Background:
Primary prevention strategies for myocardial infarction typically focus on the identification and management of the classical cardiovascular risk factors. However, studies have shown that around 15-20% of individuals who experience a first myocardial infarction do not have any of those risk factors. The aim of this study was to identify novel mechanisms that may contribute to the development of a future primary myocardial infarction.
Methods:
Data from the prospective and population-based Gutenberg Health Study (GHS) were analyzed. At baseline, plasma levels of 5,416 proteins were measured using the proximity extension assay technology (Olink Proteomics, Uppsala, Sweden). An elastic net-regularized Cox proportional hazards model under consideration of stability selection (1,000 bootstrap samples, selection probability >50%), adjusted for age, sex, and relevant medication intake, was used to identify plasma proteins associated with the combined endpoint of primary myocardial infarction or cardiac death. A weighted protein score was developed from the identified protein signature and subsequently validated in the ProsPECTUS cohort, a prospective study evaluating the diagnosis and treatment of coronary heart disease.
Results:
The analysis sample comprised 950 GHS participants (mean age: 59.8 ± 10.3 years; 37.2% women) without prior myocardial infarction at enrollment and a follow-up period of 10 years. A total of 43 plasma proteins were identified as being reliably associated with a future primary myocardial infarction (C-index = 0.781). The weighted protein score was a strong predictor of primary myocardial infarction (hazard ratio [95% confidence interval]: 2.7 [2.38-3.06], p-value <0.0001). In addition, the protein score discriminated between individuals with acute myocardial infarction and individuals without acute coronary syndrome (odds ratio [95% CI]: 1.28 [1.05-1.55], p-value = 0.015) in the ProsPECTUS cohort (n = 891). Regression analyses revealed a subset of 28 plasma proteins that show a relevant association with classical cardiovascular risk factors and organ markers. These proteins were found to be involved in processes like inflammatory response, lipid metabolism, and protein transport. Conversely, 15 proteins demonstrated no relevant association with the analyzed markers. These proteins play a role in DNA repair mechanisms, transcriptional regulation, transport, and fertilization.
Conclusion:
This study reported the discovery of a novel plasma protein signature associated with a future primary myocardial infarction using comprehensive targeted proteomics. These proteins may provide novel insights into mechanisms leading to a primary myocardial infarction that are not yet addressed by current therapeutics, thereby supporting the development of novel therapeutics.
