Cardiovascular toxicities of immune therapies for cancer - a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Rapid Uptitration of Guideline-Directed Medical Therapies in Acute Heart Failure With and Without Atrial Fibrillation.

BACKGROUND: Rapid uptitration of guideline-directed medical therapy (GDMT) before and after discharge in hospitalized heart failure (HF) patients is feasible, is safe, and improves outcomes; whether this is also true in patients with coexistent atrial fibrillation/flutter (AF/AFL) is not known. OBJECTIVES: This study sought to investigate whether rapid GDMT uptitration before and after discharge for HF is feasible, safe and beneficial in patients with and without AF/AFL. METHODS: In this secondary analysis of the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) trial, GDMT uptitration and patient outcomes were analyzed by AF/AFL status and type (permanent, persistent, paroxysmal). RESULTS: Among 1,078 patients enrolled in STRONG-HF, 496 (46%) had a history of AF, including 238 assigned to high-intensity care (HIC) and 258 to usual care (UC), and 581 did not have a history of AF/AFL, including 304 assigned to HIC and 277 to UC. By day 90, the average percent optimal dose of neurohormonal inhibitors achieved in the HIC arm was similar in patients with and without AF/AFL, reaching approximately 80% of the optimal dose (average absolute difference between AF/AFL and non-AF/AFL groups: -0.81%; 95% CI: -3.51 to 1.89). All-cause death or HF readmission by day 180 occurred less frequently in the HIC than the UC arm, both in patients with and without AF (adjusted HR: 0.75 [95% CI: 0.48-1.19] in AF vs adjusted HR: 0.50 [95% CI: 0.31-0.79] in non-AF/AFL patients; P for interaction = 0.2107). Adverse event rates were similar in patients with and without AF/AFL. AF/AFL type did not affect either uptitration or patient outcomes. CONCLUSIONS: Nearly half of acute HF patients have AF/AFL history. Rapid GDMT uptitration before and early after discharge is feasible, is safe, and may improve outcomes regardless of AF presence or type. (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies [STRONG-HF]; NCT03412201).

Implementation of a cardiogenic shock team in a tertiary academic center.

OBJECTIVE: Observational studies have shown that the management of patients with cardiogenic shock (CS) by dedicated multidisciplinary teams improves clinical outcomes. Nevertheless, these studies reflect a specific organizational setting with most patients being transferred from referring hospitals, hospitalized in cardiac intensive care units (ICU), or treated with mechanical circulatory support (MCS) devices. The purpose of this study was to document the organization and outcomes of a CS team offering acute care in an all-comer population. METHODS: A CS team was developed in a large academic tertiary institution. The team consisted of emergency care physicians, critical care cardiologists, interventional cardiologists, cardiac surgeons, ICU physicians, and heart failure specialists and was supported by a predefined operating protocol, a dedicated communication platform, and regular team meetings. RESULTS: Over 12 months, 70 CS patients (69 ± 13 years old, 67% males) were included. Acute myocardial infarction (AMI-CS) was the most common cause (64%); 31% of the patients presented post-resuscitated cardiac arrest and 56% needed invasive mechanical ventilation (IMV). Coronary angiography was performed in 70% and 53% had percutaneous coronary intervention. MCS was used in 10% and 6% were referred for urgent cardiac surgery. The in-hospital mortality in our center was 40% with 39% of the patients dying within 24 h from presentation. Overall, 76% of the live patients were discharged home. CONCLUSION: Across an all-comer population, AMI was the most common cause of CS. A significant number of patients presented post-cardiac arrest, and the majority required IMV. Mortality was high with a significant number dying within hours of presentation.

Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.

Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include ß-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.

Revisiting Cardiovascular Benefits of Blood Pressure Reduction in Primary and Secondary Prevention: Focus on Targets and Residual Risk-A Systematic Review and Meta-Analysis.

BACKGROUND: Previous meta-analyses resurrected the debated statement "the lower, the better" following blood pressure (BP)-lowering treatment. We investigated the benefits of BP-lowering treatment at different BP targets by prevention category. METHODS: The meta-analysis protocol was registered at the International Prospective Register of Systematic Reviews (CRD42022379249). The database included 115 BP-lowering or comparison trials from patients with (n=241 089) or without (n=198 937) previous cardiovascular events. Prevention disease groups were stratified by in-treatment achieved BP, drug class versus placebo, and drug class versus other classes. Risk ratios and 95% CIs of major adverse cardiovascular events were calculated. RESULTS: Following a standard (10/5 mm Hg) BP reduction, major adverse cardiovascular event relative risk reductions were not different between prevention groups (primary, 25% [95% CI, 18%-31%]; secondary, 28% [95% CI, 20%-37%]). For achieved systolic BP of at least 140 mm Hg, between 130 and 140 mm Hg, and <130 mm Hg (nadir, 125 mm Hg), (1) risk ratios of major adverse cardiovascular events and absolute risk reductions were not different between prevention groups across systolic BP strata, and (2) residual risk, though 4.1× greater in secondary than primary prevention, decreased in primary prevention from higher to lower systolic BP targets. The effect of separate drugs versus others on the primary outcome was not different between prevention groups. CONCLUSIONS: BP-lowering treatment benefits did not differ by prevention group to a nadir of 125 mm Hg for systolic BP. Although residual risk in secondary prevention is higher than in primary prevention, it gradually decreases at progressively lower systolic BP targets in primary prevention. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022379249.

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.

High-sensitivity cardiac troponin I for cardiovascular risk stratification in apparently healthy individuals.

Troponin I and T as cardiac-specific biomarkers are highly useful tools not only in the diagnosis of acute coronary syndromes but also as independent predictors of several other clinical conditions. High-sensitivity cardiac troponin (hs-cTn) assays allow the detection of considerably low concentrations of cardiac troponin in apparently healthy and asymptomatic individuals, being a candidate tool for cardiovascular risk stratification in the general population. A group of Greek experts summarized the bulk of evidence regarding the use of hs-cTnI as a predictor of cardiovascular events and mortality in apparently healthy individuals and its additive value on top of existing risk stratification methods. This document could serve as a guide for the incorporation of hs-cTnI as an additional risk stratification tool in cardiovascular prevention strategies in apparently healthy individuals.

Epidemiology, pathophysiology, diagnosis and management of chronic right-sided heart failure and tricuspid regurgitation. A clinical consensus statement of the Heart Failure Association (HFA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

Right-sided heart failure and tricuspid regurgitation are common and strongly associated with poor quality of life and an increased risk of heart failure hospitalizations and death. While medical therapy for right-sided heart failure is limited, treatment options for tricuspid regurgitation include surgery and, based on recent developments, several transcatheter interventions. However, the patients who might benefit from tricuspid valve interventions are yet unknown, as is the ideal time for these treatments given the paucity of clinical evidence. In this context, it is crucial to elucidate aetiology and pathophysiological mechanisms leading to right-sided heart failure and tricuspid regurgitation in order to recognize when tricuspid regurgitation is a mere bystander and when it can cause or contribute to heart failure progression. Notably, early identification of right heart failure and tricuspid regurgitation may be crucial and optimal management requires knowledge about the different mechanisms and causes, clinical course and presentation, as well as possible treatment options. The aim of this clinical consensus statement is to summarize current knowledge about epidemiology, pathophysiology and treatment of tricuspid regurgitation in right-sided heart failure providing practical suggestions for patient identification and management.

European Society of Cardiology Core Curriculum for cardio-oncology.

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists.

Incidence, risk assessment and prevention of sudden cardiac death in cardiomyopathies.

Cardiomyopathies are a significant contributor to cardiovascular morbidity and mortality, mainly due to the development of heart failure and increased risk of sudden cardiac death (SCD). Despite improvement in survival with contemporary treatment, SCD remains an important cause of mortality in cardiomyopathies. It occurs at a rate ranging between 0.15% and 0.7% per year (depending on the cardiomyopathy), which significantly surpasses SCD incidence in the age- and sex-matched general population. The risk of SCD is affected by multiple factors including the aetiology, genetic basis, age, sex, physical exertion, the extent of myocardial disease severity, conduction system abnormalities, and electrical instability, as measured by various metrics. Over the past decades, the knowledge on the mechanisms and risk factors for SCD has substantially improved, allowing for a better-informed risk stratification. However, unresolved issues still challenge the guidance of SCD prevention in patients with cardiomyopathies. In this review, we aim to provide an in-depth discussion of the contemporary concepts pertinent to understanding the burden, risk assessment and prevention of SCD in cardiomyopathies (dilated, non-dilated left ventricular, hypertrophic, arrhythmogenic right ventricular, and restrictive). The review first focuses on SCD incidence in cardiomyopathies and then summarizes established and emerging risk factors for life-threatening arrhythmias/SCD. Finally, it discusses validated approaches to the risk assessment and evidence-based measures for SCD prevention in cardiomyopathies, pointing to the gaps in evidence and areas of uncertainties that merit future clarification.

Hospitalization for acute heart failure during non-working hours impacts on long-term mortality: the REPORT-HF registry.

AIMS: Hospital admission during nighttime and off hours may affect the outcome of patients with various cardiovascular conditions due to suboptimal resources and personnel availability, but data for acute heart failure remain controversial. Therefore, we studied outcomes of acute heart failure patients according to their time of admission from the global International Registry to assess medical practice with lOngitudinal obseRvation for Treatment of Heart Failure. METHODS AND RESULTS: Overall, 18 553 acute heart failure patients were divided according to time of admission into 'morning' (7:00-14:59), 'evening' (15:00-22:59), and 'night' (23:00-06:59) shift groups. Patients were also dichotomized to admission during 'working hours' (9:00-16:59 during standard working days) and 'non-working hours' (any other time). Clinical characteristics, treatments, and outcomes were compared across groups. The hospital length of stay was longer for morning (odds ratio: 1.08; 95% confidence interval: 1.06-1.10, P < 0.001) and evening shift (odds ratio: 1.10; 95% confidence interval: 1.07-1.12, P < 0.001) as compared with night shift. The length of stay was also longer for working vs. non-working hours (odds ratio: 1.03; 95% confidence interval: 1.02-1.05, P < 0.001). There were no significant differences in in-hospital mortality among the groups. Admission during working hours, compared with non-working hours, was associated with significantly lower mortality at 1 year (hazard ratio: 0.88; 95% confidence interval: 0.80-0.96, P = 0.003). CONCLUSIONS: Acute heart failure patients admitted during the night shift and non-working hours had shorter length of stay but similar in-hospital mortality. However, patients admitted during non-working hours were at a higher risk for 1 year mortality. These findings may have implications for the health policies and heart failure trials.

State-of-the-art document on optimal contemporary management of cardiomyopathies.

Cardiomyopathies represent significant contributors to cardiovascular morbidity and mortality. Over the past decades, a progress has occurred in characterization of the genetic background and major pathophysiological mechanisms, which has been incorporated into a more nuanced diagnostic approach and risk stratification. Furthermore, medications targeting core disease processes and/or their downstream adverse effects have been introduced for several cardiomyopathies. Combined with standard care and prevention of sudden cardiac death, these novel and emerging targeted therapies offer a possibility of improving the outcomes in several cardiomyopathies. Therefore, the aim of this document is to summarize practical approaches to the treatment of cardiomyopathies, which includes the evidence-based novel therapeutic concepts and established principles of care, tailored to the individual patient aetiology and clinical presentation of the cardiomyopathy. The scope of the document encompasses contemporary treatment of dilated, hypertrophic, restrictive and arrhythmogenic cardiomyopathy. It was based on an expert consensus reached at the Heart Failure Association online Workshop, held on 18 March 2021.

Cardioprotective Agents for the Primary Prevention of Trastuzumab-Associated Cardiotoxicity: A Systematic Review and Meta-Analysis.

There are significant considerations about the prevention of cardiotoxicity caused by trastuzumab therapy in patients with breast cancer, leading to discontinuation. Recently, randomized controlled trials (RCTs) have evaluated the effects of early commitment of beta-blockers (BBs), angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) during trastuzumab chemotherapy in order to prevent the related cardiotoxicity. The present systematic review and meta-analysis of six RCTs included patients who have predominantly non-metastatic, HER2-positive, breast cancer and received trastuzumab as primary or adjuvant therapy. Those patients did not have any obvious cardiac dysfunction or any previous therapy with cardioprotective agent. We evaluated the efficacy of the aforementioned medications for primary prevention of cardiotoxicity, using random effects models. Any preventive treatment did not reduce cardiotoxicity occurrence compared to controls (Odds ratios (OR) = 0.92, 95% CI 0.54-1.56, p = 0.75). Results were similar for ACEIs/ARBs and beta-blockers. Treatment with ACEIs/ARBs led to a slight, but significant, increase in LVEF in patients compared to the placebo group. Only two studies reported less likelihood of discontinuation of trastuzumab treatment. More adequately powered RCTs are needed to determine the efficacy of routine prophylactic therapy.