Ken Cheung

Left Atrial Enlargement and Stroke Recurrence The Northern Manhattan Stroke Study

Background and Purpose— Although left atrial enlargement (LAE) increases incident stroke risk, the association with recurrent stroke is less clear. Our aim was to determine the association of LAE with recurrent stroke most likely related to embolism (cryptogenic and cardioembolic) and all ischemic stroke recurrences. Methods— We followed 655 first ischemic stroke patients in the Northern Manhattan Stroke Study for ⩽5 years. LA size from 2D echocardiography was categorized as normal LAE (52.7%), mild LAE (31.6%), and moderate–severe LAE (15.7%). We used Cox proportional hazard models to calculate the hazard ratios and 95% confidence intervals for the association of LA size and LAE with recurrent cryptogenic/cardioembolic and total recurrent ischemic stroke. Results— LA size was available in 529 (81%) patients. Mean age at enrollment was 69±13 years; 45.8% were male, 54.0% Hispanic, and 18.5% had atrial fibrillation. Over a median of 4 years, there were 65 recurrent ischemic strokes (29 were cardioembolic or cryptogenic). In multivariable models adjusted for confounders, including atrial fibrillation and heart failure, moderate–severe LAE compared with normal LA size was associated with greater risk of recurrent cardioembolic/cryptogenic stroke (adjusted hazard ratio 2.83, 95% confidence interval 1.03–7.81), but not total ischemic stroke (adjusted hazard ratio 1.06, 95% confidence interval, 0.48–2.30). Mild LAE was not associated with recurrent stroke. Conclusion— Moderate to severe LAE was an independent marker of recurrent cardioembolic or cryptogenic stroke in a multiethnic cohort of ischemic stroke patients. Further research is needed to determine whether anticoagulant use may reduce risk of recurrence in ischemic stroke patients with moderate to severe LAE.

The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose‐escalation study of high‐dose lovastatin in acute ischemic stroke

There is growing experimental and clinical evidence that by reducing downstream products of the mevalonate pathway other than cholesterol, HMG-CoA reductase inhibitors (‘statins’) have beneficial effects on endothelial function, coronary and cerebral blood flow, inflammation, and hemostasis. Statins have been shown in rodent models of acute ischemic stroke to reduce neuronal injury and infarct size in a dose-dependent fashion. The objective of this early phase trial will be to determine the maximal-tolerated dose of lovastatin for short-term acute stroke therapy. In this multicenter phase 1B dose-escalation and dose-finding study, 33 patients with acute ischemic stroke will be administered lovastatin in increasing doses from one to 10 mg/kg daily for 3 days beginning within 24 hours after symptom onset. The primary safety outcome will be occurrence of myotoxicity

High-Dose Lovastatin for Acute Ischemic Stroke: Results of the Phase I Dose Escalation Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART)

Background: Hydroxymethylglutaryl coenzyme A reductase inhibitors (‘statins’) reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke. Methods: We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7–13% toxicity. Results: We enrolled 33 patients (16 men/17 women, age range 23–82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg. Conclusions: Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.

Electrocardiographic Left Atrial Abnormality and Risk of Stroke Northern Manhattan Study

Background and Purpose— Electrocardiographic left atrial abnormality has been associated with stroke independently of atrial fibrillation (AF), suggesting that atrial thromboembolism may occur in the absence of AF. If true, we would expect an association with cryptogenic or cardioembolic stroke rather than noncardioembolic stroke. Methods— We conducted a case-cohort analysis in the Northern Manhattan Study, a prospective cohort study of stroke risk factors. P-wave terminal force in lead V1 was manually measured from baseline ECGs of participants in sinus rhythm who subsequently had ischemic stroke (n=241) and a randomly selected subcohort without stroke (n=798). Weighted Cox proportional hazard models were used to examine the association between P-wave terminal force in lead V1 and stroke etiologic subtypes while adjusting for baseline demographic characteristics, history of AF, heart failure, diabetes mellitus, hypertension, tobacco use, and lipid levels. Results— Mean P-wave terminal force in lead V1 was 4452 (±3368) &mgr;V*ms among stroke cases and 3934 (±2541) &mgr;V*ms in the subcohort. P-wave terminal force in lead V1 was associated with ischemic stroke (adjusted hazard ratio per SD, 1.20; 95% confidence interval, 1.03–1.39) and the composite of cryptogenic or cardioembolic stroke (adjusted hazard ratio per SD, 1.31; 95% confidence interval, 1.08–1.58). There was no definite association with noncardioembolic stroke subtypes (adjusted hazard ratio per SD, 1.14; 95% confidence interval, 0.92–1.40). Results were similar after excluding participants with a history of AF at baseline or new AF during follow-up. Conclusions— ECG-defined left atrial abnormality was associated with incident cryptogenic or cardioembolic stroke independently of the presence of AF, suggesting atrial thromboembolism may occur without recognized AF.

The Association between a Mediterranean-Style Diet and Kidney Function in the Northern Manhattan Study Cohort

BACKGROUND AND OBJECTIVES Various dietary strategies have been investigated to slow kidney function decline. However, it is unknown whether a Mediterranean diet, which has been associated with improved cardiovascular risk, is associated with change in kidney function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study used the Northern Manhattan Study, a prospective, multiethnic, observational cohort of participants who were stroke free at baseline. Data were collected between 1993 and 2008. Serum creatinine measurements were taken a mean 6.9 years apart. A baseline dietary questionnaire was extrapolated into a previously used 9-point scoring system (MeDi). The primary outcome was incident eGFR<60 ml/min per 1.73 m(2)using the Modification of Diet in Renal Disease formula. A secondary outcome was the upper quartile of annualized eGFR decline (≥ 2.5 ml/min per 1.73 m(2) per year). Conditional logistic regression models adjusted for demographics and baseline vascular risk factors. RESULTS Mean baseline age was 64 years, with 59% women and 65% Hispanics (N=900); mean baseline eGFR was 83.1 ml/min per 1.73 m(2). Incident eGFR<60 ml/min per 1.73 m(2) developed in 14% . In adjusted models, every 1-point increase in the MeDi score, indicating increasing adherence to a Mediterranean diet, was associated with decreased odds of incident eGFR<60 ml/min per 1.73 m(2) (odds ratio, 0.83; 95% confidence interval, 0.71 to 0.96) and decreased odds of being in the upper quartile of eGFR decline (odds ratio, 0.88; 95% confidence interval, 0.79 to 0.98). CONCLUSIONS A Mediterranean diet was associated with a reduced incidence of eGFR<60 ml/min per 1.73 m(2) and upper quartile of eGFR decline in a multiethnic cohort.

Population Attributable Risks of Hypertension and Diabetes for Cardiovascular Disease and Stroke in the Northern Manhattan Study

Background Understanding the population‐level risk factor contribution to disease incidence is critical for effective allocation of resources for prevention. There are little data on the contribution of cardiovascular disease (CVD) risk factors in multiethnic elderly populations. Methods and Results The Northern Manhattan Study (n=3298) is a population‐based prospective cohort study of CVD outcomes in a multiethnic urban population. Multivariable Coxs models were used to calculate hazard ratios, population attributable risk (PAR), and 95% confidence intervals (CIs) for (1) combined vascular event (VE) endpoint of stroke/myocardial infarction/vascular death (n=835) and (2) stroke (n=347). The PAR resulting from hypertension (HTN) was 24.3% (95% CI, 13.2 to 35.4) for VE and 29.9% (95% CI, 12.5 to 47.4) for stroke; PAR resulting from diabetes was 12.7% (95% CI, 8.2 to 17.2) for VE and 19.5% (95% CI, 12.4 to 26.5) for stroke. The PAR resulting from HTN and diabetes for stroke differed by race‐ethnicity and age (P for differences <0.05). PAR for stroke reslting from HTN was greater among Hispanics (50.6%; 95% CI, 29.2 to 71.9) than non‐Hispanic whites (2.6%; 95% CI, −33.2 to 38.6) and in those <80 years of age (35.6%; 95% CI, 18.9 to 52.3) than in those ≥80 (−0.3%; 95% CI, −34.2 to 33.6). Similarly, the PAR for stroke resulting from diabetes was 23.6% among those <80 years of age (95% CI, 15.7 to 31.5) and 2.3% among those ≥80 (95% CI, −8.2 to 12.7; P for difference=0.001). The PAR for VE did not differ by age/sex/race‐ethnicity. Conclusions HTN and diabetes have important effects on the burden of stroke, particularly among those younger than age 80 and Hispanics. Public health campaigns targeted at specific risk factors in specific populations can lead to a greater reduction in CVD.

Elevated Homocysteine and Carotid Plaque Area and Densitometry in the Northern Manhattan Study

Background and Purpose— Studies have linked elevated total homocysteine (tHcy) levels to atherosclerotic carotid plaque development, but data are limited to predominantly white populations. We examined the association between tHcy and carotid plaque burden and morphology in a multiethnic cohort. Methods— In the Northern Manhattan Study, we conducted a cross-sectional analysis among 1327 stroke-free subjects (mean age, 66±9; 41% men; 19% black; 62% Hispanic; 17% white) with serum tHcy and ultrasonographic assessment of plaque morphology measured by gray-scale median (GSM) and total plaque area (TPA). GSM and TPA were examined in 4 categories. High and low GSM categories were considered echodense and echolucent plaque, respectively, and compared with no plaque. Logistic regression models were used to assess the associations of tHcy with GSM and TPA adjusting for demographics, vascular risk factors, renal insufficiency, and B12 deficiency. Results— The mean tHcy was 9.4±4.8 µmol/L (median=8.6). The prevalence of carotid plaque was 57% (52% among Hispanics, 58% black, and 70% white). Among those with plaque, the mean TPA was 20.3±20.6 mm2 (median=13.6) and mean GSM 90.9±28.5 (median=93.0). The top 2 tHcy quartiles (versus quartile 1) had an elevated risk of having either echolucent plaque (tHcy Q3, odds ratio [OR]=1.8; [95% confidence interval {CI} 1.2–2.8]; tHcy Q4, OR=1.9 [95% CI 1.2–3.1]) or echodense plaque (tHcy Q3, OR=1.7 [95% CI, 1.1–2.7]; tHcy Q4, OR=1.9 [95% CI, 1.2–3.2]). The top 2 tHcy quartiles were also more likely to be in the highest TPA category (tHcy Q3, OR=1.8 [95% CI, 1.1–3.0]; tHcy Q4, OR=2.2 [95% CI, 1.3–3.7]). Conclusions— In this population-based multiethnic cohort, elevated tHcy was independently associated with plaque morphology and increased plaque area, subclinical markers of stroke risk.

Pulsatile and steady components of blood pressure and subclinical cerebrovascular disease: the Northern Manhattan Study.

Objectives: To assess whether pulse pressure (PP) is associated, independently of mean arterial pressure (MAP), with perivascular spaces (PVS), lacunar lesions presumably ischemic (LPI), and white matter hyperintensity volume (WMHV) seen on brain MRI. Methods: Participants in the Northern Manhattan Study had their blood pressure (BP) taken during their baseline enrollment visit and again during a visit for a brain MRI a mean of 7 years later. We assessed small and large PVS, lacunar LPI, and WMHV on MRI. We examined the association of SBP, DBP, MAP, and PP at baseline with subclinical markers of cerebrovascular disease using generalized linear models and adjusting for vascular risk factors. Results: Imaging and BP data were available for 1009 participants (mean age 68 ± 8 years, 60% women, 60% Hispanic). DBP was associated with lacunar LPI and WMHV, whereas SBP was associated with small and large PVS. Using MAP and PP together disclosed that the effect size for PP was greater for large PVS, whereas the effect of MAP was greater for lacunar LPI and WMHV. The effects of DBP were flat or negative at any degree of SBP higher than 120 mmHg for small and large PVS, whereas a positive association was noted for lacunar LPI and WMHV with any DBP increase over any degree of SBP. Conclusion: We report here a segregated association between the pulsatile and steady components of the BP with subclinical markers of cerebrovascular disease. These differential associations may reflect the underlying disease of these biomarkers.

Mediterranean diet and carotid atherosclerosis in the Northern Manhattan Study

OBJECTIVE Adherence to a Mediterranean-style diet (MeDi) may protect against clinical vascular events by reducing atherosclerosis, but data is limited. This is the first observational study of the association between MeDi adherence and carotid plaque thickness and area. METHODS The study included 1374 participants of the population-based Northern Manhattan Study with diet assessed and carotid intima-media thickness (cIMT) and plaque measured using B-mode ultrasound (mean age 66 ± 9 years, 60% female, 60% Hispanic, 18% White, 19% Black). A MeDi adherence score (range = 0-9, 9 representing maximal adherence) was examined continuously and in quintiles (3/4/5/6-9 vs. 0-2). RESULTS Mean cIMT = 0.9 ± 0.1 mm and 57% had plaque (median plaque thickness = 1.5 mm, 75th percentile = 2.2; median plaque area = 4.2 mm(2), 75th percentile = 15.8). There was no association between MeDi and cIMT or plaque presence. MeDi adherence was inversely associated with the 75th percentile of plaque thickness and median of plaque area in quantile regression analyses. These associations persisted after controlling for demographics, smoking, physical activity, and total energy consumption (effect of a 1-point increase in MeDi score on the 75th percentile of plaque thickness = -0.049 mm, p = 0.03; median of plaque area = -0.371 mm(2), p = 0.03), and when additionally controlling for vascular disease biomarkers, medication use, BMI, and previous cardiac disease. The protective associations appeared strongest for those with a MeDi score of 5 (4th quintile) vs. 0-2 (bottom quintile). Differential effects of a MeDi on plaque thickness and area across race/ethnic groups was suggested. CONCLUSIONS Moderate and strict adherence to a MeDi may protect against a higher burden of carotid atherosclerotic plaque, which may mediate the protection against clinical vascular events. Efforts to improve adherence to a MeDi are critical to reducing the burden of atherosclerotic disease.

Ideal Cardiovascular Health and Cognitive Aging in the Northern Manhattan Study

Background The American Heart Association defined target levels for 7 cardiovascular health (CVH) factors: smoking, body mass index, physical activity, diet, blood pressure, cholesterol, and glucose. We hypothesized that a greater number of American Heart Association ideal CVH metrics would be associated with less decline in cognitive performance in our multiethnic population. Methods and Results A subsample from the population‐based Northern Manhattan Study underwent repeated neuropsychological testing (mean interval 6±2 years). Domain‐specific Z scores were derived by using factor analysis for the domains of Episodic Memory, Semantic Memory, Executive Function, and Processing Speed, based on initial performance and decline over time. Linear regression models were constructed to examine the relationship between the number of ideal CVH metrics at enrollment with later cognitive performance and decline, adjusting for sociodemographics and magnetic resonance imaging brain markers. Among 1033 participants (mean age at initial cognitive assessment 72±8 years, 39% male, 19% black, 16% white, 65% Hispanic; n=722 with repeat testing), 3% had 0 ideal factors, 15% had 1 factor, 33% had 2 factors, 30% had 3 factors, 14% had 4 factors, 4% had 5 factors, 1% had 6 factors, and 0% had 7 factors. An increasing number of ideal CVH factors was associated with better processing speed at initial assessment and less decline. The association was driven by nonsmoking and glucose. Among those with better cognitive performance at initial assessment, positive associations were observed between the number of ideal CVH factors and less decline in the domains of Executive Function and Episodic Memory. Conclusions The number of ideal CVH metrics was associated with less decline in the domains of Processing Speed and, to a lesser extent, of Executive Function and Episodic Memory. Ideal CVH promotion benefits brain health and cognitive aging.