Type 2 diabetes mellitus (T2DM) is a multifactorial disease associated with complications that significantly affect both survival and quality of life, including cardiovascular, renal, cognitive, sexual, and reproductive dysfunctions. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) have emerged as a transformative class of drugs, demonstrating benefits that extend beyond glycemic control. Large clinical trials have shown that SGLT2is reduce hospitalization for heart failure by 25-35% and slow progression of chronic kidney disease by 30-45%, with variation based on the specific agent, dose, and patient population. This narrative review examines not only these well-established benefits but also emerging evidence regarding their effects in less-explored domains. SGLT2is have been associated with improved cognitive performance, potentially through reductions in neuroinflammation and oxidative stress. In the sexual and reproductive domains, studies in men with diabetes mellitus suggest potential benefits of SGLT2is in improving erectile function, sperm motility, and testosterone levels, likely mediated by antioxidant and anti-inflammatory mechanisms. By integrating current evidence across multiple systems, this review emphasizes the role of SGLT2is in a holistic, multidisciplinary approach to the management of patients with T2DM.

The Cardiovascular-Kidney-Metabolic (CKM) syndrome is a systemic disorder involving obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease, characterized by complex pathophysiological mechanisms that interact and lead to increased morbidity and mortality. In recent years, sodium-glucose transport protein 2 inhibitors (SGLT2i), as a new class of antidiabetic medications, have shown remarkable efficacy in the management of diabetes, renal and cardiovascular diseases. Research has confirmed their ability to reduce cardiovascular events and all-cause mortality. These inhibitors lower blood glucose levels by decreasing renal reabsorption of glucose and sodium, and offer multiple benefits, including lowering blood pressure, reducing body weight, exerting antioxidant, anti-inflammatory, and anti-fibrotic effects, as well as reducing proteinuria and improving glomerular filtration rate. These effects collectively contribute to the improvement of cardiovascular and renal health. Furthermore, SGLT2i have shown potential therapeutic roles at various stages of CKM syndrome, including improving cardiac function, slowing CKD progression, promoting weight loss, and improving lipid profiles. However, the precise mechanisms of action and off-target effects of SGLT2i still require further investigation to evaluate their efficacy and safety under different clinical conditions. Future research directions should include strategies for multiple disease management, combination therapy effects, interdisciplinary collaboration, and long-term follow-up studies to fully understand and optimize the application of SGLT2i in the treatment of CKM syndrome.

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.

This study aims to evaluate the effect of dapagliflozin (DAPA) on malignant ventricular arrhythmias (MVA) after acute myocardial infarction (AMI).

A single-center, prospective and observational cohort study was conducted. We enrolled AMI patients from the ChangZhou Acute Myocardial Infarction Registry between January 2018 and November 2023. They were divided into two groups according to the use of dapagliflozin. The median follow-up time was 211 days. The primary endpoint of the study was the incidence of MVA during hospitalization, and the secondary endpoint was all-cause mortality rate during the follow-up period. Kaplan-Meier survival analysis and multifactorial logistic regression analysis were performed to assess the association between DAPA and the risk of MVA. Enrolled patients were matched on a 1:1 propensity score.

Of the 2607 AMI patients enrolled, MVA were reported postoperatively in 123 (4.7%)patients. Cardiovascular death occurred in 93 (3.6%) patients. The average age of the enrolled patients was 65.03 ± 0.27 years. Of participants assigned to dapagliflozin, 8 out of 363 patients (2.2%) experienced MVA compared with 115 out of 2244 patients (5.1%) in the control group (odds ratio, OR = 0.392; 95% confidence interval, 95% CI: 0.171-0.900; P = 0.027). After 1:1 propensity score matching, DAPA remained able to reduce the risk of MVA in patients with AMI. (OR = 0.340; 95% CI: 0.121-0.960; P = 0.042). At a median follow-up of 211 days, all-cause mortality remained lower in the DAPA group than in the control group after matching (P = 0.033).

Dapagliflozin may attenuate the risk of MVA and all-cause mortality in elderly AMI patients, highlighting its potential as a therapeutic adjunct. However, these findings require validation in large-scale randomized trials.

This review examines the evolving role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in acute cardiac care. Originally developed as antidiabetic agents, SGLT2i have demonstrated significant and early benefits in chronic heart failure by reducing hospitalizations and cardiovascular mortality across all the ejection fraction spectrum. Recent evidence now suggests that these agents may also offer advantages in acute settings, including acute decompensated heart failure (ADHF) and post - acute myocardial infarction (AMI). Several clinical trials have explored early SGLT2i initiation during hospitalization, reporting improvements in diuretic efficiency, cardiac biomarkers, and favorable remodeling, without notable safety concerns. The present review discusses the multifaceted mechanisms underlying these benefits, which include osmotic diuresis, modulation of neurohormonal activation, anti-inflammatory effects, and direct myocardial protection. Together, these actions not only facilitate decongestion and renal preservation but also enhance cardiac energetics. Current data are promising and support a pivotal role of a SGLT2i as a therapeutic strategy in the whole acute cardiac care setting for their short and long-term benefit. Future research is essential to validate these findings and refine the best patients to be treated with early SGLT2i implementation in the acute cardiac care spectrum.

Sodium-glucose-transporter-2-inhibitors (SGLT2i) reduce ventricular-tachycardia (VT) and cardiac deaths in diabetic patients with internal-cardioverter-defibrillators (ICD) and/or cardiac-resynchronization-therapy (CRT). SGLT2i might improve cardiac electrophysiological-properties, reducing inflammation and sympathetic tone. We evaluated SGLT2i effects on lead-parameters, arrhythmias, ICDs' interventions, and heart failure (HF) hospitalizations and cardiac deaths in diabetics at 1 year of follow-up. At 1 year of follow-up, 334 SGLT2i-users vs. 794 non-users patients had lower heart rate, best clinical status, lowest B-type-natriuretic-peptide (BNP) and N-terminal pro-BNP, and inflammatory markers and catecholamines (p < 0.05). SGLT2i-users vs. non-users showed cardiac remodeling and increased cardiac pump (p < 0.05), significant reduction of right-ventricle (RV) and left-ventricle (LV) pacing, increase of RV/LV impedance and sensing at follow-up end (p < 0.05). C-reactive-protein (CRP) inversely linked to RV sensing and linearly to RV pacing. CRP and tumor-necrosis-alpha (TNFa) inversely linked to RV and shock impedance (p < 0.05). At follow-up end, SGLT2i-users vs. non-users showed lower rate of VT (36 (10.8 %) vs. 138 (17.4 %)), inappropriate-shocks (32 (9.6 %) vs. 118 (14.9 %)), HF hospitalizations (50 (15.0 %) vs. 216 (27.2 %)), and cardiac deaths (10 (3.0 %) vs. 53 (6.7 %)), (p < 0.05). BNP (HR 1.101, CI 95 % 1.000-1.305), CRP (HR 1.034, CI 95 % 1.007-1.061), and SGLT2i (HR 0.592, CI 95 % 0.410-0.854) predicted VT; SGLT2i (HR 0.611, CI 95 % 0.413-0.903) predicted inappropriate-shocks; BNP (HR 1.012, CI 95 % 1.001-1.040) predicted appropriate-shocks. CRP (HR 1.102, 1.077-1.127), ischemic cardiomyopathy (HR 1.284, CI 95 % 1.14-1.870), and SGLT2i (HR 0.497, CI 95 % 0.365-0.677) predicted HF-hospitalizations. SGLT2i (HR 0.677, CI 95 % 0.222-0.860) predicted cardiac deaths. SGLT2i improve electrophysiological-properties and reduce arrhythmias in diabetics with ICD/CRT.

Background and Objective: Implantable Cardioverter Defibrillators (ICDs) are crucial in treating ventricular tachyarrhythmias (VTs) and preventing sudden cardiac death. However, ICD shocks are linked to higher mortality and a lower quality of life. Many patients suffer from recurrent VTs despite concomitant antiarrhythmic drug (AAD) therapy with amiodarone, and it is unclear if changing the AAD while on chronic amiodarone therapy is beneficial. Hence, we investigated the impact of changing the AAD on the incidence of appropriate ICD shocks in patients on chronic amiodarone, impaired LV function, and at least one previous VT ablation. Methods and Results: We retrospectively analyzed 131 ICD patients (LVEF < 40%) from a single-center registry. All were on chronic amiodarone and had undergone VT ablation. The mean age was 66.0 ± 12.8 years; 82.4% were male; and the follow-up period averaged 5.8 ± 0.6 years. Ischemic cardiomyopathy was present in 52.7% of patients. AAD therapy was changed in 49 patients (37.4%), primarily due to inefficacy (40.8%), intolerance (16.3%), or other reasons (42.9%). Of those, 8 received flecainide (≥200 mg) and 41 sotalol (≥240 mg); 82 (62.6%) continued amiodarone. VT re-ablation was performed in 23.7%. During follow-up, 11 patients (8.4%) died and 18 (13.7%) received appropriate ICD shocks-17 with changed AAD vs. 1 with continued amiodarone (p ≤ 0.01). A multivariate regression showed that switching from amiodarone to flecainide or sotalol was significantly associated with increased ICD shock risk (OR 34.9; 95% CI 4.3-283.8; p < 0.01). Conclusions: In patients on chronic amiodarone with severely impaired LV function and at least one previous VT ablation, changing AAD therapy to flecainide or sotalol is associated with an increased incidence of appropriate ICD shocks.

Guidelines for management of heart failure with reduced ejection fraction (HFrEF) emphasize personalized care, patient engagement, and shared decision-making. Medications and cardiac rhythm management (CRM) devices are recommended with a high level of evidence. However, there are significant disparities: patients who could benefit from devices are frequently referred too late or not at all. Misconceptions about device therapy and the notion that the needs of patients (especially the prevention of sudden cardiac death) can now be met by expanding drug therapies may play a role in these disparities. This state-of-the-art review is produced by members of the DIRECT HF initiative, a patient-centred, expert-led educational programme that aims to advance guideline-directed use of CRM devices in patients with HFrEF. This review discusses the latest evidence on the role of CRM devices in reducing HFrEF mortality and morbidity, and provides practical guidance on patient referral, device selection, implant timing and patient-centred follow-up.

Cardiac arrhythmias pose a major public health problem, and pharmacologic intervention remains key to their therapy. The 1970 landmark Vaughan Williams (VW) classification utilizing known actions of then available antiarrhythmic drugs (AADs) became and remains central to management, but it requires revision in response to extensive subsequent advances. Our modernized AAD classification reflected and sought to facilitate such fundamental physiological and clinical development. Here we respond to requests for an adaptation of our scheme specifically focused on clinical practice. (1) This adaptation improves the accessibility of our original scheme to clinical practice, focusing on key AADs in clinical use rather than investigational new drugs (INDs) while conserving and encompassing the classic VW scheme. (2) We preserve a rational conceptual framework based on current understanding of the relevant electrophysiological events, their underlying cellular or molecular cardiomyocyte targets, and the functional mechanisms they mediate. (3) The adopted subclasses within each AAD class parallel clinical practice by including only subclasses containing established AADs, or approved potential off-label drugs, as opposed to those only including INDs. (4) The simplified scheme remains flexible, permitting drugs to be placed in multiple classes where required, and the addition of classes and subclasses in light of future investigations and clinical approvals. Thus, we derive from our comprehensive modernized AAD classification a more focused and simpler scheme for clinical use. This both modernizes yet preserves the classic VW classification and remains flexible, thus accommodating future developments.

The aim of our study was to evaluate the effects of dapagliflozin on the ventricular arrhythmia burden (VAb) in patients with heart failure with reduced ejection fraction (HFrEF) and an implantable cardioverter defibrillator (ICD), correlating the possible reduction in arrhythmic events and ICD therapies with the basal functional capacity, as well as the remodeling parameters induced by treatment.

A total of 117 outpatient ICD patients with a known diagnosis of HFrEF who underwent treatment with dapagliflozin were evaluated according to a prospective observational protocol. VAb (including sustained ventricular tachycardia, non-sustained ventricular tachycardia, ventricular fibrillation, and total ventricular events) and specific ICD therapies (anti-tachycardia pacing (ATP) and ICD shocks) were extrapolated from the devices' memory (events per patient per month) by comparing events in the observation period before and after the introduction of dapagliflozin.

The VAb was significantly reduced after dapagliflozin introduction (2.9 ± 1.8 vs. 4.5 ± 2.0, P = 0.01). The burden of appropriate ATPs was significantly reduced (0.57 ± 0.80 vs. 0.65 ± 0.91, P = 0.03), but not for ICD shocks. In patients with a more advanced functional class, a greater reduction in VAb was observed than in patients with a better initial functional capacity (2.2 ± 0.8 vs. 5.5 ± 1.8, P = 0.001 in the New York Heart Association (NYHA) III/IV group; 3.5 ± 2.1 vs. 4.5 ± 2.2, P = 0.02 in the NYHA I/II group). Considering two independent groups according to reverse remodeling (Δleft ventricular ejection fraction (LVEF) > 15%), a significant reduction in VAb was observed only in those patients who presented significant reverse remodeling (2.5 ± 1.1 vs. 5.1 ± 1.6, P = 0.01). A statistically significant interaction between the variation of total ventricular arrhythmias (VTA) and the basal NYHA class (F(1,115) = 142.25, P < 0.0001, partial η2 = 0.553), as well as between the variation of VTA and the ΔLVEF (F(1,115) = 107.678, P < 0.0001, partial η2 = 0.484) has been demonstrated using a two-way analysis of variance (ANOVA) test.

In ICD outpatients with HFrEF, dapagliflozin treatment produces a reduction in arrhythmic ventricular events. This improvement is more evident in patients who have a worse functional class and thus a more precarious hemodynamic state, and in patients who present with significant ventricular reverse remodeling. Therefore, we can hypothesize that the hemodynamic and structural improvements induced by treatment represent, at least in the short-medium term, some of the principal elements justifying the significant reduction in VAb.

The main function of the implantable cardioverter-defibrillator (ICD) is to protect against sudden cardiac death (SCD) due to ventricular tachyarrhythmia (VTA). Current guidelines provide a recommendation to implant a prophylactic ICD for the primary prevention of SCD in individuals having heart failure with reduced ejection fraction (HFrEF) who never experienced a previous sustained VTA. However, these recommendations are based on clinical trials conducted more than 20 years ago and may not be applicable to contemporary patients with HFrEF who have a lower arrhythmic risk as a result of advances in heart failure medical therapies. Thus, there is an unmet need for more appropriate selection of contemporary patients with HFrEF for a primary prevention ICD. In this article, we review data underlying the current clinical equipoise on the need for routine implantation of a primary prevention ICD in patients with HFrEF and the rationale for conducting clinical trials that aim to reassess the role of the ICD in this population.

SGLT-2 inhibitors, initially developed for type 2 diabetes, demonstrate profound cardiorenal and metabolic benefits. This review synthesizes evidence from clinical trials and mechanistic studies to elucidate their roles in cardiovascular diseases, chronic kidney disease, and non-alcoholic fatty liver disease. Key findings include a notable reduction in cardiovascular death/heart failure hospitalization, a marked decrease in heart failure hospitalization risk, and significant improvements in renal and hepatic outcomes. Emerging mechanisms, such as autophagy induction, ketone utilization, and anti-inflammatory effects, underpin these benefits. Ongoing trials explore their potential in non-diabetic populations, positioning SGLT-2 inhibitors as transformative agents in multisystem disease management.

With the increasing incidence of cancer among the adult population, radiotherapy (RT) is frequently used as a critical component in the treatment of various cancer types. Due to the nature of ionizing radiation, damage usually occurs within the tissues in anatomical neighborhood with the primary tumor localization. Dapagliflozin (DAPA), originally developed as an oral anti-diabetic medication, has been shown to have potent cardioprotective effects in the DAPA-HF trial. The cardioprotective effects of DAPA against RT induced cardiac cellular damage were investigated in this study.

A total of 40 male Wistar albino rats were obtained and were subjected to a 10-day pretreatment period to accommodate laboratory settings. Afterwards, the rats were divided into 4 groups consisting of 10 each (control = 10, DAPA = 10, RT = 10, RT + DAPA = 10). Meanwhile, the RT and RT + DAPA groups received a single dose of 20 Gray (Gy) x-ray to 4 × 4 cm area at 0.60 Gy/min, and DAPA and RT + DAPA groups were gavaged daily with 10 mg/kg DAPA. In the second week of the study, rats were examined by echocardiography and electrocardiogram. Furthermore, histopathological method was used to evaluate the level of cardiotoxicity.

The ejection fraction value decreased by 17.3% lower in the DAPA + RT group compared with the RT group (P < .001). In addition, corrected QT interval prolongation and QRS widening were 11.5% and 17.4% higher in the RT group compared with the DAPA + RT group, respectively (P < .001 for both values). While sarcomyolysis, inflammatory cell infiltration, and necrotic changes were found to be severe in the RT group, the DAPA + RT group had 68% less sarcomyolysis, 64% less inflammatory cell infiltration, and 55% less necrosis (P < .001 for all values).

The protective effects of DAPA against left ventricular remodeling and dysfunction in RT-induced cardiomyopathy model were observed in this study.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized the therapeutic scenario of heart failure, demonstrating favorable effects on mortality and quality of life. Previous studies have yielded conflicting data regarding the effects on ventricular arrhythmias.

A prospective observational study was conducted to investigate the anti-arrhythmic properties of SGLT2 inhibitors evaluating the intra-patient difference in major adverse arrhythmic cardiac events (MAACE) over a six-month period in patients with chronic heart failure who were undergoing continuous monitoring using a cardiac implantable electronic device.

From January 2022 to January 2023, 82 patients [median age 63 years (IQR 15), male 87 %] were enrolled in the study, with a median follow-up of 28 weeks (IQR 5). The rate of MAACE at baseline was 11 %, without relevant differences in the follow up in terms of major and minor arrhythmic events. In patients with an arrhythmic phenotype at baseline, a mild but non statistically significant reduction of MAACE (from 36 % to 28 %, p = 0.727) was observed and a significant decrease of non-sustained ventricular tachycardia (from 68 % to 32 %, p = 0.022).

Our findings suggest potential anti-arrhythmic properties of SGLT2 inhibitors, evident in patients with arrhythmic events before the initiation of the drug.

Patient characteristics, technology and clinical practice surrounding primary prevention implantable cardioverter defibrillators have evolved continuously over time.

To explore the temporal changes in patient characteristics, pharmacological therapy and device types among implantable cardioverter defibrillator recipients implanted for the primary prevention of sudden cardiac death over the last two decades in France.

Characteristics of participants and type of device from the retrospective DAI-PP Pilot Study (2002-2012) were compared with those from the ongoing prospective DAI-PP Consortium (2018 onwards).

This study included 9588 participants overall (DAI-PP Pilot Study, n=5539; DAI-PP Consortium, n=4049). Compared with the DAI-PP Pilot Study, the DAI-PP Consortium subjects were older at implantation (62.5 vs 65.2 years; P=0.001) and had a higher proportion of women (15.1% vs 20.6%; P<0.001), a similar proportion of ischaemic heart disease (60.2% vs 60.2%; P=0.98), a higher left ventricular ejection fraction (27±7% vs 30±8%; P<0.001) and more patients with narrow QRS complexes (30.5% vs 46.0%; P<0.001). The proportion of patients treated with heart failure drugs increased significantly (70.1% vs 83.1%; P<0.001), whereas the use of amiodarone became much less frequent (22.7% vs 14.7%; P<0.001). Finally, the proportions of cardiac resynchronization therapy defibrillators (53.8% vs 46.4%; P<0.001) and dual-chamber defibrillators (23.3% vs 17.3%; P<0.001) decreased, whereas subcutaneous implantable cardioverter defibrillators now account for a sizeable proportion of implants (14.6%).

Over a 20-year period, the primary prevention implantable cardioverter defibrillator population has evolved significantly, with an older age and a higher proportion of women. The type of device has changed, with fewer cardiac resynchronization therapy defibrillators and more subcutaneous implantable cardioverter defibrillators.

Sudden cardiac death (SCD) remains a pressing health issue, affecting hundreds of thousands each year globally. The heterogeneity among people who suffer a SCD, ranging from individuals with severe heart failure to seemingly healthy individuals, poses a significant challenge for effective risk assessment. Conventional risk stratification, which primarily relies on left ventricular ejection fraction, has resulted in only modest efficacy of implantable cardioverter-defibrillators for SCD prevention. In response, artificial intelligence (AI) holds promise for personalized SCD risk prediction and tailoring preventive strategies to the unique profiles of individual patients. Machine and deep learning algorithms have the capability to learn intricate nonlinear patterns between complex data and defined end points, and leverage these to identify subtle indicators and predictors of SCD that may not be apparent through traditional statistical analysis. However, despite the potential of AI to improve SCD risk stratification, there are important limitations that need to be addressed. We aim to provide an overview of the current state-of-the-art of AI prediction models for SCD, highlight the opportunities for these models in clinical practice, and identify the key challenges hindering widespread adoption.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to lower the risk of re-hospitalization and cardiovascular mortality among heart failure (HF) patients. Nevertheless, the impact of these agents on ventricular arrhythmias (VAs) has not been thoroughly investigated. To assess the beneficial impact of SGLT2 inhibitors on VAs in patients at various stages of HF, a systematic review and meta-analysis of randomized controlled trials involving SGLT2 inhibitors in this patient population was performed.

A comprehensive search of the PubMed, Embase, Ovid, ProQuest, Scopus, and Cochrane databases was performed for clinical trials published up to November 21, 2024. The primary outcomes of interest were incidences of VAs and sudden cardiac death (SCD) between the groups receiving SGLT2 inhibitors and the control drugs. For the outcomes observed in the populations of the included trials and in specific subgroups, hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled and meta-analysed across the analyses.

A total of 23 randomized trials (22 placebo-controlled trials and 1 active-controlled trial) involving 74,380 patients (37,372 receiving SGLT2 inhibitors and 37,008 in the control group) were included. The analysed SGLT2 inhibitors included canagliflozin, dapagliflozin, empagliflozin, bexagliflozin, sotagliflozin, and ertugliflozin. The participants were non-advanced HF patients, including at-risk for HF, pre-HF, and symptomatic HF, with follow-up duration ranging from 12 to 296 weeks. Compared with the control, treatment with SGLT2 inhibitors was associated with significantly reduced risk of VAs (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74-0.98; P = 0.02) and SCD (RR 0.79, 95% CI 0.64-0.98; P = 0.03). Subgroup analyses indicated that longer follow-up (≥ 1 year) taking SGLT2 inhibitors can still reduce the risk of VAs (RR 0.79, 95% CI 0.65-0.96; P = 0.02) and SCD (RR 0.80, 95% CI 0.65-0.99; P = 0.04).

SGLT2 inhibitors have beneficial effects on lowering risks of VAs and SCD in patients with type 2 diabetes, cardiovascular diseases, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF), with longer follow-up duration reinforcing these findings. However, future prospective trials are needed to verify the effects of SGLT2 inhibitors on VAs and SCD.

PROSPERO (CRD42024601914).

In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy.

The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo.

VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

Background: In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated significant cardiovascular and renal benefits in patients with heart failure (HF), in addition to their established antidiabetic effects. However, their role in arrhythmia prevention remains unclear. This study aimed to assess the effect of SGLT2 inhibitors on the incidence of supraventricular tachycardia (SVT) and ventricular tachycardia (VT) in patients with HF with reduced ejection fraction (HFrEF) during an extended follow-up period. Methods: This retrospective cohort study was conducted between January 2019 and November 2024 at the Ulm University Heart Center. All patients exhibited severely reduced left ventricular function and underwent primary prophylactic implantable cardioverter-defibrillator (ICD) implantation. Half of the cohort initiated SGLT2 inhibitor therapy alongside optimal medical HF treatment (the SGLT2 group). Patients were followed for approximately three years (846.2 ± 520.0 days) and the incidence of SVT and VT was analyzed using intracardiac Holter records of the ICD. Results: The study population consisted of 78 patients with a mean age of 66.6 ± 12.9 years. Over the follow-up period, a significant prolongation in the time to first occurrence of SVT was observed in the SGLT2 group (Log-Rank p = 0.03), suggesting a potential protective effect of SGLT2 inhibitors. However, regarding VT, additional SGLT2 inhibitor therapy did not show an additional benefit to optimal medical HF treatment. Conclusions: This study suggests that SGLT2 inhibitors may play a beneficial role in reducing the incidence of SVT in patients with HFrEF. These results highlight the importance of further investigating the antiarrhythmic potential of SGLT2 inhibitors through large-scale, prospective studies to better understand their clinical implications and mechanisms of action.

Implantable cardioverter-defibrillators (ICDs) are recommended to reduce the risk of sudden cardiac death (SCD) in patients with heart failure with reduced ejection fraction (HFrEF). The landmark studies leading to the current guideline recommendations preceded the 4 pillars of guideline-directed medical therapies (GDMTs). Therefore, some have questioned the role of ICDs for primary prevention in current clinical practice. In this paper, the authors provide an overview of the current ICD recommendations, including the instrumental clinical trials, the risk of SCD as observed in clinical trials vs real-world scenarios, disparities in ICD use among different patient populations, the impact of contemporary GDMT on outcomes, and ongoing and future trials and methodologies to help identify patients who are at an increased risk of SCD and who may benefit from an ICD. The authors also propose a pragmatic guidance for clinicians when they engage in the shared decision-making discussions for primary ICD implantation.

Sodium/glucose cotransporter 2 inhibitors (SGLT2is) like empagliflozin have demonstrated cardioprotective effects in patients with or without diabetes. SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late INa). Induction of late INa is the primary mechanism in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene encoding Nav1.5. We investigated empagliflozin's effect on late INa in thirteen known LQT3 mutations located in distinct regions of the channel.

The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin on late INa in recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation-contraction coupling.

Empagliflozin selectively inhibited late INa in LQT3 mutations in the inactivation gate region of Nav1.5, without affecting peak current or channel kinetics. In contrast, empagliflozin inhibited both peak and late INa in mutations in the S4 voltage-sensing regions, altered channel gating, and slowed recovery from inactivation. Empagliflozin had no effect on late/peak INa or channel kinetics in channels with mutations in the putative empagliflozin binding region. Simulation results predict that empagliflozin may have a desirable therapeutic effect in LQT3 mutations in the inactivation gate region.

Empagliflozin selectively inhibits late INa, without affecting channel kinetics, in LQT3 mutations in the inactivation gate region. Empagliflozin may thus be a promising precision medicine approach for patients with specific LQT3 mutations.

Background/Objectives: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose co-transporter 2 inhibitors (SGLT2i) are essential medications in heart failure (HF) therapy, and their potential antiarrhythmic effects have been reported. Recently, ARNI and SGLT2i use for HF in adult congenital heart disease (ACHD) has been studied. However, whether any beneficial effects may be achieved on the arrhythmic burden in the complex population of ACHD with a systemic right ventricle (sRV) is still to be determined. Methods: We retrospectively collected all significant arrhythmic events from a cohort of patients with a failing sRV attending our tertiary care center on optimal guideline-directed medical therapy (GDMT) with ARNI and/or SGLT2i. Results: A total of 46 patients (mean age 38.2 ± 10.7 years, 58% male) on sacubitril/valsartan were included. Twenty-three (50%) patients were also started on dapagliflozin. After a median follow-up of 36 [Q1-Q3: 34-38] months, arrhythmic events occurred globally in 13 (28%) patients. Survival analysis showed significant reduction of clinically relevant atrial and ventricular arrhythmia at follow-up (p = 0.027). Conclusions: Our findings suggest that GDMT including sacubitril/valsartan and dapagliflozin may also offer an antiarrhythmic effect in ACHD patients with a failing sRV, by reducing the incidence of arrhythmic events at follow-up.

Sodium-glucose transporter 2 (SGLT2) inhibitors such as empagliflozin are one of the main treatments for type 2 diabetes mellitus (DM2) and heart failure (HF). They have also demonstrated anti-arrhythmic effects in some preclinical and clinical studies. The purpose of this study was to assess the effects of empagliflozin on ventricular arrhythmias in HF patients with an implantable cardioverter-defibrillator (ICD). In a prospective double-blinded, randomized controlled trial of Iran County, Mashhad (72 patients 1:1), we compared the frequency and proportion of ventricular arrhythmias and ICD therapies during the 24 weeks to the prior 24 weeks. Results revealed that empagliflozin significantly reduced the frequency and proportion of ventricular tachycardia (VT)/fibrillation (VF) episodes (P = 0.019 and 0.039, respectively). Moreover, it tended to reduce the frequency and proportion of ICD therapies, including anti-tachycardia pacing (ATP) and shock. Subgroup analysis of patients with or without any antiarrhythmic drugs (digoxin, mexiletine, amiodarone, or sotalol) revealed that only patients who were previously on the antiarrhythmic drugs benefit from empagliflozin antiarrhythmic effects. In conclusion, empagliflozin exhibits anti-arrhythmic effects in HF patients with an ICD. Larger and long-term clinical studies are still needed to investigate and confirm all positive effects of SGLT2 inhibitors in this regard. Trial registration number: IRCT20120520009801N7 (Approval date: June 11, 2022).

This study is aimed at evaluating the effect of empagliflozin in preventing atrial fibrillation after coronary artery bypass grafting (CABG). Eighty-two patients who fulfilled the inclusion criteria were allocated to the empagliflozin group (n = 43) or placebo group (n = 39). In two groups, patients received empagliflozin or placebo tablets 3 days before surgery and on the first three postoperative days (for 6 days) in addition to the standard regimen during hospitalization. During the first 3 days after surgery, types of arrhythmias after cardiac surgery, including supraventricular arrhythmias, especially postoperative atrial fibrillation (POAF), ventricular arrhythmias, and heart blocks, were assessed by electrocardiogram monitoring. C-reactive protein (CRP) levels were evaluated pre-operatively and postoperative on the third day. The incidence of POAF in the treatment group was lower compared to the control group; however, this reduction was statistically non-significant (p = 0.09). The frequency of ventricular tachycardia was reduced significantly in the treatment group versus patients in the control (p = 0.02). Also, a significant reduction in the frequency of premature ventricular contractions (PVCs) was seen in the treatment group in comparison with the control group (p = 0.001). After the intervention, CRP levels were significantly less in the empagliflozin group compared to the control group in the third postoperative day (p = 0.04). The prophylactic use of empagliflozin effectively reduced the incidence of ventricular arrhythmia in patients undergoing CABG surgery.

There are limited data on clinical and arrhythmic outcomes after a first ventricular tachyarrhythmia (VTA) in heart failure (HF) patients who receive a primary prevention implantable cardioverter-defibrillator (ICD).

This study was designed to quantify the burden of and to identify risk factors for recurrent VTA in this population and to evaluate the risk of all-cause mortality associated with recurrent VTA.

The study comprised 789 patients who experienced VTA following primary prevention ICD implantation in 5 ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). Landmark analysis was used to quantify the burden and to identify predictors of recurrent VTA. Time-dependent analysis was used to evaluate the association of VTA recurrence with subsequent mortality.

The mean age of the study patients was 63 years, and 17% were women. The cumulative probability of experiencing at least 1 recurrent VTA episode at 3 years after a first VTA episode was 60%; the recurrent VTA burden after a first event during 3 years was 2.8 episodes per patient. The risk of recurrent VTA remained ≥56% at 3 years regardless of baseline clinical and echocardiographic risk factors. VTA recurrence was associated with a significant 2-fold increased risk of subsequent all-cause mortality.

Patients with a primary prevention ICD who experience an episode of VTA are at high risk of recurrent VTA, regardless of baseline risk factors. Recurrent VTA is associated with a pronounced increase in the risk of death. These findings suggest a need for early intervention after a first VTA in patients who receive a primary prevention ICD.

Risk stratification of sudden cardiac death after myocardial infarction and prevention by defibrillator rely on left ventricular ejection fraction (LVEF). Improved risk stratification across the whole LVEF range is required for decision-making on defibrillator implantation.

The analysis pooled 20 data sets with 140 204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging. Separate analyses were performed in patients (i) carrying a primary prevention cardioverter-defibrillator with LVEF ≤ 35% [implantable cardioverter-defibrillator (ICD) patients], (ii) without cardioverter-defibrillator with LVEF ≤ 35% (non-ICD patients ≤ 35%), and (iii) without cardioverter-defibrillator with LVEF > 35% (non-ICD patients >35%). Primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy. Using a competing risk framework and systematic internal-external cross-validation, a model using LVEF only, a multivariable flexible parametric survival model, and a multivariable random forest survival model were developed and externally validated. Predictive performance was assessed by random effect meta-analysis.

There were 1326 primary outcomes in 7543 ICD patients, 1193 in 25 058 non-ICD patients ≤35%, and 1567 in 107 603 non-ICD patients >35% during mean follow-up of 30.0, 46.5, and 57.6 months, respectively. In these three subgroups, LVEF poorly predicted sudden cardiac death (c-statistics between 0.50 and 0.56). Considering additional parameters did not improve calibration and discrimination, and model generalizability was poor.

More accurate risk stratification for sudden cardiac death and identification of low-risk individuals with severely reduced LVEF or of high-risk individuals with preserved LVEF was not feasible, neither using LVEF nor using other predictors.

Heart failure (HF) is a chronic disease associated with high morbidity and mortality rates. Renin-angiotensin-aldosterone system blockers (including angiotensin receptor/neprilysin inhibitors), beta-blockers, and mineralocorticoid receptor blockers remain the mainstay of pharmacotherapy for HF with reduced ejection fraction (HFrEF). However, despite the use of guideline-directed medical therapy, the mortality from HFrEF remains high. HF with preserved ejection fraction (HFpEF) comprises approximately half of the total incident HF cases; however, unlike HFrEF, there are no proven therapies for this condition. Sodium glucose cotransporter-2 inhibitors (SGLT-2is) represent a new class of pharmacological agents approved for diabetes mellitus (DM) that inhibit SGLT-2 receptors in the kidney. A serendipitous finding from seminal trials of SGLT-2is in DM was the significant improvement in renal and cardiovascular (CV) outcomes. More importantly, the improvement in HF hospitalization (HHF) in the CV outcomes trials of SGLT-2is was striking. Multiple mechanisms have been proposed for the pleiotropic effects of SGLT-2is beyond their glycemic control. However, as patients with HF were not included in any of these trials, it can be considered as a primary intervention. Subsequently, two landmark studies of SGLT-2is in patients with HFrEF, namely, an empagliflozin outcome trial in patients with chronic HF and a reduced ejection fraction (EMPEROR-Reduced) and dapagliflozin and prevention of adverse outcomes in HF (DAPA-HF), demonstrated significant improvement in HHF and CV mortality regardless of the presence of DM. These impressive results pitchforked these drugs as class I indications in patients with HFrEF across major guidelines. Thereafter, empagliflozin outcome trial in patients with chronic HF with preserved ejection fraction (EMPEROR-Preserved) and dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction HF (DELIVER) trials successively confirmed that SGLT-2is also benefit patients with HFpEF with or without DM. These results represent a watershed as they constitute the first clinically meaningful therapy for HFpEF in the past three decades of evolution of HF management. Emerging positive data for the use of SGLT-2is in acute HF and post-myocardial infarction scenarios have strengthened the pivotal role of these agents in the realm of HF. In a short span of time, these classes of drugs have captivated the entire scenario of HF.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial pleiotropic effects, contributing to improved cardiovascular and renal outcomes for patients with and without diabetes. The impact of SGLT2is on arrhythmic burden remains largely unexplored through randomized trials.

In this multicenter, double-blind, randomized, placebo-controlled trial, we investigated the effects of ertugliflozin on arrhythmic burden among patients with heart failure with an ejection fraction less than 50%. All patients had an implantable cardioverter-defibrillator (ICD) with or without a cardiac resynchronization therapy device (CRT-D) and were randomized (1:1) to receive either ertugliflozin 5 mg once daily or placebo. The primary end point was the number of incident sustained (>30 seconds) ventricular tachycardia or ventricular fibrillation events from baseline to week 52. Secondary end points included the total number of non-sustained ventricular tachycardias, appropriate ICD therapies, changes in N-terminal pro-brain-type natriuretic peptide (NTproBNP) levels, and the number of heart failure hospitalizations.

Randomization was prematurely terminated, after class IA guideline recommendations were published for SGLT2is in patients with heart failure regardless of the ejection fraction. The final analysis included 46 patients (11% of the originally planned sample size). The yearly rate of the primary end point was 3.5 (95% confidence interval [CI] 2.8 to 4.4) with ertugliflozin compared with 13.3 with placebo (95% CI 11.8 to 14.8; rate ratio 0.16, 95% CI 0.04 to 0.61; P<0.001). There were no apparent differences in appropriate ICD therapies, hospitalizations, NTproBNP levels, or predefined adverse and serious adverse events.

Ertugliflozin reduced sustained ventricular tachycardia or ventricular fibrillation events in adults with heart failure and an ICD compared with placebo; however, our trial ended early and thus results should be interpreted with caution. (Funded by Investigator-initiated Studies Program of Merck Sharp & Dohme Corp and Pfizer; EudraCT number, 2020-002581-14; ClinicalTrials.gov number NCT04600921.).

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective in adults with diabetes mellitus (DM) and heart failure (HF) based on randomized clinical trials. We compared SGLT2 inhibitor uptake and outcomes in two cohorts: a population-based cohort of all adults with DM and HF in Alberta, Canada and a specialized heart function clinic (HFC) cohort.

The population-based cohort was derived from linked provincial healthcare datasets. The specialized clinic cohort was created by chart review of consecutive patients prospectively enrolled in the HFC between February 2018 and August 2022. We examined the association between SGLT2 inhibitor use (modeled as a time-varying covariate) and all-cause mortality or deaths/cardiovascular hospitalizations.

Of the 4,885 individuals from the population-based cohort, 64.2% met the eligibility criteria of the trials proving the effectiveness of SGLT2 inhibitors. Utilization of SGLT2 inhibitors increased from 1.2% in 2017 to 26.4% by January 2022. In comparison, of the 530 patients followed in the HFC, SGLT2 inhibitor use increased from 9.8% in 2019 to 49.1 % by March 2022. SGLT2 inhibitor use in the population-based cohort was associated with fewer all-cause mortality (aHR 0.51, 95%CI 0.41-0.63) and deaths/cardiovascular hospitalizations (aHR 0.65, 95%CI 0.54-0.77). However, SGLT2 inhibitor usage rates were far lower in HF patients without DM (3.5% by March 2022 in the HFC cohort).

Despite robust randomized trial evidence of clinical benefit, the uptake of SGLT2 inhibitors in patients with HF and DM remains low, even in the specialized HFC. Clinical care strategies are needed to enhance the use of SGLT2 inhibitors and improve implementation.