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Bempedoic acid is a selective inhibitor of the adenosine triphosphate citrate lyase that reduces low-density lipoprotein cholesterol (LDLc) levels by 17% to 28%. Although the Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (CLEAR-OUTCOMES) trials demonstrated the efficacy on cardiovascular outcomes there is a controversy related to the possible net clinical benefit. Thereafter, we performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome of the metanalysis was the incidence of major adverse cardiovascular events, defined by each study protocol. Secondary outcomes for the analyses were myocardial infarction, stroke, myocardial revascularization, cardiovascular death, and all-cause death. Results of 4 clinical trials evaluated contained a total of 17,324 patients; 9,236 received bempedoic acid for a median of 46.6 months. The mean baseline LDLc was 129.4 (22.8) mg/100 ml and treatment was associated with a mean LDLc reduction of 26.0 (12.6) mg/100 ml. Treatment with bempedoic acid significantly reduced the incidence of major adverse cardiovascular events (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.81 to 0.96), myocardial infarction (HR 0.76, 95% CI 0.66 to 0.89) and myocardial revascularization (HR 0.82, 95% CI 0.73 to 0.92); the crude incidence of stroke, cardiovascular or all-cause mortality were lower in patients in the bempedoic acid groups although no significant risk reduction was observed. No heterogeneity was observed in any of the end points. In conclusion, the metanalysis of the 4 clinical trials currently available with bempedoic acid provides reliable evidence of its clinical benefit with no signs of heterogeneity or harm., Competing Interests: Declaration of Competing Interest Dr. Cordero reports honoraria for lectures from AstraZeneca, AMGEN, Bristol-Myers Squibb, Ferrer, Boehringer Ingelheim, Merck Sharp & Dohme, Daiichy Sankio, Novartis, Novo Nordisk, Sanofi and Amarin; and consulting fees from AstraZeneca, Ferrer, Sanofi, AMGEN, Novartis, Lilly, Novo Nordisk and Amarin. Dr. Fernández reports honoraria for lectures from AstraZeneca, AMGEN, Ferrer, Merck Sharp & Dohme, Daiichi Sankio, Novartis, Novo Nordisk, Sanofi, and Amarin; and consulting fees from AstraZeneca, Sanofi, AMGEN, Novartis, Novo Nordisk, and Amarin. Dr. Castellano reports honoraria from Ferrer, Servier, Daiichi Sankyo, and Pfizer. Dr. Fácila reports honoraria for lectures from Eli Lilly Co, Daiichi Sankyo, Inc., Bayer, Pfizer, Novartis Boehringer Ingelheim, and consulting fees from AstraZeneca, Boehringer, Bayer. Dr. Rodriguez-Mañero reports research grants from Fundación Mutua Madrileña, Biosense Webster, Medtronic, and the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain). Dr. Bonanad has received fees from AstraZeneca; Amgen, Bayer; Boehringer; Bristol-Myers Squibb; Daiichi Sankyo; Ferrer; Novartis AG; Pfizer; Roche Pharma; Sanofi Pharma. Dr. González Juanatey reports honoraria for lectures from Eli Lilly Co, Daiichi Sankyo, Inc., Bayer, Pfizer, Abbott, Boehringer Ingelheim, Merck Sharp & Dohme, Ferrer, and Bristol-Myers Squibb; consulting fees from AstraZeneca, Ferrer, Bayer, Boehringer Ingelheim; and research grants from AstraZeneca, Boehringer Ingelheim and Daichi-Sankyo. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Statins are the cornerstone of lipid-lowering therapy (LLT) for reduction of low-density lipoprotein cholesterol (LDLc) levels and high percentage of patients require LLT combinations or alternative treatments for adequate LDLc control., Methods: We performed an intention-to-treat meta-analysis of published data of phase III trials evaluating LLT efficacy on major adverse cardiovascular events (MACE). The primary endpoint was MACE incidence, as reported in each trial, and secondary analyses included myocardial infarction, stroke and mortality., Results: Eleven clinical trials and 135,688 patients were included; seven trials tested high intensity LLT and 4 LLT combinations. Intensive LLT reduced MACE risk by 15% (12.03% vs. 13.79%, HR: 0.85 95% CI 0.80-0.90; p<0.001). The number needed to treat was 56 patients. Meta-regression analyses showed a linear correlation between absolute LDLc reductions and the risk of MACE. Significant reductions in myocardial infarction (HR: 0.83, 95% CI 0.80-0.86) and stroke (HR: 0.81, 95% CI 0.75-0.87) were observed. Cardiovascular death rate was 3.32% in LLT treatment arm vs. 3.56% in controls, resulting in a HR: 0.94 (95% CI 0.88-0.99; p = 0.03); no effect on all-cause mortality was observed (HR: 0.97 95% CI 0.93-1.01; p = 0.09). The sensitivity analyses verified the lack of heterogeneity, except for MACE that was mainly driven by the divergent results of the 2 trials. Small study effect was detected for the assessment of mortality., Conclusions: Current evidence consistently supports the efficacy of available intensity LLT for LDLc decrease on MACE and cardiovascular mortality reduction., (Copyright © 2023. Published by Elsevier Inc.)

Background: SGLT2i (sodium-glucose cotransporter-2 inhibitors) improve clinical outcomes in patients with heart failure, but the mechanisms of action are not completely understood. SGLT2i increases circulating levels of ketone bodies, which has been demonstrated to enhance myocardial energetics and induce reverse ventricular remodeling. However, the role of SGLT2i or ketone bodies on myocardial ischemia reperfusion injury remains in the dark. The objective of this study is to investigate the cardioprotective potential of empagliflozin and ketone bodies during acute myocardial infarction (MI)., Methods: We used a nondiabetic porcine model of ischemia reperfusion using a percutaneous occlusion of proximal left anterior descending artery for 45 minutes. Animals received 1-week pretreatment with either empagliflozin or placebo prior to MI induction. Additionally, a third group received intravenous infusion of the ketone body BOHB (beta-hydroxybutyrate) during the MI induction. Acute effects of the treatments were assessed 4-hour post-MI by cardiac magnetic resonance and histology (thioflavin for area at risk, triphenyltetrazolium chloride staining for MI size). All animals were euthanized immediately postcardiac magnetic resonance, and heart samples were collected., Results: The area at risk was similar in all groups. Empagliflozin treatment increased BOHB levels. Empagliflozin-treated animals showed significantly higher myocardial salvage, smaller MI size (both by cardiac magnetic resonance and histology), less microvascular obstruction, and improved cardiac function (left ventricle ejection fraction and strain). Furthermore, empagliflozin-treated animals demonstrated reduced biomarkers of cardiomyocyte apoptosis and oxidative stress compared with placebo. The BOHB group showed similar results to the empagliflozin group., Conclusions: One-week pretreatment with empagliflozin ameliorates ischemia reperfusion injury, reduces MI size and microvascular obstruction, increases myocardial salvage, preserves left ventricle systolic function, and lowers apoptosis and oxidative stress. Periprocedural intravenous infusion of BOHB during myocardial ischemia also induces cardioprotection, suggesting a role for BOHB availability as an additional mechanism within the wide spectrum of actions of SGLT2i.

Background: Pulsed field ablation (PFA) has recently been shown to penetrate ischemic scar, but details on its efficacy, risk of arrhythmias, and imaging insights are lacking. In a porcine model of myocardial scar, we studied the ability of ventricular PFA to penetrate scarred tissue, induce ventricular arrhythmias, and assess the influence of QRS gating during pulse delivery., Methods: Of a total of 6 swine, 5 underwent coronary occlusion and 1 underwent radiofrequency ablation to create infarct scar and iatrogenic scar models, respectively. Two additional swine served as healthy controls. An 8 Fr focal PFA catheter was used to deliver bipolar, biphasic PFA (2.0 kV) lesions guided by electroanatomical mapping, fluoroscopy, and intracardiac echocardiography over both scarred and healthy myocardium. Swine underwent magnetic resonance imaging 2-7 days post-PFA., Results: PFA successfully penetrated scar without significant difference in lesion depth between lesion at the infarct border (5.9±1.0 mm, n=41) and healthy myocardium (5.7±1.3 mm, n=26; P =0.53). PFA penetration of both infarct and iatrogenic radiofrequency abalation scar was observed in all examined sections. Sustained ventricular arrhythmias requiring defibrillation occurred in 4 of 187 (2.1%) ungated applications, whereas no ventricular arrhythmias occurred during gated PFA applications (0 of 64 [0%]). Dark-blood late-gadolinium-enhanced sequences allowed for improved endocardial border detection as well as lesion boundaries compared with conventional bright-blood late-gadolinium-enhanced sequences., Conclusions: PFA penetrates infarct and iatrogenic scar successfully to create deep lesions. Gated delivery eliminates the occurrence of ventricular arrhythmias observed with ungated porcine PFA. Optimized magnetic resonance imaging sequences can be helpful in detecting lesion boundaries.

Objectives: The sodium-glucose cotransporter type 2 inhibitors reduce mortality and heart failure (HF) hospitalizations. The underlying mechanisms remain unclear but seem to be irrespective of glucose-lowering properties. This study aims to evaluate the impact of empagliflozin on myocardial biomechanics and correlation with markers of adverse remodeling., Methods: Following myocardial infarct induction to create a model of HF, 14 pigs were randomly assigned in a 1:1 ratio to receive either empagliflozin 10 mg daily or placebo for 2 months. Speckle-tracking echocardiography (STE) and feature-tracking cardiac magnetic resonance (FTCMR) were performed at baseline and at the end of the study to analyze myocardial deformation. The results were correlated with markers of adverse cardiac remodeling., Results: Empagliflozin significantly improved STE indices. These parameters significantly correlated with adverse cardiac remodeling. In contrast, FTCMR indices showed only a trend toward improved myocardial deformation and without significant correlation with adverse cardiac remodeling. The correlation between both techniques to assess myocardial deformation was low., Conclusion: Empagliflozin enhances myocardial deformation, assessed by STE techniques, in a non-diabetic porcine model of ischemic HF. This may be related to a mitigation of adverse cardiac remodeling following ischemia reperfusion injury. In contrast, FTCMR technique needs further development and validation.

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., (© 2016 American Heart Association, Inc.)

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.

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., (Copyright © 2014 the American Physiological Society.)