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Mary Ann Clark,1 Francis G Duhay,2 Ann K Thompson,2 Michelle J Keyes,3 Lars G Svensson,4 Robert O Bonow,5 Benjamin T Stockwell,3 David J Cohen61The Neocure Group LLC, Washington, DC, 2Edwards Lifesciences Corporation, Irvine, CA, 3The Burgess Group LLC, Alexandria, VA, 4Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, Cleveland, OH, 5Center for Cardiovascular Innovation, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 6Saint Luke's Mid America Heart Institute, Kansas City, MO, USABackground: Aortic valve replacement (AVR) is the standard of care for patients with severe, symptomatic aortic stenosis who are suitable surgical candidates, benefiting both non-high-risk and high-risk patients. The purpose of this study was to report long-term medical resource use and costs for patients following AVR and validate our assumption that high-risk patients have worse outcomes and are more costly than non-high-risk patients in this population.Methods: Patients with aortic stenosis who underwent AVR were identified in the 2003 Medicare 5% Standard Analytic Files and tracked over 5 years to measure clinical outcomes, medical resource use, and costs. An approximation to the logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) based on administrative data was used to assess surgical risk, with a computed logistic EuroSCORE > 20% considered high-risk.Results: We identified 1474 patients with aortic stenosis who underwent AVR, of whom 1222 (82.9%) were non-high-risk and 252 (17.1%) were high-risk. Among those who were non-high-risk, the mean age was 73.3 years, 464 (38.2%) were women, and the mean logistic EuroSCORE was 7%, whereas in those who were high-risk, the mean age was 77.6 years, 134 (52.8%) were women, and the mean logistic EuroSCORE was 37%. All-cause mortality was 33.2% for non-high-risk and 66.7% for high-risk patients at 5 years. Over this time period, non-high-risk patients experienced an average of 3.9 inpatient hospitalizations and total costs of $106,277 per patient versus 4.7 hospitalizations and total costs of $144,183 for high-risk patients.Conclusion: Among elderly patients undergoing AVR, long-term mortality and costs are substantially greater for high-risk than for non-high-risk individuals. These findings indicate that further research is needed to understand whether newer approaches to aortic valve replacement such as transcatheter AVR may be a lower cost, clinically valuable alternative.Keywords: aortic valve, replacement, health economics

Background: Endothelial dysfunction is prevalent in individuals with end-stage renal disease. Whether endothelial dysfunction is present in patients with moderate chronic kidney disease (CKD) is uncertain.Study Design: Cross-sectional study.Settings& Participants: Brachial reactivity measurements were obtained during the seventh examination cycle in 2,818 (diameter measurements) and 2,256 (flow measurements) Framingham Heart Study Offspring cohort participants (53% women; mean age, 61 +/- 9 years).Predictor: Estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) derived from creatinine- and cystatin C-based estimating equations; microalbuminuria status.Outcome: Brachial reactivity measurements (baseline brachial diameter, flow-mediated dilation, baseline and hyperemic mean flow).Measurements: Linear regression models were used to model brachial measures as a function of CKD and microalbuminuria status.Results: Overall, 7.3% (n = 206) of participants had CKD, and of 2,301 with urinary measurements, 10.0% (n = 230) had microalbuminuria. Brachial reactivity measures did not differ significantly by CKD status in either creatinine- or cystatin C-based equations in either age- and sex- or multivariable-adjusted models. In age- and sex-adjusted models, microalbuminuria was associated with decreased hyperemic mean flow (47.2 +/- 1.4 versus 51.4 +/- 0.5 mg/g; P = 0.005), but the association was not significant after multivariable adjustment (P = 0.09).Limitations: Predominantly white ambulatory cohort; results may not be generalizable to other ethnic groups or individuals with severe CKD.Conclusions: Endothelial dysfunction was not a major correlate of CKD in our sample. [ABSTRACT FROM AUTHOR]

Increased triglycerides (TG) and decreased high-density lipoprotein (HDL) cholesterol are key metabolic abnormalities in patients with insulin resistance (IR) states, including diabetes mellitus. The TG/HDL cholesterol ratio was advocated as a simple clinical indicator of IR, but studies yielded inconsistent results. The total cholesterol/HDL cholesterol ratio was widely used to assess lipid atherogenesis, but its utility for assessing IR or its associated coronary heart disease (CHD) risk was unknown. TG/HDL cholesterol and total cholesterol/HDL cholesterol ratios were related to IR (top quartile of the homeostasis model assessment-IR) in 3,014 patients (mean age 54 years; 55% women). Logistic regression was used to construct receiver-operator characteristic curves for predicting IR, with lipid ratios as predictors. Multivariable Cox regression was used to evaluate whether adjusting for lipid ratios attenuated the association of IR with CHD. Cross sectionally, age- and gender-adjusted correlations of IR were 0.46 with TG/HDL cholesterol ratio and 0.38 with total/HDL cholesterol ratio. IR prevalence increased across tertiles of lipid ratios (p <0.0001). The area under the receiver-operator characteristic curves for predicting IR with TG/HDL cholesterol ratio was 0.745, slightly higher than that for total/HDL cholesterol ratio (0.707; p <0.001 for comparison). On follow-up (mean 6.4 years), 112 patients experienced initial CHD events. IR was associated with CHD risk (multivariable-adjusted hazards ratio 2.71, 95% confidence interval 1.79 to 4.11), which remained significant even after adjustment for lipid ratios. In conclusion, our observations suggested that the TG/HDL cholesterol ratio was an imperfect surrogate for IR and its associated CHD risk, and it was only slightly better than the total/HDL cholesterol ratio for this purpose. [ABSTRACT FROM AUTHOR]

Multiple studies have documented an increased incidence of cardiovascular events in the winter, but the pathophysiologic mechanisms remain incompletely understood. It was hypothesized that brachial flow and flow-mediated dilation (FMD) would vary by season and temperature. Season and temperature were related to ultrasonic brachial artery endothelium-dependent FMD% (n = 2,587), baseline flow velocity, and maximal reactive hyperemia (n = 1,973) in the Framingham Offspring Cohort (mean age 61 +/- 10 years, 53% women). Outdoor temperatures were obtained from National Climate Data Center records for Bedford, Massachusetts (about 14 miles from the testing site), and the examination room temperature was measured. In multivariate models, FMD% was highest in summer and lowest in winter (3.01 +/- 0.09% vs 2.56 +/- 0.10%, respectively, p = 0.02 for differences across all 4 seasons). FMD% was highest in the warmest and lowest in the coldest outdoor-temperature quartiles. In stepwise models adjusting for risk factors and selecting among season, outdoor temperature, and room temperature, FMD% was associated with season (p = 0.02); temperature did not enter the model. In contrast, hyperemic flow velocity was significantly lower for cooler and higher for warmer room temperatures (p = 0.02 overall); season did not enter the model. Season and outdoor and room temperature were each retained in a stepwise model of baseline flow velocity (p <0.0001, p = 0.02, and p <0.0001, respectively). In conclusion, a significant association was observed between season and FMD%. Microvascular vasodilator function, as reflected by hyperemic flow velocity, was more strongly related to temperature than season. Endothelial dysfunction may be 1 of the mechanisms influencing seasonal variation in cardiovascular events. [ABSTRACT FROM AUTHOR]

Importance: Blood pressure response during acute exercise (exercise blood pressure [EBP]) is associated with the future risk of hypertension and cardiovascular disease (CVD). Biochemical characterization of EBP could inform disease biology and identify novel biomarkers of future hypertension., Objective: To identify protein markers associated with EBP and test their association with incident hypertension., Design, Setting, and Participants: This study assayed 4977 plasma proteins in 681 healthy participants (from 763 assessed) of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE; data collection from January 1993 to December 1997 and plasma proteomics from January 2019 to January 2020) Family Study at rest who underwent 2 cardiopulmonary exercise tests. Individuals were free of CVD at the time of recruitment. Individuals with resting SBP ≥160 mm Hg or DBP ≥100 mm Hg or taking antihypertensive drug therapy were excluded from the study. The association between resting plasma protein levels to both resting BP and EBP was evaluated. Proteins associated with EBP were analyzed for their association with incident hypertension in the Framingham Heart Study (FHS; n = 1177) and validated in the Jackson Heart Study (JHS; n = 772) and Multi-Ethnic Study of Atherosclerosis (MESA; n = 1367). Proteins associated with incident hypertension were tested for putative causal links in approximately 700 000 individuals using cis-protein quantitative loci mendelian randomization (cis-MR). Data were analyzed from January 2023 to January 2024., Exposures: Plasma proteins., Main Outcomes and Measures: EBP was defined as the BP response during a fixed workload (50 W) on a cycle ergometer. Hypertension was defined as BP ≥140/90 mm Hg or taking antihypertensive medication., Results: Among the 681 participants in the HERITAGE Family Study, the mean (SD) age was 34 (13) years; 366 participants (54%) were female; 238 (35%) were self-reported Black and 443 (65%) were self-reported White. Proteomic profiling of EBP revealed 34 proteins that would not have otherwise been identified through profiling of resting BP alone. Transforming growth factor β receptor 3 (TGFBR3) and prostaglandin D2 synthase (PTGDS) had the strongest association with exercise systolic BP (SBP) and diastolic BP (DBP), respectively (TGFBR3: exercise SBP, β estimate, -3.39; 95% CI, -4.79 to -2.00; P = 2.33 × 10-6; PTGDS: exercise DBP β estimate, -2.50; 95% CI, -3.29 to -1.70; P = 1.18 × 10-9). In fully adjusted models, TGFBR3 was inversely associated with incident hypertension in FHS, JHS, and MESA (hazard ratio [HR]: FHS, 0.86; 95% CI, 0.75-0.97; P = .01; JHS, 0.87; 95% CI, 0.77-0.97; P = .02; MESA, 0.84; 95% CI, 0.71-0.98; P = .03; pooled cohort, 0.86; 95% CI, 0.79-0.92; P = 6 × 10-5). Using cis-MR, genetically predicted levels of TGFBR3 were associated with SBP, hypertension, and CVD events (SBP: β, -0.38; 95% CI, -0.64 to -0.11; P = .006; hypertension: odds ratio [OR], 0.99; 95% CI, 0.98-0.99; P < .001; heart failure with hypertension: OR, 0.86; 95% CI, 0.77-0.97; P = .01; CVD: OR, 0.84; 95% CI, 0.77-0.92; P = 8 × 10-5; cerebrovascular events: OR, 0.77; 95% CI, 0.70-0.85; P = 5 × 10-7)., Conclusions and Relevance: Plasma proteomic profiling of EBP identified a novel protein, TGFBR3, which may protect against elevated BP and long-term CVD outcomes.

Background: Female sex is frequently cited as a risk factor for anthracycline cardiotoxicity based on pediatric data, but the role of sex in the development of cardiotoxicity has not been clearly established in adults., Objectives: To assess the effect of female sex on the development of incident heart failure (HF) in adult patients treated with anthracyclines., Methods: This was a retrospective cohort study of 1525 adult patients with no prior history of HF or cardiomyopathy who were treated with anthracyclines between 1992 and 2019. The primary outcome was new HF within 5 years of the first dose of anthracyclines. The effect of sex was assessed using Cox proportional hazards and competing risk models., Results: Over a median (IQR) follow-up of 1.02 (0.30-3.01) years, 4.78% of patients developed HF (44 men and 29 women). Female sex was not associated with the primary outcome in a multivariable Cox proportional hazards model (HR 0.87; 95% CI 0.53-1.43; P = 0.58). Similar results were observed in a multivariable model accounting for the competing risk of death (HR 0.94; 95% CI 0.39-2.25; P = 0.88). Age, coronary artery disease and hematopoietic stem cell transplant were associated with the primary outcome in a multivariable Cox proportional hazards model. Age and body mass index were associated with the primary outcome in a multivariable competing risk model., Conclusions: In this large, single-center, retrospective cohort study, female sex was not associated with incident HF in adult patients treated with anthracyclines., Condensed Abstract: Female sex is frequently cited as a risk factor for anthracycline cardiotoxicity based on pediatric data, but the role of sex in the development of cardiotoxicity has not been clearly established in adults. In this retrospective cohort study, we assessed the effect of female sex on the development of incident heart failure in adult patients treated with anthracyclines. Using Cox proportional hazards and competing risk regression models, we found that there was no association between female sex and heart failure after treatment with anthracyclines., Competing Interests: DISCLOSURES AA has consulted for Sanofi, AstraZeneca, Cytokinetics, and OncLive and serves as the principal investigator for a sponsored research agreement with Genentech, all unrelated to the submitted work. JS reports grant funding from Edwards Lifesciences, Anumana, Ultromics, and HeartSciences, consulting for Bracco Diagnostics, and speaker fees from Northwest Imaging Forums, unrelated to the submitted work. The remaining authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV 1 ) and FEV 1 /forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV 1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV 1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery β = 0.0561, Q  = 4.05 × 10 -10 ; β  = 0.0421, Q  = 1.12 × 10 -3 ; and β = 0.0358, Q  = 1.67 × 10 -3 , respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV 1 decline ( Q  < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; β = -4.3 ml/yr, Q  = 0.049; β = -6.1 ml/yr, Q  = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV 1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.

Proteomics has been used to study type 2 diabetes, but the majority of available data are from White participants. Here, we extend prior work by analyzing a large cohort of self-identified African Americans in the Jackson Heart Study (n = 1,313). We found 325 proteins associated with incident diabetes after adjusting for age, sex, and sample batch (false discovery rate q < 0.05) measured using a single-stranded DNA aptamer affinity-based method on fasting plasma samples. A subset was independent of established markers of diabetes development pathways, such as adiposity, glycemia, and/or insulin resistance, suggesting potential novel biological processes associated with disease development. Thirty-six associations remained significant after additional adjustments for BMI, fasting plasma glucose, cholesterol levels, hypertension, statin use, and renal function. Twelve associations, including the top associations of complement factor H, formimidoyltransferase cyclodeaminase, serine/threonine-protein kinase 17B, and high-mobility group protein B1, were replicated in a meta-analysis of two self-identified White cohorts-the Framingham Heart Study and the Malmö Diet and Cancer Study-supporting the generalizability of these biomarkers. A selection of these diabetes-associated proteins also improved risk prediction. Thus, we uncovered both novel and broadly generalizable associations by studying a diverse population, providing a more complete understanding of the diabetes-associated proteome., (© 2023 by the American Diabetes Association.)

Background: Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant., Methods: We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals)., Results: TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (I Na ), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A down-regulation caused decreased peak I Na , and that reduced PDGF receptor ( PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late I Na . Tbx5 regulation of the PDGF axis increased arrhythmia risk due to disruption of PDGF signaling and was conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval ( P <0.001)., Conclusions: These results not only establish decreased SCN5A transcription by the TBX5 variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.

Background: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort., Methods: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women)., Results: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; β=0.04; P =2×10 -8 ; hazard ratio, 1.48; P =0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; β=0.05; P =5×10 -15 ). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P =0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups., Conclusions: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.

Maximal oxygen uptake (VO 2 max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO 2 max, and of increases of VO 2 max in response to exercise training (ΔVO 2 max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO 2 max and ΔVO 2 max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's ΔVO 2 max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans.

Recent advances in proteomic technologies have made high-throughput profiling of low-abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Furthermore, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing protein 2 (WFIKKN2) was, in turn, associated with fasting glucose, hemoglobin A1c, and HOMA-IR measurements in humans. In addition to identifying potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.

In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort ( n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort ( n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2 , exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis., Competing Interests: Competing interest statement: D.J.F. and M.R.P. are equity holders in Apolo1bio, receive research support from Vertex, and are inventors on patents related to APOL1 diagnostics and therapeutics.

Background: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals., Methods: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia., Results: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen ( P <0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF ( P <3.8×10 - 5 ; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits ( P <0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF ( P =0.001)., Conclusions: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.

Background: Emerging proteomic technologies using novel affinity-based reagents allow for efficient multiplexing with high-sample throughput. To identify early biomarkers of myocardial injury, we recently applied an aptamer-based proteomic profiling platform that measures 1129 proteins to samples from patients undergoing septal alcohol ablation for hypertrophic cardiomyopathy, a human model of planned myocardial injury. Here, we examined the scalability of this approach using a markedly expanded platform to study a far broader range of human proteins in the context of myocardial injury., Methods: We applied a highly multiplexed, expanded proteomic technique that uses single-stranded DNA aptamers to assay 4783 human proteins (4137 distinct human gene targets) to derivation and validation cohorts of planned myocardial injury, individuals with spontaneous myocardial infarction, and at-risk controls., Results: We found 376 target proteins that significantly changed in the blood after planned myocardial injury in a derivation cohort (n=20; P <1.05E-05, 1-way repeated measures analysis of variance, Bonferroni threshold). Two hundred forty-seven of these proteins were validated in an independent planned myocardial injury cohort (n=15; P <1.33E-04, 1-way repeated measures analysis of variance); >90% were directionally consistent and reached nominal significance in the validation cohort. Among the validated proteins that were increased within 1 hour after planned myocardial injury, 29 were also elevated in patients with spontaneous myocardial infarction (n=63; P <6.17E-04). Many of the novel markers identified in our study are intracellular proteins not previously identified in the peripheral circulation or have functional roles relevant to myocardial injury. For example, the cardiac LIM protein, cysteine- and glycine-rich protein 3, is thought to mediate cardiac mechanotransduction and stress responses, whereas the mitochondrial ATP synthase F 0 subunit component is a vasoactive peptide on its release from cells. Last, we performed aptamer-affinity enrichment coupled with mass spectrometry to technically verify aptamer specificity for a subset of the new biomarkers., Conclusions: Our results demonstrate the feasibility of large-scale aptamer multiplexing at a level that has not previously been reported and with sample throughput that greatly exceeds other existing proteomic methods. The expanded aptamer-based proteomic platform provides a unique opportunity for biomarker and pathway discovery after myocardial injury., (© 2017 American Heart Association, Inc.)

Background: We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology., Methods: We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from 1421 participants of the MDCS (Malmö Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels., Results: We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants., Conclusions: We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research., (© 2017 American Heart Association, Inc.)

Background: Single-stranded DNA aptamers are oligonucleotides of ≈50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts., Methods: To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform's ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait., Results: We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P<5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P<2.30E-4); >85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P=1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P=1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46; P<0.05). Framingham Heart Study analyses revealed 156 significant protein associations with the Framingham Risk Score (n=899), including aminoacylase 1 (β=0.3386, P=2.54E-22) and trigger factor 2 (β=0.2846, P=5.71E-17). Furthermore, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity., Conclusions: Our results highlight an emerging proteomics tool capable of profiling >1000 low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well., (© 2016 American Heart Association, Inc.)

Background: Acute kidney injury (AKI) occurs commonly after transcatheter aortic valve replacement (TAVR) and is associated with markedly increased postoperative mortality. We previously identified plasma metabolites predictive of incident chronic kidney disease, but whether metabolite profiles can identify those at risk of AKI is unknown., Methods and Results: We performed liquid chromatography-mass spectrometry-based metabolite profiling on plasma from patients undergoing TAVR and subjects from the community-based Framingham Heart Study (N=2164). AKI was defined by using the Valve Academic Research Consortium-2 criteria. Of 44 patients (mean age 82±9 years, 52% female) undergoing TAVR, 22 (50%) had chronic kidney disease and 9 (20%) developed AKI. Of 85 metabolites profiled, we detected markedly concordant cross-sectional metabolic changes associated with chronic kidney disease in the hospital-based TAVR and Framingham Heart Study cohorts. Baseline levels of 5-adenosylhomocysteine predicted AKI after TAVR, despite adjustment for baseline glomerular filtration rate (odds ratio per 1-SD increase 5.97, 95% CI 1.62-22.0; P=0.007). Of the patients who had AKI, 6 (66.7%) subsequently died, compared with 3 (8.6%) deaths among those patients who did not develop AKI (P=0.0008) over a median follow-up of 7.8 months. 5-adenosylhomocysteine was predictive of all-cause mortality after TAVR (hazard ratio per 1-SD increase 2.96, 95% CI 1.33-6.58; P=0.008), independent of baseline glomerular filtration rate., Conclusions: In an elderly population with severe aortic stenosis undergoing TAVR, metabolite profiling improves the prediction of AKI. Given the multifactorial nature of AKI after TAVR, metabolite profiles may identify those patients with reduced renal reserve., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Renal artery stent revascularization is commonly used for renovascular hypertension. Clinical predictors associated with blood pressure (BP) improvement after renal artery stent revascularization are not well understood., Methods: Patient-level data from 901 patients in five prospective multicenter Food and Drug Administration-approved investigational device exemption studies of renal artery stent revascularization was pooled. BP response was defined as reduction of systolic BP (SBP) by >10 mm Hg. Stent patency was defined within each study. Associations of BP reduction were determined by logistic regression., Results: Of 901 patients, complete outcome information was available in 527. Of these, 212/527 (40%) were male, mean age was 63 ± 13 years, 196/544 (36%) were diabetic and 504/527 (96%) had a SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg at baseline. Compared to baseline, 9-month systolic (164 ± 21 mm Hg vs. 146 ± 22 mm Hg, P < 0.0001) and diastolic (79 ± 13 mm Hg vs. 76 ± 12 mm Hg, P < 0.0001) BP declined significantly. Nine-month stent patency was 90% (305/339). In a univariate analysis, baseline SBP >150 mm Hg (OR = 4.09, CI = 2.74-6.12, P < 0.0001) was positively associated with BP response following renal artery stent revascularization. In a multivariable analysis, baseline SBP remained associated with a positive BP response (OR = 1.76, CI = 1.53-2.03, P < 0.0001)., Conclusions: In the largest pooled dataset of patients treated with renal artery stent revascularization, SBP and DBP were significantly lower at 9-months. Elevated baseline SBP (>150 mm Hg) was strongly associated with BP reduction after the procedure., (Copyright © 2013 Wiley Periodicals, Inc.)

Secondary prevention trials have demonstrated the efficacy of statins in reducing cardiovascular morbidity and mortality in patients with coronary artery disease and events after percutaneous coronary intervention (PCI). However, there are few data describing the clinical value of statins in patients with coronary artery disease and chronic kidney disease (CKD) undergoing PCI. Of 10,148 patients who entered into Evaluation of Drug Eluting Stents and Ischemic Events, a multicenter registry of unselected patients undergoing PCI from July 2004 to December 2007, we studied 2,306 patients with CKD (estimated glomerular filtration rate ≤60 ml/min based on the Modified Diet in Renal Disease calculation). Patients were stratified into those receiving statins at discharge (n = 1,833, 79%) or not (n = 473, 21%). Patients in the statin group had a greater prevalence of hypertension, recent myocardial infarction (MI), and use of β blockers and angiotensin-converting enzyme inhibitors. Outcomes were assessed from discharge through 1-year follow-up. One-year all-cause mortality was 5.7% in statin group versus 8.7% in the no statin group (adjusted hazard ratio 0.55, 95% confidence interval 0.34 to 0.88). The composite of death, MI, and repeat revascularization was lower in statin group (adjusted hazard ratio 0.71, 95% confidence interval 0.51 to 0.99). In conclusion, among patients with CKD undergoing PCI, the prescription of statins at hospital discharge was associated with a significant improvement in subsequent outcomes including mortality and composite end point of death, MI, and repeat revascularization., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: We sought to compare the clinical outcomes after percutaneous coronary revascularization of large coronary arteries using drug-eluting (DES) or bare-metal (BMS) stents., Background: In de novo native coronary lesions with reference diameters of 2.5-3.5 mm, DES reduce target lesion revascularization (TLR) with no increase in death or myocardial infarction (MI). The relative efficacy of DES in larger coronary artery lesions is less certain., Methods: From the prospective Evaluation of Drug-Eluting Stents and Ischemic Events registry, we identified patients undergoing stenting of de novo lesions in native coronary arteries 3.5-5.0 mm in diameter (n = 1,485). In-hospital and 1-year clinical outcomes were compared for BMS (n = 282) and DES (n = 1,203) patients, using propensity stratification to adjust for differences in potential confounding factors., Results: Most patient characteristics were similar for the two groups, but BMS patients were more likely to have been treated in the setting of ST elevation MI, whereas DES patients had more bifurcation lesions, smaller vessels, and longer total stent lengths. In risk-adjusted analyses, the composite endpoint of 1-year death, MI or TLR was similar for BMS and DES (standardized rate: 11.9% vs. 8.5%, P = 0.10). DES was associated with a 62% reduction in the risk of TLR, although the absolute difference in event rates was small (standardized rates 4.6% vs. 1.8%, P = 0.016)., Conclusions: Among relatively unselected patients undergoing PCI of large native coronary arteries, use of DES was associated with a modest reduction in rates of TLR, with a neutral effect on other ischemic endpoints., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: To compare outcomes of patients receiving drug-eluting stents (DES) versus bare metal stents (BMS) during percutaneous coronary intervention (PCI) of saphenous vein bypass grafts (SVG)., Background: Long-term benefits of DES versus BMS are well established for native vessel PCI. Benefit in patients undergoing SVG intervention is less certain. We used data from a multicenter registry (evaluation of drug eluting stents and ischemic events, EVENT) to compare outcomes among patients treated with DES versus BMS 1-year following SVG interventions., Methods: Between July 2004 and December 2007, 684 patients in EVENT underwent SVG PCI (515 DES only, 169 BMS only). The primary endpoint was a composite of death, myocardial infarction (MI), and target lesion revascularization between hospital discharge and 1-year follow-up. Propensity score stratification was used to adjust for differences between groups., Results: Baseline demographic and clinical characteristics of patients treated with DES and BMS were similar. The DES group had fewer men and a higher prevalence of prior PCI. Patients receiving DES had less angiographic thrombus, less frequent use of embolic protection devices, greater total stent length, and smaller maximum stent diameters. Unadjusted outcomes between discharge and 1-year follow-up did not differ between the groups. After risk adjustment, the primary outcome was less frequent among patients treated with DES (adjusted HR = 0.48, 95% CI = 0.27-0.84, P < 0.01) with similar relative benefits across the individual endpoints., Conclusions: Among patients undergoing SVG PCI in a "real world" registry analyzed using propensity score stratification, treatment with DES compared with BMS was associated with reduced MACE at 1 year following PCI., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Drug-eluting stents (DES) are commonly used to treat obstructive coronary disease and avoid restenosis. Newer DES have been developed to improve effectiveness and safety. We describe a clinical trial to evaluate a DES with a novel polymer that may improve the antirestenosis effectiveness while maintaining the safety standards of currently Food and Drug Administration-approved DES., Methods: The RESOLUTE US Trial is a multicenter, nonrandomized trial prospectively designed to compare the Resolute zotarolimus-eluting stent (R-ZES) to the Food and Drug Administration-approved Endeavor ZES using patient-level historical control data, adjusting for baseline covariates through propensity score. The stents differ primarily in the polymer, which, in the R-ZES, is designed to elute zotarolimus over a longer period. The study will enroll up to 1,574 patients with ischemic heart disease due to de novo native coronary lesions suitable for 1- or 2-vessel treatment with stents from 2.25 to 4.0 mm in diameter. The primary end point is target lesion failure at 12 months postprocedure, defined as the composite of cardiac death, target-vessel myocardial infarction (MI), and clinically driven target lesion revascularization by percutaneous or surgical methods. Secondary end points include device, lesion and procedural success, death, MI, cardiac death and MI, composites of these clinical events, and stent thrombosis at each follow-up assessment up to 5 years postprocedure., Conclusions: The RESOLUTE US Trial (ClinicalTrials.gov #NCT00726453) is a prospective, multicenter, observational study with a patient-level historical control designed to assess the safety and efficacy of the R-ZES for the treatment of de novo lesions in native coronary arteries., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Elevated plasma total homocysteine (tHcy) level is an established risk factor for cardiovascular disease. The relationship between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT had not been systematically studied, however. Because the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action. We examined the cross-sectional segment-specific relationships of tHcy to ICA/bulb-IMT and CCA-IMT in 2499 participants from the Framingham Offspring Study who were free of cardiovascular disease. In multivariate linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared with the other quartile categories, in both the age- and sex-adjusted and the multivariate-adjusted models (P for trend <.0001 and <.01, respectively). We observed a significant age-by-tHcy interaction for ICA/bulb-IMT (P=.03) and thus stratified the analyses by median age (58 years). A significant positive trend between tHcy and ICA/bulb-IMT was seen in individuals age ≥58 years (P for trend <.01), but not in younger individuals (P for trend=.24) in multivariate-adjusted models. For CCA-IMT, no significant trends were observed in any of the analyses. The segment-specific association between elevated tHcy level and ICA/bulb-IMT suggests an association between tHcy and plaque formation., (Copyright © 2011 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The aim of the study was to describe the incidence and consequences of minor surgery after drug-eluting stent (DES) implantation., Methods: The Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) Registry prospectively enrolled unselected patients undergoing percutaneous coronary intervention at 47 US centers between July 2004 and December 2007. We examined 8,323 patients who received a DES in EVENT to determine the frequencies of minor surgery and postoperative adverse events., Results: Minor surgery (defined as procedures not requiring a major surgical incision) was performed in 164 (2.0%) of 8,323 patients <1 year after stenting, as follows: pacemaker/defibrillator implantation (46%), eye surgery (17%), orthopedic (9%), dermatologic (8%), endovascular (6%), and gastrointestinal procedures (5%). Compared with patients who did not undergo minor surgery, those who did were older, had more comorbidities, had more extensive coronary disease, and were more likely to have received warfarin after stenting. Only 1 (0.6%, 95% CI 0.0%-3.4%) of 164 patients had an event (stent thrombosis causing myocardial infarction) during the first week after minor surgery; this rate was slightly higher than the background rate of ischemic events in the study population (exact mid P = .01). Clopidogrel use at 12 months was similar between patients who did and those who did not undergo minor surgery (65.2% vs 65.5%, P = .95)., Conclusions: In the EVENT Registry, minor surgery was performed in 2% of patients in the first year after DES implantation. The risk of stent thrombosis during the first week after surgery was increased slightly compared with background rates, but the absolute event rate was low (0.6%)., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objectives: We sought to evaluate the early drug-eluting stent (DES) era, characterized by widespread device use., Background: Contemporary clinical practice incorporating more selective DES use can only be assessed by understanding the early DES era., Methods: All patients receiving DES during the first 3 waves of the Evaluation of Drug Eluting Stents and Ischemic Events (EVENT) Registry (2004-2006) were evaluated. The primary end point was a composite of death, myocardial infarction (MI), and urgent revascularization at discharge and death, MI, or target lesion revascularization (TLR) at 1 year. The composite end point at each time point was compared across waves. Multivariable logistic regression was used for in-hospital outcomes and multivariable Cox regression was used for 1-year end points., Results: Ninety-two percent of EVENT patients received at least one DES. One third of patients were treated for Acute Coronary Syndromes (ACS) (33.8%), and later waves included lower lesion complexity. Across waves there was more frequent clopidogrel loading, a decrease in heparin and an increase in bivalirudin use (all P < .01). The primary composite end point of in-hospital death, MI or urgent revascularization occurred in 7.2% of patients, and did not differ across waves. Despite remarkably high levels of routine DES usage, the composite end point of death, MI, or TLR at 1 year averaged 13.5% and did not differ across waves. After adjustment, no statistically significant effect of wave on composite bleeding (P = .068) as well as in-hospital TLR (P = .053) was noted. At 1 year, wave was associated with a lower likelihood of TLR in the adjusted model (HR 0.81, P = .03)., Conclusions: The high-adoption DES era was associated with favorable outcomes, decreasing bleeding rates and changes in antithrombotic approach., (Copyright © 2010 Mosby, Inc. All rights reserved.)

In the setting of acute myocardial infarction, prolongation of the QRS interval on electrocardiography identifies patients at risk for needing permanent pacemaker implantation. However, the implications of prolonged QRS intervals in healthy subjects are unclear, especially given that the QRS prolongation encountered in this setting is typically mild. The aim of this study was to assess the relation between QRS duration and incident pacemaker implantation in a community-based cohort of 8,311 subjects (mean age 54 years, 55% women) who attended 17,731 routine examinations with resting 12-lead electrocardiography. QRS duration was analyzed as a continuous and a categorical variable (<100, 100 to <120, and > or =120 ms). During up to 35 years of follow-up, 157 participants (56 women) developed need for permanent pacemakers. In multivariable Cox regression models adjusting for cardiovascular risk factors and previous myocardial infarction or heart failure, mild QRS prolongation was associated with a threefold risk for pacemaker implantation (adjusted hazard ratio 2.90, 95% confidence interval 1.81 to 4.66, p <0.0001), and bundle branch block was associated with a fourfold risk for pacemaker implantation (hazard ratio 4.43, 95% confidence interval 2.94 to 6.68, p <0.0001). Each standard deviation increment in QRS duration (11 ms) was associated with an adjusted hazard ratio of 1.14 (95% confidence interval 1.11 to 1.18, p <0.0001) for pacemaker placement. This association remained significant after excluding subjects with QRS durations > or =120 ms. In conclusion, subjects with prolonged QRS durations, even without bundle branch block, are at increased risk for future pacemaker implantation. Such individuals may warrant monitoring for progressive conduction disease., (2010 Elsevier Inc. All rights reserved.)

Objective: Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear., Research Design and Methods: We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT)., Results: In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (-1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (-2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m(2)). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001)., Conclusions: Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.

Clinic-based, case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based, cross-sectional observational study included 327 men and 355 women, aged 42-83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. The polysomnographically derived apnea-hypopnea index and the hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. The baseline brachial artery diameter was significantly associated with both the apnea-hypopnea index and the hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for the apnea-hypopnea index. Age-, sex-, race- and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm for those with apnea-hypopnea index < 1.5, 1.5-4.9, 5-14.9, 15-29.9, >/= 30, respectively; p = 0.03. Baseline flow measures were associated with the apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation.

Endothelial dysfunction may link obesity to cardiovascular disease (CVD). We tested the hypothesis that visceral abdominal tissue (VAT) as compared with subcutaneous adipose tissue (SAT) is more related to endothelium-dependent vasodilation. Among Framingham Offspring and Third Generation cohorts (n = 3,020, mean age 50 years, 47% women), we used multivariable linear regression adjusted for CVD and its risk factors to relate computed tomography (CT)-assessed VAT and SAT, BMI, and waist circumference (WC), with brachial artery measures. In multivariable-adjusted models, BMI, WC, VAT, and SAT were positively related to baseline artery diameter and baseline mean flow velocity (all P < 0.001), but not hyperemic mean flow velocity. In multivariable-adjusted models, BMI (P = 0.002), WC (P = 0.001), and VAT (P = 0.01), but not SAT (P = 0.24) were inversely associated with percentage of flow-mediated dilation (FMD%). However, there was little incremental increase in the proportion of variability explained by VAT (R(2) = 0.266) as compared to SAT (R(2) = 0.265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal.

Background: Observational studies generally showed beneficial associations between supplemental vitamin E intake and cardiovascular disease (CVD) risk whereas intervention trials reported adverse effects of vitamin E supplements. We hypothesize that these discordant findings result from differing underlying health status of study participants in observational and intervention studies., Objective: Determine if the relation between supplemental vitamin E intake and CVD and all-cause mortality (ACM) depends on pre-existing CVD., Design: Proportional hazards regression to relate supplemental vitamin E intake to the 10-year incidence of CVD and ACM in 4270 Framingham Study participants stratified by baseline CVD status., Results: Eleven percent of participants used vitamin E supplements at baseline. In participants with pre-existing CVD, there were 28 (44%) and 20 (32%) incident cases of CVD and ACM in the vitamin E supplement users versus 249 (47%) and 202 (38%) in the non-users, respectively (CVD HR, 0.90; 95% CL, 0.60-1.32; ACM HR, 0.74; 95% CL, 0.46-1.17). In participants without pre-existing CVD, there were 51 (13%) and 47 (12%) cases of CVD and ACM in the vitamin E supplement group versus 428 (13%) and 342 (10%) in the non-vitamin E supplement group, respectively (CVD HR, 1.00; 95% CL, 0.75-1.34; ACM HR 1.20; 95% CL, 0.89-1.64)., Conclusion: CVD status has no apparent influence on the association of supplemental vitamin E intake and risk for CVD and ACM in this large, community-based study. Further research is needed to clarify the basis for the discrepant results between intervention and observational studies of supplemental vitamin E intake.

Context: Prolongation of the electrocardiographic PR interval, known as first-degree atrioventricular block when the PR interval exceeds 200 milliseconds, is frequently encountered in clinical practice., Objective: To determine the clinical significance of PR prolongation in ambulatory individuals., Design, Setting, and Participants: Prospective, community-based cohort including 7575 individuals from the Framingham Heart Study (mean age, 47 years; 54% women) who underwent routine 12-lead electrocardiography. The study cohort underwent prospective follow-up through 2007 from baseline examinations in 1968-1974. Multivariable-adjusted Cox proportional hazards models were used to examine the associations of PR interval with the incidence of arrhythmic events and death., Main Outcome Measures: Incident atrial fibrillation (AF), pacemaker implantation, and all-cause mortality., Results: During follow-up, 481 participants developed AF, 124 required pacemaker implantation, and 1739 died. At the baseline examination, 124 individuals had PR intervals longer than 200 milliseconds. For those with PR intervals longer than 200 milliseconds compared with those with PR intervals of 200 milliseconds or shorter, incidence rates per 10 000 person-years were 140 (95% confidence interval [CI], 95-208) vs 36 (95% CI, 32-39) for AF, 59 (95% CI, 40-87) vs 6 (95% CI, 5-7) for pacemaker implantation, and 334 (95% CI, 260-428) vs 129 (95% CI, 123-135) for all-cause mortality. Corresponding absolute risk increases were 1.04% (AF), 0.53% (pacemaker implantation), and 2.05% (all-cause mortality) per year. In multivariable analyses, each 20-millisecond increment in PR was associated with an adjusted hazard ratio (HR) of 1.11 (95% CI, 1.02-1.22; P = .02) for AF, 1.22 (95% CI, 1.14-1.30; P < .001) for pacemaker implantation, and 1.08 (95% CI, 1.02-1.13; P = .005) for all-cause mortality. Individuals with first-degree atrioventricular block had a 2-fold adjusted risk of AF (HR, 2.06; 95% CI, 1.36-3.12; P < .001), 3-fold adjusted risk of pacemaker implantation (HR, 2.89; 95% CI, 1.83-4.57; P < .001), and 1.4-fold adjusted risk of all-cause mortality (HR, 1.44, 95% CI, 1.09-1.91; P = .01)., Conclusion: Prolongation of the PR interval is associated with increased risks of AF, pacemaker implantation, and all-cause mortality.

Background: Emerging evidence suggests that different inflammatory biomarkers operate through distinct biologic mechanisms. We hypothesized that the relation to peripheral arterial disease (PAD) varies for individual markers., Methods: In a community-based sample we measured 12 biomarkers including plasma CD40 ligand, fibrinogen, lipoprotein-associated phospholipase-A2 mass and activity, osteoprotegerin, P-selectin, and tumor necrosis factor receptor 2 (TNFR2); and serum C-reactive protein, intracellular adhesion molecule-1, interleukin-6, monocyte chemoattractant protein-1, and myeloperoxidase in Framingham Offspring Study participants (n=2800, 53% women, mean age 61 years). We examined the cross-sectional relation of the biomarker panel to PAD using (1) a global test of significance to determine whether at least one of 12 biomarkers was related to PAD using the TEST statement in the LOGISTIC procedure in SAS and (2) stepwise multivariable logistic regression with forward selection of markers with separate models for (1) ankle-brachial index (ABI) category (<0.9, 0.9-1.0, >1.0) and (2) presence of clinical PAD (intermittent claudication or lower extremity revascularization)., Results: The group of inflammatory biomarkers were significantly related to both ABI and clinical PAD (p=0.01 and p=0.02, respectively, multi-marker adjusted global significance test). Multivariable forward elimination regression retained interleukin-6 and TNFR2 as significantly associated with PAD. For one standard deviation change in interleukin-6 and TNFR2 concentrations, there was a 1.21 (p=0.005) and 1.19 (p=0.009) increased odds of a change in ABI level respectively. Similar results were observed for clinical PAD., Conclusion: Interleukin-6 and TNFR2 were significantly associated with PAD independent of established risk factors and each other, suggesting that each marker represents a distinct biologic pathway.

Corneal arcus is a lipid-rich deposit at the corneoscleral limbus that shares some similarities with the lipid deposition of atherosclerosis. Epidemiologic studies examining the association between corneal arcus and coronary artery disease (CAD) have yielded mixed results. This study was conducted to determine if corneal arcus is an independent risk factor for cardiovascular disease (CVD) and CAD. A prospective analysis was performed using Cox proportional-hazards regression models in the Framingham Heart Study Original Cohort and Offspring Cohort database. This cohort included 23,376 patient-examinations, during 3,890 (17%) of which corneal arcus was identified. Corneal arcus was a predictor of CVD and CAD at 4 years (hazard ratios [HRs] 2.28 and 1.99, respectively) and 8 years (HRs 2.52 and 2.35, respectively) of follow-up (p <0.0001 for all). Corneal arcus was no longer predictive of either CVD or CAD, however, after adjustment for age and gender at 4 years (HRs 1.07 and 1.01, respectively) and 8 years (HRs 1.18 and 1.17, respectively) of follow-up (p >0.05 for all). In conclusion, corneal arcus predicted CVD and CAD in the community-based Framingham Heart Study cohort because of the strong association of corneal arcus with increasing age. To date, this is the largest and lengthiest population-based cohort study examining the direct association between corneal arcus and CVD and CAD.

The metabolic syndrome (MS), a clustering of metabolic disturbances, is associated with increased cardiovascular risk. Limited information is available about the relations between MS, insulin resistance, and vascular function. We measured brachial artery flow-mediated dilation (n = 2,123) and reactive hyperemia (n = 1,521) in Framingham Offspring participants without diabetes or clinical cardiovascular disease (mean age 59 +/- 9 years, 57% women). MS, determined by National Cholesterol Education Program criteria, was present in 36% of participants. Insulin resistance was determined using Homeostatic Model Assessment. In age- and gender-adjusted models, MS was associated with lower flow-mediated dilation and reactive hyperemia. There was progressively lower vasodilator function with increasing number of MS components (p for trend <0.0001). In multivariable models adjusting for the 5 MS components as continuous variables, MS (presence vs absence) remained associated with lower flow-mediated dilation (2.84 +/- 0.12% vs 3.17 +/- 0.08%, p = 0.0496) and reactive hyperemia (50.8 +/- 1.0 vs 54.4 +/- 0.7 cm/s, p = 0.009). Insulin resistance was inversely associated with flow-mediated dilation and reactive hyperemia in age- and gender-adjusted models, but these relations were not significant in models adjusting for the MS components. In conclusion, our observations are consistent with the hypothesis that MS and insulin resistance impair vascular function predominantly through the influence of the component metabolic abnormalities that comprise MS.

Background: The cholesterol content of LDL particles is variable, causing frequent discrepancies between concentrations of LDL cholesterol and LDL particle number. In managing patients at risk for cardiovascular disease (CVD) to LDL target levels, it is unclear whether LDL cholesterol provides the optimum measure of residual risk and adequacy of LDL lowering treatment., Objective: To compare the ability of alternative measures of LDL to provide CVD risk discrimination at relatively low levels consistent with current therapeutic targets., Methods: Concentrations of LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) were measured chemically and LDL particle number (LDL-P) and VLDL particle number (VLDL-P) were measured by nuclear magnetic resonance (NMR) in 3066 middle-aged white participants (53% women) without CVD in the Framingham Offspring cohort. The main outcome measure was incidence of first CVD event., Results: At baseline, the cholesterol content per LDL particle was negatively associated with triglycerides and positively associated with LDL-C. On follow-up (median 14.8 yrs), 265 men and 266 women experienced a CVD event. In multivariable models adjusting for non-lipid CVD risk factors, LDL-P was related more strongly to future CVD in both sexes than LDL-C or non-HDL-C. Subjects with a low level of LDL-P (<25(th) percentile) had a lower CVD event rate (59 events per 1000 person-years) than those with an equivalently low level of LDL-C or non-HDL-C (81 and 74 events per 1000 person-years, respectively)., Conclusions: In a large community-based sample, LDL-P was a more sensitive indicator of low CVD risk than either LDL-C or non-HDL-C, suggesting a potential clinical role for LDL-P as a goal of LDL management.