Association of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i) with Cardiac Arrhythmias: A Systematic Review and Meta-Analysis of Cardiovascular Outcome Trials

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of widely used hypoglycemic agents for the treatment of type 2 diabetes mellitus (T2DM). In addition to lowering blood glucose, SGLT2i protects the heart and kidney, significantly reduces cardiovascular events, and delays the progression of heart failure and chronic kidney disease. However, previous studies have not exhaustively discussed the association between SGLT2i and the risk of developing cardiac arrhythmias. The purpose of this study is to assess the association of SGLT2i with cardiac arrhythmias in patients with T2DM and without T2DM in cardiovascular outcome trials (CVOTs). Methods: We performed a meta-analysis and systematic review of CVOTs that compared SGLT2i with placebo. MEDLINE, Web of Science, The Cochrane Library and Embase were systematically searched from inception to December 2022. We included CVOTs reporting cardiovascular or renal outcomes with a follow-up duration of at least 6 months. Results: A total of 12 CVOTs with 77,470 participants were included in this meta-analysis (42,016 SGLT2i vs 35,454 control), including patients with T2DM, heart failure (HF), or chronic kidney disease (CKD). Follow-up duration ranged from 9 months to 5.65 years. Medications included empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. SGLT2i were associated with a lower risk of tachycardia (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.79–0.95), supraventricular tachycardia (SVT; RR 0.84; 95% CI 0.75–0.94), atrial fibrillation (AF; RR 0.86; 95% CI 0.75–0.97) and atrial flutter (AFL; RR 0.75; 95% CI 0.57–0.99) in patients with T2DM, HF and CKD. SGLT2i could also reduce the risk of cardiac arrest in CKD patients (RR 0.50; 95% CI 0.26–0.95). Besides, SGLT2i therapy was not associated with a lower risk of ventricular arrhythmia and bradycardia. Conclusions: SGLT2i therapy is associated with significantly reduced the risk of tachycardia, SVT, AF, and AFL in patients with T2DM, HF, and CKD. In addition, SGLT2i could also reduce the risk of cardiac arrest in CKD patients. Further researches are needed to fully elucidate the antiarrhythmic mechanism of SGLT2i

Unimodal and multimodal regions for logographic language processing in left ventral occipitotemporal cortex

The human neocortex appears to contain a dedicated visual word form area (VWFA) and an adjacent multimodal (visual/auditory) area. However, these conclusions are based on functional magnetic resonance imaging (fMRI) of alphabetic language processing, languages that have clear grapheme-to-phoneme correspondence (GPC) rules that make it difficult to disassociate visual-specific processing from form-to-sound mapping. In contrast, the Chinese language has no clear GPC rules. Therefore, the current study examined whether native Chinese readers also have the same VWFA and multimodal area. Two cross-modal tasks, phonological retrieval of visual words and orthographic retrieval of auditory words, were adopted. Different task requirements were also applied to explore how different levels of cognitive processing modulate activation of putative VWFA-like and multimodal-like regions. Results showed that the left occipitotemporal sulcus responded exclusively to visual inputs and an adjacent region, the left inferior temporal gyrus, showed comparable activation for both visual and auditory inputs. Surprisingly, processing levels did not significantly alter activation of these two regions. These findings indicated that there are both unimodal and multimodal word areas for non-alphabetic language reading, and that activity in these two word-specific regions are independent of task demands at the linguistic level

Localized‐domains staging structure and evolution in lithiated graphite

Abstract Intercalation provides to the host materials a means for controlled variation of many physical/chemical properties and dominates the reactions in metal‐ion batteries. Of particular interest is the graphite intercalation compounds with intriguing staging structures, which however are still unclear, especially in their nanostructure and dynamic transition mechanism. Herein, the nature of the staging structure and evolution of the lithium (Li)‐intercalated graphite was revealed by cryogenic‐transmission electron microscopy and other methods at the nanoscale. The intercalated Li‐ions distribute unevenly, generating local stress and dislocations in the graphitic structure. Each staging compound is found macroscopically ordered but microscopically inhomogeneous, exhibiting a localized‐domains structural model. Our findings uncover the correlation between the long‐range ordered structure and short‐range domains, refresh the insights on the staging structure and transition of Li‐intercalated/deintercalated graphite, and provide effective ways to enhance the reaction kinetic in rechargeable batteries by defect engineering

Elevated <i>OPRD1</i> promoter methylation in Alzheimer’s disease patients

<div><p>Aberrant DNA methylation has been observed in the patients with Alzheimer’s disease (AD), a common neurodegenerative disorder in the elderly. <i>OPRD1</i> encodes the delta opioid receptor, a member of the opioid family of G-protein-coupled receptors. In the current study, we compare the DNA methylation levels of <i>OPRD1</i> promoter CpG sites (CpG1, CpG2, and CpG3) between 51 AD cases and 63 controls using the bisulfite pyrosequencing technology. Our results show that significantly higher CpG3 methylation is found in AD cases than controls. Significant associations are found between several biochemical parameters (including HDL-C and ALP) and CpG3 methylation. Subsequent luciferase reporter gene assay shows that DNA fragment containing the three <i>OPRD1</i> promoter CpGs is able to regulate gene expression. In summary, our results suggest that <i>OPRD1</i> promoter hypermethylation is associated with the risk of AD.</p></div

Characteristics of AD cases and controls ^a^, ^b.

<p>Characteristics of AD cases and controls <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172335#t001fn001" target="_blank">^a</a>^, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172335#t001fn002" target="_blank">^b</a>.</p

Schematic visualization of <i>OPRD1</i> and correlation of methylation levels among three CpG sites*.

<p>*: F, R, and S stand for forward, reverse, and sequencing primers, respectively.</p

Effects of <i>OPRD1</i> promoter region on transcription activity*.

<p>*<i>OPRD1</i> (CpGs) stands for the fragment containing the pyrosequenced sequence. The pGL3-Basic as negative control and pGL3-Promoter vector as positive control are used. pRL-SV40 vector as an internal control receptor is used to normalize the differences in transfection efficiency. Relative luciferase activity is measured in triplicates.</p