BS decreases the risk of cardiovascular events by reducing the occurrence of metabolic disorders such as insulin resistance, impaired glucose tolerance, dysadipokinaemia, inflammation, and systemic lipotoxicity (including in the myocardium) 27. We hypothesised the existence of a link between changes in the profile of gastrointestinal hormones, leptin, and insulin after BS and a decrease in mortality from MI as a result of enhanced tolerance of the myocardium to ischaemia–reperfusion injury. In our study, an infarct-limiting effect and a decrease in the no-reflow phenomenon were observed in the SG and RYGB groups. We demonstrated, for the first time, that euglycemic rats subjected to SG and RYGB before the induction of MI through coronary artery ligation showed reduced MI size after ischaemia and reperfusion (by 22% and 10% of the risk zone, respectively) and a decrease in the area of no-reflow (by 38% and 32%, respectively) compared with the SHAM group. These effects did not depend on changes in body weight. Table 2 summarises the data on the effects of BS on myocardial tolerance to ischaemia–reperfusion injury and on the changes in the blood levels of several hormones with potential cardioprotective effects.
Decreased plasma ghrelin and leptin and increased GLP-1 levels were observed in post-BS rats. The rats in the SG and RYGB groups showed an increased postprandial glucose level, but only for a short period as rapid normalisation of the glucose level occurred 1 h after the OGTT. The increase in the glucose level at 30 min of the OGTT was accompanied by a significant increase in insulin secretion at 60 min, without subsequent hypoglycaemia after an hour of observation (at 120 min). All hormones analysed in this study can affect the function of the cardiovascular system and can be cardioprotective to varying degrees. Below, we will compare our findings with the literature data on the effects of various BS procedures on the levels of these hormones. We will also discuss evidence of their possible contributions to the cardioprotective effects of SG and RYGB.
Leptin
The decreased plasma level of leptin after BS restores leptin and insulin sensitivity and favourably affects the prognosis of patients with metabolic syndrome 28–30. It should be noted that data on the effect of leptin on myocardial ischaemia–reperfusion injury remain controversial 31. A number of studies reported that exogenous leptin decreased the infarct size when it was administered at the beginning of reperfusion of isolated mouse and rat hearts 32–34. Smith et al. showed that the cardioprotective effect of leptin is associated with the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, leading to a decrease in mitochondrial pore permeability. Inhibition of the JAK/STAT signalling pathway abolishes the leptin-induced cardioprotective effect 33. In 2010, Xu et al. showed that intraperitoneal administration of leptin 30 min before myocardial ischaemia–reperfusion in mice reduced reperfusion-induced inflammation and myocardial injury 35. Meanwhile, in 2018, Kain et al. demonstrated that postinfarction remodelling and myocardial dysfunction occurred due to mRNA overexpression of the leptin gene in cardiomyocytes 23. The negative effect of leptin on the processes of postinfarction remodelling was confirmed by experiments in rats through the inhibition of cardiac leptin expression 31,36. The authors showed that impairing leptin function in rats with acute MI led to reduced postinfarction remodelling. Chronically elevated leptin levels induced leptin resistance 37. In contrast, a high-fat/cholesterol diet-induced increase in leptin level was associated with decreased tissue sensitivity to leptin 38. In 2013, Nausheen et al. found that the blood levels of leptin in Sprague–Dawley rats were decreased by 57% after SG and by 59–72% after IT 39.
Our data indirectly suggest that a decrease in the plasma leptin level in post-BS rats might be involved in the reduction of infarct size and the no-reflow phenomenon in the SG and RYGB groups. In the present study, a comparable decrease in leptin was observed in the SG and RYGB groups; notwithstanding, in the IT group, in which a significant decrease in the infarction size was not obtained, the decrease in leptin (by 22%) was not significant. As the body weight of the animals did not change, the decrease in leptin levels in the present study was independent of body weight. Although the animals in our study did not have obesity, hyperleptinaemia, or systemic leptin resistance, we believe that the main mechanism of the cardioprotective effect of a reduced blood leptin level is increased sensitivity of the myocardium and vascular endothelium to leptin. It cannot be ruled out that a certain contribution is made by a redistribution between the signalling pathways of leptin and insulin, which have a number of common components. In this regard, it should be noted that insulin and leptin can both stimulate the insulin receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which is involved in the control of the survival and proliferative activity of various cell types.
Ghrelin
In alimentary obesity, ghrelin resistance is associated with hyperleptinaemia, whereas decreased body weight and leptin levels can restore ghrelin receptor sensitivity 40. The plasma ghrelin level after BS depends on the type of the anatomical modifications of the gastrointestinal tract and, possibly, the presence of postoperative vagus nerve dysfunction 41–43. In obese rats, it has been shown that SG leads to a significant decrease in ghrelin levels 44. In patients with T2DM, RYGB is more effective than SG and IT in reducing the acylated ghrelin levels 45. However, Chinese investigators have shown that SG is more effective than RYGB in reducing ghrelin levels in obese patients 42. It can be assumed that a decrease in the plasma levels of ghrelin and leptin after BS increases the sensitivity of ghrelin receptors. In the present study, the fasting ghrelin level was significantly reduced in the SG group compared with the CON and SHAM groups, whereas it was not significantly changed in the RYGB group (p = 0.08 and p = 0.06, respectively). In the RYGB and SG groups at 60 and 120 min of the OGTT, respectively, the decrease in the ghrelin level caused by glucose loading was more pronounced than that in the SHAM group. We showed that the overall course of the curves of plasma ghrelin levels in the SG and RYGB groups was lower than that in the control and SHAM groups. In the IT group, at 60 min of the OGTT, the changes in the plasma ghrelin level were smaller relative to the fasting ghrelin level, which indicates a slower ghrelin secretion in response to glucose stimulation. The cardioprotective properties of ghrelin have been proven in experimental and clinical studies 46–49. The administration of ghrelin during reperfusion improved myocardial contractility and reduced the infarct size of isolated rat hearts 16. Yang et al. administered ghrelin to rats in the early postinfarction period, which attenuated left ventricular remodelling and reduced the symptoms and severity of heart failure 50. The mechanisms of the cardioprotective action of ghrelin are mediated by the activation of the IRS/PI3K/AKT and AMP-activated protein kinase pathways 51,52 and a decrease in apoptosis 53. In our study, it is likely that the decrease in the plasma ghrelin level in SG and RYGB rats caused an increase in the sensitivity of ghrelin receptors in the heart, which contributed to increased myocardial tolerance to ischaemia–reperfusion.
GLP-1
GLP-1 is by far the most studied hormone in terms of cardiotropic effects in relation to the introduction of GLP-1 agonists and dipeptidyl peptidase-4 inhibitors into clinical practice 14–16. GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion, and exerts several extra-pancreatic effects owing to the presence of GLP-1 receptors in different cells, including endothelial and vascular smooth muscle cells 54, cardiomyocytes, and endocardial cells 54. Recently, Siraj et al. showed that the cardioprotective effect of GLP-1 may be due not to the direct interaction of this incretin with its membrane receptors but to the activation of the soluble form of adenylate cyclase in the smooth muscle and endothelial cells of coronary arteries, caused by the peptide GLP-1(28–36), a GLP-1 metabolite. This peptide is capable of penetrating vascular cells via macropinocytosis and interacts with mitochondrial trifunctional protein-α, through which it modulates the activity of soluble adenylate cyclase and cAMP-regulated effector proteins 55.
Several experimental and clinical studies have shown the ability of GLP-1 to reduce the severity of ischaemia–reperfusion injury 56,57, which is achieved through the activation of signalling pathways of ischaemic preconditioning 58. It has been previously reported that GLP-1 can attenuate (reperfusion-induced) oxidative stress and activate the RISK (reperfusion injury survival kinase) and SAFE (survivor-activating factor enhancement) signalling cascades 57, exerting a powerful cardioprotective effect through the inhibition of apoptosis and attenuation of cardiomyocyte necrosis 59. In our study, an increase in the fasting GLP-1 levels in the RYGB and SG groups was observed compared with the CON group. Hence, it can be assumed that RYGB and SG may have long-term effects on the myocardium in the form of preconditioning, as well as can change the entire profile of gastrointestinal hormones.
Ischaemic preconditioning has previously been shown to reduce the magnitude of the no-reflow phenomenon 60. We hypothesised that along with the infarct-limiting effect, increased GLP-1 secretion in animals after RYGB and SG can decrease the severity of the no-reflow phenomenon. A proof-of-concept study supporting our hypothesis showed the ability of the GLP-1 analogue liraglutide to reduce the no-reflow during percutaneous coronary intervention in patients with ST-elevation MI 61. Our study demonstrated for the first time that RYGB and SG reduced the severity of no-reflow. The protective effect of BS is most likely caused by the vasoprotective effect of GLP-1, which has oxidative stress-reducing, anti-inflammatory, and direct dose-dependent vasodilating effects 62.
On the basis of literature data, we hypothesized that IT would also lead to a pronounced increase in GLP-1 secretion 63,64. However, we observed that IT did not significantly affect the baseline GLP-1 level, and the operation itself was not effective in protecting against myocardial damage due to ischaemia and reperfusion. One of the possible reasons for this result is that we selected a model of normal euglycemic Wistar rats (specific pathogen-free [SPF] rats) without obesity and diabetes mellitus 64.
Insulin
Several recent clinical and experimental studies have demonstrated the important role of insulin in maintaining myocardial resistance to ischaemia–reperfusion, especially in the presence of diabetes mellitus or insulin resistance 65. Improvement of coronary perfusion, which protects cardiomyocytes from damage, has been reported as a potential cardioprotective mechanism of insulin through vasodilation and antiplatelet effects 66. The anti-inflammatory effect is realised by suppressing tumour necrosis factor-α (TNF-α) production 67 and is mediated through the activation of AKT protein kinase, which leads to a reduction in the size of the infarction and a decrease in myocardial contractile dysfunction. The suppression of inflammatory and oxidative stress–induced apoptosis upon the administration of insulin before ischaemia–reperfusion has been shown in in vitro and in vivo studies in the hearts of rabbits 68 and dogs 69. After the administration of insulin, a decrease in the size of necrosis was observed, along with an inhibition of apoptosis through the suppression of the activity of the pro-apoptotic enzyme caspase-3. Insulin administration caused a decrease in reperfusion injury through the activation of the protein kinase cascade, including PI3K, AKT, and p70-S6 kinase 70. In 2011, Yu et al. showed that insulin has a cardioprotective effect through the activation of IRS/PI3K/AKT/endothelial nitric oxide synthase signalling and increased nitric oxide production 71. On the basis of data showing that the cardioprotective effect of insulin in isolated rat hearts was blocked by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) protein kinase, it was concluded that mTOR is involved in the protective effects of the hormone 72.
After BS, amelioration or normalization of hyperglycaemia, which is caused by increased incretin production, occurs long before the achievement of a clinically significant weight loss 73. First, a few days after BS, an increase in insulin sensitivity in hepatocytes occurs against the background of nutrient intake deficiency. Peripheral insulin sensitivity increases later, together with a clinically significant weight loss, at 2–3 months after surgery, depending on the type of BS 74.
In animal models of congenital T2DM (Goto–Kakizaki rats) without obesity, SG and IT resulted in decreased body weight and glucose levels, as well as increased ghrelin and GLP-1 levels and insulin sensitivity 63. When IT was performed in animals without obesity and diabetes mellitus, decreased food intake and body weight, as well as increased insulin sensitivity were observed 64. Our data did not show significant changes in fasting insulin levels, although an increase was observed in the SG group 60 min after glucose loading in the OGTT. In contrast, in the IT group, decreased insulin release was observed compared with that in the CON and SHAM groups.
This study had several methodological limitations. First, we assessed changes in GLP-1, ghrelin, insulin, and leptin levels but did not analyse the levels of other humoral factors with putative cardioprotective and vasoprotective properties in the postoperative period, such as obestatin, adiponectin, and resistin. According to the literature, obestatin and adipokines (e.g., adiponectin and resistin) may exert cardioprotective effects in preclinical models of MI, and their levels are influenced by BS 13,75. Second, the mechanisms of the cardioprotective effect of BS were not investigated using pharmacological tools, such as the GLP-1 receptor antagonist exendin-α (9-39), in this study.