Studying the effect of bariatric surgery on the heart

The prevalence of obesity and therefore the number of overweight patients with associated cardiovascular diseases including hypertension, coronary heart disease and heart failure are rising worldwide. Bariatric surgery as a treatment option induces a long-lasting weight loss and has been shown to improve cardiac function and reduced cardiovascular risk factors. However, the underlying molecular mechanisms, their modulation via the entero-cardiac axis and the differences between the certain procedures are unknown. This project evaluated the influence of the procedures Rouxen-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and duodenojejunal bypass (DJB) on the cardiac gene and protein expression as well as on possible mechanisms of the entero-cardiac axis.

Wistar rats were fed a high fat diet (HFD) and randomly received a SG, RYGB or sham surgery. Sprague Dawley rats underwent a HFD and either a DJB or sham surgery. Postoperatively, the hearts of all animals were excised and analyzed by qPCR, Western blot and ELISA.

To test whether bariatric surgery improves cardiac function via the modulation of the adrenergic cascade, the expression levels of the adrenergic receptors and downstream enzymes that support (adenylate cyclases, AC) or limit (phosphodiesterases, PDE) the cascade were quantified. Bariatric surgery did not alter the expression of the adrenergic receptors. SG tended to increase the expression of AC5 and AC6, while the expression of PDE3A, PDE4A and PDE4C was significantly reduced. The results indicated that SG might increase the level of the second messenger cyclic adenosine monophosphate (cAMP) in the heart. However, the cAMP levels detected by ELISA were significantly reduced after SG.

The expression of important genes in glucose and lipid metabolism was quantified to examine whether there is an association between the improved heart function following bariatric surgery and cardiac metabolism. SG enhanced the expression of the cellular fatty acid transport protein 1 significantly and tended to induce a higher expression of fatty acid translocase, which might cause a higher fatty acid uptake. RYGB significantly reduced the expression of the beta oxidation enzyme medium-chain acyl-CoA dehydrogenase and tended to reduce the expression of its transcription factor peroxisome proliferator-activated receptor gamma coactivator 1alpha, which might indicate a suppressed lipid metabolism. The procedures did not affect the expression of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 1.

DJB enhanced the expression of the cellular glucose transporter 1 (Glut1) significantly and tended to increase the expression of hexokinase 2, a kinase involved in glycolysis. The enzyme phosphoenolpyruvate carboxykinase catalyzes the first step of gluconeogenesis and was significantly reduced after DJB. These modulations could show an elevated cardiac glucose uptake and metabolism after DJB. Furthermore, the protein expression of glycogen synthase kinase-3beta, an enzyme contributing to glycogen synthesis, was also significantly increased.

In contrast, SG decreased Glut1 expression significantly, but none of the procedures affected the glucose transporter on protein level. RYGB did not influence the expression of genes involved in glucose metabolism. In addition, the expression of glucose transporter 4 and of glucose-6-phosphate dehydrogenase, a rate-limiting enzyme within the pentose phosphate pathway, was not altered by bariatric surgery.

To analyze the modulation of the entero-cardiac axis, the expression of genes mediating the signaling pathways of the gastrointestinal hormones glucagon-like peptide 1 (GLP1) and insulin was quantified. The protein expression of the GLP1 receptor and its coupled mitogen-activated protein kinase 12 was not altered in heart tissues after all bariatric interventions. However, SG tended to decrease the mitogen-activated protein kinase p42/44 protein expression, an enzyme involved in insulin signaling. The transcription factor forkhead box protein 1, which is regulated by insulin, was also not affected by bariatric surgery.

Bariatric surgery procedures affect adrenergic signaling and cardiac metabolism on the molecular level. The interventions led according to the manipulation of the stomach and/or the intestine to opposite modulations of cardiac glucose and lipid utilization. The entero-cardiac axis seems to be influenced by additional mechanisms beside the GLP1 and insulin signaling pathway.