Preserved Ejection Fraction Heart Failure Research Articles

Role of Vascular Function in the Prognosis of Heart Failure Patients.

Background: Blood vessels have the Windkessel effect and are involved in blood circulation. The breakdown of this mechanism is also involved in the pathogenesis of heart failure (HF); however, the relationship between vascular dysfunction and HF prognosis is not fully understood. Methods: We evaluated 214 patients hospitalized for HF at our institution who underwent a cardio-ankle vascular index (CAVI), which evaluates vascular function, between January 2012 and July 2018. To investigate factors (including CAVI) associated with major adverse cardiac events (MACE) during 1 year after patients with HF were discharged, we evaluated clinical profiles, blood tests, chest X-P, 12-lead electrocardiography, and transthoracic echocardiographic findings. MACE was defined as cardiovascular death or readmission for HF. Results: The severity of HF between the MACE and non-MACE was not significantly different. Previous HF and chronic kidney disease were significantly more common in the MACE group. CAVI and % mean atrial pressure in the MACE group were statistically higher than those in the non-MACE group. The cardiac shadow as shown by chest X-P and left ventricular size in the MACE group were significantly bigger, and HF preserved ejection fraction (EF) (EF > 50%) was significantly more common in the MACE group. In multivariate analysis, CAVI was an independent predictive factor for the occurrence of MACE (model 1; hazard ratio (HR): 1.33, 95% confidence interval (CI): 1.05-1.68, p = 0.018; model 2; HR: 1.31, 95% CI: 1.07-1.60, p = 0.009). Conclusions: Because high CAVI is associated with poor prognosis of HF, these patients require more careful treatment.

Association of High-Density Lipoprotein Parameters and Risk of HeartFailure: A Multicohort Analysis.

High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease. The authors sought to evaluate the association of HDL particle concentration (HDL-P), HDL particle size (HDL-size), HDL-C, and cholesterol content per particle (HDL-C/HDL-P) with risk of overall heart failure (HF) and subtypes. Participants from the Atherosclerosis Risk In Communities Study, Dallas Heart Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-stage Disease studies without HF history were included. Associations of HDL-P, HDL-size, HDL-C, and HDL-C/HDL-P with risk of overall HF, HF with reduced and preserved ejection fraction were assessed using adjusted Cox models. Among 16,925 participants (53.5% women; 21.8% Black), there were 612 incident HF events (3.6%) (HF with reduced ejection fraction, 309 [50.5%]; HF preserved ejection fraction, 303 [49.5%]) over median follow-up of 11.4 years. In adjusted models, higher HDL-P was significantly associated with lower HF risk (HR of highest vs lowest tertile of HDL-P: 0.76 [95%CI: 0.62-0.93]). Larger HDL-size was significantly associated with higher overall HF risk (HR of largest vs smallest tertile of HDL-size: 1.27 [95%CI: 1.03-1.58]). HF risk associated with HDL-P and HDL-size was similar for HF subtypes. In adjusted analyses, there was no significant association between HDL-C and HF risk. Higher HDL-C/HDL-P was significantly associated with higher overall HF risk (HR of highest vs lowest tertile of HDL-C/HDL-P: 1.29 [95%CI: 1.04-1.60]). Higher HDL-P was associated with a lower risk of HF. In contrast, larger HDL-size was associated with higher risk of HF and there was no significant association observed between HDL-C and HF risk after accounting for cardiovascular risk factors.

Cardiac response to pharmacological stress in heart failure reduced and heart failure preserved ejection fraction

Cardiac response to pharmacological stress in heart failure reduced and heart failure preserved ejection fraction

Epicardial Adipose Tissue Thickness and Preserved Ejection Fraction Heart Failure.

Preserved ejection fraction heart failure and obesity frequently coexist. Whether obesity plays a consistent role in the pathogenesis of preserved ejection fraction heart failure is unclear. Accumulation of visceral adiposity underlies the pathogenic aftermaths of obesity. However, visceral adiposity imaging is assessed by computed tomography or magnetic resonance and thus not routinely available. In contrast, epicardial adiposity thickness is assessed by echocardiography and thus routinely available. We review the rationale for assessing epicardial adiposity thickness in patients with preserved ejection fraction heart failure and elevated body mass index. Body mass index correlates poorly with visceral, and epicardial adiposity. Visceral and epicardial adiposity enlarges as preserved ejection fraction heart failure progresses. Epicardial adiposity may hasten the progression of coronary artery disease and impairs left ventricular sub-endocardial perfusion and diastolic function. Epicardial adiposity thickness may help monitor the therapeutic response in patients with preserved ejection failure heart failure and elevated body mass index.

Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial

BackgroundAlthough sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF. ObjectivesThe goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF. MethodsTargeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed. ResultsThe mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro–B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro–B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction. ConclusionsLeveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235)

Dapagliflozin and Timing of Prior HeartFailure Hospitalization: A Patient-Level Meta-Analysis of DAPA-HF and DELIVER.

Patients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more "stable." The authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure). A total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death. In total, 12.4% were hospitalized for HF within 3months of randomization, 14.2% between 3 and 12months, and 16.8% more than 1 year before randomization, whereas 56.5% had not been hospitalized. The risk of the primary endpoint was inversely associated with time from prior HF hospitalization, and patients with a recent HF hospitalization had the highest risk. Compared with placebo, dapagliflozin reduced the risk of the primary outcome across HF hospitalization category (0-3months, HR: 0.66 [95%CI: 0.55-0.81]; 3-12months, HR: 0.73 [95%CI: 0.59-0.90]; >1year, HR: 0.91 [95%CI: 0.74-1.12]; and no prior hospitalization, HR: 0.83 [95%CI: 0.73-0.94]; Pinteraction=0.09). The number of patients needed to treat with dapagliflozin to prevent 1 event over the median follow-up of 22months was 13, 20, 23, and 28, respectively. The beneficial effect was consistent across the range of LVEF regardless of HF hospitalization category. The relative benefits of dapagliflozin were consistent across the range of LVEF regardless of the timing of the most recent HF hospitalization with a greater absolute benefit in patients with recent hospitalization.

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction

Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Frailty in clinical drug trials: Frailty assessments, subgroup analyses and outcomes.

With population ageing, drug trials are increasingly turning their attention to including older, frailer people. This review aimed to provide an overview of how frailty was assessed in published studies related to clinical pharmacological trials, and on the interaction of frailty on the efficacy of the treatments. We searched MEDLINE, EMBASE and Cochrane for clinical drug trials in older people. A total of 4031 abstracts were screened and 17 relevant studies were included in this review. We summarized the findings of these 17 trials into five main clinical areas: cardiovascular (eight studies), cognition (one study), vaccination (two studies), cancer (four studies) and other (two studies). Frailty was assessed retrospectively in most of the studies. Frailty was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non-frail) using cut-offs in some studies, and as a continuous in some other studies. The effect of frailty on the treatment efficacy was not consistent among the studies. While several trials, such as the Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation trials, the Systolic Blood Pressure Intervention Trial and the Aspirin in Reducing Events in the Elderly trial, showed some reduced effects of the treatment in frail patients, most of the trials showed that the benefits of the treatment are not affected by frailty. Some trials even showed that the benefits of the treatment were more significant in frailer patients (the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure trials). The results of this review suggest that routine measurement of frailty in participants in clinical drug trials would improve our knowledge of the effect of treatment in the frail and identify those who have more or least to gain from treatment.

Cost Effectiveness of Dapagliflozin for Heart Failure Across the Spectrum of Ejection Fraction: An Economic Evaluation Based on Pooled, Individual Participant Data From the DELIVER and DAPA-HF Trials.

The sodium glucose cotransporter-2 inhibitors are guideline-recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter-2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking. We conducted a US-based cost-effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3-state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality-adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death. The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01035255 & NCT01920711.

SGLT2 Inhibition in Heart Failure: Clues to Cardiac Effects?

Following the publication of several landmark clinical trials such as dapagliflozin in patients with heart failure and reduced ejection fraction, dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction heart failure, and empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction, sodium-glucose cotransport 2 inhibitors have been rapidly incorporated as a guideline-directed therapy in the treatment of heart failure. Moreover, their benefits appear to extend across the spectrum of left ventricular dysfunction which in some respects, can be seen as the holy grail of heart failure pharmacotherapy. Despite its plethora of proven cardioprotective benefits, the mechanisms by which it exerts these effects remain poorly understood, however, it is clear that these extend beyond that of promotion of glycosuria and natriuresis. Several hypotheses have emerged over the years including modification of cardiovascular risk profile via weight reduction, improved glucose homeostasis, blood pressure control, and natriuretic effect; however, these mechanisms do not fully explain the potent effects of the drug demonstrated in large-scale randomized trials. Other mechanisms may be at play, specifically the down-regulation of inflammatory pathways, improved myocardial sodium homeostasis, modulation of profibrotic pathways, and activation of nutrient deprivation signaling pathways promoting autophagic flux. This review seeks to summarize the cardioprotective benefits demonstrated in major clinical trials and provide a succinct review of the current theories of mechanisms of action, based on the most recent evidence derived from both clinical and laboratory data.

Inhibiting the MAPK pathway improves heart failure with preserved ejection fraction induced by salt-sensitive hypertension

Heart failure (HF) preserved ejection fraction (HFpEF) accounts for almost 50% of HF, and hypertension is one of the pathogenies. The MAPK signaling pathway is closely linked to heart failure and hypertension; however, its function in HEpEF resulting from salt-sensitive hypertension is not well understood. In this work, a salt-sensitive hypertension-induced HEpEF model was established based on deoxycorticosterone acetate-salt (DOCA-salt) hypertension mice. The impact of the MAPK inhibitor (Doramapimod) on HEpEF induced by salt-sensitive hypertension was assessed through various measures, such as blood pressure, transthoracic echocardiography, running distance, and histological analysis, to determine its therapeutic effectiveness on cardiac function. In addition, the effects of high salt on myogenic cells were also evaluated in vitro using qRTPCR. The LV ejection fractions (LVEF) in DOCA-salt hypertension mice were over 50%, indicating that the salt-sensitive hypertension-induced HFpEF model was successful. RNA-seq revealed that the MAPK signaling pathway was upregulated in the HFpEF model compared with the normal mice, accompanied by hypertension, impaired running distance, restricted cardiac function, increased cross-sectional and fibrosis area, and upregulation of heart failure biomarkers, including GAL-3, LDHA and BNP. The application of Doramapimod could improve blood pressure, cardiomyocyte hypertrophy, and myocardial fibrosis, as well as decrease the aforementioned heart failure biomarkers. The qRTPCR results showed similar findings to these observations. Our findings suggest that the use of a MAPK inhibitor (Doramapimod) could be a potential treatment for salt-sensitive hypertension-induced HFpEF.

Nationwide Trends in Hospitalizations with Heart Failure Preserved Ejection Fraction and Subsequent Cardiovascular Outcomes in Elderly Patients with Leukemia [2016-2019

Background: Leukemia and the therapeutic treatments for leukemia are both associated with cardiovascular side effects. Heart failure is one of the most identified side effects related to cancer or cancer-related therapies. Evidence suggests a higher risk of HFrEF (heart failure with reduced ejection fraction) and its consequences, there is limited data on the trends of HFpEF admissions in Leukemia patients. In this study, we are using a nationally representative population to study the trends in HFpEF-related admissions and outcomes in elderly Leukemia patients. Methods: A retrospective analysis was conducted using the National Inpatient Sample from the 2016-2019 dataset. Elderly patients older than 65 years with leukemia were selected and the trends of HFpEF were studied over these 4 years. In this study, we used both univariable and multivariable regression analysis to adjust the odds ratio and compared and followed the trends over 4 years. Co-primary outcomes were major adverse cardiac and cerebrovascular events [MACCE - all-cause mortality, acute myocardial infarction (AMI), acute ischemic stroke (AIS), and cardiac arrest] in HFpEF patients among the leukemia cohort. Results: There was a significantly higher prevalence and increasing trends of HFpEF admissions in cohort with leukemia vs non-leukemia between 2016 to 2019 (from 11.6% to 14.4% in leukemia vs. from 10.3% to 13.0%, p trend &amp;lt;0.001). A total of 66,345 admissions with HFpEF in leukemia patients were studied over a period of 4 years, with a median age of 81 [Table 1]. The majority of the patients studied were whites (87%), Medicare patients (93.6%), and urban teaching locations (66.5%). The baseline characteristics trends were matched in all the cohorts and significant comorbidities observed over a period of 2016-2019 were hypertension (75.8% and 70.2%), diabetes (35.8% and 38.7%), hyperlipidemia (46% and 52.1%), prior MI (9.5% and 9.9%), prior PCI (8.3% and 9.7%), prior CABG (10.8% and 9.5%%), alcohol use (0.9% and 1.4%), drug use (0.3% and 0.9%), chronic pulmonary disease (35.5% and 37.9%), obesity (14.5% and 18.1%), prior chemotherapy (4.4.% and 5.1%), prior radiotherapy (1.9% and 2.7%), and CKD (44.6% and 47.8%). On following the trends from 2016 to 2019 we established that Leukemia patients with HFpEF had no significant improvement in in-hospital outcomes of MACCE including all-cause mortality, myocardial Ischemia, acute ischemic stroke, and cardiac arrest between 2016 and 2019 when potential confounders were adjusted. The univariate and multivariable-adjusted odds ratios for all-cause mortality, AMI, cardiac arrest, AIS, and MACCE were 0.97 and 1.04, 1.16 and 1.21, 0.99 and 1.00, 1.49 and 1.49, and 1.06 and 1.12, respectively when compared for Leukemia-HFpEF cohort of 2019 vs. 2016 (p&amp;gt;0.05). Median hospital stay and cost were stable during the study duration without any significantly increasing or decreasing trends. Conclusion: There were significantly increasing trends in hospitalizations with HFpEF in elderly leukemia patients without any substantial improvement in acute cardiovascular events between 2016 and 2019. It has been established that cardiovascular outcomes are closely associated with leukemia and related chemotherapy, there is no standardized risk stratification or assessment tool to assess the management of MACEE in Leukemia patients. Furthermore, prospective studies are required to better understand and address the association of leukemia-related treatments and their impact on HFpEF risk and MACCE in the long term.

Sudomotor dysfunction is associated with impaired left ventricular diastolic function in persons with type 2 diabetes: a cross-sectional study.

The incidence of preserved ejection fraction heart failure has significantly increased in persons with type 2 diabetes mellitus (T2DM). Left ventricular (LV) diastolic dysfunction is an early and important manifestation of preserved ejection fraction heart failure. The onset of heart failure in persons with diabetes is associated with diabetic neuropathy. However, the relationship among sudomotor function, which is an early manifestation of small fiber neuropathy, and LV diastolic function remains unclear. This study aimed to explore the association between sudomotor function and LV diastolic function in persons with T2DM. In total, 699 persons with T2DM were enrolled and divided into three groups according to electrochemical skin conductance (ESC) assessed using the SUDOSCAN device: "no dysfunction" group (NSF), "moderate dysfunction" group (MDF), and "severe dysfunction" group (SDF). LV diastolic function was assessed using Doppler echocardiography. To evaluate the relationship between ESC and echocardiographic parameters, Pearson's correlation analysis was performed. Additionally, logistic regression analysis was used to determine the association between LV diastolic function and ESC. A receiver operating characteristic (ROC) curve was constructed to evaluate the performance of sudomotor function indicators in detecting impaired cardiac diastolic function. There were 301 persons (43.06%) in the NSF group, 232 (33.19%) in the MDF group, and 166 (23.75%) in the SDF group. Compared to the NSF group, the MDF and SDF groups had higher A and E/e' and lower e' values (all p < 0.05). Pearson's correlation analysis showed that A and E/e' were negatively associated with foot ESC (FESC) and hand ESC (HESC), whereas e' was positively associated with FESC and HESC (all p < 0.05). After adjusting for confounding factors, binary logistic regression analysis showed that ESC was independently associated with impaired LV diastolic function (p = 0.003). The area under the ROC curve values for FESC and HESC were 0.621 and 0.635, respectively (both p < 0.05). Deteriorating sudomotor function was associated with reduced diastolic function indicators. ESC can be used as a biomarker for detecting LV diastolic impairment.

Obesity-Induced Hyperglycemia and Heart Failure Preserved Ejection Fraction: Uncharted Territories to Remission.

Until the end of World War II, food security was a global challenge. Consequently, in 1948, type 2 diabetes was relatively uncommon, with the majority of cases being type 1 diabetes requiring insulin therapy. Since then, food has become increasingly palatable and readily available, leading to a rise in obesity across all age groups. Understanding the impact of obesity on our health has become crucial for optimizing healthcare. In this context, we draw attention to two significant, yet relatively uncharted pathogenic effects associated with obesity: Hyperglycemia and Heart Failure with Preserved Ejection Fraction (HFpEF). Thorough pathophysiologic, hemodynamic, and echocardiographic characterization have revealed the existence of a distinct phenotypeknown as "obese HFpEF" within the broader HFpEF population, and "obesity-induced hyperglycemia" within the diabetes population. In these phenotypes, patients often present with higher Body Mass Index and experience clinical symptoms decades earlier. Recent insights have enhanced our understanding of the mechanisms underlying obesity-mediated heart failure preserved ejection fraction and hyperglycemia. Early detection offers the potential for reversibility of many pathologies associated with obesity through adequate weight reduction. The objective of this review is to provide a deeper insight into these uncharted territories and explore the potential for improved outcomes by reframing these two narratives toward achieving remission. Such a shift has the potential to positively impact individual engagement with healthier lifestyles.

Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure. To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023. Dapagliflozin, 10 mg per day, or placebo. In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes. Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82). Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline. ClinicalTrials.gov Identifier: NCT03619213.

Sympathetic nerve activity reactivity is associated with cardiac fibrosis in humans

Abstract Background Hypertension causes cardiac remodelling and left ventricular hypertrophy (LVH) in some individuals but not others [1-3]. 90% of people with heart failure preserved ejection fraction (HFpEF) have hypertension. One possible mechanism is increased sympathetic drive resulting in cardiac fibrosis. Resting sympathetic nerve activity (SNA) is associated with cardiac remodelling in both animals and humans and progressively increases from hypertension to LVH to HFpEF. However, humans are not in a constant rested state, and are frequently exposed to multiple physiological stressors throughout the day, resulting in surges in SNA. Amplified SNA reactivity to stressors may contribute to cardiac remodelling more than elevated resting SNA levels, as intermittent β-adrenergic receptor stimulation with isoprenaline in mice has been shown to cause more severe cardiac fibrosis when compared to a sustained isoprenaline administration [4]. Purpose To determine whether resting SNA and/or SNA reactivity to a physiological stressor (cold pressor test) were associated with cardiac fibrosis in humans. Methods Nineteen (10M, 9F; 48 ± 13 years; BMI: 25.9 ± 3.2 kg/m²) participants with varying ambulatory blood pressures (SBP: 126±13 mmHg, DBP: 83±8 mmHg, SBP range: 111-153 mmHg, DBP range: 68-96 mmHg), provided written informed consent. Blood pressure (Finometer), heart rate (ECG) and muscle SNA (peroneal microneurography) were recorded simultaneously during a 5-minute baseline, and a 2-minute rest, 3-minute cold pressor test (3-4°C) and 5-minute recovery. Cardiac extracellular volume (ECV) was measured using magnetic resonance imaging (1.5T Avanto, Siemens) as an index of cardiac fibrosis. Simple linear regressions were conducted between baseline SNA and ECV, and change in SNA from rest to peak cold pressor test and ECV using SPSS. Results Resting SNA was not associated with ECV. However, the absolute change in SNA burst incidence (bursts/100 heartbeats) and burst frequency (bursts/minute, Figure 1) from rest to peak cold pressor test, were positively associated with ECV, showing that the greater the SNA response to a stressor, the higher the ECV. Specifically, for every 1 burst/100 heartbeat increase in burst incidence (from rest to peak cold pressor test), ECV increased by 0.120%, and for every 1 burst/minute increase in burst frequency (from rest to peak cold pressor test), ECV increased by 0.128%. Conclusion SNA reactivity but not resting SNA level was found to be a predictor of ECV, where the greater the SNA response to a stressor, the higher the ECV. This indicates that intermittent surges in SNA may be more important for promoting cardiac fibrosis than the overall level of resting SNA in humans.Figure 1.

Drug treatment with empagliflozin was beneficial in people with heart failure with preserved ejection fraction: plain language summary of the EMPEROR-Preserved study.

This summary describes a study of a new pill for treating chronic heart failure called empagliflozin (brand name Jardiance®). The study is called EMPEROR-Preserved and was published in the New England Journal of Medicine. Chronic heart failure is a condition where the heart does not pump blood around the body properly. Heart failure causes symptoms such as shortness of breath, tiredness and build-up of too much water in the body (fluid retention). These symptoms often need hospital treatment and increase the risk of early death. The EMPEROR-Preserved study looked at how empagliflozin works in people living with a type of heart failure called heart failure with preserved ejection fraction. In this type of heart failure, the lower left chamber (ventricle) of the heart is too stiff to fill with enough blood during each heartbeat. Almost 6000 people living with preserved ejection fraction heart failure were asked to take either a pill containing empagliflozin or a placebo, an identical pill lacking empagliflozin, daily. The choice of pill for each participant was randomly assigned. The study was double-blinded, meaning that neither the participants nor their doctors knew which pill the participants were taking. After an average of 26months of treatment, empagliflozin reduced the risk of participants needing hospital treatment for complications of heart failure by about 30%. Side effects were generally similar in participants who took empagliflozin and in those who took the placebo, except for genital infections like thrush, which happened in more people who took empagliflozin (2.2%) than in those who took the placebo (0.7%). A previous study called EMPEROR-Reduced found that empagliflozin had similar benefits in participants with heart failure with reduced ejection fraction. Therefore, the overall evidence shows that empagliflozin can help people with heart failure whether it is caused by reduced ejection fraction or preserved ejection fraction. Clinical Trial Registration: NCT03057951 (EMPEROR-Preserved study) (ClinicalTrials.gov).

Effect of dapagliflozin in patients in Asia with heart failure with mildly reduced or preserved ejection fraction: insights from DELIVER

Abstract Background A large and growing fraction of the global heart failure (HF) population lives in Asia. One-fifth of participants in the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial were enrolled from Asia, providing a rich source of contemporary data to understand their unique clinical profiles and responses to sodium-glucose cotransporter 2 (SGLT2) inhibition. Purpose To assess the differences in clinical characteristics, outcomes, and response to dapagliflozin in patients from Asia vs outside Asia among patients with HF with mildly reduced or preserved ejection fraction in the DELIVER trial. Methods DELIVER was a global randomized clinical trial enrolling across 353 sites in 20 countries. Baseline clinical characteristics from patients enrolled in DELIVER trial were compared between patients in Asia vs outside Asia. The primary outcome was a composite of worsening HF or cardiovascular (CV) death. The effect of dapagliflozin on primary and secondary outcomes were compared in patients in Asia vs outside Asia. Results Among 6,263 participants in the DELIVER trial, 1,226 (19.6%) were enrolled in Asia (310 in China, 422 in Japan, and 318 in Taiwan, and 176 in Vietnam). Compared to patients outside Asia, participants from Asia were similar in age, more likely to be men with previous HF hospitalization, less likely to have obesity, diabetes, hypertension, or history of myocardial infarction, and had lower symptom burden despite similar natriuretic peptide levels (Figure 1). After adjusting for age, sex, and baseline LVEF, those in Asia faced similar risks of HF events but lower risk of mortality compared with those enrolled outside Asia (all-cause mortality Asia vs. outside Asia: HR 0.60, 95% confidence interval [CI] 0.49 – 0.72, Table 1). Within Asia, all-cause mortality was highest in Vietnam (6.8 per 100 person-year [py]), followed by Taiwan (6.7 per 100 py), Japan (3.5 per 100 py) and China (3.3 per 100 py). Dapagliflozin reduced the primary outcome in participants enrolled in Asia (hazard ratio [HR] 0.89, 95% CI 0.67-1.18) and outside Asia (HR 0.80, 95% CI 0.71 – 0.92) to a similar extend (P-interaction = 0.54, Figure 1). Similarly, region did not modify the treatment effect of dapagliflozin on CV death, HF hospitalization, all-cause death, CV death and recurrent HF events, or changes in Kansas City Cardiomyopathy Questionnaire scores (P-interaction &amp;gt; 0.30 for all). Serious adverse events and rates of drug discontinuation were also balanced in both treatment arms, irrespective of enrollment in Asia vs. outside Asia. Conclusions In the global DELIVER trial, dapagliflozin reduced the risk of CV death or HF events and was well tolerated both among participants enrolled in Asia and other geographic regions.Figure 1Table 1

Studie DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure)

Studie DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure)

Efficacy of Dapagliflozin According to Heart Rate: A Patient-Level Pooled Analysis of DAPA-HF and DELIVER.

Although elevated resting heart rate (HR) is associated with a higher risk of cardiovascular events in patients with heart failure with reduced ejection fraction in sinus rhythm (SR), the relationship between HR and outcomes among patients with heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction and in those with atrial fibrillation (AF) is uncertain. The aims of this study were to examine the association between baseline HR and outcomes across the range of left ventricular ejection fraction, in patients with and without AF, and evaluate the effect of dapagliflozin according to HR. A patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; heart failure with reduced ejection fraction) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure trial; heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction) trials. The primary outcome of each was the composite of worsening heart failure or cardiovascular death. Among patients with SR (n=6401, 64%), the rate of the primary outcome was higher in those with higher HR: 16.8 versus 7.7 per 100 person-years for ≥80 bpm versus <60 bpm. The relationship between HR and risk was steeper in heart failure with reduced ejection fraction versus heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. HR was not associated with outcomes in patients in AF for either heart failure phenotype. The benefit of dapagliflozin on the primary outcome was consistent across the HR range in both SR (Pinteraction=0.28) and AF (Pinteraction=0.56), for example, for SR <60 bpm, hazard ratio for dapagliflozin versus placebo 0.72 (95% CI, 0.55-0.95); 60 to 69 bpm, 0.78 (0.63-0.97); 70 to 79 bpm, 0.73 (0.59-0.91); ≥80 bpm, 0.77 (0.61-0.97). The benefit was consistent across HR range in both heart failure with reduced ejection fraction and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction. The risk of worsening heart failure or cardiovascular death increased with increasing baseline HR among patients in SR, but this association was not seen among patients in AF, irrespective of left ventricular ejection fraction. The benefit of dapagliflozin was consistent across HR range, irrespective of left ventricular ejection fraction or rhythm. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03036124 and NCT03619213.