Abstract
SummaryIntroductionBody-mass index is a major determinant of left-ventricular-mass (LVM). Bariatric-metabolic surgery (BMS) reduces cardiovascular mortality. Its mechanism of action, however, often encompasses a weight-dependent effect. In this translational study, we aimed at investigating the mechanisms by which BMS leads to LVM reduction and functional improvement.MethodsTwenty patients (45.2 ± 8.5years) were studied with echocardiography at baseline and at 1,6,12 and 48 months after sleeve-gastrectomy (SG). Ten Wistar rats aged 10-weeks received high-fat diet ad libitum for 10 weeks before and 4 weeks after SG or sham-operation. An oral-glucose-tolerance-test was performed to measure whole-body insulin-sensitivity. Plasma metabolomics was analysed in both human and rodent samples. RNA quantitative Real-Time PCR and western blots were performed in rodent heart biopsies. The best-fitted partial-least-square discriminant-analysis model was used to explore the variable importance in the projection score of all metabolites.FindingsEchocardiographic LVM (-12%,-23%,-28% and -43% at 1,6,12 and 48 months, respectively) and epicardial fat decreased overtime after SG in humans while insulin-sensitivity improved. In rats, SG significantly reduced LVM and epicardial fat, enhanced ejection-fraction and improved insulin-sensitivity compared to sham-operation. Metabolomics showed a progressive decline of plasma branched-chain amino-acids (BCAA), alanine, lactate, 3-OH-butyrate, acetoacetate, creatine and creatinine levels in both humans and rodents.Hearts of SG rats had a more efficient BCAA, glucose and fatty-acid metabolism and insulin signaling than sham-operation. BCAAs in cardiomyocyte culture-medium stimulated lipogenic gene transcription and reduced mRNA levels of key mitochondrial β-oxidation enzymes promoting lipid droplet accumulation and glycolysis.InterpretationAfter SG a prompt and sustained decrease of the LVM, epicardial fat and insulin resistance was found. Animal and in vitro studies showed that SG improves cardiac BCAA metabolism with consequent amelioration of fat oxidation and insulin signaling translating into decreased intra-myocytic fat accumulation and reduced lipotoxicity.
Highlights
The prevalence of severe obesity (i.e., Body Mass Index, body mass index (BMI) 40 kg/m2) is progressively rising by exponential growth, reaching at present pandemic proportions
We have studied the cardiac function by colour Doppler/tissue Doppler imaging echocardiography before and at 1, 6, 12 and 48 months after sleeve gastrectomy (SG) in humans and at 1 month after SG or sham operation in high-fat diet (HFD) induced obesity in rats
At 1-year follow-up, body weight was reduced by 36% and weight loss maintained until the end of the study (-33%, (P < 0.0001 Holm-Bonferroni method), despite an approximate 10% weight regain by 48 months postoperatively
Summary
The prevalence of severe obesity (i.e., Body Mass Index, BMI 40 kg/m2) is progressively rising by exponential growth, reaching at present pandemic proportions. Obesity, which is generally associated with left ventricular (LV) hypertrophy,[2] is a primary risk factor for heart failure, both in men and in women.[3] obesity and, body fat distribution, are relevant in the process of myocardial remodelling. Epicardial fat is considered to be the heart-specific VAT, provided with overlapping properties and derivation. Epicardial fat is a highly metabolically active tissue, which has been suggested to exert protective functions over the cardio-metabolic system. Under pathological states, namely obesity and insulin resistance, its ability to balance the production of anti- and pro-inflammatory adipokines and bioactive molecules is altered, inducing impairment of endothelial function and detrimental changes on myocardial structure and activity.[4,5]
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