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Impact of Kidney Function on the Blood Proteome and on Protein Cardiovascular Risk Biomarkers in Patients With Stable Coronary Heart Disease.

ABSTRACT: Background Chronic kidney disease (CKD) confers increased cardiovascular risk, not fully explained by traditional factors. Proteins regulate biological processes and inform the risk of diseases. Thus, in 938 patients with stable coronary heart disease from the Heart and Soul cohort, we quantified 1054 plasma proteins using modified aptamers (SOMAscan) to: (1) discern how reduced glomerular filtration influences the circulating proteome, (2) learn of the importance of kidney function to the prognostic information contained in recently identified protein cardiovascular risk biomarkers, and (3) identify novel and even unique cardiovascular risk biomarkers among individuals with CKD. Methods and Results Plasma protein levels were correlated to estimated glomerular filtration rate (eGFR) using Spearman-rank correlation coefficients. Cox proportional hazard models were used to estimate the association between individual protein levels and the risk of the cardiovascular outcome (first among myocardial infarction, stroke, heart failure hospitalization, or mortality). Seven hundred and nine (67.3%) plasma proteins correlated with eGFR at P<0.05 (? 0.06-0.74); 218 (20.7%) proteins correlated with eGFR moderately or strongly (? 0.2-0.74). Among the previously identified 196 protein cardiovascular biomarkers, just 87 remained prognostic after correction for eGFR. Among patients with CKD (eGFR <60 mL/min per 1.73 m²), we identified 21 protein cardiovascular risk biomarkers of which 8 are unique to CKD. Conclusions CKD broadly alters the composition of the circulating proteome. We describe protein biomarkers capable of predicting cardiovascular risk independently of glomerular filtration, and those that are prognostic of cardiovascular risk specifically in patients with CKD and even unique to patients with CKD.

SUBMITTER: Yang J

PROVIDER: S-EPMC7792282 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Impact of Kidney Function on the Blood Proteome and on Protein Cardiovascular Risk Biomarkers in Patients With Stable Coronary Heart Disease.

Yang Joseph J Brody Edward N EN Murthy Ashwin C AC Mehler Robert E RE Weiss Sophie J SJ DeLisle Robert K RK Ostroff Rachel R Williams Stephen A SA Ganz Peter P

Journal of the American Heart Association 20200722 15

Background Chronic kidney disease (CKD) confers increased cardiovascular risk, not fully explained by traditional factors. Proteins regulate biological processes and inform the risk of diseases. Thus, in 938 patients with stable coronary heart disease from the Heart and Soul cohort, we quantified 1054 plasma proteins using modified aptamers (SOMAscan) to: (1) discern how reduced glomerular filtration influences the circulating proteome, (2) learn of the importance of kidney function to the progn ...[more]

PMID: 32696702

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Project description:Background Vascular risk factors have been associated with differences in cognitive performance in epidemiological studies, but evidence in patients with coronary heart disease is more limited. Methods and Results The Montreal Cognitive Assessment score obtained 3.2±0.37 years after randomization to darapladib, a reversible inhibitor of lipoprotein phospholipase A2 or placebo was evaluated for 10 634 patients with coronary heart disease from 38 countries in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial. The Montreal Cognitive Assessment scores for darapladib and placebo groups were similar (mean± SD , 25.3±3.84 versus 25.4±3.73, respectively; P=0.27) and the adjusted odds ratio ( OR ) for mild cognitive impairment (Montreal Cognitive Assessment score <26) was 1.00 (95% CI , 0.93-1.09). Mild cognitive impairment was more likely with increasing age ( OR , 1.33 [1.27-1.41], +5 years after 65). For other baseline clinical characteristics, the strongest independent predictors of cognitive impairment were education (?8 years versus college/university, OR , 2.95 [2.60-3.35]; >8 years/trade school versus college/university, OR , 1.38 [1.25-1.52] and geographic grouping). Cardiovascular risk factors independently associated with cognitive impairment were history of stroke ( OR , 1.43 [1.20-1.71]); <2.5 hours of moderate or vigorous intensity exercise/week ( OR , 1.19 [1.04-1.37]); high-density lipoprotein cholesterol <1.16 mmol/L ( OR , 1.19 [1.04-1.37]); diabetes mellitus requiring treatment ( OR , yes versus no: 1.15 [1.05-1.26]); and history of hypertension ( OR , 1.12 [1.02-1.23]). Conclusions In patients with stable coronary heart disease, cognitive performance was associated with modifiable cardiovascular risk factors, educational level, and global region, but was not influenced by darapladib. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00799903.

Project description:BACKGROUND:It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. METHODS:MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g-1·min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. RESULTS:A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38-2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84-1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9-3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3-2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6-1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3-0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. CONCLUSIONS:CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

Project description:Background Data are limited on the association of mildly reduced estimated glomerular filtration rate (eGFR 60-89 mL/min per 1.73 m2) with cardiovascular disease (CVD) in the community. Methods and Results We evaluated 3066 Framingham Offspring Study participants (55% women, mean age 58 years), without clinical CVD. Using multivariable regression, we related categories of mildly reduced eGFR (80-89, 70-79, or 60-69 versus ≥90 mL/min per 1.73 m2 [referent]) to prevalent coronary artery calcium, carotid intima media thickness, and left ventricular hypertrophy, and to circulating concentrations of cardiac stress biomarkers. We related eGFR categories to CVD incidence and to progression to ≥Stage 3 chronic kidney disease (eGFR <60 mL/min per 1.73 m2) using Cox regression. Individuals with eGFR 60-69 mL/min per 1.73 m2 (n=320) had higher coronary artery calcium score (odds ratio 1.69; 95% CI 1.02-2.80) compared with the referent group. Individuals with eGFR 60-69 and 70-79 mL/min per 1.73 m2 had higher blood growth differentiating factor-15 concentrations (β=0.131 and 0.058 per unit-increase in log-biomarker, respectively). Participants with eGFR 60-69 and 80-89 mL/min per 1.73 m2 had higher blood B-type natriuretic peptide concentrations (β=0.119 and 0.116, respectively). On follow-up (median 16 years; 691 incident CVD and 252 chronic kidney disease events), individuals with eGFR 60-69 and 70-79 mL/min per 1.73 m2 experienced higher CVD incidence (hazard ratio [HR], 1.40; 95% CI, 1.02-1.93 and 1.45, 95% CI, 1.05-2.00, respectively, versus referent). Participants with eGFR 60-69 mL/min per 1.73 m2 experienced higher chronic kidney disease incidence (HR, 2.94; 95% CI, 1.80-4.78 versus referent). Conclusions Individuals with mildly reduced eGFR 60-69 mL/min per 1.73 m2 have a higher burden of subclinical atherosclerosis cross-sectionally, and a greater risk of CVD and chronic kidney disease progression prospectively. Additional studies are warranted to confirm our findings.

Project description:BACKGROUND The obesity paradox states that patients with higher body mass index (BMI) and cardiovascular disease may experience better prognosis. However, this is less clear in patients with coronary heart disease. METHODS AND RESULTS The prospective STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial included 15 828 patients with stable coronary heart disease with 3 to 5 years' follow-up on optimal secondary preventive treatment. BMI was measured at baseline (n=15 785). Associations between BMI and cardiovascular outcomes were evaluated by Cox regression analyses with multivariable adjustments. Mean age was 64±9 years and 19% women. Most risk markers (diabetes, hypertension, inflammatory biomarkers, triglycerides) showed a graded association with higher BMI. The frequency of smoking, levels of high-density lipoprotein, growth differentiation factor 15, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) were higher at lower BMI. Low BMI (<20 kg/m2; n=244 [1.5%]) was associated with doubled risk of total death (hazard ratio [HR], 2.27; 95% CI, 1.60-3.22), cardiovascular death (HR, 2.26; 95% CI, 1.46-3.49), and heart failure (HR, 2.51; 95% CI, 1.35-4.68) compared with BMI of 25 to <30 kg/m2 (n=6752 [42.8%]) as reference. Similarly, high BMI of ≥35 kg/m2 (n=1768 [11.2%]) was associated with increased risk of the same outcomes. A BMI between 20 and <25 kg/m2 was associated with increased risk of cardiovascular death (HR, 1.26; 95% CI, 1.03-1.54) and total death (HR, 1.21; 95% CI, 1.03-1.42). CONCLUSIONS Patients with stable coronary heart disease showed a graded increase in cardiometabolic and inflammatory risk factors with increasing BMI category >25 kg/m2. All-cause and cardiovascular mortality were lowest at BMI of 25 to 35 kg/m2. Underweight with BMI of <20 kg/m2 and very high BMI of ≥35 kg/m2 were strong risk markers for poor prognosis. REGISTRATION URL: https://clinicaltrials.gov/; Unique identifier NCT00799903.

Project description:BackgroundThe purpose of the predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC) study is exploratory and hypothesis generating. We want to identify biochemical quantities which-conditionally on the values of available standard demographic, anamnestic, and biochemical data-may improve the prediction of cardiovascular outcomes and/or death in patients suffering from stable ischaemic heart disease. The candidate biochemical quantities include N-terminal pro-B-type natriuretic peptide, YKL-40, osteoprotegerin, high-sensitive assay cardiac troponin T (hs-cTnT), pregnancy-associated plasma protein-A (PAPP-A), cathepsin B, cathepsin S, soluble TNF receptor 1 and 2, neutrophil gelatinase-associated lipocalin, endostatin, and calprotectin. As an extra objective, we also want to assess if skewness in these predictors may explain why the clarithromycin for patients with stable coronary heart disease (CLARICOR) trial found increased all-cause and cardiovascular (CV) mortality on a brief clarithromycin regimen compared with placebo.MethodsBaseline data were obtained from the hospital files at five cardiology clinics covering the Copenhagen area. The CLARICOR trial included data from 4372 stable coronary artery disease patients recruited among such patients alive and diagnosed with acute myocardial infarction or unstable angina pectoris during 1993 to 1999 in Copenhagen and randomised during October 1999 to April 2000 to the CLARICOR trial of 14 days clarithromycin versus placebo.Initial follow-up lasted for 2.6 years, during which outcomes were collected through hospital and death registries and assessed by an adjudication committee. Corresponding register data later showed to produce similar results. The adjudicated outcomes were therefore replaced and augmented by register data on outcomes to cover 10 years of follow-up. Biochemical marker data were obtained from analysis of serum from the CLARICOR bio-bank collected at randomisation and stored at -80° C.Using Cox proportional hazard method, we will identify among the candidate biochemical quantities those which are significant predictors when used alone and in combination with the standard predictors as defined in the present study.DiscussionPatients who became stable during the period 1993 to 1999 and died before October 1999 are missing. The data from the placebo patients are nevertheless useful to identify new prognostic biomarkers in patients with stable coronary artery disease, and data from both trial groups are useful to assess important potential skewness between randomised groups. However, due to the potential selection bias, we do not feel that it is advisable to try to rank identified biochemical predictors relative to each other nor to use the results for predictive purposes.Trial registrationClinicalTrials.gov, NCT00121550 Date of registration 13 July 2005Date of enrolment of first participant 12 October 1999.

Dataset Information

Impact of Kidney Function on the Blood Proteome and on Protein Cardiovascular Risk Biomarkers in Patients With Stable Coronary Heart Disease.

Publications

Impact of Kidney Function on the Blood Proteome and on Protein Cardiovascular Risk Biomarkers in Patients With Stable Coronary Heart Disease.

Similar Datasets

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