Role of angiotensin receptor-neprilysin inhibitor in diabetic complications

Diabetes mellitus is a prevalent disorder with multi-system manifestations,causing a significant burden in terms of disability and deaths globally.Angio-tensin receptor-neprilysin inhibitor(ARNI)belongs to a class of medications for treating heart failure,with the benefits of reducing hospitalization rates and mortality.This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications,discussing possible physiological and molecular mechanisms,with insights for future applications.

Dysglycemia and arrhythmias

Disorders in glucose metabolism can be divided into three separate but interrelated domains,namely hyperglycemia,hypoglycemia,and glycemic variability.Intensive glycemic control in patients with diabetes might increase the risk of hypoglycemic incidents and glucose fluctuations.These three dysglycemic states occur not only amongst patients with diabetes,but are frequently present in other clinical settings,such as during critically ill.A growing body of evidence has focused on the relationships between these dysglycemic domains with cardiac arrhythmias,including supraventricular arrhythmias(primarily atrial fibrillation),ventricular arrhythmias(malignant ventricular arrhythmias and QT interval prolongation),and bradyarrhythmias(bradycardia and heart block).Different mechanisms by which these dysglycemic states might provoke cardiac arrhythmias have been identified in experimental studies.A customized glycemic control strategy to minimize the risk of hyperglycemia,hypoglycemia and glucose variability is of the utmost importance in order to mitigate the risk of cardiac arrhythmias.

Left atrial enlargement and non-paroxysmal atrial fibrillation as risk factors for left atrial thrombus/spontaneous Echo contrast in patients with atrial fibrillation and low CHA2DS2-VASc score

Objective To determine the risk factors for thromboembolism in lower risk patients with non-valvular atrial fibrillation(AF)and low CHA2DS2-VASc scores,which remain undefined.Methods We retrospectively analyzed the baseline clinical characteristics,routine laboratory parameters,and echocardiographic measurements of 705 patients(71.1%male;mean age:52.10±9.64 years)with low CHA2DS2-VASc score(0 or 1;1 point for female sex)out of 1346 consecutive patients with non-valvular AF who underwent transesophageal echocardiography(TEE)at Guangdong Cardiovascular Institute between January 2013 and December 2015.Results Patients with left atrial thrombus(LAT)or spontaneous echo contrast(SEC)on TEE(24/705,4%)showed a higher incidence rate of vascular disease(54.2%vs.32.9%,P=0.045)and non-paroxysmal AF(79.2%vs.29.4%,P<0.001),larger left atrial diameter(43.08±4.59 vs.36.02±5.53 mm,P<0.001),and lower left ventricular ejection fraction(58.23±8.82%vs.64.15±7.14%,P<0.001)than those without.Multivariate logistic regression analysis identified left atrial diameter[odds ratio(OR)=1.171,95%confidence interval(CI):1.084–1.265,P<0.001]and non-paroxysmal AF(OR=3.766,95%CI:1.282–11.061,P=0.016)as independent risk factors for LAT/SEC.In ROC curve analysis,a left atrial dimeter cutoff of 37.5 mm yielded 95.0%sensitivity and 62.7%specificity(AUC:0.847,P<0.0001,95%CI:0.793–0.914).Conclusion In patients with non-valvular AF with low CHA2DS2-VASc score,the presence of LAT or SEC was associated with left atrial enlargement,which had moderate predictive value,and non-paroxysmal AF.

Clinical, sonographic characteristics and long-term prognosis of valvular heart disease in elderly patients

Background Valvular heart disease(VHD)is expected to become more prevail as the population ages and disproportionately affects older adults.However,direct comparison of clinical characteristics,sonographic diagnosis,and outcomes in VHD patients aged over 65 years is scarce.The objective of this study was to evaluate the differences in clinical characteristics and prognosis in two age-groups of geriatric patients with VHD.Methods We retrospectively enrolled consecutive individuals aged>65 years from Guangdong Provincial Peopled Hospital and screened for VHD using transthoracic echocardiography(TTE)or transesophageal echocardiography(TEE).Finally,260(48.9%)patients were in the 65-74 years group,and 272(51.1%)were in the>75-year group.Factors that affected long-term survival was explored.A multivariable Cox hazards regression was performed to identify the predictors of major adverse cardiac events(MACEs)in each group.Results In our population,the older group were more likely to have chronic obstructive pulmonary disease(COPD),degenerative VHD,but with less rheumatic VHD,aortic stenosis(AS)and mitral stenosis(MS).Compared with those aged 65-74 years,the older group had a higher incidence of all-cause death(10.0%vs.16.5%,P=0.027),ischemic stroke(13.5%vs.20.2%,P=0.038)and MACEs(37.3%vs.48.2%,P=0.011)at long-term follow-up.In multivariable Cox regression analysis,mitral regurgitation,a history of COPD,chronic kidney disease,diabetes,hypertension,atrial fibrillation and New York Heart Association(NYHA)functional class were identified as independent predictors of MACEs in the older group.Conclusion Advanced age profoundly affect prognosis and different predictors were associated with MACEs in geriatric patients with VHD.

Simple hematological predictors of AF recurrence in patients undergoing atrial fibrillation ablation

Backgound Red cell distribution width(RDW) and neutrophil-to-lymphocyte ratio(NLR) are simple hematologic indices that have been used to predict adverse outcomes in different clinical settings. The aim of our study is to determine whether RDW and NLR can predict atrial fibrillation(AF) recurrence in patients undergoing AF ablation. Methods Consecutive patients, without known hematological disorders, who underwent AF catheter ablation between January 2014 and April 2017 were enrolled into this study. Blood samples were taken one day before and five hours after the ablation procedure. Results A total of 346 patients(224 males(65%), mean age: 59 ± 11 years old) were included. After a mean follow up of 26.2 ± 12.1 months, 80(23.1%) patients experienced late AF recurrence(defined as any recurrence after the blanking period of three months), while 97(28%) patients experienced early AF recurrence during the blanking period. Univariate analysis showed that early arrhythmia recurrence, type of AF and NLR after the procedure were significantly associated with late AF recurrence, while early arrhythmia recurrence and NLR remained significant in multivariate analysis. RDW was not associated with late AF recurrence. None of the parameters above predicted early arrhythmia recurrence. Conclusions Simple and inexpensive hematological indices such as NLR should be evaluated for their ability to predict AF recurrence in patients undergoing catheter ablation in larger prospective studies.

A meta-analysis of soluble suppression of tumorigenicity 2 （sST2） and clinical outcomes in pulmonary hypertension

Suppression of Tumorigenicity 2 （ST2） is a member of the interleukin （IL）-1 receptor family The ST2 receptor exists in two isoforms - ST2 ligand （ST2L） and soluble ST2 （sST2）.ST2L is a membrane receptor and sST2 is a trun- cated receptor which is soluble in the blood, allowing it to be detected in serum. IL-33 is a member of the IL-1 family of ligand and is the fimctional ligand of ST2L receptor. It binds to the ST2L, thereby mediating its immune function.

Novel conduction-repolarization indices for the stratification of arrhythmic risk

Sudden cardiac death （SCD） affects approximately 800,000 individuals per annum globally. It is most frequently due to cardiac tachy-arrhythmias, which include mono-morphic or polymorphic ventricular tachycardia （VT）, torsade de pointes and ventricular fibrillation （VF）. Risk stratification for SCD remains a challenging problem in clinical practice.

Both transmural dispersion of repolarization and of refractoriness are poor predictors of arrhythmogenicity： a role for iCEB （QT/QRS）？

We read the original article by Nuis, et al. and the reply by Dogan, et al. with great interest. Nuis, et al. examined whether transcatheter aortic valve implantation （TAVI） in patients suffering from severe aortic stenosis led to changes in corrected QT dispersion （cQTD）, previously used to predict arrhythmic risk. Dogan, et al. proposed that a different marker, transmural dispersion of repolariza- tion （TDR）, has better accuracy in risk prediction.

Superior safety of direct oral anticoagulants compared to Warfarin in patients with atrial fibrillation and underlying cancer: a national veterans affairs database study

Background Studies evaluating safety of warfarin and direct oral anticoagulants(DOACs) for prevention of stroke in patients with atrial fibrillation(AF) are lacking. Methods & Results All patients(n = 196,521) receiving care at veteran’s affairs with active cancer and AF from 2010–2015 were included. One-year mortality was significantly higher in unadjusted analysis with warfarin(44.9%) compared to dabigatran(25%, P < 0.001), rivaroxaban(24.4%, P < 0.001) and apixaban(30%, P < 0.001) and after adjusting for age, sex and type of cancer mortality(OR = 2.66, 95% CI: 2.52–2.82, P < 0.001). Risk of ischemic stroke(13.5% vs. 11.1%, 12.0%, 14.0%) was similar, however risk of hemorrhagic stroke was significantly higher among patients receiving warfarin(1.2%) compared to patients receiving dabigatran(0.5%), rivaroxaban(0.7%) and apixaban(0.8%) respectively, P = 0.04. Conclusions We demonstrated the superior safety profile of DOACs compared to warfarin among patients with underlying cancer and AF. Warfarin was associated with higher mortality, similar ischemic stroke risk but higher risk of hemorrhagic stroke.

Impact of SGLT2 inhibitors on major clinical events and safety outcomes in heart failure patients:a meta-analysis of randomized clinical trials

BACKGROUND Sodium-glucose co-transporter-2 inhibitors(SGLT2i)significantly reduce the risk of cardiovascular(CV)and renal adverse events in patients with diabetes mellitus,heart failure(HF)and/or chronic kidney disease.We performed a meta-analysis to explore the impact of several different SGLT2i on all-cause mortality,CV mortality,HF hospitalizations and the combined outcome CV death/HF hospitalization in HF patients across the spectrum of left ventricular ejection fraction(LVEF)phenotypes.METHODS A systematic search in MEDLINE database and Cochrane library through March 2021 was performed without limitations.Randomized clinical trials that provided data about the impact of SGLT2i on all-cause mortality,CV mortality,HF hospitalizations or the combined outcome of CV death/HF hospitalization in HF patients were included.A random effects model was used for calculating the effect estimates.RESULTS Nine studies(n=16,723 patients,mean age:65.9 years,males:70.7%)were included in the quantitative synthesis.Compared to placebo,SGLT2i use was associated with 14%lower risk of all-cause mortality[hazard ratio(HR)=0.86,95%CI:0.78−0.94,I^(2)=0,P=0.0008],32%lower risk of HF hospitalizations(HR=0.68,95%CI:0.62−0.74,I^(2)=0,P<0.001),14%lower risk of CV mortality(HR=0.86,95%CI:0.77−0.95,I^(2)=0,P=0.003)and 26%lower risk of CV death/HF hospitalization(HR=0.74,95%CI:0.68−0.80,I^(2)=0,P<0.001).Regarding the safety outcomes,our data revealed no significant differences between SGLT2i and placebo groups in drug related discontinuations,amputations,severe hypoglycemia,hypotension,volume depletion,ketoacidosis and genital infections.By contrast,a protective role of SGLT2i against placebo was found for serious adverse events and acute kidney injury.CONCLUSIONS In patients with HF,regardless of LVEF phenotype,all SGLT2i had an excellent safety profile and significantly reduced the risk of all-cause mortality,CV mortality,HF hospitalizations and CV deaths/HF hospitalizations compared to placebo.

Determination of action potential wavelength restitution in Scn5a^＋/- mouse hearts modelling human Brugada syndrome

Brugada syndrome is a primary electrical disorder of theheart, predisposing affected individuals to potentially lethal,ventricular tachy-arrhythmias. A number of mechanismshave been identified as being important increasing the riskof these rhythms. Wavelength （γ） restitution has beensuggested to predict the onset of action potential duration（APD） alternans in mouse Scn5a^＋/- hearts modelling Bru-gada syndrome.

A rare case of Staphylococcus lugdunensis septicemia associated with myocarditis and atrioventricular block

Myocarditis is a relatively rare,possibly life-threatening disease characterized by the inflammation of the myocardium.111 The disease pathogenesis is primarily initiated by acute injury and necrosis of cardiomyocytes,leading to an inflammatory response mediated by the immune system that can potentially cause further aggravation of myocardial damage and organ dysfunction.Prognosis in patients with myocarditis depends on the clinical presentation,which ranges from an asymptomatic disease course to the concomitant development of cardiac arrhythmias,heart failure,cardiogenic shock and even the occurrence of death in extreme cases[1].

Electrocardiogram-based artificial intelligence for the diagnosis of heart failure:a systematic review and meta-analysis

BACKGROUND The electrocardiogram(ECG)is an inexpensive and easily accessible investigation for the diagnosis of cardiovascular diseases including heart failure(HF).The application of artificial intelligence(AI)has contributed to clinical practice in terms of aiding diagnosis,prognosis,risk stratification and guiding clinical management.The aim of this study is to systematically review and perform a meta-analysis of published studies on the application of AI for HF detection based on the ECG.METHODS We searched Embase,PubMed and Web of Science databases to identify literature using AI for HF detection based on ECG data.The quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2(QUADAS-2)criteria.Random-effects models were used for calculating the effect estimates and hierarchical receiver operating characteristic curves were plotted.Subgroup analysis was performed.Heterogeneity and the risk of bias were also assessed.RESULTS A total of 11 studies including 104,737 subjects were included.The area under the curve for HF diagnosis was 0.986,with a corresponding pooled sensitivity of 0.95(95%CI:0.86–0.98),specificity of 0.98(95%CI:0.95–0.99)and diagnostic odds ratio of 831.51(95%CI:127.85–5407.74).In the patient selection domain of QUADAS-2,eight studies were designated as high risk.CONCLUSIONS According to the available evidence,the incorporation of AI can aid the diagnosis of HF.However,there is heterogeneity among machine learning algorithms and improvements are required in terms of quality and study design.

Variability in local action potential durations, dispersion of repolarization and wavelength restitution in aged wild-type and Scn5a^＋/- mouse hearts modeling human Brugada syndrome

Brugada syndrome is a primary arrhythmia syndrome characterized by loss-of-function mutations in the SCN5A gene, which encodes for the cardiac Na^＋ channel. In affected individuals, the risk of developing malignant ventricular arrhythmias and sudden cardiac death are increased.

Spontaneous type 1 pattern, ventricular arrhythmias and sudden cardiac death in Brugada Syndrome： an updated systematic review and meta-analysis

Brugada syndrome （BrS） is primary electrical disorder characterized by ST segment elevation with right bundle branch block morphology in patients with apparent structurally normal hearts, It predisposes affected individuals to ventricular tachycardia/fibrillation （VT/VF） and sudden cardiac death （SCD）.A number of studies have identified risk factors that are associated with a more malignant course of disease. These include male gender, syncope, a spontaneous type 1 ECG pattern, family history of SCD, family history of Brugada syndrome,

Meta-analysis of T-wave indices for risk stratification in myocardial infarction

Ventricular tachy-arrhythmias are the commonest cause of sudden cardiac death in patients with ischemie heart dis- ease. It is estimated that up to 20% patients with acute myocardial infarction suffer from these arrhythmias.There is a growing need for developing tools for risk as- sessment for sudden cardiac death （SCD） in this population.

An Open Invitation to Join the International Brugada Electrocardiographic Indices Registry

Background:The Brugada Electrocardiographic Indices Registry is a comprehensive data registry composed of patients with Brugada patterns on the electrocardiogram(ECG).The aim is to test the hypotheses that(i)ECG indices combining both depolarization and repolarization abnormalities can better predict spontaneous ventricular arrhythmias than existing ECG markers in Brugada syndrome and(ii)that serial ECG measurements will provide additional information for risk stratifi cation,especially in asymptomatic patients.Methods:Patients with both Brugada pattern ECGs and Brugada syndrome are eligible for inclusion in this registry.Baseline characteristics and ECG variables refl ecting depolarization and repolarization will be determined.The primary outcome is spontaneous ventricular tachycardia/ventricular fi brillation or sudden cardiac death.Secondary outcomes are inducible ventricular tachycardia/ventricular fi brillation and syncope.Results:As of November 15,2019,39 investigators from 32 cities in 18 countries had joined this registry.As of December 15,2019,1383 cases had been enrolled.Conclusions:The Brugada Electrocardiographic Indices Registry will evaluate the disease life course,risk factors,and prognosis in a large series of Brugada patients.It will therefore provide insights for improving risk stratification.

Telemonitoring and hemodynamic monitoring to reduce hospitalization rates in heart failure： a systematic review and meta-analysis of randomized controlled trials and real-world studies

Background Heart failure is a significant problem leading to repeated hospitalizations. Telemonitoring and hemodynamic monitoring have demonstrated success in reducing hospitalization rates, but not all studies reported significant effects. The aim of this systematic review and meta-analysis is to examine the effectiveness of telemonitoring and wireless hemodynamic monitoring devices in reducing hospitalizations in heart failure. Methods ＆ Results PubMed and Cochrane Library were searched up to 1st May 2017 for articles that investigated the effects of telemonitoring or hemodynamic monitoring on hospitalization rates in heart failure. In 31,501 patients （mean age： 68 ± 12 years; 61% male; follow-up 11 ± 8 months）, telemonitoring reduced hospitalization rates with a HR of 0.73 （95% CI： 0.65-0.83; P 〈 0.0001） with significant heterogeneity （I2 = 94%）. These effects were observed in the short-term （≤ 6 months： HR = 0.77, 95% CI： 0.65-0.89; P 〈 0.01） and long-term （≥ 12 months： HR = 0.73, 95% CI： 0.62-0.87; P 〈 0.0001）. In 4831 patients （mean age 66 ± 18 years; 66% male; follow-up 13 ± 4 months）, wireless hemodynamic monitoring also reduced hospitalization rates with a HR of 0.60 （95% CI： 0.53-0.69; P 〈 0.001） with significant heterogeneity （I2 = 64%）.This reduction was observed both in the short-term （HR = 0.55, 95% CI： 0.45-0.68; P 〈 0.001; I2 = 72%） and long-term （HR = 0.64, 95% CI： 0.57-0.72; P 〈 0.001; I2 = 55%）. Conclusions Telemonitoring and hemodynamic monitoring reduce hospitalization in both short- and long-term in heart failure patients

Electrocardiographic measures of repolarization dispersion and their relationships with echocardiographic indices of ventricular remodeling and premature ventricular beats in hypertension

Objective To examine the relationship between Tpeak- Tend interval （Tpe） and Tpe/QT ratio with occurrence of ventricular premature beats （VPBs） and left ventricular remodeling in hypertension. Methods A total of 52 patients with mild to moderate essential hypertension were included, undergoing echocardiography and 24-hours Holter monitoring. Ventricular remodeling was assessed by left ventricular mass index （LVMI） using the Devereux formula and diastolic fimction by transmitral E and A wave velocities and E/A ratio. Tpe was measured in the precordial leads. The end of the T wave was set by the method of the tangent to the steepest descending slope of the T wave. Results Tpe and Tpe/QT in leads V2 （r = 0.33, P = 0.01; r = 0.27, P = 0.04 respectively） and V3 （r = 0.40, P = 0.002; r = 0.40, P = 0.003, respectively） correlated significantly with LVMI. A significant inverse relationship was observed between E/A ratio and QT （r = -0.33, P = 0.01）, Tpe in V3 （r = -0.39, P = 0.003） and Tpe/QT in V3 （r = -0.31, P = 0.02）. Tpe in V3, V5, mean Tpe and maximum Tpe with cut-offvalues of 60 ms, 59 ms, 62 ms and 71 ms, respectively, associated with the occurrence of ventricular premature beats. Conclusions The repolarization parameters Tpe interval and Tpe/QT ratio correlate with LVMI and indices of left ventricular diastolic function and show better predictive values than traditional parameters such as QT interval and QT dispersion. Lead V3 is the best lead for measuring Tpe and Tpe/QT. These ECG indices can therefore be used in clinical practice to monitor LV remodeling and predict occurrence of VPBs.

Atypical electrocardiographic manifestations of ischemia: a case of dynamic Wellens patterns

A 55-year-old male with hypertension, hyperlipidemia, impaired fasting glucose, obesity, gout, and osteoarthritis, statin-induced myopathy, but no known cardiac disease, presented with a one day history of intermittent exertional chest discomfort without radiation. Symptoms included sweating, dyspnea, dizziness, and upper limb numbness.