Browsing by Author "Shah, Svati H"
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Item Open Access A functional polymorphism in the 5HTR2C gene associated with stress responses also predicts incident cardiovascular events.(PLoS One, 2013) Brummett, Beverly H; Babyak, Michael A; Jiang, Rong; Shah, Svati H; Becker, Richard C; Haynes, Carol; Chryst-Ladd, Megan; Craig, Damian M; Hauser, Elizabeth R; Siegler, Ilene C; Kuhn, Cynthia M; Singh, Abanish; Williams, Redford BPreviously we have shown that a functional nonsynonymous single nucleotide polymorphism (rs6318) of the 5HTR2C gene located on the X-chromosome is associated with hypothalamic-pituitary-adrenal axis response to a stress recall task, and with endophenotypes associated with cardiovascular disease (CVD). These findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository. Study population consisted of 6,126 Caucasian participants (4,036 [65.9%] males and 2,090 [34.1%] females). A total of 1,769 events occurred (1,544 deaths and 225 MIs; median follow-up time = 5.3 years, interquartile range = 3.3-8.2). Unadjusted Cox time-to-event regression models showed, compared to Cys23 G carriers, males hemizygous for Ser23 C and females homozygous for Ser23C were at increased risk for the composite endpoint of all-cause death or MI: Hazard Ratio (HR) = 1.47, 95% confidence interval (CI) = 1.17, 1.84, p = .0008. Adjusting for age, rs6318 genotype was not related to body mass index, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries, or left ventricular ejection fraction in either males or females. After adjustment for these covariates the estimate for the two Ser23 C groups was modestly attenuated, but remained statistically significant: HR = 1.38, 95% CI = 1.10, 1.73, p = .005. These findings suggest that this functional polymorphism of the 5HTR2C gene is associated with increased risk for CVD mortality and morbidity, but this association is apparently not explained by the association of rs6318 with traditional risk factors or conventional markers of atherosclerotic disease.Item Open Access Accelerated epigenetic age as a biomarker of cardiovascular sensitivity to traffic-related air pollution.(Aging, 2020-12) Ward-Caviness, Cavin K; Russell, Armistead G; Weaver, Anne M; Slawsky, Erik; Dhingra, Radhika; Kwee, Lydia Coulter; Jiang, Rong; Neas, Lucas M; Diaz-Sanchez, David; Devlin, Robert B; Cascio, Wayne E; Olden, Kenneth; Hauser, Elizabeth R; Shah, Svati H; Kraus, William EBackground
Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures.Methods
Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status.Results
We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5.Conclusion
Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.Item Open Access Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events.(Circ Cardiovasc Genet, 2010-04) Shah, Svati H; Bain, James R; Muehlbauer, Michael J; Stevens, Robert D; Crosslin, David R; Haynes, Carol; Dungan, Jennifer; Newby, L Kristin; Hauser, Elizabeth R; Ginsburg, Geoffrey S; Newgard, Christopher B; Kraus, William EBACKGROUND: Molecular tools may provide insight into cardiovascular risk. We assessed whether metabolites discriminate coronary artery disease (CAD) and predict risk of cardiovascular events. METHODS AND RESULTS: We performed mass-spectrometry-based profiling of 69 metabolites in subjects from the CATHGEN biorepository. To evaluate discriminative capabilities of metabolites for CAD, 2 groups were profiled: 174 CAD cases and 174 sex/race-matched controls ("initial"), and 140 CAD cases and 140 controls ("replication"). To evaluate the capability of metabolites to predict cardiovascular events, cases were combined ("event" group); of these, 74 experienced death/myocardial infarction during follow-up. A third independent group was profiled ("event-replication" group; n=63 cases with cardiovascular events, 66 controls). Analysis included principal-components analysis, linear regression, and Cox proportional hazards. Two principal components analysis-derived factors were associated with CAD: 1 comprising branched-chain amino acid metabolites (factor 4, initial P=0.002, replication P=0.01), and 1 comprising urea cycle metabolites (factor 9, initial P=0.0004, replication P=0.01). In multivariable regression, these factors were independently associated with CAD in initial (factor 4, odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74; P=0.02; factor 9, OR, 0.67; 95% CI, 0.52 to 0.87; P=0.003) and replication (factor 4, OR, 1.43; 95% CI, 1.07 to 1.91; P=0.02; factor 9, OR, 0.66; 95% CI, 0.48 to 0.91; P=0.01) groups. A factor composed of dicarboxylacylcarnitines predicted death/myocardial infarction (event group hazard ratio 2.17; 95% CI, 1.23 to 3.84; P=0.007) and was associated with cardiovascular events in the event-replication group (OR, 1.52; 95% CI, 1.08 to 2.14; P=0.01). CONCLUSIONS: Metabolite profiles are associated with CAD and subsequent cardiovascular events.Item Open Access Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements.(Scientific reports, 2020-04-10) Becker, Kristian C; Kwee, Lydia Coulter; Neely, Megan L; Grass, Elizabeth; Jakubowski, Joseph A; Fox, Keith AA; White, Harvey D; Gregory, Simon G; Gurbel, Paul A; Carvalho, Leonardo de Pinto; Becker, Richard C; Magnus Ohman, E; Roe, Matthew T; Shah, Svati H; Chan, Mark YChanges in platelet physiology are associated with simultaneous changes in microRNA concentrations, suggesting a role for microRNA in platelet regulation. Here we investigated potential associations between microRNA and platelet reactivity (PR), a marker of platelet function, in two cohorts following a non-ST elevation acute coronary syndrome (NSTE-ACS) event. First, non-targeted microRNA concentrations and PR were compared in a case (N = 77) control (N = 76) cohort within the larger TRILOGY-ACS trial. MicroRNA significant in this analysis plus CVD-associated microRNAs from the literature were then quantified by targeted rt-PCR in the complete TRILOGY-ACS cohort (N = 878) and compared with matched PR samples. Finally, microRNA significant in the non-targeted & targeted analyses were verified in an independent post NSTE-ACS cohort (N = 96). From the non-targeted analysis, 14 microRNAs were associated with PR (Fold Change: 0.91-1.27, p-value: 0.004-0.05). From the targeted analysis, five microRNAs were associated with PR (Beta: -0.09-0.22, p-value: 0.004-0.05). Of the 19 significant microRNAs, three, miR-15b-5p, miR-93 and miR-126, were consistently associated with PR in the TRILOGY-ACS and independent Singapore post-ACS cohorts, suggesting the measurement of circulating microRNA concentrations may report on dynamic changes in platelet biology following a cardiovascular ischemic event.Item Open Access Evaluating the precision of EBF1 SNP x stress interaction association: sex, race, and age differences in a big harmonized data set of 28,026 participants.(Translational psychiatry, 2020-10-20) Singh, Abanish; Babyak, Michael A; Sims, Mario; Musani, Solomon K; Brummett, Beverly H; Jiang, Rong; Kraus, William E; Shah, Svati H; Siegler, Ilene C; Hauser, Elizabeth R; Williams, Redford BIn prior work, we identified a novel gene-by-stress association of EBF1's common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to "racism/discrimination" (P = 0.036) and "not meeting basic needs" (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e-03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.Item Open Access Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene.(European journal of human genetics : EJHG, 2015-06) Singh, Abanish; Babyak, Michael A; Nolan, Daniel K; Brummett, Beverly H; Jiang, Rong; Siegler, Ilene C; Kraus, William E; Shah, Svati H; Williams, Redford B; Hauser, Elizabeth RWe performed gene-environment interaction genome-wide association analysis (G × E GWAS) to identify SNPs whose effects on metabolic traits are modified by chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis (MESA). In Whites, the G × E GWAS for hip circumference identified five SNPs within the Early B-cell Factor 1 (EBF1) gene, all of which were in strong linkage disequilibrium. The gene-by-stress interaction (SNP × STRESS) term P-values were genome-wide significant (Ps = 7.14E-09 to 2.33E-08, uncorrected; Ps = 1.99E-07 to 5.18E-07, corrected for genomic control). The SNP-only (without interaction) model P-values (Ps = 0.011-0.022) were not significant at the conventional genome-wide significance level. Further analysis of related phenotypes identified gene-by-stress interaction effects for waist circumference, body mass index (BMI), fasting glucose, type II diabetes status, and common carotid intimal-medial thickness (CCIMT), supporting a proposed model of gene-by-stress interaction that connects cardiovascular disease (CVD) risk factor endophenotypes such as central obesity and increased blood glucose or diabetes to CVD itself. Structural equation path analysis suggested that the path from chronic psychosocial stress to CCIMT via hip circumference and fasting glucose was larger (estimate = 0.26, P = 0.033, 95% CI = 0.02-0.49) in the EBF1 rs4704963 CT/CC genotypes group than the same path in the TT group (estimate = 0.004, P = 0.34, 95% CI = -0.004-0.012). We replicated the association of the EBF1 SNPs and hip circumference in the Framingham Offspring Cohort (gene-by-stress term P-values = 0.007-0.012) as well as identified similar path relationships. This observed and replicated interaction between psychosocial stress and variation in the EBF1 gene may provide a biological hypothesis for the complex relationship between psychosocial stress, central obesity, diabetes, and cardiovascular disease.Item Open Access Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci.(Kidney Int, 2015-10) Stafford-Smith, Mark; Li, Yi-Ju; Mathew, Joseph P; Li, Yen-Wei; Ji, Yunqi; Phillips-Bute, Barbara G; Milano, Carmelo A; Newman, Mark F; Kraus, William E; Kertai, Miklos D; Shah, Svati H; Podgoreanu, Mihai V; Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative TeamAcute kidney injury (AKI) is a common, serious complication of cardiac surgery. Since prior studies have supported a genetic basis for postoperative AKI, we conducted a genome-wide association study (GWAS) for AKI following coronary bypass graft (CABG) surgery. The discovery data set consisted of 873 nonemergent CABG surgery patients with cardiopulmonary bypass (PEGASUS), while a replication data set had 380 cardiac surgical patients (CATHGEN). Single-nucleotide polymorphism (SNP) data were based on Illumina Human610-Quad (PEGASUS) and OMNI1-Quad (CATHGEN) BeadChips. We used linear regression with adjustment for a clinical AKI risk score to test SNP associations with the postoperative peak rise relative to preoperative serum creatinine concentration as a quantitative AKI trait. Nine SNPs meeting significance in the discovery set were detected. The rs13317787 in GRM7|LMCD1-AS1 intergenic region (3p21.6) and rs10262995 in BBS9 (7p14.3) were replicated with significance in the CATHGEN data set and exhibited significantly strong overall association following meta-analysis. Additional fine mapping using imputed SNPs across these two regions and meta-analysis found genome-wide significance at the GRM7|LMCD1-AS1 locus and a significantly strong association at BBS9. Thus, through an unbiased GWAS approach, we found two new loci associated with post-CABG AKI providing new insights into the pathogenesis of perioperative AKI.Item Open Access Genome-wide linkage analysis of cardiovascular disease biomarkers in a large, multigenerational family.(PLoS One, 2013) Nolan, Daniel; Kraus, William E; Hauser, Elizabeth; Li, Yi-Ju; Thompson, Dana K; Johnson, Jessica; Chen, Hsiang-Cheng; Nelson, Sarah; Haynes, Carol; Gregory, Simon G; Kraus, Virginia B; Shah, Svati HGiven the importance of cardiovascular disease (CVD) to public health and the demonstrated heritability of both disease status and its related risk factors, identifying the genetic variation underlying these susceptibilities is a critical step in understanding the pathogenesis of CVD and informing prevention and treatment strategies. Although one can look for genetic variation underlying susceptibility to CVD per se, it can be difficult to define the disease phenotype for such a qualitative analysis and CVD itself represents a convergence of diverse etiologic pathways. Alternatively, one can study the genetics of intermediate traits that are known risk factors for CVD, which can be measured quantitatively. Using the latter strategy, we have measured 21 cardiovascular-related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment). These biomarkers belong to inflammatory and immune, connective tissue, lipid, and hemostasis pathways. Of these, 18 met our quality control standards. Using the pedigree and biomarker data, we have estimated the broad sense heritability (H2) of each biomarker (ranging from 0.09-0.56). A genome-wide panel of 6,015 SNPs was used subsequently to map these biomarkers as quantitative traits. Four showed noteworthy evidence for linkage in multipoint analysis (LOD score ≥ 2.6): paraoxonase (chromosome 8p11, 21), the chemokine RANTES (22q13.33), matrix metalloproteinase 3 (MMP3, 17p13.3), and granulocyte colony stimulating factor (GCSF, 8q22.1). Identifying the causal variation underlying each linkage score will help to unravel the genetic architecture of these quantitative traits and, by extension, the genetic architecture of cardiovascular risk.Item Open Access Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association.(Circulation, 2018-03) Benjamin, Emelia J; Virani, Salim S; Callaway, Clifton W; Chamberlain, Alanna M; Chang, Alexander R; Cheng, Susan; Chiuve, Stephanie E; Cushman, Mary; Delling, Francesca N; Deo, Rajat; de Ferranti, Sarah D; Ferguson, Jane F; Fornage, Myriam; Gillespie, Cathleen; Isasi, Carmen R; Jiménez, Monik C; Jordan, Lori Chaffin; Judd, Suzanne E; Lackland, Daniel; Lichtman, Judith H; Lisabeth, Lynda; Liu, Simin; Longenecker, Chris T; Lutsey, Pamela L; Mackey, Jason S; Matchar, David B; Matsushita, Kunihiro; Mussolino, Michael E; Nasir, Khurram; O'Flaherty, Martin; Palaniappan, Latha P; Pandey, Ambarish; Pandey, Dilip K; Reeves, Mathew J; Ritchey, Matthew D; Rodriguez, Carlos J; Roth, Gregory A; Rosamond, Wayne D; Sampson, Uchechukwu KA; Satou, Gary M; Shah, Svati H; Spartano, Nicole L; Tirschwell, David L; Tsao, Connie W; Voeks, Jenifer H; Willey, Joshua Z; Wilkins, John T; Wu, Jason Hy; Alger, Heather M; Wong, Sally S; Muntner, Paul; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics SubcommitteeEach year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA's My Life Check - Life's Simple 7 (Figure ), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions. Cardiovascular disease (CVD) and stroke produce immense health and economic burdens in the United States and globally. The Update also presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease [CHD], heart failure [HF], valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). Since 2007, the annual versions of the Statistical Update have been cited >20 000 times in the literature. From January to July 2017 alone, the 2017 Statistical Update was accessed >106 500 times. Each annual version of the Statistical Update undergoes revisions to include the newest nationally representative data, add additional relevant published scientific findings, remove older information, add new sections or chapters, and increase the number of ways to access and use the assembled information. This year-long process, which begins as soon as the previous Statistical Update is published, is performed by the AHA Statistics Committee faculty volunteers and staff and government agency partners. This year's edition includes new data on the monitoring and benefits of cardiovascular health in the population, new metrics to assess and monitor healthy diets, new information on stroke in young adults, an enhanced focus on underserved and minority populations, a substantively expanded focus on the global burden of CVD, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the AHA's 2020 Impact Goals. Below are a few highlights from this year's Update. 1Item Open Access Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association.(Circulation, 2021-01-27) Virani, Salim S; Alonso, Alvaro; Aparicio, Hugo J; Benjamin, Emelia J; Bittencourt, Marcio S; Callaway, Clifton W; Carson, April P; Chamberlain, Alanna M; Cheng, Susan; Delling, Francesca N; Elkind, Mitchell SV; Evenson, Kelly R; Ferguson, Jane F; Gupta, Deepak K; Khan, Sadiya S; Kissela, Brett M; Knutson, Kristen L; Lee, Chong D; Lewis, Tené T; Liu, Junxiu; Loop, Matthew Shane; Lutsey, Pamela L; Ma, Jun; Mackey, Jason; Martin, Seth S; Matchar, David B; Mussolino, Michael E; Navaneethan, Sankar D; Perak, Amanda Marma; Roth, Gregory A; Samad, Zainab; Satou, Gary M; Schroeder, Emily B; Shah, Svati H; Shay, Christina M; Stokes, Andrew; VanWagner, Lisa B; Wang, Nae-Yuh; Tsao, Connie W; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics SubcommitteeBackground
The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).Methods
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease.Results
Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.Conclusions
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.Item Open Access Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.(Circulation, 2023-07) Ghadimi, Kamrouz; Cappiello, Jhaymie L; Wright, Mary Cooter; Levy, Jerrold H; Bryner, Benjamin S; DeVore, Adam D; Schroder, Jacob N; Patel, Chetan B; Rajagopal, Sudarshan; Shah, Svati H; Milano, Carmelo A; INSPIRE-FLO InvestigatorsBackground
Right ventricular failure (RVF) is a leading driver of morbidity and mortality after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy.Methods
In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and mortality at 30 days, 90 days, and 1 year after surgery.Results
Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes.Conclusions
Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO.Registration
URL: https://www.Clinicaltrials
gov; Unique identifier: NCT03081052.Item Open Access Lack of Association of a Functional Polymorphism in the Serotonin Receptor Gene With Body Mass Index and Depressive Symptoms in a Large Meta-Analysis of Population Based Studies.(Frontiers in genetics, 2018-01) Brummett, Beverly H; Babyak, Michael A; Singh, Abanish; Hauser, Elizabeth R; Jiang, Rong; Huffman, Kim M; Kraus, William E; Shah, Svati H; Siegler, Ilene C; Williams, Redford BThe serotonin receptor 5-HTR2C is thought to be involved in the function of multiple brain structures. Consequently, the HTR2C gene has been studied extensively with respect to its association with a variety of phenotypes. One coding variant in the HTR2C gene, Cys23Ser (rs6318), has been associated with depressive symptoms. and adiposity; however, these findings have been inconsistent. The reasons for this mixed picture may be due to low statistical power or due to other factors such as failure to account for possible interacting environmental factors, such as psychosocial stress. Further, the literature around this polymorphism is marked by limited inclusion of persons of African ancestry. The present study sought to overcome these limitations and definitively determine the relationship of this polymorphism with depressive and obesity phenotypes in a large sample meta-analysis. Thus, we harmonized individual level data from 10 studies including the Women's Health Initiative, CARDIA, ARIC, Framingham Offspring, and the Jackson Heart Study, resulting in a sample of 27,161 individuals (10,457 Black women, 2,819 Black men, 7,419 White women, and 6,466 White men). We conducted a random effects meta-analysis using individual level data to examine whether the Cys23Ser variant-either directly, or conditionally depending on the level of psychosocial stress-was associated with depressive symptoms and body mass index (BMI). We found that psychosocial stress was associated with both depression and BMI, but that Cys23Ser was not directly associated with, nor did it modify the associations of psychosocial stress with depression or BMI. Thus, in the largest study of this polymorphism, we have determined that rs6318 is not associated with depression, or BMI.Item Open Access Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.(J Am Heart Assoc, 2016-07-29) Hunter, Wynn G; Kelly, Jacob P; McGarrah, Robert W; Khouri, Michel G; Craig, Damian; Haynes, Carol; Ilkayeva, Olga; Stevens, Robert D; Bain, James R; Muehlbauer, Michael J; Newgard, Christopher B; Felker, G Michael; Hernandez, Adrian F; Velazquez, Eric J; Kraus, William E; Shah, Svati HBACKGROUND: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. CONCLUSIONS: We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.Item Open Access Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.(PLoS Genet, 2015-11) Kraus, William E; Muoio, Deborah M; Stevens, Robert; Craig, Damian; Bain, James R; Grass, Elizabeth; Haynes, Carol; Kwee, Lydia; Qin, Xuejun; Slentz, Dorothy H; Krupp, Deidre; Muehlbauer, Michael; Hauser, Elizabeth R; Gregory, Simon G; Newgard, Christopher B; Shah, Svati HLevels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.Item Open Access Rare Things Being Common: Implications for Common Genetic Variants in Rare Diseases Like Long-QT Syndrome.(Circulation, 2020-07-27) Landstrom, Andrew P; Shah, Svati HItem Open Access The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes.(Clinical epigenetics, 2022-12) Jiang, Rong; Hauser, Elizabeth R; Kwee, Lydia Coulter; Shah, Svati H; Regan, Jessica A; Huebner, Janet L; Kraus, Virginia B; Kraus, William E; Ward-Caviness, Cavin KBackground
Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures.Methods
We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach.Results
PhenoAA (HR = 1.05, P < 0.0001), GrimAA (HR = 1.10, P < 0.0001) and HAA (HR = 1.03, P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065).Conclusions
Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks.Item Open Access The Pediatric Obesity Microbiome and Metabolism Study (POMMS): Methods, Baseline Data, and Early Insights.(Obesity (Silver Spring, Md.), 2021-03) McCann, Jessica R; Bihlmeyer, Nathan A; Roche, Kimberly; Catherine, Cameron; Jawahar, Jayanth; Kwee, Lydia Coulter; Younge, Noelle E; Silverman, Justin; Ilkayeva, Olga; Sarria, Charles; Zizzi, Alexandra; Wootton, Janet; Poppe, Lisa; Anderson, Paul; Arlotto, Michelle; Wei, Zhengzheng; Granek, Joshua A; Valdivia, Raphael H; David, Lawrence A; Dressman, Holly K; Newgard, Christopher B; Shah, Svati H; Seed, Patrick C; Rawls, John F; Armstrong, Sarah CObjective
The purpose of this study was to establish a biorepository of clinical, metabolomic, and microbiome samples from adolescents with obesity as they undergo lifestyle modification.Methods
A total of 223 adolescents aged 10 to 18 years with BMI ≥95th percentile were enrolled, along with 71 healthy weight participants. Clinical data, fasting serum, and fecal samples were collected at repeated intervals over 6 months. Herein, the study design, data collection methods, and interim analysis-including targeted serum metabolite measurements and fecal 16S ribosomal RNA gene amplicon sequencing among adolescents with obesity (n = 27) and healthy weight controls (n = 27)-are presented.Results
Adolescents with obesity have higher serum alanine aminotransferase, C-reactive protein, and glycated hemoglobin, and they have lower high-density lipoprotein cholesterol when compared with healthy weight controls. Metabolomics revealed differences in branched-chain amino acid-related metabolites. Also observed was a differential abundance of specific microbial taxa and lower species diversity among adolescents with obesity when compared with the healthy weight group.Conclusions
The Pediatric Metabolism and Microbiome Study (POMMS) biorepository is available as a shared resource. Early findings suggest evidence of a metabolic signature of obesity unique to adolescents, along with confirmation of previously reported findings that describe metabolic and microbiome markers of obesity.Item Open Access Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease.(Metabolomics : Official journal of the Metabolomic Society, 2021-12) Lunyera, Joseph; Diamantidis, Clarissa J; Bosworth, Hayden B; Patel, Uptal D; Bain, James; Muehlbauer, Michael J; Ilkayeva, Olga; Nguyen, Maggie; Sharma, Binu; Ma, Jennie Z; Shah, Svati H; Scialla, Julia JIntroduction
Urine tricarboxylic acid (TCA) cycle organic anions (OAs) are elevated in diabetes and may be biomarkers for diabetic kidney disease (DKD) progression.Objectives
We assessed associations of 10 urine TCA cycle OAs with estimated glomerular filtration rate (eGFR) and eGFR slope.Methods
This study is ancillary to the Simultaneous Risk Factor Control Using Telehealth to SlOw Progression of Diabetic Kidney Disease (STOP-DKD) Trial-a randomized trial of pharmacist-led medication and behavior management in 281 patients with early to moderate DKD at Duke from 2014 to 2015. We used linear mixed models to assess associations of urine TCA cycle OAs with outcomes and modelled TCA cycle OAs as: (1) the average of z-scores for each OA; and (2) principal component (PC) scores derived by principal component analysis (PCA). Untargeted urine metabolomics were added for additional discovery.Results
Among 132 participants with 24 h urine samples (50% men; 58% Black; mean age 64 years [SD 9]; mean eGFR 74 ml/min/1.73m2 [SD 21] and median urine albumin-to-creatinine [UACR] 20 mg/g [IQR 8-95]), PCA identified 3 OA metabolite PCs. Malate, fumarate, pyruvate, α-ketoglutarate, lactate, succinate and citrate/isocitrate loaded positively on PC1; methylsuccinate, ethylmalonate and succinate loaded positively on PC2; and methylmalonate, ethylmalonate and citrate/isocitrate loaded negatively on PC3. Over a median follow-up of 1.8 years (IQR, 1.2 to 2.2), higher average OA z-score was strongly associated with higher eGFR after covariate adjustment (p = 0.01), but not with eGFR slope (p = 0.9). Higher PC3, but not other PCs, was associated with lower eGFR (p < 0.001). Conditional random forests and smooth clipped absolute deviation models confirmed methylmalonate, citrate/isocitrate, and ethylmalonate, and added lactate as top ranked metabolites in models of baseline eGFR (R-squared 0.32 and 0.33, respectively). Untargeted urine metabolites confirmed association of urine TCA cycle OAs with kidney function.Conclusion
Thus, lower urine TCA cycle OAs, most notably lower methylmalonate, ethylmalonate and citrate/isocitrate, are potential indicators of kidney impairment in early stage DKD.