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.

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.

Cardioprotective Effects of Melatonin on Recovery of Rat Donor Hearts after 12-Hour Preservation

The cardioprotective effects of melatonin on recovery of rat donor hearts after 12 h of preservation were investigated. Wistar rats weighing 200 to 250 g ( n =24) were randomly divided into 3 groups. In the non storage group ( n =8), donor hearts were not stored. In the melatonin group ( n =8), donor hearts were stored in 4 ℃ St. Thomas solution with melatonin (0.1 mmo1/L). In the control group ( n =8), donor hearts were stored in 4 ℃ St. Thomas solution only. The coronary flow (CF), cardiac function, coronary vasodilatory response, creatine kinase (CK) and high energy phosphate levels were measured after the hearts had been preserved for 12 h. Transmission electron microscopy was used to examine the microstructural changes after 12 h of preservation. The recovery of cardiac function and coronary vasodilatory response were significantly improved in the melatonin group ( P <0.01). CK release decreased greatly in the melatonin group ( P <0.01). High energy phosphate levels were significantly better preserved in the melatonin group ( P <0.01). Histological findings were much better in the melatonin group than in the control group. These results suggest that melatonin has cardioprotective effects on the recovery of rat donor hearts after 12 h of preservation.

EXPERIMENTAL STUDY ON HEART PRESERVATION

Heart transplantation is now being accepted worldwide and has presented with good results. However,the shortage of donor hearts has become an obstacle of heart transplantation. To explore the donor heart sources and to prolong the preservation time, we chose the adult porcine heart which is similar to human’s in size, weight, coronary architecture and conduction system for experiment. In part I, a simple cold flushing and storage method was used for preservation of 11 porcine hearts for 4-6 hours. Before a heart procurement, the carotid artery and the jugular vein were cut for bleeding and collecting a total amount of 2000ml of blood. A heart-lung machine was primed with diluted blood. Before resuscitation, the heart was reperfused with warm blood cardioplegic solution to reduce reperfusion injury, and then with the normal

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.

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.

Preservation of donor's heart and lung and discrimination and postoperative immunotherapy of graft rejection:a report of 2 cases of heart-lung transplantation

Objective To summarize preservation measures of donor’s heart and lung,and postoperative imrnunotherapy,as well as clinical experience of discrimination and management for graft rejection. Methods Clinical data of 2 cases of heart - lung transplantation in our depart-

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.

Forensic interrogation of diabetic endothelitis in cardiovascular diseases and clinical translation in heart failure

Diabetic heart disease(DHD)can be classified as a primary consequence from several pathophysiological manifestation of diabetes mellitus(DM)on cardiac tissues or secondarily in extracardiac tissues and is encountered as either primary or secondary complications of DM.Endothelitis is inflammation of the vascular endothelium and is likely to be seen in the majority of patients who start to manifest an end organ complication of DM in this case DHD.Diabetes is a leading cause for many cardiovascular syndromes and diseases including congestive heart failure(CHF)however much remains unknown about the transition from diagnosed DM to clinical state and the contribution of the various mechanical and counterregulatory systems in the manifested complaint.Diastolic heart failure or heart failure with preserved ejection fraction(DHF/HFpEF),accounts for half of all CHF presentations,has DM as a major contributor,however,there remain large gaps in clinical and pathophysiological understanding.This review aims to explore the microscopic aspects in diabetic endothelitis and provide a clinical link to with context to HFpEF.

Heart‘omicsin’AGEing (HOMAGE):design,research objectives and characteristics of the common database

Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A large clinical database,based on（1） prospective population studies or（2） cross-sectional,prospective studies or randomized controlled trials（RCTs） of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ＇omics＇-based biomarkers to identify the risk of developing heart failure and/or comorbidities.Population studies,patient cohorts and RCTs are eligible for inclusion in the common database,if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors.Currently,the HOMAGE database includes 43,065 subjects,from 20 studies in eight European countries,including healthy subjects from three population studies in France,Belgium and Italy（n = 7,124）,patients with heart failure（n = 4,312） from four cohorts in the UK,Spain and Switzerland and patients at high risk for cardiovascular disease（n = 31,629） in 13 cohorts.It is anticipated that more partners will join the consortium and enlarge the pooled data.This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.

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.

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.

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.

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).

Study on the inflammatory cytokines after heterotopic transplantation of isolated mouse heart preserved in a high-pressured mixed gas chamber

Background The maintenance of heart viability is important for heart transplantation. Currently, heart preservation is limited to 6 hours of cold ischemic storage. This study explored a new heart preservation method under a high-pressured mixed gas chamber. Methods C57BL/6 male mice were used to establish the model of mice cervical heterotopic heart transplantation. Adult donor mice were randomly divided into three groups subjected to naive operation （Group A）, standard control （Group B） and experimental control （Group C）. The recipient mice were randomly divided into two groups subjected to standard control and experimental control. Group A： hearts were isolated; Group B： hearts were isolated and preserved in HTK solution at 4 ℃ for 8 h and transplanted; Group C： hearts were isolated and preserved in high pressured gas （PO2：3200 hPa ＋ PCO： 800 hPa = 4000 hPa） at 4 ℃ for 8h and transplanted. After transplantation, the state of re-beating and cardiac function were observed for Group B and C. At 24 h after transplantation, samples were collected for HE staining, cardiac cell apoptosis detection by Tunnel staining and analysis of tumor necrosis factor α （TNF-α）, interleukin-1β （IL-1β）, interleukin-6 （IL-6） and interleukin-10 （IL-10） by reverse transcriotion-polymerase chain reaction （RT-PCR）. Results In group C, 15 transplanted hearts were re-beat, while only 6 in Group B. The re-beating rate in Group C was significantly higher than Group B [75.0%（15/20） vs. 30.0%（6/20） ,P = 0.01]. The time of re-beating was significantly different between Group B, and C [（352.35 ± 61.07）s vs. （207.85 ± 71.24） s, P 〈 0.011. HE staining showed that pathologic changes such as ceil edema and inflammatory cell infiltration were more obvious in Group B and C than in Group A, but less obvious in Group C compared with Group B. Tunnel staining showed that Group B had more obvious apoptosis than Group A and C. RT-PCR results showed significant increase of TNF-α, IL-1β and IL-6 expression in Group B than Group C （P 〈 0.01, the expression of IL-10 was higher in Group C than that in Group B. Conclusion Highpressured mixed gas （PO2：3200 hPa ＋ PCO： 800 hPa = 4000 hPa） preservation can reduce cold ischemia and reperfusion injury of donor heart, therefore to maintain myocardial viability and prolong preservation time of donor heart.

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.

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.

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.