Prognostic value of 12 novel cardiological biomarkers in stable coronary artery disease. A 10-year follow-up of the placebo group of the Copenhagen CLARICOR trial

Winkel, Per; Jakobsen, Janus Christian; Hilden, Jørgen; Jensen, Gorm; Kjøller, Erik; Sajadieh, Ahmad; Kastrup, Jens; Kolmos, Hans Jørn; Iversen, Kasper; Bjerre, Mette; Larsson, Anders; Ärnlöv, Johan; Gluud, Christian

doi:10.1136/bmjopen-2019-033720

Cited by 3 publications

(3 citation statements)

References 34 publications

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“…In reports on the cardio-prognostic power of our biomarkers, OPG won a third place after NTproBNP and cTnT, but its prognostic impact appeared to be a longer-term one [5,15,16]. In the present analysis OPG, tellingly, failed to come out significant.…”

Section: Step 3: Appraisal Of Regression Findingscontrasting

confidence: 48%

“…To illustrate the application of our method we have chosen an example from cardiology using the placebo-treated cohort from the CLARICOR trial of participants with stable coronary artery disease (see Supplementary File 1) [2][3][4][5][6][7][8]. The 19 biomarkers [2][3][4][5] that we measured at randomisation were eight standard biochemistry variables (C-reactive protein/mg/L (CRP), glomerular filtration rate/ mL/min/1.73 m 2 (GFR), ApoA1 lipoprotein/g/L (ApoA1), ApoB lipoprotein/g/L (ApoB), cholesterol-high density lipoprotein/mmol/L (Ch_HDL), cholesterol-low density lipoprotein/mmol/L (Ch_LDL), cholesterol/mmol/L (cholesterol), triglyceride/mmol/L (TG)), and 11 recently introduced cardiological biomarkers (N-terminal-pro-B-type natriuretic peptide/ng/L (NTproBNP), high sensitivity cardiac TnT/ng/L (cTnT), endostatin/ng/mL (endostatin), osteoprotegerin/ng/L (OPG), soluble TNF receptor 1/ng/L (sTNFreceptor1), soluble TNF receptor 2/ng/L (sTNFreceptor2), YKL40/µg/L (YKL40), neutrophil gelatinaseassociated lipocalin/ng/L (NGAL), cathepsin-B/µg/L (Cath B), cathepsin-S/µg/L (Cath S), calprotectin/mg/L (calprotectin), see Table S2.1, Supplementary File 2).…”

Section: Materials (Illustrative Dataset)mentioning

confidence: 99%

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A screening method to spot biomarkers that may warn of serious events in a chronic disease – illustrated by cardiological CLARICOR trial data

Winkel

Hilden

Jakobsen

et al. 2021

Clinical Chemistry and Laboratory Medicine (CCLM)

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Objectives To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker’s clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. Methods The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient’s entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers. Results Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes. Conclusions For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.

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Section: Step 3: Appraisal Of Regression Findingscontrasting

confidence: 48%

Section: Materials (Illustrative Dataset)mentioning

confidence: 99%

A screening method to spot biomarkers that may warn of serious events in a chronic disease – illustrated by cardiological CLARICOR trial data

Winkel

Hilden

Jakobsen

et al. 2021

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…It was previously demonstrated that PAPP-A is involved in the development of pathological states of the heart [5,[18][19][20][21][22][23]. PAPP-A-derived IGFBP-4 proteolytic fragments are considered to be diagnostic and prognostic biomarkers of various cardiovascular diseases (CVDs), such as acute coronary syndrome (ACS) [18], acute heart failure [19], and ischemia [20].…”

Section: Introductionmentioning

confidence: 99%

PAPP-A-Specific IGFBP-4 Proteolysis in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Adasheva,

Lebedeva,

Goliusova

et al. 2023

IJMS

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The insulin-like growth factors IGF-I and IGF-II—as well as their binding proteins (IGFBPs), which regulate their bioavailability—are involved in many pathological and physiological processes in cardiac tissue. Pregnancy-associated plasma protein A (PAPP-A) is a metalloprotease that preferentially cleaves IGFBP-4, releasing IGF and activating its biological activity. Previous studies have shown that PAPP-A-specific IGFBP-4 proteolysis is involved in the pathogenesis of cardiovascular diseases, such as ischemia, heart failure, and acute coronary syndrome. However, it remains unclear whether PAPP-A-specific IGFBP-4 proteolysis participates in human normal cardiomyocytes. Here, we report PAPP-A-specific IGFBP-4 proteolysis occurring in human cardiomyocytes derived from two independent induced pluripotent cell lines (hiPSC-CMs), detected both on the cell surface and in the cell secretome. PAPP-A was measured by fluoroimmune analysis (FIA) in a conditioned medium of hiPSC-CMs and was detected in concentrations of up to 4.3 ± 1.33 ng/mL and 3.8 ± 1.1 ng/mL. The level of PAPP-A-specific IGFBP-4 proteolysis was determined as the concentration of NT-IGFBP-4 proteolytic fragments using FIA for a proteolytic neo-epitope-specific assay. We showed that PAPP-A-specific IGFBP-4 proteolysis is IGF-dependent and inhibited by EDTA and 1,10-phenanthroline. Therefore, it may be concluded that PAPP-A-specific IGFBP-4 proteolysis functions in human normal cardiomyocytes, and hiPSC-CMs contain membrane-bound and secreted forms of proteolytically active PAPP-A.

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Plasma Protein Biomarkers and Long‐Term Cardiovascular Mortality Risk in Patients With Chronic Coronary Heart Disease

Stewart,

Robledo,

Tonkin

et al. 2024

JAHA

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Background Protein biomarkers that reflect different pathophysiological pathways have been associated with the risk of adverse cardiovascular events. However, it is uncertain whether these associations are sustained with increasing years after the biomarkers are measured. Methods and Results In this cohort study, 7745 patients with coronary heart disease who participated in the LIPID (Long‐Term Intervention With Pravastatin in Ischemic Disease) trial, BNP (B‐type natriuretic peptide), troponin I, cystatin‐C, C‐reactive protein, d ‐dimer and midregional proadrenomedullin were measured at baseline and after 1 year. Discrimination of plasma biomarker concentrations for cardiovascular death were evaluated in landmark analyses from 1 year for the next 5 years of the randomized trial, and for 10 additional years after trial completion. All 6 biomarkers were associated with risk of cardiovascular death (n=1903) both during and after the clinical trial (each P <0.001). C‐statistics for BNP were 0.706 and 0.704; cystatin‐C, 0.686 and 0.693; troponin I, 0.686 and 0.689; C‐reactive protein, 0.655 and 0.684; d ‐dimer, 0.670 and 0.679, and midregional adrenomedullin, 0.686 and 0.688, respectively. In multivariable models, adding all 6 biomarkers to models with clinical risk factors increased the C‐statistic for cardiovascular death from 0.709 to 0.775 during the clinical trial, and from 0.713 to 0.751 during 10‐year follow‐up after the randomized trial ( P <0.001 for both). Conclusions In patients with chronic coronary heart disease, biomarkers that reflect different pathophysiological pathways are associated with the risk of cardiovascular death for at least the next 15 years.

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Prognostic value of 12 novel cardiological biomarkers in stable coronary artery disease. A 10-year follow-up of the placebo group of the Copenhagen CLARICOR trial

Cited by 3 publications

References 34 publications

A screening method to spot biomarkers that may warn of serious events in a chronic disease – illustrated by cardiological CLARICOR trial data

A screening method to spot biomarkers that may warn of serious events in a chronic disease – illustrated by cardiological CLARICOR trial data

PAPP-A-Specific IGFBP-4 Proteolysis in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Plasma Protein Biomarkers and Long‐Term Cardiovascular Mortality Risk in Patients With Chronic Coronary Heart Disease

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