Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension.

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.

Sex Differences in the Development of Anthracycline-Associated Heart Failure.

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.

Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations.

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.

Protein Markers of Diabetes Discovered in an African American Cohort.

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.

Human plasma proteomic profiles indicative of cardiorespiratory fitness.

Maximal oxygen uptake (VOmax) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VOmax, and of increases of VOmax in response to exercise training (ΔVOmax), 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 VOmax and ΔVOmax, respectively.

Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults.

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.

Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk.

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.

Circulating testican-2 is a podocyte-derived marker of kidney health.

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.

Proteomic Profiling in Biracial Cohorts Implicates DC-SIGN as a Mediator of Genetic Risk in COVID-19.

COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear. Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.

Aptamer-Based Proteomic Platform Identifies Novel Protein Predictors of Incident Heart Failure and Echocardiographic Traits.

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.

Genetic Architecture of the Cardiovascular Risk Proteome.

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.

Application of Large-Scale Aptamer-Based Proteomic Profiling to Planned Myocardial Infarctions.

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.

Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease.

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.

Metabolite Profiles Predict Acute Kidney Injury and Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement.

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).

Statin therapy in patients with chronic kidney disease undergoing percutaneous coronary intervention (from the Evaluation of Drug Eluting Stents and Ischemic Events Registry).

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).

Blood pressure response to renal artery stenting in 901 patients from five prospective multicenter FDA-approved trials.

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.

Clinical and economic outcomes after surgical aortic valve replacement in Medicare patients.

Background: 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.

Five-year clinical and economic outcomes among patients with medically managed severe aortic stenosis: results from a Medicare claims analysis.

Background: Patients with severe, symptomatic aortic stenosis, who do not undergo valve replacement surgery have a poor long-term prognosis. Limited data exist on the medical resource utilization and costs during the final stages of the disease.

Methods And Results: We used data from the 2003 Medicare 5% standard analytic files to identify patients with aortic stenosis and a recent hospitalization for heart failure, who did not undergo valve replacement surgery within the ensuing 2 calendar quarters.

In-hospital and one year outcomes with drug-eluting versus bare metal stents in large native coronary arteries: a report from the Evaluation of Drug-Eluting Stents and Ischemic Events registry.

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.

In-hospital and 1-year outcomes with drug-eluting versus bare metal stents in saphenous vein graft intervention: a report from the EVENT registry.

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.

Rationale and design of the clinical evaluation of the Resolute Zotarolimus-Eluting Coronary Stent System in the treatment of de novo lesions in native coronary arteries (the RESOLUTE US clinical trial).

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.

Incidence and clinical outcome of minor surgery in the year after drug-eluting stent implantation: results from the Evaluation of Drug-Eluting Stents and Ischemic Events Registry.

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.