Clinical Implications of Electrocardiographic Bundle Branch Block in Primary Care

Cardiac risk factors and prevention

Original research article Heart: first published as 10.1136/heartjnl-2018-314295 on 25 May 2019. Downloaded from Clinical implications of electrocardiographic bundle branch block in primary care Peter Vibe Rasmussen,‍ ‍ 1,2 Morten Wagner Skov,2,3 Jonas Ghouse,2,3 Adrian Pietersen,4 Steen Møller Hansen,5 Christian Torp-Pedersen,5,6 Lars Køber,3,7 Stig Haunsø,2,3,7 Morten Salling Olesen,2,8 Jesper Hastrup Svendsen,3,7 Jacob Melgaard,6 Claus Graff,6 Anders Gaardsdal Holst,3,9 Jonas Bille Nielsen2,10,11

►► Additional material is Abstract In the primary care setting, patients are referred published online only. To view Objectives Electrocardiographic bundle branch block for 12-lead standard ECG recording based on a please visit the journal online broad range of indications, ranging from typical (http://dx. doi.org/ 10.1136/ (BBB) is common but the prognostic implications in heartjnl-2018- 314295). primary care are unclear. We sought to investigate the symptoms of CV disease to more diffuse symptoms relationship between electrocardiographic BBB subtypes as well as monitoring of medical treatment (eg, QTc For numbered affiliations see and the risk of cardiovascular (CV) outcomes in a primary interval-prolonging drugs) or as part of a routine end of article. care population free of major CV disease. health check. Opportunistic ECG recordings Methods Retrospective cohort study of primary care will often result in identification of various BBB Correspondence to subtypes. However, to the best of our knowledge, Peter Vibe Rasmussen, patients referred for electrocardiogram (ECG) recording Department of Cardiology, between 2001 and 2011. Cox regression models were there are no clear and uniform recommendations or Herlev-Gentofte Hospital, used to estimate hazard ratios (HR) as well as absolute available risk prediction models aimed at handling Hellerup, Denmark ; peter.vibe. risks of CV outcomes based on various BBB subtypes. and informing general practice patients who present rasmussen@gmail. com Results We included 202 268 individuals with a with a potentially asymptomatic BBB subtype. PVR and MWS contributed median follow-up period of 7.8 years (Inter-quartile To address this, we used a middle-aged and equally. range [IQR] 4.9–10.6). Left bundle branch block (LBBB) elderly primary care population free from major was associated with heart failure (HF) in both men CV disease, to (1) Estimate prevalences of BBB. Received 16 October 2018 (HR 3.96, 95% CI 3.30 to 4.76) and women (HR 2.51, (2) Describe associations between BBB subtypes Revised 7 March 2019 and CV outcomes. (3) Test if the BBB subtypes are Accepted 15 March 2019 95% CI 2.15 to 2.94) and with CV death in men (HR Published Online First 1.80, 95% CI 1.38 to 2.35). Right bundle branch block clinically useful in improving risk prediction of CV 25 May 2019 (RBBB) was associated with pacemaker implantation in events. (4) If so, to develop a model useful in risk both men (HR 3.26, 95% CI 2.74 to 3.89) and women prediction of CV events in primary care patients http://heart.bmj.com/ (HR 3.69, 95% CI 2.91 to 4.67), HF in both sexes and with different BBB subtypes. weakly associated with CV death in men. Regarding LBBB, we found an increasing hazard of HF with Methods increasing QRS-interval duration (HR 1.25, 95% CI 1.11 Study population to 1.42 per 10 ms increase in men and HR 1.23, 95% CI The present study is a part of the Copenhagen ECG 1.08 to 1.40 per 10 ms increase in women). Absolute study, comprising all individuals referred for ECG

10-year risk predictions across age-specific and sex- on September 30, 2021 by guest. Protected copyright. recording at the Copenhagen General Practitioners’ specific subgroups revealed clinically relevant differences Laboratory (CGPL) between 2001 and 2011. CGPL between having various BBB subtypes. is a centralised core facility used by general practi- Conclusions Opportunistic findings of BBB subtypes in tioners in the area of Copenhagen for the purpose of primary care patients without major CV disease should conducting various clinical examinations including be considered warnings of future HF and pacemaker ECG recording, as described previously.6–8 implantation. Individuals were excluded if they, at the time of inclusion (date of first ECG recording), were <40 years of age, had a pacemaker or implantable cardioverter-defibrillator, had an ECG unsuitable Introduction for measurement (see section on electrocardiog- ►► http://dx. doi. org/ 10. 1136/ The use of surface 12-lead electrocardio- raphy) or had a history of myocardial infarction heartjnl-2019- 314751 gram (ECG) often results in identification of bundle (MI), atrial fibrillation (AF), ischaemic stroke, heart branch block (BBB), even in individuals free of failure (HF) or valvular heart disease. We chose known cardiopulmonary disease. BBB comprises to exclude individuals <40 years of age due to a the subtypes incomplete right bundle branch block © Author(s) (or their very low event rate and consequently low statistical (IRBBB), right bundle branch block (RBBB), left employer(s)) 2019. No power. commercial re-use. See rights bundle branch block (LBBB) and non-specific and permissions. Published intraventricular conduction defect (NIVCD). BBB by BMJ. subtypes have been associated with an adverse prog- Baseline variables and outcomes To cite: Rasmussen PV, nosis in patients with known cardiovascular (CV) Using Danish administrative healthcare registers and Skov MW, Ghouse J, et al. disease and in people recruited from the general a unique personal identification number assigned to Heart 2019;105:1160–1167. population with and without CV disease.1–5 all persons with permanent residence in Denmark,

1160 Rasmussen PV, et al. Heart 2019;105:1160–1167. doi:10.1136/heartjnl-2018-314295 Cardiac risk factors and prevention we followed individuals over time with respect to death, emigra- mortality using individuals without the BBB subtype in question, use of prescription drugs and any hospital, or outpatient tion as reference. In case of a significant association between Heart: first published as 10.1136/heartjnl-2018-314295 on 25 May 2019. Downloaded from clinic diagnoses. We identified baseline variables regarding any of the BBB subtypes and an outcome of interest, we further comorbidity and medication status as described in detail previ- tested the association between QRS duration, measured as a ously.6–8 In brief, diabetes was defined as a register diagnosis continuous variable, and the event within subjects with the of diabetes mellitus or treatment with glucose-lowering drugs. specific BBB subtype. MI, AF, HF, pacemaker implantation, valvular heart disease and Time-on-study was used as time scale in all survival ischaemic stroke were defined from hospital discharge diagnoses analyses. All Cox models were adjusted for the following and procedure codes in the Danish National Patient Registry. covariates obtained at baseline: age, hypertension, diabetes Hypertension was defined as a register diagnosis of hyperten- mellitus, a categorical variable of Charlson Comorbidity sion or simultaneous treatment with two types of antihyperten- Index (0, 1, >2 points) and left ventricular hypertrophy. As sive medication prior to or at inclusion. Finally, we constructed many CV diseases are known to present differently across the the Charlson Comorbidity Index which is a score combining two sexes, all analyses were conducted separately in men and several disease-specific comorbidities; for a list of included codes women.12 Follow-up began on the day of first ECG recording see online supplementary table 1.9 Our end points of interest and ended in case of emigration, event of interest, death or were incident HF, MI, pacemaker implantation, AF, CV death on 31 December 2013, whichever came first. Proportional and death from all causes. For a list of diagnostic codes see hazard assumptions were tested and accepted by evaluating online supplementary table 2. The use of Danish administrative log-log plots. We considered a two-sided p value <0.05 as registers ensures complete nationwide coverage. Thus, we were statistically significant. able to interpret all cases of values not observed as not present and could define all variables without missing values. Absolute risk prediction Risk predictions were performed in a competing risk setting Electrocardiography by combining a Cox model for all-cause mortality with a 13 All ECGs were digitally recorded and stored in the MUSE Cox model of the outcome in question. Absolute risks were Cardiology Information System (GE Healthcare, Wauwatosa, reported in a risk chart stratified by 10-year age groups, sex Wisconsin, USA) and were processed using version 21 of the and comorbidity (yes vs no) defined as either a Charlson Marquette 12SL algorithm.8 We excluded ECGs with rhythms Comorbidity Score >1, hypertension or diabetes mellitus. different from sinus rhythm and other findings not suitable for Differences in time-dependent area under the receiver oper- the study analyses (eg, advanced atrioventricular block, delta ating characteristics curve (AUC) were calculated to investi- waves, pace spikes, ventricular rates <30 beats per minute and gate the added discriminative value of BBB subtypes in risk 14 15 >120 beats per minute). We defined BBB subtypes according prediction of CV outcomes. Data were split into a training to the American Heart Association (AHA), American College and test set with 101 splits using randomly chosen seeds. Ulti- of Cardiology Foundation (ACCF), and Heart Rhythm Society mately, the seed with the median AUC in the models without

(HRS) recommendations for standardisation and interpretation BBB was chosen. Model performance and calibration were http://heart.bmj.com/ of the ECG implementing a few minor modifications as the evaluated and accepted using Brier scores and calibration 12SL algorithm cannot directly measure a notch or slur in the plots showing the observed frequency versus the predicted 16 17 R-wave.10 risk. We calculated 10-year absolute risks and reported Complete RBBB was defined as: (1) QRS duration >120 ms. these only in outcomes in which there was a statistically significant increase (p<0.05) in AUC when adding BBB status (2) rsr’, rsR’ or rSR’ in leads V1 and/or V2. (3) S wave of greater to a conventional risk model of CV outcomes. Furthermore, duration than R wave or >40 ms in leads I and V6. (4) Normal as an example, the relationship between QRS duration and R peak time in leads V5 and V6 but >50 ms in lead V1. Incom- plete RBBB was defined by a QRS duration between 110 ms and the 10-year risk of HF was depicted for the 60–69 years age on September 30, 2021 by guest. Protected copyright. 120 ms with other criteria being the same as for complete RBBB. group with LBBB and comorbidity. LBBB was defined accordingly as: (1) QRS duration >120 ms.

(2) Broad R wave in leads I, aVL, V5 and V6. (3) Absent Q waves Sensitivity analysis

in lead I, V5 and V6. (4) R peak time >60 ms in leads V5 and To investigate whether the associations between BBB subtypes

V6 but normal in leads V1, V2 and V3. NIVCD was defined as and the risk of HF could be due to patients already having mani- QRS duration >120 ms without meeting the criteria of RBBB or fest but yet undiagnosed disease at the time of their referral for LBBB. Left ventricular hypertrophy was defined according to the ECG recording, we performed a landmark analysis, in which we 11 Sokolow-Lyon ECG criteria. only included individuals on study with event-free survival at To verify that the algorithm used to identify BBB correctly 1 year of follow-up.18 captured the various BBB subtypes and not artefacts, premature ventricular contractions or paced rhythms despite the various Results applied filters, we randomly sampled 50 ECGs from each BBB Study population category for manual evaluation. We found that all sampled ECGs A total of 202 268 persons were eligible for inclusion. Baseline (n=200) were correctly assigned by the algorithm in agreement characteristics of the study population are provided in table 1. with the defined BBB criteria. The median follow-up time for the total study population was 7.8 years (IQR 4.9–10.6). During follow-up, we identified Statistical analysis 11 082 cases of incident HF, 7211 cases of incident MI, 2246 Association analysis pacemaker implantations, 13 648 cases of incident AF, 9184 Cox regression was used to assess the association of RBBB, CV deaths and 36 520 deaths from all causes. For number of IRBBB, LBBB and NIVCD with the hazard of incident HF, events per BBB subtype please see online supplementary table MI, pacemaker implantation, AF, CV death and all-cause 3.

Rasmussen PV, et al. Heart 2019;105:1160–1167. doi:10.1136/heartjnl-2018-314295 1161 Cardiac risk factors and prevention

Prevalence We found that the prevalence of RBBB, LBBB and NIVCD Heart: first published as 10.1136/heartjnl-2018-314295 on 25 May 2019. Downloaded from increased with age in both sexes. IRBBB and RBBB were much more prevalent in men than women, whereas LBBB was more prevalent in women (figure 1). on-specific 76 (65 - 84) 67 (6) N intraventricular conduction defect n=1071 (0.9) 463 (43) 187 (17) 742 (69) 101 (9) 139 (13) Association between BBB subtypes and CV outcomes We found IRBBB only to be associated with an increased hazard of pacemaker implantation in women (hazard ratio [HR] 2.89, 95% CI 1.71 to 4.90, p<0.001) (figure 2).

5 (1) We found that RBBB was associated with an increased hazard 53 (12) 29 (7) 47 (11) Incomplete right block bundle branch n=426 (0.4) 114 (27) 337 (79) of HF in both men (HR 1.28, 95% CI 1.13 to 1.44, p<0.001) and women (HR 1.42, 95% CI 1.22 to 1.66, p<0.001) and conferred a small increased hazard of CV death in men only (HR 1.22, 95% CI 1.07 to 1.39, p=0.005), all with reference to men and women, respectively, without RBBB. Additionally, RBBB ight bundle branch ight bundle branch 17 (1) R block n=1213(1.1) 112 (9) was associated with an increased hazard of pacemaker implantation in both sexes (figure 2). LBBB was associated with a markedly increased hazard of HF in both men (HR 3.96, 95% CI 3.30 to 4.76, p<0.001) and women (HR 2.51, 95% CI 2.15 to 2.94, p<0.001) and a modest 35 (5) 77 (11) 172 (14) eft bundle L branch block branch n=679 (0.6) 277 (41) 483 (40) 103 (15) 201 (17) 118 (17) 496 (73) 843 (70)

776 (57) association to CV death in men (HR 1.80, 95% CI 1.38 to 2.35,

114 p<0.001). Furthermore, we found that LBBB was associated

= with a small but statistically significant increased hazard of MI and pacemaker implantation in both sexes (figure 2). 60 (51 - 71) 76 (67–83) 77 (66 - 84) 65 (56 - 79) 88 (82–94) 144 (136–152) 134 (128–142) 114 (112–118)We 136 (128–146) found that NIVCD conferred increased hazards of HF in 397 (23) 815 (11) 988 (79) 573 (10)

5585 (5) 2698 (2) o conduction Women Women (%) n N defects n=111 387 (97.0) 25 11 87 11 both men (HR 2.36, 95% CI 2.11 to 2.64, p<0.001) and women (HR 2.79, 95% CI 2.46 to 3.17, p<0.001) as well as CV death for both men (HR 1.62, 95% CI 1.41 to 1.86) and women (HR 1.42, 95% CI 1.22 to 1.66, p<0.001) with reference to men and women, respectively, without NIVCD. Additionally, we found

65 (55–76) NIVCD to be modestly associated with increased hazards of MI on-specific 580 (29) 153 (8) 239 (12) 145 (7) 186 (9) intraventricular intraventricular conduction defect n=1979 (2.3) N 1539 (78) and strongly associated with pacemaker implantation for both

sexes (figure 2). http://heart.bmj.com/ We found no statistically significant associations between any BBB subtype and incident AF. Associations regarding all-cause mortality were generally in

23 (3) line with CV death but with attenuated effects (online supple- Incomplete right block bundle branch n=887 (1.0) mentary figure S1).

QRS duration in BBB on September 30, 2021 by guest. Protected copyright. In individuals with LBBB, increasing QRS duration was asso- 38 (2) 639 (28)241 (11) 150 (17) 44 (5) 358 (16) 62 (7) 282 (12) 82 (9) ight bundle

R block branch n=2297(2.6) ciated with a statistically significant increased hazard of HF in both sexes and with an increased hazard of pacemaker implantation in women and CV death in men. In individuals with RBBB, we found that increasing QRS duration conferred an increased hazard of pacemaker implantation in both men and eft bundle 111 (31) L block branch n=358 (0.4) 278 (78) 1672 (73) 761 (84) women (figure 3). Moreover, the 10-year absolute risk of HF 492 (43) increased almost linearly with QRS duration in the depicted age 87

= group (60–69 years) in both sexes with LBBB and comorbidity (figure 4). (%) n 57 (49–65) 71 (60–78) 69 (60–78) 57 (50–66) 96 (90–104) 155 (146–166) 142 (132–150) 114 (112–116) 128 (124–140) 273 (16) 853 (83)

5282 (6) 34 (9) 6515 (8) 47 (13) 7585 (9) 32 (9) o conduction Men N defects n=81 971 (93.6) 13 67 Risk prediction We calculated AUC values for the conventional risk models as well as differences in AUC when adding BBB subtypes to the

no (%) 4630 (6)model 69 (19) for all outcomes stratified by sex. We found that the AUC was significantly increased for the 10-year prediction of HF in both men (0.83%, 95% CI 0.51 to 1.16, p<0.001) and women (0.64%, 95% CI 0.40 to 0.87, p<0.001) as well as for pace- Baseline characteristics maker implantation in both men (2.48%, 95 % CI 1.45 to 3.51,

p<0.001) and women (2.44%, 95 % CI 1.40 to 3.48, p<0.001). > Hypertension Diabetes mellitus QRS duration median (IQR) Left ventricular hypertrophy, 0 points 1 point For AUC values for the conventional models, changes in AUC undle branch block subtype undle branch Age, years, median (IQR) years, Age, n (%) Medical history, B n (%) 2 points Table 1 Table

ECG variables Charlson Comorbidity Index for all outcomes, Brier scores, and calibrations plots please see

1162 Rasmussen PV, et al. Heart 2019;105:1160–1167. doi:10.1136/heartjnl-2018-314295 Cardiac risk factors and prevention Heart: first published as 10.1136/heartjnl-2018-314295 on 25 May 2019. Downloaded from

Figure 1 Prevalence of bundle branch block (BBB) subtypes by sex and age groups. IRBBB, incomplete right bundle branch block; LBBB, left bundle branch block; NIVCD, non-specific intraventricular conduction defect; RBBB, right bundle branch block. online supplementary figure S2, online supplementary table 4 generate hypothesis about causality, an association does not and online supplementary figure S3. For the full Cox models necessarily translate into clinically meaningful risk prediction used for risk prediction, please see online supplementary table for the individual patient.23 Accordingly, we first tested whether 5. Estimated absolute 10-year risks for pacemaker implanta- adding BBB subtypes to a conventional CV risk model improved tion and HF stratified by age group, sex and comorbidity are risk prediction of selected CV events and found a significant provided in figure 5. improvement in AUC for HF and pacemaker implantation. In our setting, AUC corresponds to the probability that a person http://heart.bmj.com/ Sensitivity analysis who experiences an event of interest within 10 years of follow-up We performed 1-year landmark analyses for the outcome HF receives a higher predicted risk than a person who is alive and and found that the associations were only slightly attenuated does not experience the event.24 For the outcomes pacemaker compared with the main analyses (online supplementary table implantation and HF where we found improvements in AUC, 6). we went further and estimated absolute risks of having various BBB subtypes (figure 5).

Discussion We found that both LBBB and NIVCD conferred very high on September 30, 2021 by guest. Protected copyright. In a large contemporary population of primary care patients free 10-year risks of HF in both sexes. For example, we predicted of major CV disease, we found (1) associations between several a 65-year-old male with one or more comorbidity (eg, hyper- BBB subtypes and CV death, HF, MI and pacemaker implan- tension) and LBBB to have a 32% 10-year risk of HF compared tation. (2) That increasing QRS duration was associated with with only 10% if he had no BBB. Based on our findings, we an increased risk of incident HF in both men and women with suggest that primary care patients with LBBB or NIVCD, not LBBB and pacemaker implantation in men with LBBB as well as already treated for or diagnosed with HF, should be referred for in men and women with RBBB. (3) That adding BBB subtypes to further CV evaluation and echocardiography because these BBB a conventional CV risk model improved 10-year risk prediction subtypes are likely to represent either an yet unrecognised failing of HF and pacemaker implantation. (4) And finally, several BBB heart or an individual at a very high risk of a future HF event. subtypes conferred clinically relevant differences in absolute In men and women with RBBB, we found each unit increase risks of HF and pacemaker implantation. in QRS duration associated with an increasing hazard of pace- We found relatively strong associations between LBBB, maker implantation. These findings suggest that the broader the NIVCD and incident HF as well as strong associations between RBBB QRS-complex is, the more likely it is that other parts of RBBB, LBBB, NIVCD and pacemaker implantation in both men the conduction system are affected. For LBBB, we observed that and women. We also found modest associations between LBBB, increasing QRS duration was associated with increased risks of NIVCD and MI in both men and women, between RBBB and incident HF in both sexes. In patients with mild HF, both LBBB HF in both men and women and between RBBB, LBBB, NIVCD as well as prolonged QRS duration have been associated with and CV death in men as well as NIVCD and CV death in women. a poorer prognosis and decline in left ventricular ejection frac- These findings are consistent with previous studies of BBB in the tion (LVEF).25 26 Furthermore, in patients with LBBB, an inverse general population.3 4 19–22 relationship between QRS duration and LVEF has been demon- While an association between a biomarker of interest and strated.27 Thus, both the electromechanical dyssynchrony in the an outcome on a population level can help inform biology or LBBB pattern as well as the magnitude of QRS duration seem

Rasmussen PV, et al. Heart 2019;105:1160–1167. doi:10.1136/heartjnl-2018-314295 1163 Cardiac risk factors and prevention Heart: first published as 10.1136/heartjnl-2018-314295 on 25 May 2019. Downloaded from http://heart.bmj.com/ on September 30, 2021 by guest. Protected copyright.

Figure 2 Forest plots depicting multivariable-adjusted hazard ratios (HR) by bundle branch block (BBB) and sex (A, men. B, women) for the following outcomes: incident heart failure, myocardial infarction, pacemaker implantation, atrial fibrillation and cardiovascular (CV) death using individuals without the BBB in question as reference. IRBBB, incomplete right bundle branch block; LBBB, left bundle branch block; RBBB, right bundle branch block; NIVCD, non-specific intraventricular conduction defect.

1164 Rasmussen PV, et al. Heart 2019;105:1160–1167. doi:10.1136/heartjnl-2018-314295 Cardiac risk factors and prevention Heart: first published as 10.1136/heartjnl-2018-314295 on 25 May 2019. Downloaded from

Figure 3 Forest plots depicting hazard ratios per 10 ms increase in QRS duration in individuals(A, men. B, women) with bundle branch blocks. LBBB, left bundle branch block; RBBB, right bundle branch block. to contribute to the ‘cardiac stress’ resulting in deterioration of clinical setting. The validity of many diagnoses in the registers the LVEF. is unknown but our definitions of HF, MI, AF, hypertension, The newest recommendations do not advise routine ECG and the diagnoses used in the Charlson Comorbidity Index screening as a tool for risk stratification in asymptomatic indi- have previously been validated with high positive predictive http://heart.bmj.com/ 28 viduals. However, even though we do not have access to the values.9 29 30 We did not have data on indication of why the clinical indications for ECG recording, our data indicate that ECG recording was performed but landmark analysis along with the ECG could be of value in identifying primary care patients graphical evaluations of the proportional hazard assumptions with high risk of HF and pacemaker implantation. We provide indicated that the associations we observed were not driven by a risk chart (figure 5) that can serve as an instrument for risk prediction. accumulation of events instantly after the ECG recording. This would have been expected if most patients were referred for on September 30, 2021 by guest. Protected copyright. Limitations ECG recording as a result of significant symptoms. The occur- Different electrocardiographic definitions of BBB subtypes exist rence of AF in our study might be an underestimation due to making study comparisons difficult; we chose to rely as closely the often paroxysmal nature of the arrhythmia. Patients could as possible on the most recently available AHA guideline, which potentially have a sinus rhythm ECG recorded at study inclusion is somewhat restrictive.10 As such, certain types of NIVCD in and already be suffering from yet undiagnosed AF or patients our study would likely be interpreted as LBBB or RBBB in a with incident AF never treated at a hospital could be overlooked.

Figure 4 Example of absolute 10-year risk of heart failure (HF) depicted by QRS duration in both men and women in the 60–69 years age category, with left bundle branch block (LBBB) and with comorbidity.

Rasmussen PV, et al. Heart 2019;105:1160–1167. doi:10.1136/heartjnl-2018-314295 1165 Cardiac risk factors and prevention Heart: first published as 10.1136/heartjnl-2018-314295 on 25 May 2019. Downloaded from

Figure 5 Risk chart depicting 10-year absolute risks of HF and pacemaker implantation by age group, sex and block type. Risk estimates are stratified by the presence of comorbidity at time of ECG recording. BBB, bundle branch block; IRBBB, incomplete right bundle branch block; RBBB, right bundle branch block; LBBB, left bundle branch block; NIVCD, non-specific intraventricular conduction defect.

Conclusion 3Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Using a large primary care population, consisting of more than Copenhagen, Denmark 4Copenhagen General Practitioners’ Laboratory, Copenhagen, Denmark 200 000 individuals without major CV disease, we found that 5Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, RBBB and NIVCD were much more prevalent in men than Denmark women and that LBBB was marginally more prevalent in women 6Department of Health Science and Technology, University of Aalborg, Aalborg, Denmark than men. We found significant associations between RBBB, 7 LBBB, NIVCD and the hazard of incident HF, MI as well as Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen pacemaker implantation. Absolute risk predictions of HF and 8

Department of Biomedical Sciences, University of Copenhagen, Copenhagen, http://heart.bmj.com/ pacemaker implantation revealed clinically relevant differences Denmark between having various BBB subtypes versus no BBB. 9Novo Nordisk A/S, Denmark 10Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA Key messages 11Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark What is already known on this subject? ►► Incidental discoveries of electrocardiographic bundle branch Contributors Study concept and design were determined by: PVR, JBN, MWS,

block (BBB) are frequent in primary care patients but the AGH. Acquisition of data was performed by: CG, AHP, JBN. Digital ECG analysis was on September 30, 2021 by guest. Protected copyright. prognostic implications in a primary care population free of performed by: PVR,JBN, CG, JM. Drafting of the manuscript was carried out by: PVR, MWS, JBN. Critical revision of the manuscript for important intellectual content was major cardiovascular (CV) disease remain unclear. carried out by: JBN, MWS, JG, CG, AHP, MSO, SH, JHS, LK, JM, SH, CT-P, LK, AGH. Statistical analysis and data interpretation were performed by: PVR, MWS, JBN, JG. What might this study add? Fund raising was performed by: JBN, CG, SH, AGH. ►► We provide age-specific and sex-specific absolute risks of Funding This study was supported by The Research Committee of Rigshospitalet pacemaker implantation and heart failure (HF) for various and The John and Birthe Meyer Foundation. JBN was supported by the Danish Heart BBB subtypes. Both left bundle branch block (LBBB) and Foundation (16-R107-A6779), the Lundbeck Foundation (R220-2016-1434), the AP Møller Foundation for the Advancement of Medical Science and Fondsbørsvekselerer non-specific intraventricular conduction defect (NIVCD) are Henry Hansen og Hustru Karla Hansen Født Vestergaards Legat. associated with very high 10-year risks of HF in both sexes. Furthermore, in people with BBB, increasing QRS duration Competing interests AGH is an employee of Novo Nordisk A/S. confers increased risk of HF. Patient consent for publication Not required. Ethics approval Due to no active participation from study subjects, no approval How might this impact on clinical practice? from an ethics committee was required according to Danish law. The use of register data was approved by the Danish Data Protection Agency. ►► CV healthy middle-aged and elderly primary care patients with an incidental discovery of LBBB or NIVCD are at very Provenance and peer review Not commissioned; externally peer reviewed. high risk of HF and might benefit from referral for further CV Data sharing statement There are no unpublished data from the study. evaluation and echocardiography. References 1 abdel-Qadir HM, Tu JV, Austin PC, et al. Bundle branch block patterns and long-term Author affiliations outcomes in heart failure. Int J Cardiol 2011;146:213–8. 1Department of Cardiology, Herlev-Gentofte Hospital, Hellerup, Denmark 2 Zimetbaum PJ, Buxton AE, Batsford W, et al. Electrocardiographic predictors of 2Laboratory for Molecular Cardiology, University Hospital Copenhagen, arrhythmic death and total mortality in the multicenter unsustained tachycardia trial. Rigshospitalet, Copenhagen, Denmark Circulation 2004;110:766–9.

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