Martin G Larson

Boston University, Boston, Massachusetts, United States

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Publications (501)5373.82 Total impact

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    ABSTRACT: Comprehensive long-term data on atrial fibrillation trends in men and women are scant. We aimed to provide such data through analysis of the Framingham cohort over 50 years. We investigated trends in incidence, prevalence, and risk factors for atrial fibrillation and its association with stroke and mortality after onset in 9511 participants enrolled in the Framingham Heart Study between 1958 and 2007. We analysed trends within 10 year groups (1958-67, 1968-77, 1978-87, 1988-97, and 1998-2007), stratified by sex. During 50 years of observation (202 417 person-years), 1544 cases of new-onset atrial fibrillation occurred (of whom 723 [47%] were women). Between 1958-67 and 1998-2007, age-adjusted prevalence of atrial fibrillation quadrupled from 20·4 to 96·2 cases per 1000 person-years in men and from 13·7 to 49·4 cases per 1000 person-years in women; age-adjusted incidence increased from 3·7 to 13·4 new cases per 1000 person-years in men and from 2·5 to 8·6 new cases per 1000 person-years in women (ptrend<0·0001 for all comparisons). For atrial fibrillation diagnosed by electrocardiograph (ECG) during routine Framingham examinations, age-adjusted prevalence per 1000 person-years increased (12·6 in 1958-67 to 25·7 in 1998-2007 in men, ptrend=0·0007; 8·1 to 11·8 in women, ptrend=0·009). However, age-adjusted incidence of atrial fibrillation by Framingham Heart Study ECGs did not change significantly with time. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 74% (95% CI 50-86%) decrease in stroke (hazards ratio [HR] 3·77, 95% CI 1·98-7·20 in 1958-1967 compared with 1998-2007; ptrend=0·0001) and a 25% (95% CI -3-46%) decrease in mortality (HR 1·34, 95% CI 0·97-1·86 in 1958-1967 compared with 1998-2007; ptrend=0·003) in 20 years following atrial fibrillation onset. Trends of increased incidence and prevalence of atrial fibrillation in the community were probably partly due to enhanced surveillance. Measures are needed to enhance early detection of atrial fibrillation, through increased awareness coupled with targeted screening programmes and risk factor-specific prevention. NIH, NHLBI, NINDS, Deutsche Forschungsgemeinschaft. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet 05/2015; DOI:10.1016/S0140-6736(14)61774-8 · 45.22 Impact Factor
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    ABSTRACT: Background-—Concerns have been raised that the 2013 atherosclerotic cardiovascular disease (ASCVD) risk estimator overpredicts risk in contemporary cohorts. Whether suboptimal calibration will lead to overtreatment with statins is unknown. We investigated the numbers of people eligible for statin treatment in the Framingham Heart Study Offspring Cohort, based on the 2013 cholesterol guidelines, and estimated the proportion that may be overtreated as a result of potential miscalibration of the ASCVD estimator. Methods and Results-—During a median follow-up of 10 years, we observed 285 ASCVD events (8.4%; comprising ischemic stroke, myocardial infarction, and coronary artery disease death) among 3396 men and 112 events (2.9%) among 3838 women. Hosmer–Lemeshow chi-square statistics were 16.3 in men (340 predicted versus 285 observed events) and 29.1 in women (166 predicted versus 112 observed events). Overprediction predominantly occurred among women in the highest risk decile and among men in the ≥7th risk deciles, for which observed ASCVD event rates were ≥7.5%. In total, 2615 participants (36%; 867 women) were eligible for statins based on the new guidelines. Of these, 171 women (20%) and 154 men (9%) were reclassified downward (as not eligible for statin therapy) using a recalibrated ASCVD estimator. In the latter group, 18 women (10.5%; 95% CI 5.9% to 15.2%) and 11 men (7.1%; 95% CI 3.0% to 11.3%) experienced ASCVD. Conclusions-—The risk estimator overpredicted ASCVD risk but did so mainly among high-risk participants who would be considered eligible for statin use anyway. Our findings may mitigate concerns regarding the potential impact of miscalibration of the ASCVD estimator in contemporary cohorts. (J Am Heart
    Journal of the American Heart Association 04/2015; 4(4). DOI:10.1161/JAHA.115.001888 · 2.88 Impact Factor
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    ABSTRACT: Alterations in metabolism influence lifespan in experimental models, but data in humans are lacking. Here we use liquid chromatography/mass spectrometry to quantify 217 plasma metabolites and examine their relation to longevity in a large cohort of men and women followed for up to 20 years. We find that, higher concentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, are associated with lower odds of longevity, defined as attaining 80 years of age. Higher concentrations of isocitrate, but not taurocholate, are also associated with worse cardiovascular health at baseline, as well as risk of future cardiovascular disease and death. None of the metabolites identified are associated with cancer risk. Our findings suggest that some, but not all, metabolic pathways related to human longevity are linked to the risk of common causes of death.
    Nature Communications 04/2015; 6:6791. DOI:10.1038/ncomms7791 · 10.74 Impact Factor
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    ABSTRACT: Inflammation and inflammatory biomarkers have emerged as integral components and predictors of incident cardiovascular (CV) disease. Omega-3 fatty acids, particularly eicosapentaenoic and docosahexaenoic acids (EPA and DHA) have anti-inflammatory properties, and have been variably associated with lower blood pressure, favorable blood lipid changes, and reduced CV events. We examined the cross-sectional association of red blood cell (RBC) fatty acids, representative of body membrane fatty acid composition, with 10 biomarkers active in multiple inflammatory pathways in 2724 participants (mean age 66 ± 9 years, 54% women, 8% minorities) from the Framingham Offspring and minority Omni Cohorts. After multivariable adjustment, the RBC EPA and DHA content was inversely correlated (all P ≤ 0.001) with 8 biomarkers: urinary isoprostanes (r = -0.16); and soluble interleukin-6 (r = -0.10); C-reactive protein (r = -0.08); tumor necrosis factor receptor 2 (r = -0.08); intercellular adhesion molecule-1 (r = -0.08); P-selectin (r = -0.06); lipoprotein-associated phospholipase-A2 mass (r = -0.11) and activity (r = -0.08). The correlations for monocyte chemoattractant protein-1 was -0.05, P = 0.006 and osteoprotegerin (r = -0.06, P = 0.002) were only nominally significant. In our large community-based study, we observed modest inverse associations between several types of inflammatory biomarkers with RBC omega-3 fatty acid levels. Our findings are consistent with the hypothesis that omega-3 fatty acids have anti-inflammatory properties. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 04/2015; 240(2). DOI:10.1016/j.atherosclerosis.2015.03.043 · 3.97 Impact Factor
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    ABSTRACT: Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into regulatory mechanisms of microRNA transcription, and can help elucidate the role of microRNA as mediators of complex traits. Here we present a miR-eQTL mapping study of whole blood from 5,239 individuals, and identify 5,269 cis-miR-eQTLs for 76 mature microRNAs. Forty-nine per cent of cis-miR-eQTLs are located 300-500 kb upstream of their associated intergenic microRNAs, suggesting that distal regulatory elements may affect the interindividual variability in microRNA expression levels. We find that cis-miR-eQTLs are highly enriched for cis-mRNA-eQTLs and regulatory single nucleotide polymorphisms. Among 243 cis-miR-eQTLs that were reported to be associated with complex traits in prior genome-wide association studies, many cis-miR-eQTLs miRNAs display differential expression in relation to the corresponding trait (for example, rs7115089, miR-125b-5p and high-density lipoprotein cholesterol). Our study provides a roadmap for understanding the genetic basis of miRNA expression, and sheds light on miRNA involvement in a variety of complex traits.
    Nature Communications 03/2015; 6:6601. DOI:10.1038/ncomms7601 · 10.74 Impact Factor
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    ABSTRACT: -Guidelines have proposed that atrial fibrillation (AF) can occur as an isolated event, particularly when precipitated by a secondary, or reversible, condition. However, knowledge of long-term AF outcomes after diagnosis during a secondary precipitant is limited. -In 1409 Framingham Heart Study participants with new-onset AF, we examined associations between first-detected AF episodes occurring with and without a secondary precipitant, and both long-term AF recurrence and morbidity. We selected secondary precipitants based on guidelines (surgery, infection, acute myocardial infarction, thyrotoxicosis, acute alcohol consumption, acute pericardial disease, pulmonary embolism, or other acute pulmonary disease). Among 439 (31%) people with AF diagnosed during a secondary precipitant, cardiothoracic surgery (n=131, 30%), infection (n=102, 23%), non-cardiothoracic surgery (n=87, 20%), and acute myocardial infarction (n=78, 18%) were most common. AF recurred in 544 of 846 eligible individuals without permanent AF (5-, 10-, and 15-year recurrences of 42%, 56% and 62% with versus 59%, 69% and 71% without secondary precipitants; multivariable-adjusted hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.54-0.78). Stroke risk (n=209/1262 at risk, HR 1.13, 95%CI 0.82-1.57) and mortality (n=1098/1409 at risk, HR 1.00, 95%CI 0.87-1.15) were similar between those with and without secondary precipitants, though heart failure risk was reduced (n=294/1107 at risk, HR 0.74, 95%CI 0.56-0.97). -AF recurs in most individuals, including those diagnosed with secondary precipitants. Long-term AF-related stroke and mortality risks were similar between individuals with and without secondary AF precipitants. Future studies may determine whether increased arrhythmia surveillance or adherence to general AF management principles in patients with reversible AF precipitants will reduce morbidity.
    Circulation 03/2015; 131(19). DOI:10.1161/CIRCULATIONAHA.114.014058 · 14.95 Impact Factor
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    ABSTRACT: Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk of cardiovascular disease; however, it is not known whether NAFLD contributes to cardiovascular disease independent of established risk factors. We examined the association between NAFLD and vascular function. We conducted a cross-sectional study of 2284 Framingham Heart Study participants without overt cardiovascular disease who had liver fat attenuation measured on computed tomography and who had measurements of vascular function and covariates. We evaluated the association between NAFLD and vascular function using multivariable partial correlations adjusting for age, sex, cohort, smoking, diabetes mellitus, hyperlipidemia, hypertension, body mass index, and visceral adipose tissue. The prevalence of NAFLD in our sample (mean age, 52±12 years; 51.4% women) was 15.3%. In age-, sex-, and cohort-adjusted analyses, greater liver fat was modestly associated with lower flow-mediated dilation (r=-0.05; P=0.02), lower peripheral arterial tonometry ratio (r=-0.20; P<0.0001), higher carotid-femoral pulse wave velocity (r=0.13; P<0.0001), and higher mean arterial pressure (r=0.11; P<0.0001). In multivariable-adjusted models, NAFLD remained associated with higher mean arterial pressure (r=0.06; P=0.005) and lower peripheral arterial tonometry ratio (r=-0.12; P<0.0001). The association between NAFLD and peripheral arterial tonometry ratio persisted after further adjustment for body mass index and visceral adipose tissue. For multiple measures of vascular function, the relationship with NAFLD appeared largely determined by shared cardiometabolic risk factors. The persistent relationship with reduced peripheral arterial tonometry response beyond established risk factors suggests that NAFLD may contribute to microvascular dysfunction. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2015; 35(5). DOI:10.1161/ATVBAHA.114.305200 · 5.53 Impact Factor
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    ABSTRACT: Physical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated. We related objective measures of moderate- to vigorous-intensity physical activity (MVPA, assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid-femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9±21.4 and 25.5±19.4 min/day, respectively. Higher values of MVPA (per 10-minute increment) were associated with lower carotid-femoral pulse wave velocity (estimate -0.53 ms/m; P=0.006) and lower forward pressure wave (estimate -0.23 mm Hg; P=0.03) but were not associated with augmentation index (estimate 0.13%; P=0.25). MVPA was associated positively with loge left ventricular mass (estimate 0.006 loge [g/m(2)]; P=0.0003), left ventricular wall thickness (estimate 0.07 mm; P=0.0001), and left atrial dimension (estimate 0.10 mm; P=0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P=0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting <10 versus ≥10 minutes. In our community-based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association 02/2015; 4(3). DOI:10.1161/JAHA.114.001528 · 2.88 Impact Factor
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    ABSTRACT: The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study souWght to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls. At false discovery rate <0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genome-wide genotype data to investigate miRNA and mRNA associations and relationships of genetic variation with miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that seem to regulate miRNA levels. Subsequently, we explored the relationships of these complex molecular associations with CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases versus controls (80% versus 30%; P<1×10(-16)), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially coexpressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, 3 miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA coexpression module that was causally linked to CHD and reflected the dysregulation of B-cell centered immune function. Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight coexpression with mRNAs. © 2015 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2015; 35(4). DOI:10.1161/ATVBAHA.114.305176 · 5.53 Impact Factor
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    ABSTRACT: -Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2) and hepatocyte growth factor (HGF) play important roles in angiogenesis, vascular remodeling, local tumor growth and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. -We performed a genome-wide association study for circulating Ang-2, sTie-2, and HGF in 3571 Framingham Heart Study (FHS) participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania (SHIP). In multivariable-adjusted models, sTie-2 and HGF concentrations were associated with single nucleotide polymorphisms (SNPs) in the genes encoding the respective biomarkers (top p=2.40×10(-65) [rs2273720] and 3.64×10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (p=5.05×10(-8) in FHS and 8.39×10(-5) in SHIP). Furthermore, SNPs in the AB0 gene were associated with sTie-2 (top SNP rs8176693 with p=1.84×10(-33) in FHS; p=2.53×10(-30) in SHIP) and Ang-2 (rs8176746 with p=2.07×10(-8) in FHS; p=0.001 in SHIP) levels on a genome-wide significant level. The top genetic loci explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the inter-individual variation in biomarker levels. -Genetic variation contributes to the inter-individual variation in growth factor levels and explains a modest proportion of circulating HGF, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.
    Circulation Cardiovascular Genetics 12/2014; 8(2). DOI:10.1161/CIRCGENETICS.114.000597 · 6.73 Impact Factor
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    ABSTRACT: Polyunsaturated fatty acids have been associated with beneficial influences on cardiovascular health. However, the underlying mechanisms are not clear, and data on the relations of polyunsaturated fatty acids to subclinical disease measures such as vascular stiffness and cardiac function are sparse and inconclusive. In a large community-based cohort, we examined the relations of omega-3 and other fatty acids to a comprehensive panel of vascular function measures (assessing microvascular function and large artery stiffness), cardiac structure and left ventricular function. Red blood cell (RBC) membrane fatty acid composition, a measure of long-term fatty acid intake, was assessed in participants of the Framingham Offspring Study and Omni cohorts and related to tonometry-derived measures of vascular stiffness and to a panel of echocardiographic traits using partial correlations. Up to n=3055 individuals (56% women, mean age 66 years) were available for analyses. In age- and sex-adjusted models, higher RBC omega-3 content was moderately associated (p≤0.002) with several measures of vascular stiffness and function in a protective direction. However, after multivariable adjustment, only an association of higher RBC omega-3 content with lower carotid-femoral pulse wave velocity (a measure of aortic stiffness) remained significant (r = -0.06, p=0.002). In secondary analyses, higher linoleic acid, the major nutritional omega-6 fatty acid, was associated with smaller left atrial size, even after multivariable adjustment (r = -0.064, p<0.001). In conclusion, in our cross-sectional community-based study, we found several associations consistent with the notion of protective effects of omega-3 and linoleic acid. The clinical significance of these modest associations remains to be elucidated. © The Author(s) 2014.
    Vascular Medicine 12/2014; 20(1). DOI:10.1177/1358863X14560808 · 1.73 Impact Factor
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    ABSTRACT: Most genome-wide association studies have explored relationships between genetic variants and plasma phospholipid fatty acid proportions, but few have examined apparent genetic influences on the membrane fatty acid profile of red blood cells (RBC). Using RBC fatty acid data from the Framingham Offspring Study, we analyzed over 2.5 million single nucleotide polymorphisms (SNPs) for association with 14 RBC fatty acids identifying 191 different SNPs associated with at least 1 fatty acid. Significant associations (p<1×10(-8)) were located within five distinct 1MB regions. Of particular interest were novel associations between (1) arachidonic acid and PCOLCE2 (regulates apoA-I maturation and modulates apoA-I levels), and (2) oleic and linoleic acid and LPCAT3 (mediates the transfer of fatty acids between glycerolipids). We also replicated previously identified strong associations between SNPs in the FADS (chromosome 11) and ELOVL (chromosome 6) regions. Multiple SNPs explained 8-14% of the variation in 3 high abundance (>11%) fatty acids, but only 1-3% in 4 low abundance (<3%) fatty acids, with the notable exception of dihomo-gamma linolenic acid with 53% of variance explained by SNPs. Further studies are needed to determine the extent to which variations in these genes influence tissue fatty acid content and pathways modulated by fatty acids. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Prostaglandins Leukotrienes and Essential Fatty Acids 12/2014; 94. DOI:10.1016/j.plefa.2014.11.007 · 1.98 Impact Factor
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    ABSTRACT: Background Heart failure is an established risk factor for poor outcomes in patients undergoing non-cardiac surgery, yet risk stratification remains a clinical challenge. We developed an index for 30-day mortality risk prediction in this particular group.Methods and resultsAll individuals with heart failure undergoing non-cardiac surgery between October 23 2004 and October 31 2011 were included from Danish administrative registers (n = 16 827). In total, 1787 (10.6%) died within 30 days. In a simple risk score based on the variables from the revised cardiac risk index, plus age, gender, acute surgery, and body mass index category the following variables predicted mortality (points): male gender (1), age 56–65 years (2), age 66–75 years (4), age 76–85 years (5), or age >85 years (7), being underweight (4), normal weight (3), or overweight (1), undergoing acute surgery (5), undergoing high-risk procedures (intra-thoracic, intra-abdominal, or suprainguinal aortic) (3), having renal disease (1), cerebrovascular disease (1), and use of insulin (1). The c-statistic was 0.79 and calibration was good. Mortality risk ranged from <2% for a score <5 to >50% for a score ≥20. Internal validation by bootstrapping (1000 re-samples) provided c-statistic of 0.79. A more complex risk score based on stepwise logistic regression including 24 variables at P < 0.05 performed only slightly better, c-statistic = 0.81, but was limited in use by its complexity.Conclusions For patients with heart failure, this simple index can accurately identify those at low risk for perioperative mortality.
    European Journal of Heart Failure 12/2014; 16(12). DOI:10.1002/ejhf.182 · 6.58 Impact Factor
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    ABSTRACT: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
    Nature Genetics 12/2014; DOI:10.1038/ng.3014 · 29.65 Impact Factor
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    ABSTRACT: AimsNon-invasive measures of cardiac mechanical function may have the potential to serve as markers of risk for heart failure; however, limited data exist regarding clinical correlates and heritability of these measures in the community.Methods and resultsWe used speckle-tracking echocardiography to assess LV strain and synchrony in the Framingham Offspring Study (n = 2816; mean age 67 years, 54% women). In multivariable regression analyses, male gender (vs. female, P < 0.001), higher heart rate (P < 0.0001), and presence of cardiovascular disease (P < 0.001) were associated with worse global peak strains across all planes analysed (longitudinal, transverse, circumferential, and radial). Higher diastolic blood pressure and diabetes were associated with worse longitudinal strain (P < 0.01), and greater body mass index was associated with worse radial strain (P = 0.0004). Overall, however, clinical correlates accounted for only 4–19% of the variation in measures of LV mechanical function. Select measures of LV strain were heritable: longitudinal strain (h2 = 16%, P = 0.002), transverse strain (h2 = 15%, P = 0.006), and circumferential strain (h2 = 30%, P < 0.0001). Furthermore, in a subset of 14437 participants with parental data available, parental heart failure was associated with worse circumferential strain in the offspring free of heart failure (P = 0.01).Conclusions Our investigation in a large community-based sample identified heritablity and clinical correlates of LV mechanical function, and highlighted an association of parental heart failure with worse global circumferential strain in offspring.
    European Journal of Heart Failure 12/2014; 17(1). DOI:10.1002/ejhf.202 · 6.58 Impact Factor
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    ABSTRACT: Whether low diastolic blood pressure (DBP) is a risk factor for recurrent cardiovascular disease (CVD) events in persons with isolated systolic hypertension is controversial. We studied 791 individuals (mean age 75 years, 47% female, mean follow-up time: 8±6 years) with DBP <70 (n=225) versus 70 to 89 mm Hg (n=566) after initial CVD events in the original and offspring cohorts of the Framingham Heart Study. Recurrent CVD events occurred in 153 (68%) participants with lower DBP and 271 (48%) with higher DBP (P<0.0001). Risk of recurrent CVD events in risk factor-adjusted Cox regression was higher in those with DBP <70 mm Hg versus DBP 70 to 89 mm Hg in both treated (hazard ratio, 5.1 [95% confidence interval: 3.8-6.9] P<0.0001) and untreated individuals (hazard ratio, 11.7 [95% confidence interval: 6.5-21.1] P<0.0001; treatment interaction: P=0.71). Individually, coronary heart disease, heart failure, and stroke recurrent events were more likely with DBP <70 mm Hg versus 70 to 89 mm Hg (P<0.0001). To examine for an effect of wide pulse pressure on excess risk associated with low DBP, we defined 4 binary groupings of pulse pressure (≥68 versus <68 mm Hg) and DBP (<70 versus 70-89 mm Hg). CVD incidence rates were higher only in the group with pulse pressure ≥68 and DBP <70 mm Hg (76% versus 46%-54%; P<0.001). Persons with isolated systolic hypertension and prior CVD events have increased risk for recurrent CVD events in the presence of DBP <70 mm Hg versus DBP 70 to 89 mm Hg, whether treated or untreated, supporting wide pulse pressure as an important risk modifier for the adverse effect of low DBP. © 2014 American Heart Association, Inc.
    Hypertension 11/2014; 65(2). DOI:10.1161/HYPERTENSIONAHA.114.04581 · 7.63 Impact Factor
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    ABSTRACT: -Elevated blood pressure is the leading modifiable risk factor for cardiovascular disease (CVD) and premature death. The blood pressure waveform consists of discrete hemodynamic components, derived from measured central pressure and flow, which may contribute separately to risk for an adverse outcome. However, pressure-flow measures have not been studied in a large, community-based sample. -We used proportional hazards models to examine association of incident CVD with forward pressure wave amplitude, mean arterial pressure, and global reflection coefficient derived from wave separation analysis and echocardiography in 2492 participants (mean age 66 ± 9 years, 56% women) in the Framingham Heart Study. During follow up (0.04 - 6.8 years), 149 participants (6%) had a CVD event. In multivariable models adjusting for age, sex, antihypertensive therapy, body mass index, heart rate, total and high density lipoprotein cholesterol concentrations, smoking, and presence of diabetes, forward pressure wave amplitude (HR=1.40; 95% CI: 1.16, 1.67; P=0.0003) was associated with incident CVD whereas mean arterial pressure (HR=1.10; 95% CI: 0.94, 1.29; P=0.25) and global wave reflection (HR=0.93; 95% CI: 0.78, 1.12; P=0.58) were not. After adding systolic blood pressure and carotid-femoral pulse wave velocity to the model, forward pressure wave amplitude persisted as a correlate of events (HR=1.33; 95% CI, 1.05, 1.68; P=0.02). -Higher forward pressure wave amplitude (a measure of proximal aortic geometry and stiffness) was whereas mean arterial pressure and relative wave reflection (correlates of resistance vessel structure and function) were not associated with increased risk for incident CVD.
    Circulation 11/2014; 131(4). DOI:10.1161/CIRCULATIONAHA.114.011357 · 14.95 Impact Factor
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    ABSTRACT: Heritability measures the proportion of phenotypic variation attributable to genetic factors. In addition to a shared nuclear genetic component, a number of additional variance components, such as spousal correlation, sibship, household and maternal effects, may have strong contributions to inter-individual phenotype variation. In humans, the confounding effects of these components on heritability have not been studied thoroughly. We sought to obtain unbiased heritability estimates for complex traits in the presence of multiple variance components and also to estimate the contributions of these variance components to complex traits. We compared regression and variance component methods to estimate heritability in simulations when additional variance components existed. We then revisited heritability for several traits in Framingham Heart Study (FHS) participants. Using simulations, we found that failure to account for or misclassification of necessary variance components yielded biased heritability estimates. The direction and magnitude of the bias varied depending on a variance structure and an estimation method. Using the best fitted models to account for necessary variance components, we found that heritability estimates for most FHS traits were overestimated, ranging from 4 to 47 %, when we compared models that considered necessary variance components to models that only considered familial relationships. Spousal correlation explained 14-36 % of phenotypic variation in several anthropometric and lifestyle traits. Maternal and sibling effects also contributed to phenotypic variation, ranging from 3 to 5 % and 4 to 7 %, respectively, in several anthropometric and metabolic traits. Our findings may explain, in part, the missing heritability for some traits.
    Human Genetics 11/2014; 134(2). DOI:10.1007/s00439-014-1505-6 · 4.52 Impact Factor
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    ABSTRACT: -Knowledge of mitral valve prolapse (MVP) inheritance is based on pedigree observation and M-mode echocardiography. The extent of familial clustering of MVP among unselected individuals in the community based on current, more specific echocardiographic criteria is unknown. In addition, the importance of non-diagnostic MVP morphologies (NDM; first described in large pedigrees) has not been investigated in the general population. We hypothesized that parental MVP and NDM increase the risk of offspring MVP.
    Circulation 10/2014; 131(3). DOI:10.1161/CIRCULATIONAHA.114.012594 · 14.95 Impact Factor
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    ABSTRACT: BACKGROUND: Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described. METHODS: We measured plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995-1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT >1.5 mm), and mean common carotid artery IMT. We carried out multivariable regressions for carotid measurements vs biomarkers using linear and logistic models; P < 0.0056 was deemed statistically significant. RESULTS: Maximal ICA IMT was significantly associated with plasma GDF-15 [beta-estimate 0.04 per 1-U increase in log(GDF-15), SE 0.01, P < 0.0001]. Similarly, the odds of having carotid plaque increased 33% [odds ratio 1.33 per 1-U increase in log(GDF-15), 95% CI 1.20-1.48, P < 0.0001]. In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the 3 biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together. CONCLUSIONS: Increased GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted. (C) 2014 American Association for Clinical Chemistry
    Clinical Chemistry 09/2014; 60(11). DOI:10.1373/clinchem.2014.227116 · 7.77 Impact Factor

Publication Stats

49k Citations
5,373.82 Total Impact Points

Institutions

  • 1994–2015
    • Boston University
      • • Department of Biostatistics
      • • Division of Mathematics
      • • Department of Mathematics and Statistics
      • • Section of Endocrinology, Diabetes, Nutrition
      • • Section of Preventive Medicine and Epidemiology
      Boston, Massachusetts, United States
    • Lahey Hospital and Medical Center
      Burlington, Massachusetts, United States
    • Cleveland Clinic
      • Department of Cardiology
      Cleveland, OH, United States
  • 1995–2014
    • National Heart, Lung, and Blood Institute
      • Division of Cardiovascular Sciences (DCVS)
      Maryland, United States
    • University of Massachusetts Boston
      • Clinical Epidemiology Research and Training Unit
      Boston, Massachusetts, United States
  • 2013
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
    • University of California, Davis
      • Department of Public Health Sciences
      Davis, California, United States
  • 1997–2013
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 2003–2011
    • Massachusetts General Hospital
      • Division of Nephrology
      Boston, MA, United States
    • Whitaker Wellness Institute
      Newport Beach, California, United States
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 2010
    • University of Washington Seattle
      • Department of Epidemiology
      Seattle, WA, United States
    • Erasmus MC
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
  • 1992–2010
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1996–2009
    • University of Massachusetts Medical School
      • Department of Medicine
      Worcester, Massachusetts, United States
  • 2006
    • Duke University
      Durham, North Carolina, United States
  • 2004–2005
    • Northwestern University
      • • Department of Preventive Medicine
      • • Feinberg School of Medicine
      Evanston, IL, United States
    • University of California, Irvine
      Irvine, California, United States
    • Technion - Israel Institute of Technology
      H̱efa, Haifa District, Israel
  • 1986–2002
    • National Institutes of Health
      • Branch of Neuroimmunology and Virology
      Maryland, United States
  • 1984–2002
    • Beth Israel Deaconess Medical Center
      • • Department of Medicine
      • • Division of Cardiovascular Medicine
      • • Division of Rheumatology
      Boston, MA, United States
  • 2000
    • VA Puget Sound Health Care System
      Washington, Washington, D.C., United States
  • 1984–1999
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1996–1997
    • Kansai Medical University
      Moriguchi, Ōsaka, Japan
  • 1983–1996
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Division of Rheumatology, Immunology, and Allergy
      Boston, MA, United States
  • 1990
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
    • Cook Children's Health Care System
      Fort Worth, Texas, United States
  • 1988
    • Cincinnati Children's Hospital Medical Center
      • Division of Rheumatology
      Cincinnati, Ohio, United States