QRS duration is associated with all-cause mortality in type 2 diabetes: The diabetes heart study

Journal Pre-proof QRS duration is associated with all-cause mortality in type 2 diabetes: The diabetes heart study

Matthew J. Singleton, Charles German, Krupal J. Hari, Georgia Saylor, David M. Herrington, Elsayed Z. Soliman, Barry I. Freedman, Donald W. Bowden, Prashant D. Bhave, Joseph Yeboah PII:

S0022-0736(19)30739-3

DOI:

https://doi.org/10.1016/j.jelectrocard.2019.11.053

Reference:

YJELC 52975

To appear in:

Journal of Electrocardiology

Please cite this article as: M.J. Singleton, C. German, K.J. Hari, et al., QRS duration is associated with all-cause mortality in type 2 diabetes: The diabetes heart study, Journal of Electrocardiology(2019), https://doi.org/10.1016/j.jelectrocard.2019.11.053

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© 2019 Published by Elsevier.

Journal Pre-proof QRS Duration Is Associated with All-Cause Mortality in Type 2 Diabetes: The Diabetes Heart Study Short title: QRS Duration Mortality Diabetes Heart Study

Matthew J. Singleton1 MD, MBE, MSc; Charles German2 MD; Krupal J. Hari3 MD; Georgia Saylor4 BS; David M. Herrington5 MD, MS; Elsayed Z. Soliman6 MD, MSc, MS; Barry I.

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Freedman7 MD; Donald W. Bowden8 PhD; Prashant D. Bhave9 MD; Joseph Yeboah10 MD, MSc

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1. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected]

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2. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected]

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3. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected]

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4. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected] 5. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected] 6. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected] 7. Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected] 8.

Center for Genomics and Personalized Medicine Research, Wake Forest School of

Journal Pre-proof Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected] 9. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected] 10. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, North Carolina. 1 Medical Center Blvd, Winston-Salem, North Carolina, 27157, United States of America. [email protected]

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Corresponding author: Matthew J. Singleton MD, MBE, MSc 1 Medical Center Blvd. Winston-Salem, NC 27157 Tel: 443.904.0083 Fax: 336.716.9188 E-mail: [email protected]

The authors declare that they have no relevant conflicts of interest to disclose.

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Abstract word count: 246 Manuscript word count: 2,189 Number of Tables or Figures: 4 (plus one online-only)

KEYWORDS: QRS duration, diabetes, all-cause mortality, risk

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Journal Pre-proof STRUCTURED ABSTRACT Background: QRS-duration predicts mortality in patients with heart failure and, to a lesser extent, the general population. However, in patients with diabetes, its prognostic significance is unknown. To better understand how QRS-duration relates to mortality among those with diabetes, we explored survival as a function of QRS-duration in the Diabetes Heart Study.

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Methods: The study population included 1,335 participants. Cox proportional hazards modeling

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was used to evaluate the relationship between QRS-duration and all-cause mortality, comparing

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those with QRS-duration ≤120 vs. >120 (ms). Multivariable models adjusted for age, sex, race,

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hypertension, smoking, years with diabetes, BMI, systolic blood pressure, cholesterol,

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triglycerides, glomerular filtration rate, and hemoglobin A1c.

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Results and Conclusions: Participants were: mean age 61 ± 9, 55% women, 83% white; 99 participants (7.5%) had a QRS-duration >120. After 11,000 person-years of follow-up (median

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8.5 years; maximum 13.9 years), 266 participants had died (20%). Participants with baseline

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QRS-duration >120 had an adjusted hazard ratio for all-cause mortality of 1.56 (95% CI 1.05 – 2.24; p = 0.027). Modeling QRS-duration as a continuous variable, we found an 11% increase in all-cause mortality for each 10 ms increase in QRS-duration. In conclusion, QRS-duration is associated with subsequent all-cause mortality among those with type 2 diabetes—participants with QRS-duration > 120 ms had a 56% increase in all-cause mortality, even after adjustment for conventional risk factors. Given the ubiquitous presence of ECG data in the medical record, QRS-duration may prove to be a useful prognostic measure, especially among those with diabetes.

Journal Pre-proof INTRODUCTION QRS duration is the product of a complex interplay between ventricular geometry,[1, 2] cellular expression of genes coding ion channels,[3, 4] electrolyte concentrations,[5] and membrane-active drugs.[6] Despite the myriad determinants of QRS duration, there is mounting evidence that QRS duration can predict clinically-meaningful outcomes.[7] Several studies have demonstrated that QRS duration can predict mortality in patients with depressed left ventricular

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ejection fraction and implanted cardioverter-defibrillators, including MADIT-II[8] and several

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single-center studies.[9, 10] Similarly, QRS duration is associated with increased mortality in

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patients admitted with acutely-decompensated heart failure[11] and patients with chronic heart

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failure with reduced ejection fraction.[12] Among the community-dwelling general population, QRS duration was shown to correlate with mortality in a prior analysis of NHANES-III.[13]

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However, the prognostic significance of QRS duration in patients with diabetes is unknown. In

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light of the mounting evidence that many patients with diabetes have a subclinical cardiomyopathy[14] and the observation that the presence of cardiomyopathy appears to act as

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an effect-modifier of the relationship between QRS duration and all-cause mortality[8-13, 15],

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understanding how all-cause mortality varies by QRS duration among patients with diabetes is an area of clinical and epidemiological importance. To better understand how QRS duration relates to all-cause mortality among those with diabetes, we explored survival as a function of QRS duration in participants in the Diabetes Heart Study (DHS).[16]

MATERIALS AND METHODS This is a retrospective analysis of prospectively-collected data from the DHS. The design and conduct of the DHS have been described previously.[16, 17] Briefly, 1,443 participants

Journal Pre-proof from 564 families with at least two siblings afflicted with type 2 diabetes were included. Racial breakdown included Caucasians (84.6%) and African-Americans (15.4%). Participants were community-dwelling members of central North Carolina who received their care from Wake Forest University Baptist Health. They were recruited via mailed invitations to participate; eligibility was determined via structured telephone interview and enrollment was completed at the study center. All participants provided written informed consent and the study design and

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protocols were approved by the Wake Forest School of Medicine Institutional Review Board.

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The study protocol conforms to the ethical guidelines ofg the 1975 Declaration of Helsinki as

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reflected in a priori approval by the institution’s human research committee. In contrast to other

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prospective cohorts, participants with pre-existing cardiovascular disease were not excluded. As the only exclusion criteria was screening creatinine greater than 2.0 mg/dL, the study population

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is a representative sample of community-dwelling adults from families with diabetes-enriched

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family pedigrees.

Study visits included structured interviews by trained medical staff, measurements of

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vital signs and anthropometrics, 12-lead electrocardiography (ECG), and collection of fasting

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blood and urine for laboratory analyses. All study visits were conducted in the General Clinical Research Center of Wake Forest University School of Medicine. Anthropometric assessment included weight, height, and waist circumference. Laboratory assays included total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, fasting blood glucose, creatinine, and hemoglobin A1c. Estimates of glomerular filtration (eGFR) were made based on the Modification of Diet in Renal Disease equation.[18] Type 2 diabetes was defined as physiciandiagnosed diabetes with onset after age 34, no history of ketoacidosis, and no use of subcutaneous or intravenous antihyperglycemic medications for more than one year after initial

Journal Pre-proof diagnosis. Hypertension was defined by either use of antihypertensive medications or mean systolic or diastolic blood pressures above 140 mmHg and 90 mmHg, respectively. Baseline cardiovascular disease was defined by a self-reported history of any of the following: heart attack, coronary artery bypass graft, coronary angioplasty, stroke, or carotid endarterectomy. Study ECGs were obtained by trained electrocardiographers via standardized protocol on a GE Marquette (Milwaukee, WI) MAC 5000 electrocardiograph at a sampling rate of 500 Hz.

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All ECGs were digitally-transmitted to a central core laboratory for processing and coding—the

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Epidemiological Cardiology Research Center (EPICARE) at Wake Forest School of Medicine.

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Study ECGs were visually checked for quality and then automatically processed using the GE

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Marquette 12-SL program. The QRS duration was derived from automated measurements and visually confirmed by trained ECG coders at EPICARE—specifically, the QRS duration was

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defined as the interval from the earliest detection of depolarization in any lead to the latest

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detection of depolarization in any lead.[19] This process starts with filtering via signal conditioning, then signal averaging, and finally with generation of a representative QRS complex

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of the median/signal-averaged beat,[20] from which QRS onset and offset are identified. For the

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purposes of this analysis, participants with baseline ECG of inadequate quality for interpretation of QRS duration or paced QRS complexes were excluded, leaving 1,335 eligible participants. Death was ascertained via queries of the US Social Security Administration’s National Social Security Death Index, with duration of follow-up being defined by the time elapsed between study enrollment and date of confirmed death. Cause of death was determined from manual review of medical records and death certificates, which were obtained from the local vital records offices. Etiologies were categorized as cardiovascular (myocardial infarction, congestive heart failure, sudden cardiac death, arrhythmia, stroke, or peripheral vascular

Journal Pre-proof disease), renal (end-stage renal disease), cancer-related, infectious, accidental, or other, which included chronic obstructive pulmonary disease, pulmonary fibrosis, liver failure, and Alzheimer dementia). For participants still alive at the end of the study, censoring occurred on December 31st, 2011. Statistical analyses were used to calculate mean ± standard deviation for continuous variables and frequency (percentage) for categorical variables. Unadjusted comparisons used

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analysis of variance for continuous variables and Chi-square tests for categorical variables.

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Two-sided p-values below 0.05 were considered to be statistically significant. Cox proportional

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hazards modeling was used to explore differences in all-cause mortality, comparing those with

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baseline QRS duration ≤ 120 ms vs. > 120 ms. Initial analysis was unadjusted, with subsequent analyses iteratively adjusting for demographics (model 1; adjusted for age, sex, and race), then

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historical and modifiable factors (model 2; adjusted for the covariates in model 1, plus prior

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cardiovascular disease, hypertension, smoking, years since diagnosis of diabetes, BMI, and systolic blood pressure), then biochemical measures (model 3; adjusted for the covariates in

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model 2, plus cholesterol, triglycerides, eGFR, and HbA1c). Time-independent proportionality

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assumptions were tested by plotting Martingale residuals and verifying minimal departures from linearity. As a sensitivity analysis, we also modeled QRS duration as a continuous variable. In addition, we stratified participants with QRS duration > 120 ms based on QRS morphology (LBBB, RBBB, or IVCD; left bundle branch block, right bundle branch block, and intraventricular conduction delay) to determine if QRS morphology acted as an effect modifier on the observed relationships. All statistical analyses were conducted at Wake Forest University School of Medicine using JMP Pro version 16 (Cary, NC) and SAS version 9.4 (Cary, NC).

Journal Pre-proof RESULTS The study population included 1,335 participants with type 2 diabetes. Baseline characteristics are detailed in TABLE 1 (mean age 61.4 years, 55% women, 83% white). Of the total population, 7.5% (n = 99) had a baseline QRS duration greater than 120 ms. Participants with baseline QRS duration > 120 ms were older, had more years since diagnosis of diabetes, and had worse renal function.

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After 11,000 person-years of follow-up (median 8.5 years; maximum 13.9 years), 266

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participants (20%) had died. Incidence rates for death for QRS duration less than 120 ms and

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QRS duration greater than 120 ms were 22.2 and 52.5 per 1,000 person-years of follow-up,

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respectively, yielding an incidence rate ratio of 2.36. Similarly, 114 participants (8.5%) had died of a cardiovascular cause, giving incidence rates for cardiovascular death of 9.6 and 22.1 per

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1,000 person-years of follow-up when stratified by QRS duration, with an incidence rate ratio of

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2.31. After adjustment for age, sex, race, hypertension, smoking, years since diagnosis of diabetes, BMI, systolic blood pressure, cholesterol, triglycerides, eGFR, and HbA1c, participants

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with a baseline QRS duration > 120 ms had an adjusted hazard ratio for all-cause mortality of

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1.56 (95% CI 1.05 – 2.24; p = 0.027) (TABLE 2) and an adjusted hazard ratio for cardiovascular mortality of 1.51 (95% CI 0.84 – 2.56; p = 0.1637) (TABLE 3). Of our participants with QRS duration > 120 ms, 19% had LBBB, 51% had RBBB, and 30% had IVCD. Stratification by QRS morphology did not produce a statistically-significant result, as inclusion of a term in the model for QRS morphology yielded covariate-adjusted hazard ratios of 1.70 (0.71–3.47), 1.62 (0.92–2.64), and 1.33 (0.65–2.43) for LBBB, RBBB, and IVCD, respectively, with QRS ≤ 120 ms as the reference (TABLE 4 in online-only supplement). The beta-coefficient for QRS duration modeled as a continuous variable was

Journal Pre-proof 0.01007 (95% CI 0.00295 – 0.00428; p < 0.0001), such that each 10 ms increase in QRS duration is associated with an 11% increase in all-cause mortality. When plotting Kaplan-Meier survival stratified by baseline QRS duration, the curves diverged early, with higher mortality in the longer-duration QRS group (FIGURE 1).

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DISCUSSION

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In this study of largely white community-dwelling American adults with type 2 diabetes,

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we found that QRS duration was independently predictive of all-cause mortality and exhibited a

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dose-response relationship, with a 1% increase in risk of death for each 1-ms increase in QRS duration. This suggests that this ubiquitously-measured electrocardiographic parameter may

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have utility in risk-prediction models, which is of particular importance in this patient population

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with a heterogenous risk distribution. This finding is additive upon the prior measures of mortality risk elucidated from the DHS cohort, including QTc,[21] C-reactive protein,[22]

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coronary artery calcium,[23] and multi-bed vascular calcium.[24]

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It is well-established that QRS duration is predictive of all-cause mortality among populations with a history of cardiovascular disease.[8-12] The influence of longer-duration QRS among patients without prevalent cardiovascular disease is less clear. While some prior research has demonstrated the additive risk conferred by a longer-duration QRS in an unselected cross-sectional US sample,[13, 25, 26] other works have found no relationship[27] or a relationship that is highly dependent upon QRS morphology as well.[25, 28] In addition, whether any relationship between QRS duration and risk of mortality held true for those with diabetes remained unstudied.

Journal Pre-proof Here, we report that, not only is the relationship between QRS-duration and risk of mortality conserved in those with diabetes, but the magnitude of association is greater. Unadjusted incidence rates for all-cause mortality were more than doubled among those with QRS duration above 120 ms. Even after adjustment for known risk factors, a QRS duration above 120 ms still conferred a 56% increase in all-cause mortality. By comparison, prior studies of the general population have found that a QRS duration in the top quartile (>106 ms) only

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confers a hazard ratio of cardiovascular death of 1.29, with the reference group being those with

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a QRS duration in the bottom quartile (61 – 89 ms).[13] This suggestion of QRS duration being

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more predictive of all-cause mortality in those with diabetes than in the general population is

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consistent with prior literature, which has demonstrated that the risk of death attributable to QRS duration is much greater in patients with heart failure than unselected community-dwelling

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adults—in this population, longer-duration QRS is associated with hazard ratios for

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cardiovascular death and all-cause mortality between 1.40 and 2.0.[12, 15, 29, 30] The pathophysiologic processes connecting longer-duration QRS to increased all-cause

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mortality are not yet fully elucidated. Probable contributors include increased risk of ventricular

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tachyarrhythmias from regions of slow conduction,[31, 32] genetic arrhythmia syndromes,[3335] and preclinical coronary artery disease.[36-38] In a population of those with diabetes such as this, nascent coronary artery disease likely accounts for the bulk of the risk. Finally, we explored how QRS morphology mediates the relationship between QRS duration and risk of adverse events, finding progressively higher risk in participants with QRS duration ≤ 120 ms, IVCD, RBBB, and LBBB, though confidence intervals were broad and included 1.0. Our results are in accordance with the preponderance of prior studies suggesting that LBBB has a worse prognosis than RBBB and IVCD,[25, 28, 39, 40] but the lack of

Journal Pre-proof statistical significance is likely the product of the insufficient sample size to explore morphology-mediated differences in risk. Several limitations should be considered. First, we cannot infer causation from the demonstrated relationship, as both longer-duration QRS and death could be downstream sequelae of a common pathology. Second, as we only collected 12-lead ECG at baseline, these data do not capture changes in QRS duration over time, which could influence the findings. Third, this

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is an observational study and thus may be subject to bias from residual confounding. Fourth, this

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population consisted largely of Caucasian individuals—thus, generalizing the results to other

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racial groups should be done with caution. Finally, though QRS duration was associated with

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subsequent all-cause mortality, the improvement in c-statistic did not meet statistical significance. Strengths of our study include the long duration of follow-up, formal adjudication

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of outcomes, and highly representative sample of real-world patients with diabetes, owing to

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almost no exclusion criteria in the DHS.

In conclusion, we report that QRS duration is associated with all-cause mortality among

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those with diabetes, with a clear dose-response relationship and potential additive value beyond

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that of presently-used risk prediction models. Future studies should explore how presently-used risk prediction models may better risk-stratify those with diabetes by including QRS duration as a predictor variable, allowing for more precise risk estimation and targeting surveillance and therapeutics to the population at highest risk.

Journal Pre-proof ACKOWLEDGEMENTS The authors have no relevant conflicts of interest to disclose. Matthew J. Singleton takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

All authors provided final approval of the version to be published and agree to be accountable for

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of the work are appropriately investigated and resolved.

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all aspects of the work in ensuring that questions related to the accuracy or integrity of any part

Author contributions:

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drafted and revised the manuscript

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MJS – Conceived and designed the analysis; performed the analysis; interpreted the results;

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CG – Contributed substantially to the interpretation of data for the work; revised the manuscript critically for important intellectual content

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KH – Contributed substantially to the interpretation of data for the work; revised the manuscript

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critically for important intellectual content GS – Contributed data or analysis tools; contributed substantially to the interpretation of data for the work; revised the manuscript critically for important intellectual content DH – Contributed data or analysis tools; contributed substantially to the interpretation of data for the work; revised the manuscript critically for important intellectual content ES – Contributed data or analysis tools; contributed substantially to the interpretation of data for the work; revised the manuscript critically for important intellectual content

Journal Pre-proof BF – Collected the data; contributed substantially to the interpretation of data for the work; revised the manuscript critically for important intellectual content DB – Collected the data; contributed substantially to the interpretation of data for the work; revised the manuscript critically for important intellectual content PB – Contributed substantially to the interpretation of data for the work; revised the manuscript critically for important intellectual content

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JY – Contributed data or analysis tools; contributed substantially to the interpretation of data for

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the work; revised the manuscript critically for important intellectual content

Journal Pre-proof REFERENCES

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associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure, Am Heart J 143(3) (2002) 398-405. [31] G. Breithardt, M. Borggrefe, A. Martinez-Rubio, T. Budde, Pathophysiological mechanisms of ventricular tachyarrhythmias, Eur Heart J 10 Suppl E (1989) 9-18. [32] P. Debonnaire, S. Katsanos, E. Joyce, V.D.B. OV, D.E. Atsma, M.J. Schalij, J.J. Bax, V. Delgado, N.A. Marsan, QRS Fragmentation and QTc Duration Relate to Malignant Ventricular Tachyarrhythmias and Sudden Cardiac Death in Patients with Hypertrophic Cardiomyopathy, Journal of cardiovascular electrophysiology 26(5) (2015) 547-55. [33] N. Sotoodehnia, A. Isaacs, P.I. de Bakker, M. Dorr, C. Newton-Cheh, I.M. Nolte, P. van der Harst, M. Muller, M. Eijgelsheim, A. Alonso, A.A. Hicks, S. Padmanabhan, C. Hayward, A.V. Smith, O. Polasek, S. Giovannone, J. Fu, J.W. Magnani, K.D. Marciante, A. Pfeufer, S.A. Gharib, A. Teumer, M. Li, J.C. Bis, F. Rivadeneira, T. Aspelund, A. Kottgen, T. Johnson, K. Rice, M.P. Sie, Y.A. Wang, N. Klopp, C. Fuchsberger, S.H. Wild, I. Mateo Leach, K. Estrada, U. Volker, A.F. Wright, F.W. Asselbergs, J. Qu, A. Chakravarti, M.F. Sinner, J.A. Kors, A. Petersmann, T.B. Harris, E.Z. Soliman, P.B. Munroe, B.M. Psaty, B.A. Oostra, L.A. Cupples, S. Perz, R.A. de Boer, A.G. Uitterlinden, H. Volzke, T.D. Spector, F.Y. Liu, E. Boerwinkle, A.F. Dominiczak, J.I. Rotter, G. van Herpen, D. Levy, H.E. Wichmann, W.H. van Gilst, J.C. Witteman, H.K. Kroemer, W.H. Kao, S.R. Heckbert, T. Meitinger, A. Hofman, H. Campbell, A.R. Folsom, D.J. van Veldhuisen, C. Schwienbacher, C.J. O'Donnell, C.B. Volpato, M.J. Caulfield, J.M. Connell, L. Launer, X. Lu, L. Franke, R.S. Fehrmann, G. te Meerman, H.J. Groen, R.K. Weersma, L.H. van den Berg, C. Wijmenga, R.A. Ophoff, G. Navis, I. Rudan, H. Snieder, J.F. Wilson, P.P. Pramstaller, D.S. Siscovick, T.J. Wang, V. Gudnason, C.M. van Duijn, S.B. Felix, G.I. Fishman, Y. Jamshidi, B.H. Stricker, N.J. Samani, S. Kaab, D.E. Arking, Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction, Nature genetics 42(12) (2010) 1068-76. [34] K. Ohkubo, I. Watanabe, Y. Okumura, S. Ashino, M. Kofune, K. Nagashima, T. Kofune, T. Nakai, S. Kunimoto, Y. Kasamaki, A. Hirayama, Prolonged QRS duration in lead V2 and risk of life-threatening ventricular Arrhythmia in patients with Brugada syndrome, Int Heart J 52(2) (2011) 98-102. [35] R.W. Sy, M.H. Gollob, G.J. Klein, R. Yee, A.C. Skanes, L.J. Gula, P. Leong-Sit, R.M. Gow, M.S. Green, D.H. Birnie, A.D. Krahn, Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic ventricular tachycardia, Heart Rhythm 8(6) (2011) 864-71. [36] M.K. Das, B. Khan, S. Jacob, A. Kumar, J. Mahenthiran, Significance of a fragmented QRS complex versus a Q wave in patients with coronary artery disease, Circulation 113(21) (2006) 2495-501. [37] W. Zareba, A.J. Moss, S. le Cessie, Dispersion of ventricular repolarization and arrhythmic cardiac death in coronary artery disease, Am J Cardiol 74(6) (1994) 550-3. [38] A. Michaelides, J.M. Ryan, D. VanFossen, R. Pozderac, H. Boudoulas, Exercise-induced QRS prolongation in patients with coronary artery disease: a marker of myocardial ischemia, Am Heart J 126(6) (1993) 1320-5. [39] C. Lewinter, C. Torp-Pedersen, J.G. Cleland, L. Kober, Right and left bundle branch block as predictors of long-term mortality following myocardial infarction, Eur J Heart Fail 13(12) (2011) 1349-54. [40] R. Dhingra, M.J. Pencina, T.J. Wang, B.H. Nam, E.J. Benjamin, D. Levy, M.G. Larson, W.B. Kannel, R.B. D'Agostino, Sr., R.S. Vasan, Electrocardiographic QRS duration and the risk of congestive heart failure: the Framingham Heart Study, Hypertension 47(5) (2006) 861-7.

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Table 1 – Baseline Characteristics of DHS Participants Stratified by QRS Duration QRS > 120 ms n = 99 (7.5%)

p-value*

Age (years)

61.1 ± 9.2

66.7 ± 9.1

< 0.0001

Sex (% male)

42.7

65.7

< 0.0001

Race (% black)

15.6

10.1

0.1415

Prior Cardiovascular Disease (%)

29.2

53.1

< 0.0001

Hypertension (%)

84.5

89.9

0.1519

40.6 41.0 18.4

Years With Diabetes

10.2 ± 7.0

13.1 ± 8.8

0.0032

BMI (kg/m2)

32.1 ± 6.6

31.7 ± 6.8

0.6093

Systolic BP (mmHg)

139.3 ± 19.2

140.1 ± 21.2

0.6931

73.5 ± 10.4

72.0 ± 10.5

0.1171

184.3 ± 47.0

174.0 ± 47.4

0.0400

43.6 ± 14.0

42.9 ± 15.5

0.6729

103.9 ± 36.1

97.9 ± 35.2

0.1149

185.5 ± 122.8

175.1 ± 126.7

0.6729

Glucose (mg/dL)

141.1 ± 59.1

135.9 ± 52.1

0.3416

Estimated GFR (mL/min)

68.2 ± 20.3

63.8 ± 20.7

0.0428

Hemoglobin A1c (%)

7.38 ± 1.90

7.63 ± 1.90

0.2089

QRS Duration (ms)

90 ± 10

144 ± 15

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Total Cholesterol (mg/dL)

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HDL (mg/dL) LDL (mg/dL)

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QRS ≤ 120 ms n = 1,236 (92.5%)

Characteristic

0.1115

43.4 46.5 10.1

Continuous variables described as mean ± standard deviation. Categorical variables described as frequency (percentage). * p-value as calculated by ANOVA for continuous and χ2 for categorical variables.

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Table 2 – Hazard Ratios for All-Cause Mortality by QRS Duration QRS > 120 ms n = 99 (7.5%)

p-value

Unadjusted Hazard Ratio

1.0 (reference)

2.47 (1.72 – 3.43)

< 0.0001

Model 1

1.0 (reference)

1.77 (1.23 – 2.48)

0.0029

Model 2

1.0 (reference)

1.65 (1.12 – 2.38

0.012

Model 3

1.0 (reference)

1.56 (1.05 – 2.24)

0.027

of

QRS ≤ 120 ms n = 1,236 (92.5%)

.

1.11 (1.04 – 1.17)

ro

Hazard Ratio for Death per 10-ms Increase in QRS Duration

< 0.0001

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Model 1 adjusts for age, sex, and race. Model 2 adjusts for the covariates in Model 1, plus prior cardiovascular disease (heart attack, coronary artery bypass graft, coronary angioplasty, stroke, or carotid endarterectomy), hypertension, smoking, years with diabetes, BMI, and systolic blood pressure. Model 3 adjusts for the covariates in Model 2, plus cholesterol, triglycerides, eGFR, and HbA1c. Continuous analysis of risk of death per 10-ms increase in QRS duration used Model 3.

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Table 3 – Hazard Ratios for Cardiovascular Mortality by QRS Duration QRS > 120 ms n = 99 (7.5%)

pvalue

Unadjusted Hazard Ratio

1.0 (reference)

2.24 (1.37 – 3.98)

0.0011

Model 1

1.0 (reference)

1.76 (0.99 – 2.94)

0.0541

Model 2

1.0 (reference)

1.74 (0.97 – 2.95)

0.0618

Model 3

1.0 (reference)

1.50 (0.84 – 2.56)

0.1637

of

QRS ≤ 120 ms n = 1,236 (92.5%)

.

1.15 (1.06 – 1.25)

ro

Hazard Ratio for Cardiovascular Death per 10-ms Increase in QRS Duration

0.0013

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Model 1 adjusts for age, sex, and race. Model 2 adjusts for the covariates in Model 1, plus prior cardiovascular disease (heart attack, coronary artery bypass graft, coronary angioplasty, stroke, or carotid endarterectomy), hypertension, smoking, years with diabetes, BMI, and systolic blood pressure. Model 3 adjusts for the covariates in Model 2, plus cholesterol, triglycerides, eGFR, and HbA1c. Continuous analysis of risk of death per 10-ms increase in QRS duration used Model 3.

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Figure 1 – Kaplan-Meier Survival Stratified by QRS Duration

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Kaplan-Meier survival analyses was performed to compare the unadjusted mortality risk as a function of QRS width.

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Highlights

In the Diabetes Heart Study, 7.5% of study participants had QRS duration > 120 ms



Those with QRS duration > 120 ms had a substantially increased risk of death



Consideration of QRS duration may improve risk stratification in diabetic patients

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