David Lefkowitz

Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.

BACKGROUND HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease. METHODS AND RESULTS Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02). CONCLUSIONS In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.

Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.

Background and Purpose— Magnetic resonance imaging (MRI) scans in the elderly commonly show white matter findings that may raise concerns. We sought to document incidence, manifestations, and predictors of worsening white matter grade on serial imaging. Methods— The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people aged 65 years and older, of whom 1919 have had extensive initial and follow-up evaluations, including 2 MRI scans separated by 5 years. Scans were read without clinical information in standard side-by-side fashion to determine worsening white matter grade. Results— Worsening was evident in 538 participants (28%), mostly (85%) by 1 grade. Although similar at initial scan, participants with worsening white matter grade, compared with those without, experienced greater decline on modified Mini-Mental State examination and Digit-Symbol Substitution test (both P≤0.001) after controlling for potential confounding factors, including occurrence of transient ischemic attack or stroke between scans. Independent predictors of worsening white matter grade included cigarette smoking before initial scan and infarct on initial scan. Otherwise, predictors differed according to white matter grade on initial scan. For low initial grade, increased age, increased diastolic blood pressure, increased high-density lipoprotein cholesterol, and decreased low-density lipoprotein cholesterol were associated with increased risk of worsening. For high initial grade, any cardiovascular disease and low ankle–arm index were associated with decreased risk of worsening, whereas use of diuretics and statins were associated with increased risk. Conclusion— Worsening white matter grade on serial MRI scans in elderly is common, is associated with cognitive decline, and has complex relations with cardiovascular risk factors.

Daytime Sleepiness Predicts Mortality and Cardiovascular Disease in Older Adults

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.

Cognitive Impairment and Decline Are Associated with Carotid Artery Disease in Patients without Clinically Evident Cerebrovascular Disease

Context While stroke is a known cause of cognitive impairment, the relationship between carotid artery stenosis and cognitive function in people without a history of stroke is unclear. Contribution In this study of 4006 right-handed individuals 65 years of age and older, left-sided carotid artery stenosis of at least 75% was associated with cognitive impairment at baseline and cognitive decline over 5 years. This association persisted after right-sided carotid stenosis and cardiovascular risk factors were taken into account, which means that left-sided stenosis is more than simply an indicator of cardiovascular disease. Cautions This observational study does not constitute evidence that treatment of left-sided stenosis would benefit cognition. The Editors Cognitive impairment is common in elderly persons, with a prevalence of 25% in those 65 years of age or older and 65% in those 85 years of age or older (1). It is associated with disability, institutionalization, and early death (2, 3). Cerebral infarction contributes to cognitive impairment in approximately 50% of cases (3), sometimes in conjunction with Alzheimer disease (4). Imaging studies of the brain may reveal infarction in patients without history of stroke or transient ischemic attack (5), and these silent infarctions have been associated with cognitive impairment (5, 6). Furthermore, brain hypoperfusion may result in ischemic injury without evidence of infarction (7). Thus, silent cerebral infarction and brain hypoperfusion may be important causes of cognitive impairment. Markers of atherosclerotic disease of the internal carotid artery and common carotid artery have been associated with brain injury. High-grade stenosis of the internal carotid artery accounts for 20% to 30% of ischemic strokes (8). Stenosis of the internal carotid artery and intimamedia thickness of the internal and common carotid arteries are associated with silent cerebral infarction and symptomatic infarctions that are ipsilateral or contralateral to the side of maximal disease (9-11). Some studies have suggested that stenosis of the internal carotid artery may be a risk factor for cognitive impairment even in persons without a history of stroke, but other studies have not demonstrated such an association (12). Small samples, variable definitions of internal carotid artery stenosis, and case selection may have contributed to these inconsistent results. Carotid artery disease is also associated with underlying vascular disease and its risk factors. Hypertension, diabetes mellitus, cigarette smoking, and dyslipidemia are associated with an increased risk for carotid artery disease (13, 14), but these same risk factors may also cause ischemic injury to the brain independent of carotid disease (15). Furthermore, several risk factors for vascular disease are associated with cognitive impairment (16-25). This may be because carotid artery disease causes cognitive impairment, or because it is a marker for underlying risk factors and vascular disease that are themselves the cause. Epidemiologic studies have not distinguished between these possibilities (12). The distinction is important because a direct intervention, such as endarterectomy, may prevent cognitive decline if a measure of carotid artery disease is associated with a cause of decline, whereas if the disease measure is a marker for underlying risk factors, treatment of the risk factors might be more appropriate. The effect of medical or surgical management of left carotid artery disease on cognitive function has not been specifically evaluated. The Modified Mini-Mental State Examination (26, 27) primarily measures cognitive function in the dominant cerebral hemisphere (28), which is the left hemisphere in more than 98% of right-handed persons (29). Results of the Modified Mini-Mental State Examination and the similar, more familiar Mini-Mental State Examination are often normal in right-handed patients with right hemispheric strokes or mass lesions (28, 30, 31). If carotid artery disease is a cause of cognitive impairment as measured by the Modified Mini-Mental State Examination, impairment should be associated with left-sided disease but not right-sided disease. Because both arteries should be affected equally by systemic vascular risk factors, a causal association should persist after adjustment for right-sided disease and for vascular risk factors. Alternatively, if measures of carotid artery disease are markers for underlying risk factors for vascular disease, measures of both left and right carotid disease should be similarly associated with cognitive impairment. We hypothesized that high-grade stenosis of the left, but not the right, internal carotid artery is a cause of cognitive impairment as measured by the Modified Mini-Mental State Examination in right-handed persons and that an association would persist after adjustment for contralateral stenosis and risk factors for vascular disease. We also hypothesized that intimamedia thickness of both the left and right common carotid artery would be associated with cognitive impairment because we assumed that intimamedia thickness was a marker for underlying vascular disease and its risk factors rather than a direct cause of cerebral ischemia and cognitive impairment. Methods Sample The Cardiovascular Health Study is an observational, prospective study of men and women 65 years of age or older drawn from 4 U.S. communities: Sacramento County, California; Allegheny County, Pennsylvania; Washington County, Maryland; and Forsyth County, North Carolina. Participants were enrolled by random sampling of Medicare eligibility lists. The Cardiovascular Health Study enrolled 5201 participants in 1989 to 1990 and an additional 687 African-American participants in 1992 to 1993. Annual clinic examinations were conducted during follow-up. Details of recruitment into (32) and design of (33) the Cardiovascular Health Study are reported elsewhere. The study was approved by the institutional review board at each site, and all participants gave informed consent. We restricted our analysis to right-handed participants. Participants were classified as right-handed if they reported using their right hand to brush their teeth and throw a ball and were observed to write with their right hand. We excluded participants with a history of stroke, transient ischemic attack, or carotid endarterectomy as of the 19921993 examination, on the basis of self-report at study entry and surveillance during follow-up (34, 35). Data Collection The baseline examination included standard questionnaires about medical and personal history and an array of physical and laboratory evaluations (33). Testing for the apolipoprotein E 4 (ApoE 4) genotype was done in participants who consented to genetic research. Ultrasonography of the carotid arteries was performed at the 19921993 examination. Measurements were standardized among field centers and were interpreted centrally by readers who were blinded to clinical information (13, 36). The left and right common and internal carotid arteries were imaged longitudinally by using high-resolution B-mode ultrasonography. The intimamedia thickness of the common carotid artery was defined as the mean of the maximum intimamedia thicknesses of the near and far walls. Pulsed-wave Doppler frequency spectra were used to measure the peak systolic flow velocity in each internal carotid artery. Stenosis of the internal carotid artery lumen of 50% to 74% was defined as peak flow velocity of 1.5 to 2.5 m/s, and stenosis of 75% to 99% as peak velocity of 2.5 m/s or greater. No flow indicated 100% stenosis. Stenosis of 0%, 1% to 24%, or 25% to 49% was estimated visually from imaging data. Inter-reader agreement in measures of carotid disease was assessed by comparing ratings from different reviewers for more than 4800 ultrasonograms. Agreement in measurement of internal carotid artery stenosis was high ( = 0.68 for a cut-point of 75% stenosis), as was measurement of common carotid artery intimamedia thickness (Spearman rank correlation coefficient = 0.72). Cognitive function was measured annually by using the Modified Mini-Mental State Examination. Higher scores indicate greater cognitive function. Cognitive impairment was defined as a score of less than 80 of 100 points (37). The Digit Symbol Substitution Test (number of correct answers in 90 seconds) was used as a secondary measure of cognitive function (38). This test measures function in both cerebral hemispheres but is thought to be more dramatically affected by left-sided injuries. Impairment was defined as a score of less than 19; this cut-point was chosen at 1.5 SDs below the mean score. Cranial magnetic resonance imaging was performed at the 19921994 examinations. Infarct on magnetic resonance imaging was defined as an area with abnormal signal intensity in a vascular distribution, without mass effect (39). Outcome Measures We examined the association between asymptomatic carotid artery disease and cognitive impairment in a cross-sectional analysis based on data from the 19921993 examination and in a longitudinal analysis of cognitive decline during 5 years of follow-up. Carotid artery measures of primary interest were the degree of internal carotid artery stenosis and quartiles of intimamedia thickness of the common carotid artery. Results are shown for participants with 75% or greater (high-grade) stenosis compared with those with no stenosis and participants in the fourth compared with the first quartile of intimamedia thickness. Statistical Analysis Characteristics were compared between carotid artery groups by using the chi-square test or the t-test. Cognitive scores were compared between carotid groups using the Wilcoxon rank-sum test. The average rate of cognitive decline was calculated for each participant by using linear regression, based on the slope of the line fitting all cognitive measures from baseline and follow-up. Thus

Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly

Background: The authors studied mortality, vascular events, and preventive therapies following ischemic stroke among adults aged ≥65 years. Methods: The authors identified 546 subjects with first ischemic stroke during 1989 to 2001 among Cardiovascular Health Study participants. Deaths, recurrent strokes, and coronary heart disease (CHD) events were identified over 3.2 years (median) follow-up. Results: During the first year of follow-up, rates were 105.4/1,000 for recurrent stroke and 59.3/1,000 for CHD. After the first year, the stroke rate was 52.0/1,000 and the CHD rate was 46.5/1,000. Cardioembolic strokes had the highest mortality (185.4/1,000) and recurrence rates (86.6/1,000). Lacunar strokes had the lowest mortality (119.3/1,000) and recurrence rates (43.0/1,000). Age and male sex predicted death and CHD, but not recurrence. Outcomes did not differ by race. Following stroke, 47.8% used aspirin and 13.5% used other antiplatelet agents; 52.6% of patients with atrial fibrillation used warfarin; 31.3% of hyperlipidemic subjects, 57.0% of diabetic patients, and 81.5% of hypertensive patients were drug-treated; and 40.0% of hypertensive patients had blood pressure (BP) <140/90 mm Hg. Older subjects were less likely to use lipid-lowering therapy, women were less likely to have BP <140/90 mm Hg, and low-income subjects were less likely to use diabetes medications. Conclusions: Recurrent strokes were nearly twice as frequent as coronary heart disease (CHD) events during the first year after initial stroke, but stroke and CHD rates were similar after the first year. Preventive drug therapies were underused, which may reflect clinical uncertainty due to the lack of clinical trials among the elderly. Utilization was lower among the oldest patients, women, and low-income individuals.

Cerebral vasculitis associated with cocaine abuse.

Background: Earlier reports of cocaine-associated cerebral vasculitis have been based primarily on angiographic findings without pathological verification. Case Description: We present a case of acute encephalopathy following intravenous and intranasal administration of cocaine. Brain biopsy revealed vascular changes involving primarily small arteries. Findings included lymphocytic infiltration, endothelial thickening, and deposition of proteinaceous amorphous material within and around vessel walls. Conclusions: These abnormalities are consistent with pathological features of arteritis previously reported in association with amphetamine and multiple-drug abuse. Vasospasm-induced changes are an alternative explanation for the vascular picture seen in this case. The patient made modest improvement with high-dose intravenous steroids.

Asymptomatic Internal Carotid Artery Stenosis Defined by Ultrasound and the Risk of Subsequent Stroke in the Elderly: The Cardiovascular Health Study

BACKGROUND AND PURPOSE We sought in this study to relate carotid ultrasound findings in asymptomatic older adults to the 5-year risk of various cerebrovascular outcomes used in the Asymptomatic Carotid Atherosclerosis Study (ACAS). METHODS The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years and older. Analyses of internal carotid artery stenosis defined by multiple different cutoffs of peak systolic velocity, rather than one particular cutoff, were performed in the 5441 participants who underwent carotid ultrasound and lacked a history of transient ischemic attack or stroke. The 5-year risks of 7 cerebrovascular disease outcomes used in ACAS were estimated for each cutoff. RESULTS Associations with the 5-year risk of outcomes were substantially elevated only at cutoffs with high peak systolic velocities. In this population, the number of people with such high velocities was small. For example, with a cutoff of approximately 2.5 m/s, suggesting a stenosis of >70%, the 5-year risk of an ipsilateral fatal or nonfatal stroke was 5%, and only 0.5% of the group had velocities at least this high. CONCLUSIONS In a group of older adults likely to participate in a screening program, as evidenced by willingness to participate in CHS, high peak systolic velocities consistent with high-grade carotid stenosis were uncommon and risk of subsequent cerebrovascular disease outcomes was relatively low. These findings do not suggest that similar populations of older adults would benefit from a program using ultrasound to screen for asymptomatic carotid stenosis.

A multicenter validation study of Doppler ultrasound versus angiography.

The establishment of 60% or greater diameter stenosis by Doppler ultrasound is an eligibility requirement of the Asymptomatic Carotid Atherosclerosis Study (ACAS). We used a uniform statistical approach for each of 30 Doppler devices to establish a cutpoint for the peak systolic flow to insure a positive predictive value of 90% in predicting a 60%+ stenosis by angiography. Data were analyzed by device; however, performance relates to the device-sonographer-reader system. For those devices reporting in peak systolic velocity, cutpoints ranged from 151 to 390 cm/s, and for those reporting a peak systolic frequency from 5,400 to 11,250 Hz. Eighteen devices had a sensitivity above 60%, and nine devices had a sensitivity above 80%. However, for six instruments, the relationship between Doppler and angiography was too weak to establish any cutpoint. In addition, for one instrument a value could be established, but the associated sensitivity was only 18%. This remarkable variability in the performance is at odds with the high sensitivity uniformly published in the literature, suggesting (a) that the high reported sensitivity for Doppler may represent an overestimate of average performance, perhaps due to publication bias, (b) the paramount need for documented quality control measures within local laboratories to insure that Doppler examinations are performed reliably, and (c) the need for caution in the generalization of results among laboratories.

Stress-Induced Blood Pressure Reactivity and Silent Cerebrovascular Disease

Background and Purpose— Exaggerated blood pressure (BP) responses to mental stress, an index of autonomic dysregulation, have been related to enhanced risk for stroke. This study examined cross-sectional relations of stress-induced BP reactivity to silent cerebrovascular disease assessed by magnetic resonance imaging (MRI) in healthy older adults. Methods— Sixty-seven nondemented, community-dwelling older adults (ages 55 to 81; 75% male) free of major medical, neurological, or psychiatric disease, engaged in: (1) clinical assessment of resting systolic and diastolic BP; (2) assessment of systolic and diastolic BP responses to 3 laboratory-based mental stressors; and (3) MRI. MRIs were rated for small silent infarcts (≥3 mm), infarct-like lesions (<3 mm), and periventricular and deep white matter hyperintensities (WMH). Results— After adjustment for age, gender, resting clinic BP, and fasting glucose levels, higher systolic BP reactivity was associated with an increased number of small silent infarcts (r2=0.14; P=0.004) and greater severity ratings of periventricular (r2=0.08; P<0.04) and deep WMH (r2=0.06; P<0.05). Higher diastolic BP reactivity was similarly associated with an increased number of small silent infarcts (r2=0.08; P<0.04), and greater severity ratings of periventricular (r2=0.08; P<0.04) and deep WMH (r2=0.11; P=0.009). Conclusions— These results indicate that greater stress-induced BP reactivity is associated with enhanced silent cerebrovascular disease on MRI in healthy asymptomatic older adults independent of resting BP levels. Exaggerated stress-induced BP reactivity warrants further examination as a potential biobehavioral risk factor for cerebrovascular disease.

Hospitalization for Infection and Risk of Acute Ischemic Stroke: The Cardiovascular Health Study

Background and Purpose— Little is known about the acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with the short-term risk of stroke. Methods— The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days before an incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years before stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression. Confirmatory analyses assessed hazard ratios of stroke from Cox regression models, with hospitalization for infection as a time-varying exposure. Results— During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without a baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days before stroke, OR=3.4 (95% CI, 1.8 to 6.5). The point estimates of risks were higher when we examined shorter intervals: for 30 days, OR=7.3 (95% CI, 1.9 to 40.9), and for 14 days, OR=8.0 (95% CI, 1.7 to 77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted hazard ratio=2.4 (95% CI, 1.6 to 3.4). Conclusions— Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.