Role of beta1- and alpha2c-adrenergic receptor polymorphisms and their combination in heart failure: a case-control study

BACKGROUND: Adrenergic activation has a central role in the development of HF. The function of the beta1- and the alpha2C-adrenergic receptors is influenced by gene polymorphisms: the beta1Arg389 variant is associated with increased beta1-receptor sensitivity and the alpha2C-receptor Del322-325 variant is associated with decreased alpha2C receptor function and increased norepinephrine release. We hypothesised that these polymorphisms could influence the prevalence of heart failure. METHODS: The role of the beta1- and alpha2C-adrenergic receptor gene polymorphisms as risk factors for heart failure (HF) was assessed in an Italian white Caucasian population using a case-control study design. Genomic DNA was analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP). RESULTS: We compared 260 Caucasian patients with HF and 230 normal subjects. The beta1Arg389 allele was frequent both in the patients with HF (69%) and in the normal subjects (73%). The alpha2CDel322-325 variant was rare in both groups (9% and 8%, respectively). Patients homozygotes for either the beta1Arg389 or the alpha(2C)Del322-325 alleles had no increased risk of HF (odds ratio [OR], 0.8; 95%CI: 0.5-1.2 and OR, 0.8; 95% CI: 0.4-1.8, respectively). Patients homozygotes for both the beta1Arg389 and the alpha(2C)Del322-325 alleles had no increased risk of HF as well (OR: 0.6; 95% CI: 0.2-2.1). CONCLUSIONS: Beta1-ARs and alpha2C-ARs polymorphisms are not associated with an increased risk of HF in an Italian white Caucasian population.     

Ile164 variant of beta2-adrenoceptor does not influence outcome in heart failure but may interact with beta blocker treatment

BACKGROUND: The Ile164 variant of the beta2-adrenoceptor has been shown to alter cardiovascular phenotypes and adversely affect survival in heart failure patients. AIMS: We aimed to replicate this observation by genotyping a cohort of 451 heart failure patients for the Ile164 polymorphism. METHODS: Patient outcome was recorded over a median follow-up period of 3.09 years, and genotypes were derived by multiplex amplification refractory mutation system PCR. RESULTS: Genotypes were obtained for 443 patients, and 3.2% of these (14 patients) were heterozygous for the Ile164 SNP. Demographic data, cardiac function and neurohormonal profiles did not differ between genotype groups. Ile164 genotype did not significantly affect survival in this cohort (Thr164 homozygotes 48.9%, Ile164 heterozygous 42.9%, p=0.66), although multivariate analysis suggested that beta-blocker treatment may negatively impact survival in the heterozygote group. CONCLUSION: This study suggests that the Ile164 polymorphism of the beta2-adrenoceptor does not have a major impact on outcome in individuals with heart failure, although it's potential interaction with beta-blockers requires further examination.     

Regional pre- and postsynaptic sympathetic system in the failing human heart--regulation of beta ARK-1

OBJECTIVES: Regional presynaptic sympathetic innervation varies considerably in the cardiomyopathic human heart, as shown in previous studies in vivo and in vitro. The goal of the present study was to correlate markers of presynaptic sympathetic innervation with local measurement of the postsynaptic beta-adrenergic system in failing human hearts. METHODS AND RESULTS: In nine left ventricular regions of hearts explanted from patients suffering from dilated cardiomyopathy, we measured the density of uptake(1) carriers ([3H]mazindol binding) as a marker of presynaptic function as well as beta-receptor density ([3H]CGP 12177 binding) and beta ARK-1 levels as the pivotal compounds of postsynaptic adrenergic signal transduction. Additionally, a subgroup of the patients was examined in vivo by HED-PET prior to heart transplantation. The density of uptake(1) was related to local hydroxyephedrine (HED) retention (as determined by pre-operative PET, r=0.65), whereas it was inversely correlated to regional beta ARK-1 levels (r=-0.61, P=0.04). In contrast, beta-adrenergic receptor density was not significantly correlated either to uptake(1) density or to local HED retention (r=0.15 and r=0.21). CONCLUSIONS: Regional beta ARK-1 levels rather than beta-adrenergic receptor density were correlated with presynaptic alterations in cardiomyopathic human left ventricles. It can be assumed that in the cardiomyopathic human heart, regional beta-adrenergic desensitization might be determined by differences in local beta ARK levels rather than by changes in beta-receptor density.     

The Trp64Arg mutation of the adrenergic beta-3 receptor gene impairs insulin secretion: a twin study.

AIMS: The physiological role of the adrenergic beta-3 receptor is poorly understood in man but the Trp64Arg mutation of the receptor gene has been related to the insulin resistance syndrome, an earlier onset of diabetes and rapid weight gain. This study set out to examine the effects of the mutation on glycaemic responses after an oral glucose tolerance test. METHODS: A standard oral glucose tolerance test (75 g glucose) was performed in 196 dizygotic twins. Serum insulin and glucose responses were measured at 0, 30 and 120 min. RESULTS: In the twins discordant for the mutation (21 pairs), no effects of the mutation were found on the plasma glucose responses. The insulin response given as incremental area under curve (iAUC) (median 13.8 (25-75th percentile 9.3-21.0) vs. 23.3 (14.2-29.2) mmol x l(-1) x min, P<0.021) and the insulinogenic index ((insulin30min - insulin0min)/ (glucose30min - glucose0min)), a measure of the insulin secretory capacity (44 (34-58) vs. 75 (42-124), P<0.006), were considerably lower in the variant type. The results were confirmed when using non-paired statistics on all subjects. CONCLUSION: It was concluded that the adrenergic beta-3 receptor, in addition to its already known effects, may be involved in the regulation of insulin secretion and that patients with the Trp64Arg mutation present an impaired insulin secretion.     

Safety and efficacy of omecamtiv mecarbil for heart failure: A systematic review and meta-analysis

AimTo assess the safety and efficacy of omecamtiv mecarbil compared with placebo in heart failure (HF) patients.MethodsWe searched PubMed, Web of Science, Cochrane Library, and SCOPUS until August 15th, 2021. We included all randomized controlled studies comparing omecamtiv mecarbil with placebo in heart failure patients. The meta-analysis was carried out using Rev Man software V5.4.ResultsA total of eight studies were included in our systematic review. Pooled analysis showed that omecamtiv mecarbil is not associated with increased incidence of death, any adverse events, hypotension, heart failure, ventricular tachyarrhythmia, dyspnea, dizziness, and serious adverse events. Regarding the efficacy, omecamtiv mecarbil significantly reduced heart rate with some studies demonstrating its significant improvement in left ventricular ejection fraction and systolic function.Conclusion: Omecamtiv mecarbil is a well-tolerated drug in heart failure patients. The limited data regarding the efficacy suggested that it may improve ejection fraction and systolic function.     

Prediction models for heart failure in the community: A systematic review and meta-analysis

Aims

Multivariable prediction models can be used to estimate risk of incident heart failure (HF) in the general population. A systematic review and meta-analysis was performed to determine the performance of models.

Methods and results

From inception to 3 November 2022 MEDLINE and EMBASE databases were searched for studies of multivariable models derived, validated and/or augmented for HF prediction in community-based cohorts. Discrimination measures for models with c-statistic data from ≥3 cohorts were pooled by Bayesian meta-analysis, with heterogeneity assessed through a 95% prediction interval (PI). Risk of bias was assessed using PROBAST. We included 36 studies with 59 prediction models. In meta-analysis, the Atherosclerosis Risk in Communities (ARIC) risk score (summary c-statistic 0.802, 95% confidence interval [CI] 0.707–0.883), GRaph-based Attention Model (GRAM; 0.791, 95% CI 0.677–0.885), Pooled Cohort equations to Prevent Heart Failure (PCP-HF) white men model (0.820, 95% CI 0.792–0.843), PCP-HF white women model (0.852, 95% CI 0.804–0.895), and REverse Time AttentIoN model (RETAIN; 0.839, 95% CI 0.748–0.916) had a statistically significant 95% PI and excellent discrimination performance. The ARIC risk score and PCP-HF models had significant summary discrimination among cohorts with a uniform prediction window. 77% of model results were at high risk of bias, certainty of evidence was low, and no model had a clinical impact study.

Conclusions

Prediction models for estimating risk of incident HF in the community demonstrate excellent discrimination performance. Their usefulness remains uncertain due to high risk of bias, low certainty of evidence, and absence of clinical effectiveness research.     

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study

BACKGROUND: The Glycine389 variant of the beta-1 adrenergic receptor (beta1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant. AIMS: The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers. METHODS: We identified the genotype at amino acid 389 of the beta1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes. RESULTS: The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69-1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44-0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL. CONCLUSION: In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism.     

衰竭心肌能量代谢重构及β3肾上腺素能受体、过氧化物酶体增殖物激活受体α表达变化的研究

目的 通过检测衰竭与健康心肌组织代谢底物含量、相关酶活性及β3肾上腺素能受体、过氧化物酶体增殖物激活受体α（PPARα）基因和蛋白表达的变化,探讨衰竭心肌代谢重构的表现及可能机制。方法 选取6例意外伤亡健康者心肌组织和20例心外科瓣膜置换术的心力衰竭患者,检测心肌游离脂肪酸（FFA）、乳酸（LD）含量和ATP酶活力。应用逆转录聚合酶链反应、Western blot和免疫组化法分别检测心肌组织β3受体和PPARα mRNA表达以及蛋白和定位。结果 衰竭心肌FFA和LD含量明显增加（P〈0．01和P〈0．05）。Na^＋K^＋-ATP酶和Ca^2＋Mg^2＋-ATP酶活性则显著降低（P〈0．05和P〈0．01）。衰竭心肌β3肾上腺素能受体mRNA和蛋白表达明显高于正常心肌,而PPARα表达则显著低于正常心肌,但并未发生定位变化。结论心力衰竭时存在代谢重构,表现为心肌代谢底物发生转变,代谢相关酶活性下降等,β3肾上腺素能受体和PPARα在衰竭心肌分别上调和下调,可能参与心肌组织代谢重构。     

Cognitive impairment associated with increased mortality rate in patients with heart failure: A systematic review and meta-analysis

BackgroundRecent systematic review and meta-analysis showed that the prevalence of cognitive impairment was significantly increased in patients with heart failure (HF) when compared to the general population. However, the effect of cognitive impairment on cardiovascular outcome in this population is still unclear. We performed a systematic review and meta-analysis to assess whether cognitive impairment associated with worse outcome in patients with HF.MethodsWe comprehensively searched the databases of MEDLINE and EMBASE from inception to October 2018. Included studies were published cohort (prospective or retrospective) or randomized control trials that evaluate the effect of cognitive impairment mortality in HF patients. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate pooled hazard ratios (HR) and 95% confidence intervals (CI).ResultsEight studies were included in the analysis involving 3318 participants (951 participants had cognitive impairment). In a random-effects model, our analysis demonstrated that cognitive impairment significantly increased the risk of mortality in HF patients (pooled HR = 1.64, 95% CI = 1.42–1.88, I² = 0.0%, p < 0.001).ConclusionOur systematic review and meta-analysis showed that the presence of cognitive impairment is strongly associated with an increased mortality risk in the HF population. Further research is needed to explore the pathophysiology of this association.     

Vitamin D receptor gene polymorphisms and colorectal cancer risk: a systematic meta-analysis

AIM:To investigate the relationship between polymorphisms present in the vitamin D receptor(VDR) gene and colorectal cancer risk,a systematic meta-analysis of population-based studies was performed.METHODS:A total of 38 relevant reports published between January 1990 and August 2010 were identified,of which only 23 qualified for this meta-analysis based on our selection criteria.Five polymorphic variants of the VDR gene,including Cdx-2(intron 1e) and FokI(exon 2) present in the 5' region of the gene,and BsmI(intron 8),ApaI(intron 8),and TaqI(exon 9) sites present in the 3' untranslated region(UTR),were evaluated for possible associations with colorectalcancer risk.Review manager 4.2 was used to perform statistical analyses.RESULTS:In the meta-analysis performed,only the BsmI polymorphism was found to be associated with colorectal cancer risk.In particular,the BsmI B genotype was found to be related to an overall decrease in the risk for colorectal cancer [BB vs bb:odds ratio(OR) = 0.87,95% CI:0.80-0.94,P = 3 × 10-4;BB vs Bb + bb:OR = 0.90,95% CI:0.84-0.97,P = 5 × 10-4].Moreover,in subgroup analyses,the BsmI B genotype was significantly associated with colon cancer,and not rectal cancer.An absence of between-study heterogeneity was also observed.CONCLUSION:A meta-analysis of 23 published studies identified the BsmI polymorphism of the VDR gene to be associated with an increased risk of colon cancer.     

An evaluation of the safety of the beta-modulator cicloprolol in chronic heart failure.

The new beta-adrenoceptor partial agonist cicloprolol acts as a beta-agonist at normal levels and as a beta-antagonist at high levels of adrenergic discharge. Treatment with cicloprolol should protect the heart against excessive stimulation, while providing a baseline level of sympathetic drive. The clinical interest of such a profile is, however, not yet established in heart failure. Accordingly this study examined the safety of oral cicloprolol, a step necessary before undertaking efficacy comparison with other compounds recently proposed to treat heart failure. Twenty-five patients were studied. Cicloprolol was given once a day for 2 weeks in a crossover double-blind placebo-controlled design. Follow-ups were obtained at baseline and at the end of each period. At baseline all patients had clear evidence of heart failure. Cicloprolol did not affect resting heart rate and blood pressure, but it reduced significantly peak exercise heart rate and peak rate-pressure product. The effect was especially significant in patients with sinus rhythm. The drug did not induce bradycardia or arrhythmias. Resting and exercise ejection rate were not affected. Cicloprolol improved the quality of life and the work capacity of 5 of 12 patients with congestive failure due to ischemic etiology. Side effects were few and similar with placebo and cicloprolol. Thus, short-term administration of cicloprolol is safe in moderate heart failure.     

Coronary revascularization for heart failure with coronary artery disease: A systematic review and meta-analysis of randomized trials

Aims

Coronary artery disease (CAD) is a common cause of heart failure (HF). Whether coronary revascularization improves outcomes in patients with HF receiving guideline-recommended pharmacological therapy (GRPT) remains uncertain; therefore, we conducted a systematic review and meta-analysis of relevant randomized controlled trials (RCTs).

Methods and results

We searched in public databases for RCTs published between 1 January 2001 and 22 November 2022, investigating the effects of coronary revascularization on morbidity and mortality in patients with chronic HF due to CAD. All-cause mortality was the primary outcome. We included five RCTs that enrolled, altogether, 2842 patients (most aged <65 years; 85% men; 67% with left ventricular ejection fraction ≤35%). Overall, compared to medical therapy alone, coronary revascularization was associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.79–0.99; p = 0.0278) and cardiovascular mortality (HR 0.80, 95% CI 0.70–0.93; p = 0.0024) but not the composite of hospitalization for HF or all-cause mortality (HR 0.87, 95% CI 0.74–1.01; p = 0.0728). There were insufficient data to show whether the effects of coronary artery bypass graft surgery or percutaneous coronary intervention were similar or differed.

Conclusions

For patients with chronic HF and CAD enrolled in RCTs, the effect of coronary revascularization on all-cause mortality was statistically significant but neither substantial (HR 0.88) nor robust (upper 95% CI close to 1.0). RCTs were not blinded, which may bias reporting of the cause-specific reasons for hospitalization and mortality. Further trials are required to determine which patients with HF and CAD obtain a substantial benefit from coronary revascularization by either coronary artery bypass graft surgery or percutaneous coronary intervention.     

Prevalence of sarcopenia in heart failure: A systematic review

ObjectiveHeart Failure (HF) is emerging as a crucial factor promoting muscle wasting and dysfunction contributing to sarcopenia. This modulates disease severity and reduces exercise capacity and leading to poorer outcomes. Therefore, we aimed to systematically investigate the overall prevalence of sarcopenia in HF.MethodsAn electronic search was carried out in selected databases until 21st January, 2021. Data was pooled from the included articles and represented as pooled prevalence of sarcopenia. Subgroup analysis was undertaken between methods of diagnosis of sarcopenia, gender, ejection fraction, median time point and geographical region.ResultsAmongst 32,643 citations imported from selected databases, 12 articles were included in final analysis. Analysis for prevalence of sarcopenia was 34%, with prevalence rates ranging from 10.1% to 68%. Subgroup analysis revealed strong associations between Dual-energy X-ray Absorptiometry (DXA) and Asian Working Group for Sarcopenia (AWGS) (chi square = 3.24; p < 0.001), with a good level of agreement (kappa = 0.76 [95% CI: 0.70–0.82]; p < 0.001). Gender wise analysis revealed higher prevalence of sarcopenia among males (66%) than females (34%).ConclusionSarcopenia is highly prevalent among those with HF (irrespective of type of HF) and is more commonly seen in males compared to females.     

The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure

OBJECTIVE: Discordant results have been published regarding a possible association between beta-adrenoreceptor (betaAR) gene polymorphisms and survival in patients with congestive heart failure (CHF). The aim of the study was to analyze the impact of five functional betaAR gene polymorphisms in patients with stable CHF. METHODS: We prospectively studied 444 consecutive patients with CHF related to left ventricular systolic dysfunction. The beta1ARSer49Gly, beta1ARGly389Arg, beta2AR Arg16Gly, beta2AR Gln27Glu and beta2AR Thr164Ile polymorphisms were determined. Patients underwent echocardiography, radionuclide angiography and a cardiopulmonary exercise test. RESULTS: Mean age was 56.6+/-11.9 years old, left ventricular ejection fraction (LVEF) was 32+/-12%, and peak VO2 was 15.5+/-4.9 ml/min/kg or 63+/-18% of maximal predicted VO2. Most of the patients (95%) were receiving angiotensin converting enzyme inhibitors and 91% beta-blockers. There was no statistically significant differences between baseline characteristics among beta1AR and beta2AR genotypes. During a median follow-up period of 1232 days, there were 110 cardiac-related deaths and five urgent transplantations. Independent predictors of survival were percent (%) of maximal predicted VO2 (p<0.0001), age (p<0.0001), LVEF (p=0.004), creatinine (p=0.02) and atrial fibrillation (p=0.04). No betaAR polymorphisms were associated with survival. However, patients with the combined beta2ARGly16Gly/beta2ARGln27Gln genotype, who express receptors highly sensitive to down-regulation, had a significantly lower survival rate than patients with other genotypes but only in univariate analysis. CONCLUSIONS: In this prospective study, we found no association between five functional betaAR polymorphisms and survival in patients with stable CHF. However, we demonstrated, only in univariate analysis, a possible association between the combined beta2ARGly16Gly/beta2ARGln27Gln genotype and survival.     

Exercise training in chronic heart failure: effects on pro-inflammatory markers

BACKGROUND: Acute bouts of exercise have been shown to induce inflammatory cytokine activation and peripheral hypoxia in patients with chronic heart failure (CHF). In this study, we set out to investigate the impact of chronic exercise training on pro-inflammatory cytokines and markers of endothelial damage. METHODS AND RESULTS: We measured tumor necrosis factor alpha (TNFalpha), its soluble TNF-receptors 1 and 2, interleukin 6 (IL-6), soluble e-selectin, soluble intracellular adhesion molecule-1 (sICAM) and sCD14 in 18 patients with CHF and 9 age-matched controls in a randomized cross-over study of 8 weeks of exercise training (5 days/week, submaximal bicycle ergometer training, 30 min/day; calisthenics 9 min/day) versus 8 weeks of rest. At baseline, patients had a lower peak Vo(2) (p=0.009) and a trend for higher levels of e-selectin (p=0.08) and sCD14 (p=0.06), in addition to significantly elevated levels of sICAM (p=0.02), TNFalpha (p=0.02) and TNF-R2 (p=0.002); TNF-R1 and IL-6 were not elevated. Although exercise training was effective and led to an increase in peak Vo(2) in CHF (p<0.003), there was no activation of any of the above variables observed, neither in patients nor controls. CONCLUSIONS: Chronic heart failure is associated with increased levels of TNFalpha and markers of endothelial damage. Whereas acute bouts of exercise have been reported to lead to an increase in pro-inflammatory cytokines and markers of endothelial damage, these effects are not seen when exercise is performed chronically.     

β2肾上腺素能受体基因多态性与岳西地区高血压患者血压的关系

目的探讨岳西地区人群β2肾上腺素能受体（ADRB2）基因Arg16Gly多态性与血压相关性。方法用RFLP方法对安徽省岳西地区487例高血压病患者及672例家属的B：。肾上腺素能受体基因的Arg16／Gly多态性位点进行了检测,应用了以家系为基础的分析方法,分析了岳西地区成年高血压人群ADRB2多态位点与高血压的相关性。结果在岳西人群中,带有ADRB2 Arg16等位基因的高血压病患者的收缩压（P=0．003）和舒张压（P=0．003）水平都较低,遗传对血压的影响更适合于共显性模型。结论ADRB2基因Gly16等位基因与高血压可能存在相关关系。     

卡维地洛对心力衰竭病人肾上腺素能受体自身抗体及镁代谢的影响

目的 探讨卡维地洛对慢性心力衰竭病人肾上腺素能受体β1、β2、α1自身抗体及Mg2＋代谢的影响.方法 慢性心功能不全病人60例,分为卡维地洛组36例和常规治疗组24例,正常对照为健康体检者30例.常规治疗组用血管紧张素转化酶抑制药、利尿剂和强心苷.卡维地洛组在常规治疗的基础上加用卡维地洛.随访6个月,用超声心动图测定心功能参数,酶联免疫吸附实验测定血浆β1、β2、α1自身抗体,测外周单核细胞Mg2＋含量及24 h尿Mg2＋排泄量.结果 治疗后,卡维地洛组左心室舒张末内径和收缩末内径分别为（57±6）mm和（43±6）mm,显著低于常规治疗组的（64±4）mm和（52±5）mm,差异有统计学意义（P＜0.01）;左心室射血分数为0.51±0.08,显著高于常规治疗组的0.42±0.06（P＜0.01）.治疗后卡维地洛组3种抗体阳性率及抗体滴度均显著低于治疗前（P＜0.01）,且卡维地洛组3种抗体阳性率及抗体滴度均显著低于常规治疗组,差异有统计学意义（P＜0.01）.心力衰竭病人尿Mg2＋排泄量明显升高（P＜0.01）,单核细胞Mg2＋含量降低（P＜0.01）.结论 β1、β2、α1受体参与心力衰竭的发生和发展过程,卡维地洛通过阻断β1、β2、α1受体改善心功能,同时减少尿镁排泄,增加细胞内镁水平.     

SGLT2 inhibitors and cardiovascular outcomes in heart failure with mildly reduced and preserved ejection fraction: A systematic review and meta-analysis

AimTo provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: ≥50%) or/and mildly reduced EF (HFmrEF: 41–49%) regardless of baseline diabetes.MethodsWe systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model.ResultsWe identified six RCTs, pooling data retrieved from 15,769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p < 0.001, I² = 0%). When separately analyzed, benefits of SGLT2i remained significant across HFpEF (N = 8891, HR 0.79, 95% CI: 0.71, 0.87, p < 0.001, I² = 0%) and HFmrEF (N = 4555, HR 0.77, 95% CI: 0.67, 0.89, p < 0.001, I² = 40%). Consistent benefits were observed also in HFmrEF/HFpEF subgroup without baseline diabetes (N = 6507, HR 0.80, 95% CI: 0.70, 0.91, p < 0.001, I² = 0%). Sensitivity analysis including the DELIVER and EMPEROR-Preserved trials found a trend towards significant beneficial effects on CV deaths with no heterogeneity (HR 0.90, 95% CI: 0.79, 1.02, p = 0.08, I² = 0%).ConclusionsThis meta-analysis established the place of SGLT2i as a foundational therapy among patients with HF with preserved and mildly reduced EF regardless of diabetes.