https://doi.org/10.1007/s00392-024-02526-y
1Universitätsklinikum OWL Klinik für Kardiologie und intern. Intensivmedizin Bielefeld, Deutschland; 2Herzzentrum Leipzig - Universität Leipzig Klinik für Innere Medizin/Kardiologie Leipzig, Deutschland; 3IMISE der Universität Leipzig Leipzig, Deutschland; 4LMU Klinikum der Universität München Institut für Laboratoriumsmedizin München, Deutschland; 5Dekanat der Medizinischen Fakultät Kiel, Deutschland
Objective: Despite advances in the revascularisation techniques their net clinical benefit differs substantially between patients presenting with myocardial infarction (ACS) and chronic coronary syndrome (CCS) due to obstructive coronary atherosclerosis.
Considering that leukocytes represents a key pathophysiological component of myocardial ischaemia, exploration of mononuclear blood cell (PBMC) gene expression profile in CCS and ACS setting could reveal clinically relevant transcriptomic signals. The aim of the present study was to identify differences in PBMC transcriptome between ACS and CCS patients which are linked to mortality after revascularisation.
Methods and Results: We analysed PBMC transcriptomes from 719 ACS and 486 CCS patients creating discovery cohort. The results of transcriptomic analysis were verified in replication cohort (ACS: N=682 for CCS: N=489) generated on the basis of propensity score matching. Median time revascularisation to blood collection (IQR) was 15.68 (-4.52, 23.23) hrs. Patients with ACS showed consistent differential expression of 8173 genes (4544 upregulated, 3629 downregulated) when compared with CCS patients.
The subsequent pathway analysis also showed significant enrichment of several canonical pathways involved in major cardiovascular pathologies i.e. atherosclerosis (p = 1.22-06, enrichment = 3.39), vascular endothelial growth factor production (p = 1.16-06, enrichment = 16.73), positive regulation of vascular development (p = 2.78-06, enrichment = 5.30) and heterotopic cell adhesion including also the enriched gene desmocollin 2 (DSC2, p = 3.64-04, enrichment = 6.30). In the multivariate survival analysis with differentially expressed genes, increased expression of DCS2, lamin A/C (LMNA), and UGGT2, and decreased expression of SNRNP70 predicted poor survival during the median follow-up 10.1 yrs. Consistently, controlling the false discovery rate (FDR) at ≤ 5% these genes enriched pathways involved in cardiomyopathies such as arrhythmogenic right-ventricular cardiomyopathy (p = 4.19x10-4, enrichment = 58.9) and collagen disease (p = 2.29x10-3, enrichment = 23.8).
Conclusion: We found altered PBMC expression of multiple genes between revascularised patients presenting with ACS and CCS. Several differentially expressed genes included in cardiomyopathy pathways predicted long-term all-cause mortality in these patients.
Keywords: acute coronary syndrome, chronic coronary syndrome, peripheral mononuclear cells, transcriptomics, revascularisation outcome.