Multimorbidity increases susceptibility to myocardial injury following cardiac surgery via dysregulated macrophage activation and the development of a cardiomyopathy phenotype

BackgroundThis study investigated mechanisms underlying the association between multimorbidity (MM) and increased susceptibility to myocardial injury and organ failure following cardiac surgery.

MethodsK-means clustering was performed using data from five cardiac surgery cohorts with high prevalence of MM. The resulting Clusters were explored using single nuclei RNA sequencing (snRNAseq) of atrial biopsies collected at surgery from one of the study cohorts. Mechanisms were validated using causal inference methods in UK Biobank and aged cardiomyocytes exposed to ischaemia reperfusion injury (IRI) in vitro.

ResultsK-means clustering using pre-surgery biomarkers of haematopoietic, cardiac, metabolic, liver, and renal disease identified two MM clusters. Cluster 1, characterised by higher baseline troponin I and interleukin-6 values, iron deficiency, anaemia, and immunological ageing, demonstrated significantly higher rates of myocardial injury (66% versus 52%) and multiple organ dysfunction (81% versus 57%) relative to Cluster 2.

snRNAseq data from Cluster 1 demonstrated inflammageing characterised by enrichment for cardiomyopathy networks in cardiomyocytes, NF-kB and IL2 in monocyte derived macrophages (MDM), and pro-fibrotic and redox inflammation signaling in tissue resident macrophages (TRM). Cluster 2 showed enrichment for translation and type 1 immune activation in cardiomyocytes and MDM and trans-differentiation genes in TRM.

In UK Biobank, genetic modification of genes differentially expressed between clusters altered 90-day mortality post-surgery. Gene silencing of key regulatory nodes enriched in Cluster 1 cardiomyocytes including GATA4 (dedifferentiation) and ERBB3 (mTOR), attenuated cardiomyocyte de-differentiation and susceptibility to IRI in vitro.

ConclusionsInflammageing associated cardiomyocyte dedifferentiation represents a target for myocardial protection in people with MM.

Study Schematic

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org.highwire.dtl.DTLVardef@14563aaorg.highwire.dtl.DTLVardef@926c19org.highwire.dtl.DTLVardef@f6fb59org.highwire.dtl.DTLVardef@efc2d1_HPS_FORMAT_FIGEXP M_FIG C_FIG MaRACAS, the Observational Case Control Study to Identify the Role of MV and MV Derived Micro-RNA in Post CArdiac Surgery AKI, REVAKI-2, Revatio(R) for the Prevention of AKI -2 trial, REDWASH, Red Cell washing for the Prevention of Organ Injury after Cardiac Surgery Trial, OBCARD, the Case Control Study to Identify the Role of Epigenetic Regulation of Genes Responsible for Energy Metabolism and Mitochondrial Function in the Obesity Paradox in Cardiac Surgery, COPTIC, the Coagulation and Platelet Laboratory Testing in Cardiac Surgery study.