Adaptive immune response modulation has taken a central position in cancer therapy in recent decades. Treatment with immune checkpoint inhibitors (ICIs) is now indicated in many cancer types with exceptional results. The two major inhibitory pathways involved are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). Unfortunately, immune activation is not tumor-specific, and as a result, most patients will experience some form of adverse reaction. Most immune-related adverse events (IRAEs) involve the skin and gastrointestinal (GI) tract; however, any organ can be involved. Cardiotoxicity ranges from arrhythmias to life-threatening myocarditis with very high mortality rates. To date, most treatments of ICI cardiotoxicity include immune suppression, which is also not cardiac-specific and may result in hampering of tumor clearance. Understanding the mechanisms behind immune activation in the heart is crucial for the development of specific treatments. Histological data and other models have shown mainly CD4 and CD8 infiltration during ICI-induced cardiotoxicity. Inhibition of CTLA4 seems to result in the proliferation of more diverse T0cell populations, some of which with autoantigen recognition. Inhibition of PD-1 interaction with PD ligand 1/2 (PD-L1/PD-L2) results in release from inhibition of exhausted self-recognizing T cells. However, CTLA4, PD-1, and their ligands are expressed on a wide range of cells, indicating a much more intricate mechanism. This is further complicated by the identification of multiple co-stimulatory and co-inhibitory signals, as well as the association of myocarditis with antibody-driven myasthenia gravis and myositis IRAEs. In this review, we focus on the recent advances in unraveling the complexity of the mechanisms driving ICI cardiotoxicity and discuss novel therapeutic strategies for directly targeting specific underlying mechanisms to reduce IRAEs and improve outcomes.

Heart failure with reduced ejection fraction (HFrEF) is a clinical condition associated with cardiac contractility impairment. HFrEF is a significant public health issue with a high morbidity and mortality burden. Pathological left ventricular (LV) remodeling and progressive dilatation are hallmarks of HFrEF pathogenesis, ultimately leading to adverse clinical outcomes. Therefore, cardiac remodeling attenuation has become a treatment goal and a standard of care over the last three decades. Guideline-directed medical therapy mainly targeting the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) has led to improved survival and a reduction in HF hospitalization in this population. More recently, novel pharmacological therapies targeting other pathways implicated in the pathophysiology of HFrEF have emerged at an exciting rate, with landmark clinical trials demonstrating additive clinical benefits in patients with HFrEF. Among these novel therapies, angiotensin receptor–neprilysin inhibitors (ARNI), sodium–glucose cotransporter-2 inhibitors (SGLT2i), vericiguat (a novel oral guanylate cyclase stimulator), and omecamtiv mecarbil (a selective cardiac myosin activator) have shown improved clinical benefit when added to the traditional standard-of-care medical therapy in HFrEF. These new comprehensive data have led to a remarkable change in the medical therapy paradigm in the setting of HFrEF. This article will review the pivotal studies involving these novel agents and present a suggestive paradigm of pharmacological therapy representing the 2021 European Society of Cardiology (ESC) guidelines for the treatment of chronic HFrEF.

(1) Introduction: Most studies rely on in-hospital data to predict cardiovascular risk and do not include prehospital information that is substantially important for early decision making. The aim of the study was to define clinical parameters in the prehospital setting, which may affect clinical outcomes. (2) Methods: In this population-based study, we performed a retrospective analysis of emergency calls that were made by patients to the largest private emergency medical services (EMS) in Israel, SHL Telemedicine Ltd., who were treated on-site by the EMS team. Demographics, clinical characteristics, and clinical outcomes were analyzed. Mortality was evaluated at three time points: 1, 3, and 12 months’ follow-up. The first EMS prehospital measurements of the systolic blood pressure (SBP) were recorded and analyzed. Logistic regression analyses were performed. (3) Results: A total of 64,320 emergency calls were included with a follow-up of 12 months post index EMS call. Fifty-five percent of patients were men and the mean age was 70.2 ± 13.1 years. During follow-up of 12 months, 7.6% of patients died. Age above 80 years (OR 3.34; 95% CI 3.03–3.69, p < 0.005), first EMS SBP ≤ 130 mm Hg (OR 2.61; 95% CI 2.36–2.88, p < 0.005), dyspnea at presentation (OR 2.55; 95% CI 2.29–2.83, p < 0001), and chest pain with ischemic ECG changes (OR 1.95; 95% CI 1.71–2.23, p < 0.001) were the highest predictors of 1 month mortality and remained so for mortality at 3 and 12 months. In contrast, history of hypertension and first EMS prehospital SBP ≥ 160 mm Hg were significantly associated with decreased mortality at 1, 3 and 12 months. (4) Conclusions: We identified risk predictors for all-cause mortality in a large cohort of patients during prehospital EMS calls. Age over 80 years, first EMS-documented prehospital SBP < 130 mm Hg, and dyspnea at presentation were the most profound risk predictors for short- and long-term mortality. The current study demonstrates that in prehospital EMS call settings, several parameters can be used to improve prioritization and management of high-risk patients.