Association of Circulating Monocyte Chemoattractant Protein-1 Levels With Cardiovascular Mortality: A Meta-analysis of Population-Based Studies

Marios K Georgakis, James A de Lemos, Colby Ayers, Biqi Wang, Harry Björkbacka, Tiberiu A Pana, Barbara Thorand, Caroline Sun, Lana Fani, Rainer Malik, Josée Dupuis, Gunnar Engström, Marju Orho-Melander, Olle Melander, S Matthijs Boekholdt, Astrid Zierer, Mohamed A Elhadad, Wolfgang Koenig, Christian Herder, Ron C HoogeveenMaryam Kavousi, Christie M Ballantyne, Annette Peters, Phyo K Myint, Jan Nilsson, Emelia J Benjamin, Martin Dichgans* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Importance: Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored.

Objective: To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population.

Data Sources and Selection: Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points.

Data Extraction and Synthesis: Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses.

Main Outcomes and Measures: Incident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes).

Results: The meta-analysis included 7 cohort studies involving 21 401 individuals (mean [SD] age, 53.7 [10.2] years; 10 012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326 392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11]; P = .01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13]; P = .02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20]; P < .001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity; the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein.

Conclusions and Relevance: Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease.

Original languageEnglish
Pages (from-to)587-592
Number of pages6
JournalJAMA cardiology
Volume6
Issue number5
Early online date4 Nov 2020
DOIs
Publication statusPublished - 1 May 2021

Bibliographical note

Funding/Support: Dr Georgakis has received funding from the Onassis Foundation and the German Academic Exchange Service. The Atherosclerosis Risk in Communities study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, (contracts HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I). The Dallas Heart Study was funded by a grant from the Donald W. Reynolds Foundation. The European Prospective Investigation Into Cancer in Norfolk Prospective Population study has received funding from the Medical Research Council (grants MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (grant C864/A14136). The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (contracts N01-HC-25195, HHSN268201500001I, and 75N92019D00031) and is additionally supported by grants from the National Institute of Aging and the National Institute of Neurological Disorders and Stroke (grants RO1 HL 064753, RO1 HL076784, and R01 AG028321). The Monitoring of Trends and Determinants in Cardiovascular Disease–Kooperative Gesundheitsforschung in der Region Augsburg study was initiated and financed by the Helmholtz Zentrum München–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and the state of Bavaria. Support for the establishment of the case-cohort study and MCP-1 measurements was obtained through a grant from the German Research Foundation (grants TH-784/2-1 and TH-784/2-2) and additional funds provided by the University of Ulm, the Federal Ministry of Health, the Ministry of Innovation, Science, Research and Technology of the state North Rhine–Westphalia. Data analysis was supported by funding from the Helmholtz Alliance “Aging and Metabolic Programming.” The German Diabetes Center is funded by the German Federal Ministry of Health, the Ministry of Culture and Science of the state of North Rhine–Westphalia, and grants from the Federal Ministry of Education and Research. The Malmö Diet and Cancer Study–Cardiovascular Subcohort study has been supported with funding from the Swedish Research Council, Swedish Heart and Lung Foundations, and the Swedish Foundation for Strategic Research. This project has received funding from the European Union’s Horizon 2020 research and innovation programme (grant 666881), SVDs@target (to Dr Dichgans; grant 667375), CoSTREAM (to Dr Dichgans); the German Research Foundation as part of the Munich Cluster for Systems Neurology (grant EXC 2145 SyNergy, ID 390857198) and the Collaborative Research Center 1123 (B3; to Dr Dichgans); the Corona Foundation (to Dr Dichgans); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain; to Dr Dichgans); the e:Med program (e:AtheroSysMed; to Dr Dichgans) and the European Union project CVgenes@target (project FP7/2007-2103; grant agreement number Health-F2-2013-601456; to Dr Dichgans).

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