Doxorubicin (DOX) is the most widely used anthracycline anticancer agent; however, its cardiotoxicity limits its clinical efficacy. Numerous studies have elucidated the mechanisms underlying DOX-induced cardiotoxicity, wherein apoptosis has been reported as the most common final step leading to cardiomyocyte death. However, in the past two years, the involvement of ferroptosis, a novel programmed cell death, has been proposed. The purpose of this review is to summarize the historical background that led to each form of cell death, focusing on DOX-induced cardiotoxicity and the molecular mechanisms that trigger each form of cell death. Furthermore, based on this understanding, possible therapeutic strategies to prevent DOX cardiotoxicity are outlined. DNA damage, oxidative stress, intracellular signaling, transcription factors, epigenetic regulators, autophagy, and metabolic inflammation are important factors in the molecular mechanisms of DOX-induced cardiomyocyte apoptosis. Conversely, the accumulation of lipid peroxides, iron ion accumulation, and decreased expression of glutathione and glutathione peroxidase 4 are important in ferroptosis. In both cascades, the mitochondria are an important site of DOX cardiotoxicity. The last part of this review focuses on the significance of the disruption of mitochondrial homeostasis in DOX cardiotoxicity.

The pathogenesis of heart failure with preserved ejection fraction (HFpEF) in obese diabetic patients has been implicated in metainflammation. Increased expression of inducible nitric oxide synthase (iNOS) and dysfunction of the unfolded protein response (UPR), especially inositol-requiring enzyme 1α-X-box binding protein 1 (IRE1α-Xbp1s) signaling in the heart, have been associated with HFpEF. We investigated the effect of imeglimin, a potential new treatment for type 2 diabetes, on the pathogenesis of HFpEF. We induced obesity, impaired glucose tolerance, and cardiac hypertrophy with fibrosis, fat accumulation, and diastolic dysfunction in wild-type mice with a high-fat diet (HFD) and the nitric oxide synthase (NOS) inhibitor l-NAME for 16 weeks. Treatment with imeglimin starting at 10 weeks not only improved their abnormal systemic glucose metabolism and visceral obesity but also their cardiac abnormalities. We found that imeglimin suppressed the upregulation of iNOS, and restored the expression of Xbp1s and the expression of the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1), which is responsible for the degradation of Forkhead box protein O1 (FoxO1), a direct transcriptional target of Xbp1s. It also suppressed the excessive transcriptional activity of FoxO1, which is located downstream of Xbp1s and is involved in the form development of HFpEF and cardiac adipogenesis. Imeglimin also restored the expression of Glutathione peroxidase 4 (GPX4), which protects cells against excess lipid peroxidation and governs a novel form of programmed cell death, called ferroptosis.

Systemic inflammation and hypercoagulopathy are known pathophysiological processes of coronavirus disease 2019 (COVID-19), particularly in patients with known cardiovascular disease or its risk factors (CVD). However, whether a cumulative assessment of these biomarkers at admission could contribute to the prediction of in-hospital outcomes remains unknown. The CLAVIS-COVID registry was a Japanese nationwide retrospective multicenter observational study, supported by the Japanese Circulation Society. Consecutive hospitalized patients with pre-existing CVD and COVID-19 were enrolled. Patients were stratified by the tertiles of CRP and D-dimer values at the time of admission. Multivariable Cox proportional hazard models were constructed. In 461 patients (65.5% male; median age, 70.0), the median baseline CRP and D-dimer was 58.3 (interquartile range, 18.2–116.0) mg/L and 1.5 (interquartile range, 0.8–3.0) mg/L, respectively. Overall, the in-hospital mortality rate was 16.5%, and the rates steadily increased in concordance with both CRP (5.0%, 15.0%, and 28.2%, respectively p < 0.001) and D-dimer values (6.8%, 19.6%, and 22.5%, respectively p = 0.001). Patients with the lowest tertiles of both biomarkers (CRP, 29.0 mg/L; D-dimer, 1.00 mg/L) were at extremely low risk of in-hospital mortality (0% until day 50, and 1.4% overall). Conversely, the elevation of both CRP and D-dimer levels was a significant predictor of in-hospital mortality (Hazard ratio, 2.97; 95% confidence interval, 1.57–5.60). A similar trend was observed when the biomarker threshold was set at a clinically relevant threshold. In conclusion, the combination of these abnormalities may provide a framework for rapid risk estimation for in-hospital COVID-19 patients with CVD.