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Association of Circulating Tissue Inhibitor of Metalloproteinases-1 and Procollagen Type III Aminoterminal Peptide Levels With Incident Heart Failure and Chronic Kidney Disease.

ABSTRACT: Background Tissue inhibitor of metalloproteinases-1 ( TIMP -1) and procollagen type III aminoterminal peptide are established circulating markers of extracellular matrix remodeling and associated with cardiovascular disease. The association of both biomarkers with incident congestive heart failure and chronic kidney disease ( CKD ) in the community is not well studied. Methods and Results We measured plasma total TIMP -1 and procollagen type III aminoterminal peptide levels in 922 Framingham participants (mean age, 57 years; 57% women) and related both biomarkers to the risk of incident CKD and congestive heart failure in multivariable-adjusted Cox regression models. Plasma total TIMP -1 levels were positively associated with risk of incident CKD (164 events; hazard ratio per 1 SD in log-biomarker, 1.90; 95% CI , 1.53-2.37) in multivariable models, including adjustments for left ventricular mass, C-reactive protein, and B-type natriuretic peptide levels. The association of total TIMP -1 with risk of congestive heart failure was statistically significant in an age- and sex-adjusted model, but was attenuated upon adjustment for conventional risk factors. Blood procollagen type III aminoterminal peptide levels were not related to the risk of CKD or congestive heart failure. Conclusions Higher baseline levels of total TIMP -1 conferred an increased risk for incident CKD , independent of conventional risk factors and circulating biomarkers of chronic systemic inflammation and neurohormonal activation. Our prospective observations in a large community-based sample support the role of matrix remodeling in the pathogenesis of CKD .

SUBMITTER: Lieb W

PROVIDER: S-EPMC6509733 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Association of Circulating Tissue Inhibitor of Metalloproteinases-1 and Procollagen Type III Aminoterminal Peptide Levels With Incident Heart Failure and Chronic Kidney Disease.

Lieb Wolfgang W Song Rebecca J RJ Xanthakis Vanessa V Vasan Ramachandran S RS

Journal of the American Heart Association 20190401 7

Background Tissue inhibitor of metalloproteinases-1 ( TIMP -1) and procollagen type III aminoterminal peptide are established circulating markers of extracellular matrix remodeling and associated with cardiovascular disease. The association of both biomarkers with incident congestive heart failure and chronic kidney disease ( CKD ) in the community is not well studied. Methods and Results We measured plasma total TIMP -1 and procollagen type III aminoterminal peptide levels in 922 Framingham par ...[more]

PMID: 30890055

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Project description:AIMS:Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch-induced circulating biomarkers for predicting hypertension-associated HF. METHODS AND RESULTS:Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4742 individuals from the Malmö Diet and Cancer study. Protein levels were compared with stretch-activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVMs) in response to 1-48 h of mechanical stretch. We also studied the association between protein levels and hypertension and HF incidence using respectively binary logistic and Cox regressions. Levels of 35 proteins were differentially expressed after Bonferroni correction in incident HF vs. control (P < 3.4E-4). Growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), IL-1 receptor type 1, and urokinase plasminogen activator surface receptor had corresponding mRNA levels up-regulated by stretch in NRVMs at all time points (P < 0.05). These four proteins were individually associated with increased risk of HF after age and sex adjustment [hazard ratio (HR) per standard deviation: 1.19 ? HR ? 1.49, P ? 4.90E-3]. GDF-15 and IL-6 were associated with HF independently of each other (1.22 ? HR ? 1.33, P ? 0.001). In subjects with hypertension, these associations remained significant after further adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (1.23 ? HR ? 1.45, P ? 0.001). A higher fasting value of a GDF-15, IL-6 score aggregate was associated with increased risk of hypertensive HF after adjustment for all traditional risk factors for HF and NT-proBNP (HR = 1.31, P = 2.19E-4). CONCLUSIONS:Cardiomyocyte mRNA levels of GDF-15 and IL-6 are consistently up-regulated by stretch, and their circulating protein levels predict HF in hypertensive subjects independently of NT-proBNP during long-term follow-up. Our results encourage further studies on lower blood pressure goals in hypertensive subjects with high GDF-15 and IL-6, and interventions targeted at stretch-induced cardiomyocyte expressed biomarkers.

Project description:Importance:Cardiac troponin is associated with incident heart failure and greater left ventricular (LV) mass. Its association with LV systolic and diastolic functions is unclear. Objectives:To define the association of high-sensitivity cardiac troponin T (hs-cTnT) with LV systolic and diastolic functions in the general population, and to evaluate the extent to which that association accounts for the correlation between hs-cTnT concentration and incident heart failure overall, heart failure with preserved LV ejection fraction (LVEF; HFpEF), and heart failure with LVEF less than 50%. Design, Setting, and Participants:This analysis of the Atherosclerosis Risk in Communities (ARIC) Study, an ongoing epidemiologic cohort study in US communities, included participants without cardiovascular disease (n = 4111). Available hs-cTnT measurements for participants who attended ARIC Study visits 2 (1990 to 1992), 4 (1996 to 1998), and 5 (2011 to 2013) were assessed cross-sectionally against echocardiographic measurements taken at visit 5 and against incident health failure after visit 5. Changes in hs-cTnT concentrations from visits 2 and 4 were also examined. Data analyses were performed from August 2017 to July 2018. Main Outcomes and Measures:Cardiac structure and function by echocardiography at visit 5, and incident heart failure during a median 4½ years follow-up after visit 5. Results:Of the 6538 eligible participants, 4111 (62.9%) without cardiovascular disease were included. Among these participants, 2586 (62.9%) were female, and the mean (SD) age was 75 (5) years. Median (interquartile range) hs-cTnT concentration at visit 5 was 9 (7-14) ng/L and was detectable in 3946 participants (96.0%). After adjustment for demographic and clinical covariates, higher hs-cTnT levels were associated with greater LV mass index (adjusted mean [SE] for group 1: 33.8 [0.5] vs group 5: 40.1 [0.4]; P?for trend <?.001) and with worse diastolic function, including lower tissue Doppler imaging e' (6.00 [0.07] vs 5.54 [0.06]; P?for trend <?.001), higher E/e' ratio (11.4 [0.2] vs 12.9 [0.1]; P?for trend <?.001), and greater left atrial volume index (23.4 [0.4] vs 26.4 [0.3]; P?for trend <?.001), independent of LV mass index; hs-cTnT level was not associated with measures of LV systolic function. Accounting for diastolic function attenuated the association of hs-cTnT concentration with incident HFpEF by 41% and the association with combined heart failure with midrange and reduced ejection fraction combined (LVEF <50) by 17%. Elevated hs-cTnT concentration and diastolic dysfunction were additive risk factors for incident heart failure. For any value of late-life hs-cTnT levels, longer duration of detectable hs-cTnT from midlife to late life was associated with greater LV mass in late life but not with worse LV systolic or diastolic function. Conclusions and Relevance:This study shows that higher hs-cTnT concentrations were associated with worse diastolic function, irrespective of LV mass, but not with systolic function; these findings suggest that high levels of hs-cTnT may serve as an early marker of subclinical alterations in diastolic function that may lead to a predisposition to heart failure.

Dataset Information

Association of Circulating Tissue Inhibitor of Metalloproteinases-1 and Procollagen Type III Aminoterminal Peptide Levels With Incident Heart Failure and Chronic Kidney Disease.

Publications

Association of Circulating Tissue Inhibitor of Metalloproteinases-1 and Procollagen Type III Aminoterminal Peptide Levels With Incident Heart Failure and Chronic Kidney Disease.

Similar Datasets

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