T2D triggers distinct cardiac transcriptomic signatures in patients with severe aortic stenosis
Authors: Cherpaz M , Meugnier E , Seillier G , Le Dantec G , Bergerot C , Pozzi M , Pierrard R , Chalabreysse L , May C , Farhat F , Vola M , Obadia J F , Amaz C , Paillard M , Thibault H 
Published: November 2023

Abstract
Type 2 diabetes (T2D) is often associated to left ventricular (LV) pressure overload, as in aortic stenosis (AS). We reported, on DIAPASON cohort, that T2D increases adverse cardiac remodelling and dysfunction in patients with severe AS referred for aortic valve replacement. We aimed to study the underlying molecular mechanisms by a transcriptomic approach.
We realised a transcriptomic analysis of LV cardiac biopsies obtained during aortic valve surgery from 17 T2D and 30 non-diabetic patients. Principal component analysis (PCA), on the 1029 significantly differentially expressed genes, shows a general segregation between T2D and non-diabetic patients. Functional enrichment maps reveal that 4 major biological processes are upregulated in T2D patients: regulation of inflammation, adaptation to cardiac hypertrophy, regulation of endothelial function/angiogenesis, and organisation of extracellular matrix. Decreased gene expression by T2D gathers 4 major biological processes: regulation of cardiac muscle contraction, mitochondrial organization, organization of mitochondrial respiratory chain and amino acid metabolism. After adjustment with other T2D comorbidities (age, sex, hypertension, BMI or the 4 combined), T2D effect remains mainly significant on the upregulated biological processes whereas the downregulation of amino acid metabolism, regulation of cardiac muscle contraction and mitochondrial transport processes seems to depend on hypertension and age.
As an overlap was still present between T2D and non-diabetics transcriptomes in the PCA, we decided to use Factor Analysis of Mixed Data to identify potential subgroups of patients among the whole cohort. 84 patients have been clustered into 3 groups. Cluster 1 is associated with a patient profile without T2D and displaying a mild cardiac dysfunction, contrary to cluster 3 which includes mainly male T2D patients with a pronounced structural and functional cardiac alteration. Cluster 2 is only composed of female patients with higher BMI and leptin serum level, diastolic alteration and a moderately increased hypertrophy. Biological processes were differently affected between cluster 1 and cluster 2 or 3. Cluster 2 presents a decrease in gene expression involved in histone and protein demethylation. As for cluster 3, the expression of genes involved in immune response processes is increased while the one for the regulation of cardiac muscle organisation is decreased. To conclude, T2D is specifically associated with a reduction of gene expression involved in mitochondrial function, and an upregulation of angiogenesis, inflammation, and organisation of extracellular matrix. The unsupervised analysis revealed different clusters with specific gene expression and more specifically an association of female sex and metabolic syndrome with demethylation processes, and an association of T2D in men with inflammation and dysregulation of cardiac muscle contraction processes.Biological process in T2D patients