The prognostic significance of low QRS voltage (LQRSV) in the electrocardiogram (ECG) of individuals free of cardiovascular disease (CVD) is unclear. We evaluated the association between LQRSV and all-cause mortality in 6,440 participants (53% women, mean age 60 years) from the Third National Health and Nutrition Examination Survey, a representative sample of the US population. Participants with history of CVD or major ECG abnormalities were excluded. LQRSV was automatically defined from standard 12-lead ECG as QRS complex amplitudes of <0.5 mV in all frontal leads and/or <1.0 mV in all precordial leads. Mortality data through 2006 were obtained from National Death Index records. LQRSV was detected in 1.4% (n = 89) of the participants. During a median follow-up of 13.8 years, 2,000 deaths occurred. The mortality rate in individuals with LQRSV was almost twice that in those without LQRSV (51.1 vs 23.5 events per 1,000 person-years, p <0.01). In a demographic-adjusted model, LQRSV was associated with 63% increased risk of mortality (hazard ratio 1.63, 95% confidence interval [1.21, 2.18]). The magnitude of this risk did not appreciably change after additional adjustment for body mass index, smoking status, systolic blood pressure, blood pressure medication use, dyslipidemia, diabetes, cancer, pulmonary disease, and ECG abnormalities (hazard ratio 1.61, 95% confidence interval [1.20, 2.16]) and was consistent across age, race, and sex subcategories. In conclusion, LQRSV is associated with an increased risk of mortality in individuals free of apparent CVD. More research is warranted to determine the mechanisms by which LQRSV is associated with increased risk of mortality in apparently healthy individuals.
Low QRS voltage (LQRSV), defined as QRS complex amplitudes of <0.5 mV in all frontal leads and/or <1.0 mV in all precordial leads, is present in about 1% to 2% of normal lean individuals. In principle, LQRSV may stem from an increased distance from the heart to the skin where the recording electrodes are placed or from a pathological impairment in voltage generation from the myocardium. Hence, LQRSV has been linked to obesity, pericardial and pleural effusions, left ventricular hypertrophy, diffuse myocardial necrosis or fibrosis, emphysema, pulmonary infiltration, and hypothyroidism. LQRSV has also been used as a prognostic indicator in patients with cardiac amyloidosis and heart failure. Despite the established links between LQRSV and various cardiovascular pathologies, there are no much data on the long-term outcomes associated with LQRSV especially if present in individuals free of cardiovascular disease (CVD). Therefore, we examined the relationship between LQRSV and all-cause mortality in the US Third National Health and Nutrition Examination Survey (NHANES III), a study with a representative sample of the US population.
Methods
The NHANES is a periodic survey of a representative sample of the civilian noninstitutionalized US population. Its principal aim is to determine estimates of disease prevalence and health status of the US population. The National Center for Health Statistics of the Center for Disease Control and Prevention institutional review board approved the protocol for NHANES III. All participants gave written informed consent.
Of the 8,426 participants in the NHAHNES III who underwent 12-lead electrocardiogram (ECG), we excluded those with missing mortality data (n = 4), with known coronary artery disease (n = 603) or known congestive heart failure (n = 204), and those with major ECG abnormalities as defined by the Minnesota Code for ECG analysis (n = 1,175). After all exclusions, 6,440 participants remained and were included in this analysis.
NHANES III baseline data were collected during an in-home interview and a subsequent visit to a mobile examination center from 1988 to 1994. The data collected during the in-home interview included demographics and past history including smoking status and use of medications. Blood pressure data were the averaged reading from 3 in home measurements and 3 mobile center measurements. Hypertension was defined as systolic and/or diastolic blood pressure >140/90 mm Hg or taking blood pressure-lowering drugs. Using the height and weight measured during the visit to mobile examination center, the body mass index was calculated as the weight in kilograms divided by the height in meters squared. Diabetes was defined as fasting plasma glucose ≥126 mg/dl, a nonfasting plasma glucose ≥200 mg/dl, or concurrent use of antidiabetic medications. Diagnosis of dyslipidemia, history of cancer, and smoking was self-reported.
Standard 12-lead ECG was recorded on a Marquette MAC 12 system (Marquette Medical Systems, Milwaukee, Wisconsin) by trained technicians during the participant’s visit to a mobile examination center. Computerized automated analysis of the electrocardiographic data was performed, which included selective averaging to obtain the representative durations and amplitudes of electrocardiographic components. LQRSV was defined as QRS complex amplitudes of <0.5 mV in all frontal leads and/or <1.0 mV in all precordial leads.
The NHANES III participants have been followed up for mortality through December 31, 2006. The method of probabilistic matching was used to link the NHANES III participants with the National Death Index. The follow-up period for each study participant was calculated as the interval between their NHANES III examination and the date of death or December 31, 2006, whichever occurred first.
Frequency distributions of all variables were first inspected to identify anomalies and outliers possibly caused by measurement artifacts. Continuous data were described by their mean and SD and categorical data as proportions (percentage). Differences in characteristics by QRS voltage status (low vs normal) were assessed by chi-square (for categorical variables) and unpaired t (for continuous variables) tests.
Cox proportional hazards analysis was used to calculate the unadjusted and multivariate-adjusted hazard ratios and 95% confidence intervals of LQRSV for all-cause mortality, in a series of incremental models as follows: first adjusted for demographics (age, sex, and race; model 1), then adjusted for CVD risk factors (body mass index, smoking status, systolic blood pressure, blood pressure medication use, cholesterol, and diabetes; model 2), and then additionally adjusted for noncardiac diseases including cancer and pulmonary disease (asthma and chronic obstructive pulmonary disease) as well as any other remaining ECG abnormalities (model 3).
We also examined the association between LQRSV with all-cause mortality, across subgroups of the study participants stratified by age, sex, and race.
All analyses were done using SAS 9.3 (SAS Institute Inc., Cary, North Carolina). Statistical significance was determined as a two-sided p <0.05.
Results
A total of 6,440 participants (49% women, age 65.1 ± 13.7 years) were included in this study. LQRSV was detected in 1.4% (n = 89) of the participants. Table 1 lists the characteristics of the study population by the status of QRS voltage amplitude. As shown, LQRSV was slightly more common in women than in men. Participants with LQRSV were more likely to be black (non-Hispanic) and older, have pulmonary disease, and have other concurrent malignancies.
| Variable | LQRSV | ||
|---|---|---|---|
| No (n = 6,355) | Yes (n = 89) | p Value | |
| Age, mean (yrs) | 65.1 ± 13.7 | 58.5 ± 13.2 | <0.001 |
| Women | 3,142 (49.4) | 48 (54.4) | 0.35 |
| Black, non-Hispanic | 571 (9.0) | 20 (22.8) | 0.002 |
| Hispanic | 1,357 (21.3) | 21 (23.3) | 0.66 |
| Body mass index (kg/m 2 ) | 27.6 (5.5) | 25.8 (6.4) | 0.52 |
| Hypertension | 1,571 (24.7) | 29 (32.8) | 0.10 |
| Hyperlipidemia | 1,285 (20.2) | 21 (23.2) | 0.50 |
| Diabetes mellitus | 714 (11.2) | 9 (10.0) | 0.72 |
| Current smoker | 1,714 (27.0) | 20 (22.8) | 0.34 |
| Systolic blood pressure (mm Hg) | 123.8 ± 17.1 | 131.4 ± 19.1 | <0.001 |
| Pulmonary disease | 1,785 (28.1) | 9 (10.6) | <0.001 |
| Cancer | 1,071 (16.9) | 9 (10.6) | 0.05 |
| Minor ECG abnormalities | 1,642 (25.8) | 23 (25.72) | 0.98 |
During a median follow-up of 14.1 years, a total of 2,000 deaths occurred. In participants with LQRSV, the rate of all-cause mortality was almost twice the rate in those without LQRSV (p <0.01; Table 2 ). Figure 1 shows the Kaplan-Meier survival curve of participants with and without LQRSV.
| n | Event Rate/1,000 Person years | Model 1 ∗ Demographic Model | Model 2 † Demographics and CVD Risk Factors Model | Model 3 ‡ Demographics, CVD Risk Factors, ECG Abnormalities, and Noncardiac Disease Model | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | p Value | HR (95% CI) | p Value | HR (95% CI) | p Value | |||
| LQRSV-absent | 89 | 23.5 | Reference | — | Reference | — | Reference | — |
| LQRSV-present | 6,355 | 51.1 | 1.63 (1.21, 2.18) | <0.01 | 1.68 (1.26, 2.25) | <0.01 | 1.61 (1.20, 2.16) | <0.01 |
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