The sGCa Vericiguat Exhibit Cardioprotective and Anti-Sarcopenic Effects through NLRP-3 Pathways: Potential Benefits for Anthracycline-Treated Cancer Patients.

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.

PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology.

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.

Combination of Spirulina platensis, Ganoderma lucidum and Moringa oleifera Improves Cardiac Functions and Reduces Pro-Inflammatory Biomarkers in Preclinical Models of Short-Term Doxorubicin-Mediated Cardiotoxicity: New Frontiers in Cardioncology?

Anthracyclines are essential adjuvant therapies for a variety of cancers, particularly breast, gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Spirulina, Reishi (Ganoderma lucidum) and Moringa are three nutraceuticals with anti-inflammatory effects that are currently used in cancer patients as complementary and alternative medicines to improve quality of life and fatigue. We hypothesize that the nutraceutical combination of Spirulina, Reishi and Moringa (Singo) could reduce inflammation and cardiotoxicity induced by anthracyclines. Female C57Bl/6 mice were untreated (Sham, n = 6) or treated for 7 days with short-term doxorubicin (DOXO, n = 6) or Singo (Singo, n = 6), or pre-treated with Singo for 3 days and associated with DOXO for remaining 7 days (DOXO−Singo, n = 6). The ejection fraction and radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100, Fujifilm, Tokyo, Japan). The myocardial expressions of NLRP3, DAMPs (galectin-3 and calgranulin S100) and 13 cytokines were quantified through selective mouse ELISA methods. Myocardial fibrosis, necrosis and hypertrophy were analyzed through immunohistochemistry (IHC). Human cardiomyocytes were exposed to DOXO (200 nM) alone or in combination with Singo (at 10, 25 and 50 µg/mL) for 24 and 48 h. Cell viability and inflammation studies were also performed. In preclinical models, Singo significantly improved ejection fraction and fractional shortening. Reduced expressions of myocardial NLRP3 and NF-kB levels in cardiac tissues were seen in DOXO−Singo mice vs. DOXO (p < 0.05). The myocardial levels of calgranulin S100 and galectin-3 were strongly reduced in DOXO−Singo mice vs. DOXO (p < 0.05). Immunohistochemistry analysis indicates that Singo reduces fibrosis and hypertrophy in the myocardial tissues of mice during exposure to DOXO. In conclusion, in the preclinical model of DOXO-induced cardiotoxicity, Singo is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis.

Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production.

The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab. Trastuzumab cardiotoxicity was accompanied by elevations in natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated with co-treatment with ranolazine. Trastuzumab also increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Interestingly, Neonatal Rat Ventricular Myocytes (NRVMs), labeled with MitoTracker Red and treated with trastuzumab, showed only a small increase in ROS compared to baseline conditions. We then stressed trastuzumab-treated cells with the beta-agonist isoproterenol to increase workload, and we observed a significant increase of probe fluorescence, compared with cells treated with isoproterenol alone, reflecting induction of oxidative stress. These effects were blunted by ranolazine, supporting a role for INa inhibition in the regulation of redox balance also in trastuzumab cardiotoxicity.

Antineoplastic-related cardiotoxicity, morphofunctional aspects in a murine model: contribution of the new tool 2D-speckle tracking.

OBJECTIVE: Considering that global left ventricular systolic radial strain is a sensitive technique for the early detection of left ventricular dysfunction due to antineoplastics and the analysis of segmental myocardial contractility, we evaluated this technique for early detection of trastuzumab-related cardiotoxicity by comparing it with cardiac structural damage. METHODS: Groups of six mice were injected with trastuzumab or doxorubicin, used either as single agents or in combination. Cardiac function was evaluated by transthoracic echocardiography measurements before and after treatment for 2 or 7 days, by using a Vevo 2100 high-resolution imaging system. After echocardiography, mice were euthanized, and hearts were processed for histological evaluations, such as cardiac fibrosis, apoptosis, capillary density, and inflammatory response. RESULTS: Trastuzumab-related cardiotoxicity was detected early by 2D strain imaging. Radial strain was reduced after 2 days in mice treated with trastuzumab alone (21.2%±8.0% vs 40.5%±4.8% sham; P<0.01). Similarly, trastuzumab was found to induce apoptosis, capillary density reduction, and inflammatory response in cardiac tissue after 2 days of treatment, in a fashion similar to doxorubicin. On the contrary, fractional shortening reduction and cardiac fibrosis were observed only after 7 days of trastuzumab treatment, in contrast to doxorubicin treatment which induced early fibrosis and fractional shortening reduction. CONCLUSION: The reduction of left ventricular systolic strain after 2 days of trastuzumab treatment may indicate early myocardial functional damage before the reduction in left ventricular ejection fraction and this early dysfunction is well correlated with structural myocardial damage, such as apoptosis and inflammatory response. Fractional shortening reduction after 7 days of trastuzumab treatment is related to fibrosis in cardiac tissue.

Trastuzumab and target-therapy side effects: Is still valid to differentiate anthracycline Type I from Type II cardiomyopathies?

The improvement in cancer therapy and the increasing number of long term survivors unearth the issue of cardiovascular side effects of anticancer treatments. As a paradox in cancer survivors, delayed cardiotoxicity has emerged as a significant problem. Two categories of cardiotoxic side effects of antineoplastic drugs have been previously proposed: Type I cardiotoxicity, defined as permanent cardiotoxicity, is usually caused by anthracyclines; Type II cardiotoxicity, considered as reversible cardiotoxicity, has been mainly related to monoclonal antibodies. The cardiotoxicity of antibodies has been associated to trastuzumab, a humanized anti-ErbB2 monoclonal antibody currently in clinical use for the therapy of breast carcinomas, which induces cardiac dysfunction when used in monotherapy, or in combination with anthracyclines. Furthermore, recent retrospective studies have shown an increased incidence of heart failure and/or cardiomyopathy in patients treated with trastuzumab, that can persist many years after the conclusion of the therapy, thus suggesting that the side toxic effects are not always reversible as it was initially proposed. On the other hand, early detection and prompt therapy of anthracycline associated cardiotoxicity can lead to substantial recovery of cardiac function. On the basis of these observations, we propose to find a new different classification for cardiotoxic side effects of drugs used in cancer therapy.

The emerging issue of cardiac dysfunction induced by antineoplastic angiogenesis inhibitors.

Left ventricular dysfunction from anticancer drugs has emerged as a relevant problem in the clinical and scientific communities. Anthracycline toxicity has always been the most relevant, but with the increasing use of biological targeted therapies in treatment protocols, with an increasing number of cancer survivors, new toxicities have been increasing in more recent years. Cardiomyopathy after ErbB2 inhibitors has been intensively studied. Another important class of biological anticancer drugs are vascular endothelial growth factor (VEGF) inhibitors. VEGF signalling is crucial for vascular growth, but it also has a major impact on myocardial function. Also, it is important to note that such angiogenesis inhibitors are multitargeted in most cases, and can produce a broad spectrum of cardiovascular side effects. Here we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of antiangiogenic drugs, and particular attention is drawn to LV dysfunction, discussing the assessment and management on the basis of the most recent cardio-oncological findings and heart failure guidelines.