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1.  Follow-Up Association Study of Linkage Regions Reveals Multiple Candidate Genes for Carotid Plaque in Dominicans 
Atherosclerosis  2012;223(1):177-183.
Carotid plaque is a marker of subclinical atherosclerosis with a genetic component. The aim of this follow-up fine mapping study was to identify candidate genes for carotid plaque within four linkage regions.
We successfully genotyped 3,712 single nucleotide polymorphisms (SNPs) under the four linkage regions that were previously identified in 100 extended Dominican families. Family-based association tests were performed to investigate their associations with carotid plaque. Promising SNPs were evaluated in an independent population-based subcohort (N=941, 384 Dominicans) from the Northern Manhattan Study (NOMAS).
In the family study, evidence for association (p<0.0005) was found regarding several genes (NAV2, EFCAB11/TDP1, AGBL1, PTPN9, LINGO1 and LOC730118), with the strongest association at rs4143999 near EFCAB11/TDP1 (p=0.00001 for carotid presence and 0.00003 for plaque area, multiple testing corrected p≤0.02). The association in AGBL1 and PTPN9 was mainly driven by the families with linkage evidence (p=0.00008~0.00001 and 0.76~0.32, respectively, in the families with and without linkage evidence). However, these associations explained only a small portion of the observed linkage. In NOMAS, replication (p<0.05 in the whole NOMAS subcohort and p<0.10 in the smaller Dominican subcohort) was found for SNPs within/near EFCAB11, NAV2, AGBL1 and other genes.
This follow-up study has identified multiple candidate genes for carotid plaque in the Dominican population. Many of these genes have been implicated in neurodegenerative and cardiovascular diseases. Further studies with in-depth re-sequencing are needed to uncover both rare and common functional variants that contribute to the susceptibility to atherosclerosis.
PMCID: PMC3389282  PMID: 22503546
Carotid plaque; Linkage; Fine mapping; Atherosclerosis; Hispanics
2.  Fine Mapping Study Reveals Novel Candidate Genes for Carotid Intima-Media Thickness in Dominican Families 
Carotid intima-media thickness (CIMT) is a subclinical measure for atherosclerosis. Previously, we have mapped quantitative trait loci (QTLs) for CIMT to chromosomes 7p (MLOD=3.1) and to 14q (MLOD=2.3). We sought to identify the underlying genetic variants within those QTLs,
Methods and Results
Using the 100 extended Dominican Republican (DR) families (N=1312) used in the original linkage study, we fine mapped the QTLs with 2031 tagging single nucleotide polymorphisms (SNPs). Promising SNPs in the family dataset were examined in an independent population-based subcohort comprised of DR individuals (N=553) from the Northern Manhattan Study. Among the families, evidence for association (P<0.001) was found in multiple genes (ANLN, AOAH, FOXN3, CCDC88C, PRiMA1, and an intergenic SNP rs1667498), with the strongest association at PRiMA1 (P=0.00007, corrected P=0.047). Additional analyses revealed that the association at these loci, except PRiMA1, was highly significant (P= 0.00004~0.00092) in families with evidence for linkage but not in the rest of families (P=0.13~0.80) and the population-based cohort, suggesting the genetic effects at these SNPs are limited to a subgroup of families. In contrast, the association at PRiMA1 was significant in both families with and without evidence for linkage (P=0.002 and 0.019, respectively), and the population-based subcohort (P=0.047), supporting a robust association.
We identified several candidate genes for CIMT in DR families. Some of the genes manifest genetic effects within a specific subgroup and others were generalized to all groups. Future studies are needed to further evaluate the contribution of these genes to atherosclerosis.
PMCID: PMC3341091  PMID: 22423143
3.  Ideal Cardiovascular Health Predicts Lower Risks of Myocardial Infarction, Stroke, and Vascular Death across Whites, Blacks and Hispanics: the Northern Manhattan Study 
Circulation  2012;125(24):2975-2984.
Evidence regarding the relationship of cardiovascular health (CVH) defined by the American Heart Association (AHA) and specific cardiovascular outcomes is lacking, particularly among Hispanics. This study sought to evaluate the relationship between the number of ideal CVH metrics and cardiovascular risk, overall and by event subtype, in a multiethnic community-based prospective cohort.
Methods and Results
2981 subjects (mean age 69±10 years, 54% Caribbean Hispanic, 25% black, 21% white) free of myocardial infarction (MI) and stroke at baseline in the Northern Manhattan Study were prospectively followed (median follow-up 11 years). The relationship between the number of ideal CVH metrics and the risk of cardiovascular disease (CVD), including MI, stroke and vascular death was investigated. Overall, a strong gradient relationship was observed between the adjusted hazard ratios for CVD and the number of ideal CVH metrics: 0.73 (95% CI: 0.60–0.89), 0.61 (0.50–0.76), 0.49 (0.38–0.63) and 0.41 (0.26–0.63), respectively, for those having 2, 3, 4, and 5–6 ideal CVH metrics compared with those having 0–1 ideal CVH metrics (P for trend <0.0001). Similar graded relationships were found between the number of ideal CVH metrics and the adjusted incidence rate for each specific outcome and among whites, blacks, and Caribbean Hispanics.
Our findings demonstrated a steep gradient relationship between ideal CVH and individual CVD endpoints, including stroke, which was similar for whites, blacks and Caribbean Hispanics. This evidence supports the application of the AHA ideal cardiovascular health metrics for CVD risk assessment and health promotion for all Americans regardless of race-ethnic background.
PMCID: PMC3396556  PMID: 22619283
epidemiology; myocardial infarction; race/ethnicity; stroke; Cardiovascular health
4.  Carotid plaque and candidate genes related to inflammation and endothelial function in Hispanics from northern Manhattan 
The genetic influence on carotid atherosclerotic plaque is mostly unknown. This study examines the association between carotid plaque and single nucleotide polymorphisms (SNPs) in selected genes implicated in inflammation and endothelial function.
A total of 43 genes (197 SNPs) involved in inflammation and endothelial function were interrogated in 287 Dominicans from the Northern Manhattan Study (mean age 64±7 years, 58% women) who had undergone high-resolution B-mode ultrasound for examination of carotid plaque. Using an additive genetic model, multiple logistic regression analyses were conducted, a within gene haplotype analysis was performed and interactions between genes were examined. Results were validated in an independent set of 301 Dominicans.
Carotid plaque was present in 143(47%) participants. Nine genes had at least one SNP associated (p≤0.01) with carotid plaque phenotypes: TNF, NOS2A, IL6R, TNFSF4, PPARA, IL1A, TLR4, ITGA2, HABP2. SNPs in TNFSF4, PPARA, TLR4, ITGA2, and HABP2 were also implicated with the same carotid phenotype in the validation analysis. Haplotype analysis revealed an additional gene of interest, VCAM1.
We report novel associations between variations in ten genes involved in inflammation and endothelial function and carotid plaque phenotypes in a Dominican sample, with replication for five genes in an independent Dominican sample.
PMCID: PMC3116444  PMID: 21393601
candidate gene; single nucleotide polymorphisms; carotid plaque; inflammation; Caribbean Hispanic
5.  A comprehensive genetic study on left atrium size in Caribbean Hispanics identifies candidate genes in 17p10 
Left atrial enlargement is associated with cardiovascular disease. Genetic factors contributing to the left atrium (LA) dimension are poorly understood. We sought to map susceptibility genes for LA size in a large Dominican family dataset and an independent population-based cohort from the Northern Manhattan Study (NOMAS).
Methods and Results
100 Dominican families consisting of 1350 individuals were used to estimate heritability and map quantitative trait loci for LA size using variance components analysis. LA dimension was measured by transthoracic echocardiography. A polygenic covariate screening was used to identify significant covariates. LA size had a moderate estimate of heritability (h2=0.42), after adjusting for significant covariates. Linkage analysis of 405 microsatellite markers revealed suggestive evidence on chromosome 10p19 (D10S1423, MLOD=2.00) and 17p10 (D17S974, MLOD=2.05). Ordered subset analysis found significantly enhanced (p<0.05 for increase of LOD score) evidence for linkage at 17p10 (MLOD=2.9) in families with lower LDL level. 2233 single nucleotide polymophisms (SNPs) were used to perform a peak-wide association mapping across 17p10 in 825 NOMAS individuals. Strong evidence for association were found in NTN1, MYH10, COX10, and MYOCD genes (p=0.00005 to 0.005).
Using non-biased genome-wide linkage followed by peak-wide association analysis, we identified several possible susceptibility genes affecting LA size. Among them, MYOCD has been shown to serve as a key transducer of hypertrophic signals in cardiomyocytes in vitro. Evidence from our linkage and association study, together with the known function, strongly suggests that polymorphisms in MYOCD gene modify LA size.
PMCID: PMC2923674  PMID: 20562446
Left atrium; Genetics; Myocardin; MYH10; COX10
6.  Genomewide Linkage and Peakwide Association Analyses of Carotid Plaque in Caribbean Hispanics 
Background and Purpose
Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples.
B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18 904 single nucleotide polymorphisms under the 1-logarithm of odds unit down regions of linkage peaks in an independent community-based data set (N=941, 41% Dominicans) from the Northern Manhattan Study.
After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h2=0.50±0.14, P<0.0001) and plaque area (h2=0.17±0.04, P<0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores ≥2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near SOX6, FSD2, AP3S2, EFTUD1, and MYOD1 were associated with carotid plaque traits with a nominal P≤0.0005 in the Northern Manhattan Study data set and with a P≤0.01 in Northern Manhattan Study Dominican subset.
Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The SOX6 gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings.
PMCID: PMC3004531  PMID: 20966410
association; Caribbean Hispanics; carotid plaque; heritability; linkage
7.  Improving Global Vascular Risk Prediction with Behavioral and Anthropometric Factors: The Multi-ethnic Northern Manhattan Cohort Study 
To improve global vascular risk prediction with behavioral and anthropometric factors.
Few cardiovascular risk models are designed to predict the global vascular risk of MI, stroke, or vascular death in multi-ethnic individuals, and existing schemes do not fully include behavioral risk factors.
A randomly-derived, population-based, prospective cohort of 2737 community participants free of stroke and coronary artery disease were followed annually for a median of 9.0 years in the Northern Manhattan Study (mean age 69 years; 63.2% women; 52.7% Hispanic, 24.9% African-American, 19.9% white). A global vascular risk score (GVRS) predictive of stroke, myocardial infarction, or vascular death was developed by adding variables to the traditional Framingham cardiovascular variables based on the likelihood ratio criterion. Model utility was assessed through receiver operating characteristics, calibration, and effect on reclassification of subjects.
Variables which significantly added to the traditional Framingham profile included waist circumference, alcohol consumption, and physical activity. Continuous measures for blood pressure and fasting blood sugar were used instead of hypertension and diabetes. Ten -year event-free probabilities were 0.95 for the first quartile of GVRS, 0.89 for the second quartile, 0.79 for the third quartile, and 0.56 for the fourth quartile. The addition of behavioral factors in our model improved prediction of 10 -year event rates compared to a model restricted to the traditional variables.
A global vascular risk score that combines both traditional, behavioral, and anthropometric risk factors, uses continuous variables for physiological parameters, and is applicable to non-white subjects could improve primary prevention strategies.
PMCID: PMC2812026  PMID: 19958966
Cardiovascular Disease; Cerebrovascular Disease; Prevention; Risk Factors; Epidemiology
8.  Physical activity and cognition in the Northern Manhattan Study 
Neuroepidemiology  2013;42(2):100-106.
To test the hypothesis that leisure time PA is associated with cognitive status.
We assessed cognition using the Mini-Mental Status Examination (MMSE) at enrollment, and using the modified Telephone Interview for Cognitive Status (TICS-m) administered annually since 2001 in the Northern Manhattan Study. Baseline measures of leisure-time PA were collected via in-person questionnaires. Total PA was categorized in three groups based on the metabolic equivalent (MET) score, a composite of total reported intensity and time. We used linear regression models to examine the association of PA with MMSE, and generalized estimating equations for change in TICS-m over time.
There were 3298 stroke-free participants with MMSE data (mean MMSE 26.0±3.8) and 2279 with TICS-m scores available. Compared to no PA, those with the upper quartile ofMET-score had greater baseline MMSE scores (adjusted β=0.4,p=0.01) but no association with change in TICS-m over time. There were interactions (p<0.05) between PA and both insurance and education; compared to no PA those in the upper quartile of MET-score had a greater MMSE score only among those with Medicaid/no insurance (adjusted β =0.83,p=0.0005) and those who did not complete high school (adjusted β=0.68, p=0.001).
Increased levels of physical activity were associated with better baseline MMSE, particularly among those with socioeconomic disadvantages, but not with cognitive decline.
PMCID: PMC3942085  PMID: 24335048
physical activity; cognition; dementia
9.  Heritability and Linkage Analysis for Carotid Intima-Media Thickness: The Family Study of Stroke Risk and Carotid Atherosclerosis 
Background and Purpose
The aim was to identify quantitative trait loci (QTL) for carotid intima-media thickness (CIMT) a risk factor for stroke and cardiovascular disease.
Probands were selected from Caribbean Hispanic subjects of the population-based Northern Manhattan Study. CIMT was measured by high resolution B-mode ultrasound and expressed as the mean (IMTx) and mean of the maximum (IMTm). Variance components methodology was used to detect linkage using SOLAR and calculate locus-specific heritability. Ordered-subset Analysis was done based on history of hypertension and total cholesterol levels.
Among 100 Dominican families, 1390 subjects had CIMT measured (848 females; mean age 46.2 years). CIMT had a heritability of 0.65 after adjusting for age, ageˆ2, sex, cigarette pack-years, waist hip ratio, and BMI. Adjusted maximum multipoint LOD scores > 2 were found on chromosomes 14q (D14S606) and 7p (D7S817). Linkage to chromosome 14q was significantly increased in a subset of families with the greatest history of hypertension (MLOD=4.12). The QTL on Ch14q accounted for 0.21 of the heritability of IMTm, and on Ch7p 0.27 of the heritability of BIFm.
Several QTLs for CIMT were found on chromosomes 7p and 14q. The QTL on 14q replicates a suggestive linkage peak delimited in the Framingham Heart Study. These QTLs accounted for a substantial amount of trait heritability and warrant further fine mapping.
PMCID: PMC2737512  PMID: 19498180
Carotid Disease; Genetics; Linkage; Quantitative Traits; Risk Factors
10.  Stroke in Heart Failure in Sinus Rhythm: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial 
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses.
We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions.
Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3–5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups.
The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.
PMCID: PMC4256381  PMID: 23921215
Aspirin; Cardiac embolism; Heart failure; Stroke prevention
11.  Quantifying and Addressing Persistent Stroke Disparities in Hispanics 
Annals of neurology  2013;74(6):759-761.
PMCID: PMC4007247  PMID: 24114772
12.  Cognitive Function in Ambulatory Patients with Systolic Heart Failure: Insights from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial 
PLoS ONE  2014;9(11):e113447.
We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE <24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (β-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.
PMCID: PMC4245133  PMID: 25426862
13.  Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm 
Circulation. Heart failure  2013;6(5):988-997.
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.
Methods and Results
We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03).
In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.
Clinical Trial Registration
URL: Unique identifier: NCT00041938.
PMCID: PMC4242511  PMID: 23881846
aspirin; heart failure; sinus rhythm; stroke; warfarin
14.  The 2006 William Feinberg Lecture 
By the year 2010, it is estimated that 18.1 million people worldwide will die annually because of cardiovascular diseases and stroke. “Global vascular risk” more broadly includes the multiple overlapping disease silos of stroke, myocardial infarction, peripheral arterial disease, and vascular death. Estimation of global vascular risk requires consideration of a variety of variables including demographics, environmental behaviors, and risk factors. Data from multiple studies suggest continuous linear relationships between the physiological vascular risk modulators of blood pressure, lipids, and blood glucose rather than treating these conditions as categorical risk factors. Constellations of risk factors may be more relevant than individual categorical components.
Exciting work with novel risk factors may also have predictive value in estimates of global vascular risk. Advances in imaging have led to the measurement of subclinical conditions such as carotid intima-media thickness and subclinical brain conditions such as white matter hyperintensities and silent infarcts. These subclinical measurements may be intermediate stages in the transition from asymptomatic to symptomatic vascular events, appear to be associated with the fundamental vascular risk factors, and represent opportunities to more precisely quantitate disease progression. The expansion of studies in molecular epidemiology and detection of genetic markers underlying vascular risks also promises to extend our precision of global vascular risk estimation.
Global vascular risk estimation will require quantitative methods that bundle these multi-dimensional data into more precise estimates of future risk. The power of genetic information coupled with data on demographics, risk-inducing behaviors, vascular risk modulators, biomarkers, and measures of subclinical conditions should provide the most realistic approximation of an individual's future global vascular risk. The ultimate public health benefit, however, will depend on not only identification of global vascular risk but also the realization that we can modify this risk and prove the prediction models wrong.
PMCID: PMC2701234  PMID: 17495216
cerebrovascular disease; epidemiology; prevention; risk factors
15.  Carotid Plaque Surface Irregularity Predicts Ischemic Stroke The Northern Manhattan Study 
Background and Purpose
There is scant population-based evidence regarding extracranial carotid plaque surface irregularity and ischemic stroke. Using a prospective cohort design, we evaluated the association of carotid plaque surface irregularity and the risk of ischemic stroke in a multiethnic population.
High-resolution B-mode ultrasound of the carotid arteries was performed in 1939 stroke-free subjects (mean age 69±10.0 years; 59% women; 53% Hispanic, 25% black, 22% white). Plaque was defined as a focal protrusion 50% greater than the surrounding area and localized along the extracranial carotid tree (internal carotid artery/bifurcation vs common carotid artery). Plaque surface was categorized as regular or irregular. Cox proportional hazard models were used to assess the association of surface characteristics and the risk of ischemic stroke.
Among 1939 total subjects, carotid plaque was visualized in 56.3% (1 plaque: 21.6%, >1 plaque: 34.7%, irregular plaque: 5.5%). During a mean follow up of 6.2 years after ultrasound examination, 69 ischemic strokes occurred. Unadjusted cumulative 5-year risks of ischemic stroke were: 1.3%, 3.0%, and 8.5% for no plaque, regular plaque, and irregular plaque, respectively. After adjusting for demographics, traditional vascular risk factors, degree of stenosis, and plaque thickness, presence of irregular plaque (vs no plaque) was independently associated with ischemic stroke (Hazard ratio, 3.1; 95% CI, 1.1 to 8.5).
The presence of irregular carotid plaque independently predicted ischemic stroke in a multiethnic cohort. Plaque surface irregularities assessed by B-mode ultrasonography may help identify intermediate- to high-risk individuals beyond their vascular risk assessed by the presence of traditional risk factors.
PMCID: PMC2654324  PMID: 17008627
carotid artery; irregular plaque; stroke; ultrasound
17.  Stroke Genetics Network (SiGN) Study: Design and rationale for a genome-wide association study of ischemic stroke subtypes 
Background and Purpose
Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The NINDS Stroke Genetics Network (SiGN) contributes substantially to meta-analyses that focus on specific subtypes of stroke.
The NINDS Stroke Genetics Network (SiGN) includes ischemic stroke cases from 24 Genetic Research Centers (GRCs), 13 from the US and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating GRCs. Through the Center for Inherited Diseases Research (CIDR), SiGN plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide SNP arrays, and add to these another 4,253 previously genotyped cases for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. CIDR-generated genotypes and corresponding phenotypic data will be shared with the scientific community through dbGaP, and brain MRI studies will be centrally archived.
The SiGN consortium, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
PMCID: PMC4056331  PMID: 24021684
ischemic stroke; genetics; genomics
18.  Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010 
The Lancet. Global health  2013;1(5):e259-e281.
The burden of ischaemic and haemorrhagic stroke varies between regions and over time. With differences in prognosis, prevalence of risk factors, and treatment strategies, knowledge of stroke pathological type is important for targeted region-specific health-care planning for stroke and could inform priorities for type-specific prevention strategies. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010.
We searched Medline, Embase, LILACS, Scopus, PubMed, Science Direct, Global Health Database, the WHO library, and regional databases from 1990 to 2012 to identify relevant studies published between 1990 and 2010. We applied the GBD 2010 analytical technique (DisMod-MR) to calculate regional and country-specific estimates for ischaemic and haemorrhagic stroke incidence, mortality, mortality-to-incidence ratio, and disability-adjusted life-years (DALYs) lost, by age group (aged <75 years, ≥75 years, and in total) and country income level (high-income and low-income and middle-income) for 1990, 2005, and 2010.
We included 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). Worldwide, the burden of ischaemic and haemorrhagic stroke increased significantly between 1990 and 2010 in terms of the absolute number of people with incident ischaemic and haemorrhagic stroke (37% and 47% increase, respectively), number of deaths (21% and 20% increase), and DALYs lost (18% and 14% increase). In the past two decades in high-income countries, incidence of ischaemic stroke reduced significantly by 13% (95% CI 6–18), mortality by 37% (19–39), DALYs lost by 34% (16–36), and mortality-to-incidence ratios by 21% (10–27). For haemorrhagic stroke, incidence reduced significantly by 19% (1–15), mortality by 38% (32–43), DALYs lost by 39% (32–44), and mortality-to-incidence ratios by 27% (19–35). By contrast, in low-income and middle-income countries, we noted a significant increase of 22% (5–30) in incidence of haemorrhagic stroke and a 6% (–7 to 18) non-significant increase in the incidence of ischaemic stroke. Mortality rates for ischaemic stroke fell by 14% (9–19), DALYs lost by 17% (–11 to 21%), and mortality-to-incidence ratios by 16% (–12 to 22). For haemorrhagic stroke in low-income and middle-income countries, mortality rates reduced by 23% (–18 to 25%), DALYs lost by 25% (–21 to 28), and mortality-to-incidence ratios by 36% (–34 to 28).
Although age-standardised mortality rates for ischaemic and haemorrhagic stroke have decreased in the past two decades, the absolute number of people who have these stroke types annually, and the number with related deaths and DALYs lost, is increasing, with most of the burden in low-income and middle-income countries. Further study is needed in these countries to identify which subgroups of the population are at greatest risk and who could be targeted for preventive efforts.
PMCID: PMC4181351  PMID: 25104492
19.  Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010 
Lancet  2014;383(9913):245-254.
Although stroke is the second leading cause of death worldwide, no comprehensive and comparable assessment of incidence, prevalence, mortality, disability, and epidemiological trends has been estimated for most regions. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the global and regional burden of stroke during 1990–2010.
We searched Medline, Embase, LILACS, Scopus, PubMed, Science Direct, Global Health Database, the WHO library, and WHO regional databases from 1990 to 2012 to identify relevant studies published between 1990 and 2010. We applied the GBD 2010 analytical technique (DisMod-MR), based on disease-specific, pre-specified associations between incidence, prevalence, and mortality, to calculate regional and country-specific estimates of stroke incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) lost by age group (<75 years, ≥75 years, and in total) and country income level (high-income, and low-income and middle-income) for 1990, 2005, and 2010.
We included 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). From 1990 to 2010, the age-standardised incidence of stroke significantly decreased by 12% (95% CI 6–17) in high-income countries, and increased by 12% (–3 to 22) in low-income and middle-income countries, albeit non-significantly. Mortality rates decreased significantly in both high income (37%, 31–41) and low-income and middle-income countries (20%, 15–30). In 2010, the absolute numbers of people with first stroke (16·9 million), stroke survivors (33 million), stroke-related deaths (5·9 million), and DALYs lost (102 million) were high and had significantly increased since 1990 (68%, 84%, 26%, and 12% increase, respectively), with most of the burden (68·6% incident strokes, 52·2% prevalent strokes, 70·9% stroke deaths, and 77·7% DALYs lost) in low-income and middle-income countries. In 2010, 5·2 million (31%) strokes were in children (aged <20 years old) and young and middle-aged adults (20–64 years), to which children and young and middle-aged adults from low-income and middle-income countries contributed almost 74 000 (89%) and 4·0 million (78%), respectively, of the burden. Additionally, we noted significant geographical differences of between three and ten times in stroke burden between GBD regions and countries. More than 62% of new strokes, 69·8% of prevalent strokes, 45·5% of deaths from stroke, and 71·7% of DALYs lost because of stroke were in people younger than 75 years.
Although age-standardised rates of stroke mortality have decreased worldwide in the past two decades, the absolute number of people who have a stroke every year, stroke survivors, related deaths, and the overall global burden of stroke (DALYs lost) are great and increasing. Further study is needed to improve understanding of stroke determinants and burden worldwide, and to establish causes of disparities and changes in trends in stroke burden between countries of different income levels.
Bill & Melinda Gates Foundation.
PMCID: PMC4181600  PMID: 24449944
20.  Relation Between Long Sleep and Left Ventricular Mass (from a Multiethnic Elderly Cohort) 
The American journal of cardiology  2013;112(4):599-603.
Short-sleep and long-sleep duration are associated with prevalent hypertension, poor cardiovascular health, and mortality. The relation of sleep hours with increased left ventricular (LV) mass, a strong correlate of elevated blood pressure (BP) values, is not established. We conducted a cross-sectional analysis among the participants of the population-based Cardiovascular Abnormalities and Brain Lesions study. LV mass was estimated by transthoracic echocardiography. Sleep duration was assessed by reported hours of sleep on a diary kept during 24-hour BP monitoring. Multivariate linear regression models were constructed to assess the relation between sleep hours and LV mass index (LV mass divided by body surface area). Analysis of sleep hour categories (short and long sleep) was performed. Among 756 participants (mean age 71 ± 9 years, 60% women, and 71% Hispanics), the mean sleep duration was 8.6 ± 1.8 hours, and LV mass index was 103 ± 26 g/m2. A J-shaped relation between sleep hours squared and LV mass index was observed adjusting for demographics and cardiovascular risk factors. Categorical analysis showed an association between long-sleep duration (>11 hours) and LV mass index (β = 7.4; p = 0.013). Long sleepers had higher diurnal systolic BP (p = 0.012) and nocturnal systolic BP (p <0.001) compared with the reference group. A great part of the variance between sleep duration and LV mass was explained by 24-hour systolic BP (β = 0.45; p <0.0001). In conclusion, self-reported long-sleep duration was associated with increased LV mass. Higher systolic BP, especially nocturnal, may account for part of the observed association.
PMCID: PMC3770129  PMID: 23711813
21.  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 outcomewill be occurrence of myotoxicity or hepatotoxicity, defined by clinical and laboratory criteria, and the study is designed to determine the highest dose of lovastatin that can be administered with <10% risk of myotoxicity or hepatotoxicity. The statistical design of the study utilizes an adaptive design, the Continual Reassessment Method, which is novel to stroke trials, to find the optimal dosage. The dose–toxicity model is calibrated such that the method will eventually select a dose that causes 7–13% dose-limiting toxicity (within 3% of target). A sample size of 33 will ensure that estimates of any binary variables will have a 95% confidence interval of width ≤0·34, and enable us to detect any unexpected toxicity that occurs at 5% rate (in a non-dose-dependent fashion) with probability 0·82. The probability of choosing a dose for further trials with 25% or higher likelihood of toxicity is no more than 23%. The presently described trial represents a new approach for treatment of acute ischemic stroke, as well as a novel way of conducting a phase I trial, evaluating safety and determining an optimal dose of a potential neuroprotectant drug.
PMCID: PMC4130457  PMID: 18705902
stroke; neuroprotection; statins; clinical trial
22.  Relationship of Multidirectional Myocardial Strain with Radial Thickening and Ejection Fraction and Impact of Left Ventricular Hypertrophy. A Study in a Community-Based Cohort 
Left ventricular (LV) systolic strain provides additional prognostic value to LV ejection fraction (LVEF) and wall motion analysis. However, the relationship between myocardial multidirectional strain and LVEF, and the effect of LV hypertrophy on this relationship, are not completely understood especially in unselected populations.
LV global longitudinal (εL) and circumferential (εC) systolic strain analysis was performed by two-dimensional speckle-tracking echocardiography in 215 participants from a community-based study. LV radial wall thickening was measured as global radial strain (εR), and LVEF was assessed by biplane Simpson’s method.
εR was significantly associated with εC (β=−0.56, p<0.01) and with εL (β= −0.18, p<0.01). The contribution of εL to εR was especially evident in subjects with lower εC and in presence of LV hypertrophy (β= −0.30, p<0.01). εL and εC were significantly associated with LVEF (β= −0.36 and β=−0.49, both p<0.01) independent of LV mass and other confounders, and their interaction significantly improved the prediction of LVEF (R-square change=0.14) but not of εR (R-square change=0.002).
εR is mainly related to εC with a smaller contribution of εL, which becomes especially evident in subjects with lower εC and in presence of LV hypertrophy. Therefore, radial thickening may not detect subclinical LV longitudinal function reduction in normal ventricles and when εC is preserved. While a reduction in εL has a limited impact on εR, it exerts a greater effect on global LVEF, therefore for a more accurate LVEF prediction both εL and εC need to be considered.
PMCID: PMC3640730  PMID: 23360509
Left ventricle; Systolic function; Strain; Ejection fraction; Speckle-tracking; Echocardiography
23.  Traditional Risk Factors are Not Major Contributors to the Variance in Carotid Intima-Media Thickness 
Background and Purpose
Carotid Intima-Media Thickness (cIMT) was a widely accepted ultrasound marker of subclinical atherosclerosis in the past. Although traditional risk factors may explain approximately 50% of the variance in plaque burden, they may not explain such a high proportion of the variance in IMT, especially when measured in plaque free-locations. We aimed this study to identify individuals with cIMT unexplained by traditional risk factors for future environmental and genetic research.
As part of the Northern Manhattan Study, 1,790 stroke-free individuals (mean age 69±9; 60% women; 61% Hispanic, 19% black, 18% white) were assessed for cIMT using B-mode carotid ultrasound. Multiple linear regression models were evaluated: (1) incorporating pre-specified traditional risk factors; and (2) including less traditional factors, such as inflammation biomarkers, adiponectin, homocysteine and kidney function. Standardized cIMT residual scores were constructed to select individuals with unexplained cIMT.
Mean total cIMT was 0.92±0.09 mm. The traditional model explained 11% of the variance in cIMT. Age (7%), male sex (3%), glucose (<1%), pack years of smoking (<1%), and LDL-cholesterol (<1%) were significant contributing factors. The model including inflammatory biomarkers explained 16% of the variance in cIMT. Adiponectin was the only additional significant contributor to the variance in cIMT. We identified 358 (20%) individuals with cIMT unexplained by the investigated risk factors.
Vascular risk factors explain only a small proportion of variance in cIMT. Identification of novel genetic and environmental factors underlying unexplained subclinical atherosclerosis is of outmost importance for future effective prevention of vascular disease.
PMCID: PMC3738011  PMID: 23704105
carotid ultrasound; carotid intima-media thickness; risk factors
25.  Stroke Location and Association With Fatal Cardiac Outcomes 
Background and Purpose
Cardiac mortality after stroke is common, and small studies have suggested an association of short-term cardiac mortality with insular location of cerebral infarction. Few population-based studies with long-term follow-up have evaluated the effect of stroke location on the long-term risk of cardiac death or myocardial infarction (MI) after first ischemic stroke. We sought to determine the association between stroke location and cardiac death or MI in a multiethnic community-based cohort.
The Northern Manhattan Study is a population-based study designed to determine stroke incidence, risk factors, and prognosis in a multiethnic urban population. First ischemic stroke patients age 40 or older were prospectively followed up for cardiac death defined as fatal MI, fatal congestive heart failure, or sudden death/arrhythmia and for nonfatal MI. Primary brain anatomic site was determined by consensus of research neurologists. Hazard ratios (HRs) and 95% CIs were calculated by Cox proportional-hazards models and adjusted for vascular risk factors (age, sex, history of coronary disease, hypertension, diabetes, cholesterol, and smoking), stroke severity, infarct size, and stroke etiology.
The study population consisted of 655 patients whose mean age was 69.7 ± 12.7 years; 44.6% were men and 51.3% were Hispanic. During a median follow-up of 4.0 years, 44 patients (6.7%) had fatal cardiac events. Of these, fatal MI occurred in 38.6%, fatal congestive heart failure in 18.2%, and sudden death in 43.2%. In multivariate models, clinical diagnosis of left parietal lobe infarction was associated with cardiac death (adjusted HR = 4.45; 95% CI, 1.83 to 10.83) and cardiac death or MI (adjusted HR = 3.30; 95% CI, 1.45 to 7.51). When analysis of anatomic location was restricted to neuroimaging (computed tomography, magnetic resonance imaging, or both [n = 447]), left parietal lobe infarction was associated with cardiac death (adjusted HR = 3.37; 95% CI, 1.26 to 8.97), and both left (adjusted HR = 3.49; 95% CI, 1.38 to 8.80) and right (adjusted HR = 3.13; 95% CI, 1.04 to 9.45) parietal lobe infarctions were associated with cardiac death or MI. We did not find an association between frontal, temporal, or insular stroke and fatal cardiac events, although the number of purely insular strokes was small.
Parietal lobe infarction is an independent predictor of long-term cardiac death or MI in this population. Further studies are needed to confirm whether parietal lobe infarction is an independent predictor of cardiac events and death. Surveillance for cardiac disease and implementation of cardioprotective therapies may reduce cardiac mortality in patients with parietal stroke.
PMCID: PMC4112463  PMID: 18635863
acute stroke; cardiac arrhythmia; epidemiology; sudden death

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