ABSTRACT

The number of patients at the intersection of cancer and cardiovascular disease (CVD) is increasing, reflecting ageing global populations, rising burden of shared cardiometabolic risk factors, and improved cancer survival. Many cancer treatments carry a risk of cardiotoxicity. Baseline cardiovascular risk assessment is recommended in all patients with cancer and requires consideration of individual patient risk and the cardiotoxicity profile of proposed anticancer therapies. Patients with pre-existing CVD are potentially at high or very high risk of cancer-therapy related cardiovascular toxicity. The detection of pre-existing CVD should prompt cardiac optimisation and planning of surveillance during cancer treatment. In patients with severe CVD, the risk of certain cancer therapies may be prohibitively high. Such decisions require multidisciplinary discussion with consideration of alternative anti-cancer therapies, risk-benefit assessment, and patient preference. Current practice is primarily guided by expert opinion and data from select clinical cohorts. There is need for development of a stronger evidence base to guide clinical practice in cardio-oncology. The establishment of multicentre international registries and national-level healthcare data linkage projects are important steps towards facilitating enrichment of cardio-oncology research programmes. In this narrative review, we consider epidemiological trends of cancer and CVD comorbidities and the impact of their co-occurrence on clinical outcomes, current approach to supporting cancer patients with pre-existing CVD and gaps in existing knowledge.

PMID:37321830 | DOI:10.1136/heartjnl-2022-321324

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PubMed articles on: Cardio-Oncology

Amentoflavone mitigates doxorubicin-induced cardiotoxicity by suppressing cardiomyocyte pyroptosis and inflammation through inhibition of the STING/NLRP3 signalling pathway

Phytomedicine. 2023 Aug;117:154922. doi: 10.1016/j.phymed.2023.154922. Epub 2023 Jun 10.

ABSTRACT

BACKGROUND: Doxorubicin (DOX) is a potent anticancer chemotherapeutic agent whose clinical application is substantially constrained by its cardiotoxicity. The pathophysiology of DOX-induced cardiotoxicity manifests as cardiomyocyte pyroptosis and inflammation. Amentoflavone (AMF) is a naturally occurring biflavone possessing anti-pyroptotic and anti-inflammatory properties. However, the mechanism through which AMF alleviates DOX-induced cardiotoxicity remains undetermined.

PURPOSE: This study aimed at investigating the role of AMF in alleviating DOX-induced cardiotoxicity.

STUDY DESIGN AND METHODS: To assess the in vivo effect of AMF, DOX was intraperitoneally administered into a mouse model to induce cardiotoxicity. To elucidate the underlying mechanisms, the activities of STING/NLRP3 were quantified using the NLRP3 agonist nigericin and the STING agonist amidobenzimidazole (ABZI). Primary cardiomyocytes isolated from neonatal Sprague-Dawley rats were treated with saline (vehicle) or DOX with or without AMF and/or ABZI. The echocardiogram, haemodynamics, cardiac injury markers, heart/body weight ratio, and pathological alterations were monitored; the STING/NLRP3 pathway-associated proteins were detected by western blot and cardiomyocyte pyroptosis was analysed by immunofluorescence staining of cleaved N-terminal GSDMD and scanning electron microscopy. Furthermore, we evaluated the potential of AMF in compromising the anticancer effects of DOX in human breast cancer cell lines.

RESULTS: AMF substantially alleviated cardiac dysfunction and reduced heart/body weight ratio and myocardial damage in mice models of DOX-induced cardiotoxicity. AMF effectively suppressed DOX-mediated upregulation of IL-1β, IL-18, TNF-α, and pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and cleaved N-terminal GSDMD. The levels of apoptosis-related proteins, namely Bax, cleaved caspase-3, and BCL-2 were not affected. In addition, AMF inhibited STING phosphorylation in DOX-affected hearts. Intriguingly, the administration of nigericin or ABZI dampened the cardioprotective effects of AMF. The in vitro anti-pyroptotic effect of AMF was demonstrated in attenuating the DOX-induced reduction in cardiomyocyte cell viability, upregulation of cleaved N-terminal GSDMD, and pyroptotic morphology alteration at the microstructural level. AMF exhibited a synergistic effect with DOX to reduce the viability of human breast cancer cells.

CONCLUSION: AMF alleviates DOX-induced cardiotoxicity by suppressing cardiomyocyte pyroptosis and inflammation via inhibition of the STING/NLRP3 signalling pathway, thereby validating its efficacy as a cardioprotective agent.

PMID:37321078 | DOI:10.1016/j.phymed.2023.154922

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PubMed articles on: Cardio-Oncology

Doxorubicin Interaction with Lipid Monolayers Leads to Decreased Membrane Stiffness when Experiencing Compression-Expansion Dynamics

Langmuir. 2023 Jun 15. doi: 10.1021/acs.langmuir.3c00250. Online ahead of print.

ABSTRACT

Physical membrane models permit to study and quantify the interactions of many external molecules with monitored and simplified systems. In this work, we have constructed artificial Langmuir single-lipid monolayers with dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylserine (DPPS), or sphingomyelin to resemble the main lipid components of the mammalian cell membranes. We determined the collapse pressure, minimum area per molecule, and maximum compression modulus (Cs-1) from surface pressure measurements in a Langmuir trough. Also, from compression/expansion isotherms, we estimated the viscoelastic properties of the monolayers. With this model, we explored the membrane molecular mechanism of toxicity of the well-known anticancer drug doxorubicin, with particular emphasis in cardiotoxicity. The results showed that doxorubicin intercalates mainly between DPPS and sphingomyelin, and less between DPPE, inducing a change in the Cs-1 of up to 34% for DPPS. The isotherm experiments suggested that doxorubicin had little effect on DPPC, partially solubilized DPPS lipids toward the bulk of the subphase, and caused a slight or large expansion in the DPPE and sphingomyelin monolayers, respectively. Furthermore, the dynamic viscoelasticity of the DPPE and DPPS membranes was greatly reduced (by 43 and 23%, respectively), while the reduction amounted only to 12% for sphingomyelin and DPPC models. In conclusion, doxorubicin intercalates into the DPPS, DPPE, and sphingomyelin, but not into the DPPC, membrane lipids, inducing a structural distortion that leads to decreased membrane stiffness and reduced compressibility modulus. These alterations may constitute a novel, early step in explaining the doxorubicin mechanism of action in mammalian cancer cells or its toxicity in non-cancer cells, with relevance to explain its cardiotoxicity.

PMID:37320858 | DOI:10.1021/acs.langmuir.3c00250

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PubMed articles on: Cardio-Oncology

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis

Circulation. 2023 Jun 15. doi: 10.1161/CIRCULATIONAHA.123.062405. Online ahead of print.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established.

METHODS: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne: Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry.

RESULTS: Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001P<0.001)P<0.001),P<0.001),

CONCLUSIONS: cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32

PMID:37317858 | DOI:10.1161/CIRCULATIONAHA.123.062405

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PubMed articles on: Cardio-Oncology

Comparing Renin-Angiotensin-Aldosterone Blockade Regimens for Long-Term Chemotherapy-Related Cardiac Dysfunction: A Network Meta-Analysis

Cardiovasc Drugs Ther. 2023 Jun 14. doi: 10.1007/s10557-023-07457-w. Online ahead of print.