Lawton S. Cooper

Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure: HF-ACTION Randomized Controlled Trial

CONTEXT Guidelines recommend that exercise training be considered for medically stable outpatients with heart failure. Previous studies have not had adequate statistical power to measure the effects of exercise training on clinical outcomes. OBJECTIVE To test the efficacy and safety of exercise training among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial of 2331 medically stable outpatients with heart failure and reduced ejection fraction. Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) were randomized from April 2003 through February 2007 at 82 centers within the United States, Canada, and France; median follow-up was 30 months. INTERVENTIONS Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, or usual care alone. MAIN OUTCOME MEASURES Composite primary end point of all-cause mortality or hospitalization and prespecified secondary end points of all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or heart failure hospitalization. RESULTS The median age was 59 years, 28% were women, and 37% had New York Heart Association class III or IV symptoms. Heart failure etiology was ischemic in 51%, and median left ventricular ejection fraction was 25%. Exercise adherence decreased from a median of 95 minutes per week during months 4 through 6 of follow-up to 74 minutes per week during months 10 through 12. A total of 759 patients (65%) in the exercise training group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93 [95% confidence interval {CI}, 0.84-1.02]; P = .13). There were nonsignificant reductions in the exercise training group for mortality (189 patients [16%] in the exercise training group vs 198 patients [17%] in the usual care group; HR, 0.96 [95% CI, 0.79-1.17]; P = .70), cardiovascular mortality or cardiovascular hospitalization (632 [55%] in the exercise training group vs 677 [58%] in the usual care group; HR, 0.92 [95% CI, 0.83-1.03]; P = .14), and cardiovascular mortality or heart failure hospitalization (344 [30%] in the exercise training group vs 393 [34%] in the usual care group; HR, 0.87 [95% CI, 0.75-1.00]; P = .06). In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81-0.99; P = .03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82-1.01; P = .09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74-0.99; P = .03) for cardiovascular mortality or heart failure hospitalization. Other adverse events were similar between the groups. CONCLUSIONS In the protocol-specified primary analysis, exercise training resulted in nonsignificant reductions in the primary end point of all-cause mortality or hospitalization and in key secondary clinical end points. After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modest significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study

OBJECTIVE To develop protocols to photograph and evaluate retinal vascular abnormalities in the Atherosclerosis Risk in Communities (ARIC) Study; to test reproducibility of the grading system; and to explore the relationship of these microvascular changes with blood pressure. DESIGN Population-based, cross-sectional study. PARTICIPANTS Among 4 examination centers, 11,114 participants (48-73 years of age) at their third triennial examination, after excluding persons with diabetes from this analysis. METHODS One eye of each participant was photographed by technicians with nonmydriatic fundus cameras. Reading center graders evaluated focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy by examining slides on a light box and measured diameters of all vessels in a zone surrounding the optic disc on enhanced digitized images. To gauge generalized narrowing, vessel diameters were combined into central arteriolar and venular equivalents with formulas adjusting for branching, and the ratio of equivalents (A/V ratio) was calculated. MAIN OUTCOME MEASURES Retinal vascular abnormalities, mean arteriolar blood pressure (MABP). RESULTS Among 11,114 participants, photographs were obtained of 99%, with quality sufficient to perform retinal evaluations in 81%. In the 9040 subjects with usable photographs, A/V ratio (lower values indicate generalized arteriolar narrowing) ranged from 0.57 to 1.22 (median = 0.84, interquartile range = 0.10), focal arteriolar narrowing was found in 7%, AV nicking in 6%, and retinopathy in 4%. Because of attrition of subjects and limitation of methods, prevalence of abnormality was likely underestimated. Controlling for gender, race, age, and smoking status, these retinal changes were associated with higher blood pressure. For every 10-mmHg increase in MABP, A/V ratio decreased by 0.02 unit (P < 0.0001), focal arteriolar narrowing had an odds ratio (OR) of 2.00 (95% confidence interval [CI] = 1.87-2.14), AV nicking had an OR of 1.25 (95% CI = 1.16-1.34), and retinopathy had an OR of 1.25 (95% CI = 1.15-1.37). For any degree of generalized narrowing, individuals with focal narrowing had MABP approximately 8 mmHg higher than those without (P < 0.0001). Masked replicate assessment of a sample found the following reproducibility: for A/V ratio, correlation coefficient = 0.79 and median absolute difference = 0.03; for focal arteriolar narrowing, kappa = 0.45; for AV nicking, kappa = 0.61; and for retinopathy, kappa = 0.89. CONCLUSION Protocols have been developed for nonmydriatic fundus photography and for evaluation of retinal vascular abnormalities. Several microvascular changes were significantly associated with higher blood pressure; follow-up will show whether these are predictive of later cerebrovascular or cardiovascular disease independently of other known risk factors.

Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994.

BACKGROUND AND METHODS To clarify the determinants of contemporary trends in mortality from coronary heart disease (CHD), we conducted surveillance of hospital admissions for myocardial infarction and of in-hospital and out-of-hospital deaths due to CHD among 35-to-74-year-old residents of four communities of varying size in the United States (a total of 352,481 persons in 1994). Between 1987 and 1994, we estimate that there were 11,869 hospitalizations for myocardial infarction (on the basis of 8572 hospitalizations sampled) and 3407 fatal coronary events (3023 sampled). RESULTS The largest average annual decrease in mortality due to CHD occurred among white men (change in mortality, -4.7 percent; 95 percent confidence interval, -2.2 to -7.1 percent), followed by white women (-4.5 percent; 95 percent confidence interval, -0.7 to -8.2 percent), black women (-4.1 percent; 95 percent confidence interval, -10.3 to +2.5 percent), and black men (-2.5 percent; 95 percent confidence interval, -6.9 to +2.2 percent). Overall, in-hospital mortality from CHD fell by 5.1 percent per year, whereas out-of-hospital mortality declined by 3.6 percent per year. There was no evidence of a decline in the incidence of hospitalization for a first myocardial infarction among either men or women; in fact, such hospital admissions increased by 7.4 percent per year (95 percent confidence interval for the change, +0.5 to +14.8 percent) among black women and 2.9 percent per year (95 percent confidence interval, -3.6 to +9.9 percent) among black men. Rates of recurrent myocardial infarction decreased, and survival after myocardial infarction improved. CONCLUSIONS From 1987 to 1994, we observed a stable or slightly increasing incidence of hospitalization for myocardial infarction. Nevertheless, there were significant annual decreases in mortality from CHD. The decline in mortality in the four communities we studied may be due largely to improvements in the treatment and secondary prevention of myocardial infarction.

Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study

BACKGROUND Retinal microvascular abnormalities reflect damage from hypertension and other vascular processes. We examined the relation of such abnormalities to incident stroke. METHODS A cohort of 10358 men and women (aged 51 to 72 years) living in four US communities underwent retinal photography and standard grading for retinal microvascular abnormalities. The calibres of all retinal arterioles and venules were measured after digital conversion of the photographs, and a summary arteriole-to-venule ratio (AVR) was calculated as an index of arteriolar narrowing (smaller AVR indicates greater narrowing). Cases of incident stroke admitted to hospital were identified and validated by case record reviews. FINDINGS Over an average of 3.5 years, 110 participants had incident strokes. After adjustment for age, sex, race, 6-year mean arterial blood pressure, diabetes, and other stroke risk factors, most retinal microvascular characteristics were predictive of incident stroke, with adjusted relative risks of 2.58 (1.59-4.20) for any retinopathy, 3.11 (1.71-5.65) for microaneurysms, 3.08 (1.42-6.68) for soft exudates, 2.55 (1.27-5.14) for blot haemorrhages, 2.26 (1.00-5.12) for flame-shaped haemorrhages, and 1.60 (1.03-2.47) for arteriovenous nicking. The relative risk of stroke increased with decreasing AVR (p=0.03). The associations were similar for ischaemic strokes specifically, and for strokes in individuals with hypertension, either with or without diabetes. INTERPRETATION Retinal microvascular abnormalities are related to incident stroke. The findings support a microvascular role in the pathogenesis of stroke. They suggest that retinal photography may be useful for cerebrovascular-risk stratification in appropriate populations.

Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease

BACKGROUND Many patients have symptoms suggestive of coronary artery disease (CAD) and are often evaluated with the use of diagnostic testing, although there are limited data from randomized trials to guide care. METHODS We randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure. RESULTS The mean age of the patients was 60.8±8.3 years, 52.7% were women, and 87.7% had chest pain or dyspnea on exertion. The mean pretest likelihood of obstructive CAD was 53.3±21.4%. Over a median follow-up period of 25 months, a primary end-point event occurred in 164 of 4996 patients in the CTA group (3.3%) and in 151 of 5007 (3.0%) in the functional-testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; P=0.75). CTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%, P=0.02), although more patients in the CTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%). The median cumulative radiation exposure per patient was lower in the CTA group than in the functional-testing group (10.0 mSv vs. 11.3 mSv), but 32.6% of the patients in the functional-testing group had no exposure, so the overall exposure was higher in the CTA group (mean, 12.0 mSv vs. 10.1 mSv; P<0.001). CONCLUSIONS In symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550.).

Prospective study of markers of hemostatic function with risk of ischemic stroke

BACKGROUND Several markers of hemostatic function and inflammation have been associated with increased risk of coronary heart disease, but prospective evidence for their role in ischemic stroke is scant. METHODS AND RESULTS The Atherosclerosis Risk in Communities (ARIC) Study measured several of these markers in more than 14 700 participants 45 to 64 years old who were free of cardiovascular disease and were followed up for 6 to 9 years for occurrence of ischemic stroke (n=191). There was no apparent association between ischemic stroke incidence and factor VIIc, antithrombin III, platelet count, or activated partial thromboplastin time. After adjustment for multiple cardiovascular risk factors, von Willebrand factor, factor VIIIc, fibrinogen, and white blood cell count were positively associated and protein C was negatively but nonsignificantly associated with ischemic stroke incidence in regression analyses based on either continuous variables or fourths of the variable distributions. The adjusted relative risk (and 95% CI) for ischemic stroke in those in the highest versus lowest fourth were: von Willebrand factor, 1.71 (1.1 to 2.7); factor VIIIc, 1.93 (1.2 to 3.1); white blood cell count, 1.50 (0.9 to 2.4); fibrinogen, 1.26 (0.8 to 2.0); and protein C, 0.65 (0.4 to 1.0). CONCLUSIONS This study offers modest support for the hypothesis that some markers of hemostatic function and inflammation can identify groups of middle-aged adults at increased risk of stroke. These factors may play a role in the pathogenesis of ischemic stroke.

Presence and Severity of Cerebral White Matter Lesions and Hypertension, Its Treatment, and Its Control The ARIC Study

BACKGROUND AND PURPOSE White matter lesions (WML) may result from cerebral hypoperfusion or ischemia. We investigated the association of WML with blood pressure, hypertension, and its treatment and control. METHODS A random sample of 1920 participants aged 55 to 72 years in the Atherosclerosis Risk in Communities Study (ARIC) was examined. Spin-density 1.5-T MRI scan images were coded from 0 for normal to 9 for most severe WML. Hypertension was defined as systolic or diastolic pressure > or = 140/90 mm Hg or use of antihypertensive medication. RESULTS The percentages of persons with WML grades 0 through 2 and 3 through 9, respectively, were as follow: normotensive, 92.4% and 7.6%, versus all hypertensive subjects, 83% and 17% (P < .001); and treated controlled hypertensive, 86% and 14%, versus treated uncontrolled hypertensive subjects, 76% and 24% (P = .003). Multivariable adjusted odds ratios (95% confidence intervals) for WML grade > or = 3 relative to normotensive subjects was 2.34 (1.71 to 3.20) for all hypertensives, 1.99 (1.19 to 3.08) for untreated hypertensives, 1.94 (1.32 to 2.85) for treated controlled hypertensives, and 3.40 (2.30 to 5.03) for treated uncontrolled hypertensives. After additional adjustment for hypertension duration, treatment, and control status, the odds ratios (95% confidence intervals) for a 1 SD increase of systolic and diastolic blood pressure were 1.43 (1.11 to 1.85) and 1.16 (0.94 to 1.43), respectively. CONCLUSIONS Hypertension is associated with increased odds of WML, and treated uncontrolled hypertensive subjects have greater odds of WML than those with treated controlled hypertension. The data suggest that the level of blood pressure, especially systolic blood pressure, is related to WML, additional to the effects of categorically defined hypertension and its treatment and control status.

The Prevalence and Severity of White Matter Lesions, Their Relationship with Age, Ethnicity, Gender, and Cardiovascular Disease Risk Factors: The ARIC Study

White matter lesions (WMLs) detected by cerebral magnetic resonance imaging (MRI) are putatively a consequence of cerebral hypoperfusion or ischemia. We investigated the prevalence, severity and correlates of WMLs in a population-based sample of 1,920 African-American and European-American men and women aged 55-72 years, during the second follow-up examination of the Atherosclerosis Risk in Communities Study. The spin density images from 1.5-tesla MRI scans were used to define WMLs using a 0-9 scale with 0 for normal and 9 for most severe WMLs. Age was positively associated with the prevalence (percent) and severity of WMLs. African-Americans had lower overall prevalence of WMLs, but a higher prevalence of relatively more severe WMLs, than European-Americans. After adjusting for age, sex, and ethnicity, WMLs were significantly associated with smoking, lower education, hypertension, systolic blood pressure, and pulse pressure, and weakly associated with diastolic blood pressure. The associations of smoking, alcohol intake, systolic and diastolic blood pressure, pulse, pressure, and hypertension were stronger in African-Americans than in European-Americans (p < 0.15 for interactions by ethnicity). This population-based MRI study documents significant relationships between several cardiovascular disease risk factors and WMLs. The findings suggest that such factors play a role in the pathogenesis of WMLs, an elements linked to hypoperfusion and/or fluid accumulation, which presumably lead to WMLs. African-Americans exhibited both a higher proportion of normal white matter and a higher proportion of relatively more severe WMLs than European-Americans.

Are Retinal Arteriolar Abnormalities Related to Atherosclerosis? The Atherosclerosis Risk in Communities Study

The objective of this study was to describe associations of retinal arteriolar abnormalities with clinical and subclinical manifestations of atherosclerosis and a broad group of risk factors for vascular disease. A biracial population of 8772 adults (aged 48 to 72 years) living in 4 communities was examined from 1993 to 1995 were studied for that purpose. Retinal arteriovenous nicking and focal arteriolar narrowing were determined by light-box grading of a 45 degrees fundus photograph by use of a standardized protocol. Diameters of arterioles and venules were measured in digitized photographs, and a summary arteriolar-to-venular ratio was derived as an index of generalized arteriolar narrowing. Focal arteriolar narrowing was associated only with hypertension. Generalized arteriolar narrowing was associated with carotid plaque but not with any other evidence of atherosclerosis, either clinical (cardiovascular disease or stroke) or subclinical (carotid or popliteal artery thickness or lower limb obstructive disease), or with plasma cholesterol. It was also associated with smoking, with inflammatory markers (white blood cell count, fibrinogen, and reduced albumin), and with the triglyceride and high density lipoprotein cholesterol changes associated with inflammation. Arteriovenous nicking was inconsistently associated with subclinical atherosclerosis. It was not associated with cardiovascular disease, stroke, or plasma cholesterol. Arteriovenous nicking was associated with markers of inflammation and vascular endothelial dysfunction (von Willebrand factor and factor VIII). Arteriolar narrowing and nicking appear to be related to hypertension and inflammatory factors. Nicking may also be related to endothelial dysfunction. Results suggest that these arteriolar changes are pathologically distinct from atherosclerosis. Including their measurement in population studies may permit evaluation of the independent contribution of arteriolar disease to various ischemic diseases of the heart, brain, and other organs.

Cigarette Smoking and Other Risk Factors for Silent Cerebral Infarction in the General Population

BACKGROUND AND PURPOSE Silent cerebral infarctions (SCIs) have a prevalence between 10% and 40% in the transient ischemic attack population and have been associated with increased mortality and morbidity; however, little is known about the prevalence and risk factors for SCI in the general population. This report focuses on the role of cigarette smoking and other risk factors for SCI in the general population. METHODS MRI scans were performed on 1737 participants selected from the general population as part of the Atherosclerosis Risk in Communities Study. Smoking status and other major cerebrovascular risk factors were assessed, and associations between smoking status and SCIs were established with the use of ANCOVA. RESULTS Overall, the prevalence of SCI in this population aged 55 to 70 years was 11%. Cigarette smoking had an ordered association (P=0.029) with the presence of SCI, with the odds ratio (OR) of nonsmoking participants exposed to environmental tobacco smoke being 1.06 (95% confidence interval [CI], 0.64 to 1.75) times as great as for nonsmokers not exposed; the OR of past smokers was 1.16 (95% CI, 0.74 to 1.83) times greater, and the OR of current smokers was 1.88 (95% CI, 1.13 to 3.13) times greater. An increased prevalence was also noted among black, older, and hypertensive participants. CONCLUSIONS This report is among the first to examine the risk factors for SCI in the general population and finds a relatively high overall prevalence (11%). There is an ordered relationship between increasing exposure to cigarette smoke and the presence of SCI that parallels the relationship between smoking and carotid atherosclerosis. The magnitude of the association with smoking is substantial compared with the effect of hypertension and other traditional cerebrovascular risk factors. The reduction in prevalence of SCI between current and past smokers and the trend that increased pack-years of smoking is related to increased prevalence of SCI are both additional arguments for smoking avoidance and cessation.