Welcome to the EAS 2023 Interactive Program

Background and Aims

Obesity is a main risk factor of atherosclerosis, characterized by excessive deposition of visceral white adipose tissue (vWAT). In obese humans increased calcium sensitivity may result in increased activation of the calcium-sensing-receptor (CaSR), thereby driving disease development. Genome wide association studies already demonstrated a correlation between diabetes, obesity and genetic variants of CaSR. Furthermore, recent in-vitro studies demonstrated that CaSR plays an important role in adipocyte-driven metabolic processes. Nevertheless, the exact role of adipocyte CaSR in-vivo remains elusive.

Methods

Adipocyte-specific CaSR-deficient mice (Adipoq^CreCaSR^floxAAV8-PCSK9) were fed an obesity diet (60% fat) for 12 weeks in order to provide new in-vivo insights into the function of adipocyte CaSR in AT inflammation and atherosclerosis development. Lipid levels were measured in the plasma, vWAT and liver and inflammatory cytokine in the plasma. Plaque size was evaluated in the aortic root.

Results

Adipocyte-specific CaSR deficiency in female mice led to a relative increase in vWAT weight. Interestingly, while circulating and liver lipid levels were elevated in female mice, no changes were observed in the lipid content of vWAT. However, the absence of adipocyte-CaSR resulted in a sharp decrease of the inflammatory cytokines IL-6, TNF-α and CCL2 in vWAT in both genders. Furthermore and in line with this anti-inflammatory AT phenotype, a trend towards less atherosclerotic plaque formation could be observed in adipocyte-specific CaSR deficient mice.

Conclusions

In conclusion, our findings indicate that adipocyte-specific CaSR increases inflammatory processes in AT in a mouse model of obesity, which seems to overrule effects and lipid levels and thereby exacerbates atherosclerosis development.

Background and Aims

Treatment with sodium-glucose co-transporter 2(SGLT2)-inhibitors reduces risk of cardiovascular disease and all-cause mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in SLC5A2, known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and all-cause mortality.

Methods

We examined 112,745 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS+CGPS), 488,682 from the UK Biobank, and 309,154 from FinnGen, all genotyped for SLC5A2 rs61742739,c.1961A>G; p.(Asn654Ser). First, we examined risk of cardiovascular disease and all-cause mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and all-cause mortality.

Results

In the CCHS+CGPS, carriers vs. non-carries had 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three included studies were lower risk by 10%, 9%, 7%, and 9%, respectively. Of the lower risks in CCHS+CGPS, lower plasma glucose mediated 2.0%(P=0.004) on heart failure, 3.1%(P=0.09) on myocardial infarction, 4.1%(P=0.02) on ischemic heart disease, and 6.0%(P=0.39) on all-cause mortality.

Conclusions

A functional genetic variant in SLC5A2, encoding SGLT2, was associated with lower risk of heart failure, myocardial infarction, ischemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose.

Background and Aims

Type 2 diabetes mellitus (T2DM) is a health problem, where coronary heart disease is the main cause of death. T2DM is associated with an increase in epicardial adipose tissue (EAT), physiological conditions with a buffer effect protecting the heart, pathological conditions that damage the vascular endothelium, inducing myocardial infarction.

Aims: To assess the association between EAT and high sensitivity c-reactive protein (hs-CRP) and lipoprotein levels in T2DM with preserved systolic function.

Methods

Observational, descriptive, cross-sectional study, 195 T2DM versus 110 controls, attended IMEDIX Dominican Republic, 2019 - 2021, began prior approval of the local ethics committee and signing of informed consent according to the Helsinki declaration of patients with inclusion criteria. and exclusion. Sociodemographic, anthropometric, biochemical, and echocardiographic characteristics were determined.

Results

T2DM had higher levels of: blood glucose (p=2.21e-08), glycosylated hemoglobin (HbA1c) (p=2.26e-06), LDL cholesterol (LDL-C) (p=0.0258), LDL-C/HDL-C ratio (p=0.0054), lower cholesterol HDL (HDL-C) (p=0.0349); echocardiographic behavior increased EAT (p=0.0003), higher indexed volume: left ventricular end-diastolic (p=0.0022) and end-systolic (p=0.0181), right atrium (RA) (p=0.0410), left atrium (LA) (p=0.0186), septum interventricular (p=0.0269), posterior wall (p=0.0454), ventricular mass (p=0.0005). Positive correlation between EAT thickness and triglyceride (TG) values (p=0.0008), hs-CRP (p=0.0083).

Conclusions

T2DM patients, non-hypertensive, Caribbean, with preserved systolic function, presented characteristics of Diabetic Cardiomyopathy; greater thickness of EAT in individuals up to 64 years of age, with BMI up to 29.9 kg/m2, waist/hip ratio for women ≥ 0.85, abdominal circumference for men ≥ 94 cm, plasma TG levels ≥ 301 mg/dL, remnant cholesterol (RC) ≤ 30 mg/dL, and hs-CRP > 2 mg/L.

Background and Aims

Serum lipids and metabolic diseases, in particular type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), predict the atherosclerotic diseases coronary artery disease (CAD) and peripheral arterial disease (PAD). However, it is not known in how far a more detailed characterization including serum lipids improves discrimination of PAD from CAD.

Methods

A cohort of 274 statin-naïve patients with either PAD (n = 89) or stable CAD (n = 185) were referred to metabolic screening and were characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry based advanced lipid and lipoprotein analysis. Results were validated in an independent cohort of 1239 patients with PAD or CAD.

Results

We found a significant difference in T2D prevalence and in the ceramide-based lipid profile between PAD and CAD patients. However, neither cholesterol-based markers (including LDL-C, HDL-C) and detailed lipoprotein profiles nor the NAFLD status differed significantly between PAD and CAD patients (figure). The difference between ceramide-based lipid profiles of CAD and PAD remained significant also after adjusting for body composition, smoking, inflammatory parameters, and T2D.

Conclusions

We conclude that PAD and CAD differ in ceramide-based lipid profiles and T2D status, but not in other lipid characteristics or metabolic diseases.

Background and Aims

Changing lifestyle behavior is the first-line treatment for cardiometabolic disorders. Though the health benefits of lifestyle modifications through weight loss have been recognized, little is known about the effect of weight loss on plasma lipidome. Here we aimed to determine (1) lipidomic signature of obesity, (2) alterations in lipidomic profiles with changes in adiposity measures in longitudinal cohort, and (3) reversibility of altered lipidomic profile in obesity by weight loss.

Methods

Lipidomic profiles (179 lipid species) for 4,488 individuals from Finnish GeneRISK cohort at baseline and ~1.5-year follow-up were measured by mass spectrometry-based analysis and differences between the two time-points were calculated after log2 transformation. P values <7.0´10^-4 (0.05/179) were considered significant.

Results

Obesity (BMI³30kg/m²) was associated with altered levels of 135 lipid species, with strong associations with cholesteryl esters, ceramides and triacylglycerides, and decrease in lysophospholipids and ether-linked phospholipids (Figure 1). Analyses of longitudinal data also showed that changes in BMI and waist circumference were associated with significant alterations in the lipidomic profiles (137 and 142 lipids, respectively). We further found that weight loss in obese individuals could change plasma levels of lipid species associated with obesity in favorable directions (Figure 1). Contrary to previous reports, we did not find major effect of baseline lipidome on the changes in adiposity measures.

Conclusions

The longitudinal study of lipidomic profiles demonstrate profound effect of changes in adiposity measures on lipidome and suggest that weight loss could lead to favorable lipidome profile, and hence could reduce risk for associated cardiometabolic disorders.