Demonstration of Arrhythmia Substrate-Associated Dispersion of Repolarization by Epicardial Unipolar Mapping in Brugada Syndrome.

BACKGROUND: Epicardial unipolar mapping has not been thoroughly investigated in Brugada syndrome (BrS). OBJECTIVES: This study aims to examine the characteristics of epicardial unipolar potentials in BrS and investigate the differences from overt cardiomyopathy. METHODS: Epicardial mapping was performed in 8 patients with BrS and 6 patients with cardiomyopathy. We investigated the J-wave amplitudes using unipolar recordings at delayed potential (DP) sites via bipolar recordings. The repolarization time (RT) at and around the DP recording sites was measured, and maximum dispersion of the RT divided by the distance was defined as the RT dispersion index. RESULTS: Epicardial mapping at baseline revealed significantly higher J-wave amplitude with bipolar DP in patients with BrS than in patients with cardiomyopathy. J-wave amplitude ≥0.42 mV had 99.1% sensitivity and 100% specificity for diagnosing BrS. The RT dispersion index was significantly higher in patients with BrS than in patients with cardiomyopathy at baseline. In all patients with BrS, coved-type unipolar electrograms without negative T waves (short RT) appeared close to coved-type electrograms with negative T waves (long RT) at the DP recording sites after pilsicainide administration. Thus, a steep RT dispersion was observed in this region, and ventricular arrhythmias emerged from this shorter RT area in all 3 patients with BrS in whom ventricular arrhythmias were induced. CONCLUSIONS: Bipolar DP-related prominent unipolar J waves and steep repolarization gradients may be more specific for characterizing BrS than for overt cardiomyopathy. Ventricular arrhythmias in BrS are associated with a steep repolarization gradient, indicating phase 2 re-entry as a possible cause.

Evaluation of synchronized left ventricular pacing rate over biventricular pacing in cardiac resynchronization therapy.

BACKGROUND: The adaptive cardiac resynchronization therapy (aCRT) algorithm enables synchronized left ventricular pacing (sLVP) to achieve fusion with intrinsic right ventricular activation. Although sLVP presents benefits over biventricular pacing, the adequate sLVP rate for better clinical outcomes remains unclear. We aimed to assess the association between sLVP rates and clinical outcomes. METHODS: Our study cohort included 271 consecutive patients, who underwent CRT implantation between April 2016 and August 2021. RESULTS: We evaluated 63 patients on whom we applied the aCRT algorithm [48 men, mean age: 64 ±â€¯14 years; median follow-up period: 316 days (interquartile range: 212-809 days)]. At the 6-month follow-up after CRT implantation, the frequency of CRT responders was 71 % (n = 45). The sLVP rate was significantly higher in responders than in non-responders (75 ±â€¯30 % vs. 47 ±â€¯40 %, p = 0.003). Receiver operating characteristics curve analysis revealed that the optimal cut-off value during the sLVP rate was 59.4 % for the prediction of CRT responders (area under the curve, 0.70; sensitivity, 80 %; specificity, 61 %; positive predictive value, 84 %; and negative predictive value, 55 %). Kaplan-Meier analysis demonstrated that the higher-sLVP group (sLVP ≧59.4 %, n = 43) had a better prognosis (cardiac death and heart failure hospitalization) than the lower-sLVP group (sLVP <59.4 %, n = 20) (log-rank p < 0.001). Multivariate Cox hazard analysis revealed that a higher sLVP rate was associated with a good prognosis (p < 0.001). CONCLUSIONS: sLVP was associated with CRT response, and a higher sLVP rate (≧59.4 %) was important for good prognosis in patients with aCRT.

Effect of adaptive cardiac resynchronization therapy in heart failure patients with pacemaker dependency.

BACKGROUND: An adaptive cardiac resynchronization therapy (aCRT) algorithm allows continuous adjustments of pacing timings of atrioventricular delays by periodic automatic evaluation of electrical conduction. This applies to patients with an atrioventricular block and is effective in cardiac resynchronization therapy (CRT) devices; however, whether this algorithm benefits patients with pacemaker dependency is uncertain. METHODS: This study examined the clinical impact of an aCRT algorithm in patients diagnosed with heart failure with reduced ejection fraction and pacemaker dependency. A total of 359 patients underwent CRT between January 2016 and December 2022. Patients undergoing pacemaker-dependent CRT with the aCRT algorithm function were selected. Sixty-four patients with pacemaker dependency (31 with aCRT algorithm and 33 without) were included. Pacemaker dependency was defined as the absence of spontaneous ventricular activity during the sensing test at VVI 30 bpm or prolonged atrioventricular delay (> 300 ms). The primary endpoint was the composite clinical outcome of all-cause death or hospitalization for heart failure. RESULTS: No significant differences were observed in baseline characteristics between groups. During a median follow-up of 1,067 days (interquartile range 553-1,776 days), aCRT reduced the risk of composite clinical outcomes in patients with pacemaker dependency (log-rank P = 0.028). In addition, using the aCRT algorithm was an independent predictor of the composite clinical outcomes in the multivariate analysis (hazard ratio 0.34, 95% confidence interval: 0.12-0.94, P = 0.038). CONCLUSION: The aCRT algorithm significantly reduced the risk of adverse clinical outcomes in patients with pacemaker dependency. This algorithm may be an important tool for managing such patients.

Clinical utility of QRS duration normalized to left ventricular volume for predicting cardiac resynchronization therapy efficacy in patients with "mid-range" QRS duration.

BACKGROUND: Cardiac resynchronization therapy (CRT) is effective for patients with heart failure with QRS duration (QRSd) ≥150 ms. However, its beneficial effect seems to be limited for those with "mid-range" QRSd (120-149 ms). Recent studies have demonstrated that modifying QRSd to left ventricular end-diastolic volume (LVEDV)-modified QRSd-improves the prediction of clinical outcomes of CRT. OBJECTIVE: The purpose of this study was to investigate the clinical impact of the modified QRSd on the efficacy of CRT in patients with "mid-range" QRSd. METHODS: We conducted a retrospective, multicenter, observational study, with heart failure hospitalization (HFH) after CRT as the primary endpoint. Modified QRSd is defined as QRSd divided by LVEDV, determined through the Teichholtz method of echocardiography. RESULTS: Among the 506 consecutive patients considered, 119 (mean age 61 ± 15 years; 80% male, QRSd 135 ± 9 ms) with a "mid-range" QRSd who underwent de novo CRT device implantation were included for analysis. During median follow-up of 878 days [interquartile range 381-1663 days], HFH occurred in 45 patients (37%). Fine-Gray analysis revealed modified QRSd was an independent predictor of HFH (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.96-0.99; P <.01). Receiver operating characteristic curve analysis revealed a cutoff value of 0.65 ms/mL for the modified QRSd in predicting HFH. Patients above the threshold exhibited a significantly lower incidence of HFH than patients below the threshold (HR 0.46; 95% CI 0.25-0.86; P = .01). CONCLUSION: Modified QRSd can effectively predict the efficacy of CRT in patients with a "mid-range" QRSd.

Late life-threatening arrhythmia in patients with Brugada syndrome: Results from long-term follow-up in a large Japanese cohort.

INTRODUCTION: Most patients with Brugada syndrome (BrS) are first diagnosed in their 40s, with sudden cardiac death (SCD) often occurring in their 50s. Ventricular fibrillation (VF) may occur in some patients with BrS despite having been asymptomatic for a long period. This study aimed to assess the incidence and risk factors for late life-threatening arrhythmias in patients with BrS. METHODS: Patients with BrS (n = 523; mean age, 51 ± 13 years; male, n = 497) were enrolled. The risk of late life-threatening arrhythmia was investigated in 225 patients who had experienced no cardiac events (CEs: SCD or ventricular tachyarrhythmia) for at least 10 years after study enrollment. The incidence of CEs during the follow-up period was examined. RESULTS: During the follow-up of the 523 patients, 59 (11%) experienced CEs. The annual incidences of CEs were 2.87%, 0.77%, and 0.09% from study enrollment to 3, 3-10, and after 10 years, respectively. Among 225 patients who had experienced no CEs for at least 10 years after enrollment, four patients (1.8%) subsequently experienced CEs. Kaplan-Meier analysis revealed significant differences in the incidence of late CEs between patients with and without a history of symptoms (p = .032). The positive and negative predictive values of late CEs for the programmed electrical stimulation (PES) test were 2.9% and 100%, respectively. CONCLUSION: Our results suggest that patients with BrS who are asymptomatic and have no ventricular tachycardia/VF inducibility by PES are at extremely low risk of experiencing late life-threatening arrhythmias.

Local dispersion of repolarization in the occurrence of ventricular fibrillation in Brugada syndrome: Possibility of phase 2 reentry?

To date, there have been no reports of recording epicardial electrograms at the onset of spontaneous ventricular fibrillation (VF) in patients with Brugada syndrome (BrS). In the case of BrS, unipolar and bipolar electrogram recording on the right ventricular epicardium revealed that dispersion of repolarization with delayed potential was associated with spontaneous occurrence of VF. Phase 2 reentry associated with shortening and dispersion of action potential could have been recorded for the first time in BrS. Epicardial unipolar mapping can guide accurate and appropriate ablation for the elimination of arrhythmia substrate in J wave syndrome.

Implications of ventricular arrhythmia after cardiac resynchronization therapy.

BACKGROUND: Conflicting data are available on whether ventricular arrhythmia (VA) or shock therapy increases mortality. Although cardiac resynchronization therapy (CRT) reduces the risk of VA, little is known about the prognostic value of VA among patients with CRT devices. OBJECTIVES: The purpose of this study was to evaluate the implications of VA as a prognostic marker for CRT. METHODS: We investigated 330 CRT patients within 1 year after CRT device implantation. The primary endpoint was the composite endpoint of all-cause death or hospitalization for heart failure. RESULTS: Forty-three patients had VA events. These patients had a significantly higher risk of the primary endpoint, even among CRT responders (P = .009). Fast VA compared to slow VA was associated with an increased risk of the primary endpoint (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.06-4.34; P = .035). Shock therapy was not associated with a primary endpoint (shock therapy vs antitachycardia pacing: HR 1.49; 95% CI 0.73-3.03; P = .269). The patients with VA had a lower prevalence of response to CRT (23 [53%] vs 202 [70%]; P = .031) and longer left ventricular paced conduction time (174 ± 23 ms vs 143 ± 36 ms; P = .003) than the patients without VA. CONCLUSION: VA occurrence within 1 year was related to paced electrical delay and poor response to CRT. VA could be associated with poor prognosis among CRT patients.

Fatal Arrhythmic Risks in Cardiac Sarcoidosis With Mildly Impaired Cardiac Function.

Background: The prognosis and later fatal arrhythmia in cardiac sarcoidosis (CS) with relatively preserved cardiac function were unclear. Objectives: This study aimed to evaluate the prognosis and arrhythmic events in patients with CS and mildly impaired cardiac function. Methods: Data were collected from a nationwide Japanese cohort survey conducted in 57 hospitals (n = 420); 322 patients with CS with left ventricular ejection fraction (LVEF) >35% were investigated. Results: Ventricular tachycardia (VT) manifestation was present in 50 patients (16%) and absent in 272 (84%), of whom 36 (72%) and 46 (17%), respectively, had an implantable cardioverter-defibrillator (ICD). Over a median of 5 years, 23 all-cause deaths and 31 appropriate ICD discharges were observed. In Kaplan-Meier analysis, all-cause death did not differ between patients with and without VT manifestation (P = 0.660), although appropriate ICD therapy was significantly less used in patients without VT manifestation than in those with VT manifestation (P < 0.001). Of the 272 patients without VT manifestation, 18 had ventricular arrhythmic events (VAEs), including 3 sudden cardiac deaths and 15 appropriate ICD discharges. In multivariate analysis, concomitant nonsustained ventricular tachycardia (NSVT) with atrioventricular block (AVB), lower LVEF, abnormal gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography of the heart (Ga/PET), and concomitant NSVT with abnormal Ga/PET at CS diagnosis were independent predictors of VAEs (P = 0.008, P = 0.021, P = 0.049, and P = 0.024, respectively). Conclusions: If concomitant NSVT with AVB, concomitant NSVT with abnormal Ga/PET, or abnormal Ga/PET is observed in patients with CS and mildly impaired cardiac function (LVEF >35%), ICD should be considered as primary prevention.

Clinical Significance of Atrial Tachyarrhythmia Duration for Ventricular Arrhythmia in Patients With Cardiac Resynchronization Therapy.

BACKGROUND: Atrial tachyarrhythmias (ATAs) are reportedly associated with ventricular arrhythmias (VAs). However, little is known about the association between ATA duration and the risk of VA. We investigated the relationship between ATA duration and subsequent VA in patients with a cardiac resynchronization therapy defibrillator (CRT-D).Methods and Results: We investigated associations between the longest ATA duration during the first year after cardiac resynchronization therapy (CRT) implantation and VA and VA relevant to ATA (VAATA) in 160 CRT-D patients. ATAs occurred in 63 patients in the first year. During a median follow-up of 925 days from 1 year after CRT implantation, 40 patients experienced 483 VAs. Kaplan-Meier analysis showed a significantly higher risk of VA in patients with than without ATA in the first year (log rank P=0.0057). Hazard ratios (HR) of VA (HR 2.36, 2.10, and 3.04 for ATA >30s, >6 min and >24 h, respectively) and only VAATA (HR 4.50, 5.59, and 11.79 for ATA >30s, >6 min and >24 h, respectively) increased according to the duration of ATA. In multivariate analysis, ATA >24 h was an independent predictor of subsequent VA (HR 2.42; P=0.02). CONCLUSIONS: Patients with ATA >24 h in the first year after CRT had a higher risk of subsequent VA and VAATA. The risk of VA, including VAATA, increased with the longest ATA duration.

N-terminal pro atrial natriuretic peptide as a prognostic marker of cardiac resynchronization therapy recipients.

Background: Although the dynamic changes of atrial natriuretic peptide (ANP) expressions in a failing heart are well-documented, the clinical implications of detailed measurements of each ANP molecular form processed from proANP remain unclear. Methods: Patients screening was conducted on patients who were eligible for cardiac resynchronization therapy (CRT) between 2014 and 2019 in our institution. Blood samples and echocardiographic parameters were collected on the day before and six months after implantation. Total ANP, proANP, and N-terminal fragment of proANP (NT-proANP) were examined as predictive biomarkers for cardiac death, left ventricular assist device implantation, and heart failure hospitalization following CRT implantation. Results: A total of 86 subjects (mean age 70 years, 64 males) who underwent successful CRT implantation were enrolled. Plasma levels of total ANP, proANP, and NT-proANP were not normally distributed [25.8 pM (interquartile range: 11.1-53.1), 2.2 pM (1.0-5.4), and 4.1 nM (2.4-7.1), respectively]. Over a median follow-up of 2.7 years, 31 patients (2 deaths and 29 heart failure hospitalizations) reached the endpoints. Among the different ANP forms, only NT-proANP emerged as an independent predictor of the composite outcome (adjusted odds ratio of 2.542 in those with levels above vs. below the median, 95 % confidence interval 1.151-5.615, p = 0.021). NT-proANP levels were associated with left atrial volume and left diastolic functional parameters and decreased in response to echocardiographic improvements at six months post-implantation (16 ± 44 % decrease in responders vs 18 ± 60 % increase in non-responders, p = 0.005). Conclusion: Pre-implantation NT-proANP levels could serve as a predictive factor for clinical outcomes in recipients of CRT.

Electrophysiologic Determinants of Isoelectric Intervals on Surface Electrocardiograms During Atrial Tachycardia: Insights From High-Density Mapping.

BACKGROUND: Substrate abnormalities can alter atrial activation during atrial tachycardias (ATs) thereby influencing AT-wave morphology on the surface electrocardiogram. OBJECTIVES: This study sought to identify determinants of isoelectric intervals during ATs with complex atrial activation patterns. METHODS: High-density activation maps of 126 ATs were studied. To assess the impact of the activated atrial surface on the presence of isoelectric intervals, this study measured the minimum activated area throughout the AT cycle, defined as the smallest activated area within a 50-millisecond period, by using signal processing algorithms (LUMIPOINT). RESULTS: ATs with isoelectric intervals (P-wave ATs) included 23 macro-re-entrant ATs (40%), 26 localized-re-entrant ATs (46%), and 8 focal ATs (14%), whereas those without included 46 macro-re-entrant ATs (67%), 21 localized-re-entrant ATs (30%), and 2 focal ATs (3%). Multivariable regression identified smaller minimum activated area and larger very low voltage area as independent predictors of P-wave ATs (OR: 0.732; 95% CI: 0.644-0.831; P < 0.001; and OR: 1.042; 95% CI: 1.006-1.080; P = 0.023, respectively). The minimum activated area with the cutoff value of 10 cm2 provided the highest predictive accuracy for P-wave ATs with sensitivity, specificity, and positive and negative predictive values of 96%, 97%, 97%, and 95%, respectively. In re-entrant ATs, smaller minimum activated area was associated with lower minimum conduction velocity within the circuit and fewer areas of delayed conduction outside of the circuit (standardized ß: 0.524; 95% CI: 0.373-0.675; P < 0.001; and standardized ß: 0.353; 95% CI: 0.198-0.508; P < 0.001, respectively). CONCLUSIONS: Reduced atrial activation area and voltage were associated with isoelectric intervals during ATs.

Abnormal Atrial Potentials Recorded During Sinus Rhythm or Pacing Represent Substrates for Reentrant Atrial Tachycardia.

BACKGROUND: Abnormal atrial potentials (AAPs) recorded during sinus rhythm/atrial pacing may indicate areas of slow conduction capable of supporting reentrant atrial tachycardia (AT). Therefore, we sought to examine the relationship between AAPs and AT circuits. METHODS: One hundred twenty-three reentrant ATs in 104 patients were analyzed. AAPs, consisting of fragmented potentials and split potentials, were assessed using the Rhythmia LUMIPOINT algorithm. RESULTS: There was 93±13% overlap between areas with AAPs during sinus rhythm/atrial pacing and areas of slow conduction along the reentry circuit during AT. The cumulative area of AAPs was smaller in patients with localized-reentrant ATs compared with anatomic macro-reentrant ATs (20.0 [14.6-30.5] versus 28.9 [21.8-35.6] cm2; P=0.021). Patients with perimitral ATs had larger areas of AAPs on the lateral wall whereas patients with roof-dependent ATs had larger areas of AAPs on the roof and posterior wall (P≤0.018 for all comparisons). The patchy scar that was associated with localized-reentrant AT exhibited a larger area of AAPs at its periphery than the scar that did not participate in localized-reentrant AT (3.1 [2.4-4.5] versus 1.0 [0.7-1.6] cm2; P<0.001). CONCLUSIONS: AAPs recorded during sinus rhythm/atrial pacing are associated with areas of slow conduction during reentrant AT. The burden and distribution of AAPs may provide actionable insights into AT circuit features, including in cases in which ATs are difficult to map.

Interference of cardiac implantable electronic devices and computed tomography imaging in the current era with a phantom model.

Introduction: Cardiac implantable electronic devices are used in patients with cardiac rhythm disorders. Computed tomography irradiation is not prohibited for patients with cardiac implantable electronic devices, despite adverse events being reported. Hence, appropriate preparation and knowledge are required before computed tomography irradiation can be carried out in these patients. Since there is limited knowledge or literature about the influence of computed tomography irradiation in cases with recent cardiac implantable electronic devices, we aimed to evaluate the adverse events and elucidate the necessary and sufficient safety measures associated with this therapy. Methods and Results: We placed cardiac implantable electronic devices on an anthropomorphic phantom model and observed their electrical activity in electrograms, while various protocols of computed tomography irradiation were implemented and adverse events evaluated. Oversensing with pauses of up to 3.2 s was observed in standard computed tomography protocols, but ventricular tachyarrhythmia or other clinically significant events could not be confirmed. Oversensing with pauses of up to 8.0 s was observed and ventricular tachyarrhythmia was detected in the maximum-dose protocols. However, treatments such as antitachycardia pacing or shock therapy for ventricular tachyarrhythmia were not observed because of their absence. Conclusion: Computed tomography irradiation for patients using cardiac implantable electronic devices is highly unlikely to cause clinically significant adverse events with the device settings and computed tomography protocols currently being used. Changing or monitoring the device settings routinely before computed tomography irradiation is not necessarily required for most patients.

Left Ventricular Abnormal Substrate in Brugada Syndrome.

BACKGROUND: Slow-conductive structural abnormalities located in the epicardium of the right ventricle (RV) underlie Brugada syndrome (BrS). The extent of such substrate in the left ventricle (LV) has not been investigated. OBJECTIVES: This study sought to characterize the extent of epicardial substrate abnormalities in BrS. METHODS: We evaluated 22 consecutive patients (mean age 46 ± 11 years, 21 male) referred for recurrent ventricular arrhythmias (mean 10 ± 13 episodes) in the setting of BrS. The patients underwent clinical investigations and wide genetic screening to identify SCN5A mutations and common risk variants. High-density biventricular epicardial mapping was performed to detect prolonged (>70 ms) fragmented electrograms, indicating abnormal substrate area. RESULTS: All patients presented with abnormal substrate in the epicardial anterior RV (27 ± 11 cm2). Abnormal substrate was also identified on the LV epicardium in 10 patients (45%), 9 at baseline and 1 after ajmaline infusion, covering 15 ± 11 cm2. Of these, 4 had severe LV fascicular blocks. Patients with LV substrate had a longer history of arrhythmia (11.4 ± 6.7 years vs 4.3 ± 4.3 years; P = 0.003), longer PR (217 ± 24 ms vs 171 ± 14 ms; P < 0.001) and HV (60 ± 12 ms vs 46 ± 5 ms; P = 0.005) intervals, and abnormal substrate also extending into the inferior RV (100% vs 33%; P = 0.001). SCN5A mutation was present in 70% of patients with LV substrate (vs 25%; P = 0.035). SCN5A BrS patients with recurrent ventricular arrhythmias present a higher polygenic risk score compared with a nonselected BrS population (median of differences: -0.86; 95% CI: -1.48 to -0.27; P = 0.02). CONCLUSIONS: A subset of patients with BrS present an abnormal substrate extending onto the LV epicardium and inferior RV that is associated with SCN5A mutations and multigenic variants.