Specific biological processes associated with T2D-induced left ventricular dysfunction in patients with aortic stenosis pressure overload

Methods

We combined a profound clinical and echocardiography phenotype of patients with severe AS+/-T2D (without overt heart disease) referred for a valve replacement with histolog-ical and transcriptomic analyses of an intra-operative myocardial LV biopsy and ELISA measurement of circulating levels of different biomarkers. Results: 84 patients, including 34 with T2D, were included with median age (67 YO), and 38% were females.

Hypertension (p<0.01) and dyslipidemia (p<0.01) coexisted more frequently in T2D patients. T2D patients had greater BMI (p<0.01) and BSA (p=0.034). T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics.

At the tissue level, T2D was associated with worse cardiomyocyte hypertrophy and apoptosis with a structural reticulum-mitochondria Ca2+ uncoupling. Regarding metabolic biomarkers, leptin and FABP3 were significantly increased in T2D patients compared to non-diabetics, correlating respectively with diastolic dysfunction and hypertrophy. Endothelin-1 was also significantly increased in the T2D group and associated with hypertrophy and systolic dysfunction.

Importantly, in agreement with the myocardial analyses, inflammatory and fibrotic circulating markers were not different between groups. Regarding the transcriptomic analysis, the upregulated pathways in T2D gathered regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy and remained T2D-specific despite comorbidity adjustment. Gene sets downregulated in T2D patients were related to mitochondrial respiratory chain organization/function, mitochondrial organization, amino acid metabolism, and regulation of muscle contraction.

The mitochondrial respiratory chain process and mitochondrial organization were independently associated with T2D, while the other downregulated pathways were no longer significantly associated with T2D after adjusting for covariates. Conclusion: Increased adverse LV remodeling and dysfunction in T2D with severe AS is associated with specific processes which may lead to potential therapeutic targets.