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Epidemiology
Original article
Competing cardiovascular outcomes associated with electrocardiographic left ventricular hypertrophy: the Atherosclerosis Risk in Communities Study
  1. Chintan S Desai1,
  2. Hongyan Ning2,
  3. Donald M Lloyd-Jones2,3
  1. 1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  2. 2Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  3. 3Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Dr Donald M Lloyd-Jones, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1402, Chicago, IL 60611, USA; dlj{at}northwestern.edu

Abstract

Background Individuals with electrocardiographically determined left ventricular hypertrophy (ECG LVH) are at risk of multiple cardiovascular disease (CVD) outcomes simultaneously. The study sought to characterise the competing incidences for subtypes of first CVD events or non-CVD death in those with and without ECG LVH.

Methods Participants in the Atherosclerosis Risk in Communities (ARIC) Study were included. ECG LVH was defined according to Sokolow–Lyon criteria. Competing Cox models were used to compare hazards for diverse outcomes within groups (eg, among those with ECG LVH) and for a given event between groups (ECG LVH vs no ECG LVH).

Results After 15 years, men with ECG LVH at baseline (N=383) had a cumulative incidence of first CVD events and non-CVD deaths of 29.2% and 6.1%, respectively (HR 4.86; 95% CI 3.04 to 7.77). In men without ECG LVH (N=6576) the incidence of any first CVD event and non-CVD death was 18.9% and 6.9%, respectively (HR 2.67; 2.39 to 2.98). Similar associations were observed in women (N=381 with and N=8187 without ECG LVH). Coronary heart disease (CHD) was the most common first event in men with ECG LVH (15.0%) and heart failure was the most common first event in women with ECG LVH (10.5%). After adjustment for risk factors including systolic blood pressure, any CVD event remained the most likely first event.

Conclusions Among middle-aged individuals with ECG LVH, the most likely first events are CHD in men and heart failure in women; these results may have implications for preventive approaches.

  • Cardiovascular disease
  • coronary heart disease
  • electrocardiography
  • heart failure
  • left ventricular hypertrophy
  • stroke

https://doi.org/10.1136/heartjnl-2011-300819

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    Left ventricular hypertrophy (LVH) is most commonly a manifestation of end-organ damage due to hypertension.1–3 When detected by 12-lead ECG, LVH is strongly predictive of cardiovascular disease (CVD) including myocardial infarction (MI), sudden cardiac death, stroke and congestive heart failure.1 4 5 Other investigations have revealed that echocardiographically determined LVH and increased left ventricular mass are associated with an increased risk of CVD.6

    Individuals are at risk of death from competing non-cardiovascular events, particularly as they are followed for longer periods of time, and are not accounted for in standard survival analyses. Furthermore, individuals at risk of CVD are at risk of multiple potential manifestations (eg, coronary heart disease (CHD), stroke, heart failure) simultaneously, not independently. This distinction is important as different CVD events are associated with greater or lesser morbidity and mortality and they may confer differential risks of subsequent CVD events. Furthermore, different strategies may be needed to prevent diverse first CVD events. No previous study has examined which CVD event occurs first after ECG LVH diagnosis.

    The method described by Lunn and McNeil7 utilises competing Cox models to compare HR and CI for diverse competing outcomes within a group (eg, those with ECG LVH). Fine and Gray8 described a complementary method that facilitates the comparison of HR and CI for a given event, such as the risk of specific CVD events, between different strata (eg, comparing those with and without ECG LVH). The objective of our study was to determine the competing risks of different first CVD events and non-CVD deaths in individuals with ECG LVH.

    Methods

    Study population

    We included subjects from the Atherosclerosis Risk in Communities (ARIC) Study and details of the study design have been published.9 We used a limited access dataset from the National Heart, Lung and Blood Institute (NHLBI). The study population comprises 15 792 individuals recruited in 1987–9 from Forsyth County, North Carolina, Jackson, Mississippi, Minneapolis, Minnesota, and Washington County, Maryland. The overall cohort was aged 45–64 years at enrolment and consisted of 55% women and 27% African-American individuals. All subjects were free of clinical CVD at the baseline examination.

    Electrocardiography

    Patients underwent standard supine 12-lead ECG, with each tracing consisting of 10 s of each of the 12 leads simultaneously. Electrocardiographic data processing, monitoring and quality control have been described elsewhere.10 All ECG were classified by the Minnesota code at a single reading centre.11 ECG LVH was defined according to the Sokolow–Lyon criteria: sum of S wave in V1 and R wave in V5 or V6 ≥3.5 mV (35 mm) and/or R wave in aVL ≥1.1 mV (11 mm).12 For this analysis, ECG LVH status was determined at the initial baseline examination. Continuous ECG measurements including the QRS interval were also recorded.

    Baseline measurements

    Race and smoking status were determined by self-report. Resting systolic and diastolic blood pressure was measured by a random zero sphygmomanometer. Diabetes was defined as fasting glucose of 126 mg/dl or greater, random glucose of 200 mg/dl or greater, a previous diagnosis of diabetes, or pharmacological therapy for diabetes. Body mass index was calculated as the weight in kilogrammes divided by the height in metres squared.

    Ascertainment of outcomes

    Events were ascertained as previously described.9 The duration of follow-up was 15 years. Deaths were investigated by a review of death certificates, coroner records and contact with physicians and patient families (when available). Outcomes of interest were death caused by CHD, non-fatal MI, stroke or transient ischaemic attack, heart failure, other cardiovascular death and non-cardiovascular death.

    Statistical analysis

    Baseline characteristics were compared by ECG LVH status using general linear models for continuous variables and χ2 tests for categorical variables. Sex differences in the prevalence of cardiovascular risk factors and in CVD rates have been well described;13 14 thus, we performed all analyses after stratification of the study sample by sex. All participants were followed until the occurrence of a CVD event, non-CVD death, or censoring for end of follow-up at 15 years. Adjusted risks for CVD events were calculated separately for men and women stratified by ECG LVH status. Standard errors and 95% CI were estimated. We then determined the first event occurring during the follow-up, whether it was a CVD event or non-CVD death. If a CVD event occurred on the same day as the day of death, then the CVD event was coded as occurring first. When multiple CVD events were diagnosed as occurring on the same date, we arbitrarily assigned one as occurring first; for example, an individual was assigned with MI as occurring before heart failure if both were diagnosed on the same date. Competing Cox regression models were used to analyse the competing risks separately for men and women and by ECG LVH status. We used the data augmentation method as described by Lunn and McNeil7 to fit Cox proportional hazards15 models for all CVD events combined compared with non-CVD death as a first event. Standard Kaplan–Meier survival analyses are typically used in situations in which one event is considered, and the time to event is considered the failure time. In the competing risks model we used in this study, a participant may fail from only one of the competing risks, and the time to the first event is considered the failure time. The hazards and the event-free survival are obtained from the augmented model and the competing cumulative incidence rate is the product of these two quantities. Therefore, we were able to estimate HR and cumulative incidences for competing CVD events compared with non-CVD death within a given group (eg, those with ECG LVH).

    In separate analyses, we used the method described by Fine and Gray8 and Pintilie16 to estimate the subdistribution hazard separately for men and women and by ECG LVH status for each of five competing outcomes: (1) CHD death or non-fatal MI; (2) heart failure; (3) fatal or non-fatal stroke or transient ischaemic attack; (4) other cardiovascular death; and (5) non-cardiovascular death. The Fine and Gray8 model is a modified Cox proportional hazards model that accounts for competing risks for different outcomes. The subdistribution hazards are modelled by keeping the competing risk observations in the risk set with diminishing weights. Therefore, the effect estimated from the Fine and Gray8 model shows the current and real differences between the two groups in terms of subdistribution hazards. This model also utilises time-dependent covariates to model the non-proportionality of hazards. We further adjusted for age, race, systolic blood pressure (SBP), QRS duration, total cholesterol, diabetes and smoking status. R version 2.10.1 and its competing risk library were used for these analyses.

    Results

    Baseline characteristics

    The ARIC sample for this study included 6959 men and 8568 women, of whom 383 men and 381 women had ECG LVH. The median duration of follow-up was 11.2 years and very few participants were lost to follow-up with regard to vital status (<1%). Baseline characteristics by sex and ECG LVH status are shown in table 1. Participants with ECG LVH were older and more likely to be black. Higher SBP and higher body mass index were associated with the presence of ECG LVH. Total cholesterol was associated with ECG LVH in men but not in women, and high-density lipoprotein cholesterol was associated with ECG LVH in women but not in men. The prevalence of smoking tended to be higher in those without ECG LVH. Men and women with ECG LVH were more likely to have diabetes mellitus. The QRS interval was longer in both men and women with ECG LVH compared with men and women without ECG LVH. In addition, the QRS interval was greater in men with ECG LVH compared with women with ECG LVH (p<0.001).

    View this table:
    Table 1

    Characteristics of ARIC participants by sex and ECG LVH status

    Competing Cox regression models

    Table 2 shows data from Cox models representing competing cumulative incidences of CVD events versus non-CVD deaths, stratified by sex and ECG LVH status and using the methods of Lunn and McNeil7 on the left and Fine and Gray8 on the right. In men without ECG LVH, the cumulative incidence of any CVD as a first event was 18.9% and the incidence of non-CVD death was 6.9%, for a HR of 2.67 (95% CI 2.39 to 2.98). In men with ECG LVH, the cumulative incidence of CVD events and non-CVD deaths was 29.2% and 6.1%, respectively, for a HR of 4.86 (95% CI 3.04 to 7.77). Therefore, any CVD event was more likely to occur first regardless of ECG LVH status, although the HR was greater in men with ECG LVH. The competing cumulative incidence curves for CVD events and non-CVD deaths are shown in figure 1.

    View this table:
    Table 2

    Summary table of HR and competing cumulative incidences for CVD events by LVH status

    Figure 1
    Figure 1

    Cumulative incidence of events (occurring as first events) in men in the Atherosclerosis Risk in Communities (ARIC) Study by electrocardiographically determined left ventricular hypertrophy (ECG LVH) status. CVD, cardiovascular disease.

    The relative HR for specific CVD events or non-CVD deaths for those with ECG LVH compared with those without ECG LVH are shown on the right side of table 2. The most likely first event in men with and without ECG LVH was CHD/non-fatal MI, with an incidence of 15.0% and 10.7%, respectively. Therefore, the relative HR for CHD/non-fatal MI occurring first in men with ECG LVH compared with men without ECG LVH was 1.41 (95% CI 1.07 to 1.89). The cumulative incidence of heart failure as a first event in men with and without ECG LVH was 9.7% and 5.3%, respectively; the relative HR was 1.96 (95% CI 1.36 to 2.83). Men with ECG LVH also appeared more likely to be diagnosed with stroke as a first event.

    In women, the relative HR for any CVD event versus non-CVD death occurring first was significantly greater in individuals with ECG LVH, compared with those without ECG LVH, as shown in table 2 and figure 2. Similar to men, the incidence of any CVD as a first event was higher in women with ECG LVH, and there was no statistically significant difference in non-CVD death as a first event between women with and without ECG LVH. Women with ECG LVH were more likely to experience any CVD event during the follow-up period and this association remained significant in the analysis of specific events, including for CHD/non-fatal MI, heart failure and stroke. The most likely first event in women with ECG LVH was heart failure (10.5%), followed closely by CHD/non-fatal MI (10.2%); the most likely first CVD event in women without ECG LVH was CHD/non-fatal MI (4.5%).

    Figure 2
    Figure 2

    Cumulative incidence of events (occurring as first events) in women in the Atherosclerosis Risk in Communities (ARIC) Study by electrocardiographically determined left ventricular hypertrophy (ECG LVH) status. CVD, cardiovascular disease.

    We adjusted for the effects of age and race in model 2 of table 2. The HR for any CVD event occurring first in men with ECG LVH compared with those without ECG LVH was 1.54 (95% CI 1.25 to 1.90); before adjustment for age and race the HR was 1.66 (95% CI 1.35 to 2.04). In women, the adjusted HR for any CVD event occurring first in those with ECG LVH was 1.80 (1.44 to 2.26); before adjustment for age and race, the HR was 2.78 (95% CI 2.23 to 3.45). Therefore, a greater magnitude of attenuation was observed in women compared with men. Model 3 of table 2 shows HR for any CVD event occurring first in individuals with ECG LVH compared with those without ECG LVH, adjusted for age, race and SBP. The HR in men and women were further attenuated to 1.36 (95% CI 1.10 to 1.68) and 1.43 (95% CI 1.17 to 1.94), respectively. In model 4 of table 2, we adjusted for age, race, SBP and QRS duration, and the HR were attenuated for both men and women. Model 5 shows no further attenuation of HR after additional adjustment for total cholesterol, diabetes and smoking status. We observed similar patterns when we stratified the sample into white and black participants and repeated the analysis (data not shown).

    Discussion

    Findings

    When detected by the 12-lead ECG, LVH is known to carry a poor prognosis. We used competing Cox regression models to determine that men and women in the community with ECG LVH were more likely to experience any CVD event before non-CVD death over 15 years of follow-up, independently of other cardiovascular risk factors. Our analysis of competing cumulative incidences and HR demonstrates that CHD/non-fatal MI was the most likely first event in men with ECG LVH. In women with ECG LVH, the first event was more likely to be heart failure, followed closely by CHD/non-fatal MI.

    Implications

    To the best of our knowledge, survival analysis in a competing risk framework has not been applied to individuals with ECG LVH. This method of analysis may reflect a more ‘real-world’ approach, in which individuals are at risk of multiple competing disease states simultaneously, which are associated with varying degrees of morbidity. Knowledge of the most likely first event, whether cardiovascular or non-cardiovascular, could inform primary prevention efforts and facilitate risk communication to patients. We found a somewhat different pattern of first events compared with a similar analysis of incident individuals with hypertension.17 Although CHD remained the most common first event in men, heart failure was the most common first event in women in our cohort; in the previous study, stroke was the most common first event in women with hypertension. These results support the idea that LVH represents an intermediate phenotype in the progression of hypertensive heart disease, which may transition to cardiac failure.3

    Cardiac dyssynchrony has been recognised as an increasingly important component in the pathophysiology of heart failure, and was recently found to be associated with increased left ventricular mass and volume.18 In our study, QRS duration was greater in men with ECG LVH compared with women with ECG LVH. However, women were more likely to experience heart failure as a first event. Potential explanations for this finding include a well-described ‘lag’ of 10 years in CHD-related mortality in women compared with men;13 14 the lower incidence of CHD in women in the age group in our analysis may partly account for the greater incidence of heart failure as a first event.

    We confirmed the finding that individuals with ECG LVH were at a significantly higher risk of any cardiovascular events compared with those without ECG LVH, independent of other established risk factors for CVD. The prevalence of ECG LVH was higher in black individuals, who also have greater competing risks for non-CVD death in middle age; thus, the finding that cardiovascular events are more likely to occur first was not a foregone conclusion. Given the high prevalence of ECG LVH among black men and women in this cohort, we suspected that race was a key confounder in the analysis, and adjustment for age and race attenuated the HR, but the results remained significant. The other important potential confounder was SBP, and the HR for CVD events after adjustment for age, race and SBP remained significant. Possible mechanisms for the increased risk of CVD in patients with ECG LVH are complex and probably include myocardial ischaemia, diastolic dysfunction and arrhythmia, as well as the associated burden of risk factors.19

    Our results for middle-aged women are particularly notable. The third report of the National Cholesterol Education Program's Adult Treatment Panel (ATP-III) is one of the most common tools used in cardiovascular risk assessment.20 However, the ATP-III algorithm has well-described limitations, notably that women are nearly always classified as low risk.21 We found that the cumulative incidence of CVD events in women with ECG LVH was 26.3% over 15 years, suggesting that women with ECG LVH are at a particularly elevated risk beyond that associated with established risk factors in the Framingham risk score,22 and should be considered for more intensive primary prevention efforts. Given the high risks for the blood pressure-related outcomes of heart failure and stroke and the documented benefits of blood pressure lowering for patients with ECG LVH,23 attempts to lower blood pressure and regress ECG LVH may be particularly warranted.

    Subclinical evidence of end-organ damage may be an effective method of determining the detrimental effects of a single uncontrolled risk factor. Regression of ECG LVH was found to reduce the risk of cardiovascular events in the Framingham Heart Study24 in a retrospective analysis. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study prospectively demonstrated that regression of ECG LVH reduced the risk of CVD endpoints, including cardiovascular death, non-fatal MI and stroke.23 25 26 The benefit was greater in those treated with losartan and part of the overall effect was independent of the reduction in blood pressure. Regression of ECG LVH by the ACE inhibitor ramipril has also been shown to reduce cardiovascular risk in the Heart Outcome Prevention Evaluation.27

    Limitations of our study include the absence of QRS voltage-duration products, which may increase the sensitivity of the ECG to detect LVH, particularly the Cornell voltage-duration product.28 However, the Sokolow–Lyon method has been well characterised, is easy to use in clinical practice, and was also used to define LVH in the Heart Outcome Prevention Evaluation and LIFE trials.23 28 Cardiac imaging with echocardiography or magnetic resonance is more sensitive for detecting LVH;29 30 however, ECG remains the first-line screening tool for the diagnosis of LVH due to widespread availability, low cost and simplicity. Despite these limitations, ECGs are commonly obtained in clinical practice for a variety of indications, and our study provides important prognostic information in men and women who are found to have ECG LVH. Another limitation is that subjects were classified based on a single baseline examination, and the subsequent development of ECG LVH during the follow-up period is not considered.

    Conclusions

    In individuals in the ARIC study, middle-aged men and women with ECG LVH had a significantly higher risk of cardiovascular events over 15 years of follow-up than those without ECG LVH. Individuals with ECG LVH are more likely to have a CVD event occur first before non-CVD death, and types of first CVD events are more likely to be CHD in men and heart failure in women, independent of the effect of other risk factors including hypertension. These results support the use of ECG LVH as an important risk marker in the epidemiology and prevention of CVD.

    Acknowledgments

    The Atherosclerosis Risk in Communities (ARIC) Study is conducted and supported by the NHLBI in collaboration with the ARIC study investigators. The authors wish to thank the participants of the ARIC Study. This paper was prepared using limited access datasets obtained from the NHLBI and does not necessarily reflect the opinions or views of ARIC or the NHLBI.

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    Footnotes

    • Funding This work was supported in part by grant R21 HL085375 from the National Heart, Lung, and Blood Institute. Dr. Desai is supported by T32 HL069771 from the National Heart, Lung, and Blood Institute.

    • Competing interests None.

    • Ethics approval Ethics approval was received from the institutional review board.

    • Provenance and peer review Not commissioned; externally peer reviewed.