Empagliflozin confers cardioprotective benefits among patients with heart failure, across the range of ejection fraction (EF), regardless of type 2 diabetes status. The long-term cost-effectiveness of empagliflozin for the treatment of heart failure (HF) in the Philippines remains unclear. This study aims to determine the economic benefit of adding empagliflozin to the standard of care (SoC) vs the SoC alone for HF in the Philippines.

Using a Markov model, we predicted lifetime costs and clinical outcomes associated with treating HF in the Philippine setting. We used estimates of treatment efficacy, event probabilities, and derivations of utilities from the EMPEROR trials. Costs were derived from hospital tariffs and expert consensus. Separate analyses were performed for patients with left ventricular EF > 40%, categorized under mid-range ejection fraction or preserved ejection fraction (HFmrEF/HFpEF), and patients with left EF ≤ 40%, categorized under HF with reduced ejection fraction (HFrEF).

Our model predicted an average of 0.09 quality-adjusted life year (QALY) gains among HFmrEF/HFpEF patients and HFrEF patients when empagliflozin was compared to SoC. The addition of empagliflozin in the treatment results in a discounted incremental lifetime cost of PHP 62,692 (USD 1,129.99) and PHP 17,215 (USD 308.67) for HFmrEF/HFpEF and HFrEF, respectively. The incremental cost-effectiveness ratio (ICER) of empagliflozin is PHP 198,270 (USD 3,570.72)/QALY and PHP 742,604 (USD 13,385.08)/QALY for HFrEF and HFmrEF/HFpEF, respectively.

This study employed parameters derived from short-term clinical trial data, alongside metrics representative of Asian populations, which are not specific to the Philippine cohort.

Adding empagliflozin to the SoC in comparison to the SoC is associated with improved clinical outcomes and quality-of-life, at additional costs for both HFrEF and HFmrEF/HFpEF.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease. This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.

Guideline-directed medical therapy (GDMT) is recommended for all patients with heart failure with reduced ejection fraction (HFrEF). Despite this, little data exist describing GDMT use in diverse, real-world populations including the use of vasodilators, prescribed primarily to Black populations. We sought, among a diverse population of HFrEF patients, to determine (1) GDMT use rates and target dosing by medication class and (2) predictors of GDMT use and target dosing by medication class.

We utilized electronic health records (EHRs) from Kaiser Permanente (KP) Mid-Atlantic States, a large integrated health system. Included patients had heart failure and left ventricular ejection fraction (EF) of ≤40% between 2015 and 2021. GDMT was defined by five medication classes-angiotensin-converting enzyme (ACE) inhibitors (ACEis)/angiotensin receptor blockers (ARBs)/angiotensin receptor-neprilysin inhibitors (ARNis), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is) and vasodilators (Black patients only). Proportions of patients on GDMT and target dose rates were examined. Logistic regression determined, within each class, predictors of medication use and being at ≥80% of the target dose.

A total of 3154 patients were included. Among the 93.8% on some form of GDMT, 82.8%, 81.4%, 23.5%, 3.6% and 13.4% were on ACEis/ARBs/ARNis, BBs, MRAs, SGLT2is and vasodilators (Black patients only), respectively. Among treated patients, 45.8%, 21.4%, 77.6%, 100% and 14.7% were treated at ≥80% of the target dose for ACEis/ARBs/ARNis, BBs, MRAs, SGLT2is and vasodilators, respectively. Overall, increasing age, higher EF, atrial fibrillation/flutter, chronic obstructive pulmonary disease (COPD), prior stroke and dementia were associated with decreased odds of GDMT use. Conversely, higher body mass index (BMI), Black race, higher glomerular filtration rate (GFR), recent echo and cardiac defibrillator were associated with increased odds of GDMT use. Among treated, higher BMI, higher systolic blood pressure, haemoglobin A1C ≥ 6.5% and cardiac defibrillator were associated with higher odds of being at ≥80% of the target dose.

Our study using real-world data from a diverse health system demonstrated gaps in GDMT use among patients with HFrEF, specifically older patients with more comorbidities.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have shown promise in reducing cardiovascular mortality and hospitalization due to heart failure (HF), a significant global health issue. This study aims to evaluate the incremental net benefit (INB) of SGLT-2i in HF patients through a systematic review and meta-analysis of cost-utility studies.

We searched five databases from their inception until Aug 30, 2024, economic evolution studies reporting cost-effectiveness and cost-utility analyses comparing SGLT-2i combined with standard triple-therapy versus standard triple-therapy alone in HF patients were selected. INB as the primary outcome was calculated in monetary units adjusted for purchasing power parity in 2022 US dollars.

This review included 46 studies, with 41 studies (55 comparisons) pooled into meta-analysis. Adding SGLT2is was cost-effective compared to standard triple-therapy alone, from both healthcare system perspective (INB, $4042.08; 95 % CI, $1758.70-$6325.46) and payer perspective (INB, $12,972.84; 95 % CI, $4711.5-$21,234.22). However, subgroup analyses showed non-significant economic benefit in HF patients with preserved ejection fraction (HFpEF) both from the healthcare system perspective (INB, -$639.32; 95 % CI, -$1850.09-$571.44) and the payer perspective (INB, $3611.07; 95 % CI, -$208.49-$7430.64). Additionally, HF patients from low- and middle-income countries did not show significant economic benefit from the payer perspective (INB, $55,645.70; 95 % CI, -$51,000.00-$160,000.00).

The findings suggest that adding SGLT-2i is cost-effective compared to conventional standard triple-therapy alone, from both healthcare system and payer perspectives. Nevertheless, the economic benefits are limited in HFpEF and those from low- and middle-income countries. Further research is needed to explore the cost-effectiveness from a broader societal perspective.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve health status and outcomes in the setting of heart failure (HF) across the range of ejection fraction (EF). Baseline kidney disease is common in HF, complicates HF management and is strongly linked to worse health status. This study aimed to assess whether the treatment effects of dapagliflozin on health status vary based on estimated glomerular filtration rate (eGFR).

We conducted a pooled participant-level analysis of two double-blind, randomized trials, DEFINE-HF (n = 236) and PRESERVED-HF (n = 324), which evaluated dapagliflozin versus placebo. Both multicentre studies enrolled adults with HF, New York Heart Association Class II or higher, elevated natriuretic peptides, and an EF < 40% in DEFINE-HF or >45% in PRESERVED-HF. The primary exposure was eGFR. The main outcome was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 12 weeks. Across both trials, there were 583 (99.3%) participants with a baseline eGFR. The median (25th, 75th) eGFR was 59 (46, 77) mL/min/1.73 m2. Dapagliflozin improved KCCQ-CSS at 12 weeks [placebo-adjusted difference, +5.0 points, 95% confidence interval (CI) 2.6-7.5; P < 0.001], and this was consistent in participants with an eGFR ≥ 60 (+6.0 points, 95% CI 2.4-9.7; P = 0.001) and eGFR < 60 (+4.1 points, 95% CI 0.5-7.7; P = 0.025) (P interaction = 0.46). The benefits of dapagliflozin on KCCQ-CSS remained robust across eGFR when modelled as a continuous variable (P interaction = 0.48).

Dapagliflozin led to early and clinically meaningful improvements in health status in HF patients, regardless of EF or baseline eGFR.

The last released European guidelines on the management of heart failure (HF) recommend in patients with chronic HF with reduced ejection fraction (HFrEF) a pharmacological approach based on four fundamental drugs to be rapidly implemented and then uptitrated to modify disease progression. The aim of the Optimization of Therapy in the Italian Management of Heart Failure (OPTIMA-HF) registry is to collect data on chronic HF outpatients in different settings of care. In the present analysis, we report the first analysis of the OPTIMA-HF registry, focusing on the real-life use of guideline-directed medical therapy in patients affected by HFrEF.

OPTIMA-HF is an observational, cross-sectional, multicentre, real-life Italian registry conducted in two different clinical settings: HF outpatients' clinics of Italian hospitals and community HF outpatients' services. The study comprises a T0 phase-retrospective data collection, in which data of consecutive HF outpatients seen between January and October 2022 were collected; an educational activity phase; and a T1 phase-prospective data collection, in which data of consecutive HF outpatients seen between September 2023 and November 2023 were collected. In the present analysis, we describe the T0 phase focusing on HFrEF drug prescription rates, types, doses, combination therapy, the presence of contraindications and reasons of non-optimized treatment.

Twenty-nine centres enrolled 2110 HF patients, of which 1390 (65.9%) had HFrEF [69.5 ± 11.9 years, 76.2% males, 4.1 years since HF diagnosis, median ejection fraction (EF) 33%]. Among HFrEF patients, 89.1% were on treatment with renin-angiotensin-aldosterone system inhibitor (RAASi)/angiotensin receptor neprilysin inhibitor (ARNI) (72% ARNI and 17.1% RAASi), 95.1% with beta-blockers, 75.8% with mineralocorticoid receptor antagonists (MRA) and 63.2% with sodium/glucose cotransporter 2 inhibitors (SGLT2i). Despite high prescription rates, a non-negligible number of patients with no contraindications were not treated with each specific drug. Patients taking all four drug classes, as recommended by guidelines, were mere 46.9%. Regarding doses, a still low number of patients on RAASi/ARNI and beta-blockers were treated with a dose ≥50% of the target doses recommended by the European guidelines.

The OPTIMA-HF registry reported that HFrEF fundamental drugs are prescribed in most Italian patients; however, <50% of patients receive optimal combination therapy, and still not a satisfying number of patients receive target doses. Strategies to improve implementation of guideline-directed medical therapy are needed to improve HF prognosis.

Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the effect on mitochondria is not clear.

Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq.

Gαq and wild type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow).

From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis - all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by 31P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU.

The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, and was associated with increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.

Understanding heart failure (HF) characteristics is essential to improve patient outcomes. Categorizing HF beyond left ventricular ejection fraction (LVEF) is challenging due to heterogeneous clinical presentation and aetiologies. Despite global studies on HF, the role of LVEF on mortality remains controversial. We explored the association of LVEF with mortality, considering sex differences and comorbidities in a cohort from the largest tertiary cardiovascular centre in Switzerland.

HF patients admitted to the University Hospital of Bern from January 2015 to December 2019 were evaluated. LVEF was used to classify patients into HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced preserved ejection fraction (HFrEF) categories. Cox proportional hazard models and time-stratified analyses adjusted for potential confounders were employed.

A total of 5824 HF patients were included, and 2912 died over a median follow-up time of 3.39 years. Mortality rates across LVEF categories showed no significant differences, while overall, women showed significantly higher mortality; 30 day mortality was lower in the HFpEF category [hazard ratio (HR) 0.67, 95% confidence interval (CI): 0.52-0.88, P = 0.003], with persistent effects upon stratification in males (HR 0.59, 95% CI: 0.42-0.81, P < 0.001) and non-diabetics (HR 0.62, 95% CI: 0.44-0.87, P = 0.005). An isolated reduction in HFpEF mortality was observed in females after 1 year (HR 0.72, 95% CI: 0.53-0.98, P = 0.035).

The prognostic role of LVEF on all-cause mortality remains unclear, while differences in mortality rate distribution between women and men mirror established HF pathophysiological sex differences. Future HF studies should focus on HF aetiology and include measures beyond LVEF for comprehensive characterization.

Real-world evidence involving healthcare database studies is well established for making causal inferences in post-market drug safety studies and methods, data, and research infrastructure for evaluating effectiveness have advanced in recent years. The rapidly expanding field of etiologic research using insurance claims and electronic health records databases is being evaluated for supporting effectiveness claims. One such use case to support regulatory decision-making on effectiveness is for expanding indications beyond existing effectiveness claims. Confidence in the validity of findings from cohort studies conducted using databases (hereafter "database study") to support indication expansions could be increased through a structured benchmarking process of an initial database study against RCT evidence followed by calibration of a subsequent database study based on differences in results observed in the initial RCT-database pair. This paper proposes a benchmark, expand, and calibration (BenchExCal) approach to trial emulation and describes the design and process for evaluating the performance of the approach through both simulation studies; five planned empirical examples are also described. The project will provide insights regarding how a first-stage benchmarking emulation of a completed trial for an existing indication can be used to calibrate, increase confidence, and improve interpretation of the results for a second-stage emulation of a hypothetical trial that could potentially provide evidence for an expanded indication. Although the examples have been selected to provide a variety of learnings, five use cases do not address all clinical and data scenarios that may be encountered when seeking a supplemental indication for a marketed drug.

We conducted a systematic review with pairwise (PMA) and network meta-analyses (NMA) to evaluate sodium-glucose transport protein 2 inhibitor (SGLT2i) effects in patients with both heart failure (HF) and type 2 diabetes mellitus (T2DM). Five databases were searched up to April 15, 2025. Primary outcomes were all-cause mortality (ACM), cardiovascular death (CVD), all-cause hospitalization (ACH), and hospitalization for heart failure (HHF). SGLT2i class effects versus control were assessed via PMA and individual SGLT2i comparative efficacy via NMA plus ranking using p-scores. Seventeen randomized controlled trials (n = 17,809) were included. Arms included canagliflozin (n = 2), dapagliflozin (n = 6), empagliflozin (n = 6), ertugliflozin (n = 1), ipragliflozin (n = 1), sotagliflozin (n = 1), placebo (n = 13), and standard of care (n = 4). Compared to control, SGLT2i significantly reduced ACM (HR 0.87, 95 %CI 0.78 to 0.98, low quality of evidence [QoE]), ACH (HR 0.74, 95 %CI 0.62 to 0.88, high QoE), and HHF (HR 0.70, 95 %CI 0.63 to 0.77, low QoE); but not CVD (HR 0.87, 95 %CI 0.76 to 1.00, very low QoE). Canagliflozin ranked highest in decreasing ACM (p-score = 0.86), CVD (p-score = 0.82), and HHF (p-score = 0.88). In patients with HF and T2DM, SGLT2i class effects include ACM, ACH, and HHF reduction. Among SGLT2i, canagliflozin showed greatest ACM, CVD, and HHF benefit.

Outcomes of stopping sodium-glucose cotransporter 2 inhibitors (SGLT2i) 5 days before open heart surgery (euglycemic diabetic ketoacidosis [eDKA] rate, mortality, infection, hospital, and cardiovascular intensive care unit [CVICU] length of stay [LOS]).

Retrospective study.

Academic university hospital.

Adult open heart surgery patients.

Patients on SGLT2i who stopped medications 5 days before open heart surgery versus non-SGLT2i-using patients.

We evaluated patients who were told to stop SGLT2i 5 days before receiving open heart surgery for eDKA development within 24 hours of hospital admission (12/14/2022 to 10/25/2023). Non-eDKA outcomes were compared between SGLT2i users and non-users using Wilcoxon rank sum and Chi-square testing as appropriate. Of 540 open heart surgery patients, 48 (8.9%) were prescribed SGLT2i's before surgery; of these, 0 (0%) developed eDKA within 24 hours of hospital admission. Hospital LOS was statistically longer for patients with SGLT2i use (median [interquartile range]: 4 [4-5] v 4 [3-6] days, p = 0.003; mean [standard deviation]: 4 [3] v 5 [2], p = 0.03). We found no significant difference between patients with and without SGLT2i use in CVICU LOS (median [interquartile range]: 1.67 [0.95-2.09] v 1.17 [0.96-1.88] days, p = 0.14), in-hospital mortality (2.1% [1] v 0.6% [3], p = 0.3), or sternal infections (0 [0.0%] v 2 [0.4%], p > 0.9).

Postoperative eDKA was absent in SGLT2i patients told to stop medications 5 days before open heart surgery. LOS and infection and mortality rates appeared similar between the two cohorts. Stopping SGLT2i medications 5 days before open heart surgery appears safe.

Patients with non-ischaemic cardiomyopathy (NICMP) have a class IIa primary prevention indication for an implantable cardioverter-defibrillator (ICD). Recent studies have shown that the evidence for a survival benefit following ICD implantation in this patient group is not particularly robust. In 2023, the Dutch Society of Cardiology published an update of the ESC guideline to better select patients with NICMP for ICD implantation. The objective of this study was to analyse the impact of this guideline on the number of indications in a retrospective cohort of patients who had received an ICD and whether the patients without an indication were also without appropriate ICD therapy.

A single-centre, retrospective observational study was performed in 134 patients with NICMP who underwent ICD implantation for primary prevention between 2015 and 2020.

After applying the new Dutch guideline, 74 out of 134 patients with NICMP without a high-risk phenotype (35 patients) had no ICD indication (group 2). The remaining 25 patients were considered to have an ICD indication (group 1). During a median follow-up of 66 months (interquartile range 52-81) the incidence of appropriate ICD therapy (antitachycardia pacing and shock) was comparable in both groups: 4 patients in group 1 (16%) and 9 in group 2 (12%), p = 0.623.

The new 2023 guideline for ICD implantation in NICMP patients does indeed rule out a significant group of patients from ICD implantation. Nevertheless, our data show that patients without an indication still had comparable rates of appropriate ICD therapy.

Despite availability of an array of antihypertensive drugs, malignant hypertension remains a life-threatening condition, and new therapeutic strategies for the treatment of malignant hypertension and malignant hypertension-associated organ damage are needed. The aim of the present study was to assess the effects of nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulator on the course of malignant hypertension. The second aim was to investigate if the treatment with sodium-glucose cotransporter type 2 (SGLT2) inhibitor would augment the expected beneficial actions of the sGC stimulation on the course of malignant hypertension.

As a model of malignant hypertension, Ren-2 transgenic rats (TGR) treated with nonspecific NO synthase inhibitor (Nω-nitro- l -arginine methyl ester, l -NAME) was used. Blood pressure (BP) was monitored by radiotelemetry, and the treatment was started 3 days before administration of l -NAME.

The treatment with sGC stimulator BAY 41-8543, alone or combined with SGLT2 inhibitor empagliflozin, abolished malignant hypertension-related mortality in TGR receiving l -NAME. These two treatment regimens also prevented BP increases after l -NAME administration in TGR, and even decreased BP below values observed in control TGR, and prevented cardiac dysfunction and malignant hypertension-related morbidity. The treatment with the SGLT2 inhibitor empagliflozin did not further augment the beneficial actions of sGC stimulator on the course of malignant hypertension-related mortality.

The treatment with NO-independent sGC stimulator displayed marked protective actions on the course of malignant hypertension-related mortality and malignant hypertension-related cardiac damage. This suggests that application of sGC stimulator could be a promising therapeutic means for the treatment of malignant hypertension.

Over the past few decades, the rising burden of metabolic disease, including type 2 diabetes, prediabetes, obesity, and metabolic dysfunction-associated steatotic liver disease, has corresponded with fundamental shifts in the landscape of heart failure (HF) epidemiology, including the rising prevalence of HF with preserved ejection fraction. It has become increasingly important to understand the role of extracardiac contributors and interorgan communication in the pathophysiology and phenotypic heterogeneity of HF. Whereas traditional epidemiological strategies have separately examined individual contributions of specific comorbidities to HF risk, these approaches may not capture the shared mechanisms and more complex, bidirectional relationships between cardiac and noncardiac comorbidities. In this review, we highlight the cardiac, kidney, liver, and metabolism multiorgan interactions and pathways that complicate HF development and progression and propose research strategies to further understand HF in the context of multiple organ disease. This includes evolving epidemiological approaches such as multiomics and machine learning which may better capture common underlying mechanisms and interorgan crosstalk. We review existing preclinical models of HF and how they have enhanced our understanding of the role of multiorgan disease in the development of HF subtypes. We suggest recommendations as to how clinical practice across multiple specialties should screen for and manage multiorgan involvement in HF. Finally, recognizing the advent of novel combinatorial therapeutic agents that may have multiple indications across the cardiac-kidney-liver metabolism continuum, we review the current clinical trials landscape. We specifically highlight a pressing need for the design of more inclusive trials that examine the contributions of multimorbidity and incorporate multiorgan end points, which we propose may lead to outcomes that are evermore clinically relevant today.

Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.

Microvascular endothelial cells dysfunction can significantly worsen ischaemic stroke outcomes by disrupting tight junctions and increasing the acquisition of adhesion molecules, accelerating blood-brain barrier (BBB) disruption and pro-inflammatory response. The identification of drugs that improve endothelial cell function may be crucial for ischaemic stroke. It has been validated that empagliflozin (EMPA), a novel antidiabetic drug, protects endothelial cells regardless of the diabetic status of the patient. However, the impact of EMPA on stroke outcomes is unclear. We hypothesized that EMPA would exert a beneficial effect on ischaemic stroke outcome by protecting microvascular endothelial cells against tight junction disruption and the increase of adhesion molecules.

Young adult male mice were administered with EMPA or vehicle (dimethyl sulfoxide) daily for 7 days before being subjected to transient middle cerebral artery occlusion (tMCAO). Neurological deficits were evaluated for up to 28 days post-tMCAO. Infarct volume, BBB disruption, and inflammatory status were assessed 1 day after tMCAO.bEnd.3 cells and primary brain microvascular endothelial cells were treated with EMPA or vehicle under oxygen and glucose deprivation/reperfusion (OGD/R), and the lactate dehydrogenase release, transendothelial electrical resistance, leakage of fluorescein isothiocyanate-dextran, and tight junction and adhesion molecules proteins were examined. Mechanistic studies probing the effect of EMPA on endothelial cells were conducted by RNA-seq. EMPA treatment before ischaemia markedly improved infarct volume, BBB disruption, and inflammation 1-day post-tMCAO, and further enhanced neurobehavioral function up to 28 days. Pre-treatment of EMPA attenuated endothelial cell dysfunction under OGD/R conditions. In mechanistic terms, RNA-seq data from isolated cerebral microvessels revealed that the Wnt/β-catenin signalling pathway was preserved in the EMPA group, in contrast to the vehicle group. Pre-treatment with EMPA inhibited β-catenin ubiquitination and promoted β-catenin translocation from the cytoplasm to the nucleus to improve endothelial cell function. Importantly, the β-catenin inhibitor XAV-939 eliminated this protective function of EMPA.

EMPA administration before tMCAO attenuated ischaemia/reperfusion-induced BBB disruption and inflammation via β-catenin-mediated protection of cerebral microvascular endothelial cells. Therefore, EMPA shows potential for improving stroke outcomes as an adjunctive preventive strategy.

The purpose of the current study is to evaluate the role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the treatment of patients with diabetes with newly diagnosed acute myocardial infarction (AMI).

This multicenter, prospective, cohort study included 1161 patients with diabetes with newly diagnosed AMI. The primary endpoint events included rehospitalization for heart failure (HF) and major adverse cardiovascular events (MACEs). The secondary endpoint events were recurrent MI and cardiac death.

Patients were categorized into the SGLT2i group and the non-SGLT2i group. During a median follow-up of 1.8 (1.5-2.3) years, the risk of hospitalization for HF (HR 0.58; 95% CI 0.36-0.94; P = 0.026) and MACEs (HR 0.59; 95% CI 0.40-0.86; P = 0.006) were lower in the SGLT2i group, with a similar trend observed for cardiac death (HR 0.51; 95% CI 0.27-0.99; P = 0.046). SGLT2i appears to be a better choice for all such patients. However, our research further found the above trends were observed mainly in the LVEF < 50% subgroup. In addition, our study also revealed novel findings that the protective effect of SGLT2i was not altered by baseline levels of HbA1c in these patients, nor by different SGLT2i medications.

The outcomes of the current investigation suggest that SGLT2i is preferred as a hypoglycemic and cardiovascular protective drug for patients with diabetes with newly diagnosed AMI. It could improve cardiovascular outcomes, reducing the risk of rehospitalization for HF and MACEs, particularly in patients with reduced LVEF.

Role of SGLT2I in Patients with Myocardial Infarction, NCT06245980. https://clinicaltrials.gov/ct2/show/NCT06245980 . Retrospectively registered.

Overweight and obesity are major risk factors for heart failure (HF), contributing to its development through metabolic, neurohormonal, haemodynamic, and inflammatory alterations. While overweight/obesity increases the risk of developing HF, its impact on patient outcomes remains complex. The "obesity paradox" suggests that a higher BMI may be associated with improved survival in patients with established HF. However, recent GLP-1 receptor agonist (GLP-1 RA) trials suggest that intentional weight loss positively influences outcomes in overweight/obese patients with HF. This seemingly contradictory evidence highlights the need for a deeper understanding of the mechanisms linking adiposity to HF outcomes. A more precise characterization of adiposity phenotypes using alternative and accurate measures of pathological fat accumulation is crucial in identifying individuals who may benefit most from anti-obesity treatments. In this context, recent research underscores the role of epicardial adipose tissue (EAT) in HF pathophysiology, as it directly influences cardiac function and structure through inflammatory, metabolic, and mechanical effects. This narrative review summarises current evidence on the impact of weight loss on HF outcomes, focusing on recent GLP-1 RA trial results. Additionally, it highlights epidemiological and molecular data supporting EAT as a novel adiposity measure that might allow refining patient selection for pharmacological weight-loss treatments. Finally, it emphasizes the need for future research to identify causal pathways linking alternative measures of visceral fat accumulation to HF outcomes. These efforts will be essential in optimizing the benefits of novel weight-loss treatments, ensuring effective and individualized therapeutic strategies for overweight or obese patients with HF.

To compare long-term complications for people with type 2 diabetes mellitus (T2DM) following second-line treatment in routine practice with sulphonylureas (SU), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose co-transporter-2 inhibitors (SGLT2i) added to metformin.

We used the RAPIDS microsimulation model to predict diabetes complications over 5 years after second-line treatment initiation. We combined information on 'real-world' treatment duration in England from the Clinical Practice Research Datalink with evidence on treatment effectiveness from Randomised Controlled Trials (RCTs). We estimated between-treatment differences in the probabilities of end-stage kidney disease (ESKD), heart failure hospitalisation (HF), diabetic eye disease, myocardial infarction (MI), and lower-extremity amputation (LEA).

The predicted probabilities of complications within 5 years were lower following second-line treatment with SGLT2i compared to SU and DPP4i. The mean (95% CI) difference (reduction) in the predicted probability of ESKD following SGLT2i versus SU was -0.81% (-0.89, -0.73), and for SGLT2i versus DPP4i the corresponding difference was -0.87% (-0.95, -0.79). The reduction in the probability of HF following SGLT2i versus SU was -0.90% (-1.01, -0.80), and for SGLT2i versus DPP4i it was -0.95% (-1.06, -0.84). The corresponding differences in the probabilities of diabetic eye disease following SGLT2i versus SU were -1.41% (-1.57, -1.26), and for SGLT2i versus DPP4i was -0.44% (-0.59, -0.29). The predicted probabilities of LEA were similar across treatments. Pre-existing CVD did not modify the predicted probabilities of complications.

For a general T2DM population, second-line treatment with SGLT2i rather than SU or DPP4i can reduce the probability of complications within 5 years.

Primary percutaneous coronary intervention (PCI) with stenting is recommended in ST-segment-elevation myocardial infarction. Immediate stenting may cause distal embolization, microvascular damage, and flow disturbances, leading to adverse outcomes. We report the 10-year clinical outcomes of deferred stenting versus conventional PCI in patients with ST-segment-elevation myocardial infarction.

We conducted a 10-year follow-up study of the open-label, randomized DANAMI-3-DEFER trial (Third Danish Study of Optimal Acute Treatment of Patients With STEMI - Deferred Stent Implantation Versus Conventional Treatment), conducted in 4 PCI centers in Denmark. Patients with ST-segment-elevation myocardial infarction and acute chest pain <12 hours were randomized to deferred stenting >24 hours after the index procedure or conventional PCI with immediate stenting. In the deferred group, immediate stable Thrombolysis in Myocardial Infarction flow II to III was established, and intravenous administration of either a glycoprotein IIb/IIIa antagonist or bivalirudin for >4 hours after the index procedure was recommended. The primary outcome was a composite of hospitalization for heart failure or all-cause mortality. Key secondary outcomes included individual components of the primary outcome and target vessel revascularization.

Of 1215 patients, 603 were randomized to deferred stenting and 612 to conventional PCI. After 10 years, deferred stenting did not significantly reduce the primary composite outcome (hazard ratio, 0.82 [95% CI, 0.67-1.02]; P=0.08). In the deferred group, 124 (24%) died versus 150 (25%) in the conventional PCI group (hazard ratio, 0.95 [95% CI, 0.75-1.19]). Hospitalization for heart failure was lower in patients treated with deferred stenting compared with conventional PCI (odds ratio, 0.58 [95% CI, 0.39-0.88]). Target vessel revascularization was similar in both groups (odds ratio, 1.20 [95% CI, 0.81-1.79]).

Deferred stenting did not reduce all-cause mortality or the composite primary outcome after 10 years but reduced hospitalization for heart failure compared with conventional PCI.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT01435408.

This report presents the baseline characteristics of patients enrolled in the DIGIT-HF trial and compares them with participants from recent trials with improved outcomes in patients with heart failure (HF) and a reduced ejection fraction (HFrEF).

DIGIT-HF, a randomized, double-blind, placebo-controlled, multicentre trial enrolling patients with symptomatic HFrEF (New York Heart Association [NYHA] functional class II and left ventricular ejection fraction [LVEF] ≤30%, or NYHA class III-IV and LVEF ≤40%), compares the efficacy and safety of digitoxin versus placebo in addition to standard treatment. Most baseline characteristics of the intention-to-treat population (1212 patients, mean age 66 ± 11 years, 20% women, mean LVEF 29 ± 7%) were similar to those in recent HFrEF trials. The distribution of NYHA class II, III, and IV was 30%, 66% and 4%, respectively, and indicates that the patients were sicker than in comparator HFrEF trials. Less patients had atrial fibrillation (27%) than those in recent HFrEF trials, but prescription rates of background therapy with beta-blockers (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (95%), mineralocorticoid receptor antagonists (76%), and diuretics (87%) were high and similar. Overall, 40% of patients were on angiotensin receptor-neprilysin inhibitors, 19% on sodium-glucose cotransporter 2 inhibitors, and 9% on ivabradine. Rates of implantable cardioverter-defibrillator (ICD, 64%) and cardiac resynchronization therapy (CRT, 25%) devices were much higher than in recent HFrEF trials.

Patients included in DIGIT-HF display a more severe HF symptom burden and higher rates of ICD/CRT implants compared to participants in recent HFrEF trials, while pharmacotherapy was largely similar.

EudraCT (2013-005326-38).

Sarcopenia is common in patients with heart failure (HF) and it is frequently associated with other comorbidities. Sarcopenia has been linked to an increased risk of major adverse cardiovascular events (MACE) in HF patients.

The aim of the present study was to evaluate, in a cohort of older adult's patients affected by HF with reduced ejection fraction (HFrEF) and sarcopenia, already being treated with sacubitril/valsartan, the effect of add-on therapy with SGLT2i on clinical, functional abilities, muscle performance and effects on quality of life.

We enrolled 147 outpatients. A simple linear regression analysis was performed to assess the correlation between the change in Cardiac Index (CI) and Short physical performance battery (SPPB) values, expressed as (Δ) between baseline and follow-up (ΔT0-12), and several covariates.

After 12 months of treatment, we observed an improvement in the inflammatory profile, moreover there was a reduction of the oxidative stress (p < 0.0001) and platelets activation (p < 0.0001) parameters. In addition, there was a significant increase in CI and global longitudinal strain and a statistically significant improvement in cognitive function, as shown by Mini-Mental State examination (MMSE) (p < 0.0001) score and SPPB (p < 0.0001). Considering ΔCI as dependent variation, Δ8-isoprotane resulted the major predictor, justifying 13.3% of its variation. When ΔSPPB was considered as dependent variable, Δ8-Isoprostane was the main predictor of ΔSPPB, justifying 54.6% of its variation.

This study demonstrated that the addition of SGLT2i to therapy leads to improvements in echocardiographic and sarcopenia-related parameters and biomarkers of oxidative stress and platelet activation.

Loop diuretics alleviate symptoms in heart failure (HF), but despite recommendations for dynamic dosing, implementation in practice remains challenging. The EASY-STOP trial investigated whether ambulatory urinary sodium monitoring using a point-of-care sensor could guide diuretic down-titration.

This prospective, single-centre study enrolled 50 euvolaemic HF patients on stable guideline-directed medical therapy for ≥3 months and receiving maintenance loop diuretic (≥20 mg furosemide equivalent daily). After a 1-week baseline phase of daily self-measured first-void and post-diuretic urinary sodium assessment, loop diuretics were gradually reduced by 50% and discontinued when ≤20 mg furosemide equivalents. Urinary monitoring continued for another 3 weeks. Successful down-titration was defined as remaining congestion-free (no rise in New York Heart Association class ≥I, oedema, pleural effusion, ascites, rise in right ventricular systolic pressure ≥10 mmHg, or worsening diastolic dysfunction ≥1 grade). Investigators and patients were blinded for urinary sodium analysis during the study. Patients were 75 (68-79) years old, had left ventricular ejection fraction 46 (± 11)%, estimated glomerular filtration rate 47 (35-65) ml/min and N-terminal pro-B-type natriuretic peptide 899 (326-2558) ng/L. Among the 50 patients, 62 diuretic down-titrations were performed, of which 34 (55%) were successful. Baseline urinary sodium before loop diuretic down-titration was similar between groups. However, patients who successfully achieved down-titration exhibited a significant increase in first-void urinary sodium following down-titration (53-74 mmol/L, p < 0.001), whereas those requiring reinitiation showed no significant change (56-58 mmol/L, p = 0.331). A 10 mmol/L increase predicted successful down-titration with 79.4% sensitivity and 78.6% specificity (area under the curve = 0.851).

Point-of-care urinary sodium monitoring may represent a non-invasive and personalized approach to diuretic titration in HF management. Further trials are warranted to validate its clinical utility and long-term benefits.

The management of complex congenital heart disease has advanced over the years. While certain complex congenital heart diseases are not compatible with life, palliative surgeries have developed to allow these children to survive into adulthood. Consequently, there are more children surviving into adulthood who have previously undergone complex palliative surgeries and have complex anatomy and physiology. There is a high prevalence of heart failure in adults with complex congenital heart disease due to its progressive nature. Often, anatomical and physiological sequelae of the disease itself or its surgical palliation lead to heart failure signs and symptoms over time. The nature of heart failure in this population is different than that of normal adults, and so management strategies must be adjusted based on the unique anatomy and physiology of these patients. While there are guidelines for monitoring and managing adults with complex congenital heart disease, there are limited data for medical therapies that improve symptom burden and mortality. Once these patients have worsening or decompensated heart failure, they often must be considered for advanced therapies, mechanical circulatory support, and transplant. There is still a need for further research and highly powered trials to elucidate how to optimally treat heart failure in adults with complex congenital heart disease.

Heart failure (HF) is a life-threatening cardiovascular disease associated with high mortality, diminished quality of life, and a significant economic burden on both patients and society. The pathogenesis of HF is closely related to the endothelium, where endothelial ion channels play an important role in regulating intracellular Ca2+ signals. These ion channels are essential to maintain vascular function, including endothelium-dependent vascular tone, inflammation response, and oxidative stress. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promising cardiovascular benefits in HF patients, reducing mortality risk and hospitalization in several large clinical trials. Clinical and preclinical studies indicate that the cardioprotective effects of SGLT2i in HF are mediated by endothelial nitric oxide (NO) pathways, as well as by reducing inflammation and reactive oxygen species in cardiac endothelial cells. Additionally, SGLT2i may confer endothelial protection by lowering intracellular Ca2+ level through the inhibition of sodium-hydrogen exchanger 1 (NHE1) and sodium-calcium exchanger (NCX) in endothelial cells. In this review, we discuss present knowledge regarding the expression and role of Ca2+-related ion channels in endothelial cells in HF, focusing on the effects of SGLT2i on endothelial NHE1, NCX as well as on vascular tone.

Heart failure with reduced or preserved ejection fraction is associated with elevated left atrial pressure at rest due to fluid overload or during exercise, leading to pulmonary venous congestion. Even with available treatments, heart failure hospitalizations remain high, and improvements in quality-of-life scores and functional capacity are modest. Thus, there is growing interest in non-pharmacological methods to decompress the left atrium and improve heart failure symptoms and outcomes. Left-to-right shunts have emerged as a potential therapeutic option to reduce left atrial hypertension, improve quality of life, and impact long-term outcomes. This nascent field carries both potential therapeutic promise and many unanswered questions. Recent data have questioned whether the effects of this therapy vary based on the left ventricular ejection fraction, pulmonary vascular resistance, and/or right ventricular structure and function. This review discusses the basis for left-to-right shunt therapies, synthesizes past and ongoing clinical trials, and offers future directions.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors stimulate erythropoiesis, but the mechanisms and clinical relevance of the effect of SGLT2 inhibitors on systemic iron metabolism in patients with heart failure is not well understood.

The authors sought to characterize a comprehensive suite of iron metabolism biomarkers-particularly the erythroblast signaling molecule, erythroferrone-in patients with heart failure before and after short- and long-term treatment with empagliflozin in patients with heart failure and a reduced or preserved ejection fraction.

We measured serum iron metabolism biomarkers at baseline, 12 weeks, and 52 weeks in 1,139 patients who were treated with placebo or empagliflozin in the EMPEROR (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure) program, and we characterized the inter-relationships of these biomarkers with clinical status and with the effect of empagliflozin on erythropoiesis and heart failure outcomes.

Correlations among iron biomarkers indicated the presence of a functional erythropoietin-erythroferrone-transferrin-receptor-protein-1 (TfR1)-hepcidin axis. As heart failure advanced, patients showed higher levels of erythropoietin, erythroferrone, and TfR1 (P trend <0.01), and levels of these proteins predicted a heightened risk of cardiovascular death or heart failure hospitalization (all P < 0.01). Compared with placebo, at 12 weeks, empagliflozin increased hemoglobin by 0.6 to 0.9 g/dL (P < 0.001), an effect that was accompanied by further activation of the erythropoietin-erythroferrone-TfR1 axis and increased iron use. Empagliflozin increased serum levels of erythroferrone by >40% (along with increases in erythropoietin and TfR1), while simultaneously decreasing hepcidin levels and reducing serum iron concentrations and transferrin saturation (all P < 0.01). When treated with empagliflozin, patients with evidence of iron deficiency at baseline showed attenuation of the erythrocytic response (P trend = 0.04) but no diminution of the heart failure benefits.

The erythropoietin-erythroferrone-TfR1-hepcidin axis is activated in patients with heart failure as the disease advances and is further heightened by SGLT2 inhibitors, in parallel with their effect to enhance erythropoiesis and iron mobilization and use. These changes have important implications for understanding the mechanism of action of SGLT2 inhibitors and for monitoring the response to treatment.

Patients diagnosed with both aortic stenosis (AS) and diabetes mellitus (DM) encounter a distinctive set of challenges due to the interplay between these two conditions. This study aimed to investigate the effects of DM on the left ventricle in AS patients, specifically focusing on the inflammatory response, oxidative stress, and their implications for cardiomyocyte function, titin phosphorylation, and the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway.

Left ventricular myocardial biopsies (in total: n = 28) were obtained from patients with diabetic AS (n = 11) and compared with those from non-diabetic AS patients (n = 17). Enzyme-linked immunosorbent assay (ELISA) demonstrated significantly elevated levels of pro-inflammatory mediators, including high mobility group box protein 1 (HMGB1) and calprotectin, as well as receptors associated with the inflammatory response, such as Toll-like receptor 2 (TLR2), 4 (TLR4), and receptor for advanced glycation endproducts (RAGE). These were correlated with an enhanced NOD-like receptor protein 3 (NLRP3) inflammasome and the release of interleukins (IL) 1, 6, and 18 in diabetic AS patients compared to their non-diabetic counterparts. Additionally, in the diabetic AS cohort, there was an increase in oxidative stress markers (hydrogen peroxide (H2O2), 3-nitrotyrosine, lipid peroxidation (LPO), oxidative glutathione (GSSG)/reduced glutathione (GSH) ratio) within the myocardium and mitochondria, accompanied by impaired NO-sGC-cGMP-PKG signaling, decreased titin phosphorylation, and increased passive stiffness (Fpassive) of cardiomyocytes relative to non-diabetic AS patients. In vitro anti-inflammatory treatment with an IL-6 inhibitor and antioxidant treatment with GSH effectively normalized the elevated Fpassive observed in AS patients with DM to levels comparable to the non-diabetic group. Furthermore, treatment with PKG and the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin also resulted in a reduction of Fpassive in cardiomyocytes from diabetic AS patients, although not to the levels observed in non-diabetic AS patients.

DM exacerbates inflammation and oxidative stress in AS patients, leading to impaired NO-sGC-cGMP-PKG signaling and increased cardiomyocyte Fpassive. These conditions are reminiscent of the pathophysiology of heart failure with preserved ejection fraction (HFpEF). These alterations can be ameliorated through anti-inflammatory and antioxidant therapies, indicating potential therapeutic strategies for diabetic patients suffering from AS.