Drug therapy and catheter ablation for management of arrhythmias in continuous flow left ventricular assist device's patients. A Clinical Consensus Statement of the European Heart Rhythm Association and the Heart Failure Association of the ESC.

Left ventricular assist devices (LVADs) are an increasingly used strategy for the management of patients with advanced heart failure. Although these devices effectively improve survival, atrial and ventricular arrhythmias are common with a prevalence of 20-50% at one year after LVAD implantation. Arrhythmias predispose these patients to additional risk and are associated with considerable morbidity from recurrent implantable cardioverter-defibrillator (ICD) shocks, progressive failure of the unsupported right ventricle, and herald an increased risk of mortality. Management of patients with arrhythmias and LVAD differs in many aspects from the general population heart failure patients. These include ruling out the reversible causes of arrhythmias that in LVAD patients may include mechanical irritation from the inflow cannula and suction events. For patients with symptomatic arrhythmias refractory to medical treatment, catheter ablation might be relevant. There are specific technical and procedural challenges perceived to be unique to LVAD-related ventricular tachycardia ablation such as vascular and LV access, signal filtering, catheter manoeuvrability within decompressed chambers, and electroanatomic mapping system interference. In some patients, the arrhythmogenic substrate might not be readily accessible by catheter ablation after LVAD implantation. In this regard, the peri-implantation period offers a unique opportunity to surgically address arrhythmogenic substrate and suppress future ventricular tachycardia recurrences. This document aims to address specific aspects of the management of arrhythmias in LVAD patients focusing on anti-arrhythmic drug therapy and ablations.

Heart transplantation: focus on donor recovery strategies, left ventricular assist devices, and novel therapies.

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

Advanced Heart Failure: Definition, Epidemiology, and Clinical Course.

Advanced heart failure (HF) is characterized by a progressive worsening of symptoms disabling for daily life, refractory to all therapies, and with high mortality. These patients may be candidates for life-prolonging therapies, such as heart transplantation (HT) or long-term (LT) mechanical circulatory support (MCS) or must just require palliative therapies. The 1-year survival after HT and/or LT-MCS is approaching 80% to 90%, being patient selection and timely referral to advanced HF centers critical for optimal outcomes. There is no single symptom, sign, or test that can identify these patients and different classifications are complementary and helpful for clinical decision-making.

Usefulness of carotid ultrasonography in the assessment of coronary artery disease extension in patients undergoing exercise echocardiography.

OBJECTIVES: To evaluate whether carotid disease is associated with coronary artery disease (CAD) extension in patients undergoing treadmill exercise stress echocardiography (EE). METHODS: We retrospectively studied 156 patients without previous vascular disease who underwent EE, carotid ultrasonography, and coronary angiography between 2002 and 2013. Low-, intermediate-, and high-risk EE were defined as negative, localized ischemia, and multivessel/extensive ischemia EE respectively; carotid disease according to Mannheim and American Society of Echocardiography Consensus and CAD extension from zero to three vessel disease as stenosis ≥50% by visual assessment. RESULTS: Of the 156 patients, 67 (42.9%), 43 (27.6%), 22 (14.1%), and 24 (15.4%) had zero, one, two, and three vessel disease respectively. Age (P = 0.047), male sex (P = 0.010), diabetes mellitus (P = 0.039), smoking habit (P = 0.015), fasting plasma glucose (P = 0.021), European Systematic COronary Risk Evaluation (P = 0.003), pretest CAD probability (P = 0.003), high-risk EE (P < 0.001), and carotid plaque presence (CP) (P < 0.001) were associated in univariate analysis with more extensive CAD. Predictors of CAD extension in multivariate analysis were high-risk EE (odds ratio [OR] 2.42, P < 0.001), CP presence (OR 1.75, P = 0.004), and pretest CAD probability >65% (OR 1.49, P = 0.023). CP was also associated with multivessel CAD in the 53 patients with low- or intermediate-risk EE (P = 0.001). CONCLUSIONS: CP is associated with CAD extension in patients with ischemic heart disease suspicion undergoing EE. Patients with CP could benefit from a more aggressive therapeutic strategy regarding patients without carotid disease and similar risk EE, especially in intermediate- and/or low-risk test where guidelines recommend initially optimal medical treatment.

Usefulness of carotid ultrasonography in the diagnosis of coronary artery disease in patients undergoing exercise echocardiography.

BACKGROUND: Relationship between carotid and coronary artery disease (CAD) in patients undergoing invasive and non-invasive test is unclear. The aim of the study is to evaluate whether carotid disease is associated with CAD in patients submitted to exercise echocardiography (EE) and if it improves the EE ability to predict CAD. METHODS: We retrospectively studied 156 subjects without previous vascular disease who underwent EE, carotid ultrasonography and coronary angiography between 2002 and 2013. Positive EE was defined as exercise induced wall motion abnormalities, carotid disease according to Manheim and American Society of Echocardiography Consensus and significant CAD as stenosis ≥50%. RESULTS: Eighty-nine (57.1%) subjects had significant CAD. Factors associated with CAD in multivariate analysis were fasting plasma glucose (odds ratio [OR] 1.02, p = 0.031), pre-test probability of CAD > 65% (OR 3.71, p < 0.001), positive EE (OR 10.51, p < 0.001) and carotid plaque (CP) presence (OR 2.95, p = 0.013). There was neither statistical significant difference in area under the curve after addition of CP to EE results (0.77 versus 0.81, p = 0.525) nor sensitivity, specificity, predictive values or efficiency. CP presence reclassified as very high-risk according to Systematic COronary Risk Evaluation 13 patients (34.2%) with negative EE and 22 (33.3%) without CAD. CONCLUSION: CP is associated with CAD in patients undergoing EE, however its addition to EE does not improve CAD prediction, probably due to insufficient statistical power. CP reclassified one third of patients to very high-risk category despite negative EE or CAD absence, these subjects benefit from aggressive primary prevention interventions.

Repetitive ambulatory levosimendan as a bridge to heart transplantation.

INTRODUCTION AND OBJECTIVES: Repetitive ambulatory doses of levosimendan are an option as a bridge to heart transplantation (HT), but evidence regarding the safety and efficacy of this treatment is scarce. The objective of the LEVO-T Registry is to describe the profile of patients on the HT list receiving levosimendan, prescription patterns, and clinical outcomes compared with patients not on levosimendan. METHODS: We retrospectively reviewed all patients listed for elective HT from 2015 to 2020 from 14 centers in Spain. RESULTS: A total of 1015 consecutive patients were included, of whom 238 patients (23.4%) received levosimendan. Patients treated with levosimendan had more heart failure (HF) admissions in the previous year and a worse clinical profile. The most frequent prescription pattern were fixed doses triggered by the patients' clinical needs. Nonfatal ventricular arrhythmias occurred in 2 patients (0.8%). No differences in HF hospitalizations were found between patients who started levosimendan in the first 30 days after listing and those who did not (33.6% vs 34.5%; P=.848). Among those who did not, 102 patients (32.9%) crossed over to levosimendan after an HF admission. These patients had a rate of 0.57 HF admissions per month before starting levosimendan and 0.21 afterwards. Propensity score matching analysis showed no differences in survival at 1 year after listing between patients receiving levosimendan and those who did not (HR, 1.03; 95%CI, 0.36-2.97; P=.958) or in survival after HT (HR, 0.97; 95%CI, 0.60-1.56; P=.958). CONCLUSIONS: Repetitive levosimendan in an ambulatory setting as a bridge to heart transplantation is commonly used, is safe, and may reduce HF hospitalizations.

2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.

Document Reviewers: Rudolf A. de Boer (CPG Review Co-ordinator) (Netherlands), P. Christian Schulze (CPG Review Co-ordinator) (Germany), Elena Arbelo (Spain), Jozef Bartunek (Belgium), Johann Bauersachs (Germany), Michael A. Borger (Germany), Sergio Buccheri (Sweden), Elisabetta Cerbai (Italy), Erwan Donal (France), Frank Edelmann (Germany), Gloria Färber (Germany), Bettina Heidecker (Germany), Borja Ibanez (Spain), Stefan James (Sweden), Lars Køber (Denmark), Konstantinos C. Koskinas (Switzerland), Josep Masip (Spain), John William McEvoy (Ireland), Robert Mentz (United States of America), Borislava Mihaylova (United Kingdom), Jacob Eifer Møller (Denmark), Wilfried Mullens (Belgium), Lis Neubeck (United Kingdom), Jens Cosedis Nielsen (Denmark), Agnes A. Pasquet (Belgium), Piotr Ponikowski (Poland), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Bianca Rocca (Italy), Xavier Rossello (Spain), Leyla Elif Sade (United States of America/Türkiye), Hannah Schaubroeck (Belgium), Elena Tessitore (Switzerland), Mariya Tokmakova (Bulgaria), Peter van der Meer (Netherlands), Isabelle C. Van Gelder (Netherlands), Mattias Van Heetvelde (Belgium), Christiaan Vrints (Belgium), Matthias Wilhelm (Switzerland), Adam Witkowski (Poland), and Katja Zeppenfeld (Netherlands) All experts involved in the development of this Focused Update have submitted declarations of interest. These have been compiled in a report and simultaneously published in a supplementary document to the Focused Update. The report is also available on the ESC website www.escardio.org/guidelines See the European Heart Journal online for supplementary documents that include evidence tables.

Heart failure in Europe: Guideline-directed medical therapy use and decision making in chronic and acute, pre-existing and de novo, heart failure with reduced, mildly reduced, and preserved ejection fraction - the ESC EORP Heart Failure III Registry.

AIMS: We analysed baseline characteristics and guideline-directed medical therapy (GDMT) use and decisions in the European Society of Cardiology (ESC) Heart Failure (HF) III Registry. METHODS AND RESULTS: Between 1 November 2018 and 31 December 2020, 10 162 patients with acute HF (AHF, 39%, age 70 [62-79], 36% women) or outpatient visit for HF (61%, age 66 [58-75], 33% women), with HF with reduced (HFrEF, 57%), mildly reduced (HFmrEF, 17%) or preserved (HFpEF, 26%) ejection fraction were enrolled from 220 centres in 41 European or ESC-affiliated countries. With AHF, 97% were hospitalized, 2.2% received intravenous treatment in the emergency department, and 0.9% received intravenous treatment in an outpatient clinic. AHF was seen by most by a general cardiologist (51%) and outpatient HF most by a HF specialist (48%). A majority had been hospitalized for HF before, but 26% of AHF and 6.1% of outpatient HF had de novo HF. Baseline use, initiation and discontinuation of GDMT varied according to AHF versus outpatient HF, de novo versus pre-existing HF, and by ejection fraction. After the AHF event or outpatient HF visit, use of any renin-angiotensin system inhibitor, angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist and loop diuretics was 89%, 29%, 92%, 78%, and 85% in HFrEF; 89%, 9.7%, 90%, 64%, and 81% in HFmrEF; and 77%, 3.1%, 80%, 48%, and 80% in HFpEF. CONCLUSION: Use and initiation of GDMT was high in cardiology centres in Europe, compared to previous reports from cohorts and registries including more primary care and general medicine and regions more local or outside of Europe and ESC-affiliated countries.

Review of the allocation criteria for heart transplant in Spain in 2023. SEC-Heart Failure Association/ONT/SECCE consensus document.

Heart transplant (HT) remains the best therapeutic option for patients with advanced heart failure (HF). The allocation criteria aim to guarantee equitable access to HT and prioritize patients with a worse clinical status. To review the HT allocation criteria, the Heart Failure Association of the Spanish Society of Cardiology (HFA-SEC), the Spanish Society of Cardiovascular and Endovascular Surgery (SECCE) and the National Transplant Organization (ONT), organized a consensus conference involving adult and pediatric cardiologists, adult and pediatric cardiac surgeons, transplant coordinators from all over Spain, and physicians and nurses from the ONT. The aims of the consensus conference were as follows: a) to analyze the organization and management of patients with advanced HF and cardiogenic shock in Spain; b) to critically review heart allocation and priority criteria in other transplant organizations; c) to analyze the outcomes of patients listed and transplanted before and after the modification of the heart allocation criteria in 2017; and d) to propose new heart allocation criteria in Spain after an analysis of the available evidence and multidisciplinary discussion. In this article, by the HFA-SEC, SECCE and the ONT we present the results of the analysis performed in the consensus conference and the rationale for the new heart allocation criteria in Spain.

Structural heart transcatheter interventions in orthotopic cardiac transplant and left ventricular assist devices recipients: A nationwide study.

BACKGROUND: The current incidence and outcomes of structural transcatheter procedures in heart transplant (HTx) recipients and left-ventricular assist devices (LVAD) carriers is unknown. AIMS: To provide insights on structural transcatheter procedures performed across HTx and LVAD patients in Spain. METHODS: Multicenter, ambispective, observational nationwide registry. RESULTS: Until May/2023, 36 percutaneous structural interventions were performed (78% for HTx and 22% for LVAD) widely varying among centers (0%-1.4% and 0%-25%, respectively). Percutaneous mitral transcatheter edge-to-edge (TEER) was the most common (n = 12, 33.3%), followed by trancatheter aortic valve replacement (n = 11, 30.5%), and tricuspid procedures (n = 9, 25%). Mitral TEER resulted in mild residual mitral regurgitation in all but one case, mean gradient was <5 mmHg in 75% of them at 1-year, with no mortality and 8.3% re-admission rate. Tricuspid TEER resulted in 100% none/mild residual regurgitation with a 1-year mortality and readmission rates of 22% and 28.5%, respectively. Finally, trancatheter aortic valve replacement procedures (n = 8 in LVADs due to aortic regurgitation and n = 3 in HTx), were successful in all cases with one prosthesis degeneration leading to severe aortic regurgitation at 1-year, 18.2% mortality rate and no re-admissions. Globally, major bleeding rates were 7.9% and 12.5%, thromboembolic events 3.7% and 12.5%, readmissions 37% and 25%, and mortality 22% and 25%, in HTx and LVADs respectively. No death was related to the implanted transcatheter device. CONCLUSIONS: Most centers with HTx/LVAD programs perform structural percutaneous procedures but with very inconsistent incidence. They were associated with good safety and efficacy, but larger studies are required to provide formal recommendations.

Mortality After the First Hospital Admission for Acute Heart Failure, De Novo Versus Acutely Decompensated Heart Failure With Reduced Ejection Fraction.

It is not clear to date whether a first admission in heart failure (HF) marks a worse evolution in patients not previously diagnosed with HF ("de novo HF") than those already diagnosed as outpatients ("acutely decompensated HF"). The aim of the study was to analyze whether survival in patients admitted for de novo HF differs from the survival in those admitted for a first episode of decompensation but with a previous diagnosis of HF. This study includes an analysis of 1,728 patients admitted for decompensated HF during 9 years. Readmissions and patients with left ventricular ejection fraction ≥50% were excluded (finally, 524 patients analyzed). We compared de novo HF (n = 186) in patients not diagnosed with HF, although their structural heart disease was defined, versus acutely decompensated HF (n = 338). The clinical profiles in both groups were similar. The de novo HF group more frequently presented with normal right ventricular function, with less presence of severe tricuspid regurgitation. The probability of survival was low in both groups. Thus, the median life in the de novo HF group was 2.1 years and in the acutely decompensated HF group, 3.5 years. There was a lower probability of long-term survival in the de novo HF group (p = 0.035). The variables associated with mortality were age (p <0.0001), ischemic heart disease (p <0.0001), hypertension (p = 0.009), obesity (p = 0.025), diabetes (p = 0.001), and N-terminal pro-brain natriuretic peptide at admission (p <0.0001). A higher glomerular filtration rate was associated with better survival (p = 0.033). De novo HF was associated with a higher mortality than chronic HF with acute decompensation (hazard ratio 1.53, 95% confidence interval 1.03 to 2.27, p = 0.036). In conclusion, the first admission for HF decompensation in patients with no previous diagnosis of HF identifies a subgroup of patients with higher long-term mortality.

Conduction system pacing and atrioventricular node ablation in heart failure: The PACE-FIB study design.

AIMS: Atrial fibrillation (AF) worsens the prognosis of patients with heart failure (HF). Successful treatments are still very scarce for those with permanent AF and preserved (HFpEF) or mildly reduced (HFmrEF) ejection fraction. In this study, the long-term benefits and safety profile of heart rate regularization through left-bundle branch pacing (LBBP) and atrioventricular node ablation (AVNA) will be explored in comparison with pharmacological rate-control strategy. METHODS AND RESULTS: The PACE-FIB trial is a multicentre, prospective, open-label, randomized (1:1) clinical study that will take place between March 2022 and February 2027. A total of 334 patients with HFpEF/HFmrEF and permanent AF will receive either LBBP followed by AVNA (intervention arm) or optimal pharmacological treatment for heart rate control according to European guideline recommendations (control arm). All patients will be followed up for a minimum of 36 months. The primary outcome measure will be the composite of all-cause mortality, HF hospitalization, and worsening HF at 36 months. Other secondary efficacy and safety outcome measures such as echocardiographic parameters, functional status, and treatment-related adverse events, among others, will be analysed too. CONCLUSION: LBBP is a promising stimulation mode that may foster the clinical benefit of heart rate regularization through AV node ablation compared with pharmacological rate control. This is the first randomized trial specifically addressing the long-term efficacy and safety of this pace-and-ablate strategy in patients with HFpEF/HFmrEF and permanent AF.

Prevalence, Characteristics, and Prognostic Relevance of Donor-Transmitted Coronary Artery Disease in Heart Transplant Recipients.

BACKGROUND: The reported prevalence of donor-transmitted coronary artery disease (TCAD) in heart transplantation (HT) is variable, and its prognostic impact remains unclear. OBJECTIVES: The goal of this study was to characterize TCAD in a contemporary multicentric cohort and to study its prognostic relevance. METHODS: This was a retrospective study of consecutive patients >18 years old who underwent HT in 11 Spanish centers from 2008 to 2018. Only patients with a coronary angiography (c-angio) within the first 3 months after HT were studied. Significant TCAD (s-TCAD) was defined as any stenosis ≥50% in epicardial coronary arteries, and nonsignificant TCAD (ns-TCAD) as stenosis <50%. Clinical outcomes were assessed by means of Cox regression and competing risks regression. Patients were followed-up for a median period of 6.3 years after c-angio. RESULTS: From a cohort of 1,918 patients, 937 underwent c-angio. TCAD was found in 172 patients (18.3%): s-TCAD in 65 (6.9%) and ns-TCAD in 107 (11.4%). Multivariable Cox regression analysis did not show a statistically significant association between s-TCAD and all-cause mortality (adjusted HR: 1.44; 95% CI: 0.89-2.35; P = 0.141); however, it was an independent predictor of cardiovascular mortality (adjusted HR: 2.25; 95% CI: 1.20-4.19; P = 0.011) and the combined event cardiovascular death or nonfatal MACE (adjusted HR: 2.42; 95% CI: 1.52-3.85; P < 0.001). No statistically significant impact of ns-TCAD on clinical outcomes was detected. The results were similar when reassessed by means of competing risks regression. CONCLUSIONS: TCAD was not associated with reduced survival in patients alive and well enough to undergo post-HT angiography within the first 3 months; however, s-TCAD patients showed increased risk of cardiovascular death and MACE.

Rationale and design of the ESC Heart Failure III Registry - Implementation and discovery.

AIMS: Heart failure outcomes remain poor despite advances in therapy. The European Society of Cardiology Heart Failure III Registry (ESC HF III Registry) aims to characterize HF clinical features and outcomes and to assess implementation of guideline-recommended therapy in Europe and other ESC affiliated countries. METHODS: Between 1 November 2018 and 31 December 2020, 10 162 patients with chronic or acute/worsening HF with reduced, mildly reduced, or preserved ejection fraction were enrolled from 220 centres in 41 European or ESC affiliated countries. The ESC HF III Registry collected data on baseline characteristics (hospital or clinic presentation), hospital course, diagnostic and therapeutic decisions in hospital and at the clinic visit; and on outcomes at 12-month follow-up. These data include demographics, medical history, physical examination, biomarkers and imaging, quality of life, treatments, and interventions - including drug doses and reasons for non-use, and cause-specific outcomes. CONCLUSION: The ESC HF III Registry will provide comprehensive and unique insight into contemporary HF characteristics, treatment implementation, and outcomes, and may impact implementation strategies, clinical discovery, trial design, and public policy.

Specific test panels for patients with heart failure: implementation and use in the Spanish National Health System.

Objectives: The use of specific test panels (STP) for heart failure (HF) could help improve the management of this condition. The purpose of this study is to gain an insight into the level of implementation of STPs in the management of HF in Spain and gather the opinions of experts, with a special focus on parameters related to iron metabolism. Methods: The opinions of experts in HF were gathered in three stages STAGE 1 as follows: level of implementation of STPs (n=40). STAGE 2: advantages and disadvantages of STPs (n=12). STAGE 3: level of agreement with the composition of three specific STPs for HF: initial evaluation panel, monitoring panel, and de novo panel (n=16). Results: In total, 62.5% of hospitals used STPs for the clinical management of HF, with no association found between the use of STPs and the level of health care (p=0.132) and location of the center (p=0.486) or the availability of a Heart Failure Unit in the center (p=0.737). According to experts, the use of STPs in clinical practice has more advantages than disadvantages (8 vs. 3), with a notable positive impact on diagnostics. Experts gave three motivations and found three limitations to the implementation of STPs. The composition of the three specific STPs for HF was viewed positively by experts. Conclusions: Although the experts interviewed advocate the use of diagnostic and monitoring STPs for HF, efforts are still necessary to achieve the standardization and homogenization of test panels for HF in Spanish hospitals.

Cardiac protection induced by urocortin-2 enables the regulation of apoptosis and fibrosis after ischemia and reperfusion involving miR-29a modulation.

Urocortin-2 (Ucn-2) has demonstrated cardioprotective actions against myocardial ischemia-reperfusion (I/R) injuries. Herein, we explored the protective role of Ucn-2 through microRNAs (miRNAs) post-transcriptional regulation of apoptotic and pro-fibrotic genes. We determined that the intravenous administration of Ucn-2 before heart reperfusion in a Wistar rat model of I/R recovered cardiac contractility and decreased fibrosis, lactate dehydrogenase release, and apoptosis. The infusion of Ucn-2 also inhibited the upregulation of 6 miRNAs in revascularized heart. The in silico analysis indicated that miR-29a and miR-451_1∗ are predicted to target many apoptotic and fibrotic genes. Accordingly, the transfection of neonatal rat ventricular myocytes with mimics overexpressing miR-29a, but not miR-451_1∗, prevented I/R-induced expression of pro- and anti-apoptotic genes such as Apaf-1, Hmox-1, and Cycs, as well as pro-fibrotic genes Col-I and Col-III. We also confirmed that Hmox-1, target of miR-29a, is highly expressed at the mRNA and protein levels in adult rat heart under I/R, whereas, Ucn-2 abolished I/R-induced mRNA and protein upregulation of HMOX-1. Interestingly, a significant upregulation of Hmox-1 was observed in the ventricle of ischemic patients with heart failure, correlating negatively with the left ventricle ejection fraction. Altogether, these data indicate that Ucn-2, through miR-29a regulation, provides long-lasting cardioprotection, involving the post-transcriptional regulation of apoptotic and fibrotic genes.

Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca2+ Handling and NRF2 Activation.

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.