Comparison of the relation of the ESC 2021 and ESC 2013 definitions of left bundle branch block with clinical and echocardiographic outcome in cardiac resynchronization therapy.

INTRODUCTION: We aimed to investigate the impact of the 2021 European Society of Cardiology (ESC) guideline changes in left bundle branch block (LBBB) definition on cardiac resynchronization therapy (CRT) patient selection and outcomes. METHODS: The MUG (Maastricht, Utrecht, Groningen) registry, consisting of consecutive patients implanted with a CRT device between 2001 and 2015 was studied. For this study, patients with baseline sinus rhythm and QRS duration ≥ 130ms were eligible. Patients were classified according to ESC 2013 and 2021 guideline LBBB definitions and QRS duration. Endpoints were heart transplantation, LVAD implantation or mortality (HTx/LVAD/mortality) and echocardiographic response (LVESV reduction ≥15%). RESULTS: The analyses included 1.202, typical CRT patients. The ESC 2021 definition resulted in considerably less LBBB diagnoses compared to the 2013 definition (31.6% vs. 80.9%, respectively). Applying the 2013 definition resulted in significant separation of the Kaplan-Meier curves of HTx/LVAD/mortality (p < .0001). A significantly higher echocardiographic response rate was found in the LBBB compared to the non-LBBB group using the 2013 definition. These differences in HTx/LVAD/mortality and echocardiographic response were not found when applying the 2021 definition. CONCLUSION: The ESC 2021 LBBB definition leads to a considerably lower percentage of patients with baseline LBBB then the ESC 2013 definition. This does not lead to better differentiation of CRT responders, nor does this lead to a stronger association with clinical outcomes after CRT. In fact, stratification according to the 2021 definition is not associated with a difference in clinical or echocardiographic outcome, implying that the guideline changes may negatively influence CRT implantation practice with a weakened recommendation in patients that will benefit from CRT.

Reduction in the QRS area after cardiac resynchronization therapy is associated with survival and echocardiographic response.

INTRODUCTION: Recent studies have shown that the baseline QRS area is associated with the clinical response after cardiac resynchronization therapy (CRT). In this study, we investigated the association of QRS area reduction (∆QRS area) after CRT with the outcome. We hypothesize that a larger ∆QRS area is associated with a better survival and echocardiographic response. METHODS AND RESULTS: Electrocardiograms (ECG) obtained before and 2-12 months after CRT from 1299 patients in a multi-center CRT-registry were analyzed. The QRS area was calculated from vectorcardiograms that were synthesized from 12-lead ECGs. The primary endpoint was a combination of all-cause mortality, heart transplantation, and left ventricular (LV) assist device implantation. The secondary endpoint was the echocardiographic response, defined as LV end-systolic volume reduction ≥ of 15%. Patients with ∆QRS area above the optimal cut-off value (62 µVs) had a lower risk of reaching the primary endpoint (hazard ratio: 0.43; confidence interval [CI] 0.33-0.56, p < .001), and a higher chance of echocardiographic response (odds ratio [OR] 3.3;CI 2.4-4.6, p < .0001). In multivariable analysis, ∆QRS area was independently associated with both endpoints. In patients with baseline QRS area ≥109 µVs, survival, and echocardiographic response were better when the ∆QRS area was ≥62 µVs (p < .0001). Logistic regression showed that in patients with baseline QRS area ≥109 µVs, ∆QRS area was the only significant predictor of survival (OR: 0.981; CI: 0.967-0.994, p = .006). CONCLUSION: ∆QRS area is an independent determinant of CRT response, especially in patients with a large baseline QRS area. Failure to achieve a large QRS area reduction with CRT is associated with a poor clinical outcome.

Sex-related differences in risk factors, outcome, and quality of life in patients with permanent atrial fibrillation: results from the RACE II study.

AIMS: Atrial fibrillation (AF) risk factors translate into disease progression. Whether this affects women and men differently is unclear. We aimed to investigate sex differences in risk factors, outcome, and quality of life (QoL) in permanent AF patients. METHODS AND RESULTS: The Rate Control Efficacy in Permanent Atrial Fibrillation (RACE II) randomized 614 patients, 211 women and 403 men, to lenient or strict rate control. In this post hoc analysis risk factors, cardiovascular events during 3-year follow-up (cardiovascular death, heart failure hospitalization, stroke, systemic embolism, bleeding, and life-threatening arrhythmic events), outcome parameters, and QoL were compared between the sexes. Women were older (71 ± 7 vs. 66 ± 8 years, P < 0.001), had more hypertension (70 vs. 57%, P = 0.002), and heart failure with preserved ejection fraction (36 vs. 17%, P < 0.001), but less coronary artery disease (13 vs. 21%, P = 0.02). Women had more risk factors (3.7 ± 1.2 vs. 2.9 ± 1.4, P < 0.001) Cardiovascular events occurred in 46 (22%) women and 59 (15%) men (P = 0.03). Women had a 1.52 times [95% confidence interval (CI) 1.03-2.24] higher yearly cardiovascular event-rate [8.2% (6.0-10.9) vs. 5.4% (4.1-6.9), P = 0.03], but this was no longer significant after adjusting for the number of underlying risk factors. Women had reduced QoL, irrespective of age and heart rate but negatively influenced by their risk factors. CONCLUSION: In this permanent AF population, women had more accumulation of AF risk factors than men. The observed higher cardiovascular event rate in women was no longer significant after adjusting for the number of risk factors. Further, QoL was negatively influenced by the higher number of risk factors in women. This suggests that sex differences may be driven by the greater risk factor burden in women.

Sex differences in catheter ablation of atrial fibrillation: results from AXAFA-AFNET 5.

AIMS: Study sex-differences in efficacy and safety of atrial fibrillation (AF) ablation. METHODS AND RESULTS: We assessed first AF ablation outcomes on continuous anticoagulation in 633 patients [209 (33%) women and 424 (67%) men] in a pre-specified subgroup analysis of the AXAFA-AFNET 5 trial. We compared the primary outcome (death, stroke or transient ischaemic attack, or major bleeding) and secondary outcomes [change in quality of life (QoL) and cognitive function] 3 months after ablation. Women were older (66 vs. 63 years, P < 0.001), more often symptomatic, had lower QoL and a longer history of AF. No sex differences in ablation procedure were found. Women stayed in hospital longer than men (2.1 ± 2.3 vs. 1.6 ± 1.3 days, P = 0.004). The primary outcome occurred in 19 (9.1%) women and 26 (6.1%) men, P = 0.19. Women experienced more bleeding events requiring medical attention (5.7% vs. 2.1%, P = 0.03), while rates of tamponade (1.0% vs. 1.2%) or intracranial haemorrhage (0.5% vs. 0%) did not differ. Improvement in QoL after ablation was similar between the sexes [12-item Short Form Health Survey (SF-12) physical 5.1% and 5.9%, P = 0.26; and SF-12 mental 3.7% and 1.6%, P = 0.17]. At baseline, mild cognitive impairment according to the Montreal Cognitive Assessment (MoCA) was present in 65 (32%) women and 123 (30%) men and declined to 23% for both sexes at end of follow-up. CONCLUSION: Women and men experience similar improvement in QoL and MoCA score after AF ablation on continuous anticoagulation. Longer hospital stay, a trend towards more nuisance bleeds, and a lower overall QoL in women were the main differences observed.

Characteristics and outcomes of atrial fibrillation in patients without traditional risk factors: an RE-LY AF registry analysis.

AIMS: Data on patient characteristics, prevalence, and outcomes of atrial fibrillation (AF) patients without traditional risk factors, often labelled 'lone AF', are sparse. METHODS AND RESULTS: The RE-LY AF registry included 15 400 individuals who presented to emergency departments with AF in 47 countries. This analysis focused on patients without traditional risk factors, including age ≥60 years, hypertension, coronary artery disease, heart failure, left ventricular hypertrophy, congenital heart disease, pulmonary disease, valve heart disease, hyperthyroidism, and prior cardiac surgery. Patients without traditional risk factors were compared with age- and region-matched controls with traditional risk factors (1:3 fashion). In 796 (5%) patients, no traditional risk factors were present. However, 98% (779/796) had less-established or borderline risk factors, including borderline hypertension (130-140/80-90 mmHg; 47%), chronic kidney disease (eGFR < 60 mL/min; 57%), obesity (body mass index > 30; 19%), diabetes (5%), excessive alcohol intake (>14 units/week; 4%), and smoking (25%). Compared with patients with traditional risk factors (n = 2388), patients without traditional risk factors were more often men (74% vs. 59%, P < 0.001) had paroxysmal AF (55% vs. 37%, P < 0.001) and less AF persistence after 1 year (21% vs. 49%, P < 0.001). Furthermore, 1-year stroke occurrence rate (0.6% vs. 2.0%, P = 0.013) and heart failure hospitalizations (0.9% vs. 12.5%, P < 0.001) were lower. However, risk of AF-related re-hospitalization was similar (18% vs. 21%, P = 0.09). CONCLUSION: Almost all patients without traditionally defined AF risk factors have less-established or borderline risk factors. These patients have a favourable 1-year prognosis, but risk of AF-related re-hospitalization remains high. Greater emphasis should be placed on recognition and management of less-established or borderline risk factors.

Comparing biomarker profiles of patients with heart failure: atrial fibrillation vs. sinus rhythm and reduced vs. preserved ejection fraction.

Aims: The clinical correlates and consequences of atrial fibrillation (AF) might be different between heart failure with reduced vs. preserved ejection fraction (HFrEF vs. HFpEF). Biomarkers may provide insights into underlying pathophysiological mechanisms of AF in these different heart failure (HF) phenotypes. Methods and results: We performed a retrospective analysis of the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which was an observational cohort. We studied 2152 patients with HFrEF [ejection fraction (EF < 40%)], of which 1419 were in sinus rhythm (SR) and 733 had AF. Another 524 patients with HFpEF (EF ≥50%) were studied, of which 286 in SR and 238 with AF. For the comparison of biomarker profiles, 92 cardiovascular risk markers were measured (Proseek® Olink Cardiovascular III panel). The circulating risk marker pattern observed in HFrEF was different than the pattern in HFpEF: in HFrEF, AF was associated with higher levels of 77 of 92 (84%) risk markers compared to SR; whereas in HFpEF, many more markers were higher in SR than in AF. Over a median follow-up of 21 months, AF was associated with increased mortality risk [multivariable hazard ratio (HR) of 1.27; 95% confidence interval (CI) 1.09-1.48, P = 0.002]; there was no significant interaction between heart rhythm and EF group on outcome. Conclusion: In patients with HFrEF, the presence of AF was associated with a homogeneously elevated cardiovascular risk marker profile. In contrast, in patients with HFpEF, the presence of AF was associated with a more scattered risk marker profile, suggesting differences in underlying pathophysiological mechanisms of AF in these HF phenotypes.

Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodelling: results from the Markers and Response to CRT (MARC) study.

Aims: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in systolic heart failure patients with ventricular conduction delay. Variability of individual response to CRT warrants improved patient selection. The Markers and Response to CRT (MARC) study was designed to investigate markers related to response to CRT. Methods and results: We prospectively studied the ability of 11 clinical, 11 electrocardiographic, 4 echocardiographic, and 16 blood biomarkers to predict CRT response in 240 patients. Response was measured by the reduction of indexed left ventricular end-systolic volume (LVESVi) at 6 months follow-up. Biomarkers were related to LVESVi change using log-linear regression on continuous scale. Covariates that were significant univariately were included in a multivariable model. The final model was utilized to compose a response score. Age was 67 ± 10 years, 63% were male, 46% had ischaemic aetiology, LV ejection fraction was 26 ± 8%, LVESVi was 75 ± 31 mL/m2, and QRS was 178 ± 23 ms. At 6 months LVESVi was reduced to 58 ± 31 mL/m2 (relative reduction of 22 ± 24%), 130 patients (61%) showed ≥ 15% LVESVi reduction. In univariate analysis 17 parameters were significantly associated with LVESVi change. In the final model age, QRSAREA (using vectorcardiography) and two echocardiographic markers (interventricular mechanical delay and apical rocking) remained significantly associated with the amount of reverse ventricular remodelling. This CAVIAR (CRT-Age-Vectorcardiographic QRSAREA -Interventricular Mechanical delay-Apical Rocking) response score also predicted clinical outcome assessed by heart failure hospitalizations and all-cause mortality. Conclusions: The CAVIAR response score predicts the amount of reverse remodelling after CRT and may be used to improve patient selection. Clinical Trials: NCT01519908.

Atrial Fibrillation During Cardiac Resynchronization Therapy.

The landmark trials on cardiac resynchronization therapy (CRT) have focused on patients with sinus rhythm at inclusion. Little data are available on the efficacy of CRT in patients with atrial fibrillation (AF), while AF has a high prevalence (20-40%) among patients receiving CRT. This review focuses on the detrimental effect of AF on CRT response and discusses management of patients with AF during CRT. Uncertainty remains as to which thresholds of AF burden can lead to a reduced response to CRT and every effort should be made in trying to assess and guarantee successful biventricular pacing in patients with AF.

Atrial reverse remodelling is associated with outcome of cardiac resynchronization therapy.

AIMS: To study the prognostic effect of atrial reverse remodelling on outcome of cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Patients receiving a CRT device in the University Medical Centre Groningen were included. Atrial reverse remodelling was defined as a ≥10% reduction in left atrial volume index at 6-month follow-up. Success of CRT was defined as ventricular reverse remodelling with a reduction in left ventricular end-systolic volume of ≥15% at 6-month follow-up. Primary endpoint was all-cause mortality or heart failure hospitalizations. A total of 365 patients (mean age 65.1 ± 11.0 years, 73% men) were included; among them, 221 (61%) were in sinus rhythm and had no prior atrial fibrillation (AF), and 144 patients (39%) had a history of AF. During a mean follow up of 2.0 ± 1.0 years, 49 patients died. Cox regression analysis revealed that patients with no atrial and no ventricular reverse remodelling had the worst outcome (hazard ratio 3.1, 95% confidence interval 1.4-7.1, P = 0.006). Outcome in patients with only atrial reverse remodelling was comparable with outcome in patients with both atrial and ventricular reverse remodelling (hazard ratio 2.0, 95% confidence interval 0.7-5.6, P = 0.21). CONCLUSION: Patients without atrial and ventricular reverse remodelling have the worst outcome. Patients with only atrial reverse remodelling have improved left ventricular diastolic filling during follow-up and demonstrate a comparable outcome with patients with both atrial and ventricular reverse remodelling. Assessment of atrial reverse remodelling may provide additional prognostic information in determining CRT outcome.

Spontaneous resolution of left bundle branch block and biventricular stimulation lead to reverse remodeling in dyssynchronopathy.

Left bundle branch block (LBBB) is considered a marker of underlying structural cardiac disease. To determine whether LBBB is cause or consequence of deterioration of left ventricular (LV) function is difficult as both are often diagnosed concomitantly. We discuss a patient where reversal of LBBB and subsequent normalization of LV function was observed after 2 different therapies, first after start of heart failure medication, and years later after implantation of a cardiac resynchronization device. This indicates that LBBB per se may result in the development of non-ischemic cardiomyopathy and that LBBB resolution can lead to reverse remodeling in dyssynchronopathy.

Cardiac Resynchronization Therapy beyond Nominal Settings: An IEGM-Based Approach for Paced and Sensed Atrioventricular Delay Offset Optimization in Daily Clinical Practice.

Optimization of the atrioventricular (AV) delay has been performed in several landmark trials in cardiac resynchronization therapy (CRT), although it is often not performed in daily practice. Our aim was to study optimal AV delays and investigate a simple intracardiac electrogram (IEGM)-based optimization approach. 328 CRT patients with paired IEGM and echocardiography optimization data were included in our single-center observational study. Sensed (sAV) and paced (pAV) AV delays were optimized using an iterative echocardiography method. The offset between sAV and pAV delays was calculated using the IEGM method. The mean age of the patients was 69 ± 12 years; 64% were men, 48% had ischemic etiology of heart failure. During echocardiographic optimization, an offset of 73 ± 18 ms was found, differing from nominal AV settings (p < 0.001). Based on the IEGM method, the optimal offset was 75 ± 25 ms. The echocardiographic and IEGM-generated AV offset delays showed good correlation (R2 = 0.62, p < 0.001) and good agreement according to Bland-Altman plot analysis. CRT responders had a near zero offset difference between IEGM and echo optimization (-0.2 ± 17 ms), while non-responders had an offset difference of 6 ± 17 ms, p = 0.006. In conclusion, optimal AV delays are patient-specific and differ from nominal settings. pAV delay can easily be calculated from IEGM after sAV delay optimization.

Pathophysiological pathways in patients with heart failure and atrial fibrillation.

AIMS: Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. METHODS AND RESULTS: From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were up-regulated in patients with AF and HF. In the validation cohort, eight biomarkers were up-regulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, P = 1.33 × 10-12), insulin-like growth factor-binding protein-1 (fold change 1.32, P = 1.08 × 10-8), and insulin-like growth factor-binding protein-7 (fold change 1.33, P = 1.35 × 10-18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort. CONCLUSION: In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies.

Association of ECG characteristics with clinical and echocardiographic outcome to CRT in a non-LBBB patient population.

PURPOSE: Effectiveness of cardiac resynchronization therapy (CRT) in patients without left bundle branch block (non-LBBB) QRS morphology is limited. Additional selection criteria are needed to identify these patients. METHODS: Seven hundred ninety consecutive patients with non-LBBB morphology, who received a CRT-device in 3 university centers in the Netherlands, were selected. Pre-implantation 12-lead ECGs were evaluated on morphology, duration, and area of the QRS complex, as well as on PR interval, left ventricular activation time (LVAT), and the presence of fragmented QRS (fQRS). Association of these ECG features with the primary endpoint: a combination of left ventricular assist device (LVAD) implantation, cardiac transplantation and all-cause mortality, and secondary endpoint-echocardiographic reduction of left ventricular end-systolic volume (LVESV)-were evaluated. RESULTS: The primary endpoint occurred more often in non-LBBB patients with with PR interval ≥ 230ms, QRS area < 109µVs, and with fQRS. Multivariable regression analysis showed independent associations of QRS area (HR 2.33 [1.44, 3.77], p = 0.001) and PR interval (HR 2.03 [1.51, 2.74], p < 0.001) only. Mean LVESV reduction was significantly lower in patients with baseline RBBB, QRS duration < 150 ms, PR interval ≥ 230 ms, and in QRS area < 109 µVs. Multivariable regression analyses only showed significant associations between QRS area ≥ 109 µVs (OR 2.00 [1.09, 3.66] p = 0.025) and probability of echocardiographic response to CRT. CONCLUSIONS: In the heterogeneous non-LBBB patient population, QRS area and PR prolongation rather than traditional QRS duration and morphology are associated to both clinical and echocardiographic outcomes of CRT.

Heart Size Corrected Electrical Dyssynchrony and Its Impact on Sex-Specific Response to Cardiac Resynchronization Therapy.

BACKGROUND: Women are less likely to receive cardiac resynchronization therapy, yet, they are more responsive to the therapy and respond at shorter QRS duration. The present study hypothesized that a relatively larger left ventricular (LV) electrical dyssynchrony in smaller hearts contributes to the better cardiac resynchronization therapy response in women. For this, the vectorcardiography-derived QRS area is used, since it allows for a more detailed quantification of electrical dyssynchrony compared with conventional electrocardiographic markers. METHODS: Data from a multicenter registry of 725 cardiac resynchronization therapy patients (median follow-up, 4.2 years [interquartile range, 2.7-6.1]) were analyzed. Baseline electrical dyssynchrony was evaluated using the QRS area and the corrected QRS area for heart size using the LV end-diastolic volume (QRSarea/LVEDV). Impact of the QRSarea/LVEDV ratio on the association between sex and LV reverse remodeling (LV end-systolic volume change) and sex and the composite outcome of all-cause mortality, LV assist device implantation, or heart transplantation was assessed. RESULTS: At baseline, women (n=228) displayed larger electrical dyssynchrony than men (QRS area, 132±55 versus 123±58 µVs; P=0.043), which was even more pronounced for the QRSarea/LVEDV ratio (0.76±0.46 versus 0.57±0.34 µVs/mL; P<0.001). After multivariable analyses, female sex was associated with LV end-systolic volume change (ß=0.12; P=0.003) and a lower occurrence of the composite outcome (hazard ratio, 0.59 [0.42-0.85]; P=0.004). A part of the female advantage regarding reverse remodeling was attributed to the larger QRSarea/LVEDV ratio in women (25-fold change in ß from 0.12 to 0.09). The larger QRSarea/LVEDV ratio did not contribute to the better survival observed in women. In both volumetric responders and nonresponders, female sex remained strongly associated with a lower risk of the composite outcome (adjusted hazard ratio, 0.59 [0.36-0.97]; P=0.036; and 0.55 [0.33-0.90]; P=0.018, respectively). CONCLUSIONS: Greater electrical dyssynchrony in smaller hearts contributes, in part, to more reverse remodeling observed in women after cardiac resynchronization therapy, but this does not explain their better long-term outcomes.

Association between heart failure aetiology and magnitude of echocardiographic remodelling and outcome of cardiac resynchronization therapy.

AIMS: Echocardiographic response after cardiac resynchronization therapy (CRT) is often lesser in ischaemic cardiomyopathy (ICM) than non-ischaemic dilated cardiomyopathy (NIDCM) patients. We assessed the association of heart failure aetiology on the amount of reverse remodelling and outcome of CRT. METHODS AND RESULTS: Nine hundred twenty-eight CRT patients were retrospectively included. Reverse remodelling and endpoint occurrence (all-cause mortality, heart transplantation, or left ventricular assist device implantation) was assessed. Two response definitions [≥15% reduction left ventricular end systolic volume (LVESV) and ≥5% improvement left ventricular ejection fraction] and the most accurate cut-off for the amount of reverse remodelling that predicted endpoint freedom were assessed. Mean follow-up was 3.8 ± 2.4 years. ICM was present in 47%. ICM patients who were older (69 ± 7 vs. 63 ± 11), more often men (83% vs. 58%), exhibited less LVESV reduction (13 ± 31% vs. 23 ± 32%) and less left ventricular ejection fraction improvement (5 ± 11% vs. 10 ± 12%) than NIDCM patients (all P < 0.001). Nevertheless, every 1% LVESV reduction was associated with a relative reduction in endpoint occurrence: NIDCM 1.3%, ICM 0.9%, and absolute risk reduction was similar (0.4%). The most accurate cut-off of LVESV reduction that predicted endpoint freedom was 17.1% in NIDCM and 13.2% in ICM. CONCLUSIONS: ICM patients achieve less reverse remodelling than NIDCM, but the prognostic gain in terms of survival time is the same for every single percentage of reverse remodelling that does occur. The assessment and expected magnitude of reverse remodelling should take this effect of heart failure aetiology into account.

Evaluating Electrocardiography-Based Identification of Cardiac Resynchronization Therapy Responders Beyond Current Left Bundle Branch Block Definitions.

OBJECTIVES: This study aimed to evaluate the association of 4 left bundle branch block (LBBB) definitions and their individual ECG characteristics with clinical outcome. Furthermore, it aimed to combine relevant outcome-associated electrocardiographic (ECG) characteristics into a novel outcome-based definition. BACKGROUND: LBBB morphology is associated with positive response to cardiac resynchronization therapy. However, there are multiple LBBB definitions. Associations with outcomes may differ between definitions and depend on varying contributions of the individual ECG characteristics that these LBBB definitions are composed of. METHODS: A retrospective multicenter study was conducted in 1,492 cardiac resynchronization therapy patients. Patients were classified as LBBB or non-LBBB according to definitions provided by the European Society of Cardiology, American Heart Association, MADIT-CRT (Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy) trial, and according to Strauss et al., the primary endpoint was left ventricular assist device implantation, cardiac transplantation, and all-cause mortality. RESULTS: LBBB classification differed significantly between the 4 definitions (kappa coefficients ranging from 0.09 to 0.92). The American Heart Association definition correlated the least (0.09 to 0.12) with the other definitions. Only 13.8% of patients were classified as LBBB by all definitions. During a follow-up period of 3.4 ± 2.4 years, 472 (32%) patients experienced the primary endpoint. For each LBBB definition survival analysis showed a significant association of LBBB with outcome, with relative risk reduction ranging from 39% to 43%. Each LBBB definition included characteristics that were not associated with outcome. Combining outcome-associated ECG characteristics into a novel prediction model did not significantly improve diagnostic performance (relative risk reduction 43%). CONCLUSIONS: The classification of LBBB is highly dependent on the LBBB definition used. However, each LBBB definition provides a comparable difference in risk of adverse clinical events between LBBB and non-LBBB patients. Combining individual outcome-associated ECG-characteristics into a novel prediction model does not improve association with outcome.

Genetic risk and atrial fibrillation in patients with heart failure.

AIMS: To study the association between an atrial fibrillation (AF) genetic risk score with prevalent AF and all-cause mortality in patients with heart failure. METHODS AND RESULTS: An AF genetic risk score was calculated in 3759 European ancestry individuals (1783 with sinus rhythm, 1976 with AF) from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) by summing 97 single nucleotide polymorphism (SNP) alleles (ranging from 0-2) weighted by the natural logarithm of the relative SNP risk from the latest AF genome-wide association study. Further, we assessed AF risk variance explained by additive SNP variation, and performance of clinical or genetic risk factors, and the combination in classifying AF prevalence. AF was classified as AF or atrial flutter (AFL) at baseline electrocardiogram and/or a history of AF or AFL. The genetic risk score was associated with AF after multivariable adjustment. Odds ratio for AF prevalence per 1-unit increase genetic risk score was 2.12 (95% confidence interval 1.84-2.45, P = 2.15 × 10-24 ) in the total cohort, 2.08 (1.72-2.50, P = 1.30 × 10-14 ) in heart failure with reduced ejection fraction (HFrEF) and 2.02 (1.37-2.99, P = 4.37 × 10-4 ) in heart failure with preserved ejection fraction (HFpEF). AF-associated loci explained 22.9% of overall AF SNP heritability. Addition of the genetic risk score to clinical risk factors increased the C-index by 2.2% to 0.721. CONCLUSIONS: The AF genetic risk score was associated with increased AF prevalence in HFrEF and HFpEF. Genetic variation accounted for 22.9% of overall AF SNP heritability. Addition of genetic risk to clinical risk improved model performance in classifying AF prevalence.