Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Prevalence and prognostic value of electrocardiographic abnormalities in hypokalemia: A multicenter cohort study.

BACKGROUND: Hypokalemia is common in hospitalized patients and associated with ECG abnormalities. The prevalence and prognostic value of ECG abnormalities in hypokalemic patients are, however, not well established. METHODS: The study was a multicentered cohort study, including all ault patients with an ECG and potassium level <4.4 mmol/L recorded at arrival to four emergency departments in Denmark and Sweden. Using computerized measurements from ECGs, we investigated the relationship between potassium levels and heart rate, QRS duration, corrected QT (QTc) interval, ST-segment depressions, T-wave flattening, and T-wave inversion using cubic splines. Within strata of potassium levels, we further estimated the hazard ratio (HR) for 7-day mortality, admission to the intensive care unit (ICU), and diagnosis of ventricular arrhythmia or cardiac arrest, comparing patients with and without specific ECG abnormalities matched 1:2 on propensity scores. RESULTS: Among 79,599 included patients, decreasing potassium levels were associated with a concentration-dependent increase in all investigated ECG variables. ECG abnormalities were present in 40% of hypokalemic patients ([K+ ] <3.5 mmol/L), with T-wave flattening, ST-segment depression, and QTc prolongation occurring in 27%, 16%, and 14%. In patients with mild hypokalemia ([K+ ] 3.0-3.4 mmol/L), a heart rate >100 bpm, ST-depressions, and T-wave inversion were associated with increased HRs for 7-day mortality and ICU admission, whereas only a heart rate >100 bpm predicted both mortality and ICU admission among patients with [K+ ] <3.0 mmol/L. HR estimates were, however, similar to those in eukalemic patients. The low number of events with ventricular arrhythmia limited evaluation for this outcome. CONCLUSIONS: ECG abnormalities were common in hypokalemic patients, but they are poor prognostic markers for short-term adverse events under the current standard of care.

Age-Stratified Clinical Outcome in Patients with Known Heart Failure Who Receive Pacemaker, Resynchronization Therapy, or Defibrillator Implants.

INTRODUCTION: Patients with heart failure (HF) and bradycardia may be eligible for different types of cardiac implantable electronic devices (CIED), depending on the presence of atrioventricular conduction disease, age, and comorbidities. We aimed to assess the prognosis for these patients, after CIED implantation, stratified for the type of CIED device. METHODS: All patients with preexisting HF diagnosis who received a CIED with a right ventricular lead during the period 2005-2018 in Sweden were identified via the pacemaker registry. Data were crossmatched with the population registry and national disease registries. The outcome was 5-year risk of HF hospitalization and mortality. RESULTS: A total of 37,745 patients were included in the study. Comparing demographics for implantable cardioverter defibrillator versus pacemaker implants, median age was 66 years versus 83 years, 20% versus 41% were female, 64% versus 50% had ischemic heart disease, and 35% versus 67% had atrial fibrillation (all p < 0.001). Five-year mortality was highest in single-chamber pacemaker recipients (61% compared to average 40%, p < 0.001), but the proportion of cardiovascular mortality was highest for cardiac resynchronization therapy (CRT) recipients (68% vs. 63% p < 0.001). Adjusted mortality was higher for pacemaker patients in all age decile groups (ranging from <60 to >90 years old, all p < 0.001), HF hospitalization occurred in 28% (dual-chamber pacemaker) to 39% (CRT-P) of patients, and cause of death was HF in 15% (dual-chamber pacemaker) to 25% (CRT-D), all p < 0.001. CONCLUSION: In this large real-world cohort of CIED-treated patients with prior HF, demography and mortality data indicate that clinicians chose devices according to the overall status of the patient. HF-related events occurred in all groups but were more common in CRT-treated patients.

Prevalence of left atrial appendage thrombus and spontaneous echo contrast on transesophageal echocardiography in patients scheduled for pulmonary vein isolation.

BACKGROUND: To avoid causing a thromboembolic event in patients undergoing catheter ablation for atrial fibrillation (AF), patients are treated with oral anticoagulants (OAC) prior to the procedure. Despite being on anticoagulants, some patients develop a left atrial appendage thrombus (LAAT). To exclude the presence of LAAT, transesophageal ultrasound (TEE) is performed in all patients prior to the procedure. We hypothesized continuous treatment with anticoagulants would result in a low prevalence of LAAT, in patients with low CHA2DS2-VASc score. METHOD: Medical records of consecutive patients planned to undergo AF ablation at Lund University Hospital during the years 2018-2020 were reviewed retrospectively. Examination protocols from transesophageal and transthoracic echocardiography were examined for LAAT and spontaneous echo contrast (SEC). Patients with LAAT and SEC were compared to patients without using Mann-Whitney U-test and Pearson Chi-squared analysis to test for correlation. RESULTS: Of 553 patients, three patients (0.54%) had LAAT, and 18 (3.25%) had spontaneous contrast (SEC). Patients with LAAT or SEC had a higher CHA2DS2-VASc score, more often presented in AF at TEE and less often had a normal sized left atrium. CONCLUSION: There is a low prevalence of LAAT and SEC in patients with AF scheduled for pulmonary vein isolation. Patients with SEC or LAAT tend to have paroxysmal AF less often and more often presented in AF at admission. No patients with CHA2DS2-VASc 0, paroxysmal AF, normal sized left atrium and sinus rhythm at TEE were found to have LAAT or SEC.

ISE/ISHNE expert consensus statement on the ECG diagnosis of left ventricular hypertrophy: The change of the paradigm.

The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria. The classical paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces, reflected in the augmented QRS amplitude. However, the low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm. The theoretical background for voltage measured at the body surface is defined by the solid angle theorem, which relates the measured voltage to spatial and non-spatial determinants. The spatial determinants are represented by the extent of the activation front and the distance of the recording electrodes. The non-spatial determinants comprise electrical characteristics of the myocardium, which are comparatively neglected in the interpretation of the QRS patterns. Various clinical conditions are associated with LVH. These conditions produce considerable diversity of electrical properties alterations thereby modifying the resultant QRS patterns. The spectrum of QRS patterns observed in LVH patients is quite broad, including also left axis deviation, left anterior fascicular block, incomplete and complete left bundle branch blocks, Q waves, and fragmented QRS. Importantly, the QRS complex can be within normal limits. The new paradigm stresses the electrophysiological background in interpreting QRS changes, i.e., the effect of the non-spatial determinants. This postulates that the role of ECG is not to estimate LV size in LVH, but to understand and decode the underlying electrical processes, which are crucial in relation to cardiovascular risk assessment.

P-wave characteristics as electrocardiographic markers of atrial abnormality in prediction of incident atrial fibrillation - The Malmö Preventive Project.

BACKGROUND: P-wave indices reflect atrial abnormalities contributing to atrial fibrillation (AF). We aimed to assess a comprehensive set of P-wave characteristics for prediction of incident AF in a population-based setting. METHODS: Malmö Preventative Project (MPP) participants were reexamined in 2002-2006 with electrocardiographic (ECG) and echocardiographic examinations and followed for 5 years. AF-free subjects (n = 983, age 70 ± 5 years, 38% females) with sinus rhythm ECGs were included in the study. ECGs were digitally processed using the Glasgow algorithm. P-wave duration, axis, dispersion, P-terminal force in lead V1 and interatrial block (IAB) were evaluated. ECG risk score combining the morphology, voltage and length of P-wave (MVP score) was calculated. New-onset diagnoses of AF were obtained from nation-wide registers. RESULTS: During follow up, 66 patients (7%) developed AF. After adjustment for age and gender, the independent predictors of AF were abnormal P-wave axis > 75° (HR 1.63 CI95% 1.95-11.03) and MVP score 4 (HR 6.17 CI 95% 1.76-21.64), both correlated with LA area: Person r - 0.146, p < 0.001 and 0.192, p < 0.001 respectively. Advanced IAB (aIAB) with biphasic P-wave morphology in leads III and aVF was the most prevalent variant of aIAB and predicted AF in a univariate model (HR 2.59 CI 95% 1.02-6.58). CONCLUSION: P-wave frontal axis and MVP score are ECG-based AF predictors in the population-based cohort. Our study provides estimates for prevalence and prognostic importance of different variants of aIAB, providing a support to use biphasic P-wave morphology in lead aVF as the basis for aIAB definition.

Programmed Ventricular Stimulation as an Additional Primary Prevention Risk Stratification Tool in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Study.

BACKGROUND: A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value. METHODS: All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia [VT] or fibrillation, [aborted] sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period. RESULTS: Two hundred eighty-eight patients (41.0±14.5 years, 55.9% male, right ventricular ejection fraction 42.5±11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 [2.89-10.17] years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (P<0.001). Inducible ventricular tachycardia predicted clinical sustained VA during the 5-year follow-up and remained an independent predictor after accounting for the calculator-predicted risk (HR, 2.52 [1.58-4.02]; P<0.001). Compared with ARVC risk calculator predictions in isolation (C-statistic 0.72), addition of PVS inducibility showed improved prediction of VA events (C-statistic 0.75; log-likelihood ratio for nested models, P<0.001). PVS inducibility had a 76% [67-84] sensitivity and 68% [61-74] specificity, corresponding to log-likelihood ratios of 2.3 and 0.36 for inducible (likelihood ratio+) and noninducible (likelihood ratio-) patients, respectively. In patients with a ARVC risk calculator-predicted risk of clinical VA events <25% during 5 years (ie, low/intermediate subgroup), PVS had a 92.6% negative predictive value. CONCLUSIONS: PVS significantly improved risk stratification above and beyond the calculator-predicted risk of VA in a primary prevention cohort of patients with ARVC, mainly for patients considered to be at low and intermediate risk by the clinical risk calculator.

Age-stratified comparison of prognosis in cardiac resynchronization therapy with or without prophylactic defibrillator for nonischemic cardiomyopathy-a nationwide cohort study.

AIMS: Prior studies have suggested that the benefit from primary preventive defibrillator treatment for patients with nonischemic cardiomyopathyy, treated with cardiac resynchronization therapy, may be age-dependent. We aimed to compare age-stratified mortality rates and mode of death in patients with nonischemic cardiomyopathy who are treated with either primary preventive cardiac resynchronization therapy with defibrillator (CRT-D) or CRT with pacemaker (CRT-P). METHODS AND RESULTS: All patients with nonischemic cardiomyopathy and CRT-P or primary preventive CRT-D who were implanted in Sweden during the period 2005-2020 were included. Propensity scoring was used to create a matched cohort. Primary outcome was all-cause mortality within 5 years. In all, 4027 patients were included: 2334 with CRT-P and 1693 with CRT-D. Crude 5-year mortality was 635 (27%) vs. 246 (15%), P < 0.001. In Cox regression analysis, adjusted for clinically relevant covariables, CRT-D was independently associated with higher 5-year survival [0.72 (0.61-0.85), P < 0.001]. Cardiovascular mortality was similar between groups (62 vs. 64%, P = 0.64), but death from heart failure was more common in the CRT-D group (46 vs. 36%, P = 0.007). In the matched cohort (n = 2414), 5-year mortality was 21% (24 vs. 16%, P < 0.001). In age-stratified analyses, CRT-P was associated with higher mortality in age groups <60 years and 70-79 years, but there was no difference in age groups 60-69 years or 80-89 years. CONCLUSION: In this nationwide registry-based study, patients with CRT-D had better 5-year survival compared to patients with CRT-P. The interaction between age and mortality reduction was not consistent, but patients with CRT-D aged <60 years had the largest absolute mortality reduction.

Associations between physical activity and autonomic function during deep breathing test: the Swedish CArdioPulmonary bioImage Study (SCAPIS).

PURPOSE: The deep breathing test (DBT) is a sensitive test of cardiovagal function. The aim of this study was to explore associations between physical activity and sedentary time, measured by accelerometer, and autonomic function, using DBT. METHODS: In the Swedish Cardio-Pulmonary bioImage Study, men and women aged 50-64 were randomly invited from the general population. A total of 4325 subjects who underwent DBT and assessment of physical activity and sedentary time by accelerometery were included. ECG files from 1-min DBT were used to calculate measures of respiratory sinus arrhythmia [RSA; expiration-inspiration (E-I) difference and E/I ratio], heart rate variability [HRV; root mean square of successive differences (RMSSD), standard deviation of heart rates and mean circular resultant]. Low RSA and HRV was defined as the lowest 10% in the population. RESULTS: For accelerometer-assessed physical activity, there were significant associations between high percentage of sedentary time and low E/I (p < 0.01), and low RMSSD (p < 0.01) in an age- and sex-adjusted model, and between percentage of sedentary time and low RMSSD (p = 0.04) in a risk factor-adjusted model. Low RMSSD was less common in those with a high percentage of moderate to vigorous physical activity (p = 0.04, after risk-factor adjustment). These associations became non-significant when further adjusting for heart rate. CONCLUSION: We report associations between degree of physical activity and indices of autonomic dysfunction in a large population. The relationships were no longer significant after adjustments for heart rate, indicating that the relationship between physical activity and cardiovagal function partly is accounted for by reduced heart rate.

Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course. METHODS: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed. RESULTS: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among PKP2 than DSC2/DSG2/DSP carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01). CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.

Left atrial dyssynchrony in veteran endurance athletes with and without paroxysmal atrial fibrillation.

BACKGROUND: Prolonged endurance exercise increase the risk of atrial fibrillation (AF) in men. Functional parameters may help separate physiological from pathological atrial remodeling in athletes. LA mechanical dispersion (LA MD) is associated with AF in the general population, but the associations between prolonged exercise, LA MD and AF are not known. PURPOSE: To describe LA MD in veteran athletes with and without paroxysmal AF (pAF) and to investigate LA MD's ability to identify veteran athletes with pAF. METHODS: Two hundred and ninety-three men, skiers with (n = 57) and without (n = 87) pAF, and controls with (n = 61) and without pAF (n = 88) underwent an echocardiographic exam in sinus rhythm. LA reservoir strain (LASr) was measured, and LA MD defined as the standard deviation of time-to-peak strain (SD-TPS). RESULTS: Skiers (mean age 70.7 ± 6.7 years) reported an average of 40-50 years of endurance exercise. LA volumes were associated with pAF and athletic status (p < .001). SD-TPS was associated with pAF (p < .001) but not athletic status (p = .173). We found no significant trend between years of exercise and SD-TPS in individuals without AF (p = .893). SD-TPS did not add incremental value in identifying athletes with pAF in addition to clinical markers, QRS width, LA volume, and LASr (p = .056). CONCLUSION: LA MD was associated with pAF regardless of athletic status but not related to years of endurance exercise, suggesting LA MD could be a promising marker of pathological atrial remodeling in athletes. However, we found no incremental value of LA MD identifying athletes with pAF when LASr was included in the model.

Study of ECG-derived atrial fibrillatory rate for prediction of the outcome of cardioversion of short duration atrial fibrillation (CASAF).

AIMS: The present study aimed at testing the hypothesis that atrial fibrillatory rate (AFR) is predictive of sinus rhythm maintenance after electrical cardioversion. METHODS AND RESULTS: The study comprised 32 patients admitted for cardioversion of atrial fibrillation of short duration (mean duration 3.8 ± 7.7 days). AFR was estimated using frequency power spectrum analysis of QRST-cancelled ECG. At six-weeks follow-up 22% of the patients had relapsed to AF. The pre-cardioversion mean AFR of those was 332 ± 64 fpm compared to 378 ± 59 fpm among patients maintaining sinus rhythm (p = 0.12). CONCLUSION: AFR was not predictive of sinus rhythm maintenance in patients of short duration AF undergoing cardioversion. This is in stark contrast with the earlier reported findings. CLINICAL TRIAL REGISTRATION: NCT02112318 (http://www. CLINICALTRIALS: gov).

ISE/ISHNE Expert Consensus Statement on ECG Diagnosis of Left Ventricular Hypertrophy: The Change of the Paradigm. The joint paper of the International Society of Electrocardiology and the International Society for Holter Monitoring and Noninvasive Electrocardiology.

The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria, i.e. the increased QRS complex amplitude in defined leads. The classical ECG diagnostic paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces. These increased forces are reflected in the augmented QRS amplitude in the corresponding leads. However, the clinical observations document increased QRS amplitude only in the minority of patients with LVH. The low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

Complications of implantable cardioverter-defibrillator treatment in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Treatment with implantable cardioverter-defibrillators (ICD) is a cornerstone for prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at describing the complications associated with ICD treatment in a multinational cohort with long-term follow-up. METHODS AND RESULTS: The Nordic ARVC registry was established in 2010 and encompasses a large multinational cohort of ARVC patients, including their clinical characteristics, treatment, and events during follow-up. We included 299 patients (66% males, median age 41 years). During a median follow-up of 10.6 years, 124 (41%) patients experienced appropriate ICD shock therapy, 28 (9%) experienced inappropriate shocks, 82 (27%) had a complication requiring surgery (mainly lead-related, n = 75), and 99 (33%) patients experienced the combined endpoint of either an inappropriate shock or a surgical complication. The crude rate of first inappropriate shock was 3.4% during the first year after implantation but decreased after the first year and plateaued over time. Contrary, the risk of a complication requiring surgery was 5.5% the first year and remained high throughout the study period. The combined risk of any complication was 7.9% the first year. In multivariate cox regression, presence of atrial fibrillation/flutter was a risk factor for inappropriate shock (P < 0.05), whereas sex, age at implant, and device type were not (all P > 0.05). CONCLUSION: Forty-one percent of ARVC patients treated with ICD experienced potentially life-saving ICD therapy during long-term follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority.

Critical appraisal of technologies to assess electrical activity during atrial fibrillation: a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology.

We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter-electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future.

Baseline QRS Area and Reduction in QRS Area Are Associated with Lower Mortality and Risk of Heart Failure Hospitalization after Cardiac Resynchronization Therapy.

INTRODUCTION: Cardiac resynchronization therapy (CRT) is an established treatment for heart failure in selected patients. However, current guideline indications do not accurately predict individual prognosis with CRT, and up to 30% are nonresponders. Previous studies have shown that QRS area reduction following CRT is associated with improved survival. This study evaluates the incremental value of using QRS area derived from digital electrocardiogram (ECG) recordings, preoperatively and during CRT pacing. METHODS: Medical records of 445 patients receiving CRT implants at a large-volume tertiary care center in Sweden were retrospectively evaluated. Digital ECG before and after CRT implantation were collected, and ECG parameters were analyzed in relation to a primary composite endpoint of heart failure hospitalization or death from any cause. RESULTS: 147 patients (33%) reached the primary endpoint (93 deaths and 103 heart failure hospitalizations) over a median follow-up time of 2.7 years. A larger preimplant QRS area (HR, 0.89; [0.85-0.93]; p = <0.0001; adjusted HR, 0.93; [0.88-0.98]; p = 0.011) and a larger QRS area reduction (HR, 0.92; [0.88-0.96]; p = <0.0001; adjusted HR, 0.95; [0.90-0.99]; p = 0.042) postimplant correlated with a reduced risk of reaching the primary endpoint. This association was seen in patients with native left bundle branch block morphology, nonspecific intraventricular conduction delay, or paced ECG morphology but not in patients with right bundle branch block. CONCLUSION: Larger preimplant QRS area and QRS area reduction were associated with better clinical outcome following CRT in this retrospective material. This knowledge could help optimize patient selection and postoperative management.

Terminal T-wave inversion predicts reperfusion tachyarrhythmias in STEMI.

INTRODUCTION: A reliable electrocardiographic predictor of ventricular fibrillation (VF) in patients with ST elevation myocardial infarction (STEMI) is lacking so far. Previous experimental/simulation study suggested a terminal T-wave inversion (TTWI) in ischemia-related ECG leads corresponding to anterior infarct localization as an independent predictor of reperfusion VF (rVF). This T-wave characteristic has never been tested as a rVF predictor in clinical settings. The aim of this study was to test if terminal T-wave inversion (TTWI) at admission ECG (before reperfusion) can serve as a predictor of ventricular fibrillation during reperfusion (rVF) in patients with anterior STEMI undergoing primary PCI. METHODS AND RESULTS: Study population included consecutive patients with anterior infarct localization admitted for primary PCI (n = 181, age 65 [57; 76] years, 66% male). Of those, 14 patients had rVF (rVF group, age 59 [47; 76] years, 64% male) and patients without rVF comprised the No-rVF group (n = 167, age 65 [57; 76] years, 66% male). Association of TTWI with rVF was analyzed using logistic regression analysis adjusted for relevant clinical and electrocardiographic covariates. The prevalence of TTWI in rVF group was 62% comparing to 23% in the No-rVF group, p = 0.005. TTWI was associated with increased risk of rVF (OR 5.51; 95% CI 1.70-17.89; p = 0.004) and remained a significant predictor after adjustment for age, gender, history of MI prior to index admission, VF before reperfusion, Tpeak-Tend, maximal ST elevation, and QRS duration (OR 23.49; 95% CI 3.14-175.91; p = 0.002). CONCLUSIONS: The terminal T-wave inversion in anterior leads before PCI independently predicted rVF in patients with anterior MI thus confirming the previous experimental/simulation findings.

ECG Markers of Acute Melatonin Treatment in a Porcine Model of Acute Myocardial Ischemia.

In myocardial ischemia, melatonin confers antiarrhythmic action, but its electrocardiographic expression is unclear. We aimed to evaluate the effects of melatonin treatment on electrocardiogram (ECG) parameters reflecting major arrhythmogenic factors and to test the association of these parameters with ventricular fibrillation (VF) incidence. Myocardial ischemia was induced by 40 min coronary artery occlusion in 25 anesthetized pigs. After induction of ischemia, 12 and 13 animals were given melatonin or placebo, respectively. Twelve-lead ECGs were recorded and durations of QRS, QT, Tpeak-Tend intervals and extrasystolic burden were measured at baseline and during occlusion. During ischemia, VF episodes clustered into early and delayed phases (<10 and >20 min, respectively), and QRS duration was associated with VF incidence. QT interval and extrasystolic burden did not differ between the groups. The Tpeak-Tend interval was progressively prolonged, and the prolongation was less pronounced in the treated animals. QRS duration increased, demonstrating two maxima (5−10 and 25 min, respectively). In the melatonin group, the earlier maximum was blunted, and VF development in this period was prevented. Thus, acute melatonin treatment prevented excessive prolongation of the QRS and Tpeak-Tend intervals in the porcine myocardial infarction model, and QRS duration can be used for the assessment of antiarrhythmic action of melatonin.

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.