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.

To investigate the efficacy of SGLT2 inhibitors on multiple cardiorenal outcomes across different racial/ethnic groups and regions.

We searched PubMed, Cochrane Library, Web of Science, and Embase databases in April 2024 for a systematic review and meta-analysis. Owing to inconsistencies in the reporting of the racial/ethnic and regional demographics, participants were grouped into three racial groups (Asian, Black, and White) and four regional (Asia, Central/South America, Europe, North America) groups. We compared the efficacy of SGLT2 inhibitors among these racial/ethnic and regional groups by calculating the ratio of hazard ratios (RHR). We evaluated the composite of cardiovascular death or hospitalization for heart failure (HHF), cardiovascular death, HHF, all-cause death, major adverse cardiac events, and cardiorenal composite outcomes.

We included 14 randomized placebo-controlled trials with 94,445 participants. Across the three racial/ethnic groups, SGLT2 inhibitors showed comparable efficacy. Compared with White patients, the efficacy of SGLT2 inhibitors on HHF was more pronounced in Black patients (RHR, 0.64; 95 % confidence interval [CI], 0.44-0.94), and a numerically lower risk was associated with Asian patients (RHR, 0.62; 95 % CI, 0.38-1.01). A consistent reduction in cardiovascular events with SGLT2 inhibitors was observed across all regions, while the efficacy of SGLT2 inhibitors on HHF was more pronounced in Asia than in other regions (RHR, 0.52; 95 % CI, 0.33-0.81).

SGLT2 inhibitors showed generally consistent efficacy across various racial/ethnic and regional groups, with some differences noted in specific populations. Ensuring adequate representation of diverse populations in clinical trials would be key to addressing healthcare disparities.

Chronic kidney disease (CKD) affects 50% of patients with heart failure. The pathophysiology of CKD in heart failure is proposed to be driven by macrocirculatory hemodynamic changes, including reduced cardiac output and elevated central venous pressure. However, our understanding of renal microcirculation in heart failure and CKD remains limited. This is largely due to the lack of noninvasive techniques to assess renal microcirculation in patients. Moreover, there is a lack of clinically relevant animal models of heart failure and CKD to advance our understanding of the timing and magnitude of renal microcirculatory dysfunction. Patients with heart failure and CKD commonly require cardiac surgery with cardiopulmonary bypass (CPB) to improve their prognosis. However, acute kidney injury (AKI) is a frequent unresolved clinical complication in these patients. There is emerging evidence that renal microcirculatory dysfunction, characterized by renal medullary hypoperfusion and hypoxia, plays a critical role in the pathogenesis of cardiac surgery-associated AKI. In this review, we consolidate the preclinical and clinical evidence of renal macro- and microcirculatory perturbations in heart failure and cardiac surgery requiring CPB. We also examine emerging biomarkers and therapies that may improve health outcomes for this vulnerable patient population by targeting the renal microcirculation.

There are relevant sex-specific differences for coronary heart disease, heart failure, takotsubo syndrome and atrial fibrillation. The underrepresentation of women in clinical studies and the fact that sex-specific aspects and analyses are still insufficiently taken into consideration in preclinical and clinical research raises questions on the transferability of research results to women and strongly contrasts with the generally agreed requirements of evidence-based medicine. Sex-specific aspects are not always adequately addressed even in guidelines. Less than half of 24 ESC guidelines from 2018-2023 contain a corresponding section. In more recent recommendations, such as the guidelines on hypertension from 2024, sex-specific considerations are discussed, also with regards to the "gaps of evidence". In this context, in addition to the demands for more prospective sex-specific studies and data on epidemiology, risk factors, pathophysiology and outcomes, the importance of providing evidence with respect to sex-specific optimal dosages, effects and undesired side effects of drugs are also the subjects of discussion.

Sodium-glucose co-transporter inhibitors (SGLTis) have cardiovascular protective effects. We aimed to assess the effects of SGLTis on individual hard clinical endpoints and quality of life (QoL) in patients with cardiovascular risk factors.

Data was searched in PubMed, Embase, Cochrane Library and clinicaltrials.gov databases up to February 2024. Randomized controlled trials (RCTs) comparing SGLTis with placebo were included. The primary outcomes were individual hard clinical endpoints (Subset A) and QoL (Subset B). For Subset A, 13 RCTs including 90 413 patients were enrolled (age 66 ± 10.1 years, 35.7% female, follow-up 2.4 ± 0.3 years); as compared with placebo, SGLTis were associated with significantly lower risk of all-cause mortality [risk ratio (RR): 0.90, 95% confidence interval (CI): 0.86-0.94, P < 0.01], cardiovascular mortality (RR: 0.87, 95% CI: 0.82-0.92, P < 0.01), hospitalization for heart failure (HF) (RR: 0.72, 95% CI: 0.68-0.76, P < 0.01), HF events (RR: 0.72, 95% CI: 0.68-0.75, P < 0.01), hospitalization for any cause (RR: 0.91, 95% CI: 0.88-0.93, P < 0.01) and myocardial infarction (MI) (RR: 0.92, 95% CI: 0.85-0.99, P = 0.03). Notably, the favourable effect of SGLTis on all-cause mortality was more pronounced in younger (<65 years) patients (RR: 0.86, 95% CI: 0.81-0.92) and in studies with less female (RR: 0.84, 95% CI: 0.79-0.90). The favourable effect of SGLTis on MI was only observed in patients who received sotagliflozin (RR: 0.47, 95% CI: 0.31-0.73). For Subset B, nine RCTs including 2552 HF patients were enrolled (age 67.8 ± 12.4 years, 36.4% female, follow-up 3.4 ± 1.9 months); SGLTis were associated with significant improvement in QoL as compared with placebo.

In patients with a broad spectrum of cardiovascular risk factors, SGLTis substantially improve individual hard clinical outcomes and QoL.

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are a novel class of oral antidiabetic drugs (ADDs). Studies evaluating the appropriateness of SGLT2is prescribing, and the factors associated with their initiation in the Middle East region are lacking.

This study aimed to evaluate the appropriateness of prescribing SGLT2is based on indication, dosing, and contraindication and determine the factors associated with their initial prescribing.

In this cross-sectional study, a cohort of 650 patients newly prescribed SGLT2is (n = 400) and/or any other oral ADDs (n = 250) during 2020 were included. Data were extracted from an electronic medical record system. Multivariate logistic regression was conducted to investigate factors associated with prescribing SGLT2is.

SGLT2is were prescribed for appropriate indication in 400 patients (100%), while inappropriately prescribed in relation to contraindication and dosing in 14 patients (3.5%). Male patients were more likely to be prescribed SGLT2is (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.02-2.82). Patients with a baseline glycated hemoglobin (HbA1c) above 7% and atherosclerotic cardiovascular disease (ASCVD) were more likely to be prescribed SGLT2is (OR, 3.22; 95% CI, 1.84-5.64) and (OR, 2.18; 95% CI, 1.05-4.52), respectively. Patients receiving metformin (OR, 7.56; 95% CI, 4.46-12.80), sulfonylureas (OR, 2.30; 95% CI, 1.16-4.56), and dipeptidyl peptidase 4 inhibitors (OR, 3.43; 95% CI, 2.00-5.87) were more likely to be prescribed SGLT2is.

SGLT2is were found to be typically prescribed for the appropriate indication. Among the most important factors associated with prescribing SGLT2is are having uncontrolled HbA1c, history of ASCVD, and using other ADDs.

Heart failure with preserved ejection fraction (HFpEF) is characterized by a lack of a specific targeted treatment and a complex, partially unexplored pathophysiology. Common comorbidities associated with HFpEF are hypertension, atrial fibrillation, obesity and diabetes. These comorbidities, combined with advanced age, play a crucial role in the initiation and development of the disease through the promotion of systemic inflammation and consequent changes in cardiac phenotype. In this context, we suggest platelets as important players due to their emerging role in vascular inflammation. This review provides an overview of the role of platelets in HFpEF and its associated comorbidities, including hypertension, atrial fibrillation, obesity and diabetes mellitus, as well as the impact of age and sex on platelet function. These major HFpEF-associated comorbidities present alterations in platelet behaviour and in features linked to platelet size, content and reactivity. The resulting dysfunctional platelets can contribute to further increase inflammation, oxidative stress and endothelial dysfunction, suggesting an active role of these cells in the initiation and progression of HFpEF. Recent evidence shows that reduced platelet count and elevated mean platelet volume are associated with worsening heart failure in HFpEF patients. However, the specific mechanisms by which platelets contribute to HFpEF development and progression are still largely unexplored, with only a few studies investigating platelet function in HFpEF. We discuss the limited yet significant body of research investigating platelet function in HFpEF, emphasizing the need for more comprehensive studies. Additionally, we explore the potential mechanisms through which platelets may influence HFpEF, such as their interactions with the vascular endothelium and the secretion of bioactive molecules like cytokines, chemokines and RNA molecules. These interactions and secretions may play a role in modulating vascular inflammation and contributing to the pathophysiological landscape of HFpEF. The review underscores the necessity for future research to elucidate the precise contributions of platelets to HFpEF, aiming to potentially identify novel therapeutic targets and improve patient outcomes. The evidence presented herein supports the hypothesis that platelets are not merely passive bystanders but active participants in the pathophysiology of HFpEF and its comorbidities.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasinglyrecognized cause of heart failure with preserved ejection fraction (HFpEF), which may be diagnosed non-invasively using 99 mTc 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy-based diagnostic criteria. Our aim was to determine the prevalence of ATTR-CM in an undifferentiated HFpEF cohort with a DPD scintigraphy-based screening protocol.

Patients with HFpEF [ejection fraction (EF) ≥50%] aged ≥60 years and no prior evaluation for cardiac amyloidosis or known monoclonal gammopathy attending a regional cardiology network were screened with DPD scintigraphy. Patients with positive myocardial uptake (Perugini grade 2 or 3) were tested for a monoclonal protein and transthyretin gene variant.

Eighty-six subjects were prospectively enrolled: 56% female, mean age 77 ± 8 years, 63% New York Heart Association (NYHA) Class III and median N-terminal pro-brain natriuretic peptide (NT-proBNP) 1766 ng/L [inter-quartile range (IQR) 731-3703]. DPD scintigraphy was positive in seven patients (8%). Monoclonal gammopathy of undetermined significance was present in one out of seven patients, and no pathogenic TTR gene variant was identified. The prevalence of wild-type ATTR-CM was 8% of this cohort. Compared with the HFpEF DPD scintigraphy-negative cohort, DPD scintigraphy-positive patients were older (86 ± 3 vs. 76 ± 8 years), more frequently male (16% vs. 2%, P = 0.02), and had significantly greater left ventricular (LV) wall thickness (16 vs. 12 mm; P = 0.002) and higher high-sensitivity troponin levels at diagnosis [78 ng/L (IQR 21-116) vs. 11 ng/L (IQR 9-17); P < 0.001].

In an undifferentiated HFpEF cohort, 8% were found to have wild-type ATTR-CM using a DPD scintigraphy-based screening protocol. Screening undifferentiated HFpEF patients is associated with a significant diagnostic yield, which can be further increased by targeting older males with increased LV wall thickness and elevated high-sensitivity troponin levels.

The "2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes" incorporates new evidence since the "2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction" and the corresponding "2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes" and the "2015 ACC/AHA/SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction." The "2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes" and the "2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization" retire and replace, respectively, the "2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease."

A comprehensive literature search was conducted from July 2023 to April 2024. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline.

Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

SGLT2 inhibitors may be underused in older adults with type 2 diabetes due to concerns about safety and tolerability. This pooled analysis of the CANVAS Program and CREDENCE trial examined the efficacy and safety of canagliflozin according to age.

Pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401) were analysed by baseline age (<65 years, 65 to <75 years, and ≥75 years). A range of adjudicated clinical outcomes were assessed, including major adverse cardiovascular events and CKD progression, as well as safety outcomes. Cox proportional hazards models and Fine and Gray competing risk analysis were used.

Among the 14 543 participants, 7927 (54.5%) were <65 years, 5281 (36.3%) were 65 to <75 years and 1335 (9.2%) were ≥75 years. Older participants had higher rates of atherosclerotic cardiovascular disease and heart failure, longer diabetes duration and lower mean eGFR. Reductions in cardiovascular and kidney outcomes with canagliflozin were consistent across age categories (all p trend >0.10), although there was some evidence that effects on cardiovascular death and all-cause death were attenuated with older age (p trend = 0.02 and 0.03, respectively). Although the incidence of adverse events increased with age, effects of canagliflozin on safety outcomes including acute kidney injury, volume depletion, urinary tract infections and hypoglycaemia, were not modified by age (all p trend >0.10).

In patients with varying degrees of kidney function, canagliflozin reduced cardiovascular and kidney outcomes, regardless of age, with no additional safety concerns identified in older patients.

Coronary microvascular dysfunction (CMD) is a prevalent and often underdiagnosed condition with significant implications for adverse cardiovascular outcomes. The pathophysiology of CMD includes structural and functional abnormalities in the coronary microvasculature and epicardial atherosclerosis contributes to downstream reduction in myocardial perfusion and symptoms. Diagnosis relies on advanced invasive or noninvasive imaging techniques, such as PET and cardiac magnetic resonance, capable of quantifying myocardial perfusion and myocardial blood flow reserve. Effective management includes optimizing cardiovascular risk factors and symptom control. Novel therapeutic strategies recently approved for management of diabetes, obesity, and heart failure with preserved ejection fraction offer potentially powerful options for management of CMD.

Dapagliflozin (Dapa) is a novel hypoglycaemic agent with multiple cardiovascular protective effects, and it is widely used in treatment of heart failure patients, but whether it can improve obese phenotype of heart failure and its mechanism is still unclear. Ferroptosis is an iron dependent form of cell death and has been proved to be an important role in heart failure. The aim of this study is to determine whether Dapa improves obesity-related heart failure by regulating ferroptosis in high-fat diet rats.

Male SD rats were fed a high-fat diet for 12 weeks and confirmed of obese heart failure by metabolic parameters and cardiac ultrasound. Being overweight by 20% compared with the normal group, with elevated systolic blood pressure and abnormal levels of insulin and blood lipid (TG and LDL-c), is recognized as obesity. The obese rats with reduced EF, FS, and E/A shown on ultrasound are defined as the obese heart failure (OHF) group. Histological tests confirmed the more pronounced cardiac fibrosis, mitochondrial volume and collagen deposition in OHF group. Dapa treatment effectively reduced body weight, INS, ISI/IRI index, TG and HDL-C levels (P < 0.05). Also, Dapa administration can slightly decrease the SBP and DBP levels; however, there was no statistical difference among those four groups. Furthermore, Dapa treatment can significantly improve high-fat induced systolic and diastolic dysfunction via regulating cardiac histological abnormalities, including less obvious mitochondrial swelling, muscle fibre dissolution and collagen deposition. Additionally, genes from the OHF group were used by GO enrichment analysis, and it shows that ferroptosis metabolic pathway participated in the development of obese phenotype of heart failure. More importantly, Dapa significantly inhibited Fe2+ and MDA levels (P < 0.05), but augmented GSH content (P < 0.05). In addition, the mRNAs and protein expression of some important regulators of ferroptosis, like GPX4, SLC7A11, FTH1 and FPN1, were all decreased after Dapa intervention.

Dapa improved high-fat induced obese cardiac dysfunction via regulating ferroptosis pathway.

The circadian system influences the pathophysiology of many cardiovascular diseases; however, circadian variations in patients with heart failure with preserved ejection fraction (HFpEF) are unknown. Thus, this study aimed to compare the clinical characteristics and risk factors for in-hospital mortality between patients with daytime- versus nighttime-onset HFpEF.

This multicenter retrospective study included 3875 consecutive patients with acute HFpEF. Daytime and nighttime periods were defined as 6:00-17:59 and 18:00-5:59, respectively. Potential prognostic factors for in-hospital mortality were selected using univariable analyses. Those with P values of <0.10 were used in multivariable logistic regression analyses with forward selection (likelihood ratios) to identify significant prognostic factors.

The incidence of daytime-onset HFpEF was significantly lower but the in-hospital mortality was significantly higher than that of nighttime-onset HFpEF. Independent prognostic factors for in-hospital mortality in patients with daytime-onset HFpEF were age (odds ratio [OR], 1.057) and systolic blood pressure (OR: 0.979). In contrast, age (OR: 1.067), coexisting atrial fibrillation/flutter (OR: 2.023), systolic blood pressure (OR: 0.989), estimated glomerular filtration rate (OR: 0.971), treatment with diuretics (OR: 0.282), and treatment with beta-blockers (OR: 0.514) were independent prognostic factors in patients with nighttime-onset HFpEF.

The incidence of acute HFpEF exhibits circadian variations, and onset-related differences in clinical characteristics and prognostic factors for in-hospital mortality were identified. These findings may provide new insights for future research and guide individualized patient management strategies.

This review focuses on p21-activated kinase 1 (Pak1), a multifunctional, highly conserved enzyme that regulates multiple downstream effectors present in many tissues. Upstream signaling via Ras-related small G-proteins, Cdc42/Rac1 promotes the activity of Pak1. Our hypothesis is that this signaling cascade is an important element in communication among the myocardium, adipose tissue, and pancreatic β-cells. Evidence indicates that a shared property of these tissues is that structure/function stability requires homeostatic Pak1 activity. Increases or decreases in Pak1 activity may promote dysfunction or increase susceptibility to stressors. Evidence that increased levels of Pak1 activity may be protective provides support for efforts to develop therapeutic approaches activating Pak1 with potential use in prevalent disorders associated with obesity, diabetes, and myocardial dysfunction. On the other hand, since increased Pak1 activity is associated with cancer progression, there has been a significant effort to develop Pak1 inhibitors. These opposing therapeutic approaches highlight the need for a deep understanding of Pak1 signaling in relation to the development of effective and selective therapies with minimal or absent off-target effects.

Physicians' adherence to guideline-recommended heart failure (HF) treatment remains suboptimal, especially regarding the target doses. In particular, there is evidence that non-cardiologists are less compliant with HF guideline recommendations. This is likely to have a detrimental impact on patients' survival, readmissions and quality of life. Thus, the present document aims to address the reasons underlying low implementation and under-dosing of guideline-directed medical therapy in HF and to update a guidance for the initiation and rapid titration of HF drugs. In particular, aim of this document is to provide practical indications for drug implementation, to be applied not only by cardiologists but also by GPs and internal medicine doctors.

Sodium-glucose co-transporter (SGLT)-2 inhibitors have shown consistent benefit in improving heart failure-related outcomes but not ischaemic cardiovascular events such as myocardial infarction or stroke. We assessed if the dual SGLT1/2 inhibitor sotagliflozin improves ischaemic outcomes.

We did a prespecified secondary analysis of the SCORED trial, which was a double-blind, placebo-controlled, randomised clinical trial enrolling patients (aged ≥18 years) with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate [eGFR] 25-60 mL/min per 1·73 m2), and additional cardiovascular risk factors. Patients at 750 sites in 44 countries were randomly assigned (1:1) to oral sotagliflozin or placebo via an interactive response technology system (block size of four; stratified by heart failure-related criteria and geographical region), with participants, investigators, and study staff, including those who assessed outcomes, masked to group assignment. Sotagliflozin treatment was prescribed at 200 mg once a day, with the dose increased to 400 mg once a day within the first 6 months if tolerated. Matching placebo was prescribed at the same treatment frequency as the intervention regimen. A prespecified secondary outcome was total major adverse cardiovascular events (MACE), which was defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, assessed as first and subsequent events. Other outcomes included total myocardial infarction and total stroke (fatal and non-fatal events) as individual post-hoc endpoints. Outcomes were assessed by intention to treat with competing-risk proportional hazard models in the overall population, and, for total MACE, in prespecified subgroups stratified by baseline demographic and clinical features (sex, age, geographical region, heart failure-related criteria, eGFR, urine albumin-creatinine ratio, and cardiovascular disease history). The SCORED trial was registered at ClinicalTrials.gov, NCT03315143, and was ended early due to loss of funding.

10 584 patients were enrolled and randomly assigned to sotagliflozin (n=5292 [50·0%]) or placebo (n=5292 [50·0%]) between Dec 8, 2017 and Jan 20, 2020 (median age 69 years [IQR 63-74]; 4754 [44·9%] female patients and 5830 [55·1%] male patients). 5144 (48·6%) patients had a history of cardiovascular disease, of whom 2108 (19·9% of the total population) had a history of myocardial infarction, 946 (8·9%) had a history of stroke, and 2375 (22·4%) had a history of coronary revascularisation. Patients in the sotagliflozin group had a significantly lower rate of total MACE than those in the placebo group (4·8 events per 100 person-years vs 6·3 events per 100 person-years; hazard ratio [HR] 0·77 [95% CI 0·65-0·91]; p=0·0020). Interaction analyses suggested a consistent effect of sotagliflozin on total MACE among stratified subgroups without evidence of heterogeneity. Additionally, sotagliflozin significantly reduced the rate of myocardial infarction (1·8 events per 100 person-years vs 2·7 events per 100 person-years; HR 0·68 [0·52-0·89]; p=0·0041) and stroke (1·2 events per 100 person-years vs 1·8 events per 100 person-years; HR 0·66 [0·48-0·91]; p=0·012) compared with placebo.

Sotagliflozin reduced MACE, with independent reductions in myocardial infarction and stroke, among patients with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk. The ischaemic benefit on both myocardial infarction and stroke has not been previously observed with other SGLT inhibitors and warrants investigation of combined SGLT1 and SGLT2 inhibition as a possible underlying mechanism.

Lexicon Pharmaceuticals.

Novel antidiabetic drugs, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have significantly transformed the management landscape for type 2 diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, owing to their well-established cardiorenal protective effects. Given the shared risk factors and comorbidities, it is relevant to consider the potential risk of venous thromboembolism (VTE) in individuals prescribed these novel antidiabetic medications. This literature review aims to summarize currently available evidence on VTE risk associated with novel antidiabetic drugs, including GLP-1 receptor agonists, dipeptidyl-peptidase IV (DPP-4) inhibitors, and SGLT2 inhibitors. Following a comprehensive search on PubMed using relevant keywords and backward reference searching, we identified 25 publications that directly reported on associations between these medications and VTE risk. Findings from these studies, including seven meta-analyses, reveal inconsistent results: some studies suggest that GLP-1 receptor agonists or DPP-4 inhibitors may be associated with increased risk of VTE, whereas SGLT2 inhibitors do not appear to be associated with VTE and may even be a protective factor. A notable limitation of the existing studies is the significant challenge posed by confounding in observational studies, while the randomized controlled trials (RCTs) often concluded with a limited number of VTE events, if it was studied. Furthermore, all identified studies focused on the risk of primary VTE, leaving an important knowledge gap regarding whether these novel antidiabetic drugs may influence the efficacy or safety of anticoagulants used for preventing VTE recurrence. Addressing these gaps presents an important avenue for future research.

Heart failure (HF) is increasingly recognized as a heterogeneous cardiometabolic disorder, often in the context of overweight/obesity independently from diabetes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce HF hospitalizations and cardiovascular mortality across ejection fraction (EF) categories, yet their early hemodynamic effects in cardiometabolic HF, and with preserved ejection fraction (HFpEF) in particular, remain underexplored.

A prospective, single-center study included 20 consecutive HF patients receiving SGLT2i alongside optimized therapy. Transthoracic echocardiography and non-invasive bioimpedance assessments (NICaS system) were performed at baseline and after 4 weeks.

The median patient age was 75 years [58-84], with 14 patients (70%) being overweight/obese, and only 4 patients with diabetes. The majority (65%) had HF with preserved EF (HFpEF), 25% with mildly reduced EF (HFmrEF), and 10% with reduced EF (HFrEF). At a median follow-up of 33 days [30-68], significant reductions were observed in body weight (67.65 kg [46-99.20] to 65.50 kg [46.30-97], p = 0.027) and systolic blood pressure (130 mmHg [100-150] to 116.50 mmHg [100-141], p = 0.015). Hemodynamic assessments revealed a significant decrease in total peripheral resistance index (TPRi, 3616.50 dynes·sec·cm3 [1600-5024] to 3098.50 dynes·sec·cm3 [1608-4684], p = 0.002). The left atrial volume index decreased significantly (42.84 ml/m² [27-69.40] to 41.15 ml/m² [26-62.60], p < 0.001); a significant decrease in peak tricuspid regurgitation velocity [2.52 m/Sect. (1.30-3.20]), vs. 2.21 m/Sect. (1.44-2.92), p = 0.023] and in pulmonary artery systolic pressure (PASP) [31.0 mmHg (15.0-40.0) vs. 25.50 mmHg (15.0-38.0-), p = 0.010] was observed. Patients with HFrEF or HFmrEF showed significant reduction in total body water (66.33 [51.45-74.45] vs. 58.68 [55.13-66.50]), while HFpEF patients (overweight/obese, n = 11, 79%) had a significant reduction in TPRi (3681 dynes·sec·cm3 [1600-5024] vs. 3085 dynes·sec·cm3 [1608-4684] p = 0.005).

Early hemodynamic responses to SGLT2i may differ across HF subtypes. In overweight patients with cardiometabolic HFpEF, our preliminary findings suggest an association with reduced vascular resistance, while in HFrEF/HFmrEF, the primary benefit appears to be volume unloading. However, the vascular effects of SGLT2i remain uncertain, and given the small sample size, these results should be interpreted as hypothesis-generating. Our findings also highlight the potential role of non-invasive hemodynamic monitoring in guiding therapy in HF.

The global burden of HFpEF is high and, despite developments in available therapies, patient outcomes have not improved significantly. This study aimed to explore the optimal approaches to the diagnosis and treatment of patients with HFpEF and to develop recommendations on how guideline directed medical therapy can be introduced in a more equitable and universal manner.

Using a modified Delphi methodology led by an independent facilitator, a steering group of healthcare practitioners with experience of managing HFpEF identified 41 Likert scale statements across five main domains of focus. This generated an online survey distributed by a third-party provider using a convenience sampling approach to HCPs with experience managing patients with HFpEF.

A total of 213 responses were analyzed with 35/41 statements attaining very strong (≥90%) agreement, 4/41 strong (≥75%) agreement, and 2/41 failing to meet the threshold established for consensus (75%). From these results, a total of 8 recommendations to define the optimal approach to diagnosis and treatment of patients with HFpEF are proposed.

The burden of HFpEF is set to increase in the future. The high levels of consensus achieved in this study show that there is willingness to implement change and improve patient outcomes for those with this condition. A series of actionable recommendations have been developed based on the levels of agreement attained. It is hoped that the putting the current recommendations into practice will support international efforts to improve HFpEF care.

Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent worldwide due to aging and comorbidities. Epicardial adipose tissue (EAT), favored by diabetes and obesity, was shown to contribute to HFpEF pathophysiology and is an emerging therapeutic target. This study explored the relationship between ventricular EAT measured by cardiovascular magnetic resonance (CMR), metabolic factors, and imaging characteristics in controls, pre-HF patients, and HFpEF patients.

Patients from a Belgian cohort enrolled from December 2015 to June 2017 were categorized by HF stage: pre-HF (n = 16), HFpEF (n = 104) and compared to matched controls (n = 26) and to pre-HF (n = 191) from the Beta3-LVH cohort. Biventricular EAT volume was measured in end-diastolic short-axis cine stacks. In the Belgian cohort, associations between EAT, HF stage, and various biological and imaging markers were explored. The clinical endpoint was a composite of mortality or first HF hospitalization in the HFpEF group.

EAT significantly differed between groups, with higher values in HFpEF patients compared to pre-HF and controls (72.4 ± 20.8ml/m2vs. 55.0 ± 11.8ml/m2 and 48 ± 8.9ml/m2, p < 0.001) from the Belgian cohort and to pre-HF (52.0 ± 15.0 ml/m2, p < 0.001) from the Beta3-LVH cohort. Subsequent analyses focused on the Belgian cohort. In contrast to atrial fibrillation, diabetes prevalence and body mass index (BMI) did not differ between pre-HF and HFpEF patients. Multivariable logistic regression and random forest classification identified EAT, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and H2FPEF score as strong markers of HFpEF status. EAT was significantly correlated with H2FPEF score (r = 0.41, p = 0.003), BMI (r = 0.30, p < 0.001), high-sensitive troponin T (r = 0.41, p < 0.001), NT-proBNP (r = 0.37, p < 0.001), soluble suppression of tumorigenicity-2 (sST2) (r = 0.30, p < 0.001), E/e' ratio (r = 0.33, p < 0.001), and left ventricular global longitudinal strain (r = 0.35, p < 0.001). In HFpEF patients, diabetes, ischemic cardiomyopathy, and elevated sST2 were independently associated with elevated EAT. In contrast with diabetes and BMI, increased EAT was not associated with prognosis.

EAT assessed by CMR was significantly higher in HFpEF patients compared to controls and pre-HF patients, irrespective of diabetes and BMI. EAT was moderately associated with HFpEF status. HFpEF patients with elevated EAT exhibited a marked diabetic, ischemic, and inflammatory profile, highlighting the potential role of drugs targeting EAT.

Characterization of Heart Failure With Preserved Ejection Fraction; Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure (Beta3_LVH).

ClinicalTrials.gov. Identifier: NCT03197350; NCT02599480.

It is imperative to maintain the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2is) in patients with diabetes both after the index diagnosis of heart failure (HF) and even prior to the index diagnosis of HF. We aimed to investigate whether timing of SGLT-2 is before the index diagnosis of HF, and second, adherence to SGLT-2is in the form of the proportion of days covered metric matter in patients with HF and diabetes.

All-cause death up to 7 years were evaluated in HF with diabetes from the subgroup analysis of TRends-HF (TRends in Heart Failure in Türkiye). Patients with HF and diabetes, who were prescribed an SGLT-2i either before or after the index diagnosis of HF were identified, categorized according to duration of exposure before the index HF diagnosis and according to proportion of days covered after the index diagnosis of HF, and compared with nonusers. There were 1 229 833 patients with HF and diabetes in the cohort. A total of 247 987 were on an SGLT-2i and had available timing data, and 14.06% had SGLT-2i on board before the index HF diagnosis. Median duration of SGLT-2i exposure before the index HF diagnosis was 417 days. Prognosis was the best among patients with diabetes who were prescribed an SGLT-2i before the index diagnosis of HF with an exposure more than median duration. Of note, among patients who were prescribed an SGLT-2i after the index HF diagnosis; there was a numerically graded increase in all-cause mortality rate such that a >10% decrease in SGLT-2i proportion of days covered was associated with a 59% increase in all-cause death (hazard ratio, 1.21-2.09).

Regardless of time or adherence, SGLT-2is offer a remarkable all-cause death benefit to patients with HF and diabetes. SGLT-2is' all-cause death benefit for patients with HF and diabetes was greatest when it was prescribed before the HF index diagnosis. Poor adherence to SGLT-2is was associated with worsening survival in patients with HF and diabetes following the diagnosis of index HF.

Heart failure (HF) is a significant global health issue, categorized by left ventricular ejection fraction, being either reduced (HFrEF: <0.40) or preserved (HFpEF: >0.50), or in the middle of this range. While the overall incidence of HF remains stable, HFpEF cases are increasing, representing about 50% of all HF cases. Outcomes for HFpEF are similar to HFrEF, leading to substantial healthcare resource utilization. Despite extensive research over the past two decades, the prognosis and mortality rates for HFpEF remain high. A key feature of HFpEF is exercise intolerance, characterized by severe exertional dyspnea and fatigue, which significantly impacts quality of life. The underlying mechanisms of exercise intolerance are not fully understood due to the complex pathophysiology and multi-system involvement. Obesity is a common comorbidity in HFpEF, especially in North America, leading to worsening symptoms, hemodynamics, and mortality rates. Increased adiposity leads to inflammation, hypertension, dyslipidemia, and insulin resistance, and impairing cardiac, vascular, pulmonary, and skeletal muscle function. Therefore, managing obesity is crucial in treating HFpEF. This review explores the pathophysiologic mechanisms of HFpEF, emphasizing obesity's role, and discusses current management strategies while identifying areas needing further research.

Despite significant efforts to understand pathophysiological processes underlying cardiac diseases, the molecular causes for the most part remain unresolved. Rapid advancements in -omics technologies, and their application in cardiac research, offer new insight into cardiac remodeling in disease states. This review aims to provide an accessible overview of recent advances in omics approaches for studying cardiac remodeling, catering to readers without extensive prior expertise.

We provide a methodologically focused overview of current methods for performing transcriptomics and proteomics, including their extensions for single-cell and spatial measurements. We discuss approaches to integrate data across modalities, resolutions and time. Key recent applications within the cardiac field are highlighted. Each -omics modality can provide insight, yet each existing experimental method has technical or conceptual limitations. Integrating data across multiple modalities can leverage strengths and mitigate weaknesses, ultimately enhancing our understanding of cardiac pathophysiology.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with vast prevalence worldwide. Despite recent advances in understanding its pathophysiology, HFpEF remains under-diagnosed in clinical practice. Obesity-related HFpEF is a distinct and frequent phenotype with an additionally challenging diagnosis. We address the importance of overweight and obesity in HFpEF, focusing on the influence of adipose tissue in inflammation and neurohormonal activity. We also discuss atrial and ventricular remodelling in obesity-related HFpEF and potential clinical implications. Obesity is an independent risk factor for HFpEF. Adipose tissue synthesizes aldosterone, causing lower levels of natriuretic peptide. Adipocytes dysfunction promotes a pro-inflammatory state and leads to extracellular matrix remodelling and consequently stiffening of the heart and vessels. Thus, the quantity, distribution and quality of the excess fat influences cardiovascular risk. Visceral and epicardial adipose tissue are often associated with an increased likelihood of developing HFpEF. Obesity-related HFpEF presents higher risk of left ventricular concentric remodelling and inadequate accommodation of the expanded volume due to the obesity, resulting in higher left ventricular filling pressure. Nevertheless, microvascular endothelium inflammation modifies cardiomyocyte elasticity and increases collagen deposition, which enhances myocardial fibrosis and results in HFpEF. Furthermore, neurohormonal activation may also contribute to cardiac remodelling by inducing plasma volume expansion. In turn, leptin also stimulates aldosterone synthesis and enhances renin-angiotensin-aldosterone system. Obesity-related HFpEF presents worse overall prognosis, with increased risk of heart failure hospitalization and all-cause mortality. Intentional weight loss through caloric restriction, physical activity, pharmacological intervention and/or bariatric surgery are promising strategies.

To analyze in a contemporary registry of heart failure (HF) patients followed in specialized HF units in Spain, the differences in clinical features, treatment, and 1-year outcomes in HF with reduced, mildly reduced, and preserved left ventricular ejection fraction.

We analyzed data from the registry of the SEC-Excelente-IC quality accreditation program of the Spanish Society of Cardiology, with 1716 patients with HF included between 2019 and 2021 by 45 specialized HF units accredited by the SEC. Treatment and 1-year mortality, HF hospitalizations and decompensations of HF used were compared according to the type of HF. Of the 1,716 patients, 55.5% had HFrEF, 11.9% had HFmrEF, and 32.6% had HFpEF. HFpEF patients were older and had a higher proportion of women, atrial fibrillation, and hypertension. Sacubitril-valsartan and mineral receptor antagonists were used in greater proportion in HFrEF (56.5% and 73%, respectively, p < 0.001), but also in 10.3 and 33% in HFpEF. One-year mortality (17.3 vs 20.9 vs 15.6/100 persons-year; p = 0.321), 1-year HF hospitalizations (34.4 vs 29.5 vs 26.7/100 persons-year; p = 0.330), and 1-year decompensations of HF without hospitalization (13.1 vs 10.4 vs 11.1; p = 0.393) were similar for the 3 types of HF.

In our contemporary cohort of real-life HF patients, slight differences were observed in clinical features and treatment between the 3 types of HF, but the prevalence of most of the major comorbidities and 1-year outcomes (mortality, hospitalizations and decompensations of HF) were similar in the 3 groups.

Heart failure with preserved ejection fraction (HFpEF) is an ongoing challenge for healthcare systems. Major limitations that hinder adequate control of the disease, including an incomplete understanding of its pathophysiology, limited therapy options, and the absence of sufficient information on the management of comorbidities. Diagnosis and management of HFpEF in Egypt lack standardization as they are complicated with multiple comorbidities and limited by the lack of resources and data on epidemiology and patient characteristics. Diagnostic procedures for HFpEF should be implemented through guideline-specified scoring systems, due to the heterogeneity of clinical presentations and the absence of a golden standard for confirming HFpEF. In Egypt, the H2FPEF scoring system is more commonly used for establishing HFpEF diagnosis. All HFpEF patients should be treated through multidrug regimens tailored for their state, symptoms, and comorbidities, with sodium-glucose cotransporter-2 (SGLT2) inhibitors as the mainstay of treatment together with either one or a combination of loop diuretic and aldosterone antagonists. This paper provides an integrated review of epidemiology, means of diagnosis, current and novel pharmacological therapy options for HFpEF patients in the light of the recent advances in treatment of HFpEF, discussing means of healthcare delivery and unmet needs, and proposing recommendations for clinical practice and pathways for future research.

Current ESC guidelines introduced a four-pillar approach for the treatment of HFrEF, and a Class IA recommendation for Empagliflozin and Dapagliflozin in HFmrEF and HFpEF.

BRING-UP-3 Heart Failure (HF) study was designed to guide the Guideline implementation recommendations in HF patients enrolled by a large sample of Italian cardiology sites.

BRING-UP-3 HF study is an observational, prospective, nationwide investigation encompassing 179 sites enrolling ambulatory and hospitalized HF patients. The study includes an educational intervention followed by two three-month enrolment periods and by a 6-month follow-up period with end-point evaluation. For HFrEF patients, the objective is to describe the proportion of patients who receive the four pillars. Here we present the baseline data of the ambulatory cohort.

A total of 3,830 ambulatory patients were included in the study. The mean age was 70±12 years (34.5% over 75 years), females were 21.9%. The most prevalent group was HFrEF (58.4%), followed by HFimpEF (17.4%), HFmrEF (14.4%), and HFpEF (9.8%). Hypertension, atrial fibrillation, diabetes mellitus, and chronic kidney disease were reported in 68.2%, 40.4%, 31.0%, and 33.1%, respectively. In HFrEF patients, a high prescription rate (65%) for the four therapeutic pillars was observed; beta-blockers and RASi (mostly ARNIs) were prescribed in over 90% while SGLT2i and MRAs were prescribed in over 80% of cases. In HFmrEF and HFpEF, SGLT2i prescription rates reached 72.1% and 50.1%, respectively.

A comprehensive analysis of a large sample of Italian cardiology sites revealed a high prevalence of prescription of guideline-recommended treatments.

GOV: NCT06279988.

Heart failure with preserved ejection fraction (HFpEF) remains a significant challenge in modern healthcare. It accounts for the majority of heart failure cases and their number worldwide is steadily increasing. With its high prevalence and substantial clinical impact, therapeutic strategies for HFpEF are still inadequate. This review focuses on the cardiometabolic phenotype of HFpEF which is characterised by such conditions as obesity, type 2 diabetes mellitus, and hypertension. Various murine models that mimic this phenotype are discussed. Each model's pathophysiological aspects, namely inflammation, oxidative stress, endothelial dysfunction, changes in cardiomyocyte protein function, and myocardial metabolism alterations are examined in detail. Understanding these models can provide insight into the mechanisms underlying HFpEF and aid in the development of effective therapeutic interventions.

Due to insufficient evidence and a lack of cohesive guidelines, the management and use of fluid restriction in patients with heart failure (HF) may vary among healthcare professionals. However, the extent of this variation is unknown. The aim of this study was to describe physicians' and registered nurses' (RN) clinical practice regarding fluid intake and fluid restriction in adult patients with HF.

Physicians and RNs treating patients with HF at 75 hospitals across all healthcare regions in Sweden were invited to answer a web-based survey regarding management on fluid intake and fluid restriction. Data were analysed with descriptive statistics and chi-square test. A total of 646 physicians and RNs across 45 hospitals in Sweden completed the survey. Significant differences in recommendations and management were found in relation to professional role, care setting and work experience. Overall, 93.8% recommend fluid restriction for all or some patients with HF. RNs recommend fluid restriction for all patients with HF to a significantly higher extent compared with physicians (34.5% vs. 14.9%; P < 0.001). Additionally, 49.2% believe that fluid restriction is an effective treatment strategy to prevent congestion, and 29.3% recommend fluid restriction routinely. One-third lacked knowledge of existing local guidelines regarding fluid restriction.

This study shows that there are differences in clinical practice regarding healthcare professionals' recommendations on fluid intake and fluid restriction. These differences may result in patients with HF receiving varied and inconsistent care. Recommendations were primarily based on each healthcare professional's individual opinion rather than on evidence and guidelines.

Heart failure (HF) is a complex, heterogeneous syndrome with rising prevalence and high morbidity and mortality. The pathophysiology and diverse etiologies of HF present significant challenges for developing effective therapies. Omics technologies-including genomics, proteomics, transcriptomics, metabolomics, and epigenomics-have reshaped our understanding of HF at the molecular level, uncovering new biomarkers and potential therapeutic targets. Omics also enable insights into individualized treatment responses, the risks of adverse drug effects, and patient stratification for clinical trials. This review explores how multi-omics can enhance heart failure drug discovery and development across all stages of the therapeutic pipeline: (1) target selection and lead identification, (2) preclinical studies, and (3) clinical trials. By integrating omics approaches throughout the drug development process, we can accelerate the discovery of more effective and personalized therapies for heart failure.

Advanced heart failure (AHF) represents the terminal stage of heart failure (HF), characterized by persistent symptoms and functional limitations despite optimal guideline-directed medical therapy (GDMT). This review explores the clinical definition, pathophysiology, and therapeutic approaches for AHF. Characterized by severe symptoms, New York Heart Association (NYHA) class III-IV, significant cardiac dysfunction, and frequent hospitalizations, AHF presents substantial challenges in prognosis and management. Pathophysiological mechanisms include neurohormonal activation, ventricular remodeling, and systemic inflammation, leading to reduced cardiac output and organ dysfunction. Therapeutic strategies for AHF involve a multidisciplinary approach, including pharmacological treatments, device-based interventions like ventricular assisted devices, and advanced options such as heart transplantation. Despite progress, AHF management faces limitations, including disparities in access to care and the need for personalized approaches. Novel therapies, artificial intelligence, and remote monitoring technologies offer future opportunities to improve outcomes. Palliative care, which focuses on symptom relief and quality of life, remains crucial for patients ineligible for invasive interventions. Early identification and timely intervention are pivotal for enhancing survival and functional outcomes in this vulnerable population. This review underscores the necessity of integrating innovative technologies, personalized medicine, and robust palliative strategies into AHF management to address its high morbidity and mortality.