients with non-valvular atrial fibrillation: the Hokuriku-Plus AF Registry.

Evidence suggests that atrial fibrillation (AF) could increase the risk of worsening kidney function (WKF) which is linked to an increased risk of stroke, bleeding, and death in AF patients. However, limited data exist regarding the factors that could lead to WKF in these patients. Therefore, we sought to identify the potential factors associated with the development of WKF in patients with non-valvular AF (NVAF). We analyzed prospectively recruited 1122 NVAF patients [men 71.9%, median age 73.0 years (interquartile range: 66.0-79.0)] with a baseline estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 from the Hokuriku-Plus AF Registry. The primary outcome was incident WKF, defined as the %eGFR change from the baseline ≥ 30% during the follow-up period. We evaluated the association between baseline variables and incident WKF using univariate and multivariate Cox proportional hazard models. We also evaluated the non-linear association between the identified factors and incident WKF. During a median follow-up period of 3.0 years (interquartile range: 2.7-3.3), incident WKF was observed in 108 patients (32.6 per 1000 person-years). Compared to the patients without incident WKF, the patients with incident WKF were older and had a higher prevalence of heart failure (HF), diabetes mellitus (DM), and vascular disease at baseline. Those who experienced incident WKF also had higher diastolic blood pressure, lower hemoglobin, lower eGFR, higher B-type natriuretic peptide (BNP) and used warfarin more frequently. Upon multivariate analysis, age ≥ 75 years, HF, DM, and anemia were independently associated with incident WKF. Additionally, age and hemoglobin were linearly associated with the risk of incident WKF, whereas a J- or U-shaped association was observed for HbA1c and BNP. Age ≥ 75 years, HF, DM, and anemia were associated with the development of WKF in Japanese patients with NVAF. In patients with these risk factors, a careful monitoring of the kidney function and appropriate interventions may be important when possible.

Prediction of atrioventricular conduction disturbance after ablation of persistent atrial fibrillation.

The prevalence of atrioventricular conduction disturbance (AVCD) in patients with persistent atrial fibrillation (AF) has not yet been fully investigated. We sought to identify the predictors of AVCD in patients with AF by analyzing the relationship between pre-ablation heart rate during AF and the PR interval in sinus rhythm after ablation. We analyzed pre-ablation 24-h Holter electrocardiogram (ECG) and 12 lead ECG 12 months after ablation of 121 consecutive patients with persistent AF who underwent their first ablation procedure and maintained sinus rhythm at 12 months. AVCD was defined as a first-degree atrioventricular block (AVB), second-degree AVB, high-degree AVB, or third-degree AVB observed on ECG at 12 months after ablation. Seventeen out of 121 patients (14.0%) had AVCD at 12 months. In the group with AVCD, total heartbeat (THB) and maximum heart rate (Max HR) were significantly lower, and the prevalence of concomitant Cavo-tricuspid isthmus-dependent atrial flutter before ablation and the appearance of macro reentrant atrial tachycardia (AT) during the procedure were significantly higher than those in the group without AVCD. Multiple regression analysis revealed that maximum HR and macro reentrant AT were significant predictors of AVCD. Receiver operating characteristic curve analysis revealed that Max HR of <165.0 bpm predicts AVCD with a sensitivity of 76.47% and a specificity of 74.00%. In patients with persistent AF, low Max HR and the presence of macro reentrant AT during the ablation procedure were predictors of AVCD.

Impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after catheter ablation of atrial fibrillation: insights from AF frontier ablation registry.

The impact of catheter ablation for atrial fibrillation (AF) on cardiovascular events and mortality is controversial. We investigated the impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after AF ablation from a Japanese multicenter cohort of AF ablation. We investigated 3326 consecutive patients (25.8% female, mean age 63.3 ± 10.3 years) who underwent catheter ablation for AF from the atrial fibrillation registry to follow the long-term outcomes and use of anti coagulants after ablation (AF frontier ablation registry). The primary endpoint was a composite of stroke, transient ischemic attack, cardiovascular events, and all-cause death. During a mean follow-up of 24.0 months, 2339 (70.3%) patients were free from AF after catheter ablation, and the primary composite endpoint occurred in 144 (4.3%) patients. The AF nonrecurrence group had a significantly lower incidence of the primary endpoint (1.8 per 100 person-years) compared with the AF recurrence group (3.0 per 100 person-years, p = 0.003). The multivariate analysis revealed that freedom from AF (hazard ratio 0.61, 95% confidence interval 0.44-0.86, p = 0.005) was independently associated with the incidence of the composite event. In the multicenter cohort of AF ablation, sinus rhythm maintenance after catheter ablation was independently associated with lower rates of major adverse cardiac and cerebrovascular events.

A Novel Risk Stratification System for Ischemic Stroke in Japanese Patients With Non-Valvular Atrial Fibrillation.

BACKGROUND: Recently, identification of independent risk factors for ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients was made by analyzing the 5 major Japanese registries: J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and the Hokuriku-Plus AF Registry.Methods and Results:The predictive value of the risk scheme in Japanese NVAF patients was assessed. Of 16,918 patients, 12,289 NVAF patients were analyzed (mean follow up, 649±181 days). Hazard ratios (HRs) of each significant, independent risk factor were determined by using adjusted Cox-hazard proportional analysis. Scoring system for ischemic stroke was created by transforming HR logarithmically and was estimated by c-statistic. During the 21,820 person-years follow up, 241 ischemic stroke events occurred. Significant risk factors were: being elderly (aged 75-84 years [E], HR=1.74), extreme elderly (≥85 years [EE], HR=2.41), having hypertension (H, HR=1.60), previous stroke (S, HR=2.75), type of AF (persistent/permanent) (T, HR=1.59), and low body mass index <18.5 kg/m2(L, HR=1.55) after adjusting for oral anticoagulant treatment. The score was assigned as follows: 1 point to H, E, L, and T, and 2 points to EE and S (HELT-E2S2score). The C-statistic, using this score, was 0.681 (95% confidence interval [CI]=0.647-0.714), which was significantly higher than those using CHADS2(0.647; 95% CI=0.614-0.681, P=0.027 for comparison) and CHA2DS2-VASc scores (0.641; 95% CI=0.608-0.673, P=0.008). CONCLUSIONS: The HELT-E2S2score may be useful for identifying Japanese NVAF patients at risk of ischemic stroke.

Optimization of the hot balloon ablation strategy using real-time pulmonary vein potential monitoring.

INTRODUCTION: Optimal radiofrequency-generated thermal energy applications have not been established for hot balloon ablation (HBA) systems. We investigated the feasibility of real-time monitoring of pulmonary vein (PV) potentials and optimal time-to-isolation (TTI)-guided application strategies in HBAs. METHODS AND RESULTS: Real-time monitoring of PV potentials was performed using a four-electrode unidirectional catheter in 34 consecutive patients. Acute isolation was achieved when PV potentials disappeared during HBAs and were undetected by high-resolution mapping. The TTI, the difference between TTI and the time to reach target temperature (TTRT), and ablation time after isolation were examined for 177 applications in 136 PVs. Real-time monitoring of PV activity was obtained in 167 out of 177 applications (94.3%) and acute isolation was achieved in 97 out of 177 (54.8%) applications. TTI-TTRT was significantly shorter, and ablation times after isolation were significantly longer in the acute isolation group than in the other groups. TTI-TTRT <4.5 seconds and TTIs <33.5 seconds predicted acute isolation (sensitivity 74.2%, specificity 88.4%; sensitivity 76.3%, specificity 76.7%, respectively). Ablation time after isolation >148.5 seconds (sensitivity 93.6%, specificity 51.7%) and >120.5 seconds (sensitivity 84.0%, specificity 78.6%) predicted acute isolation in superior PVs and inferior PVs, respectively. CONCLUSIONS: Real-time assessment of PV isolation can be achieved during HBAs with single-shot techniques. (TTI-TTRT)s <4.5 seconds and TTIs <33.5 seconds predicted for acute isolation. Ablation time after isolation >148.5 seconds in superior PVs and >120.5 seconds in inferior PVs were effective application durations.

Prolongation of QT interval after pulmonary vein isolation for paroxysmal atrial fibrillation.

INTRODUCTION: Pulmonary vein isolation (PVI) affects the ganglionated plexi (GP) around the atrium leading to a modification of intrinsic cardiac autonomic system (ANS). In animal models, GP ablation has the potential risk of QT prolongation and ventricular arrhythmias. However, the impact of PVI on QT intervals in human remains unclear. METHODS AND RESULTS: We analyzed electrocardiograms of 117 consecutive patients with paroxysmal atrial fibrillation (AF) who underwent their first PVI procedures and maintained sinus rhythm without antiarrhythmic drugs at all evaluation points (4 h, 1 day, 1 month, and 3 months after PVI). Heart rate significantly increased at 4 h, 1 day, and 1 month. Raw QT interval prolonged at 4 h (417.1 ± 41.6 ms, p < .001) but shortened at 1 day (376.4 ± 34.1 ms, p < .001), 1 month (382.2 ± 31.5 ms, p < 0.001), and 3 months (385.1 ± 32.8 ms, p < 0.001) compared with baseline (391.6 ± 31.4 ms). Bazett-corrected QTc intervals were significantly prolonged at 4 h (430.8 ± 27.9 ms, p < .001), 1 day (434.8 ± 22.3 ms, p < .001), 1 month (434.8 ± 22.3 ms, p < .001), and 3 months (420.1 ± 21.8 ms, p < .001) compared with baseline (404.9 ± 25.2 ms). Framingham-corrected QTc intervals significantly prolonged at 4 h (424.1 ± 26.6 ms, p < .001) and 1 day (412.3 ± 29.3 ms, p < .01) compared with baseline (399.2 ± 22.7 ms). Multiple regression analysis revealed that female sex is a significant predictor of raw QT and QTc interval increase at 4 h after PVI. CONCLUSION: Raw QT and QTc were prolonged after PVI, especially in the acute phase. Female sex is a risk factor for QT increase.

Cost-effectiveness for prevention of thromboembolism by anticoagulants in non-valvular atrial fibrillation: additional analysis from the Hokuriku-Plus AF Registry.

Although benefits of direct oral anticoagulants (DOAC) for treatment of non-valvular atrial fibrillation (AF) were well demonstrated, few data exist regarding cost-effectiveness between DOAC and warfarin uses in real-world clinical practice. Therefore, we estimated total cost of treatment for AF by authorized cardiologists in Japan. We studied consecutive 617 anticoagulated non-valvular AF patients (418 men, mean age 68.8, 54% warfarin) consulted by authorized cardiologists. The mean time in therapeutic range of warfarin was 71.8%. Under these conditions, we calculated the cost of anticoagulants, laboratory examination, and hospitalization due to thromboembolism or bleeding during follow-up for 3.1 years. Thromboembolism occurred in 26 patients (4.2%, 1.3/100 person-year) and hemorrhagic events in 20 patients (3.2%, 1.0/100 person-year). There was no significant difference in the occurrence rate of thromboembolism (log rank P = 0.16) or hemorrhagic events (log rank P = 0.83) between these two groups. Importantly, warfarin group showed lower cost than DOAC group (117,361 ± 743,710 yen/year vs. 310,436 ± 1,075,639 yen/person, P = 0.009) in terms of cost including drug, medical check, and hospitalization. These results demonstrate that the total cost with warfarin can be lower than DOAC in treatment for AF by authorized cardiologists in Japan, although further prospective randomized cost calculation is necessary including post-discharge care fee.

Functional analysis of KCNH2 gene mutations of type 2 long QT syndrome in larval zebrafish using microscopy and electrocardiography.

Heterologous expression systems play a vital role in the characterization of potassium voltage-gated channel subfamily H member 2 (KCNH2) gene mutations, such as E637K which is associated with long QT syndrome type 2 (LQT2). In vivo assays using zebrafish provide a means for testing genetic variants of cardiac disease; however, limited information on the role of the E637K mutation is available from in vivo systems and their utility has yet to be fully exploited in the context of LQT2. We sought to evaluate the ability of the E637K mutant channel to restore normal repolarization in larval zebrafish with a human KCNH2 orthologue, kcnh2a-knockdown. A morpholino (MO) targeting kcnh2a was injected alone or with wild type (WT) or E637K KCNH2 cRNA into zebrafish embryos at the 1-2 cell stage. Cardiac repolarization phenotypes were screened using light microscopy and the QT interval was measured by single lead electrocardiograph (ECG) analysis at 72-h post-fertilization. In the MO alone group, 17% of zebrafish had a normal phenotype; this rate increased to 60% in the WT KCNH2 cRNA injected zebrafish and to 35% in the E637K injected zebrafish. The ECG of larval zebrafish revealed that QTc was significantly prolonged in the MO alone group compared to the control group. Co-injection of WT KCNH2 cRNA shortened the QTc interval, however, that of the E637K did not. We suggest that this in vivo cardiac assay using microscopy and ECG in larval zebrafish offers a reliable approach for risk discrimination of KCNH2 mutations.

Impact of B-Type Natriuretic Peptide Level on Risk Stratification of Thromboembolism and Death in Patients With Nonvalvular Atrial Fibrillation　- The Hokuriku-Plus AF Registry.

BACKGROUND: B-type natriuretic peptide (BNP) may be a predictor of stroke risk in patients with nonvalvular atrial fibrillation (NVAF); because heart failure is associated with the incidence of stroke in AF patients. However, limited data exist regarding the association between BNP at baseline and risks of thromboembolic events (TE) and death in NVAF patients. Methods and Results: We prospectively studied 1,013 NVAF patients (725 men, 72.8±9.7 years old) from the Hokuriku-plus AF Registry to determine the relationship between BNP at baseline and prognosis among Japanese NVAF patients. During the follow-up period (median, 751 days); 31 patients experienced TE and there were 81 cases of TE/all-cause death. For each endpoint we constructed receiver-operating characteristic curves that gave cutoff points of BNP for TE (170 pg/mL) and TE/all-cause death (147 pg/mL). Multivariate analysis with the Cox-proportional hazards model indicated that high BNP was significantly associated with risks of TE (hazard ratio [HR] 3.86; 95% confidence interval [CI] 1.83-8.67; P=0.0003) and TE/all-cause death (HR 2.27; 95% CI 1.45-3.56; P=0.0003). Based on the C-index and net reclassification improvement, the addition of BNP to CHA2DS2-VASc statistically improved the prediction of TE. CONCLUSIONS: In a real-world cohort of Japanese NVAF patients, high BNP was significantly associated with TE and death. Plasma BNP might be a useful biomarker for these adverse clinical events.

Late Gadolinium Enhancement for Prediction of Mutation-Positive Hypertrophic Cardiomyopathy on the Basis of Panel-Wide Sequencing.

BACKGROUND: Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) revealed a substantial variation in the extent of myocardial scarring, a pathological hallmark of hypertrophic cardiomyopathy (HCM). However, few data exist regarding the relationship between the presence of gene mutations and the extent of LGE. Therefore, we aimed to investigate whether variations in the extent of LGE in HCM patients can be explained by the presence or absence of disease-causing mutations.Methods and Results:We analyzed data from 82 unrelated HCM patients who underwent both LGE-CMR and next-generation sequencing. We identified disease-causing sarcomere gene mutations in 44 cases (54%). The extent of LGE on CMR was an independent factor for predicting mutation-positive HCM (odds ratio 2.12 [95% confidence interval 1.51-3.83], P<0.01). The area under the curve of %LGE was greater than that of the conventional Toronto score for predicting the presence of a mutation (0.96 vs. 0.69, P<0.01). Sensitivity, specificity, positive predictive value, and negative predictive value of %LGE (cutoff >8.1%) were 93.2%, 89.5%, 91.1%, and 91.9%, respectively. CONCLUSIONS: The results demonstrated that %LGE clearly discriminated mutation-positive from mutation-negative HCM in a clinically affected HCM population. HCM with few or no myocardial scars may be genetically different from HCM with a higher incidence of myocardial scars.

T wave amplitude in lead aVR as a novel diagnostic marker for cardiac sarcoidosis.

It is vital to identify cardiac involvement (CI) in patients with sarcoidosis as the condition could initially lead to sudden cardiac death. Although the T wave amplitude in lead aVR (TWAaVR) is reportedly associated with adverse cardiac events in various cardiovascular diseases, only scarce data are available concerning the utility of lead aVR in identifying CI in patients with sarcoidosis. We retrospectively investigated the diagnostic values of TWAaVR in patients with sarcoidosis in comparison with conventional electrocardiography parameters such as bundle branch block (BBB). From January 2006 to December 2014, 93 consecutive patients with sarcoidosis were enrolled (mean age, 55.7 ± 15.7 years; male, 31 %; cardiac involvement, n = 26). TWAaVR showed the greatest sensitivity (39 %) and specificity (92 %) in distinguishing between sarcoidosis patients with and without CI, at a cutoff value of -0.08 mV. The diagnostic value of BBB for cardiac involvement was significantly improved when combined with TWAaVR (sensitivity: 61-94 %, specificity: 97-89 %, area under the curve: 0.79-0.92, p = 0.018). Multivariate logistic regression analysis indicated that TWAaVR and BBB were independent electrocardiography parameters associated with CI. In summary, we observed that sarcoidosis patients exhibiting a high TWAaVR were likely to have CI. Thus, the application of a combination of BBB with TWAaVR may be useful when screening for CI in sarcoidosis patients.

Impact of T wave amplitude in lead aVR on predicting cardiac events in ischemic and nonischemic cardiomyopathy patients with an implantable cardioverter defibrillator.

BACKGROUND: T wave amplitudes during ventricular repolarization in the lead aVR (TAaVR) are shown to be associated with adverse cardiac events in patients with several cardiovascular diseases, such as postmyocardial infarction. However, the utility of TAaVR has not been previously evaluated in patients with cardiomyopathy who have received implantable cardioverter defibrillators (ICD). Patients with ischemic or nonischemic cardiomyopathy (ICM or NICM, respectively) and who received an ICD may experience worsening of their condition due to the introduction of electric shock during treatment. This study aimed to investigate the utility of TAaVR in the prediction of cardiac events in ICM or NICM patients with ICD. METHODS: Ninety-three consecutive ICM or NICM patients with ICD were retrospectively analyzed (median age: 64 years; male: 77.4%; ICD for secondary prevention: 76.3%; NICM: 64.5%). The median follow-up period was 31 months. The primary endpoint was defined as composite cardiac events, including cardiac death, major ventricular arrhythmic events (MVAE), or hospitalization due to heart failure (HHF). RESULTS: Multivariate Cox regression analysis demonstrated that less negative TAaVR (-0.1 mV ≤ TAaVR <0 mV and 0 mV ≤ TAaVR) was independently associated with the primary endpoint (HR: 3.75; 95% confidence interval [CI]: 1.09-23.7; p = .04). Kaplan-Meier curve also revealed that the event free survival rate in the less negative TAaVR group was significantly lower than that in the normal TAaVR group (<-0.1 mV) (p < .01). CONCLUSIONS: TAaVR is useful in risk stratification for cardiac events in ICM or NICM patients with ICD.

Fragmented QRS predicts heart failure progression in patients with hypertrophic cardiomyopathy.

BACKGROUND: Although fragmented QRS complex (frag-QRS) reflecting intra-ventricular conduction delay has been shown to be a prognostic marker for cardiac events, few data exist regarding the impact of frag-QRS on cardiac events in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Ninety-four HCM patients (56 male; mean age, 58 ± 17 years) were retrospectively investigated. Frag-QRS was defined as the presence of various RsR' patterns in at least 2 contiguous ECG leads. Major arrhythmic events (MAE) were defined as sudden cardiac death, and combined sustained ventricular tachycardia/ventricular fibrillation. New-onset atrial fibrillation (AF) was diagnosed based on ECG during provisional or routine medical examination. Heart failure (HF) with hospitalization was defined as hospital admission due to subjective or objective symptoms. Frag-QRS was detected in 31 patients (33%).TNNI3 was the most frequent disease-causing gene. Median follow-up was 4.6 years. The 4-year cumulative survival rates of cardiac death, MAE, new-onset AF and HF with hospitalization were 97.6%, 94.6%, 87.5% and 89.3%, respectively. On multivariate analysis, frag-QRS was significantly associated with HF with hospitalization (adjusted hazard ratios [95% confidence intervals]: 5.4 [1.2-36], P=0.03). Moreover, HF-free survival was significantly lower in the frag-QRS (+) group compared to the frag-QRS (-) group (79.0% vs. 95.1%, P=0.03). CONCLUSIONS: Frag-QRS is associated with HF with hospitalization in HCM patients who had a unique distribution of gene mutations.

Detection of Epicardial Connection Through Intercaval Bundle Involving Right Pulmonary Veins After Ipsilateral Circumferential Ablation by Intra-Atrial Activation Sequence Pacing From the Right Pulmonary Vein.

BACKGROUND: An epicardial connection (EC) through the intercaval bundle (EC-ICB) between the right pulmonary vein (RPV) and right atrium (RA) is one of the reasons for the need for carina ablation for PV isolation and may reduce the acute and chronic success of PV isolation. We evaluated the intra-atrial activation sequence during RPV pacing after failure of ipsilateral RPV isolation and sought to identify specific conduction patterns in the presence of EC-ICB. METHODS AND RESULTS: This study included 223 consecutive patients who underwent initial catheter ablation of atrial fibrillation. If the RPV was not isolated using circumferential ablation or reconnected during the waiting period, an exit map was created during mid-RPV carina pacing. If the earliest site on the exit map was the RA, the patient was classified into the EC-ICB group. The exit map, intra-atrial activation sequence, and RPV-high RA time were evaluated. First-pass isolation of the RPV was not achieved in 36 patients (16.1%), and 22 patients (9.9%) showed reconnection. Twelve and 28 patients were classified into the EC-ICB and non-EC-ICB groups, respectively, after excluding those with multiple ablation lesion sets or incomplete mapping. The intra-atrial activation sequence showed different patterns between the 2 groups. The RPV-high RA time was significantly shorter in the EC-ICB than in the non-EC-ICB group (69.2±15.2 versus 148.6±51.2 ms; P<0.001), and RPV-high RA time<89.0 ms was highly predictive of the existence of an EC-ICB (sensitivity, 91.7%; specificity, 89.3%). CONCLUSIONS: An EC-ICB can be effectively detected by intra-atrial sequencing during RPV pacing, and an RPV-high RA time of <89.0 ms was highly predictive.