Premature ectopic beats are frequently detected on routine 12-lead screening electrocardiograms (ECGs). However, their prognostic importance in subjects without known cardiovascular disease (CVD) is not well established. We evaluated prognostic value of atrial premature complexes (APCs) and ventricular premature complexes (VPCs) detected by a single 12-lead electrocardiography. A prospective cohort of 7,504 participants selected from nationally representative community-dwelling subjects living in the United States, enrolled in the Third National Health and Nutrition Examination Survey III from 1988 to 1994 with follow-up through December 2006 without known CVD. The main outcomes were all-cause mortality, CVD-related mortality, and ischemic heart disease (IHD)–related mortality. Of 7,504 participants (mean age 60 ± 14 years, 47% women, 49% whites), 89 (1.2%) had APCs and 110 (1.5%) had VPCs on 12-lead ECGs. During a follow-up of up to 18 years, 2,386 deaths occurred, of which 963 were due to CVD and 511 were due to IHD. In a multivariate analysis adjusted for demographics, clinical variables, and electrocardiographic measures, APCs were significantly associated with all-cause mortality (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.08 to 1.80), CVD death (HR 1.78, 95% CI 1.26 to 2.44), and IHD death (HR 2.40, 95% CI 1.59 to 3.47). For VPCs, however, there were no significant associations with all-cause mortality (HR 1.05, 95% CI 0.80 to 1.36), CVD death (HR 0.96, 95% CI 0.62 to 1.43), and IHD death (HR 0.89, 95% CI 0.47 to 1.52). In conclusion, APCs, but not VPCs, on routine screening ECGs are predictive of adverse events in community-dwelling subjects without known CVD.
Physicians frequently perform electrocardiographic screening based on pertinent historical and objective evaluation of subjects at risk for cardiovascular events. Atrial premature complexes (APCs) are commonly encountered during these electrocardiographic evaluations and are known to be present in 10% to 20% of the general population. More serious forms of cardiac ectopy are ventricular premature complexes (VPCs), found to be present in 5% to 10% of the general population. However, these data are from the studies that have used 24 hours of ambulatory electrocardiography. Prognosis of APCs and VPCs on a 12-lead electrocardiogram (ECG) has been conflicting in the absence of ischemic heart disease (IHD) and is not well studied. We examined the prognostic significance of APCs and VPCs in a representative sample of the population of the United States without known cardiovascular disease (CVD).
Methods
The National Health and Nutrition Examination Survey (NHANES) III was a survey administered to a representative sample of the noninstitutionalized population of the United States. NHANES III baseline data were collected from participants during an in-home interview and a subsequent visit to a mobile examination center from 1988 to 1994.
The survey design and data are available at the Web site of the US Centers for Disease Control and Prevention ( http://www.cdc.gov/nchs/nhanes/nh3data.htm ). For the purpose of this study, we included all available NHANES III participants aged ≥20 years, who had good quality ECGs showing sinus rhythm without major intraventricular conduction delay (including complete bundle branch blocks and/or QRS duration >120 ms), who also had medical, anthropometric measurement, and mortality data available by 2006. Subjects with known CVD, electrocardiographic evidence of myocardial infarction, paced rhythms, or atrial fibrillation were excluded.
Covariate data were obtained by in-home interview and included demographics, medical history including smoking status, and use of medications. Body mass index was calculated as the weight in kilograms divided by the height in meters squared. Blood pressure was measured 3 times during the in-home interview and 3 additional times during the visit to the mobile examination center. All blood pressure measurements for each participant were averaged for the purpose of this study. Medical conditions and medication use were assessed by self-report. The total serum cholesterol level was measured enzymatically.
Standard 12-lead ECG was recorded on a ECG machine (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 classification of electrocardiographic abnormalities using Minnesota Code for electrocardiographic classification. APCs and VPCs were initially detected by software then visually confirmed by an ECG coder.
The NHANES III participants were 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 to identify vital status and, for those who died, the cause of death. These participants were matched on 12 identifiers, including Social Security number, gender, and date of birth. Follow-up duration was defined as the time period between NHANES III examination and date of death or December 31, 2006, whichever occurred first. The cause of death was determined using the underlying cause listed on the death certificates. The International Classification of Diseases, Ninth Revision was used for deaths occurring from 1988 to 1998 and International Classification of Diseases, Ninth Revision and/or International Classification of Diseases, Tenth Revision for deaths occurring from 1999 to 2006.
Descriptive statistics are used to summarize the data. Continuous variables are expressed as mean ± SD, and categorical variables are given as percentages. For examination of differences, analysis of variance was used for continuous variables and Fisher’s exact test or chi-square for categorical variables, as appropriate. Incidence rates for all-cause, CVD, and IHD mortalities were calculated for APCs and VPCs, which are expressed as 100 person-years. Rate ratios were calculated and 95% confidence intervals are expressed. Assumptions for Cox proportional hazards model were tested. Adjusted Cox proportional hazards models were used to evaluate the association of APCs and VPCs (compared with no APCs or VPCs) with all-cause, CVD, and IHD mortalities. Two adjusted models were evaluated: model 1 adjusted for demographics (age, gender, and race or ethnicity) and model 2 adjusted for model 1 variables plus smoking status, systolic blood pressure, body mass index, blood pressure medications, total cholesterol, diabetes mellitus, cancer and pulmonary disease (bronchial asthma and chronic obstructive pulmonary disease), electrocardiographic left ventricular hypertrophy, and corrected QT (QTc) interval. Consistency of the results was examined across subgroups of the participants stratified by age, gender, and race or ethnicity using Cox proportional hazards adjusted in a similar fashion to model 2. Survival analysis was performed by the Kaplan-Meier method to compare APC versus VPC versus controls, and significance was tested by log-rank test. p Value of <0.05 was considered significant. Analysis was performed on SAS, v. 9.3 (SAS Inc., Cary, North Carolina), and PASW, v. 18.0 (IBM, Chicago, Illinois).
Results
Of the 7,504 participants (mean age 60 ± 14, women 47%, 49% whites) in this study, there were 89 subjects (1.2%) who were found to have APCs and 110 (1.5%) who were found to have VPCs. Table 1 lists baseline characteristics of subjects stratified by presence and absence of APCs and VPCs. Participants with premature complexes were more likely to be older, male, of white race, with higher systolic blood pressure, and greater prevalence of pulmonary disease and electrocardiographic evidence of left ventricular hypertrophy. In contrast, they were less likely to be Mexicans. Participants with APCs were more likely to have cancer, whereas participants with VPCs were more likely to be female.
| Variable | No Ectopic Beats (n = 7305) | Ventricular Premature Complexes (VPCs) (n = 110) | Atrial Premature Complexes (APCs) (n = 89) | p |
|---|---|---|---|---|
| Age (years) | 59 ± 13 | 69 ± 12 | 72 ± 11 | <0.0001 |
| Women | 3413 (47%) | 74 (67%) | 54 (61%) | <0.0001 |
| White | 3545 (48%) | 67 (61%) | 58 (65%) | <0.0001 |
| Black | 1706 (23%) | 25 (23%) | 21 (24%) | 0.66 |
| Mexican | 1691 (23%) | 15 (13%) | 8 (9%) | <0.0001 |
| Other races | 295 (8%) | 3 (4%) | 2 (3%) | 0.003 |
| Smoking status | ||||
| Ever smoker | 3970 (54%) | 70 (64%) | 55 (62%) | 0.81 |
| Never | 3335 (46%) | 40 (36%) | 39 (44%) | 0.31 |
| Corrected QT duration (ms) | 431 ± 24 | 432 ± 25 | 430 ± 27 | 0.84 |
| Left ventricular hypertrophy | 723 (10%) | 15 (14%) | 16 (18%) | 0.02 |
| Antihypertensive medication | 1599 (22%) | 32 (29%) | 27 (30%) | 0.03 |
| Cancer | 372 (5%) | 4 (4%) | 11 (12%) | 0.02 |
| Pulmonary disease | 754 (10%) | 17 (15%) | 23 (26%) | <0.0001 |
| Systolic blood pressure (mm Hg) | 132 ± 20 | 136 ± 18 | 146 ± 27 | <0.0001 |
| Diabetes mellitus | 775 (11%) | 12 (11%) | 8 (9%) | 0.88 |
| Total cholesterol (mg/dL) | 217 ± 44 | 225 ± 45 | 223 ± 44 | 0.10 |
| Body mass index (kg/m 2 ) | 27.6 ± 5.5 | 27.5 ± 5.4 | 26.2 ± 4.8 | 0.05 |
During a mean follow-up period of 13 ± 4 years, 2,386 deaths occurred (incidence 2.5 per 100 person-years). Of these, 983 were due to CVD (incidence 1.03 per 100 person-years) and 511 deaths were due to IHD (incidence 0.55 per 100 person-years). There was increased incidence of all-cause mortality, CVD mortality, and IHD mortality in both APCs and VPCs groups ( Table 2 ). The highest incidence rate ratio was for APCs and IHD mortality (incidence rate ratio 5.84, 95% confidence interval 3.97 to 8.61). In Cox proportional hazards analysis adjusted for demographics, co-morbid conditions, and electrocardiographic indexes, the presence of APCs was associated with 41% increased hazard of all-cause mortality, 64% increased hazard of CVD mortality, and 106% increased hazard of IHD mortality. Although incidence rates for all types of mortalities were significantly elevated for VPCs, the Cox proportional adjusted analyses did not show VPCs as a significant independent risk factor for any type of mortality ( Table 3 ). Survival analyses by the Kaplan-Meier method demonstrate increased all-cause mortality ( Figure 1 ), CVD mortality ( Figure 2 ), and IHD mortality ( Figure 3 ) in subjects with APCs and VPCs. The probability of all-cause mortality, CVD mortality, and IHD mortality for subjects with APCs is the highest compared with subjects with VPCs and those without any ectopic beats. The aforementioned results were consistent across several subgroups of participants stratified by age, gender, and race or ethnicity with no observed significant interactions between the components of each subgroup ( Table 4 ).
| Outcomes | No Ectopic Beats (n = 7305) | Atrial Premature Complexes (n = 89) | Ventricular Premature Complexes (n = 110) | |||||
|---|---|---|---|---|---|---|---|---|
| Events | Event Rate ∗ | Events | Event Rate ∗ | Rate Ratio (95% CI) | Events | Event Rate ∗ | Rate Ratio (95% CI) | |
| All-cause mortality | 2386 | 2.54 | 72 | 8.58 | 3.38 (2.67–4.27) | 72 | 5.63 | 2.21 (1.88–2.62) |
| CVD mortality | 963 | 1.03 | 37 | 4.41 | 4.27 (3.08–5.94) | 32 | 2.50 | 2.43 (1.9–3.09) |
| IHD mortality | 511 | 0.55 | 27 | 3.21 | 5.84 (3.97–8.61) | 16 | 1.25 | 2.27 (1.66–3.12) |
| Outcomes | Atrial Premature Complexes | Ventricular Premature Complexes | ||
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| Model 1 | Model 2 | Model 1 | Model 2 | |
| All-cause mortality | 1.50 (1.18–1.89) | 1.41 (1.08–1.80) | 1.11 (0.87–1.39) | 1.05 (0.80–1.36) |
| CVD mortality | 1.78 (1.26–2.44) | 1.64 (1.13–2.36) | 1.17 (0.80–1.64) | 0.96 (0.62–1.43) |
| IHD mortality | 2.40 (1.59–3.47) | 2.06 (1.28–3.13) | 1.07 (0.62–1.71) | 0.89 (0.47–1.52) |
