The role of SGLT2i in attenuating residual cardiovascular risk through blood pressure-lowering: mechanistic insights and perspectives

Sodium glucose cotransporter 2 inhibitors (SGLT2) have been increasingly pursued as a promising target for addressing residual cardiovascular risk. Prior trials demonstrated that SGLT2i not only promotes glucose-lowering, but also improves endothelial dysfunction, adiposity, fluid overload, and insulin sensitivity thus contributing to hemodynamic changes implicated in its cardiorenal benefits. The mechanisms in the effect of SGLT2i on blood pressure and their potential role in preventing cardiovascular events are hereby revised

Statin short-term inhibition of insulin sensitivity and secretion during acute phase of ST-elevation myocardial infarction

Hyperglycemia during myocardial infarction (MI) has a strong and direct association with mortality. In stable patients and experimental models, statins favor the elevation of glycaemia. The present study investigated whether short-course treatment with statins during MI can influence glucose homeostasis and thus the clinical outcome. In this prospective study, euglycemic hyperinsulinemic clamp (EHC) was performed at second (D2) and sixth (D6) day after MI in patients randomized to simvastatin (S)10 or 80 mg/day during hospitalization (n = 27). In addition, patients (n = 550) were treated without (WS) or with simvastatin (S) at 20, 40 or 80 mg/day had HOMA2S on admission (D1) and fifth (D5) day after MI. According to EHC, insulin sensitivity increased by 20 +/- 60% in S10 and decreased by -6 +/- 28% in S80 (p = 0.025). Consistently, the changes in HOMA2S between D1 and D5 were 40 +/- 145% (WS), 22 +/- 117% (S20), 16 +/- 61% (S40) and -2% +/- 88% (S80) (p = 0.001). In conclusion, statin during the acute phase of MI reduces insulin sensitivity in a dose-dependent manner.9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ301465/2017-

Omega-3 intake is associated with attenuated inflammatory response and cardiac remodeling after myocardial infarction

Myocardial infarction (MI) elicits an intense acute inflammatory response that is essential for cardiac repair. However, an excessive inflammatory response also favors myocardial apoptosis, cardiac remodeling, and cardiovascular mortality. Omega-3 polyunsaturated fatty acids (-3) bear anti-inflammatory effects, which may mitigate the inflammatory response during MI. This study investigated whether -3 intake is associated with attenuation of the MI-related inflammatory response and cardiac remodeling. ST-elevation MI (STEMI) patients (n=421) underwent clinical, biochemical, nutritional, 3D echocardiogram, Cardiac Magnetic Resonance imaging (CMRi) at 30 days and 3D echocardiogram imaging at six months after the MI. Blood tests were performed at day one (D1) and day five (D5) of hospitalization. Changes in inflammatory markers (D5-D1) were calculated. A validated food frequency questionnaire estimated the nutritional consumption and -3 intake in the last 3months before admission. The intake of -3 below the median (<1.7g/day) was associated with a short-term increase in hs-C-reactive protein [OR:1.96(1.24-3.10); p=0.004], Interleukin-2 [OR:2.46(1.20-5.04); p=0.014], brain-type natriuretic peptide [OR:2.66(1.30-5.44); p=0.007], left-ventricle end-diastolic volume [OR:5.12(1.11-23.52)]; p=0.036] and decreases in left-ventricle ejection fraction [OR:2.86(1.47-6.88); p=0.017] after adjustment for covariates. No differences were observed in the extension of infarcted mass obtained by CMRi. These findings suggest that a reduced daily intake of -3 may intensify outcome-determining mechanisms after STEMI, such as acute inflammatory response and late left ventricular remodeling.18CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ308550/2010-

Lower bone mass is associated with subclinical atherosclerosis, endothelial dysfunction and carotid thickness in the very elderly

Osteoporosis and coronary heart disease (CHD) are very common conditions among elderly people, and both represent a public health concern due to their prognostic consequences. Osteoporosis and CHD share many risk factors and pathophysiological mechanisms, such as calcification pathways. Clinical evidence associates lower bone mass with cardiovascular diseases and endothelial dysfunction. Hence, this study aims to investigate whether bone mass density is associated with subclinical atherosclerosis and/or endothelial dysfunction in the very elderly. We performed a cross-sectional study of cohort enrolled individuals, ages 80 years or older (n = 208), who had never manifested cardiovascular diseases. Medical evaluation, blood tests, flow-mediated dilation (FMD), carotid intimal-media thickness (IMT), Dual Energy X-ray Absorptiometry (DEXA) and Coronary Calcium Score (CCS) were obtained. Odds Ratio (OR) was calculated by multivariate logistic regression models using CCS, FMD and IMT categories. Adjustments for covariates were done. Overall bone mass was independently and inversely associated with CCS categories [OR:1.68(1.16–8.85); p = 0.024] and IMT categories [OR:2.97(1.11–7.90); p = 0.030]. Conversely, overall bone mass was independent and directly associated with FMD categories [OR:2.73(1.36–70.39); p = 0.023]. This study indicates that overall bone mass is independently and inversely associated with subclinical atherosclerosis, endothelial dysfunction and thickness of carotid in the very elderly2927074CNPQ - Conselho Nacional de Desenvolvimento Científico e Tecnológico301465/2017-

475 Genetic risk factors for drug-induced long QT syndrome: Findings from a large real-world clinical cohort.

OBJECTIVES/GOALS: The objective of this research was to determine the associations of candidate genetic variants withdrug-induced long QT syndrome (diLQTS) risk, an adverse effect of over 150 FDA-approved drugsthat can lead to cardiac arrhythmias and sudden cardiac death. METHODS/STUDY POPULATION: This was a retrospective observational study of the genomic biobank at the University of Michigan Health System. Patients treated with a high-risk QT-prolonging drug and ECG measurements were included. The primary outcome was exaggerated prolongation of the QTc interval (i.e., >60 ms change from baseline and/or >500 ms absolute value) corrected using Bazett. We analyzed 3 genetic variants: KCNE1-D85N (rs1805128), SCN5A-G615E (rs12720452) and KCNE2-I57T (rs7415448) in the dominant genetic model. A Bonferroni-corrected p-value of 0.017 was considered statistically significant using logistic regression adjusted for clinical covariates. RESULTS/ANTICIPATED RESULTS: In total 6,083 self-reported white patients were included (12% event rate). The adjusted odd ratio for KCNE1-D85N was 2.24 (95%CI: 1.35-3.57; p=0.0011). The adjusted odds ratio forKCNE2-I57T was 1.40 (95%CI: 0.26-5.78, p=0.662). Only 4 total patients carried the SCN5A-G615E variant, and none of the carriers had prolonged QTc. DISCUSSION/SIGNIFICANCE: This is the largest study of candidate genetic variants in cardiac ion channels associated with the diLQTS risk. KCNE1-D85N was associated with diLQTS risk, while KCNE2-I57T was suggestive of a potential association. KCNE1-D85N should be considered in clinical guidelines as a risk factor of diLQTS