Incremental changes in QRS duration as predictor for cardiovascular disease: a 21-year follow-up of a randomly selected general population (2024)

Study population

“The study of Men Born in 1943” is a longitudinal, prospective, population-based study of men born in 1943 and living in the city of Gothenburg in western Sweden¹¹. In 1993, the local tax authority generated a random sample of 50% of all men who were born in 1943 and were resident in the city of Gothenburg. These1463 men were invited to participate in an examination, and 798 men (54.5%) agreed to participate. Informed consent was obtained from all participants. The study complied with the Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of Gothenburg (DNR 157–93, 0067–03 and 649–13).

Data collection

All 798 men who were examined in 1993 were invited to a re-examination in 2003 all at age 60years, where 655 out of 773 who were still alive (84.7%) were re-examined, and in 2014, at the age of 71years 536 out of 688 men still alive (77.9%) were re-examined. The follow-up procedure is previously described in detail^12,13,14.

At each examination, clinical examination and laboratory analysis were performed. Data on smoking habits, leisure time physical activity, previous disease and pharmacological treatment were collected by questionnaire. Leisure time physical activity was assessed by the Saltin-Grimby questionnaire¹⁵, and coded as: 1 = sedentary (physically inactive), 2 = some light physical activity such as walking, riding a bicycle, or light gardening for at least 4 h per week, 3 = regular, moderate physical activity for a minimum of 3 h per week; and 4 = regular, vigorous physical training. Men who were current smoker or had quit smoking < 1 month before the examination were categorized as smokers. Former smokers were defined as those who had quit smoking ≧1 month previously and never-smoker as those who had never used cigarettes, cigars, or a pipe on the regular basis.

Clinical examination

Height and weight (in light indoor clothing) were measured and body mass index (weight in kg/ height in m²) was calculated. A standard cuff and a mercury manometer were used to measure blood pressure. Hypertension was diagnosed based on either medical history with current antihypertensive therapy or current blood pressure ≧140 (systolic), ≧90 mmHg (diastolic), or both. Fasting venous blood samples were drawn in the morning for analysis of blood glucose, serum cholesterol, and triglyceride measurements were analysed at the local accredited laboratory. Hyperlipidemia was defined as total cholesterol > 6.2 mmol/L or using lipid-lowering medication. Diabetes mellitus was defined as fasting blood glucose > 7 mmol/L or using oral medication and/or insulin.

ECG recordings and measurement of QRS duration

Heart rate was measured by 12-lead ECG in the supine position in 1993, 2003 and 2014. Paper speed was 50mm/s and the calibration was 1mV:10mm. All ECGs were evaluated by a physician, who was blinded to all clinical data. The QRS- duration was automatically measured by the ECG.

Participants who had developed CVD before 2003 were excluded from the study, however, we did not exclude individuals with bundle branch blocks. The change of QRS (ΔQRS) was defined as QRS duration in 2003 minus QRS duration in 1993. ΔQRS < 0ms, 0– < 4ms, 4–8ms and > 8ms represented the approximate quartiles forQRS change in our database. Since long ΔQRS was considered as most clinically important, the lower two ΔQRS quartiles were combined to one group: thus group 1 had ΔQRS < 4ms, group 2 had 4ms ≤ ΔQRS < 8ms, and group 3: ΔQRS ≥ 8ms.

Follow-up procedures and end-point

All men in the study were followed from the baseline examination, 1993, until August 31, 2014. Data on hospital admissions were obtained for the complete study population from the National Hospital Discharge Register, covering all hospital admissions in the country, for all participants from 1993 to 2014 and by collecting and reviewing medical charts. Mortality data were obtained from the Cause of Death Register.

As endpoint we used any major adverse cardiovascular event (MACE) defined as the occurrence of myocardial infarction, heart failure, death resulting from coronary heart disease, stroke, intermittent claudication, revascularization procedure, death resulting from coronary heart disease, or other cardiovascular death.

Statistical analysis

For the baseline characteristics of participants, continuous variables were described by mean and standard deviation (SD), while categorical variables were reported as frequencies (%). Differences in the distribution of baseline characteristics in different QRS categories were examined using Kruskal–Wallis test (continuous variables) and chi-square tests (categorical variables).

Crude incidence rates were expressed as event rates, calculated as the number of events divided by the sum of follow-up years per 1000 person-years. Univariable and multivariable-adjusted Cox proportional hazard models were used to examine the associations of different QRS duration change with outcomes, using group 1 (ΔQRS < 4ms) as reference group, unadjusted and multivariate-adjusted hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated for each QRS group. The multivariable model was adjusted for body mass index, systolic blood pressure, smoking, hyperlipidemia, diabetes and heart rate.

All statistical tests were 2-tailed with 95% confidence levels and p values of < 0.05 were considered significant. IBM SPSS Statistics for Windows, Version 22 was used for data analyses.

Of the 798 men, 86 had developed cardiovascular disease before the re-examination in 2003 while another 127 did not participate in the re-examination and consequently had missing value of QRS duration in 2003. These 213 men were excluded, leaving 585 men in the final study. Of those, 379 (64.7%) men had an increase in QRS duration. Changes in QRS duration over the 21-year follow-up are shown in Fig.1. The mean QRS duration in 1993, 2003 and 2014 were 93.8 ± 12.1ms, 97.2 ± 12.3ms and 101.6 ± 18.3ms, respectively. Mean QRS duration increased from 93.8ms at baseline to 101.6ms at the examination 21years later (Fig.1).

Baseline characteristics

Baseline characteristics were similar among the three groups, and participants in group 3 only differed by having slightly higher triglycerides compared to men in group 1 and 2 (Table 1).

The relationship between QRS duration change and outcome

The QRS change observed between 1993 and 2003 was not related to the 2014 data of systolic, diastolic or mean blood pressure levels (data not shown), but to increasing echocardiographically calculated LV mass (91.1 ± 22.4, 94 ± 23.9 and 99.3 ± 24.5g, in the three ΔQRS groups, p = 0.01). Of the 585 participants included in the analysis, 155 (26.4%) experienced MACE, during a follow-up of 11years from 60 to 71years of age. The occurrence of MACE was not related to the absolute QRS duration in 2003. Figure2 shows time to MACE for the three groups of change in QRS duration. In univariate analysis, men in group 2 (QRS change 4ms ≤ ΔQRS < 8ms) had an HR of 1.27 (95% CI: 0.86–1.88) and men in group 3 (increase in QRS duration ≥ 8ms ) an HR of 1.59 (95% CI: (1.10–2.31) for MACE compared to group 1 (with ΔQRS < 4ms), Table 2. The HRs were not much changed by adjustments in multivariate Cox proportional hazard model including 2003 data on BMI, systolic blood pressure, smoking, hyperlipidemia, diabetes and heart rate, yielding for group 2 an HR of 1.26 (95% CI: 0.85–1.86) and group 3 an HR of 1.56 (95% CI 1.07–2.27), Table 2.

This longitudinal follow-up of a general population sample showed a prolongation of the QRS duration in most men without cardiovascular disease at baseline between the age 50 and 71. Individuals with increased ΔQRS between1993 and 2003 were at increased risk for developing cardiovascular disease in the next eleven years the risk of MACE were highest for participants with the highest increase in ΔQRS.

The QRS duration represents the time taken for the electrical wave of myocardial depolarization to move from the His-Purkinje system through the ventricular myocardium and physiological or pathological changes in the myocardial conduction velocity could explain some of the variation in QRS duration. The QRS duration has been found to be dependent on both LV mass and LV volume in a large group of subjects at high CV risk⁹. In our study, we found a relation between increasing QRS duration during a 10-year period, and the LV mass another 11years later.

It is well known that among patients with established heart disease, a prolonged QRS duration on ECG is an independent predictor of adverse outcome^4,5. In most patients with systolic left ventricular dysfunction, increased QRS duration is associated with a worse prognosis^16,17. Among patients with coronary artery disease, QRS prolongation has been associated with a 50% increased risk of both arrhythmic and total mortality¹⁸. In a study of 1227 patients with suspected coronary artery disease referred for noninvasive evaluation of myocardial ischemia, QRS duration was found to be an independent predictor of cardiac death and nonfatal infarction¹⁹.

When referred to the general population, prolonged QRS duration usually indicates myocardial changes in response to underlying CVD and has been associated with decreased LV systolic and diastolic function, arrhythmia, ischemic cardiac disease, and LV hypertrophy⁹. However, few studies have examined change in QRS duration and its prognostic value in a general population sample, and results from previous studies are deverging. In a large Veteran's Administration study of more than 45 000 patients with an average age of 56 ± 15years (90% were male), investigators found that every 10-ms prolongation of the QRS duration was associated with an 18% increase in risk for cardiovascular death¹. The LIFE study reported that QRS duration predicts mortality and, importantly, sudden cardiac death in hypertensive patients on intensive medical therapy²⁰. The Strong Heart Study found that QRS duration was independently associated with incident MACE, CAD, and myocardial infarction in American Indian women, but not in men²¹. Conversely, one prior study , on participants in the Framingham Heart Study with ages ranging from 44 to 78years, reported no association between age-adjusted incidence of myocardial infarction, angina pectoris, and coronary death and baseline QRS prolongation in men and women²².The DIAMOND-HF study investigated the importance of incremental change in QRS duration over time on several echocardiographic outcomes and found that increment in QRS duration over time was significantly associated with deterioration of ventricular function and increase in filling pressures, and that QRS duration over time was superior to baseline QRS only in predicting a worse outcome⁸. Change in QRS duration over time was strongly associated with mortality²³. In our study, we found that individuals with increased ΔQRS over ten years, from age 50 to 60, were at increased risk for developing cardiovascular disease during the next eleven years, but the absolute QRS duration in 2003 had no relationship with the CV outcome within another 11years (until 2014). Thus, the present study suggests that monitoring the change in QRS duration over time can add independent prognostic information.

Authors and Affiliations

1. Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

   Xiaojing Chen

2. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

   Xiaojing Chen,Per-Olof Hansson,Erik Thunström,Zacharias Mandalenakis,Kenneth Caidahl&Michael Fu

3. Department of Medicine, Geriatrics and Emergency Medicine, Sahlgrenska University Hospital, Gothenburg, Region Västra Götaland, Sweden

   Per-Olof Hansson,Erik Thunström,Zacharias Mandalenakis&Michael Fu

4. Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Region Västra Götaland, Sweden

   Kenneth Caidahl

5. Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska Universtity Hospital, Stockholm, Sweden

   Kenneth Caidahl

Contributions

P.-O.H., M.F. and X.C. contributed to the conception or design of the work, X.C. analysis the data and draft the article, E.T., Z.M. and K.C. revised it critically for important intellectual content, and all authors reviewed the manuscript.

Corresponding author

Correspondence to Xiaojing Chen.

Competing interests

The authors declare no competing interests.

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