Impact of left ventricular assist device therapy on the cardiac proteome and metabolome composition in ischemic cardiomyopathy

Abstract

The changes in the myocardial proteome and metabolome associated with left ventricular assist device (LVAD) therapy in patients with ischemic cardiomyopathy (ICM) are poorly characterized. We investigated the impact of mechanical unloading following LVAD therapy on the myocardial proteome and metabolome. Matched samples of 5 patients’ myocardial tissue, harvested at the time of LVAD implant (“pre‐LVAD”) or heart transplant (“post‐LVAD”), were studied by quantitative proteomics and metabolomics as well as being probed for T‐tubule structure and connexin‐43 distribution. Moreover, pre‐LVAD proteome profiles of ICM context were bioinformatically compared to pre‐LVAD proteome profiles of dilated cardiac myopathy (DCM). More than 2120 proteins were reliably identified and quantified in paired patient samples. LVAD therapy led to proteomic remodeling, including reduced levels of α‐1‐antichymotrypsin together with an overall decrease of immune response proteins and an increase of proteins involved in membrane biology. Metabolomics highlighted increased glucose and glucose‐6‐phosphate levels in the left ventricle upon LVAD therapy. Wheat germ agglutinin staining demonstrated improved T‐tubule structure. Connexin‐43 displayed a trend for more pronounced intercalated disc localization. In comparing pre‐LVAD proteome profiles of ICM context with pre‐LVAD proteome profiles of dilated cardiac myopathy (DCM), we noticed an overrepresentation in ICM of proteins associated with humoral immune response. Our findings underline an impact of LVAD therapy on left ventricular biology in ICM. The proteomic, metabolomic, and structural alterations described here are typically associated with cardiac recovery. On the molecular level, our findings indicate the possibility of cardiac remodeling under LVAD therapy in ICM.

Myocardial Remodeling with Ventricular Assist Devices

“…These metabolic improvements enhanced the glycosylation of α-dystroglycan, which maintains integrity between cytoskeleton and ECM [18]. Moreover, using high-resolution respirometry, a reduction in mitochondrial ROS up to 40% [153] and increased MPC1 abundance and glucose and glucose-6-phosphate levels, particularly, in mechanically unloaded hearts of ischemic HF patients has been demonstrated [154].…”

Mitochondrial Metabolism in Myocardial Remodeling and Mechanical Unloading: Implications for Ischemic Heart Disease

“…Except for glucose oxidation, the metabolites of glycolysis may be channeled to accessory pathways of glycolysis. Clinically, LVAD implantation enhances levels of glucose and glucose-6-phosphate in patients with ICM ( 149 ). Compared with post-LVAD non-responders, rate-limiting enzymes of PPP and one-carbon metabolism, which protect myocardium through producing NADPH to promote biosynthesis and antagonizing oxidative stress, are significantly increased in post-LVAD responders ( 150 ).…”

Metabolomic profile of patients with left ventricular assist devices: a pilot study

“…To date, data regarding the metabolic profile of chronic HF patients who receive mechanical circulatory support with left ventricular assist devices (LVADs) are scarce. Shahinian et al reported proteome remodeling associated with post-LVAD cardiac remodeling in patients with ischemic cardiomyopathy (8). Weitzel et al measured different cardiac metabolites in failing hearts post-LVAD support, and showed that while metabolites related to glucose metabolism recovered their values post-LVAD, amino acid levels, creatine, and the citric acid cycle intermediate succinate, did not show a similar pattern (9).…”