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Papers by Daniel Levy

Cleveland Clinic Journal of Medicine, 2007

Medical Grand Rounds articles are based on edited transcripts from Division of Medicine Grand Rou... more Medical Grand Rounds articles are based on edited transcripts from Division of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed. Complication rates rise sharply with increasing blood pressure in even the oldest age groups CREDIT CME on November 24, 2021. For personal use only. All other uses require permission.

European heart journal, Jan 21, 2014

The management of heart failure with reduced ejection fraction (HF-REF) has improved significantl... more The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes...

Journal of the American College of Cardiology, 1995

Human molecular genetics, 2015

Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigene... more Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2,097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed effects regression models were used to test the association of methylation beta value with concurrent BMI and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole blood DNA from 2,377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the GOLDN Study was followed by testing using adipose tissue DNA from 648 women in the MuTHER cohort. Seventy-six (76) BMI-related probes, 164 WC-related probes, and 8 BMI change-related probes passed the th...

Hypertension, Jan 31, 2015

make every effort to avoid any actual or potential conflicts of interest that may arise as a resu... more make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

Nature communications, Jan 20, 2015

Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into ... more 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 cholestero...

Circulation, Jan 10, 2015

Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wid... more Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose,...

Journal of Clinical Investigation, 2015

Circulation, Jan 12, 2014

Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studie... more Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studies have explored epigenetic effects. Genome-wide surveys of DNA methylation may uncover epigenetic factors influencing lipid metabolism. To identify whether differential methylation of cytosine-(phosphate)-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T cells and quantified the proportion of sample methylation at >450 000 CpGs by using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled the percentage of methylation at individual CpGs as a function of fasting very-low-density lipoprotein cholesterol and triglycerides (TGs) by using mixed linear regression adjusted for age, sex, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, and cg09737197) in intron 1 of carnitine palmitoyltransferase 1A (CPT1A) were strongly a...

Physiological Genomics, 2011

Despite a growing number of reports of gene expression analysis from blood-derived RNA sources, t... more Despite a growing number of reports of gene expression analysis from blood-derived RNA sources, there have been few systematic comparisons of various RNA sources in transcriptomic analysis or for biomarker discovery in the context of cardiovascular disease (CVD). As a pilot study of the Systems Approach to Biomarker Research (SABRe) in CVD Initiative, this investigation used Affymetrix Exon arrays to characterize gene expression of three blood-derived RNA sources: lymphoblastoid cell lines (LCL), whole blood using PAXgene tubes (PAX), and peripheral blood mononuclear cells (PBMC). Their performance was compared in relation to identifying transcript associations with sex and CVD risk factors, such as age, high-density lipoprotein, and smoking status, and the differential blood cell count. We also identified a set of exons that vary substantially between participants, but consistently in each RNA source. Such exons are thus stable phenotypes of the participant and may potentially beco...

The Journal of Clinical Endocrinology & Metabolism, 2010

Background: Neck circumference, a proxy for upper-body sc fat, may be a unique fat depot that con... more Background: Neck circumference, a proxy for upper-body sc fat, may be a unique fat depot that confers additional cardiovascular risk above and beyond central body fat. Methods and Results: Participants with neck circumference measures who underwent multidetector computed tomography to assess visceral adipose tissue (VAT) were included [n ϭ 3307, 48% women; mean age ϭ 51 yr; mean body mass index (BMI) ϭ 27.8 kg/m 2 ; mean neck circumference ϭ 40.5 cm (men) and 34.2 cm (women)]. Sex-specific linear regression models were used to assess the association between SD increase in neck circumference and cardiovascular disease (CVD) risk factors (systolic and diastolic blood pressure; total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglycerides; and fasting plasma glucose, insulin, proinsulin, and homeostasis model assessment of insulin resistance). Neck circumference was correlated with VAT [r ϭ 0.63 (men); r ϭ 0.74 (women); P Ͻ 0.001] and BMI [r ϭ 0.79 (men); r ϭ 0.80 (women); P Ͻ 0.001]. After further adjustment for VAT, neck circumference was positively associated with systolic blood pressure, diastolic blood pressure in men only, triglycerides, fasting plasma glucose in women only, insulin, proinsulin, and homeostasis model assessment of insulin resistance and was inversely associated with high-density lipoprotein (all P values Ͻ0.01). Similar results were observed in models that adjusted for both VAT and BMI. In a secondary analysis of incident CVD as an outcome, there was no statistically significant association observed for neck circumference in multivariable-adjusted models. Conclusions: Neck circumference is associated with CVD risk factors even after adjustment for VAT and BMI. These findings suggest that upper-body sc fat may be a unique, pathogenic fat depot.

Journal of Cardiovascular Magnetic Resonance, 2008

Circulation, 2008

Background— Heart failure (HF) developing in hypertensive patients may occur with preserved or re... more Background— Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction (PEF [≥50%] or REF [<50%]). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin, providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF. Methods and Results— HF diagnostic criteria were prespecified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography, or radionuclide study was available in 910 of 1367 patients (66.6%) with hospitalized events meeting ALLHAT criteria. Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF (overall and by PEF and REF). HF case fatality rates were examined. Of those with EF data, 44.4% had HFPEF and 55.6% had HFREF. Chlorthal...

Circulation, 2008

Background— Although mortality after myocardial infarction (MI) has declined in the United States... more Background— Although mortality after myocardial infarction (MI) has declined in the United States in recent decades, there have been few community-based investigations of the long-term trends in the incidence of heart failure after MI, and their results appear to be conflicting. Methods and Results— We evaluated 676 Framingham Heart Study participants between 45 and 85 years of age (mean age 67 years, 34% women) who developed a first MI between 1970 and 1999. We assessed the incidence rates of heart failure and of death without heart failure in each of 3 decades (1970 to 1979, 1980 to 1989, and 1990 to 1999). We estimated the multivariable-adjusted risk of events in the latter 2 decades, with the period 1970 to 1979 serving as the referent. The 30-day incidence of heart failure after MI rose from 10% in 1970 to 1979 to 23.1% in 1990 to 1999 ( P for trend 0.003), whereas 30-day mortality after MI declined from 12.2% (1970 to 1979) to 4.1% (1990 to 1999). The 5-year incidence of heart...

Annals of Noninvasive Electrocardiology, 2012

Background: The association between QT interval and mortality has been demonstrated in large, pro... more Background: The association between QT interval and mortality has been demonstrated in large, prospective population-based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT-mortality relationship in the Framingham Heart Study (FHS). Methods: Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a reproducible digital caliper technique. Results: Using Cox proportional hazards regression adjusting for age and sex, a 20 millisecond increase in QTc (using Bazett's correction; QT/RR 1/2 interval) was associated with a modest increase in risk of all-cause mortality (

European Heart Journal, 2008

The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdo... more The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdominal adipose tissue (VAT) are associated with the prevalence of cardiovascular disease (CVD). Methods and results Participants from the Framingham Heart Study Offspring cohort underwent abdominal and chest multidetector computed tomography to quantify volumes of pericardial fat, intrathoracic fat, and VAT. Relations between each fat depot and CVD were assessed using logistic regression. The analysis of 1267 participants (mean age 60 years, 53.8% women, 9.7% with prevalent CVD) demonstrated that pericardial fat [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.11-1.57; P ¼ 0.002] and VAT (OR 1.35, 95% CI 1.11-1.57; P ¼ 0.003), but not intrathoracic fat (OR 1.14, 95% CI 0.93-1.39; P ¼ 0.22), were significantly associated with prevalent CVD in age-sex-adjusted models and after adjustment for body mass index and waist circumference. After multivariable adjustment, associations were attenuated (P. 0.14). Only pericardial fat was associated with prevalent myocardial infarction after adjusting for conventional measures of adiposity (OR 1.37, 95% CI 1.03-1.82; P ¼ 0.03). Conclusion Pericardial fat and VAT, but not intrathoracic fat, are associated with CVD independent of traditional measures of obesity but not after further adjustment for traditional risk factor. Taken together with our prior work, these findings may support the hypothesis that pericardial fat contributes to coronary atherosclerosis.

Molecular systems biology, 2015

Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressu... more Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a signific...

NDT Plus, 2009

METHODS: Plasma/serum samples were obtained after 30 weeks of gestation from 130 pregnant primigr... more METHODS: Plasma/serum samples were obtained after 30 weeks of gestation from 130 pregnant primigravid women with singleton pregnancies, 120 with PE and 100 normotensive pregnancies. PE was defined as new onset of elevated blood pressure> 140/90 mm Hg along with≥ 2+ proteinuria on two occasions at least 4 hours apart after 20 weeks of gestation in previously normotensive subjects. Circulating sFlt-1, sEng and PlGF levels were estimated using commercially available ELISA kits (R&D systems, USA). ...

Hypertension (Dallas, Tex. : 1979), 2017

Cleveland Clinic Journal of Medicine, 2007

Medical Grand Rounds articles are based on edited transcripts from Division of Medicine Grand Rou... more Medical Grand Rounds articles are based on edited transcripts from Division of Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed. Complication rates rise sharply with increasing blood pressure in even the oldest age groups CREDIT CME on November 24, 2021. For personal use only. All other uses require permission.

European heart journal, Jan 21, 2014

The management of heart failure with reduced ejection fraction (HF-REF) has improved significantl... more The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes...

Journal of the American College of Cardiology, 1995

Human molecular genetics, 2015

Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigene... more Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2,097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed effects regression models were used to test the association of methylation beta value with concurrent BMI and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole blood DNA from 2,377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the GOLDN Study was followed by testing using adipose tissue DNA from 648 women in the MuTHER cohort. Seventy-six (76) BMI-related probes, 164 WC-related probes, and 8 BMI change-related probes passed the th...

Hypertension, Jan 31, 2015

make every effort to avoid any actual or potential conflicts of interest that may arise as a resu... more make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

Nature communications, Jan 20, 2015

Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into ... more 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 cholestero...

Circulation, Jan 10, 2015

Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wid... more Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose,...

Journal of Clinical Investigation, 2015

Circulation, Jan 12, 2014

Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studie... more Genetic research regarding blood lipids has largely focused on DNA sequence variation; few studies have explored epigenetic effects. Genome-wide surveys of DNA methylation may uncover epigenetic factors influencing lipid metabolism. To identify whether differential methylation of cytosine-(phosphate)-guanine dinucleotides (CpGs) correlated with lipid phenotypes, we isolated DNA from CD4+ T cells and quantified the proportion of sample methylation at >450 000 CpGs by using the Illumina Infinium HumanMethylation450 Beadchip in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. We modeled the percentage of methylation at individual CpGs as a function of fasting very-low-density lipoprotein cholesterol and triglycerides (TGs) by using mixed linear regression adjusted for age, sex, study site, cell purity, and family structure. Four CpGs (cg00574958, cg17058475, cg01082498, and cg09737197) in intron 1 of carnitine palmitoyltransferase 1A (CPT1A) were strongly a...

Physiological Genomics, 2011

Despite a growing number of reports of gene expression analysis from blood-derived RNA sources, t... more Despite a growing number of reports of gene expression analysis from blood-derived RNA sources, there have been few systematic comparisons of various RNA sources in transcriptomic analysis or for biomarker discovery in the context of cardiovascular disease (CVD). As a pilot study of the Systems Approach to Biomarker Research (SABRe) in CVD Initiative, this investigation used Affymetrix Exon arrays to characterize gene expression of three blood-derived RNA sources: lymphoblastoid cell lines (LCL), whole blood using PAXgene tubes (PAX), and peripheral blood mononuclear cells (PBMC). Their performance was compared in relation to identifying transcript associations with sex and CVD risk factors, such as age, high-density lipoprotein, and smoking status, and the differential blood cell count. We also identified a set of exons that vary substantially between participants, but consistently in each RNA source. Such exons are thus stable phenotypes of the participant and may potentially beco...

The Journal of Clinical Endocrinology & Metabolism, 2010

Background: Neck circumference, a proxy for upper-body sc fat, may be a unique fat depot that con... more Background: Neck circumference, a proxy for upper-body sc fat, may be a unique fat depot that confers additional cardiovascular risk above and beyond central body fat. Methods and Results: Participants with neck circumference measures who underwent multidetector computed tomography to assess visceral adipose tissue (VAT) were included [n ϭ 3307, 48% women; mean age ϭ 51 yr; mean body mass index (BMI) ϭ 27.8 kg/m 2 ; mean neck circumference ϭ 40.5 cm (men) and 34.2 cm (women)]. Sex-specific linear regression models were used to assess the association between SD increase in neck circumference and cardiovascular disease (CVD) risk factors (systolic and diastolic blood pressure; total, low-density lipoprotein, and high-density lipoprotein cholesterol and triglycerides; and fasting plasma glucose, insulin, proinsulin, and homeostasis model assessment of insulin resistance). Neck circumference was correlated with VAT [r ϭ 0.63 (men); r ϭ 0.74 (women); P Ͻ 0.001] and BMI [r ϭ 0.79 (men); r ϭ 0.80 (women); P Ͻ 0.001]. After further adjustment for VAT, neck circumference was positively associated with systolic blood pressure, diastolic blood pressure in men only, triglycerides, fasting plasma glucose in women only, insulin, proinsulin, and homeostasis model assessment of insulin resistance and was inversely associated with high-density lipoprotein (all P values Ͻ0.01). Similar results were observed in models that adjusted for both VAT and BMI. In a secondary analysis of incident CVD as an outcome, there was no statistically significant association observed for neck circumference in multivariable-adjusted models. Conclusions: Neck circumference is associated with CVD risk factors even after adjustment for VAT and BMI. These findings suggest that upper-body sc fat may be a unique, pathogenic fat depot.

Journal of Cardiovascular Magnetic Resonance, 2008

Circulation, 2008

Background— Heart failure (HF) developing in hypertensive patients may occur with preserved or re... more Background— Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction (PEF [≥50%] or REF [<50%]). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin, providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF. Methods and Results— HF diagnostic criteria were prespecified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography, or radionuclide study was available in 910 of 1367 patients (66.6%) with hospitalized events meeting ALLHAT criteria. Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF (overall and by PEF and REF). HF case fatality rates were examined. Of those with EF data, 44.4% had HFPEF and 55.6% had HFREF. Chlorthal...

Circulation, 2008

Background— Although mortality after myocardial infarction (MI) has declined in the United States... more Background— Although mortality after myocardial infarction (MI) has declined in the United States in recent decades, there have been few community-based investigations of the long-term trends in the incidence of heart failure after MI, and their results appear to be conflicting. Methods and Results— We evaluated 676 Framingham Heart Study participants between 45 and 85 years of age (mean age 67 years, 34% women) who developed a first MI between 1970 and 1999. We assessed the incidence rates of heart failure and of death without heart failure in each of 3 decades (1970 to 1979, 1980 to 1989, and 1990 to 1999). We estimated the multivariable-adjusted risk of events in the latter 2 decades, with the period 1970 to 1979 serving as the referent. The 30-day incidence of heart failure after MI rose from 10% in 1970 to 1979 to 23.1% in 1990 to 1999 ( P for trend 0.003), whereas 30-day mortality after MI declined from 12.2% (1970 to 1979) to 4.1% (1990 to 1999). The 5-year incidence of heart...

Annals of Noninvasive Electrocardiology, 2012

Background: The association between QT interval and mortality has been demonstrated in large, pro... more Background: The association between QT interval and mortality has been demonstrated in large, prospective population-based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT-mortality relationship in the Framingham Heart Study (FHS). Methods: Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a reproducible digital caliper technique. Results: Using Cox proportional hazards regression adjusting for age and sex, a 20 millisecond increase in QTc (using Bazett's correction; QT/RR 1/2 interval) was associated with a modest increase in risk of all-cause mortality (

European Heart Journal, 2008

The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdo... more The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdominal adipose tissue (VAT) are associated with the prevalence of cardiovascular disease (CVD). Methods and results Participants from the Framingham Heart Study Offspring cohort underwent abdominal and chest multidetector computed tomography to quantify volumes of pericardial fat, intrathoracic fat, and VAT. Relations between each fat depot and CVD were assessed using logistic regression. The analysis of 1267 participants (mean age 60 years, 53.8% women, 9.7% with prevalent CVD) demonstrated that pericardial fat [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.11-1.57; P ¼ 0.002] and VAT (OR 1.35, 95% CI 1.11-1.57; P ¼ 0.003), but not intrathoracic fat (OR 1.14, 95% CI 0.93-1.39; P ¼ 0.22), were significantly associated with prevalent CVD in age-sex-adjusted models and after adjustment for body mass index and waist circumference. After multivariable adjustment, associations were attenuated (P. 0.14). Only pericardial fat was associated with prevalent myocardial infarction after adjusting for conventional measures of adiposity (OR 1.37, 95% CI 1.03-1.82; P ¼ 0.03). Conclusion Pericardial fat and VAT, but not intrathoracic fat, are associated with CVD independent of traditional measures of obesity but not after further adjustment for traditional risk factor. Taken together with our prior work, these findings may support the hypothesis that pericardial fat contributes to coronary atherosclerosis.

Molecular systems biology, 2015

Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressu... more Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a signific...

NDT Plus, 2009

METHODS: Plasma/serum samples were obtained after 30 weeks of gestation from 130 pregnant primigr... more METHODS: Plasma/serum samples were obtained after 30 weeks of gestation from 130 pregnant primigravid women with singleton pregnancies, 120 with PE and 100 normotensive pregnancies. PE was defined as new onset of elevated blood pressure> 140/90 mm Hg along with≥ 2+ proteinuria on two occasions at least 4 hours apart after 20 weeks of gestation in previously normotensive subjects. Circulating sFlt-1, sEng and PlGF levels were estimated using commercially available ELISA kits (R&D systems, USA). ...

Hypertension (Dallas, Tex. : 1979), 2017