Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed for cancer therapy, opening to advantages in cancer outcomes. However, several ICI-induced side effects have emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the cytotoxic and pro-inflammatory properties of Ipilimumab and Nivolumab, the underlying pathways and cytokine storm involved. Methods: Co-cultures of human cardiomyocytes and lymphocytes were exposed to Ipilimumab or Nivolumab; cell viability and expression of leukotrienes, NLRP3, MyD88, and p65/NF-kB were performed. C57 mice were treated with Ipilimumab (15 mg/kg); analysis of fractional shortening, ejection fraction, radial and longitudinal strain were made before and after treatments through 2D-echocardiography. Expression of NLRP3, MyD88, p65/NF-kB, and 12 cytokines were analyzed in murine myocardium. Results: Nivolumab and Ipilimumab exert effective anticancer, but also significant cardiotoxic effects in co-cultures of lymphocytes and tumor or cardiac cells. Both ICIs increased NLRP3, MyD88, and p65/NF-kB expression compared to untreated cells, however, the most pro-inflammatory and cardiotoxic effects were seen after exposure to Ipilimumab. Mice treated with Ipilimumab showed a significant decrease in fractional shortening and radial strain with respect to untreated mice, coupled with a significant increase in myocardial expression of NLRP3, MyD88, and several interleukins. Conclusions: Nivolumab and Ipilimumab exert cytotoxic effects mediated by the NLRP3/IL-1β and MyD88 pathways, leading to pro-inflammatory cytokine storm in heart tissue.

Cancer patients treated with immune checkpoint inhibitors (ICIs) are exposed to a high risk of atherosclerosis and cardiometabolic diseases due to systemic inflammatory conditions and immune-related atheroma destabilization. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein involved in metabolism of low-density lipoprotein (LDL) cholesterol. PCSK9 blocking agents are clinically available and involve monoclonal antibodies, and SiRNA reduces LDL levels in high-risk patients and atherosclerotic cardiovascular disease events in multiple patient cohorts. Moreover, PCSK9 induces peripheral immune tolerance (inhibition of cancer cell- immune recognition), reduces cardiac mitochondrial metabolism, and enhances cancer cell survival. The present review summarizes the potential benefits of PCSK9 inhibition through selective blocking antibodies and siRNA in patients with cancer, especially in those treated with ICIs therapies, in order to reduce atherosclerotic cardiovascular events and potentially improve ICIs-related anticancer functions.

Cardiovascular–kidney–metabolic (CKM) syndrome represents a complex interplay between cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic disorders, significantly impacting cancer patients. The presence of CKM syndrome in cancer patients not only worsens their prognosis but also increases the risk of major adverse cardiovascular events (MACE), reduces quality of life (QoL), and affects overall survival (OS). Furthermore, several anticancer therapies, including anthracyclines, tyrosine kinase inhibitors, immune checkpoint inhibitors, and hormonal treatments, can exacerbate CKM syndrome by inducing cardiotoxicity, nephrotoxicity, and metabolic dysregulation. This review explores the pathophysiology of CKM syndrome in cancer patients and highlights emerging therapeutic strategies to mitigate its impact. We discuss the role of novel pharmacological interventions, including sodium-glucose cotransporter-2 inhibitors (SGLT2i), proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), and soluble guanylate cyclase (sGC) activators, as well as dietary and lifestyle interventions. Optimizing the management of CKM syndrome in cancer patients is crucial to improving OS, enhancing QoL, and reducing MACE. By integrating cardiometabolic therapies into oncologic care, we can create a more comprehensive treatment approach that reduces the burden of cardiovascular and renal complications in this vulnerable population. Further research is needed to establish personalized strategies for CKM syndrome prevention and treatment in cancer patients.

The coronavirus disease-2019 (COVID-19) is a highly transmissible viral illness caused by SARS-CoV-2, which has been defined by the World Health Organization as a pandemic, considering its remarkable transmission speed worldwide. SARS-CoV-2 interacts with angiotensin-converting enzyme 2 and TMPRSS2, which is a serine protease both expressed in lungs, the gastro-intestinal tract, and cardiac myocytes. Patients with COVID-19 experienced adverse cardiac events (hypertension, venous thromboembolism, arrhythmia, myocardial injury, fulminant myocarditis), and patients with previous cardiovascular disease have a higher risk of death. Cancer patients are extremely vulnerable with a high risk of viral infection and more negative prognosis than healthy people, and the magnitude of effects depends on the type of cancer, recent chemotherapy, radiotherapy, or surgery and other concomitant comorbidities (diabetes, cardiovascular diseases, metabolic syndrome). Patients with active cancer or those treated with cardiotoxic therapies may have heart damages exacerbated by SARS-CoV-2 infection than non-cancer patients. We highlight the cardiovascular side effects of COVID-19 focusing on the main outcomes in cancer patients in updated perspective and retrospective studies. We focus on the main cardio-metabolic risk factors in non-cancer and cancer patients and provide recommendations aimed to reduce cardiovascular events, morbidity, and mortality.

Cancer patients, especially long cancer survivors, are exposed to several cardio-metabolic diseases, including diabetes, heart failure, and atherosclerosis, which increase their risk of cardiovascular mortality. Therapy with glucagon-like peptide 1 (GLP1) receptor agonists demonstrated several beneficial cardiovascular effects, including atherosclerosis and heart failure prevention. Cardiovascular outcome trials (CVOTs) suggest that GLP-1 RA could exert cardiorenal benefits and systemic anti-inflammatory effects in patients with type-2 diabetes through the activation of cAMP and PI3K/AkT pathways and the inhibition of NLRP-3 and MyD88. In this narrative review, we highlight the biochemical properties of GLP-1 RA through a deep analysis of the clinical and preclinical evidence of the primary prevention of cardiomyopathies. The overall picture of this review encourages the study of GLP-1 RA in cancer patients with type-2 diabetes, as a potential primary prevention strategy against heart failure and atherosclerosis.

Anthracycline-induced cardiomyopathies and sarcopenia are frequently seen in cancer patients, affecting their overall survival and quality of life; therefore, new cardioprotective and anti-sarcopenic strategies are needed. Vericiguat is a new oral guanylate cyclase activator that reduces heart failure hospitalizations or cardiovascular death. This study highlighted the potential cardioprotective and anti-sarcopenic properties of vericiguat during anthracycline therapy. Human cardiomyocytes and primary skeletal muscle cells were exposed to doxorubicin (DOXO) with or without a pre-treatment with vericiguat. Mitochondrial cell viability, LDH, and Cytochrome C release were performed to study cytoprotective properties. Intracellular Ca⁺⁺ content, TUNEL assay, cGMP, NLRP-3, Myd-88, and cytokine intracellular levels were quantified through colorimetric and selective ELISA methods. Vericiguat exerts significant cytoprotective and anti-apoptotic effects during exposure to doxorubicin. A drastic increase in cGMP expression and reduction in NLRP-3, MyD-88 levels were also seen in Vericiguat-DOXO groups vs. DOXO groups (p < 0.001) in both cardiomyocytes and human muscle cells. GCa vericiguat reduces cytokines and chemokines involved in heart failure and sarcopenia. The findings that emerged from this study could provide the rationale for further preclinical and clinical investigations aimed at reducing anthracycline cardiotoxicity and sarcopenia in cancer patients.