Non-diabetic Heart Failure Research Articles

Empagliflozin treatment rescues abnormally reduced Na+ currents in ventricular cardiomyocytes from dystrophin-deficient mdx mice

Abstract Background Cardiac arrhythmias represent a major cause of death in Duchenne muscular dystrophy (DMD), a devastating muscle disease caused by dystrophin deficiency. An important source for arrhythmia vulnerability in DMD patients is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, and the development of reentrant circuits. Using the dystrophin-deficient mdx mouse model for DMD, we and others previously reported that the absence of dystrophin results in a significant peak Na+ current (INa) loss both in ventricular cardiomyocytes of the working myocardium, and in Purkinje fibers, ventricular myocytes specialized for rapid electrical impulse conduction. This finding provided a mechanistic explanation for ventricular conduction defects and concomitant arrhythmias in the dystrophic heart. Purpose In the present study, we tested the hypothesis that empagliflozin (EMPA), an inhibitor of sodium/glucose cotransporter 2 in clinical use to treat type II diabetes and nondiabetic heart failure, rescues the loss of peak INa in dystrophin-deficient ventricular cardiomyocytes. Methods In a first set of experiments, we treated a cohort of mdx mice with 15 mg/kg body weight/day EMPA via the drinking water. After 4 weeks of treatment, ventricular cardiomyocytes were isolated from these mice, as well as from untreated wild-type and mdx control mice, via Langendorff heart perfusion and enzymatic digestion. Peak INa was measured using the whole cell patch clamp technique. In a second experimental approach, peak INa was compared after a 24 hour exposure of isolated mdx ventricular cardiomyocytes with 1 µM EMPA, 10 µM of the Na+-H+ exchanger 1 inhibitor cariporide, or 10 µM cariporide in combination with 1 µM EMPA. In a third set of experiments, we superfused freshly isolated mdx ventricular cardiomyocytes with 1 or 10 µM EMPA in order to examine the acute action of the drug on peak INa. Results Consistent with the literature, we found peak INa of mdx ventricular cardiomyocytes to be substantially decreased compared to wild-type. Peak INa of ventricular cardiomyocytes derived from mdx mice, which had received EMPA for 4 weeks, was restored to wild-type level. Moreover, incubation of isolated mdx ventricular cardiomyocytes with EMPA for 24 hours significantly increased their peak INa. This effect did not depend on Na+-H+ exchanger 1 inhibition by the drug. The voltage dependencies of INa activation and fast inactivation were neither modified by long-term treatment nor incubation with EMPA. Finally, acute application of EMPA did not influence peak INa. Conclusion Our findings indicate that EMPA treatment can correct abnormally reduced peak INa of dystrophin-deficient ventricular cardiomyocytes. Long-term EMPA administration may diminish arrhythmia vulnerability in DMD patients.

Impact of Diabetes Mellitus on Heart Failure Patients: Insights from a Comprehensive Analysis and Machine Learning Model Using the Jordanian Heart Failure Registry.

Heart failure (HF) is a common final pathway of various insults to the heart, primarily from risk factors including diabetes mellitus (DM) type 2. This study analyzed the clinical characteristics of HF in a Jordanian population with a particular emphasis on the relationship between DM and HF. This prospective study used the Jordanian Heart Failure Registry (JoHFR) data. Patients with HF were characterized by DM status and HF type: HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF). Demographics, clinical presentations, and treatment outcomes were collected. Statistical analyses and machine learning techniques were carried out for the prediction of mortality among HF patients: Recursive Feature Elimination with Cross-Validation (RFECV) and Synthetic Minority Over-sampling Technique with Edited Nearest Neighbors (SMOTEENN) were employed. A total of 2007 patients with HF were included. Notable differences between diabetic and non-diabetic patients are apparent. Diabetic patients were predominantly male, older, and obese (p < 0.001 for all). A higher incidence of HFpEF was observed in the diabetes cohort (p = 0.006). Also, diabetic patients had significantly higher levels of cholesterol (p = 0.008) and LDL (p = 0.003), reduced hemoglobin levels (p < 0.001), and more severe renal impairment (eGFR; p = 0.006). Machine learning models, particularly the Random Forest Classifier, highlighted its superiority in mortality prediction, with an accuracy of 90.02% and AUC of 80.51%. Predictors of mortality included creatinine levels >115 µmol/L, length of hospital stay, and need for mechanical ventilation. This study underscores notable differences in clinical characteristics and outcomes between diabetic and non-diabetic heart failure patients in Jordan. Diabetic patients had higher prevalence of HFpEF and poorer health indicators such as elevated cholesterol, LDL, and impaired kidney function. High creatinine levels, longer hospital stays, and the need for mechanical ventilation were key predictors of mortality.

Empagliflozin treatment rescues abnormally reduced Na+ currents in ventricular cardiomyocytes from dystrophin-deficient mdx mice.

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a severe muscle illness caused by mutations in the gene encoding for the intracellular protein dystrophin. A major source for arrhythmia vulnerability in patients with DMD is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, decreased cardiac output, and the development of reentrant circuits. Using the dystrophin-deficient mdx mouse model for human DMD, we previously reported that the lack of dystrophin causes a significant loss of peak Na+ current (INa) in ventricular cardiomyocytes. This finding provided a mechanistic explanation for ventricular conduction defects and concomitant arrhythmias in the dystrophic heart. In the present study, we explored the hypothesis that empagliflozin (EMPA), an inhibitor of sodium/glucose cotransporter 2 in clinical use to treat type II diabetes and nondiabetic heart failure, rescues peak INa loss in dystrophin-deficient ventricular cardiomyocytes. We found that INa of cardiomyocytes derived from mdx mice, which had received clinically relevant doses of EMPA for 4 wk, was restored to wild-type level. Moreover, incubation of isolated mdx ventricular cardiomyocytes with 1 µM EMPA for 24 h significantly increased their peak INa. This effect was independent of Na+-H+ exchanger 1 inhibition by the drug. Our findings imply that EMPA treatment can rescue abnormally reduced peak INa of dystrophin-deficient ventricular cardiomyocytes. Long-term EMPA administration may diminish arrhythmia vulnerability in patients with DMD.NEW & NOTEWORTHY Dystrophin deficiency in cardiomyocytes leads to abnormally reduced Na+ currents. These can be rescued by long-term empagliflozin treatment.

SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1

BackgroundEndothelial–mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium–glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated.MethodsIsoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs).ResultsBoth our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT.ConclusionsOur study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.Graphical

Effect of Metformin on Oxidative Stress and Left Ventricular Geometry in Nondiabetic Heart Failure Patients: A Randomized Controlled Trial.

Introduction: There is an increasing interest in using metformin in cardiovascular diseases and its potential new roles. Only two randomized controlled trials investigated the effect of metformin in nondiabetic heart failure (HF) patients. However, none of these studies assess the role of metformin in reducing oxidative stress. We hypothesized that metformin might improve oxidative stress and left ventricular remodeling in nondiabetic HF patients with reduced ejection fraction (HFrEF). Methods and Methods: Seventy HFrEF patients (EF 37% ± 8%; median age 66 years) were randomized to metformin (n = 35) or standard of care (SOC) for HF (n = 35) for 6 months in addition to standard therapy. Outcomes included the difference in the change (Δ) in total antioxidant capacity (TAC) and malondialdehyde (MDA), both assessed colorimetrically and left ventricular mass index (LVMI) assessed through transthoracic echocardiography. Results: Compared with the SOC, metformin treatment increased TAC [Δ = 0.12 mmol/L, confidence intervals (95% CIs): 0.03-0.21; P = 0.007]. TAC increased significantly only in the metformin group (0.90 ± 0.08 mmol/L at baseline vs. 1.04 ± 0.99 mmol/L at 6 months, P < 0.05). Metformin therapy preserved LVMI (Δ = -23 g/m2, 95% CI: -42.91 to -4.92; P = 0.014) and reduced fasting plasma glucose (Δ = -6.16, 95% CI: -12.31 to -0.02, P = 0.047) compared with the SOC. Results did not change after adjusting for baseline values. Changes in MDA left ventricular ejection fraction (LVEF) and blood pressure were not significantly different between groups. Conclusion: Metformin treatment in HF patients with reduced LVEF improved TAC and prevented the increase in LVMI compared with the SOC. These effects of metformin warrant further research in HF patients without diabetes to explore the potential benefits of metformin. Trial Registration Number: This protocol was registered in ClinicalTrials.gov under the number NCT05177588.

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Lower low density lipoprotein cholesterol associates to higher mortality in non-diabetic heart failure patients

BackgroundIn patients with established heart failure (HF) low total cholesterol levels associate with worse prognosis. Evidence concerning the impact of Low-density lipoprotein cholesterol (LDL-c) in HF is scarce. We aimed to evaluate the prognostic impact of LDL-c in patients with HF, both with and without diabetes mellitus (DM). MethodsWe retrospectively analyzed outpatients with chronic HF with systolic dysfunction followed in our HF clinic from January/2012 to May/2018. LDL-c was calculated using the Friedewald's formula. Patients without a complete lipid profile were excluded. The endpoint under analysis was all-cause mortality. Patients were followed until January/2021. A Cox-regression analysis was used to study the prognostic impact of LDL-c. The LDL-c cut-off used was 100 mg/dL (mean value). Analysis was stratified according to the coexistence of DM. Multivariate models were built adjusting for age, sex, coronary artery disease, atherosclerotic non-coronary artery disease, arterial hypertension, smoking status, statin use, severity of systolic dysfunction, creatinine clearance and evidence-based therapy. ResultsWe studied 522 chronic HF patients, mean age was 70 years, 66.5% males. Severe systolic dysfunction was present in 42.7%, 30.5% had coronary heart disease, 60.5% had arterial hypertension, 41.6% had DM. A total of 92.0% were treated with beta blocker, 87.5% with an ACEi/ARB and 29.1% with a MRA. During a median follow-up of 53 (interquartile range 33–73) months, 235 (45%) patients died. Patients with LDL-c ≤100 mg/dL presented increased multivariate-adjusted risk of all-cause mortality: HR = 1.58 (95% CI: 1.08–2.30), p = 0.02. When patients were stratified according to DM, LDL-c ≤100 mg/dL was independently associated with increased death risk – HR = 1.55 (95% CI:1.05–2.30), p = 0.03 in patients without DM; in patients with DM no association was detected – multivariate-adjusted HR = 1.18 (95% CI: 0.77–1.80), p = 0.44. ConclusionNon-DM HF patients with LDL-c>100 mg/dL have a 35% reduction in the mortality risk when compared with those with lower values. The “cholesterol paradox” in HF also applies to LDL-c in non-DM patients.

Amino acid homeostasis is a target of metformin therapy

ObjectiveUnexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we have investigated mechanisms underlying this effect. MethodsWe used cellular approaches, including single gene/protein measurements, as well as systems-level proteomics. Findings were then cross-validated with electronic health records and other data from human material. ResultsIn cell studies, we observed diminished uptake/incorporation of amino acids following metformin treatment of liver cells and cardiac myocytes. Supplementation of media with amino acids attenuated known effects of the drug, including on glucose production, providing a possible explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics identified that SNAT2, which mediates tertiary control of BCAA uptake, was the most strongly suppressed amino acid transporter in liver cells following metformin treatment. Other transporters were affected to a lesser extent. In humans, metformin attenuated increased risk of left ventricular hypertrophy due to the AA allele of KLF15, which is an inducer of BCAA catabolism. In plasma from a double-blind placebo-controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin caused selective accumulation of plasma BCAA and glutamine, consistent with the effects in cells. ConclusionsMetformin restricts tertiary control of BCAA cellular uptake. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of the drug.

Dipeptidyl peptidase 4 inhibition rescues PKA-eNOS signaling and suppresses aortic hypercontractility in male rats with heart failure

AimsVascular dysfunction and elevated circulating dipeptidyl peptidase 4 (DPP4) activity are both reported to be involved in the progression of heart failure (HF). While the cardiac benefits of DPP4 inhibitors (DPP4i) have been extensively studied, little is known about the effects of DPP4i on vascular dysfunction in nondiabetic HF. This study tested the hypothesis that vildagliptin (DPP4i) mitigates aortic hyperreactivity in male HF rats. Materials and methodsMale Wistar rats were subjected to left ventricle (LV) radiofrequency ablation to HF induction or sham operation (SO). Six weeks after surgery, radiofrequency-ablated rats who developed HF were treated with vildagliptin (120 mg⸱kg−1⸱day−1) or vehicle for 4 weeks. Thoracic aorta reactivity, dihydroethidium fluorescence, immunoblotting experiments, and enzyme-linked immunosorbent assays were performed. Key findingsDPP4i ameliorated the hypercontractility of HF aortas to the α-adrenoceptor agonist phenylephrine towards SO levels. In HF, the reduced endothelium and nitric oxide (NO) anticontractile effect on phenylephrine response was restored by DPP4i. At the molecular level, this vasoprotective effect of DPP4i was accompanied by (i) reduced oxidative stress and NADPH oxidase 2 (Nox2) expression, (ii) enhanced total endothelial nitric oxide synthase (eNOS) expression and phosphorylation at Ser1177, and (iii) increased PKA activation, which acts upstream of eNOS. Additionally, DPP4i restored the higher serum angiotensin II concentration towards SO. SignificanceOur data demonstrate that DPP4i ameliorates aortic hypercontractility, most likely by enhancing NO bioavailability, showing that the DPP4i-induced cardioprotection in male HF may arise from effects not only in the heart but also in conductance arteries.

Identification and verification of immune-related biomarkers and immune infiltration in diabetic heart failure.

Diabetic heart failure (DHF) or cardiomyopathy is a common complication of diabetes; however, the underlying mechanism is not clear. In the present study, the authors searched for differentially expressed genes associated with DHF and the molecular types of immune cells based on bioinformatics. The RNA expression dataset of DHF was obtained from the NCBI Gene Expression Omnibus (GEO) database. After preprocessing the data, the differentially expressed genes (DEGs) between the DHF group and the non-diabetic heart failure (NHF) group were screened and intersected with immune-related genes (IRGs) in the ImmPort database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID tool. The ssGSEA algorithm was used to evaluate immune infiltration of the heart tissue in each group. In addition, the protein-protein interaction (PPI) network and miRNA-mRNA network were constructed using the STRING online website and Cytoscape program. Finally, validation analysis was performed using animal models. Eight immune-related core genes were identified. GO and KEGG showed that core genes were mainly enriched in angiogenesis and cytokine-cytokine receptor interaction. Immune infiltration results showed that activated dendritic cells, central memory CD4 T cells, central memory CD8 T cells, myeloid-derived suppressor cells (MDSCs), neutrophils, and regulatory T cells may be involved in DHF. Neutrophils may play a key role in the pathogenesis of HF in diabetes. Immune-related core genes and immune infiltrating cells provide a new perspective on the pathogenesis of DHF.

In-hospital glycemic variability and all-cause mortality in patients hospitalized with acute heart failure: analysis of the KorAHF registry

Abstract Introduction Glycemic variability (GV) is known to be a poor prognostic marker in various diseases including cardiovascular disease. Purpose We investigated the association of GV with all-cause mortality in patients with acute heart failure (HF). Methods The Korean Acute Heart Failure registry enrolled patients hospitalized for acute HF from 2011 to 2014. Among survivors of the index hospitalization, we analyzed those who had ≥3 blood glucose measurements before discharge. Patients were divided into two groups based on their coefficient of variation (%CV) as an indicator of GV. We investigated all-cause mortality at 6 month and 1 year after discharge. Results The study analyzed 2,617 patients (median age 72 years, 53% male). During the median follow-up period of 11 months, 583 (22%) patients died. Compared to alive patients, patients who died had a significantly higher diabetes prevalence (46% vs. 41%, P=0.035) and higher %CV (31.0% vs. 27.5%, P&amp;lt;0.001). Kaplan-Meier curve analysis revealed that a high GV (%CV &amp;gt;21%) was associated with lower cumulative survival to all-cause death compared with a low GV (%CV ≤21%) (log-rank P&amp;lt;0.001). Multivariate Cox proportional analysis showed that a high GV was associated with an increased risk of 6-month mortality (hazard ratio [HR] 2.02, 95% CI 1.58–2.59, P&amp;lt;0.001) and one-year mortality (HR 1.57, 95% CI 1.29–1.91, P&amp;lt;0.001). The risk of high GV for one-year mortality was significant in non-diabetic patients (HR 1.98, 95% CI 1.55–2.53, P&amp;lt;0.001), but not in diabetic patients (HR 1.24, 95% CI 0.91–1.69, P=0.176; P-for-interaction=0.030). Conclusion A high GV (%CV &amp;gt;21%) before discharge was associated with all-cause mortality within 1 year, especially in non-diabetic acute HF patients. Funding Acknowledgement Type of funding sources: None.

Safety and efficacy of SGLT2 inhibitors in diabetic and non-diabetic heart failure patients, a meta-analysis of randomized controlled trials

Abstract Background Heart failure (HF) is the most common cardiovascular causes of hospitalization in people over 60 years affecting about 64.3 million people worldwide. Few studies have investigated sodium glucose like transporter-2 inhibitors (SGLT-2I) role in diabetic and non-diabetic patients with HF. Objective We conducted our meta-analysis to further investigate SGLT-2I role in diabetic and non-diabetic HF patients. Methods PubMed, Scopus, web of science, and Embase were searched. All clinical trials that compared the effect of SGLT2 inhibitors versus placebo on heart failure patients were included. Dichotomous data were extracted, pooled as risk ratio (RR) with 95% confidence interval, and analyzed via RevMan version 5.3 for windows using Mantel Haenszel (M-H) method. Results Twelve randomized clinical trials were included for analysis with a total number of 69024 patients. SGLT2I significantly lowered the risk of hospitalization for heart failure (HHF) in diabetic (RR=0.68, 95% CI 0.63–0.74) and non-diabetic patients (RR=0.75, 95% CI 0.62–0.89). Also, it significantly lowered mortality risk in both diabetic (RR=0.87, 95% CI 0.77–0.99) and non-diabetic patients (RR=0.93, 95% CI 0.70–1.23). Further analyses for serious adverse events were conducted, and SGLT-2I showed a significant lower risk in diabetic (RR=0.94, 95% CI 0.90–0.98) and non-diabetic patients (RR=0.72, 95% CI 0.38–1.39), yet with no observed difference over placebo in the risk of stroke. Conclusion SGLT2 inhibitors showed a favorable effect in lowering cardiovascular mortality, HHF, and stroke in diabetic patients with heart failure. In non-diabetic patients, they significantly reduce HHF, yet with no difference on cardiovascular mortality and stroke. Therefore, more trials are needed to establish their effect in non-diabetic patients. Funding Acknowledgement Type of funding sources: None.

Diabetic Cardiomyopathy: A Case Report

Diabetes has become in a few years a veritable epidemic affecting several million people in the world. The cardiovascular complications are the leading cause of death in diabetics. More particularly, cardiac involvement is essentially summarized in ischemic heart disease, cardiac autonomic neuropathy and more recently described diabetic cardiomyopathy, a specific entity responsible for – or contributing to – the onset of heart failure which is related to a diastolic dysfunction preceding an alteration of the systolic function and whose prognosis makes all the seriousness of this pathology. Indeed, large epidemiological studies have demonstrated that diabetes is an independent risk factor for heart failure. These data are supported by numerous preclinical studies, highlighting metabolic abnormalities, calcium homeostasis, or even neuro-hormonal, in models of diabetes. Optimal glycemic control appears to limit the incidence and severity of heart failure in diabetics. The treatment of diabetic cardiomyopathy is no different from that of non-diabetic heart failure patients. A better understanding of this entity therefore necessitates close collaboration between cardiologists and diabetologists.

Dapagliflozin Impact on the Exercise Capacity of Non-Diabetic Heart Failure with Reduced Ejection Fraction Patients.

Background: Dapagliflozin has been shown to reduce morbidity and mortality in Heart Failure with reduced Ejection Fraction (HFrEF), but its impact on exercise capacity of non-diabetic HF outpatients is unknown. Methods: Adult non-diabetic HF patients with a left ventricular ejection fraction (LVEF) <50% were randomized 1:1 to receive dapagliflozin 10 mg or to continue with HF medication. Patients underwent an initial evaluation which was repeated after 6 months. The variation of several clinical parameters was compared, with the primary endpoint being the 6 month peak oxygen uptake (pVO2) variation. Results: A total of 40 patients were included (mean age 61 ± 13 years, 82.5% male, mean LVEF 34 ± 5%), half being randomized to dapagliflozin, with no significant baseline differences between groups. The reported drug compliance was 100%, with no major safety events. No statistically significant difference in HF events was found (p = 0.609). There was a 24% reduction in the number of patients in New York Heart Association (NYHA) class III in the treatment group as opposed to a 15.8% increase in the control group (p = 0.004). Patients under dapagliflozin had a greater improvement in pVO2 (3.1 vs. 0.1 mL/kg/min, p = 0.030) and a greater reduction in NT-proBNP levels (−217.6 vs. 650.3 pg/mL, p = 0.007). Conclusion: Dapagliflozin was associated with a significant improvement in cardiopulmonary fitness at 6 months follow-up in non-diabetic HFrEF patients.

Can glucose-lowering medications improve outcomes in non-diabetic heart failure patients? A Bayesian network meta-analysis.

AimsThe cardioprotective effects of glucose‐lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose‐lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta‐analysis to evaluate the impact of various glucose‐lowering medications on the outcomes of non‐diabetic HF patients.Methods and resultsMedline and Embase were searched for RCTs investigating the use of glucose‐lowering medications in non‐diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre‐defined datasheet. Primary outcomes include serum N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO2). A Bayesian network meta‐analysis was performed to compare the effectiveness of different classes of glucose‐lowering medications in improving HF outcomes. Risk‐of‐bias was assessed using Cochrane Risk‐of‐Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium‐glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT‐proBNP, with the significant reduction in NT‐proBNP when compared with glucagon‐like peptide‐1 receptor agonists (GLP1‐RA) [mean differences (MD): −229.59 pg/mL, 95%‐credible intervals (95%‐CrI): −238.31 to −220.91], metformin (MD: −237.15 pg/mL, 95%‐CrI: −256.19 to −218.14), and placebo (MD: −228.00 pg/mL, 95%‐CrI: −233.99 to −221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1‐RA (MD: 8.09%, 95%‐CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%‐CrI: 4.37 to 7.84). SGLT2i and GLP1‐RA were more favourable to placebo in improving PVO2, with significant increase of PVO2 at a MD of 1.60 mL/kg/min (95%‐CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%‐CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo.ConclusionsThis Bayesian network meta‐analysis demonstrated that SGLT2i, when compared with GLP1‐RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO2 and NT‐proBNP in non‐diabetic HF patients. Further large‐scale prospective studies are needed to confirm these preliminary findings.

Prognostic value of sST2 in heart failure patients with diabetes

Abstract Background Soluble suppression of tumorigenesis-2 (sST2) is released in response to inflammation and vascular injury, and holds prognostic value in heart failure (HF). Type 2 diabetes (T2D) is characterized by a pro-inflammatory status and is highly prevalent among HF patients, with adverse impact on outcomes. The clinical value of sST2 in HF patients with T2D has never been characterized. Purpose We aimed to assess sST2 clinical correlates and prognostic value in HF patients with T2D. Methods Individual data of 3476 patients with stable chronic HF from 5 cohorts from the BIOS (Biomarkers In Heart Failure Outpatient Study) dataset were analysed, with available N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and sST2 levels. Results Mean age was 65±12 years (75% males). T2D was present in 1386 patients (40%), who had higher body mass index (BMI, 27 [24–30] vs. 26 [23–29] kg/m2, p&amp;lt;0.001), lower estimated glomerular filtration rate (eGFR, 56±22 vs. 60±19 mL/min/1,73 m2, p&amp;lt;0.001), higher sST2 (33 [24–47] vs. 27 [20–40] ng/mL, p&amp;lt;0.001), NT-proBNP (1735 [742–3963] vs. 1450 [514–3299] ng/L, p&amp;lt;0.001), hs-TnT (28 [16.2–51.5] vs. 17 [9–31] ng/L, p&amp;lt;0.001) and high-sensitivity C-reactive protein (hs-CRP, 6 [2–11] vs. 4. [2–9] mg/L, p=0.003) (Figure). Differences between sST2 levels in patients with or without T2D were influenced by hs-CRP (p for interaction=0.010) and hs-TnT (p=0.031), but not by NT-proBNP and eGFR. At multivariate linear regression analysis, NT-proBNP, hs-TnT and hs-CRP were independently associated with sST2 levels in both T2D and non-T2D patients. Compared with patients without T2D, those with T2D showed higher 1-year all-cause mortality (12% vs. 10%, p=0.034), cardiovascular mortality (9% vs. 7%, p=0.011), and HF hospitalization rate (22% vs. 12%, p&amp;lt;0.001). In a prognostic model including age, sex, eGFR, ischemic vs- non-ischemic aetiology, left ventricular ejection fraction class, New York Heart Association class, NT-proBNP, hs-TnT, and hs-CRP, sST2 retained independent prognostic value in both patients with or without T2D for 1-year all-cause and cardiovascular mortality, and 1-year HF hospitalization, with higher optimal cut-offs for mortality prediction in T2D vs. non-T2D (39 and 45 vs. 29 and 29 ng/mL respectively for 1-year all-cause and cardiovascular mortality). Conclusions sST2 is higher in HF patients with T2D and likely linked to a pro-inflammatory status. sST2 maintains its prognostic value both in diabetic and non-diabetic HF patients, independently of NT-proBNP, hs-TnT and hs-CRP. Funding Acknowledgement Type of funding sources: None. Figure 1

Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a global cause of morbidity and mortality with over 60 million estimated cases worldwide. The burden of HF care is expected to increase with an ageing population as evidenced by the fact that 80% of HF-related hospitalizations occur in those aged above 65. Given the significant morbidity and mortality associated with HFrEF, there is a need for new prognostic therapies that have an impact on morbidity and mortality. In February of 2021, the National institute for Health and Care Excellence (NICE) released new guidance on the utility of Dapagliflozin for the management of heart failure with reduced ejection fraction (HFrEF). NICE advocated that dapagliflozin is a viable treatment option in symptomatic HFrEF patients on optimal medical management. The current list price of dapagliflozin is around £36.59 per 28-tablet pack with an estimated annual cost of £476.98 equating to £6939 per quality-adjusted life year. The guidance was mainly based on evidence produced from the 2019 DAPA-HF trial. This demonstrated that in HFrEF population, the use of dapagliflozin led to a significant reduction in worsening HF events, cardiovascular, and all-cause death. In this article, we summarize the evidence base for sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Sodium-Glucose Cotransporter-2 Inhibitor–Associated Euglycemic Diabetic Ketoacidosis After Orthotopic Heart Transplant in a Prediabetic Patient: A Case Report

Postoperative euglycemic diabetic ketoacidosis (euDKA) associated with sodium-glucose cotransporter-2 (SGLT2) inhibitor use has been well-documented and carries a Food and Drug Administration recommendation to hold SGLT2 inhibitors 3 to 4 days before a planned surgical procedure. Unfortunately, many surgical procedures, such as orthotopic heart transplant (OHT), are unplanned and unpredictable. With the increasing use of SGLT2 inhibitors in diabetic and non-diabetic heart failure patients, new challenges in patient management and perioperative risk have arisen. We report a case in which SGLT2 inhibitor-associated euDKA complicated the postoperative course of a prediabetic patient who had undergone OHT.

Overview of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors for the Treatment of Non-diabetic Heart Failure Patients.

Heart failure (HF) is a clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood, and results in low life quality and expectancy, creating a significant burden on the healthcare system. The pharmacological HF management has remained unchanged for a decade, however, several randomized clinical trials have demonstrated the potential clinical benefits of sodium-glucose cotransporter-2 inhibitors, an antidiabetic agent, by reducing the rate of hospitalizations for HF, cardiovascular death, and all-cause death. The cardioprotective effects are characterized by reduction of inflammatory, metabolic and ionic dyshomeostasis despite the diabetic status. Since the United States Food and Drug Administration (FDA) approval in May 2020, SGLT2 inhibitors have been used mostly in heart failure with reduced ejection fraction (HFrEF). In this review article, we provide a comprehensive overview of the potential benefits, effectiveness, and safety profile of SGLT2 inhibitors used in HF patients with no history of diabetes mellitus.