Left ventricular dimensions and cardiovascular outcomes in systolic heart failure: the WARCEF trial.

AIMS: There is limited information on the association between left ventricular (LV) dimensions and cardiovascular (CV) outcomes in patients with heart failure (HF) with reduced LV ejection fraction (HFrEF) receiving recommended HF treatment. We investigated the association between LV dimensions and CV outcomes in HFrEF patients receiving recommended HF treatment. METHODS AND RESULTS: We investigated the association between LV echocardiographic dimensions and CV outcomes using conventional Cox models in 1138 HFrEF patients in sinus rhythm randomized to warfarin or aspirin treatment in the Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. LV enlargement, whether by diameter [LV end-diastolic diameter index (LVEDDI) and LV end-systolic diameter index (LVESDI)] or volume [LV end-diastolic volume index (LVEDVI) and LV end-systolic volume index (LVESVI)], was independently associated with all-cause death [LVEDDI: hazard ratio (HR) per cm/m2 1.53, LVESDI: HR per cm/m2 1.65, LVEDVI: HR per 10 mL/m2 1.07, and LVESVI: HR per 10 mL/m2 1.10; all P values < 0.001], CV death (HR 1.68, 1.79, 1.09, and 1.12, respectively; all P values < 0.001), and HF hospitalization (HR 1.59, 1.79, 1.06, and 1.08, respectively; all P values < 0.001). No association was observed with myocardial infarction or stroke. The associations were independent of LV ejection fraction values, and incremental to them. LV volumes conferred additional predictive value over LV diameters. CONCLUSIONS: Left ventricular enlargement is an independent predictor of CV events in patients with HFrEF and recommended HF treatment. LV dimensions should be considered in the risk assessment.

Sequencing of Linkage Region on Chromosome 12p11 Identifies PKP2 as a Candidate Gene for Left Ventricular Mass in Dominican Families.

Increased left ventricular mass (LVM) is an intermediate phenotype for cardiovascular disease (CVD) and a predictor of stroke. Using families from the Dominican Republic, we have previously shown LVM to be heritable and found evidence for linkage to chromosome 12p11. Our current study aimed to further characterize the QTL by sequencing the 1 LOD unit down region in 10 families from the Dominican Republic with evidence for linkage to LVM. Within this region, we tested 5477 common variants [CVs; minor allele frequency (MAF) ≥5%] using the Quantitative Transmission-Disequilibrium Test (QTDT). Gene-based analyses were performed to test rare variants (RVs; MAF < 5%) in 181 genes using the family-based sequence kernel association test. A sample of 618 unrelated Dominicans from the Northern Manhattan Study (NOMAS) and 12 Dominican families with Exome Array data were used for replication analyses. The most strongly associated CV with evidence for replication was rs1046116 (Discovery families P = 9.0 × 10-4; NOMAS P = 0.03; replication families P = 0.46), a missense variant in PKP2 In nonsynonymous RV analyses, PKP2 was one of the most strongly associated genes (P = 0.05) with suggestive evidence for replication in NOMAS (P = 0.05). PKP2 encodes the plakophilin 2 protein and is a desmosomal gene implicated in arrythmogenic right ventricular cardiomyopathy and recently in arrhythmogenic left ventricular cardiomyopathy, which makes PKP2 an excellent candidate gene for LVM. In conclusion, sequencing of our previously reported QTL identified common and rare variants within PKP2 to be associated with LVM. Future studies are necessary to elucidate the role these variants play in influencing LVM.

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) µV*ms among stroke cases and 3934 (±2541) µV*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.

Aortic arch atherosclerosis in patients with severe aortic stenosis can be argued by greater day-by-day blood pressure variability.

BACKGROUND AND PURPOSE: Although it is well known that the prevalence of aortic arch plaques, one of the risk factors for ischemic stroke, is high in patients with severe aortic stenosis, the underlying mechanisms are not well understood. Increased day-by-day blood pressure (BP) variability is also known to be associated with stroke; however, little is known on the association between day-by-bay BP variability and aortic arch atherosclerosis in patients with aortic stenosis. Our objective was to clarify the association between day-by-day BP variables (average values and variability) and aortic arch atherosclerosis in patients with severe aortic stenosis. METHODS: The study population consisted of 104 consecutive patients (mean age 75 ± 8 years) with severe aortic stenosis who were scheduled for aortic valve replacement. BP was measured in the morning in at least 4 consecutive days (mean 6.8 days) prior to the day of surgery. Large (≥4 mm), ulcerated, or mobile plaques were defined as complex plaques using transesophageal echocardiography. RESULTS: Cigarette smoking and all systolic BP variables were associated with the presence of complex plaques (p < 0.05), whereas diastolic BP variables were not. Multiple regression analysis indicated that day-by-day mean systolic BP and day-by-day systolic BP variability remained independently associated with the presence of complex plaques (p < 0.05) after adjustment for age, male sex, cigarette smoking, hypertension, hypercholesterolemia, and diabetes mellitus. CONCLUSIONS: These findings suggest that higher day-by-day mean systolic BP and day-by-day systolic BP variability are associated with complex plaques in the aortic arch and consequently stroke risk in patients with aortic stenosis.

Arterial wave reflection and aortic valve calcification in an elderly community-based cohort.

BACKGROUND: Aortic valve calcification (AVC) without stenosis is common in the elderly, is associated with cardiovascular morbidity and mortality, and may progress to aortic valve stenosis. Arterial stiffness and pulse-wave reflection are important components of proximal aortic hemodynamics, but their relationship with AVC is not established. METHODS: To investigate the relationship of arterial wave reflection and stiffness with AVC, pulse wave analysis and AVC evaluation by echocardiography were performed in 867 participants from the Cardiovascular Abnormalities and Brain Lesions study. Participants were divided into four categories on the basis of the severity and extent of AVC: (1) none or mild focal AVC, (2) mild diffuse AVC, (3) moderate to severe focal AVC, and (4) moderate to severe diffuse AVC. Central blood pressures and pulse pressure, total arterial compliance, augmentation index, and time to wave reflection were assessed using applanation tonometry. RESULTS: Indicators of arterial stiffness and wave reflection were significantly associated with AVC severity, except for central systolic and diastolic pressures and time to reflection. After adjustment for pertinent covariates (age, sex, race/ethnicity, and estimated glomerular filtration rate), only augmentation pressure (P = .02) and augmentation index (P = .002) were associated with the severity of AVC. Multivariate logistic regression analysis revealed that augmentation pressure (odds ratio per mm Hg, 1.14; 95% confidence interval, 1.02-1.27; P = .02) and augmentation index (odds ratio per percentage point, 1.07; 95% confidence interval, 1.01-1.13; P = .02) were associated with an increased risk for moderate to severe diffuse AVC, even when central blood pressure value was included in the same model. CONCLUSIONS: Arterial wave reflection is associated with AVC severity, independent of blood pressure values. Increased contribution of wave reflection to central blood pressure could be involved in the process leading to AVC.

Cognitive function in ambulatory patients with systolic heart failure: insights from the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.

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 (ß-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.

Systemic inflammation and brachial artery endothelial function in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND OBJECTIVE: Inflammation and endothelial dysfunction have been implicated in the pathogenesis of atherosclerotic vascular disease. Brachial artery flow-mediated dilation (FMD) is a reliable, non-invasive method of assessing endothelial function. We hypothesised that increased levels of systemic inflammatory markers are associated with impaired endothelial function as assessed by FMD in a multi-ethnic cohort. METHODS: We assessed brachial artery FMD in 3501 participants (1739 men, 1762 women; median age 61 years) in the Multi-Ethnic Study of Atherosclerosis and measured serum concentrations of interleukin (IL)-6, C reactive protein (CRP) and tumour necrosis factor (TNF)-α receptor 1. Spearman correlation coefficients were used to evaluate the association of each inflammatory marker with FMD, adjusting for the effect of other variables associated with FMD. RESULTS: There was a significant inverse correlation between IL-6 levels and FMD (-0.042; p=0.02) after adjustment for age, gender, race/ethnicity, education, income, low-density lipoprotein, diabetes, glucose, hypertension status and treatment, waist circumference, triglycerides, baseline brachial diameter, recent infection and use of medications that may alter inflammation. There was no significant correlation between CRP and FMD (0.008; p=0.64) or TNF-α receptor 1 and FMD (0.014; p=0.57). There was no evidence of effect modification by race/ethnicity. CONCLUSIONS: In this multi-ethnic cohort, increased levels of the pro-inflammatory cytokine IL-6 were associated with impaired endothelial function assessed by FMD. Elevated IL-6 levels may reflect a state that promotes vascular inflammation and development of subclinical atherosclerosis independent of traditional cardiovascular risk factors.

Pre-operative echocardiographic features associated with persistent mitral regurgitation after left ventricular assist device implantation.

BACKGROUND: Previous studies have shown remarkable decrease in size of the left ventricle after left ventricular assist device (LVAD) implantation due to mechanical unloading. However, a certain number of patients continue to have significant mitral regurgitation (MR) under LVAD support. We investigated pre-operative echocardiographic features associated with persistent MR after LVAD implantation. METHODS: We retrospectively reviewed 82 consecutive patients undergoing continuous-flow LVAD implantation between 2007 and 2010. We obtained echocardiograms performed within 2 weeks before and 1 week after surgery. We investigated the pre-operative echocardiographic findings associated with significant MR post-LVAD and compared 1-year mortality after LVAD surgery between patients with and without significant MR post-LVAD. RESULTS: MR was significant in 43 patients (52.4%) before LVAD surgery. Among those, 5 underwent concomitant mitral valve repair (MVr) at the time of LVAD implantation. Of the remaining 38 patients, 25 (65.8%) showed improvement of MR, whereas 13 patients (34.2%) continued to have significant MR post-LVAD. Multivariate analysis revealed that posterior displacement of the coaptation point of mitral leaflets was significantly associated with significant MR post-LVAD (hazard ratio, 1.335; 95% confidence interval, 1.035-1.721; p = 0.026) even after adjusting for the amount of pre-operative MR flow. Post-LVAD 1-year survival of patients with and without significant MR post-LVAD was not significantly different (92.3% vs 89.1%, p = 0.826). CONCLUSIONS: Pre-LVAD posterior displacement of mitral leaflets may be indicative of post-operative significant MR, which would help identify echocardiographic features of functional MR refractory to simple volume reduction of the ventricle.

An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke.

OBJECTIVE: We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO. METHODS: Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates. RESULTS: Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%-26%) in those with 0 to 3 points to 73% (95% CI: 66%-79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%-28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%-4%) in the highest. CONCLUSION: Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.

Higher ambulatory blood pressure is associated with aortic valve calcification in the elderly: a population-based study.

Aortic valve calcification (AVC) without outflow obstruction (stenosis) is common in the elderly and increases the risk of cardiovascular morbidity and mortality. Although high blood pressure (BP) measured at the doctor's office is known to be associated with AVC, little is known about the association between 24-hour ambulatory BP (ABP) and AVC. Our objective was to clarify the association between ABP variables and AVC. The study population consisted of 737 patients (mean age, 71±9 years) participating in the Cardiovascular Abnormalities and Brain Lesions study who underwent 24-hour ABP monitoring. Each aortic valve leaflet was graded on a scale of 0 (normal) to 3 (severe calcification). A total valve score (values 0-9) was calculated as the sum of all leaflet scores. Advanced AVC (score ≥4) was present in 77 subjects (10.4%). All of the systolic ABP variables (except systolic BP nocturnal decline) and mean asleep diastolic BP were positively associated with advanced calcification, whereas normal dipping status and diastolic BP nocturnal decline were negatively associated. Multiple regression analysis indicated that mean awake diastolic BP (odds ratio, 1.31 [95% CI, 1.01-1.71]) and asleep diastolic BP (odds ratio, 1.34 [95% CI, 1.04-1.72]) remained independently associated with advanced calcification after adjustment for age, sex, cigarette smoking, diabetes mellitus, hypercholesterolemia, hypertension, serum creatinine, and any degree of aortic insufficiency. Diastolic ABP is independently associated with advanced calcification. This finding may have important implications in gaining further insight into the mechanism of AVC.

Relationship between ambulatory blood pressure and aortic arch atherosclerosis.

OBJECTIVE: Atherosclerotic plaque in the aortic arch is an independent risk factor for ischemic stroke. Although high blood pressure (BP) measured at the doctor's office is known to be associated with aortic atherosclerosis, little is known on the association between 24-h ambulatory BP and aortic arch plaque presence and severity. Our objective was to clarify the association between ambulatory BP variables and aortic arch atherosclerosis in a community-based cohort. METHODS: The study population consisted of 795 patients (mean age 71 ± 9 years) participating in the Cardiovascular Abnormalities and Brain Lesions (CABL) study who underwent 24-h ambulatory BP monitoring (ABPM). Arch plaque was evaluated by 2D transthoracic echocardiography from a suprasternal window. RESULTS: All systolic ABPM variables (24-h/daytime/nighttime mean systolic BP, daytime/nighttime systolic BP variability) were associated with the presence of any plaque and large (≥ 4 mm) plaque, whereas diastolic BP variables were not associated with aortic atherosclerosis. Multiple regression analysis indicated that nighttime systolic BP variability (expressed as the standard deviation of nighttime systolic BP) remained independently associated with large plaque after adjustment for age, sex, cigarette smoking, history of hypertension, diabetes mellitus, hypercholesterolemia, anti-hypertensive medication and nighttime mean systolic BP (odds ratio 1.39 per 1 standard deviation increase, 95% CI 1.00-1.93, P<0.05). CONCLUSION: Systolic ABPM variables are significantly associated with the presence of arch plaque. Nighttime systolic BP variability is independently associated with large arch plaque. These findings may have important implications in gaining further insights into the mechanism of arch plaque formation and progression.

Aortic valve calcification in mild primary hyperparathyroidism.

CONTEXT: It is unclear whether cardiovascular disease is present in primary hyperparathyroidism (PHPT). OBJECTIVE: Aortic valve structure and function were compared in PHPT patients and population-based controls. DESIGN: This is a case-control study. SETTING: The study was conducted in a university hospital metabolic bone disease unit. PARTICIPANTS: We studied 51 patients with PHPT and 49 controls. OUTCOME MEASURES: We measured the aortic valve calcification area and the transaortic pressure gradient. RESULTS: Aortic valve calcification area was significantly higher in PHPT (0.24 ± 0.02 vs. 0.17 ± 0.02 cm(2), p<0.01), although there was no difference in the peak transaortic pressure gradient, a functional measure of valvular calcification (5.6 ± 0.3 vs. 6.0 ± 0.3 mm Hg, P = 0.39). Aortic valve calcification area was positively associated with PTH (r = 0.34; P < 0.05) but not with serum calcium, phosphorus, or 25-hydroxyvitamin D levels or with calcium-phosphate product. Serum PTH level remained an independent predictor of aortic valve calcification area after adjustment for age, sex, body mass index, smoking status, history of hypercholesterolemia and hypertension, and estimated glomerular filtration rate. CONCLUSIONS: Mild PHPT is associated with subclinical aortic valve calcification. PTH, but not serum calcium concentration, predicted aortic valve calcification. PTH was a more important predictor of aortic valve calcification than well-accepted cardiovascular risk factors.

Alteration in subendocardial and subepicardial myocardial strain in patients with aortic valve stenosis: an early marker of left ventricular dysfunction?

BACKGROUND: It has been suggested that myocardial systolic impairment may not be accurately detected by the evaluation of endocardial excursion alone. The aim of this study was to test the hypothesis that changes in left ventricular (LV) subendocardial and subepicardial strain are sensitive markers of severity of aortic stenosis (AS) and LV function in patients with AS. METHODS: Transthoracic echocardiography was performed in 73 consecutive patients with AS who had preserved systolic function and in 20 controls. Longitudinal strain, subendocardial radial strain, subepicardial radial strain, and transmural radial strain were measured using LV apical and short-axis images. RESULTS: The 73 patients enrolled in this study were classified according to AS severity: mild (n = 10), moderate (n = 15), or severe (n = 48). Although transmural and subepicardial radial strain showed similar values in all groups, subendocardial radial strain and longitudinal strain could differentiate mild or moderate AS from severe AS. Only the ratio of subendocardial to subepicardial radial strain (the bilayer ratio) decreased significantly as the severity of AS increased. Bilayer ratio showed weak correlations with LV ejection fraction (r = 0.37) and E/E' ratio (r = -0.33) and moderate correlations with LV mass (r = -0.55) and aortic valve area (r = 0.71). Moreover, bilayer ratio was independently associated with AS severity (P = .001). In 21 patients who underwent aortic valve replacement, subendocardial radial strain and bilayer ratio increased 7 days after surgery, whereas other echocardiographic parameters of LV function showed no improvement. CONCLUSIONS: Bilayer ratio can reliably differentiate patients with varying degrees of AS severity and is a sensitive marker of LV function. These findings suggest that the evaluation of subendocardial and subepicardial radial strain might be a novel method for assessing LV mechanics in patients with AS.

Alcohol consumption and atherosclerotic burden in the proximal thoracic aorta.

BACKGROUND: The relationship between alcohol consumption and ischemic stroke or aortic atherosclerosis is unclear, but a protective effect of moderate consumption on stroke risk has been suggested. We conducted a cross-sectional analysis in a population-based sample to evaluate the possible association between alcohol consumption and aortic atherosclerotic plaque (AAP), which is associated with increased stroke risk. METHODS: As part of the NINDS-funded Aortic Plaques and Risk of Ischemic Stroke (APRIS) study, 464 subjects over the age of 55 were studied (mean age 69.1 ± 9.0 with 251 males and 213 females), including 255 patients with first ischemic stroke and 209 stroke-free controls. Transesophageal echocardiogram was performed for the detection of AAP. Alcohol consumption was measured in number of drinks per week during the previous year using a standardized questionnaire, and categorized as: (1) none or minimal (<1 drink per month); (2) light to moderate (between 1 drink per month and 2 drinks daily); and (3) heavy (>2 daily). Multivariate conditional logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence interval (CI) for alcohol consumption and AAP after adjustment for the potential confounding risk factors (age, sex, hypertension, diabetes, dyslipidemia, and cigarette smoking). RESULTS: Overall, AAP was detected in 326 subjects (70.4%), and 174 subjects (37.6%) had AAP ≥ 4 mm, which carry higher stroke risk. No or minimal alcohol consumption was present in 241 subjects (53.2%), and 177 subjects (39.0%) had light to moderate consumption. Prevalence of light to moderate alcohol consumption was significantly lower in stroke patients than in controls (35.5% vs. 60.3%, p < 0.001) and in subjects who had AAP compared with those without it (41.6% vs. 58.8%, p = 0.008). After adjusting for significant predictors of atherosclerosis, alcohol consumption of any degree was inversely associated with AAP (OR 0.61; 95% CI 0.37-0.98, p = 0.042). The significance of the association was borderline for AAP ≥ 4 mm (OR 0.64, 95% CI 0.41-1.00, p = 0.054). In the dose-response analysis, only light to moderate alcohol consumption was significantly associated with a lower risk of having any AAP (adjusted OR 0.45; 95% CI 0.29-0.68, p < 0.001) or AAP ≥ 4 mm (adjusted OR 0.51; 95% CI 0.34-0.77, p = 0.001). CONCLUSIONS: Our data indicate that light to moderate alcohol consumption is associated with lower atherosclerotic burden in the proximal aortic arch. This observation may explain at least in part the lower risk of ischemic stroke observed in moderate alcohol consumers.

Impaired flow-mediated vasodilatation is associated with increased left ventricular mass in a multiethnic population. The Northern Manhattan Study.

BACKGROUND: Increased left ventricular (LV) mass and endothelial dysfunction are important risk factors for cardiovascular mortality and morbidity. However, it is not clear whether endothelial dysfunction is associated with increased LV mass. We tested the hypothesis that impaired flow-mediated vasodilatation (FMD) is associated with increased LV mass in a population-based multiethnic cohort. METHODS: As a part of the Northern Manhattan Study (NOMAS), we performed two-dimensional echocardiography and FMD assessment during reactive hyperemia by high-resolution ultrasonography in 867 stroke-free community participants. LV mass was calculated according to an established method. LV hypertrophy was defined as the 90th percentile of sex-specific LV mass indexed for body surface area among normal subjects. Multivariable models were used to test the association of FMD with LV mass. RESULTS: In multiple linear regression analysis adjusting for age, sex, body mass index, systolic blood pressure, antihypertensive medications, low-density lipoprotein cholesterol, diabetes, smoking, hematocrit, and race-ethnicity, FMD was inversely associated with LV mass (beta = -1.21 +/- 0.56, P = 0.03). The association persisted after further adjustment for any component of blood pressure (systolic, mean, and pulse pressure). In univariate logistic regression analysis, each 1% decrease in FMD was associated with an 8% higher risk of LV hypertrophy (odds ratio 1.08, 95% confidence interval 1.03-1.13 per each FMD point P < 0.01). CONCLUSIONS: Impaired FMD is associated with LV mass, independent of other factors associated with increased LV mass. Endothelial dysfunction might be a potential risk factor for LV hypertrophy.

Soluble tumor necrosis factor receptor 1 level is associated with left ventricular hypertrophy: the northern Manhattan study.

BACKGROUND: Although inflammatory markers may be associated with risk of cardiovascular events, few data are available regarding these markers and their association with left ventricular hypertrophy (LVH). We sought to evaluate whether inflammatory markers were independently associated with LVH in a multiethnic population in northern Manhattan. METHODS: A population-based cross-sectional study was conducted in 660 participants without stroke, who had undergone both transthoracic echocardiography and testing for soluble tumor necrosis factor receptor (sTNFR) 1, interleukin (IL)-6, and high-sensitivity C-reactive protein (hsCRP). LV mass was calculated according to an established formula. LVH was defined as LV mass >90th percentile of the participants. RESULTS: The mean age was 67.4 +/- 8.8 years, 35.5% were men, 61.7% were Hispanic, 19.7% were black, and 18.6% were white. In univariate analyses, hsCRP, IL-6, and sTNFR1 were significantly associated with LV mass. Multiple linear regression analyses demonstrated that sTNFR1 (P = 0.0008) was associated with LV mass after adjusting for demographic and medical risk factors, but hsCRP and IL-6 were not. When all markers were included in the same model, sTNFR1 remained significant, but hsCRP and IL-6 did not. Compared with the lowest quartile of sTNFR1, those in the highest quartile were more likely to have LVH (odds ratio = 1.84, 95% confidence interval, 0.97-3.64, P = 0.06). CONCLUSIONS: sTNFR1, but not hsCRP nor IL-6, is independently associated with increased LV mass. Chronic subclinical inflammation including the TNFR1-associated system may contribute to LVH.

Patent foramen ovale and migraine: a cross-sectional study from the Northern Manhattan Study (NOMAS).

BACKGROUND: A causal relationship between patent foramen ovale (PFO) and migraine has been hypothesized, and improvement of migraine frequency and severity after percutaneous PFO closure has been reported. Population-based data on the relationship between PFO and migraine are sparse, however. The objective of this study was to examine the association between PFO and migraine among stroke-free individuals in an urban, population-based, multiethnic cohort. METHODS AND RESULTS: As a part of the ongoing Northern Manhattan Study (NOMAS), 1101 stroke-free subjects were assessed for self-reported history of migraine. The presence of PFO was assessed by transthoracic echocardiography. The mean age of the group was 69+/-10 years; 58% were women. Forty-eight percent were Caribbean Hispanic, 24% were white, 26% were black, and 2% were another race/ethnicity. The prevalence of self-reported migraine was 16% (13% migraine with aura). The prevalence of PFO was 15%. Migraine was significantly more frequent among younger subjects, women, and Hispanics. The prevalence of PFO was not significantly different between subjects who had migraine (26/178, or 14.6%) and those who did not (138/923, or 15.0%; P=0.9). In an adjusted multivariate logistic regression model, the presence of PFO was not associated with increased prevalence of migraine (odds ratio 1.01, 95% confidence interval 0.63 to 1.61). Increasing age was associated with lower prevalence of migraine in both subjects with a PFO (odds ratio 0.94, 95% confidence interval 0.90 to 0.99 per year) and those without PFO (odds ratio 0.97, 95% confidence interval 0.95 to 0.99 per year). The observed lack of association between PFO and migraine (with or without aura) was not modified by diabetes mellitus, hypertension, cigarette smoking, or dyslipidemia. CONCLUSIONS: In this multiethnic, elderly, population-based cohort, PFO detected with transthoracic echocardiography and agitated saline was not associated with self-reported migraine. The causal relationship between PFO and migraine remains uncertain, and the role of PFO closure among unselected patients with migraine remains questionable.

Stroke location and association with fatal cardiac outcomes: Northern Manhattan Study (NOMAS).

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Genetic contribution to brachial artery flow-mediated dilation: the Northern Manhattan Family Study.

BACKGROUND: Brachial artery flow-mediated dilation (FMD) is a non-invasive measure of endothelial function. Endothelial dysfunction has been associated with traditional vascular risk factors and increased risk of cardiovascular disease. The importance of genetic contribution to FMD and baseline brachial artery diameter has not been shown in Hispanic populations. The purpose of this study was to estimate the heritability of FMD. METHODS: Flow mediated dilation and brachial artery diameter were measured in a subset of Caribbean Hispanic families from the ongoing Northern Manhattan Family Study (NOMAFS), which studies the contribution of genetics to stroke and cardiovascular risk factors. The age- and sex-adjusted heritability of FMD was estimated using variance component methods. RESULTS: The current data include 620 subjects (97 probands and 523 relatives) from 97 families. The age and sex-adjusted heritability of brachial artery diameter was 0.57 (p<0.01). The age- and sex-adjusted heritability of FMD was 0.20 (p=0.01). After additional adjustment for systolic and diastolic blood pressure, body mass index, smoking, lipid, diabetes mellitus, medication, and baseline brachial artery diameter, the heritability of FMD was 0.17 (p=0.01). CONCLUSIONS: We found modest heritability of FMD. FMD might be a reasonable phenotype for further investigation of genetic contribution to atherosclerosis.