Although asymptomatic left ventricular (LV) systolic dysfunction (ALVSD) is common, its phenotype and prognosis for incident heart failure (HF) and mortality are insufficiently understood. Echocardiography was done in 5,649 participants in the Cardiovascular Health Study (age 73.0 ± 5.6 years, 57.6% women). The clinical characteristics and cardiovascular risk factors of the participants with ALVSD were compared to those with normal LV function (ejection fraction ≥55%) and with symptomatic LV systolic dysfunction (SLVSD; ejection fraction <55% and a history of HF). Cox proportional hazards models were used to estimate the risk of incident HF and mortality in those with ALVSD. Also, comparisons were made among the LV ejection fraction subgroups using previously validated cutoff values (<45% and 45% to 55%), adjusting for the demographic and cardiovascular disease risk factors. Those with ALVSD (7.3%) were more likely to have cardiovascular risk factors than those in the reference group (without LV dysfunction or symptomatic HF) but less likely than those with SLVSD. The HF rate was 24 occurrences per 1,000 person-years in the reference group and 57 occurrences per 1,000 person-years in those with ALVSD. The HF rate was 45 occurrences per 1,000 person-years for those with ALVSD and mildly impaired LV dysfunction and 93 occurrences per 1,000 person-years for those with ALVSD and moderate to severe LV dysfunction. The mortality rate was 51 deaths per 1,000 person-years in the reference group, 90 deaths per 1,000 person-years in the ALVSD group, and 156 deaths per 1,000 person-years in the SLVSD group. Adjusting for covariates, compared to the reference group, ALVSD was associated with an increased risk of incident HF (hazard ratio 1.60, 95% confidence interval 1.35 to 1.91), cardiovascular mortality (hazard ratio 2.13, 95% confidence interval 1.81 to 2.51), and all-cause mortality (hazard ratio 1.46, 95% confidence interval 1.29 to 1.64). In conclusion, subjects with ALVSD are characterized by a greater prevalence of cardiovascular risk factors and co-morbidities than those with normal LV function and without HF. However, the prevalence is lower than in those with SLVSD. Patients with ALVSD are at an increased risk of HF and mortality, particularly those with greater severity of LV impairment.
Heart failure (HF), with and without decreased left ventricular (LV) systolic function, is common in subjects aged ≥65 years. However, asymptomatic LV systolic dysfunction (ALVSD; i.e., a decreased LV ejection fraction in the absence of HF symptoms) is an important preclinical stage of the HF continuum. Also, ALVSD is more common than symptomatic LV systolic dysfunction (SLVSD). Evidence has suggested that ALVSD is associated with an increased risk of adverse cardiovascular outcomes, including myocardial infarction and mortality. Although the clinical characteristics of SLVSD are well known, the phenotype and prognostic value of ALVSD for HF and cardiovascular mortality in older subjects have not been fully described.
In the Cardiovascular Health Study, the subjects with ALVSD had a twofold mortality risk compared to those with normal systolic function and without HF. The purpose of the present investigation was to describe the clinical characteristics of ALVSD, to assess its effect on incident HF and cardiovascular mortality in subjects ≥65 years old, and to establish the role of prevalent coronary heart disease (CHD) and interim CHD events.
Methods
The Cardiovascular Health Study (CHS) was a prospective, community-based, observational study of subjects aged ≥65 years, identified from the Medicare enrollment lists, in 4 geographically distinct communities across the United States (Sacramento County, California; Washington County, Maryland; Forsyth County, North Carolina; and Allegheny County, Pennsylvania). The purpose of the CHS was to evaluate the cardiovascular risk factors, cardiac disease, and outcomes in free-living elderly subjects. The design and selection of subjects for the study have previously been described. The initial cohort included 5,201 participants recruited from 1989 to 1990 and an enhanced minority cohort of 687 recruited from 1992 to 1993. The clinical information was obtained from interviews, physical examinations, and questionnaire-based assessments. The subjects also underwent evaluation of the blood biomarkers, electrocardiography, and echocardiography. The present analysis focused on 5,649 (99%) of the 5,888 participants from the initial CHS cohort with an interpretable echocardiographic assessment of LV systolic function. The participants were defined as having ALVSD if they did not have an adjudicated diagnosis of symptomatic HF at baseline and had qualitatively decreased LV systolic function (ejection fraction <55%). Those with ALVSD were compared to a reference group that included those without HF who had qualitatively normal LV systolic function (ejection fraction ≥55%) and those with SLVSD.
The diagnosis of HF was adjudicated by a review of the medical records for signs and symptoms of HF, the use of HF medications, and supporting diagnostic studies.
Other prevalent conditions that were assessed included CHD, diabetes, hypertension, history of cerebrovascular events, ankle-arm index, and electrocardiographically determined LV hypertrophy, ST-T segment abnormalities, and atrial fibrillation. The demographic information, including age, gender, and race, was also evaluated. The electrocardiograms were analyzed as described previously. The echocardiographic assessments included systolic function and valvular function and have been described in the following paragraphs. Fasting serum values were obtained for standard blood chemistry (i.e., creatinine, glucose, and lipid levels) and markers of anemia and inflammation as adjustments. The use of medications, including angiotensin-converting enzyme inhibitors, β-adrenergic blocking agents, digoxin, diuretics, calcium channel blockers, and lipid-lowering medications, was documented, and a composite of any use was included as a covariate in the multivariate models.
The echocardiographic assessment was done during the 1989 to 1990 clinic visit for the initial cohort and during the 1994 to 1995 clinic visit for the minority cohort; thus, these clinic visits were used as the baseline for the present analysis. The echocardiograms were obtained using a standardized protocol and interpreted at a core laboratory by 2 trained independent readers, who were unaware of the participants’ clinical information. Qualitative assessments of the LV systolic function were categorized using previously validated cutoff values and classified as normal (ejection fraction ≥55%), mildly impaired (ejection fraction 45% to 54%), or moderate to severely impaired (ejection fraction <45%), as described previously. The inter-reader agreement of LV systolic function classification was 94%, and the intrareader agreement was 99% for 150 echocardiograms that were read twice by independent readers.
In addition to the LV ejection fraction, LV fractional shortening was analyzed as a continuous measure of LV contraction and used for the confirmatory analyses.
The protocol for assessment of adverse cardiovascular outcomes during the semiannual reviews and annual examinations has been previously described. Incident HF was confirmed if there was a physician diagnosis of HF, documentation of HF signs and symptoms, supporting diagnostic data, and medical therapy for HF. Death was confirmed by review of the medical record or death certificate or through review of the Medicare database. The Events Subcommittee adjudicated cardiovascular mortality after reviewing the medical record and death certificate.
The data are presented as the mean ± SD or percentages, as appropriate. Chi-square tests were used for categorical variables and t tests for continuous variables to compare the baseline characteristics in the participants with ALVSD, the reference group with normal LV function, and those with SLVSD. To examine which variables were associated with ALVSD independently of the other covariates ( Table 1 ), multivariate logistic regression analyses were performed with ALVSD status as the dependent measure and the demographic, clinical, and biologic markers as predictors. Furthermore, comparisons among the participants with ALVSD were stratified by the severity of LV dysfunction (moderate to severely impaired ejection fraction [<45%] and mildly impaired ejection fraction [45% to 54%]).
| Characteristic | Reference (n = 4,976) | ALVSD (n = 410) | SLVSD (n = 104) | p Value | |
|---|---|---|---|---|---|
| ALVSD vs Reference | ALVSD vs SLVSD | ||||
| Age (years) | 72.7 ± 5.5 | 74.1 ± 6.0 | 73.9 ± 5.6 | <0.001 ⁎ | 0.69 |
| Men | 1,987 (39.9%) | 278 (67.8%) | 59 (56.7%) | <0.001 ⁎ | 0.034 ⁎ |
| Black race | 637 (12.8%) | 46 (11.2%) | 24 (23.1%) | 0.36 | 0.002 ⁎ |
| Systolic blood pressure (mm Hg) | 136.0 ± 21.3 | 136.8 ± 21.5 | 130.8 ± 21.7 | 0.42 | 0.011 ⁎ |
| Diastolic blood pressure (mm Hg) | 70.7 ± 11.1 | 71.1 ± 12.6 | 66.5 ± 12.2 | 0.46 | 0.001 ⁎ |
| Hypertension | 2,145 (43.2%) | 191 (46.6%) | 64 (61.5%) | 0.18 | 0.006 ⁎ |
| Ankle-arm index | 1.07 ± 0.17 | 1.04 ± 0.21 | 1.00 ± 0.25 | 0.001 ⁎ | 0.104 |
| Diabetes mellitus | 729 (14.8%) | 92 (22.6%) | 36 (35.6%) | <0.001 ⁎ | 0.007 ⁎ |
| Body mass index (kg/m 2 ) | 26.5 ± 4.5 | 27.1 ± 4.5 | 27.1 ± 5.1 | 0.018 ⁎ | 0.97 |
| Current smoker | 590 (11.9%) | 41 (10.0%) | 10 (9.6%) | 0.26 | 0.90 |
| Coronary heart disease | 767 (15.4%) | 178 (43.4%) | 77 (74.0%) | <0.001 ⁎ | <0.001 ⁎ |
| Left ventricular hypertrophy on electrocardiogram | 193 (4.0%) | 32 (8.3%) | 19 (20.2%) | <0.001 ⁎ | 0.001 ⁎ |
| ST-T abnormalities on electrocardiogram | 269 (5.6%) | 34 (8.9%) | 8 (8.3%) | 0.008 ⁎ | 0.87 |
| Atrial fibrillation | 92 (1.9%) | 23 (5.6%) | 12 (11.7%) | <0.001 ⁎ | 0.030 ⁎ |
| Valvular abnormality | 400 (8.0%) | 48 (11.7%) | 28 (26.9%) | 0.010 ⁎ | <0.001 ⁎ |
| History of stroke | 178 (3.5%) | 24 (5.9%) | 14 (13.5%) | 0.017 ⁎ | 0.008 ⁎ |
| Fractional shortening (%) | 42.6 ± 7.7 | 33.4 ± 9.3 | 25.7 ± 10.0 | <0.001 ⁎ | <0.001 ⁎ |
| Angiotensin-converting enzyme inhibitor | 289 (5.8%) | 38 (9.3%) | 40 (38.5%) | 0.004 ⁎ | <0.001 ⁎ |
| β Blocker | 626 (12.6%) | 64 (15.7%) | 9 (8.7%) | 0.072 | 0.067 |
| Diuretic | 1,199 (24.1%) | 116 (28.4%) | 82 (78.9%) | 0.051 | <0.001 ⁎ |
| Antihypertensive | 2,198 (44.2%) | 230 (56.4%) | 97 (93.3%) | <0.001 ⁎ | <0.001 ⁎ |
| Digoxin | 301 (6.1%) | 56 (13.7%) | 53 (51.0%) | <0.001 ⁎ | <0.001 ⁎ |
| Lipid-lowering drugs | 269 (5.4%) | 25 (6.1%) | 2 (1.9%) | 0.54 | 0.087 |
| Creatinine (mg/dl) | 1.04 ± 0.32 | 1.20 ± 0.55 | 1.41 ± 0.91 | <0.001 ⁎ | 0.003 ⁎ |
| Cholesterol (mg/dl) | 212.6 ± 38.8 | 205.5 ± 40.7 | 199.5 ± 42.4 | <0.001 ⁎ | 0.20 |
| Glucose (mg/dl) | 109.6 ± 34.6 | 117.4 ± 44.2 | 121.2 ± 43.3 | <0.001 ⁎ | 0.45 |
| Hemoglobin (g/dl) | 14.0 ± 1.3 | 14.4 ± 1.5 | 13.7 ± 1.7 | <0.001 ⁎ | <0.001 ⁎ |
| C-reactive protein (mg/L) | 4.46 ± 7.79 | 5.66 ± 9.82 | 9.14 ± 11.11 | 0.003 ⁎ | 0.002 ⁎ |
| Interleukin-6 (pg/ml) | 2.12 ± 1.85 | 2.51 ± 2.06 | 3.20 ± 2.17 | <0.001 ⁎ | 0.005 ⁎ |
| Fibrinogen (mg/dl) | 320.5 ± 65.3 | 328.1 ± 70.1 | 352.5 ± 80.6 | 0.026 ⁎ | 0.003 ⁎ |
The incidence of HF, cardiovascular death, and all-cause mortality are reported as percentages. Cox proportional hazards models were used to determine the hazard ratio (HR) and 95% confidence intervals (CIs) as a measure of the relative risk of incident events. The models were then adjusted for the demographic variables, including age, gender, and race. Subsequently, the covariates that have been previously validated as predictors of incident HF in the CHS were added to the models as adjustments, including CHD, valvular abnormality, a history of a cerebrovascular event, diabetes, systolic blood pressure, ankle-arm index, glucose, creatinine, C-reactive protein, electrocardiographically determined LV hypertrophy, ST-T segment abnormalities, atrial fibrillation, and the composite medication variable. Because the participants might have begun taking medications during the course of follow-up, we also adjusted for the composite medication variable that was updated over time if they had ever used the medications included in the composite variable. To account for the effect of valvular disease, medication status, and the presence of CHD at study entry, separate models were used, stratifying for these measures.
The models were constructed to analyze the effect of interim cardiovascular events on the subsequent outcomes. We examined the role of interim events as a covariate in the time-dependent Cox proportional hazards models. Two-tailed probabilities were examined at a 2-sided α level of <0.05. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, Chicago, Illinois) and STATA (StataCorp, College Station, Texas).
Results
At baseline, ALVSD was present in 410 participants (7.3%), of whom 65.6% had mildly impaired LV function and 34.4% had moderate to severely impaired LV function.
Two comparison groups were used, a “reference group” with normal LV function and no history of HF (n = 4,976), and a second group with SLVSD (n = 104). HF with a preserved ejection fraction (≥55%) was present in 159 subjects (2.8%), and these patients were not included in the remainder of the analyses.
The baseline characteristics for those with ALVSD are listed in Table 1 . Compared to the reference group, ALVSD was associated with older age, male gender, and multiple subclinical and clinical disease characteristics. Multivariate analyses indicated that the following variables were associated with ALVSD after adjusting for other demographic, clinical, and biologic markers: male gender (odds ratio [OR] 2.56, 95% CI 1.82 to 3.60), CHD (OR 3.93, 95% CI 3.00 to 5.13), LV hypertrophy (OR 1.96, 95% CI 1.24 to 3.10), atrial fibrillation (OR 2.00, 95% CI 1.03 to 3.90), BMI (OR 1.05, 95% CI 1.02 to 1.09), and angiotensin-converting enzyme inhibitor use (OR 1.64, 95% CI 1.04 to 2.58).
Compared to the participants with SLVSD, ALVSD was associated with male gender, nonblack race, and greater systolic and diastolic blood pressure but fewer characteristics of subclinical and clinical disease ( Table 1 ). Of those with SLVSD, 38 (36.5%) had mildly impaired and 66 (63.5%) had moderate to severely impaired LV systolic function, the approximate inverse of the severity of LV systolic function noted for those with ALVSD. Multivariate analyses indicated that the following variables were associated with ALVSD, compared to SLVSD, after adjusting for the other demographic, clinical, and biologic markers: less CHD (OR 0.27, 95% CI 0.13 to 0.60), systolic blood pressure (OR 1.03, 95% CI 1.00 to 1.05), less angiotensin-converting enzyme inhibitor use (OR 0.40, 95% CI 0.16 to 0.96), less diuretic use (OR 0.18, 95% CI 0.07 to 0.46), and less digoxin use (OR 0.33, 95% CI 0.14 to 0.80).
The characteristics of the participants with ALVSD stratified by the severity of LV dysfunction are listed in Table 2 . ALVSD with moderate to severe LV dysfunction (LV ejection fraction <45%) was associated with a lower ankle-arm index, less hypertension, less current smoking, CHD, LV hypertrophy, and the use of digoxin compared to those with mild LV dysfunction (LV ejection fraction 45% to 55%). Multivariate analyses revealed that, after adjusting for other demographic, clinical, and biologic markers, male gender (OR 2.31, 95% CI 1.04 to 5.15), CHD (OR 2.80, 95% CI 1.58 to 4.94), current nonsmoker (OR 0.28, 95% CI 0.10 to 0.78), and lower hemoglobin (OR 0.81, 95% CI 0.66 to 0.99) were associated with moderate to severe LV dysfunction compared to mild LV dysfunction among the participants with ALVSD.
| Characteristic | Mildly Impaired (n = 269) | Moderate/Severely Impaired (n = 141) | p Value |
|---|---|---|---|
| Age (years) | 73.9 ± 6.1 | 74.7 ± 5.9 | 0.20 |
| Men | 174 (64.7%) | 104 (73.8%) | 0.062 |
| Black race | 31 (11.5%) | 15 (10.6%) | 0.79 |
| Systolic blood pressure (mm Hg) | 136.1 ± 20.7 | 138.3 ± 23.0 | 0.31 |
| Diastolic blood pressure (mm Hg) | 70.4 ± 12.6 | 72.5 ± 12.5 | 0.10 |
| Ankle-arm index | 1.06 ± 0.20 | 1.00 ± 0.22 | 0.003 ⁎ |
| Hypertension | 136 (50.6%) | 55 (39.0%) | 0.026 ⁎ |
| Diabetes mellitus | 63 (23.5%) | 29 (20.7%) | 0.52 |
| Body mass index (kg/m 2 ) | 27.2 ± 4.6 | 26.8 ± 4.4 | 0.35 |
| Current smoker | 33 (12.3%) | 8 (5.7%) | 0.034 ⁎ |
| Coronary heart disease | 97 (36.1%) | 81 (57.5%) | <0.001 ⁎ |
| Left ventricular hypertrophy on electrocardiogram | 16 (6.3%) | 16 (12.3%) | 0.044 ⁎ |
| ST-T abnormalities on electrocardiogram | 22 (8.7%) | 12 (9.2%) | 0.85 |
| Atrial fibrillation | 13 (4.8%) | 10 (7.1%) | 0.35 |
| Valvular abnormality | 27 (10.0%) | 21 (14.9%) | 0.15 |
| History of stroke | 14 (5.2%) | 10 (7.1%) | |
| Fractional shortening (%) | 35.5 ± 8.05 | 29.4 ± 10.2 | |
| Angiotensin-converting enzyme inhibitor | 25 (9.4%) | 13 (9.2%) | 0.96 |
| β Blocker | 45 (16.9%) | 19 (13.5%) | 0.37 |
| Diuretic | 74 (27.7%) | 42 (29.8%) | 0.66 |
| Antihypertensive | 154 (57.7%) | 76 (53.9%) | 0.46 |
| Digoxin | 28 (10.5%) | 28 (19.9%) | 0.009 ⁎ |
| Lipid-lowering medication | 14 (5.2%) | 11 (7.8%) | 0.31 |
| Creatinine (mg/dl) | 1.20 ± 0.63 | 1.21 ± 0.37 | 0.78 |
| Cholesterol (mg/dl) | 206.9 ± 40.0 | 202.6 ± 42.03 | 0.31 |
| Glucose (mg/dl) | 120.0 ± 50.9 | 112.4 ± 26.6 | 0.10 |
| Hemoglobin (g/dl) | 14.38 ± 1.51 | 14.45 ± 1.38 | 0.63 |
| C-reactive protein (mg/L) | 5.42 ± 9.20 | 6.12 ± 10.93 | 0.50 |
| Interleukin-6 (pg/ml) | 2.46 ± 2.13 | 2.60 ± 1.91 | 0.53 |
| Fibrinogen (mg/dl) | 323.3 ± 65.5 | 337.5 ± 77.8 | 0.053 |
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