Melastatin-like transient receptor potential channel 2 (TRPM2) is an oxidant-sensitive and cationic non-selective channel that is expressed in mammalian vascular endothelium. Here we investigated the functional role of TRPM2 channels in hydrogen peroxide (H2O2)-induced cytosolic Ca2+ ([Ca2+]i) elavation, whole-cell current increase, and apoptotic cell death in murine heart microvessel endothelial cell line H5V. A TRPM2 blocking antibody (TM2E3), which targets the E3 region near the ion permeation pore of TRPM2, was developed. Treatment of H5V cells with TM2E3 reduced the [Ca2+]i rise and whole-cell current change in response to H2O2. Suppressing TRPM2 expression using TRPM2-specific short hairpin RNA (shRNA) had similar inhibitory effect. H2O2-induced apoptotic cell death in H5V cells was examined using MTT assay, DNA ladder formation analysis, and DAPI-based nuclear DNA condensation assay. Based on these assays, TM2E3 and TRPM2-specific shRNA both showed protective effect against H2O2-induced apoptotic cell death. TM2E3 and TRPM2-specific shRNA also protect the cells from tumor necrosis factor (TNF)-α-induced cell death in MTT assay. In contrast, overexpression of TRPM2 in H5V cells resulted in an increased response in [Ca2+]i and whole-cell currents to H2O2. TRPM2 overexpression also aggravated the H2O2-induced apoptotic cell death. Downstream pathways following TRPM2 activation was examined. Results showed that TRPM2 activity stimulated caspase-8, caspase-9 and caspase-3. These findings strongly suggest that TRPM2 channel mediates cellular Ca2+ overload in response to H2O2 and contribute to oxidant-induced apoptotic cell death in vascular endothelial cells. Down-regulating endogenous TRPM2 could be a means to protect the vascular endothelial cells from apoptotic cell death.

The renal cortical collecting duct (CCD) into collecting duct cells. Furthermore, substances such as atrial natriuretic peptide and nitric oxide, which increase cGMP, abrogate flow-induced Ca 2+ entry through PKG-mediated inhibition of these channels.

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Melastatin-like transient receptor potential channel 2 (TRPM2) is an oxidant-sensitive and cationic non-selective channel that is expressed in mammalian vascular endothelium. Here we investigated the functional role of TRPM2 channels in hydrogen peroxide (H 2 O 2 )-induced cytosolic Ca 2+ ([Ca 2+ ] i ) elavation, whole-cell current increase, and apoptotic cell death in murine heart microvessel endothelial cell line H5V. A TRPM2 blocking antibody (TM2E3), which targets the E3 region near the ion permeation pore of TRPM2, was developed. Treatment of H5V cells with TM2E3 reduced the [Ca 2+ ] i rise and whole-cell current change in response to H 2 O 2 . Suppressing TRPM2 expression using TRPM2-specific short hairpin RNA (shRNA) had similar inhibitory effect. H 2 O 2 -induced apoptotic cell death in H5V cells was examined using MTT assay, DNA ladder formation analysis, and DAPI-based nuclear DNA condensation assay. Based on these assays, TM2E3 and TRPM2-specific shRNA both showed protective effect against H 2 O 2 -induced apoptotic cell death. TM2E3 and TRPM2-specific shRNA also protect the cells from tumor necrosis factor (TNF)-a-induced cell death in MTT assay. In contrast, overexpression of TRPM2 in H5V cells resulted in an increased response in [Ca 2+ ] i and whole-cell currents to H 2 O 2 . TRPM2 overexpression also aggravated the H 2 O 2 -induced apoptotic cell death. Downstream pathways following TRPM2 activation was examined. Results showed that TRPM2 activity stimulated caspase-8, caspase-9 and caspase-3. These findings strongly suggest that TRPM2 channel mediates cellular Ca 2+ overload in response to H 2 O 2 and contribute to oxidant-induced apoptotic cell death in vascular endothelial cells. Down-regulating endogenous TRPM2 could be a means to protect the vascular endothelial cells from apoptotic cell death.

Introduction Congenital long QT syndrome (LQTS) and catecholaminergic ventricular tachycardia (CPVT) are less prevalent cardiac ion channelopathies than Brugada syndrome in Asia. The present study compared paediatric/young and adult patients with these conditions. Method This was a territory-wide retrospective cohort study of consecutive patients diagnosed with congenital LQTS and CPVT attending public hospitals in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF). Results A total of 142 congenital LQTS (mean onset age= 27±23 years old) and 16 CPVT (mean presentation age=11±4 years old) patients were included. For congenital LQTS, arrhythmias other than VT/VF (HR=4.67, 95% confidence interval = [1.53–14.3], p=0.007), initial VT/VF (HR=3.25 [1.29–8.16], p=0.012) and Schwartz score (HR=1.90 [1.11–3.26], p=0.020) were predictive of the primary outcome for the overall cohort, whilst arrhythmias other than VT/VF (HR=5.41 [1.36–21.4], p=0.016) and Schwartz score (HR=4.67 [1.48–14.7], p=0.009) were predictive for the adult subgroup (>25 years old; n=58). All CPVT patients presented before the age of 25 but no significant predictors of VT/VF were identified. A random survival forest model identified initial VT/VF, Schwartz score, initial QTc interval, family history of LQTS, initially asymptomatic, and arrhythmias other than VT/VF as the most important variables for risk prediction in LQTS, and initial VT/VF/sudden cardiac death, palpitations, QTc, initially symptomatic and heart rate in CPVT. Conclusion Clinical and ECG presentation vary between the pediatric/young and adult congenital LQTS population. All CPVT patients presented before the age of 25. Machine learning models achieved more accurate VT/VF prediction. Funding Acknowledgement Type of funding sources: None. Kaplan-Meier survival curve for LQTSKaplan-Meier survival curve for CPVT

Background The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) versus dipeptidyl peptidase-4 inhibitors (DPP4I) on the risk of new gout diagnosis have not been explored. This study aims to compare the effects of SGLT2I against DPP4I on gout risks in a Chinese population. Methods This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus treated with SGLT2I or DPP4I between January 1st, 2015 and December 31st, 2020 in Hong Kong. The study outcomes are new-onset gout and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I was performed. Univariable and multivariable Cox regression analysis models were conducted. Competing risks models and multiple approaches based on the propensity score were applied. Patients This study included 60996 patients (median age: 62.3 years old, 54.96% males; SGLTI group: n=21690; DPP4I group: n=39306). Results In the matched cohort, 1096 developed gout (IR: 2.52%) and 2195 died (IR: 5.05%). Univariable Cox regression showed that SGLT2I use was associated with lower risks of new diagnosis of gout (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.30–0.39; P-value<0.0001) and all-cause mortality (HR: 0.35; 95% CI: 0.32–0.39; P-value<0.0001) compared to DPP4I. The associated remained for both new diagnosis of gout (HR: 0.46; 95% CI: 0.37–0.57; P-value<0.0001) and all-cause mortality (HR: 0.38; 95% CI: 0.33–0.44; P-value<0.0001) after adjusting for significant demographics, past comorbidities, and non-SGLT2I/DPP4I medications. The risks of gout were lowered in each types of SGLT2I. The results were consistent on competing risk and other propensity score approaches analyses. Conclusions SGLT2I use was associated with lower risks of new gout diagnosis compared to DPP4I use. Funding Acknowledgement Type of funding sources: None.

Funding Acknowledgements Type of funding sources: None. OnBehalf Cardiovascular Analytics Group Background Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are major classes of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, they are associated with adverse cardiovascular events. Purpose To evaluate the cardiotoxicity of PD-1 and PD-L1 inhibitors, the present study aims to examine the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors. Methods Patients receiving PD-1 or PD-L1 inhibitors since their launch up to December 31st, 2019 without pre-existing cardiac complications were included. Patient data were obtained using a territory-wide electronic health record database. The primary outcome was a composite of incident heart failure (HF), acute myocardial infarction (AMI), atrial fibrillation (AF) or atrial flutter followed up to August 31st, 2020. Propensity score matching between PD-L1 and PD-1 inhibitor use with a 1:1 ratio for patient demographics and comorbidities was performed. Results A total of 1925 patients were included. Over a median follow-up of 136 days (interquartile range [IQR]: 42-279), 318 (16.51%) patients met the primary outcome after PD-1/PD-L1 treatment: 242 (incidence rate [IR]: 12.57%) with HF, 38 (IR: 1.97%) with AMI, 53 (IR: 2.75%) with AF, 6 (IR: 0.31%) with atrial flutter. Compared with PD-1 inhibitor treatment, PD-L1 inhibitor treatment was significantly associated with a lower risk of composite outcome after matching (HR: 0.78, 95% CI: [0.62-0.99], P value = 0.0417). Patients who developed cardiovascular complications had shorter average readmission intervals and more hospitalization episodes after treatment with PD-1/PD-L1 inhibitors both before and after matching (P value < 0.0001). Conclusions Compared with PD-1 inhibitor users, PD-L1 inhibitor users had a significantly lower risk of new-onset composite cardiovascular complications. Abstract Figure. Kaplan-Meier survival curve

Introduction Neutrophil-to-lymphocyte ratio (NLR) is a routinely available biomarker that reflects systemic inflammation. The study evaluated the predictive value of NLR for ischemic stroke and atrial fibrillation (AF) in patients with type 2 diabetes mellitus. Methods This was a population-based cohort study of patients with type 2 diabetes mellitus and complete blood count tests at baseline between January 1st, 2009 to December 31st, 2009 at government-funded hospitals/clinics in Hong Kong. Follow-up was until December 31st, 2019 or death. Results A total of 85351 patients (age=67.6±13.2 years old, male=48.8%, follow-up=3101±1441 days) were included. Univariable Cox regression found that increased NLR at quartiles 2, 3 and 4 was significantly associated with higher risks of new onset ischemic stroke (HR: 1.28 [1.20–1.37], P<0.001, HR: 1.41 [1.32–1.51], P<0.001 and HR: 1.38 [1.29–1.47], P<0.001) and AF (hazard ratio [HR]: 1.09 [1.02–1.17], P<0.015; HR: 1.28 [1.20–1.37], P<0.001; HR: 1.39 [1.31–1.49], P<0.001) compared to quartile 1. On multivariable analysis, NLR remained a significant predictor of ischemic stroke risk for quartiles 2 and 3 (quartile 2: HR: 1.14 [1.05, 1.22], p=0.001; quartile 3: HR: 1.14 [1.06, 1.23], p<0.001) but not quartile 4 (HR: 1.08 [0.994, 1.17], p=0.070). By contrast, NLR was not predictive of AF after adjusting for confounders (quartile 2: HR: 0.966 [0.874, 1.07], p=0.499; quartile 3: HR: 0.978 [0.884, 1.08], p=0.661; quartile 4: HR: 1.05 [0.935, 1.16], p=0.462). Conclusion NLR is a significant predictor of new onset ischaemic stroke but not AF after adjusting for significant confounders. Funding Acknowledgement Type of funding sources: None.