Epicardial adipose tissue in obesity with heart failure with preserved ejection fraction: Cardiovascular magnetic resonance biomarker study

BACKGROUND Obesity has become a serious public health issue,significantly elevating the risk of various complications.It is a well-established contributor to Heart failure with preserved ejection fraction(HFpEF).Evaluating HFpEF in obesity is crucial.Epicardial adipose tissue(EAT)has emerged as a valuable tool for validating prognostic biomarkers and guiding treatment targets.Hence,assessing EAT is of paramount importance.Cardiovascular magnetic resonance(CMR)imaging is acknowledged as the gold standard for analyzing cardiac function and mor-phology.We hope to use CMR to assess EAT as a bioimaging marker to evaluate HFpEF in obese patients.AIM To assess the diagnostic utility of CMR for evaluating heart failure with preserved ejection fraction[HFpEF;left ventricular(LV)ejection fraction≥50%]by measuring the epicardial adipose tissue(EAT)volumes and EAT mass in obese patients.METHODS Sixty-two obese patients were divided into two groups for a case-control study based on whether or not they had heart failure with HFpEF.The two groups were defined as HFpEF+and HFpEF-.LV geometry,global systolic function,EAT volumes and EAT mass of all subjects were obtained using cine magnetic resonance sequences.RESULTS Forty-five patients of HFpEF-group and seventeen patients of HFpEF+group were included.LV mass index(g/m2)of HFpEF+group was higher than HFpEF-group(P<0.05).In HFpEF+group,EAT volumes,EAT volume index,EAT mass,EAT mass index and the ratio of EAT/[left atrial(LA)left-right(LR)diameter]were higher compared to HFpEF-group(P<0.05).In multivariate analysis,Higher EAT/LA LR diameter ratio was associated with higher odds ratio of HFpEF.CONCLUSION EAT/LA LR diameter ratio is highly associated with HFpEF in obese patients.It is plausible that there may be utility in CMR for assessing obese patients for HFpEF using EAT/LA LR diameter ratio as a diagnostic biomarker.Further prospective studies,are needed to validate these proof-of-concept findings.

Heart failure with preserved ejection fraction and the first law of thermodynamics

In heart failure with preserved ejection fraction,significant left ventricular diastolic abnormalities are present,despite a normal systolic ejection fraction.This article will consider whether this is consistent with the law of conservation of energy,also know as the first law of thermodynamics.

Targeting epicardial adipose tissue:A potential therapeutic strategy for heart failure with preserved ejection fraction with type 2 diabetes mellitus

Heart failure with preserved ejection fraction(HFpEF)is a heterogeneous syndrome with various comorbidities,multiple cardiac and extracardiac pathophysiologic abnormalities,and diverse phenotypic presentations.Since HFpEF is a heterogeneous disease with different phenotypes,individualized treatment is required.HFpEF with type 2 diabetes mellitus(T2DM)represents a specific phenotype of HFpEF,with about 45%-50% of HFpEF patients suffering from T2DM.Systemic inflammation associated with dysregulated glucose metabolism is a critical pathological mechanism of HFpEF with T2DM,which is intimately related to the expansion and dysfunction(inflammation and hypermetabolic activity)of epicardial adipose tissue(EAT).EAT is well established as a very active endocrine organ that can regulate the pathophysiological processes of HFpEF with T2DM through the paracrine and endocrine mechanisms.Therefore,suppressing abnormal EAT expansion may be a promising therapeutic strategy for HFpEF with T2DM.Although there is no treatment specifically for EAT,lifestyle management,bariatric surgery,and some pharmaceutical interventions(anti-cytokine drugs,statins,proprotein convertase subtilisin/kexin type 9 inhibitors,metformin,glucagon-like peptide-1 receptor agonists,and especially sodium-glucose cotransporter-2 inhibitors)have been shown to attenuate the inflammatory response or expansion of EAT.Importantly,these treatments may be beneficial in improving the clinical symptoms or prognosis of patients with HFpEF.Accordingly,well-designed randomized controlled trials are needed to validate the efficacy of current therapies.In addition,more novel and effective therapies targeting EAT are needed in the future.

Risks of incident heart failure with preserved ejection fraction in Chinese patients hospitalized for cardiovascular diseases

Background Endogenous aldehyde damages DNA and potentiates an ageing phenotype. The aldehyde dehydrogenase 2(ALDH2) rs671 polymorphism has a prevalence of 30%–50% in Asian populations. In this study, we aimed to analyze risk factors contributing to the development of heart failure with preserved ejection fraction(HFpEF) along with the genetic exposure in Chinese patients hospitalized with cardiovascular diseases(CVD). Methods From July 2017 to October 2018, a total of 770 consecutive Chinese patients with normal left ventricular ejection fractions(LVEF) and established CVD(hypertension, coronary heart diseases, or diabetes) were enrolled in this prospective cross-sectional study. HFpEF was defined by the presence of at least one of symptom(dyspnoea and fatigue) or sign(rales and ankle swelling) related to heart failure;N-terminal pro-B-Type natriuretic peptide(NT pro-BNP ≥ 280 pg/mL);LVEF ≥ 50%;and at least one criterion related to elevated ventricular filling pressure or diastolic dysfunction(left atrial diameter > 40 mm, E/E’ ≥ 13, E’/A’ < 1 or concurrent atrial fibrillation). Logistic regression was performed to yield adjusted odds ratios(ORs) for HFp EF incidence associated with traditional and/or genetic exposures. Results Finally, among 770 patients with CVD, 92(11.9%) patients were classified into the HFpEF group according to the diagnostic criteria. The mean age of the participants was 67 ± 12 years, and 278(36.1%) patients were females. A total of 303(39.4%) patients were ALDH2*2 variant carriers. In the univariate analysis, eight exposures were found to be associated with HFpEF: atrial fibrillation, ALDH2*2 variants, hypertension, age, anaemia, smoking, alcohol consumption and sex. Multivariable logistic regression showed that 4 ‘A’ variables(atrial fibrillation, ALDH2*2 variants, age and anaemia) were significantly associated with an increased risk of HFpEF. Atrial fibrillation was associated with a 3.8-fold increased HFpEF risk(95% CI: 2.21–6.61, P < 0.001), and the other three exposures associated with increased HFpEF risk were the ALDH2*2 variant(OR = 2.41, 95% CI: 1.49–3.87, P < 0.001), age(OR = 2.14, 95% CI: 1.27–3.60, P = 0.004), and anaemia(OR = 1.79, 95% CI: 1.05–3.03, P = 0.032). These four variables predicted HFpEF incidence in Chinese CVD patients(C-statistic = 0.745, 95% CI: 0.691–0.800, P < 0.001). Conclusions 4 A traits(atrial fibrillation, ALDH2*2 variants, age and anaemia) were associated with an increased risk of HFpEF in Chinese CVD patients. Our results provide potential clues to the aetiology, pathophysiology and therapeutic targets of HFpEF.

Thirty-day readmission in patients with heart failure with preserved ejection fraction:Insights from the nationwide readmission database

BACKGROUND There are rising numbers of patients who have heart failure with preserved ejection fraction(HFpEF).Poorly understood pathophysiology of heart failure with preserved and reduced ejection fraction and due to a sparsity of studies,the management of HFpEF is challenging.AIM To determine the hospital readmission rate within 30 d of acute or acute on chronic heart failure with preserved ejection fraction and its effect on mortality and burden on health care in the United States.METHODS We performed a retrospective study using the Agency for Health-care Research and Quality Health-care Cost and Utilization Project,Nationwide Readmissions Database for the year 2017.We collected data on hospital readmissions of 60514 adults hospitalized for acute or acute on chronic HFpEF.The primary outcome was the rate of all-cause readmission within 30 d of discharge.Secondary outcomes were cause of readmission,mortality rate in readmitted and index patients,length of stay,total hospitalization costs and charges.Independent risk factors for readmission were identified using Cox regression analysis.RESULTS The thirty day readmission rate was 21%.Approximately 9.17%of readmissions were in the setting of acute on chronic diastolic heart failure.Hypertensive chronic kidney disease with heart failure(1245;9.7%)was the most common readmission diagnosis.Readmitted patients had higher in-hospital mortality(7.9%vs 2.9%,P=0.000).Our study showed that Medicaid insurance,higher Charlson co-morbidity score,patient admitted to a teaching hospital and longer hospital stay were significant variables associated with higher readmission rates.Lower readmission rate was found in residents of small metropolitan or micropolitan areas,older age,female gender,and private insurance or no insurance were associated with lower risk of readmission.CONCLUSION We found that patients hospitalized for acute or acute on chronic HFpEF,the thirty day readmission rate was 21%.Readmission cases had a higher mortality rate and increased healthcare resource utilization.The most common cause of readmission was cardio-renal syndrome.

The Relationship between Abnormal Circadian Blood Pressure Rhythm and Risk of Readmission in Patients with Heart Failure with Preserved Ejection Fraction

Objective:Abnormal circadian blood pressure rhythm has been revealed to be associated with hypertensive target organ damage and cardiovascular events,but its association with readmission risk in patients with heart failure with preserved ejection fraction(HFpEF)remains unknown.We conducted a retrospective study to explore the relationship between circadian blood pressure rhythm and readmission risk in HFpEF patients.Methods:We retrospectively collected baseline and follow-up data on HFpEF patients who underwent ambulatory blood pressure monitoring(ABPM)from May 2015 to October 2019.Patient circadian blood pressure rhythms defi ned by ABPM were grouped as dipper,nondipper,or riser patterns.Univariate and multivariate linear regression analyses were performed to assess the association between circadian blood pressure rhythm and readmission risk.Results:A total of 122 patients were enrolled in this study.The mean age and ejection fraction were 69.87 years and 61.44%,respectively,with mean the N-terminal pro-B-type natriuretic peptide(NT-proBNP)level being 1048.15 pg/mL.There were signifi cant differences in the 24-hour systolic blood pressure(SBP),sleep SBP,and sleep diastolic blood pressure(DBP)among the three groups,where the 24-hour SBP,sleep SBP,and sleep DBP in the riser pattern group were markedly higher than in the dipper pattern group.Notably,serum NT-proBNP levels,the proportion of patients readmitted for heart failure and the mean number of admissions differed markedly among three groups.Instructively,multivariate linear regression analysis showed that the riser pattern was a signifi cant and independent risk factor for increased serum NT-proBNP level(β=929.16,95%confi dence interval 178.79–1679.53,P=0.016).In multivariate logistic regression analysis,the riser pattern was demonstrated to be a signifi cant risk factor for readmission(odds ratio 11.23,95%confi dence interval 2.01–62.67,P=0.006)in HFpEF patients.Conclusion:The riser blood pressure pattern is a potential risk factor for elevated serum NT-proBNP level and readmission in HFpEF patients.

Progress in the Pathogenesis and Treatment of Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction(HFpEF)is a special and common clinical heart failure with left ventricular diastolic dysfunction.It has attracted much attention at home and abroad in recent years because of its high heterogeneity and complex pathogenesis.Compared with heart failure with reduced ejection fraction(HFrEF),HFpEF has complex clinical manifestations,many complications,limited clinical treatment,and poor prognosis.In recent years,the research on the pathogenesis and treatment of HFpEF has made certain progress,but there are no specific guidelines for clinical practice.By combing the latest research at home and abroad,the pathogenesis and treatment of HFpEF are systematically reviewed in order to provide a relevant basis for reference its clinical treatment.

Therapeutic Efficacy of Shexiang Baoxin Pill Combined with Exercise in Patients with Heart Failure with Preserved Ejection Fraction: A Single-Center, Double-Blind, Randomized Controlled Trial

Objective:To evaluate the therapeutic efficacy of Shexiang Baoxin Pill combined with exercise in heart failure patients with preserved ejection fraction(HFpEF).Methods:Sixty patients with HFpEF were randomly divided into group A(n=20),receiving Shexiang Baoxin Pill combined with home-based exercise training based on conventional drugs for 12 weeks;group B(n=20),receiving conventional drugs combined with home-based exercise training for 12 weeks;and group C(n=20),receiving conventional drug treatment only.Peak oxygen uptake(peakVO2),anaerobic threshold(AT),6-min walking test(6MWT),Pittsburgh Sleep Quality Index(PSQI),and SF-36 questionnaire(SF-36)results before and after treatment were compared among groups.Results:After the 12-week intervention,patients in group C showed significant declines in peakVO2,AT,6MWT,PSQI,and SF-36 compared with pre-treatment(P<0.01),while groups A and B both showed significant improvements in peakVO2,AT,6MWT,PSQI,and SF-36 results compared with pre-treatment(P<0.01).Compared with group C,patients in groups A and B showed significant improvements in peakVO2,AT,6MWT,PSQI,and SF-36(P<0.01).In addition,patients in group A showed more significant improvements in physical function,role-physical,vitality,and mental health scores on the SF-36 questionnaire,and PSQI scores than those in group B(P<0.01).Conclusions:Exercise training improved exercise tolerance,sleep quality and quality of life(QoL)in patients with HFpEF.Notably,Shexiang Baoxin Pill played an active role in sleep quality and QoL of patients with HFpEF.

Right ventricular-arterial uncoupling as an independent prognostic factor in acute heart failure with preserved ejection fraction accompanied with coronary artery disease

Background:Right ventricular(RV)-arterial uncoupling is a powerful independent predictor of prognosis in heart failure with preserved ejection fraction(HFpEF).Coronary artery disease(CAD)can contribute to the pathophysiological characteristics of HFpEF.This study aimed to evaluate the prognostic value of RV-arterial uncoupling in acute HFpEF patients with CAD.Methods:This prospective study included 250 consecutive acute HFpEF patients with CAD.Patients were divided into RV-arterial uncoupling and coupling groups by the optimal cutoff value,based on a receiver operating characteristic curve of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure(TAPSE/PASP).The primary endpoint was a composite of all-cause death,recurrent ischemic events,and HF hospitalizations.Results:TAPSE/PASP≤0.43 provided good accuracy in identifying patients with RV-arterial uncoupling(area under the curve,0.731;sensitivity,61.4%;and specificity,76.6%).Of the 250 patients,150 and 100 patients could be grouped into the RV-arterial coupling(TAPSE/PASP>0.43)and uncoupling(TAPSE/PASP≤0.43)groups,respectively.Revascularization strategies were slightly different between groups;the RV-arterial uncoupling group had a lower rate of complete revascularization(37.0%[37/100]vs.52.7%[79/150],P<0.001)and a higher rate of no revascularization(18.0%[18/100]vs.4.7%[7/150],P<0.001)compared to the RV-arterial coupling group.The cohort with TAPSE/PASP≤0.43 had a significantly worse prognosis than the cohort with TAPSE/PASP>0.43.Multivariate Cox analysis showed TAPSE/PASP≤0.43 as an independent associated factor for the primary endpoint,all-cause death,and recurrent HF hospitalization(hazard ratios[HR]:2.21,95%confidence interval[CI]:1.44-3.39,P<0.001;HR:3.32,95%CI:1.30-8.47,P=0.012;and HR:1.93,95%CI:1.10-3.37,P=0.021,respectively),but not for recurrent ischemic events(HR:1.48,95%CI:0.75-2.90,P=0.257).Conclusion:RV-arterial uncoupling,based on TAPSE/PASP,is independently associated with adverse outcomes in acute HFpEF patients with CAD.

Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction:Evidence from Metabolomics

Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).

Elevated level of high-sensitivity cardiac troponin I as a predictor of adverse cardiovascular events in patients with heart failure with preserved ejection fraction

Background:The relationship between the elevation of cardiac troponin and the increase of mortality and hospitalization rate in patients with heart failure with reduced ejection fraction is clear.This study investigated the association between the extent of elevated levels of high-sensitivity cardiac troponin I(hs-cTnI)and the prognosis in heart failure with preserved ejection fraction patients.Methods:A retrospective cohort study consecutively enrolled 470 patients with heart failure with preserved ejection fraction from September 2014 to August 2017.According to the level of hs-cTnI,the patients were divided into the elevated level group(hs-cTnI>0.034 ng/mL in male and hs-cTnI>0.016 ng/mL in female)and the normal level group.All of the patients were followed up once every 6 months.Adverse cardiovascular events were cardiogenic death and heart failure hospitalization.Results:The mean follow-up period was 36.2±7.9 months.Cardiogenic mortality(18.6%[26/140]vs.1.5%[5/330],P<0.001)and heart failure(HF)hospitalization rate(74.3%[104/140]vs.43.6%[144/330],P<0.001)were significantly higher in the elevated level group.The Cox regression analysis showed that the elevated level of hs-cTnI was a predictor of cardiogenic death(hazard ratio[HR]:5.578,95%confidence interval[CI]:2.995-10.386,P<0.001)and HF hospitalization(HR:3.254,95%CI:2.698-3.923,P<0.001).The receiver operating characteristic curve demonstrated that a sensitivity of 72.6%and specificity of 88.8%for correct prediction of adverse cardiovascular events when a level of hs-cTnI of 0.1305 ng/mL in male and a sensitivity of 70.6%and specificity of 90.2%when a level of hs-cTnI of 0.0755 ng/mL in female were used as the cut-off value.Conclusion:Significant elevation of hs-cTnI(≥0.1305 ng/mL in male and≥0.0755 ng/mL in female)is an effective indicator of the increased risk of cardiogenic death and HF hospitalization in heart failure with preserved ejection fraction patients.

A Data Mining-Based Study on Medication Rules of Chinese Herbs to Treat Heart Failure with Preserved Ejection Fraction

Objective:To summarize the medication rules of Chinese herbs to treat heart failure with preserved ejection fraction(HFPEF)based on data mining and to provide references for clinical utilization.Methods:The China National Knowledge Infrastructure(CNKI),Wanfang database(Wanfang),VIP database(VIP),Chinese Biomedical Literature(CBM),PubMed,Embase,and Cochrane Library databases were searched from inception to October 2021 to identify relevant literature on treating HFPEF with Chinese herbs.Microsoft Excel 2019 was used to set up a database,and then,association rule analysis and hierarchical cluster analysis were performed by using apriori algorithm and hclust function respectively in R-Studio(Version 4.0.3).Results:A total of 182 qualified papers were included,involving a total of 92 prescriptions,130 Chinese herbs,and 872 individual herbs prescribed,with an average of 9.5 herbs per prescription.The six most frequently prescribed herbs were Astragali Radix(Huangqi),Salviae Miltiorrhizae Radix Et Rhizoma(Danshen),Poria(Fuling),Glycyrrhizae Radix Et Rhizoma(Gancao),Cinnamomi Ramulus(Guizhi),and Ginseng Radix Et Rhizoma(Renshen).There were 35 herbs used more than 5 times,involving 11 efficacy categories.The top three categories were deficiency-tonifying herbs,blood-activating and stasis-removing herbs,and dampnessdraining diuretic herbs.The most commonly used herbs were mainly warm and sweet.The primary meridian tropisms were Lung Meridian,Heart Meridian and Spleen Meridian.Association rule analysis yielded 26 association rules,such as Astragali Radix(Huangqi)&Salviae Miltiorrhizae Radix Et Rhizoma(Danshen),Poria(Fuling),Cinnamomi Ramulus(Guizhi)&Atractylodis Macrocephalae Rhizoma(Baizhu).Hierarchical cluster analysis yielded four herb classes,and their functions were mainly qi-replenishing and yang-warming,bloodactivating and diuresis-inducing.Conclusions:HFPEF is the syndrome of root vacuity and tip repletion,and its core pathogenesis is"deficiency","stasis",and"wafer",with"deficiency"being the most principal,which is closely related to Xin(heart),Fei(Lung),and Pi(Spleen).The treatment of this disease occurs by improving qi,warming yang,activating blood and inducing diuresis.Astragali Radix(Huangqi)with Salviae Miltiorrhizae Radix Et Rhizoma(Danshen)is the basic combination of herbs applied.

Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction:A randomized clinical trial

Objective To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Design Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 sta- ble outpatients with HF, ejection fraction ≥ 50%, elevated N-terminal brain-type natriuretic peptide or elevat- ed invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012.

Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes melitus: from pathophysiology to therapeutics

Type 2 diabetes mellitus(T2DM or T2D)is a devastating metabolic abnormality featured by insulin resistance,hyperglycemia,and hyperlipidemia.T2D provokes unique metabolic changes and compromises cardiovascular geometry and function.Meanwhile,T2D increases the overall risk for heart failure(HF)and acts independent of classical risk factors including coronary artery disease,hypertension,and valvular heart diseases.The incidence of HF is extremely high in patients with T2D and is manifested as HF with preserved,reduced,and midrange ejection fraction(HFpEF,HFrEF,and HFmrEF,respectively),all of which significantly worsen the prognosis for T2D.HFpEFis seen in approximately half of the HF cases and is defined as a heterogenous syndrome with discrete phenotypes,particularly in close association with metabolic syndrome.Nonetheless,management of HFpEF in T2D remains unclear,largely due to the poorly defined pathophysiology behind HFpEF.Here,in this review,we will summarize findings from multiple preclinical and clinical studies as well as recent clinical trials,mainly focusing on the pathophysiology,potential mechanisms,and therapies of HFpEF in T2D.

Research progress of sacubitril/valsartan in heart failure patients with preserved ejection fraction

With the launch of sacubitril/valsartan(ARNI),there are new options for the treatment of heart failure(HF).However,ARNI is currently only used in HF patients with reduced ejection fraction(HFrEF).No evidence shows that no modern treatment can reduce mortality in HF patients with preserved ejection fraction(HFpEF).Therefore,it is urgently necessary clarify whether ARNI can be used in the treatment of HFpEF.In the present study,we summarized the research progress of ARNI in the treatment of HFpEF.

Heterogeneity in cardiorenal protection by Sodium glucose cotransporter 2 inhibitors in heart failure across the ejection fraction strata:Systematic review and meta-analysis

BACKGROUND Gliflozins or Sodium glucose cotransporter 2 inhibitors(SGLT2i)are relatively novel antidiabetic medications that have recently been shown to represent favorable effects on patients’cardiorenal outcomes.However,there is shortage of data on potential disparities in this therapeutic effect across different patient subpopulations.AIM To investigate differential effects of SGLT2i on the cardiorenal outcomes of heart failure patients across left ventricular ejection fraction(LVEF)levels.METHODS Literature was searched systematically for the large randomized double-blind controlled trials with long enough follow up periods reporting cardiovascular and renal outcomes in their patients regarding heart failure status and LVEF levels.Data were then meta-analyzed after stratification of the pooled data across the LVEF strata and New York Heart Associations(NYHA)classifications for heart failure using Stata software version 17.0.RESULTS The literature search returned 13 Large clinical trials and 13 post hoc analysis reports.Meta-analysis of the effects of gliflozins on the primary composite outcome showed no significant difference in efficacy across the heart failure subtypes,but higher efficacy were detected in patient groups at lower NYHA classifications(I2=46%,P=0.02).Meta-analyses across the LVEF stratums revealed that a baseline LVEF lower than 30%was associated with enhanced improvement in the primary composite outcome compared to patients with higher LVEF levels at the borderline statistical significance(HR:0.70,95%CI:0.60 to 0.79 vs 0.81,95%CI:0.75 to 0.87;respectively,P=0.06).Composite renal outcome was improved significantly higher in patients with no heart failure than in heart failure patients with preserved ejection fraction(HFpEF)(HR:0.60,95%CI:0.49 to 0.72 vs 0.94,95%CI:0.74 to 1.13;P=0.04).Acute renal injury occurred significantly less frequently in heart failure patients with reduced ejection fraction who received gliflozins than in HFpEF(HR:0.67,95%CI:51 to 0.82 vs 0.94,95%CI:0.82 to 1.06;P=0.01).Volume depletion was consistently increased in response to SGLT2i in all the subgroups.CONCLUSION Heart failure patients with lower LVEF and lower NYHA sub-classifications were found to be generally more likely to benefit from therapy with gliflozins.Further research are required to identify patient subgroups representing the highest benefits or adverse events in response to SGLT2i.

Shunxin decoction(顺心组方) improves diastolic function in rats with heart failure with preserved ejection fraction induced by abdominal aorta constriction through cyclic guanosine monophosphate-dependent protein kinase Signaling Pathway

OBJECTIVE: To determine whether Shunxin decoction(顺心组方) improves diastolic function in rats with heart failure with preserved ejection fraction(HFp EF) by regulating the cyclic guanosine monophosphatedependent protein kinase(c GMP-PKG) signaling pathway. METHODS: Except for control group 8 and sham surgery group 8, the remaining 32 male Sprague-Dawlay rats were developed into HFp EF rat models using the abdominal aorta constriction method. These rats in the HFp EF model were randomly divided into the model group, the Shunxin high-dose group, the Shunxin lowdose group, and the Qiliqiangxin capsule group. The three groups received high-dose Shunxin decoction, lowdose Shunxin decoction, and Qiliqiangxin capsule by gavage, respectively, for 14 d. After the intervention, the diastolic function of each rat was evaluated by testing E/A, heart index, hematoxylin-eosin staining, Masson, myocardial ultrastructure, and N-terminal pro-brain natriuretic peptide(NT-pro BNP). The Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine(BATMAN-TCM) software was used to predict targets for which Shunxin decoction acts on the c GMP-PKG pathway. Natriuretic peptide receptor A(NPRA) and guanylate cyclase(GC) were detected by immunohistochemistry, and e NOS, phosphodiesterase 5A(PDE5A), and c GMP-dependent protein kinase 1(PKG I) were determined by Western blotting. RESULTS: Compared to the model group, the thickness of the interventricular septum at the end of diastole(IVSd) and the thickness of the posterior wall at the end of diastole(PWd) of the Shunxin decoction high-dose group, Shunxin decoction low-dose group, and Qiliqiangxin capsule group were all significantly reduced(P < 0.01). Furthermore, Shunxin decoction high-dose group E/A value was decreased(P < 0.01). Compared to the model group, the expression of NPRA and GC increased in the Shunxin decoction low-dose group and the Qiliqiangxin capsule group(P < 0.01). Compared to the model group, the expressions of e NOS and PKG I increased(P < 0.05) in the Shunxin decoction high-dose group. The expression of PDE5A expression decreased in the myocardium of the Shunxin decoction high-dose group, Shunxin decoction low-dose group, and Qiliqiangxin capsule group compared to the model group(P < 0.01). CONCLUSIONS: Shunxin decoction can improve diastolic function in rats with HFp EF. It increases the expression of NPRA, GC, and e NOS in the myocardial cell c GMP-PKG signaling pathway, upregulates c GMP expression, decreases PDE5A expression to reduce the c GMP degradation. Thus, the c GMP continually stimulates PKG I, reversing myocardial hypertrophy and improving myocardial compliance in HFp EF rats.

Diagnosis and treatment of heart failure with preserved ejection fraction

Heart failure, a primary worldwide public health burden, is a complicated clinical syndrome manifested in hemodynamic and symptomatic changes. There are 2 subtypes of heart failure, with ejection frac- tion preserved （HFpEF） and reduced （HFrEF）. The morbidity of HFpEF derived from epidemic data accounts for 50% of total HF patients which is expected to continuously increase with the increase of elderly population in the future. The relevant risk factors for HFpEF include aging, female gender, hypertension, ischemic heart dis- ease, atrial fibrillation and diabetes mellitus. The essence of HFpEF is recognized as an increase in left ventricu- lar filling pressure implicated in certain interlinked physiological systems. The treatments are mainly aimed to re- lieve the symptoms and control risk factors such as anti-hypertension, prevention of myocardial ischaemia, ve- nous pressure reduction, management of atrial fibrillation and management of diabetes. In addition, some new treatments are being tested in clinical trails such as phosphodiesterase-5 （PDE5） inhibitor, tetrahydrobiopterin （BH4）, late Na current inhibitor, cardiac resynchronization therapy and angiotensin receptor neprilysin inhibitor LCZ696. Here, we briefly review the diagnosis and treatment in heart failure with preserved ejection fraction.

Sodium glucose cotransporter 2 inhibitors in the management of heart failure:Veni,Vidi,and Vici

Heart failure(HF)is a chronic disease associated with high morbidity and mortality rates.Renin-angiotensin-aldosterone system blockers(including angiotensin receptor/neprilysin inhibitors),beta-blockers,and mineralocorticoid receptor blockers remain the mainstay of pharmacotherapy for HF with reduced ejection fraction(HFrEF).However,despite the use of guideline-directed medical therapy,the mortality from HFrEF remains high.HF with preserved ejection fraction(HFpEF)comprises approximately half of the total incident HF cases;however,unlike HFrEF,there are no proven therapies for this condition.Sodium glucose cotransporter-2 inhibitors(SGLT-2is)represent a new class of pharmacological agents approved for diabetes mellitus(DM)that inhibit SGLT-2 receptors in the kidney.A serendipitous finding from seminal trials of SGLT-2is in DM was the significant improvement in renal and cardiovascular(CV)outcomes.More importantly,the improvement in HF hospitalization(HHF)in the CV outcomes trials of SGLT-2is was striking.Multiple mechanisms have been proposed for the pleiotropic effects of SGLT-2is beyond their glycemic control.However,as patients with HF were not included in any of these trials,it can be considered as a primary intervention.Subsequently,two landmark studies of SGLT-2is in patients with HFrEF,namely,an empagliflozin outcome trial in patients with chronic HF and a reduced ejection fraction(EMPEROR-Reduced)and dapagliflozin and prevention of adverse outcomes in HF(DAPA-HF),demonstrated significant improvement in HHF and CV mortality regardless of the presence of DM.These impressive results pitchforked these drugs as class I indications in patients with HFrEF across major guidelines.Thereafter,empagliflozin outcome trial in patients with chronic HF with preserved ejection fraction(EMPEROR-Preserved)and dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction HF(DELIVER)trials successively confirmed that SGLT-2is also benefit patients with HFpEF with or without DM.These results represent a watershed as they constitute the first clinically meaningful therapy for HFpEF in the past three decades of evolution of HF management.Emerging positive data for the use of SGLT-2is in acute HF and post-myocardial infarction scenarios have strengthened the pivotal role of these agents in the realm of HF.In a short span of time,these classes of drugs have captivated the entire scenario of HF.

Dapagliflozin in heart failure and type 2 diabetes:Efficacy,cardiac and renal effects,safety

BACKGROUND Heart failure(HF),especially HF with reduced ejection fraction(HFrEF),presents complex challenges,particularly in the aging population where it often coexists with type 2 diabetes mellitus(T2DM).AIM To analyze the effect of dapagliflozin treatment on cardiac,renal function,and safety in patients with HFrEF combined with T2DM.METHODS Patients with T2DM complicated with HFrEF who underwent treatment in our hospital from February 2018 to March 2023 were retrospectively analyzed as the subjects of this study.The propensity score matching method was used,and a total of 102 eligible samples were scaled.The clinical efficacy of the two groups was evaluated at the end of the treatment,comparing the results of blood glucose,insulin,cardiac function,markers of myocardial injury,renal function indexes,and 6-min walk test(6MWT)before and after the treatment.We compared the occurrence of adverse effects on the treatment process of the two groups of patients.The incidence of adverse outcomes in patients within six months of treatment was counted.RESULTS The overall clinical efficacy rate of patients in the study group was significantly higher than that of patients in the control group(P=0.013).After treatment,the pancreatic beta-cell function index,left ventricular ejection fraction,and glomerular filtration rate of patients in the study group were significantly higher than control group(P<0.001),while their fasting plasma glucose,2-h postprandial glucose,glycosylated hemoglobin,insulin resistance index,left ventricular end-systolic diameter,left ventricular end-diastolic diameter,cardiac troponin I,creatine kinase-MB,N-terminal pro b-type natriuretic peptide,serum creatinine,and blood urea nitrogen were significantly lower than those of the control group.After treatment,patients in the study group had a significantly higher 6MWT than those in the control group(P<0.001).Hypoglycemic reaction(P=0.647),urinary tract infection(P=0.558),gastrointestinal adverse effect(P=0.307),respiratory disturbance(P=0.558),and angioedema(P=0.647)were not statistically different.There was no significant difference between the incidence of adverse outcomes between the two groups(P=0.250).CONCLUSION Dapagliflozin significantly enhances clinical efficacy,cardiac and renal function,and ambulatory capacity in patients with HFrEF and T2DM without an increased risk of adverse effects or outcomes.