Subclinical cardiovascular disease in older adults: insights from the Cardiovascular Health Study

Knowledge about the epidemiology of subclinical cardiovascular disease (SCVD) in older adults may hold the key for improved opportunities for primary prevention of cardiovascular disease (CVD), a top clinical and public health priority. This review reports findings on the prevalence of SCVD and the ability of SCVD measures to predict incident and adverse outcomes from one of the largest (N=5888) and most comprehensive prospective observational studies on SCVD in older adults, the Cardiovascular Health Study. According to a composite index that combined SCVD measures from different vascular beds, the overall prevalence of SCVD was 37%, making it as common as clinically overt CVD in older adults. SCVD measures strongly predicted incident CVD, stroke, mortality, frailty, and physical and cognitive decline, even after adjustment for traditional CVD risk factors. Ongoing research will address the potential use of SCVD for clinical decision making in older adults.     

Serum androgens and risk of atrial fibrillation in older men: The Cardiovascular Health Study

Background

Decline in serum androgens is common among older men and has been associated with cardiovascular disease, although its role in risk of atrial fibrillation (AF) has not been well defined.

Hypothesis

Low serum androgens are associated with an increased risk of AF.

Methods

We examined the prospective associations between testosterone, its more active metabolite dihydrotestosterone (DHT), and sex hormone–binding globulin (SHBG) with risk of AF among 1019 otherwise healthy men with average age 76.3 ±4.9 years in the Cardiovascular Health Study.

Results

After median follow‐up of 9.5 years, 304 (30%) men developed AF. We detected a nonlinear association with risk of incident AF in both free and total DHT, in which subjects with the lowest levels had a higher risk of incident AF. After adjustment for demographics, clinical risk factors, left atrial diameter, and serum NT‐proBNP levels, men with free DHT <0.16 ng/dL were at increased risk compared with men with higher levels (hazard ratio: 1.48, 95% confidence interval: 1.01–2.17, P <0.05). Sensitivity analyses confirmed that the increased risk was not cutpoint‐specific, with a significant association noted up to cutpoints <~0.2 ng/dL. We also detected a complex nonlinear association between SHBG and incident AF, in which subjects in the middle quintile (52.9–65.3 nmol/L) had increased risk.

Conclusions

Among older men, low free DHT is associated with an increased risk of incident AF. Further studies are needed to explore mechanisms for this association.     

Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study

BACKGROUND: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population. METHODS: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI. RESULTS: The percentage of participants with ABI decline was 9.5% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in non-cases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95% CI, 1.02-2.96); hypertension, 1.64 (95% CI, 1.18-2.28); diabetes, 1.77 (95% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95% CI, 1.05-2.89). CONCLUSION: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors.     

Risk factors for cardiovascular disease across the spectrum of older age: The Cardiovascular Health Study

Objective: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age. Methods: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65–74, 75–84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP). Results: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65–74, 75–84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65–74, 75–84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45). Conclusions: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.     

Serum folate and cardiovascular disease mortality among US men and women

BACKGROUND: Folate has been linked to cardiovascular disease (CVD) through its role in homocysteine metabolism. OBJECTIVE: To assess the relationship between serum folate and CVD mortality. DESIGN: In this prospective study, serum folate concentrations were measured on a subset of adults during the Second National Health and Nutrition Examination Survey (1976-1980) and vital status ascertained after 12 to 16 years. SETTING AND PATIENTS: A national probability sample consisting of 689 adults who were 30 to 75 years of age and did not have a history of CVD at baseline. MAIN OUTCOME MEASURE: Vital status was determined by searching national databases that contained information about US decedents. RESULTS: The associations between serum folate and CVD and all-cause mortality differed by diabetes status (P =.04 and P =.03, respectively). Participants without diabetes in the lowest compared with the highest serum folate tertile had more than twice the risk of CVD mortality after adjustment for age and sex (relative risk [RR], 2.64; 95% confidence interval [CI], 1.15-6.09). This increased risk for participants in the lowest tertile was attenuated after adjustment for CVD risk factors (RR, 2.28; 95% CI, 0.96-5.40). Serum folate tertiles were not significantly associated with total mortality, although the age- and sex-adjusted risk was increased for participants in the lowest compared with highest tertile (RR, 1.74; 95% CI, 0.96-3.15). Risk estimates for participants with diabetes were unstable because of the small sample size (n = 52). CONCLUSION: These data suggest that low serum folate concentrations are associated with an increased risk of CVD mortality among adults who do not have diabetes. Arch Intern Med. 2000;160:3258-3262.     

Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group

INTRODUCTION: As part of the baseline examination in the Cardiovascular Health Study, sleep disturbance symptoms including snoring and daytime sleepiness, were assessed as potential risk factors or precipitants of cardiovascular disease (CVD). Because of the association of sleep disturbance with poorer health and the possible associations of sleep apnea with CVD, we hypothesized that those with poorer sleep or daytime sleepiness may be at increased risk of mortality or incident CVD. SETTING: Participants (n = 5888) were recruited in 1989, with an additional minority cohort recruited in 1993, in four US communities for a cohort study designed to evaluate risk factors for cardiovascular disease. METHODS: An interview-administered questionnaire regarding health and sleep habits with ongoing ascertainment of total mortality and cardiovascular disease morbidity and mortality, including total CVD morbidity and mortality, incident myocardial infarction, and congestive heart failure. RESULTS: Daytime sleepiness was the only sleep symptom that was significantly associated with mortality in both men and women. The unadjusted hazard ratio was 2.12 (1.66, 2.72) in women and 1.40 (1.12, 1.73) in men. Men who reported difficulty falling asleep also had an increased mortality rate (HR = 1.43 (1.14, 1.80)) which was not seen in women. The risks were attenuated with adjustment for age but remained significant for daytime sleepiness in women (HR = 1.82 (1.42, 2.34)) and for difficulty falling asleep in men. (HR = 1.29 (1.03, 1.63)). Frequent awakenings, early morning awakening, and snoring were not associated with a significantly increased risk of mortality in these older men and women. Crude event rates were evaluated for total incident cardiovascular morbidity and mortality, incident myocardial infarction, and incident congestive heart failure (CHF). Incident CVD rates were higher in both men and women with daytime sleepiness. The aged adjusted HR was 1.35 (95% CI = 1.03, 1.76) in men and was 1.66 (95% CI = 1.28, 2.16) in women. Incident CVD was not higher in those with any other sleep disturbance including snoring. The risk of CVD events associated with daytime sleepiness was attenuated but remained significant in women after adjustment for age. Incident myocardial infarction (MI) rates were also higher in women with daytime sleepiness but were not significantly higher in men. Incident CHF rates were increased in both men and women with daytime sleepiness. In men, the age adjusted HR was 1.49 (95% CI, 1.12- 1.98) and in women, was 2.21 (95% CI, 1.64-2.98). Women reporting both daytime sleepiness and frequent awakening had a hazard ratio of 2.34 (95% CI, 1.66-3.29) for incident CHF compared with those with daytime sleepiness but without frequent awakening. This interaction was not found in men. CONCLUSIONS: In this study, daytime sleepiness was the only sleep disturbance symptom that was associated with mortality, incident CVD morbidity and mortality, MI, and CHF. These findings were stronger in women than men, i.e., the associations persisted for mortality, CVD, and CHF in women after adjustment for age and other factors. Thus, a report of daytime sleepiness identifies older adults at increased risk for total and cardiovascular mortality, and is an independent risk factor in women.     

Health outcomes in older men with localized prostate cancer: results from the Prostate Cancer Outcomes Study

Purpose

We compared health-related quality-of-life (HRQOL) outcomes and survival of men with localized prostate cancer who received aggressive treatment with those receiving conservative management.

Methods

We conducted a population-based cohort study of men aged 75 to 84 years when diagnosed with a clinically localized cancer in 1994 or 1995. We used medical record abstractions and patient surveys to obtain clinical and HRQOL data at diagnosis and 24-month follow-up. We used a propensity score method to adjust for baseline differences between men treated with radical prostatectomy or radiation therapy (n = 175) and men who received hormone therapy or no treatment (n = 290). Propensity scores were used in regression analyses comparing HRQOL outcomes between treatment groups. Overall and disease-specific survivals were estimated with multivariate proportional hazards models.

Results

At 24 months following diagnosis, aggressively treated men were more likely to report daily urinary leakage (odds ratio [OR] = 2.9, 95% confidence interval [CI] 1.2-7.0) and to be bothered by urinary problems (OR = 5.1, 95% CI, 1.3-9.1) and sexual problems (OR = 2.8, 95% CI, 1.2-6.3). The adjusted disease-specific mortality hazard ratio was 0.43 (95% CI, 0.15, 1.28), favoring aggressive treatment. However, the absolute 5-year disease-specific survival difference was only 6% (98% vs 92%). Over 80% of all deaths were from other causes.

Conclusions

Aggressive treatment was associated with significant decreases in disease-specific HRQOL. However, men who were aggressively treated for localized cancer had a minimally reduced absolute risk of dying from prostate cancer. Physicians and older patients should consider these outcomes in making decisions about screening and treatment.     

C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study

BACKGROUND: Determination of C-reactive protein (CRP) level has been suggested to improve cardiovascular disease (CVD) risk assessment. This study examines the utility of CRP levels to assess CVD risk in a community setting. METHODS: We performed a prospective observational cohort study on a community population sample. A total of 1949 men and 2497 women without CVD from the Framingham Heart Study underwent CVD risk factor assessment. Initial CVD events during 8 years of follow-up were recorded. RESULTS: There were 283 major CVD and 160 major coronary heart disease incident events. Age-, sex-, and multivariable-adjusted analyses generally used CRP level categories of less than 1, 1 to 3, and greater than 3 mg/L. In age- and sex-adjusted models, the traditional risk factors and elevated CRP levels indicated increased risk. The age- and sex-adjusted relative risk (RR) and 95% confidence interval (CI) of CRP level greater than 3 mg/L for major CVD was elevated (RR, 1.60; 95% CI, 1.19-2.14), with evidence of attenuation (RR, 1.22; 95% CI, 0.90-1.66) in multivariable models. The C statistic, a measure of the discriminatory capability of the prediction models, was 0.74 for prediction of major CVD with age and CRP level. In multivariable models that included traditional risk factors, the C statistic was 0.78, a value that was unchanged with the addition of CRP to the multivariable model. Similar relations were noted for major coronary heart disease events. CONCLUSION: Elevated CRP level provided no further prognostic information beyond traditional office risk factor assessment to predict future major CVD and major coronary heart disease in this population sample.     

Usefulness of T-axis deviation as an independent risk indicator for incident cardiac events in older men and women free from coronary heart disease (the Cardiovascular Health Study).

T-axis shift has been reported to be an indicator of increased mortality risk. We evaluated the association of spatial T-axis deviation with incident coronary heart disease (CHD) events in older men and women free from clinically overt CHD. Spatial T-axis deviation was measured from the standard 12-lead electrocardiogram of a subgroup of 4,173 subjects considered free of CHD at baseline in the Cardiovascular Health Study, a prospective cohort study of risk factors for CHD and stroke in older men and women. Cox regression analysis was used to evaluate the association of altered repolarization with the risk of incident CHD events. The prevalence of marked T-axis deviation (> or =45 degrees ) was 12%. During the median follow-up of 7.4 years, there were 161 CHD deaths, 743 deaths from all causes, and 679 incident CHD events. Adjusting for demographic and clinical risk factors, including other electrocardiographic abnormalities, there was a nearly twofold excess risk of CHD death, and approximately a 50% excess risk of incident CHD and all-cause mortality for those with marked T-axis deviation. From other electrocardiographic abnormalities, only QT prolongation was associated with excess risk for incident CHD comparable to that for abnormal T-axis deviation. These results suggest that T-axis deviation is an easily quantified marker for subclinical disease and an independent indicator for the risk of incident CHD events in older men and women free of CHD.     

Adipose tissue fatty acids in Scottish men and women: results from the Scottish Heart Health Study.

The fatty acid composition of adipose tissue from 4114 men and women across 22 districts of Scotland is described. A biopsy of subcutaneous adipose tissue was obtained from the upper arm using a skin biopsy punch. Overall the proportion of saturated fatty acids was lower in women and those of monounsaturated and polyunsaturated higher than in men. There were significant effects of age on adipose tissue fatty acid composition, particularly in women, where the proportion of saturated fatty acids decreased and that of monounsaturated fatty acids increased with advancing age. The fatty acid composition of adipose tissue varied among the districts studied. The district standardised mortality ratio for coronary heart disease was positively correlated with the district mean oleic acid value and inversely correlated with the district mean linoleic acid value. This paper supports the importance of adipose tissue fatty acids as indicators of risk factor status for coronary heart disease.     

Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study

BACKGROUND: The association of cystatin C, a novel marker of renal function, with risk for developing complications related to peripheral arterial disease (PAD) has not been examined. METHODS: We evaluated the hypothesis that a high cystatin C concentration is independently associated with future PAD events among 4025 participants in the Cardiovascular Health Study who underwent serum cystatin C measurement at the 1992-1993 visit and who did not have PAD at baseline. The association of cystatin C quintiles with time to first lower-extremity PAD procedure (bypass surgery, angioplasty, or amputation) was evaluated using multivariable proportional hazards models. Secondary analyses were conducted using quintiles of serum creatinine level and estimated glomerular filtration rate (eGFR). RESULTS: The annualized risk of undergoing a procedure for PAD was 0.43% per year among participants in the highest cystatin C quintile (>1.27 mg/L) compared with 0.21% per year or less in all other quintiles. After multivariable adjustment for known risk factors for PAD, elevated cystatin C levels remained associated with the outcome (hazard ratio, 2.5 for highest vs lowest quintile of cystatin C, 95% confidence interval, 1.2-5.1). The highest quintiles of serum creatinine level and eGFR were not associated with future PAD events in either unadjusted or adjusted analyses. CONCLUSION: Elevated concentrations of cystatin C were independently predictive of incident PAD events among community-dwelling elderly patients.     

Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group

Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.     

Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study

OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome. DESIGN: Prospective cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline. MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly. RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95% confidence interval (CI)=0.71-1.14), 0.93 (95% CI=0.73-1.20), 0.76 (95% CI=0.53-1.10), and 0.58 (95% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9% to 10% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele. CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.     

Dementia and Alzheimer's disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort

OBJECTIVES: To determine whether coronary artery disease, peripheral arterial disease (PAD), or noninvasive markers of cardiovascular disease (CVD) predict the onset of dementia and Alzheimer's disease (AD). DESIGN: Longitudinal cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Men and women (N=3,602) with a brain magnetic resonance imaging (MRI) scan but no dementia were followed for 5.4 years. Participants with stroke were excluded. MEASUREMENTS: Neurologists and psychiatrists classified incident cases of dementia and subtype using neuropsychological tests, examination, medical records and informant interviews. CVD was defined at the time of the MRI scan. Noninvasive tests of CVD were assessed within 1 year of the MRI. Apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income were assessed as potential confounders. RESULTS: The incidence of dementia was higher in those with prevalent CVD, particularly in the subgroup with PAD. The rate of AD was 34.4 per 1,000 person-years for those with a history of CVD, versus 22.2 per 1,000 person-years without a history of CVD (adjusted hazard ratio (HR)=1.3, 95% confidence interval (CI)=1.0-1.7). Rates of AD were highest in those with PAD (57.4 vs 23.7 per 100 person-years, adjusted HR=2.4, 95% CI=1.4-4.2). Results were similar with further exclusion of those with vascular dementia from the AD group. A gradient of increasing risk was noted with the extent of vascular disease. CONCLUSION: Older adults with CVD other than stroke had a higher risk of dementia and AD than did those without CVD. The risk was highest in people with PAD, suggesting that extensive peripheral atherosclerosis is a risk factor for AD.     

Favorable cardiovascular risk profile and 10-year coronary heart disease incidence in women and men: results from the Progetto CUORE.

BACKGROUND: Cardiovascular risk factor research has recently broadened its focus based on new data indicating the benefits of low risk, i.e. favorable levels of all major risk factors. The aims of this study were to assess further the relation of low risk to coronary heart disease risk, and implications for prevention. DESIGN: We conducted a prospective population-based Italian study, of 7438 men and 13 009 women aged 35-69 years, with a mean follow-up of 10.4 years and validated first coronary events. METHODS: Baseline coronary heart disease risk was classified into three categories: low risk; unfavorable but not high risk; and high risk. To analyze the relation of these risk profiles to coronary heart disease incidence, age-adjusted, sex-averaged coronary heart disease incidence was calculated for persons free of coronary heart disease and stroke, stratified as baseline low risk, unfavorable but not high risk or high risk. To assess the independent relationship of individual risk factors to coronary heart disease incidence, multivariate proportional hazards models were computed for combinations of risk factors. RESULTS: Only 2.7% of participants met low risk criteria; 81.4% were high risk. Age-adjusted coronary heart disease incidence for the whole cohort was 37.1 out of 10000 person-years (men 59.0; women 15.3). No coronary heart disease events occurred in low-risk men, only two in low-risk women. For women and men who were not high risk, the age-sex standardized coronary heart disease rate was 62% lower than for high-risk participants. Blood pressure, need for antihypertensive medication, smoking, hyperglycemia, diabetes, total and high-density lipoprotein cholesterol were independently related to coronary heart disease risk. CONCLUSIONS: Favorable levels of all modifiable readily measured risk factors - rare among Italian adults - assure minimal coronary heart disease risk. Population-wide prevention is needed, especially improved lifestyles, to increase the proportion of the population at low risk.