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Diabetic ischaemic cardiomyopathy: Characterising the left ventricular myocardial molecular profile in advanced human heart failure

ABSTRACT: Ischaemic cardiomyopathy (ICM) is the most common cause of heart failure (HF) and often coexists with diabetes mellitus (DM). Yet, their combined effects are seldom investigated and are poorly understood. Herein, we performed multi-omic analyses of end-stage ICM with DM (ICM-DM) against ICM-No DM, non-ischaemic (dilated) cardiomyopathy with DM (NICM-DM), NICM-No DM, and healthy age-matched donors (AMD). Tissue was sourced from pre-mortem human left ventricular myocardium. Though fatty acid oxidation (FAO) proteins were down-regulated in ICM-DM relative to AMD and other HF, the unique ICM-DM down-regulation of acylcarnitines, perilipin, and ketone body, amino acid, and glucose metabolising proteins indicated FAO may not be entirely impaired. Oxidative phosphorylation appeared reduced in HF but exacerbated in ICM-DM, consistent with purportedly increased oxidative stress. Extracellular matrix proteins including collagens were up-regulated principally in ICM-DM despite the absence of macroscopic scar tissue. These findings were supported histologically and in metabolomic and RNA sequencing analyses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263297 | GEO | 2025/04/04

REPOSITORIES: GEO

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Project description:Background: Lamins A/C (encoded by the LMNA gene) can lead to dilated cardiomyopathy (DCM). Objectives: This study sought to undertake proteomic analysis of myocardial tissue to explore the postgenomic phenotype of end-stage lamin heart disease. Methods: Consecutive patients with end-stage lamin heart disease (LMNA-group, n=7) and ischaemic DCM (ICM-group, n=7) undergoing heart transplantation were enrolled. Samples were obtained from left atrium(LA), left ventricle(LV), right atrium(RA), right ventricle(RV) and interventricular septum(IVS). Liquid chromatography combined with mass-spectrometry was used for protein quantification. We compared protein concentrations in cardiac samples between LMNA and ICM groups. Proteins were considered differentially abundant if the quantitative difference was 1.5-fold and corrected p-value <0.05 at a false discovery rate of 0.01. Gene ontology(GO) enrichment analysis explored the related biological processes. Results: 4,247 proteins were identified in LMNA and ICM samples, of which 633 were differentially abundant in LA, 39 in LV, 181 in RA, 52 in RV, and 85 in IVS. Abundance of lamin A/C was reduced but lamin B (LMNB) increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM while sarcomeric proteins such as titin and cardiac myosin heavy chain were generally reduced in RA/LA of LMNA. Protein expression profiling and GO enrichment analysis revealed sarcopenia, extracellular matrix(ECM) remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Conclusion: Lamin heart disease is a biventricular and biatrial disease, characterized by sarcopenia, aberrant metabolism, and ECM remodeling. LMNB and transthyretin were unexpectedly abundant in the atria and ventricles respectively of patients with end-stage lamin heart disease potentially hinting to the possibility of compensatory responses.

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Diabetic ischaemic cardiomyopathy: Characterising the left ventricular myocardial molecular profile in advanced human heart failure

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