The Role And Mechanism Of The Sodium-Glucose Cotransport Protein 2 Inhibitor In Heart Failure With Preserved Ejection Fraction

BackgroundHeart failure(HF)is a complex clinical syndrome in which the signs and symptoms are caused by a function or structure that affects the contraction or diastole of the ventricles.According to the China Cardiovascular Health and Disease Report 2021,the prevalence of cardiovascular disease in China is increasing year by year,with an estimated 8.9 million people currently suffering from HF in China,and it has become an important public health issue affecting the field of cardiovascular disease(CVD)in China.The 2022 AHA/ACC/HFSA Guidelines for the Management of Heart Failure update the classification of HF-in the traditional triad of Heart failure with reduced ejection fraction(HFrEF),Heart failure with mildly reduced ejection fraction(HFmrEF)and Heart failure with preserved ejection fraction(HFpEF),Heart failure with improved ejection fraction(HFimpEF)have been added to the traditional triad of HF.The focus on HFimpEF began with the 2020 JACC Expert Consensus on Heart failure with recovered ejection fraction(HFrecEF),which now classifies HFrecEF as HFimpEF,although the definitions differ slightly.In terms of treatment,the guidelines recommend that such patients with recovered cardiac function based on HFrEF(HFimpEF)require continued guideline-directed management and therapy(GDMT)to prevent recurrence of HF or left ventricular insufficiency.It is worth noting,however,that recovery of cardiac function is most often achieved by improvement of the causes of normal cardiac energy metabolism,and therefore GDMT has shifted from the traditional "triad" to a"neo-quad" with the addition of sodium-glucose cotransporter 2 inhibitors(SGLT2i).The addition of SGLT2i,which improves cardiometabolic function,and the consolidation of SGLT2i as a first-line treatment in HFrEF,will help to restore cardiac function in more patients.Therefore,the first part of this topic explores the clinical characteristics and outcomes of patients with HFrecEF versus persistent HFrEF and explores the predictive value of applying SGLT2i to clinical outcome events in patients with HFrEF.Given the timeliness of guidelines and expert consensus,this part uses an expert consensus-based definition of HFrecEF.Based on the breakthrough of SGLT2i in the field of HFrEF,experts then explored whether it could be applied in the field of HFpEF for the cardiovascular benefit of HFpEF patients.HFpEF is a growing public health problem,accounting for approximately 50%of all HF patients,and is a highly heterogeneous group of diseases with predominantly impaired LV diastolic function.As the causative factors persist and HFpEF disease progresses,the LVEF trajectory may change dynamically,with LV systolic dysfunction occurring in the later stages of the disease when LVEF decreases.The limited availability of evidence-based pharmacological or therapeutic approaches for HFpEF compared to HFrEF,and the lack of suitable HFpEF models that effectively mimic the complexity of human HFpEF,has hindered the development of therapeutic approaches.Therefore,in this study,a high fat diet(HFD)combined with N[w]-nitro-1-arginine methyl ester(L-NAME)rat model(known as the ’2-Hit’ strategy)was used,compared to the previously reported HFpEF model.This model best mimics the co-morbidity,metabolic phenotype and cardiovascular profile of HFpEF compared to previously reported HFpEF models.Thus,the ’double whammy’ strategy offers the potential to investigate the prevention and treatment of diastolic dysfunction and cardiac structural remodelling in HFpEF.Dapagliflozin(DAPA),an SGLT2i,is widely used in the clinic due to its inhibition of glucose reabsorption in the kidney and,based on the beneficial results of the latest EMPEROR-Reduced and DAPA-HF studies,the guidelines recommend the use of SGLT2i in patients with chronic stable HFpEF(Class 2a recommendation).However,the mechanism by which SGLT2i prevents and treats HFpEF and improves cardiac function and structural remodelling is currently unknown.Recent studies suggest that SGLT2i may improve myocardial energy metabolism by increasing ketone body production,and that increased levels of β-hydroxybutyric acid(β-OHB)in ketone bodies activate citrate synthase(CS),a centre of the mitochondrial redox process,and thus improve mitochondrial function.Based on the finding in the first part that SGLT2i has a predictive value for clinical endpoints in patients with HFrEF,and based on its important role in metabolic phenotyping,it is hypothesized that SGLT2i could have a protective effect on HFpEF by affecting metabolic function.In the second part of this study,a "2-Hit " induced HFpEF rat model was established,followed by an investigation into whether DAPA prophylactic intervention and treatment had a cardioprotective effect on the onset and progression of HFpEF disease by increasing β-OHB levels and activating CS,thereby improving myocardial energy metabolism.Part 1 Characteristics and Outcomes of Heart Failure with Recovered Left Ventricular Ejection FractionObjectives:With the introduction of the HFrecEF as well as the HFimpEF concept,the dynamic trajectory of LVEF has attracted a lot of attention from clinicians.In this part of the study,the aim was to examine the clinical characteristics and outcomes of patients with HFrecEF compared to those with persistent HFrEF,and the predictive value of SGLT2i for clinical endpoint events in patients with HFrEF.Methods:This was a single-centre,retrospective,observational study.Patients who were hospitalized at the First Hospital of Dalian Medical University and diagnosed with HFrEF from November 1,2015 to October 31,2019 were included in the study.All enrolled patients underwent at least 2 echocardiographic examinations more than 3 months apart,and patients were divided into the HFrecEF group(LVEF>40%on the 2nd measurement and ≥10%improvement in LVEF)and the persistent HFrEF group(<10%improvement in LVEF)according to the recovery of LVEF.To further investigate the clinical prognosis of patients with HFrecEF,the group was further divided into two subgroups with 10-20%improvement in LVEF and>20%improvement in LVEF.The primary endpoint events were all-cause death and all-cause rehospitalization.Results:A total of 1160 HFrEF patients were included[70.2%male,mean(standard deviation)age:62±13 years].On the second echocardiogram,284 patients(24.5%)showed HFrecEF and 876 patients(75.5%)showed persistent HFrEF.All-cause mortality was identified in 23(8.10%)HFrecEF and 165(18.84%)persistent HFrEF,whilst 76(26.76%)and 426(48.63%)showed rehospitalizations,respectively.Survival analysis showed that the persistent HFrEF subgroup experienced a significantly higher mortality at 12 and 24 months and a higher hospitalization at 12,24,48,and more than 48 months following discharge.Multivariate Cox regression showed that persistent HFrEF had a higher risk of all-cause mortality[hazard ratio(HR)2.30,95%confidence interval(CI)1.49-3.56,P=0.000]and rehospitalization(HR 1.85,95%CI 1.45-2.36,P=0.000)than the HFrecEF group.Administration of SGLT2i was an independent predictor of all-cause mortality(HR 0.137,95%CI 0.019-0.981,P=0.048)and all-cause readmission to SGLT2i(HR 0.449,95%CI 0.222-0.905,P=0.025)in patients with HFrEF.Subgroup analysis showed that the LVEF≥20%improvement subgroup had lower rates of adverse outcomes compared with those with less improvement of 10-20%.Conclusions:Heart failure with recovered ejection fraction is a distinct HF phenotype with better clinical outcomes compared with those with persistent HFrEF.HFrecEF patients have a relatively better short-term mortality at 24 months but not thereafter.Administration of SGLT2i was an independent predictor of reduced all-cause mortality and all-cause rehospitalization in patients with HFrEF.Part 2 Sodium-Glucose Cotransport Protein 2 Inhibitor Dagliflozin Improves Heart Failure with Preserved Ejection Fraction by Modulating Myocardial Energy MetabolismObjectives:HFpEF is a growing public health problem,accounting for approximately 50%of all HF patients,and it is a highly heterogeneous group of diseases with predominantly impaired left ventricular diastolic function.The latest guidelines recommend SGLT2i for the treatment of HFpEF,but the mechanisms by which SGLT2i prevents and treats cardiac remodelling and dysfunction are currently unknown.Methods:HFD combined with L-NAME(0.5 g/L)was used to induce male Sprague-Dawley(SD)rats for 6 weeks to establish a model of HFpEF,and "2-Hit"induction for 12 weeks to establish a model of ventricular systolic dysfunction based on advanced left ventricular diastolic dysfunction in HFpEF disease.Myocardial hypertrophy,fibrosis,inflammation,oxidative stress and apoptosis were detected by western blot,qRT-PCR and histological staining.Positron emission tomography/computed tomography(PET-CT)was used to detect fluorodeoxyglucose([18F]-2-fluoro-2-deoxy-D-glucose(FDG)and[18F]-fluoro-6-thioheptadecanoic acid([18F]-thioheptadecanoic acid).(18F]-6-thia-heptadecanoic acid,FTHA),with FDG and FTHA reflecting myocardial uptake of glucose and fatty acids,respectively.Energy metabolism was further assessed by measuring β-OHB,Acetyl coenzyme A(Acetyl-CoA)and CS activity levels in clinical blood specimens and in rat heart and blood.Results:In contrast to the "2-Hit " model group,prophylactic intervention and treatment with DAPA significantly inhibited "2-Hit"-induced cardiomyocyte hypertrophy,apoptosis,inflammation,oxidative stress and fibrosis,while improving cardiac systolic dysfunction in the late progression of HFpEF disease.DAPA prophylactic intervention and treatment improved mitochondrial function by increasingβ-OHB levels,activating CS activity,reducing the Acetyl-CoA pool,regulating ATP production and increasing the expression of the mitochondrial oxidative phosphorylation system complex Ⅰ-Ⅴ(NDUFB8,SDHB,UQCRC2,MTCO2,ATP5A).In addition,PET/CT results showed that DAPA prophylactic intervention and treatment significantly inhibited fatty acid uptake.Consistent with the in vivo findings,clinical blood ELISA results showed that blood β-OHB and CS levels increased but acetyl-CoA levels decreased in HFpEF patients after clinical DAPA treatment compared to HFpEF patients who did not receive DAPA treatment.Conclusion:DAPA prophylactic intervention and treatment improves cardiac energy metabolism in HFpEF by increasing β-OHB levels and activating CS to reduce acetyl-CoA levels,thereby regulating mitochondrial function.At the same time,DAPA prophylactic intervention and treatment significantly inhibited "2-Hit"-induced cardiomyocyte hypertrophy,fibrosis,apoptosis,inflammation and oxidative stress in HFpEF,and improved cardiac remodeling and dysfunction.The results of the above two parts of the study suggest that SGLT2i can provide predictive value for clinical endpoints in patients with HFrEF and may contribute to the subsequent recovery of LVEF in such patients,and that DAPA,one of the SGLT2i,can exert a protective effect on HFpEF by affecting metabolic function.This study provides a new idea of the role of DAPA in preventive intervention and treatment of HFpEF,offering new therapeutic targets and intervention strategies for the clinical prevention and treatment of HFpEF.