Cardiometabolic Risk, Part 2: Indirect Cardiotoxicity in Cancer Survivors – The Emerging Role of Metabolic Syndrome

Felicetti, Francesco; Brignardello, Enrico; Nuver, Janine

doi:10.1159/000519414

Cited by 3 publications

(1 citation statement)

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“…Cardiometabolic syndrome (CMS) (Reaven, 2011) has a complex pathology, consisting primarily of metabolic disorders, with insulin resistance (IR) standing as the underlying mechanism. Several risk factors have correlated CMS with CTR-CVT, although the biology of this correlation is still obscure (Felicetti et al, 2021). Moreover, it is already presented that in the presence of CMS, classical cardiotoxic anticancer treatments, such as doxorubicin, exert exacerbated cardiotoxicity, probably due to enhanced cardiac lipid peroxidation and lower expression of cardiac P-glycoprotein-1 (P-gp-1) (Ogonowski et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Implications and hidden toxicity of cardiometabolic syndrome and early‐stage heart failure in carfilzomib‐induced cardiotoxicity

Efentakis,

Varela,

Lamprou

et al. 2024

British J Pharmacology

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Background and PurposeCancer therapy‐related cardiovascular adverse events (CAEs) in presence of comorbidities, are in the spotlight of the cardio‐oncology guidelines. Carfilzomib (Cfz), indicated for relapsed/refractory multiple myeloma (MM), presents with serious CAEs. MM is often accompanied with co‐existing comorbidities. However, Cfz use in MM patients with cardiometabolic syndrome (CMS) or in heart failure with reduced ejection fraction (HFrEF), is questionable.Experimental ApproachApoE−/− and C57BL6/J male mice received 14 weeks Western Diet (WD) (CMS models). C57BL6/J male mice underwent permanent LAD ligation for 14 days (early‐stage HFrEF model). CMS‐ and HFrEF‐burdened mice received Cfz for two consecutive or six alternate days. Daily metformin and atorvastatin administrations were performed additionally to Cfz, as prophylactic interventions. Mice underwent echocardiography, while proteasome activity, biochemical and molecular analyses were conducted.Key ResultsCMS did not exacerbate Cfz left ventricular (LV) dysfunction, whereas Cfz led to metabolic complications in both CMS models. Cfz induced autophagy and Ca2+ homeostasis dysregulation, whereas metformin and atorvastatin prevented Cfz‐mediated LV dysfunction and molecular deficits in the CMS‐burdened myocardium. Early‐stage HFrEF led to depressed LV function and increased protein phosphatase 2A (PP2A) activity. Cfz further increased myocardial PP2A activity, inflammation and Ca2+‐cycling dysregulation. Metformin co‐administration exerted an anti‐inflammatory potential on the myocardium without improving LV function.Conclusion and ImplicationsCMS and HFrEF seem to exacerbate Cfz‐induced CAEs, by presenting metabolism‐related hidden toxicity and PP2A‐related cardiac inflammation, respectively. Metformin retains its prophylactic potential in the presence of CMS, while mitigating inflammation and Ca2+ signalling dysregulation in the HFrEF myocardium.

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Section: Introductionmentioning

confidence: 99%