SGLT2 inhibitors reduce sudden cardiac death risk in heart failure: Meta-analysis of randomized clinical trials.

INTRODUCTION: Multiple randomized controlled trials have demonstrated sodium-glucose cotransporter-2 inhibitors (SGLT2i) decrease the composite endpoint of cardiovascular death or heart failure hospitalizations in all heart failure patients. It is uncertain whether SGLT2i impacts the risk of sudden cardiac death in patients with heart failure. METHODS: A comprehensive search was performed to identify relevant data published before August 28, 2022. Trials were included if: (1) all patients had clinical heart failure (2) SGLT2i and placebo were compared (3) all patients received conventional medical therapy and (4) reported outcomes of interest (sudden cardiac death [SCD], ventricular arrhythmias, atrial arrhythmias). RESULTS: SCD was reported in seven of the eleven trials meeting selection criteria: 10 796 patients received SGLT2i and 10 796 received placebo. SGLT2i therapy was associated with a significant reduction in the risk of SCD (risk ratios [RR]: 0.68; 95% confidence intervals [CI]: 0.48-0.95; p = .03; I2 = 0%). Absent dedicated rhythm monitoring, there were no significant differences in the incidence of sustained ventricular arrhythmias not associated with SCD (RR: 1.03; 95% CI: 0.83-1.29; p = .77; I2 = 0%) or atrial arrhythmias (RR: 0.91; 95% CI: 0.77-1.09; p = .31; I2 = 29%) between patients receiving an SGLT2i versus placebo. CONCLUSION: SGLT2i therapy is associated with a reduced risk of SCD in patients with heart failure receiving contemporary medical therapy. Prospective trials are needed to determine the long-term impact of SGLT2i therapy on atrial and ventricular arrhythmias.

SGLT2-Inhibitors on HFpEF Patients. Role of Ejection Fraction.

Results from DELIVER trial and publication of EMPEROR-Preserved with sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF) > 40% represent a significant step forward in the treatment of HF with preserved EF (HFpEF). However, detailed analysis and attenuation of effect at higher EF levels have sparked some doubts about whether empagliflozin is effective across the entire spectrum of EF. HFpEF is no longer considered as one disease entity, but has been reconceptualized as a heterogenous group of phenotypes with derangements in multiple organ systems, driven by comorbidities. This heterogeneity suggests that it should not be considered as a single group in terms of treatment goals or clinical approach. Future research at the higher range of EF should ideally tailor investigations for unequivocally preserved EF (> 50%), consider the dynamic nature of EF over time, and use low-variability imaging techniques such as CMR. Furthermore, classifications based on pathophysiology and HF phenotypes beyond the EF construct will shape the design of future trials and help narrow down groups of patients who may respond to personalized treatment.

Rationale and Design of the SOTA-P-CARDIA Trial (ATRU-V): Sotagliflozin in HFpEF Patients Without Diabetes.

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of heart failure (HF). This syndrome is associated with an elevated morbi-mortality, and effective therapies are urgently needed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the first pharmacological class that has demonstrated to reduce hospitalization and cardiovascular mortality in large clinical trials in HFpEF. Furthermore, the dual SGLT 1/2 inhibitor sotagliflozin has shown a reduction in cardiovascular outcomes in diabetic HF patients, regardless of ejection fraction Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) Trial, and prevents the development of HF in patients with diabetes and chronic kidney disease Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial. The major objective of the Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial (NCT05562063) is to investigate whether the observed cardiorenal benefits of sotagliflozin in HF patients with diabetes can be extended to a non-diabetic population. The SOTA-P-CARDIA is a prospective, randomized, double-blinded, placebo-controlled study that will randomize non-diabetic patients with the universal definition of HFpEF (ejection fraction > 50% assessed the day of randomization). Qualifying patients will be randomized, in blocks of 4, to receive either sotagliflozin or placebo for a period of 6 months. The primary outcome is changes in left ventricular mass by cardiac magnetic resonance from randomization to end of the study between the groups. Secondary end points include changes in peak VO2; myocardial mechanics, interstitial myocardial fibrosis, and volume of epicardial adipose tissue; distance in the 6-min walk test; and quality of life. Finally, the authors expect that this trial will help to clarify the potential benefits of the use of sotagliflozin in non-diabetic HFpEF patients.

Prolyl Hydroxylase Inhibitors: a New Opportunity in Renal and Myocardial Protection.

Hypoxia, via the activity of hypoxia-inducible factors (HIFs), plays a crucial role in fibrosis, inflammation, and oxidative injury, processes which are associated with progression of cardiovascular and kidney diseases. HIFs are key transcription heterodimers consisting of regulatory α-subunits (HIF-1α, HIF-2α, HIF-3α) and a constitutive ß-subunit (HIF-ß). The stability of HIFs is regulated by the prolyl hydroxylases (PHDs). Specific PHD inhibitors (PHD-i) are being investigated as a therapeutic approach to modulate the cellular signaling pathways and harness the native protective adaptive responses to hypoxia. Selective inhibition of PHD leads to the stabilization of the HIFs, which is the transcriptional gatekeeper of a multitude of genes involved in angiogenesis, energy metabolism, apoptosis, inflammation, and fibrosis. PHD-i downregulate hepcidin, improve iron absorption, and increase the endogenous production of erythropoietin. Furthermore, this pharmacological group has also been proven to ameliorate ischemic injuries in several organs, opening a new and promising field in cardiovascular research.. In this review, we present the basic and clinical potential of PHD-i treatment in different scenarios, such as ischemic heart disease, cardiac hypertrophy and heart failure, and their interplay with other pharmacological agents with proven cardiovascular benefits, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors.

In HFrEF, adding empagliflozin to medical therapy reduced a composite outcome, regardless of CKD status.

SOURCE CITATION: Zannad F, Ferreira JP, Pocock SJ, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced. Circulation. 2021;143:310-21. 33095032.

Direct Oral Anticoagulants and Coronary Artery Disease: The Debacle of the Aspirin Era?

Long-standing aspirin is the cornerstone to prevent recurrence of thrombotic events in patients with ischemic heart disease. However, clopidogrel, a more potent antiplatelet agent, is preferred over aspirin in targeted populations, including those with a high risk of gastrointestinal bleeding. In addition, clopidogrel offers superior oral tolerance, and it may reduce the rates of intracranial hemorrhages compared with aspirin. However, an extensive inhibition of the coagulation cascade seems to be reasonable to minimize thrombotic events in such patients. After several failed exploratory investigations in the past with vitamin K antagonists, the newest direct oral anticoagulants may represent an alternative. To counterbalance bleeding complications, a low dose of these agents should be considered. Few publications have already showed promising results with the combination of clopidogrel and low-dose direct oral anticoagulants. Further investigations should be addressed to elucidate whether this is the downfall of the aspirin era for secondary prevention of atherosclerotic cardiovascular events.

Rationale and Design of the EMPA-TROPISM Trial (ATRU-4): Are the "Cardiac Benefits" of Empagliflozin Independent of its Hypoglycemic Activity?

The SGLT2 inhibitor empagliflozin reduced cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in diabetic patients. We have recently demonstrated the efficacy of empagliflozin in ameliorating HF and improving cardiac function in a non-diabetic porcine model of HF mediated via a switch in myocardial metabolism that enhances cardiac energetics. Therefore, we hypothesized that the cardiac benefits of empagliflozin can also be extended to non-diabetic HF patients. The EMPA-TROPISM clinical trial is a randomized, double-blind, parallel group, placebo-controlled, trial comparing the efficacy of and safety of empagliflozin in non-diabetic HF patients. Eighty patients with stable HF for over 3 months, LVEF < 50%, and New York Heart Association functional class II to IV symptoms will be randomized to empagliflozin 10 mg for 6 months or placebo. All patients will undergo cardiac magnetic resonance (CMR), cardiopulmonary exercise test (CPET), 6-min walk test, and quality of life questionnaires. The primary outcome is the change in left ventricular end-diastolic volume measured by CMR. Secondary end-points include change in peak VO2 (CPET); change in LV mass, in LVEF, in myocardial mechanics (strains), in left atrium volumes, in RV function and volumes, in interstitial myocardial fibrosis, and in epicardial adipose tissue (CMR); change in the distance in the 6-min walk test; and changes in quality of life (Kansas Cardiomyopathy questionnaire [KCCQ-12] and the 36-Item Short Form Survey [SF-36]). Safety issues (e.g., hypoglycemia, urinary infections, ketoacidosis,…) will also be monitored. In summary, EMPA-TROPISM clinical trial will determine whether the SGLT2 inhibitor empagliflozin improves cardiac function and heart failure parameters in non-diabetic HF patients (EMPA-TROPISM [ATRU-4]: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic activity; NCT 03485222).

Inhibition of Sodium Glucose Cotransporters Improves Cardiac Performance.

The sodium-glucose cotransporter (SGLT) inhibitors represent a new alternative for treating patients with diabetes mellitus. They act primarily by inhibiting glucose reabsorption in the renal tubule and therefore, decreasing blood glucose levels. While little is yet known about SGLT subtype 1, SGLT2 inhibitors have demonstrated to significantly reduce cardiovascular mortality and heart failure hospitalizations. This cardioprotective benefit seems to be independent of their glucose-lowering properties; however, the underlying mechanism(s) remains still unclear and numerous hypotheses have been postulated to date. Moreover, preclinical research has suggested an important role of SGLT1 receptors on myocardial ischemia. Following acute phase of cardiac injury there is an increased activity of SGLT1 cotransport that ensures adequate energy supply to the cardiac cells. Nonetheless, a long-term upregulation of this receptor may not be that beneficial and whether its inhibition is positive or not should be further addressed. This review aims to present the most cutting-edge insights into SGLT receptors.

Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity?

Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the USA; it affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with substantial cardiovascular (CV) morbidity and mortality. T2DM is a pathological condition characterized by elevated levels of glucose and associated with high CV risk. Traditional hypoglycemic drugs have demonstrated their capability for effective and maintained management of high glucose levels, but they have not significantly impacted on the incidence of CV events. Recently, a new class of hypoglycemic agents, SGLT-2 receptor inhibitors, has been developed. The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk. The dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35 and 32% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively. These effects are even more important given the difficulties for treating concomitant HF in T2DM patients. These surprising results have been also corroborated by another agent of this class, canagliflozin, and the CANVAS trial. The magnitude of these somehow surprising cardiac benefits attained in the absence of major differences in glycemic, lipid, or blood pressure (BP) control has led to several groups to suggest that these benefits may be independent of its hypoglycemic activity and whether this new class could be considered a "cardiac" drug. The objective of this review has been to review the different hypotheses proposed to explain the cardiac benefits of this new class of antidiabetic drugs.

Sphingosine-1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Postinfarction Left Ventricular Remodeling in a Porcine Model of Ischemia/Reperfusion.

BACKGROUND: Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for the treatment of multiple sclerosis and exerts antiapoptotic properties. We hypothesized that sphingosine-1-phosphate receptor activation with fingolimod during acute myocardial infarction (MI) inhibits apoptosis, leading to increased myocardial salvage, reduced infarct size, and mitigated left ventricular (LV) remodeling in a porcine model of ischemia/reperfusion. METHODS AND RESULTS: Ischemia/reperfusion was induced in pigs by balloon occlusion of the left anterior descending artery, followed by reperfusion. Animals randomly received fingolimod or saline (control). In short-term experiments, fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways in the infarct border zone 24 hours after MI, leading to decreased cardiomyocyte apoptosis and reduced myocardial oxidative stress. These effects were abolished by specific inhibitors of both pathways, demonstrating that fingolimod-induced cardioprotection was mediated by reperfusion injury salvage kinase and survivor activating factor enhancement pathways. In long-term experiments, fingolimod significantly improved myocardial salvage, reduced infarct size, and improved systolic LV function measured by cardiac magnetic resonance 1 week and 1 month after MI. Importantly, fingolimod mitigated the development of adverse post-MI LV remodeling 1 month after MI. Specifically, fingolimod treatment led to a significant reduction in LV mass, LV dilatation, and neurohormonal activation, and it preserved LV geometry. Furthermore, fingolimod decreased interstitial fibrosis, cardiomyocyte hypertrophy, and chronic activation of Akt and extracellular receptor kinase 1/2 in the remote noninfarcted myocardium. CONCLUSIONS: Sphingosine-1-phosphate receptor activation with fingolimod during acute MI reduced infarct size via the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, improved systolic LV function, and mitigated post-MI LV remodeling. Our data strongly support a cardioprotective role for sphingosine-1-phosphate receptor activation during MI.

Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure.

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 10(13) vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 10(12) vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure-volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF.

Characterizing preclinical models of ischemic heart failure: differences between LAD and LCx infarctions.

Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n = 15) or the proximal left circumflex artery (LCx; n = 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 ± 3.2% vs. 10.6 ± 1.9%, P = 0.03), depressed systolic function (LV ejection fraction; 39.8 ± 7.5% vs. 54.1 ± 4.6%, P < 0.001), and more LV remodeling (end-systolic volume index; 82 ± 25 ml/m(2) vs. 51 ± 18 ml/m(2), P = 0.02, LAD vs. LCx, respectively) compared with the LCx MI approach without compromising the survival rate. At the papillary muscle level, echocardiographic strain analysis revealed no differences in radial and circumferential strain between LAD and LCx MIs. However, in contrast with the LCx MI, the LAD MI resulted in significantly decreased longitudinal strain. The proximal LAD MI model induces more LV remodeling and depressed LV function relative to the LCx MI model. Location of MI significantly impacts the severity of HF, thus careful consideration is required when choosing an MI model for preclinical HF studies.

Pathophysiology of acute coronary syndrome.

Despite improvements in interventional and pharmacological therapy for atherosclerotic disease, it is still the leading cause of death in the developed world. Hence, there is a need for further development of more effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Recent research in the last decade has changed our view of acute coronary syndrome (ACS): from a mere lipid deposition to an inflammatory disease; from ACS exclusively due to plaque rupture to the novel definitions of plaque erosion or calcified nodule; from the notion of a superimposed thrombus with necessary lethal consequences to the concept of healed plaques and thrombus contributing to plaque progression. In the hope of improving our understanding of ACS, all these recently discovered concepts are reviewed in this article.

Role of HDL in those with diabetes.

Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with an increased risk of coronary heart disease in prospective population studies and clinical trials of high-risk patients treated with a low to moderate intensity statin. As a result, therapeutic targets were developed to increase concentrations of HDL-C. Subsequently, clinical trials of high-intensity statins have not supported this previously well-established association. In trials of high-intensity statin therapy, low HDL particle concentration (HDL-P) has been associated with an increased risk of future cardiovascular events. Therefore, strategies that increase HDL-C without expanding the pool of HDL-P with its rich proteome/lipidome do not seem to be an effective strategy. In this review, we discuss potential mechanisms of action for the anti-atherogenic effect of HDL and the impact of current and emerging therapies on the functional capacity of HDL-P. Finally, we discuss emerging therapies that increase the concentration and functional properties of HDL.

Role of HDL in those with diabetes.

Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with an increased risk of coronary heart disease in prospective population studies and clinical trials of high-risk patients treated with a low to moderate intensity statin. As a result, therapeutic targets were developed to increase concentrations of HDL-C. Subsequently, clinical trials of high-intensity statins have not supported this previously well-established association. In trials of high-intensity statin therapy, low HDL particle concentration (HDL-P) has been associated with an increased risk of future cardiovascular events. Therefore, strategies that increase HDL-C without expanding the pool of HDL-P with its rich proteome/lipidome do not seem to be an effective strategy. In this review, we discuss potential mechanisms of action for the anti-atherogenic effect of HDL and the impact of current and emerging therapies on the functional capacity of HDL-P. Finally, we discuss emerging therapies that increase the concentration and functional properties of HDL.

Preclinical Study of Pulsed Field Ablation of Difficult Ventricular Targets: Intracavitary Mobile Structures, Interventricular Septum, and Left Ventricular Free Wall.

BACKGROUND: Endocardial catheter-based pulsed field ablation (PFA) of the ventricular myocardium is promising. However, little is known about PFA's ability to target intracavitary structures, epicardium, and ways to achieve transmural lesions across thick ventricular tissue. METHODS: A lattice-tip catheter was used to deliver biphasic monopolar PFA to swine ventricles under general anesthesia, with electroanatomical mapping, fluoroscopy and intracardiac echocardiography guidance. We conducted experiments to assess the feasibility and safety of repetitive monopolar PFA applications to ablate (1) intracavitary papillary muscles and moderator bands, (2) epicardial targets, and (3) bipolar PFA for midmyocardial targets in the interventricular septum and left ventricular free wall. RESULTS: (1) Papillary muscles (n=13) were successfully ablated and then evaluated at 2, 7, and 21 days. Nine lesions with stable contact measured 18.3±2.4 mm long, 15.3±1.5 mm wide, and 5.8±1.0 mm deep at 2 days. Chronic lesions demonstrated preserved chordae without mitral regurgitation. Two targeted moderator bands were transmurally ablated without structural disruption. (2) Transatrial saline/carbon dioxide assisted epicardial access was obtained successfully and epicardial monopolar lesions had a mean length, width, and depth of 30.4±4.2, 23.5±4.1, and 9.1±1.9 mm, respectively. (3) Bipolar PFA lesions were delivered across the septum (n=11) and the left ventricular free wall (n=7). Twelve completed bipolar lesions had a mean length, width, and depth of 29.6±5.5, 21.0±7.3, and 14.3±4.7 mm, respectively. Chronically, these lesions demonstrated uniform fibrotic changes without tissue disruption. Bipolar lesions were significantly deeper than the monopolar epicardial lesions. CONCLUSIONS: This in vivo evaluation demonstrates that PFA can successfully ablate intracavitary structures and create deep epicardial lesions and transmural left ventricular lesions.