Impact of SGLT2 Inhibitors on AF Recurrence After Catheter Ablation in Patients With Type 2 Diabetes.

BACKGROUND: The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) on recurrent atrial fibrillation (AF) among patients undergoing catheter ablation is not well described. OBJECTIVES: This study sought to assess the impact of SGLT2-Is on the recurrence of AF among patients with type 2 diabetes mellitus (DM) after catheter ablation. METHODS: Using the TriNetX research network, we identified, by means of Current Procedural Terminology codes, patients ≥18 years of age with type 2 diabetes mellitus (DM) who had undergone AF ablation from April 1, 2014, to November 30, 2021. Patients were stratified based on the baseline SGLT2-I use. Propensity-score matching resulted in 2,225 patients in each cohort. The primary outcome was a composite of cardioversion, new antiarrhythmic drug (AAD) therapy, or re-do AF ablation after a blanking period after the index ablation. Additional outcomes included heart failure exacerbations, ischemic stroke, all-cause hospitalization, and death during 12 months of follow-up. RESULTS: SGLT2-I use in patients with type 2 DM undergoing AF ablation was associated with a significantly lower risk of cardioversion, new AAD therapy, and re-do AF ablation (adjusted OR: 0.68; 95% CI: 0.602-0.776; P < 0.0001). At 12 months, patients on SGLT2-Is had a higher probability of event-free survival (HR: 0.85, 95% CI: 0.77-0.95; log-rank test chi-square = 8.7; P = 0.003). All secondary outcomes were lower in the SGLT2I group; however, the ischemic stroke did not differ between groups. CONCLUSIONS: Use of SGLT2-Is in patients with type 2 DM is associated with a lower risk of arrhythmia recurrence after AF ablation and thence a reduced need for cardioversion, AAD therapy, or re-do AF ablation.

Comprehensive multiomics and in silico approach uncovers prognostic, immunological, and therapeutic roles of ANLN in lung adenocarcinoma.

The anillin actin-binding protein (ANLN) is immensely overexpressed in cancers, including lung cancer (LC). Phytocompounds have gained interest due to their broader potential and reduced unwanted effects. Screening numerous compounds presents a challenge, but in silico molecular docking is pragmatic. The present study aims to identify the role of ANLN in lung adenocarcinoma (LUAD), along with identification and interaction analysis of anticancer and ANLN inhibitory phytocompounds followed by molecular dynamics (MD) simulation. Using a systematic approach, we found that ANLN is significantly overexpressed in LUAD and mutated with a frequency of 3.73%. It is linked with advanced stages, clinicopathological parameters, worsening of relapse-free survival (RFS), and overall survival (OS), pinpointing its oncogenic and prognostic potential. High-throughput screening and molecular docking of phytocompounds revealed that kaempferol (flavonoid aglycone) interacts strongly with the active site of ANLN protein via hydrogen bonds, Vander Waals interactions, and acts as a potent inhibitor. Furthermore, we discovered that ANLN expression was found to be significantly higher (p) in LC cells compared to normal cells. This is a propitious and first study to demonstrate ANLN and kaempferol interactions, which might eventually lead to removal of rout from cell cycle regulation posed by ANLN overexpression and allow it to resume normal processes of proliferation. Overall, this approach suggested a plausible biomarker role of ANLN and the combination of molecular docking subsequently led to the identification of contemporary phytocompounds, bearing symbolic anticancer effects. The findings would be advantageous for pharmaceutics but require validation using in vitro and in vivo methods. HIGHLIGHTS: • ANLN is significantly overexpressed in LUAD. • ANLN is implicated in the infiltration of TAMs and altering plasticity of TME. • Kaempferol (potential ANLN inhibitor) shows important interactions with ANLN which could remove the alterations in cell cycle regulation, imposed by ANLN overexpression eventually leading to normal process of cell proliferation.

Biochemical and structural characterization of a robust and thermostable ascorbate recycling monodehydroascorbate reductase (MDHAR) from stress adapted pearl millet.

Ascorbate (AsA) is a crucial antioxidant in plants, and its recycling is necessary for protecting cells from oxidative damage and imparting stress tolerance. The monodehydroascorbate reductase (MDHAR) enzyme of the ascorbate-glutathione pathway plays a vital role in recycling AsA from monodehydroascorbate (MDHA) radical. Pennisetum glaucum (Pg), also known as pearl millet, is known to be more tolerant to abiotic stress than other food crops, such as rice. However, the contribution of MDHAR from this sessile plant to its unique stress tolerance mechanism is not well understood. In this study, we isolated a gene encoding the MDHAR enzyme from heat stress-adapted pearl millet and characterized it using enzyme kinetics, thermal stability assays, and crystal structure determination. Our results indicate that PgMDHAR is a more robust enzyme than its rice counterpart (Oryza sativa; Os). We solved the crystal structure of PgMDHAR at 1.8 Å and found that the enzyme has a more compact structure and greater stability than OsMDHAR. Using hybrid quantum mechanics and molecular mechanics calculations, we demonstrate that the structure of PgMDHAR contributes to increased stability towards bound FAD. Overall, the higher structural stability and affinity for NADH demonstrated by PgMDHAR are expected to impart improved stress tolerance. Our findings suggest that transgenic food crops expressing MDHAR from stress-adapted pearl millet may exhibit better tolerance to oxidative stress in the unpredictable climatic conditions prevalent today.

Mechanistic Insight into the Enzymatic Inhibition of ß-Amyrin against Mycobacterial Rv1636: In Silico and In Vitro Approaches.

Mycobacterium tuberculosis has seen tremendous success as it has developed defenses to reside in host alveoli despite various host-related stress circumstances. Rv1636 is a universal stress protein contributing to mycobacterial survival in different host-derived stress conditions. Both ATP and cAMP can be bound with the Rv1636, and their binding actions are independent of one another. ß-Amyrin, a triterpenoid compound, is abundant in medicinal plants and has many pharmacological properties and broad therapeutic potential. The current study uses biochemical, biophysical, and computational methods to define the binding of Rv1636 with ß-Amyrin. A substantial interaction between ß-Amyrin and Rv1636 was discovered by molecular docking studies, which helped decipher the critical residues involved in the binding process. VAL60 is a crucial residue found in the complexes of both Rv1636_ß-Amyrin and Rv1636-ATP. Additionally, the Rv1636_ß-Amyrin complex was shown to be stable by molecular dynamics simulation studies (MD), with minimal changes observed during the simulation. In silico observations were further complemented by in vitro assays. Successful cloning, expression, and purification of Rv1636 were accomplished using Ni-NTA affinity chromatography. The results of the ATPase activity assay indicated that Rv1636's ATPase activity was inhibited in the presence of various ß-Amyrin concentrations. Additionally, circular dichroism spectroscopy (CD) was used to examine modifications to Rv1636 secondary structure upon binding of ß-Amyrin. Finally, isothermal titration calorimetry (ITC) advocated spontaneous binding of ß-Amyrin with Rv1636 elucidating the thermodynamics of the Rv1636_ß-Amyrin complex. Thus, the study establishes that ß-Amyrin binds to Rv1636 with a significant affinity forming a stable complex and inhibiting its ATPase activity. The present study suggests that ß-Amyrin might affect the functioning of Rv1636, which makes the bacterium vulnerable to different stress conditions.

Exploring the druggability of oxidized low-density lipoprotein (ox-LDL) receptor, LOX-1, a proatherogenic drug target involved in atherosclerosis.

Lectin-like oxidized low-density lipoprotein (ox-LDL) receptor 1 (LOX-1) is a vital scavenger receptor involved in ox-LDL binding, internalization, and subsequent proatherogenic signaling leading to cellular dysfunction and atherosclerotic plaque formation. Existing data suggest that modulation of ox-LDL - LOX-1 interaction can prevent or slow down atherosclerosis. Therefore, we utilized computational methods such as multi-solvent simulation and characterized two top-ranked druggable sites. Using systematic molecular docking followed by atomistic molecular dynamics simulation, we have identified and shortlisted small molecules from the NCI library that target two key binding sites. We demonstrate, using surface plasmon resonance (SPR), that four of the shortlisted molecules bind one-on-one to the purified C-terminal domain (CTLD) of LOX-1 receptor with high affinity (KD), ranging from 4.9 nM to 20.1 µM. Further, we performed WaterMap analysis to understand the role of individual water molecules in small molecule binding and the LOX-1-ligand complex stability. Our data clearly show that LOX-1 is druggable with small molecules. Our study provides strategies to identify novel inhibitors to attenuate ox-LDL - LOX-1 interaction.

Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro.

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with zinc demonstrate better clinical outcomes. The molecular targets and mechanistic details of the anti-coronaviral activity of zinc remain obscure. We show that zinc not only inhibits the SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of the Mpro-Zn2+ complex at 1.9 Å and provide the structural basis of viral replication inhibition. We show that Zn2+ coordinates with the catalytic dyad at the enzyme active site along with two previously unknown water molecules in a tetrahedral geometry to form a stable inhibited Mpro-Zn2+ complex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn2+. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn2+ mediated inhibition of Mpro may have wider implications.

Analyzing the vocal tract characteristics for out-of-breath speech.

In this work, vocal tract characteristic changes under the out-of-breath condition are explored. Speaking under the influence of physical exercise is called out-of-breath speech. The change in breathing pattern results in perceptual changes in the produced sound. For vocal tract, the first four formants show a lowering in their average frequency. The bandwidths BF1 and BF2 widen, whereas the other two get narrowed. The change in bandwidth is small for the last three. For a speaker, the change in frequency and bandwidth may not be uniform across formants. Subband analysis is carried out around formants for comparing the variation of the vocal tract with the source. A vocal tract adaptive empirical wavelet transform is used for extracting formant specific subbands from speech and source. The support vector machine performs the subband-based binary classification between the normal and out-of-breath speech. For all speakers, it shows an F1-score improvement of 4% over speech subbands. Similarly, a performance improvement of 5% can be seen for both male and female speakers. Furthermore, the misclassification amount is less for source compared to speech. These results suggest that physical exercise influences the source more than the vocal tract.

Large sub-mitral aneurysm compressing the left circumflex coronary artery presenting with atypical chest pain - Rare presentation.

Sub-mitral aneurysm (SMA) is a rare cardiac malformation commonly reported in young adults of African ancestry. SMA is considered a congenital disease caused by developmental defect due to weakness at the atrioventricular junction near the posterior mitral annulus. In the past two decades, a considerable number of cases regarding this rare disease have been reported in Asians, highlighting the importance of considering SMA in differential diagnosis of young patients presenting with mitral regurgitation and chest pain. Herein, we report the case of a young male with atypical chest pain with compression of left circumflex coronary artery by a large SMA. .

Study of Short and Intermediate Term Clinical Outcomes of Patients with Protected and Unprotected LMCA Stenting.

INTRODUCTION: Significant unprotected Left Main Coronary Artery (LMCA) disease is detected in 5%-7% of cases undergoing Coronary Angiography (CAG). Present guidelines have revealed the significance of anatomical location in left main artery stenosis and syntax scores for determination of Major Adverse Cardiac Events (MACE). Debate still persists over the best treatment regarding outcomes of Coronary Artery Bypass Grafting (CABG) and LMCA stenting for patients with LMCA disease. AIM: Aim of the study was to evaluate short and intermediate term clinical outcomes of Percutaneous Coronary Intervention (PCI) in LMCA disease in respect to mortality, Cerebrovascular Accidents (CVA), reinfarction, stent restenosis and need for repeat target lesion revascularization. MATERIALS AND METHODS: From July 2013 to February 2015, 50 patients underwent LMCA stenting. All patients underwent detailed clinical assessment, detailed 2D echocardiographic assessment. Syntax score was calculated in all patients. Clinical in hospital and outpatient follow up was obtained at one, three, six, nine months and one year. RESULTS: Mean age was 53.14±9.60 years. On CAG 16 (32%) patients had ostial LMCA lesion, 8 (16%) had mid LMCA lesion, distal LMCA was diseased in 6 (12%). In emergency situation, two bail out LMCA stenting were done for treatment of LMCA dissection. A total of 42 (84%) patients had low syntax score, 6 (12%) had intermediate and 2 (4%) had high syntax score. Only LMCA stenting was done in 22 (44%) patients, LMCA to Left Anterior Descending (LAD) stenting was done in 22 (44%) and LMCA to Left Circumflex (LCX) stenting was done in 6 (12%) patients. Drug-Eluting Stent (DES) was used in 35 (70%) cases while Bare-Metal Stent (BMS) was used in 15 (30%). An 8% mortality and 8% target lesion revascularization rate were observed in our study. CONCLUSION: Our study revealed that LMCA stenting is a safe and feasible alternative mode of revascularization in selected patients. Patients most suitable for LMCA stenting in our study were those with isolated ostial/mid LMCA disease, with protected LMCA disease and those who underwent elective stenting procedure.

AGE-Related Differences of Novel Atherosclerotic Risk Factors and Angiographic Profile Among Gujarati Acute Coronary Syndrome Patients.

CONTEXT: Although numerous risk factors have been established to predict the development of acute coronary syndrome (ACS), the risk factor profile may be different between the younger and older individuals. AIM: To analyse the frequency and pattern of atherogenic risk factors and angiographic profiles in age-stratified Gujarati patients with ACS. MATERIALS AND METHODS: ACS patients undergoing coronary angiography at U.N. Mehta Institute of Cardiology and Research, Gujarat, India between January 2008 and December 2012 were classified in to two age groups with 40y as cut-off. Patients were assessed for conventional risk factors (diabetes mellitus, dyslipidaemia, hypertension, smoking, obesity), novel risk factors (high sensitivity C-reactive protein, lipoprotein (a), homocysteine), and angiographic profiles.The statistical difference between two age groups was determined by Student's t-test for continuous variables and Chi-square or Fisher's exact test for categorical variables. RESULTS: A total of 200 patients, 100 patients ≤40 y of age and 100 patients >40 y of age, were evaluated. Older patients had higher frequency of hypertension (32 vs. 16%, p=0.008), while family history of coronary artery disease was more common among younger patients (19 vs. 9%, p=0.041). The incidence of diabetes, dyslipidaemia, smoking and tobacco chewing did not vary significantly between the two groups. Total cholesterol and low-density lipoprotein cholesterol levels were significantly higher in the younger group (p<0.05). Lipoprotein (a), homocysteine and high-sensitivity C reactive protein levels were comparable between two age groups. Multi-vessel coronary artery disease was more common among older group. The most commonly affected coronary artery was the left anterior descending artery among younger patients (44%) and the left circumflex artery among older patients (38.1%). CONCLUSION: Young patients with ACS had different atherosclerotic risk profile and less extensive coronary artery disease as compared to older counterparts. Emphasis should be given on diagnosis and management of major modifiable risk factors.

Study of Effectiveness and Safety of Percutaneous Balloon Mitral Valvulotomy for Treatment of Pregnant Patients with Severe Mitral Stenosis.

INTRODUCTION: In pregnant women mitral stenosis is the commonest cardiac valvular lesion. When it is present in majorly severe condition it leads to maternal and fetal morbidity and mortality. In mitral stenosis pregnancy can lead to development of heart failure. AIM: To evaluate the safety and efficacy of balloon mitral valvulotomy (BMV) in pregnant females with severe mitral stenosis. MATERIALS AND METHODS: A total of 30 pregnant patients who underwent BMV were included in the study from July 2011 to November 2013. Clinical follow-up during pregnancy was done every 3 months until delivery and after delivery. The mean follow up time after BMV was 6.72±0.56 months. RESULTS: From the 30 pregnant females 14 (46.67%) and 16 (53.3%) patients underwent BMV during the third and second trimester of pregnancy respectively. The mean mitral valve area was 0.85+0.16 cm(2) before BMV that increased to 1.60+0.27 cm(2) (p<0.0001) immediately after BMV. Peak and mean diastolic gradients had decreased significantly within 48 hours after the procedure (p<0.001) but remained very much unchanged at 6.72 month period of follow-up. Two patients had an increase in mitral regurgitation by 2 grades. CONCLUSION: During pregnancy BMV technique is safe and effective in patients with severe mitral stenosis. This results in marked symptomatic relief along with long term maternal and fetal outcomes.

Age and Sex Specific Reference Intervals for Modifiable Risk Factors of Cardiovascular Diseases for Gujarati Asian Indians.

Objective. We aimed to establish age and sex specific percentile reference data for cardiovascular risk factors such as lipids, sugar, blood pressure, and BMI in apparently healthy and disease-free Gujarati population. Methods. In this cross-sectional study, we enrolled 3265 apparently healthy and disease-free individuals of both genders residing in Gujarat state. Fasting samples of blood were used for biochemical estimations of lipids and sugar. The measurement of BMI and blood pressure was also done according to the standard guidelines. Age and gender specific 5th, 25th, 50th, 75th, 90th, and 95th percentiles were obtained. Results. The mean values of lipids, sugar, blood pressure, and BMI were significantly (p < 0.001) higher in males as compared to female population. Age-wise distribution trends showed increase in the risk factors from the 2nd decade until the 5th to 6th decade in most of the cases, where loss of premenopausal protection in females was also observed. Specific trends according to gender and age were observed in percentile values of various parameters. Conclusion. The outcome of current study will contribute significantly to proposing clinically important reference values of various lipids, sugar, blood pressure, and BMI that could be used to screen the asymptomatic Gujarati Indian population with a propensity of developing dyslipidemia, diabetes, blood pressure, and obesity.

Association of high density lipoprotein with platelet to lymphocyte and neutrophil to lymphocyte ratios in coronary artery disease patients.

Background. We aimed to evaluate a relationship between platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) with high density lipoprotein (HDL) cholesterol levels in coronary artery disease (CAD) patients. Methods. A total of 354 patients with angiographically confirmed coronary blockages were enrolled in the study. Hematological indices and lipid profiling data of all the patients were collected. Results. We have observed significant association between HDL and PLR (P = 0.008) and NLR (P = 0.009); however no significant relationship was obtained with HDL and isolated platelet (P = 0.488), neutrophil (P = 0.407), and lymphocyte (P = 0.952) counts in CAD patients. The association was subjected to gender specific variation as in males PLR (P = 0.024) and NLR (P = 0.03) were highly elevated in low HDL patients, whereas in females the elevation could not reach the statistically significant level. The PLR (217.47 versus 190.3; P = 0.01) and NLR (6.33 versus 5.10; P = 0.01) were significantly higher among the patients with acute coronary syndrome. In young patients the PLR (P = 0.007) and NLR (P = 0.001) were inversely associated with HDL, whereas in older population only NLR (P = 0.05) had showed a significant association. Conclusion. We conclude that PLR and NLR are significantly elevated in CAD patients having low HDL levels.

Response of blood pressure after percutaneous transluminal renal artery angioplasty and stenting.

AIM: To evaluate the short and intermediate term outcome of percutaneous transluminal renal artery angioplasty (PTRA) and stenting particularly on blood pressure (BP) control and renal function and to evaluate predictors of poor BP response after successful PTRA and stenting. METHODS: We conducted a prospective analysis of all patients who underwent PTRA and stenting in our institute between August 2010 to September 2012. A total number of 86 patients were underwent PTRA and renal stenting. Selective angiography was done to confirm at least 70% angiographic stenosis. The predilatation done except few cases with critical stenosis, direct stenting was done in the rest of cases. All patients received aspirin 325 mg orally, and clopidogrel 300 mg orally within 24 h before the procedure. Heparin was used as the procedural anticoagulant agent. Optimal results with TIMI-III flow obtained in all cases. Following stent placement, aspirin 150 mg orally once daily was continued for a minimum of 12 mo and clopidogrel 75 mg orally once daily for at least 4 wk. The clinical, radiological, electrocardiography, echocardiography and treatment data of all patients were recorded. The BP measurement, serum creatinine and glomerular filtration rate (GFR) were recorded before the procedure and 1 and 6 mo after PTRA. RESULTS: A total of 86 patients were included in the study. The mean age of study population was 55.87 ± 11.85 years old and 67 (77.9%) of patients were male. There was a significant reduction in both systolic and diastolic BP at 1 mo after the procedure: 170.15 ± 20.10 mmHg vs 146.60 ± 17.32 mmHg and 98.38 ± 10.55 mmHg vs 89.88 ± 9.22 mmHg respectively (P = 0.0000). The reduction in BP was constant throughout the follow-up period and was evident 6 mo after the procedure: 144.23 ± 18.19 and 88.26 ± 9.79 mmHg respectively (P = 0.0000). However, no improvement in renal function was observed at any time during the follow-up period. After multivariate analysis, we found male sex, low GFR (< 60 mL/min) and higher baseline mean BP as a poor predictors of successful outcome on BP response after PTRA and stenting. CONCLUSION: The PTRA and stenting can be considered as an effective therapeutic intervention for improving BP control with minimal effect on renal function. The male sex, higher baseline BP and low GFR are associated with poor BP response after successful PTRA and stenting.

Prevalence of insulin resistance in first degree relatives of type-2 diabetes mellitus patients: A prospective study in north Indian population.

A total of 172 first degree relatives (FDRs) and 178 controls were included in this study. All the cases and controls were subjected to various anthropometric measurements, fasting and postprandial glucose estimation, fasting insulin measurement and fasting lipid profile. Results revealed the prevalence of Impaired Fasting Glucose (IFG) (cases 37% Vs controls 11.6%), Impaired Glucose Tolerance (IGT) (cases 34.3% Vs controls 11.2%) and diabetes (cases 11.05% controls 3.37%) was significantly higher in first degree relatives. Insulin resistance was measured using various methods, which included fasting plasma insulin (FPI), Homeostasis Model Assessment for Insulin Resistance (HOMA(IR)), insulin sensitivity index (ISI) (Mffm/l). Prevalence of insulin resistance (Insulin Resistance) as observed comparing FPI and HOMA(IR) in cases and controls was 43.6% and 11.24% (P=0.005) and 37.8% and 12.47% (P=0.000) respectively. Prevalence of IR (Insulin Resistance) observed in cases having Normal Glucose Tolerance (NGT), Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) and diabetes mellitus measuring FPI Vs HOMA(IR) was 37.5% vs 30.2%, 45% vs 40%, 38.98% vs 37.28% and 36.84% vs 31.57% as accordingly. However, ISI (Mffm/l) was not found to be a promising index for IR due to its poor specificity. Though HOMA is taken as gold standard for measurement of IR globally, our study observed fasting plasma insulin representing high sensitivity (89.7%) and specificity (93.3%) as compared to HOMA. Thus FPI had emerged in this work as a simple and reliable test for diagnosing insulin resistance across the population susceptible to develop diabetes including FDRs.