Numerous studies have shown that chemotherapy-induced cardiotoxicity can occur through various mechanisms 1,2,3,4.
Some of these include direct cellular toxicity, leading to both diastolic and systolic dysfunction, effects on the coagulation system resulting in ischemic events and vascular toxicity, arrhythmogenic effects, hypertensive effects, and even myocardial inflammation or heart failure. Understanding these mechanisms is crucial in developing strategies to minimize the risk of cardiotoxicity during cancer treatment.
Doxorubicin is a chemotherapeutic agent used in various cancers treatment (breast, lung, bladder, ovary, stomatch, etc.) and known to induce cardiotoxic effects.
In a recent study5, Sharon A. George et al, from the Northwestern University (Chicago, Illinois, United States), highlighted that male and female mice have different responses to Doxorubicin, and that deleting specific genes in heart cells affected how the mice responded to Doxorubicin.
Mice cardiac function was assessed by echocardiography and electrocardiography (ecgTUNNEL) and fibrosis by Picrosirius red staining. Expression and activation of signaling proteins and inflammatory markers were measured by Western blot, phosphorylation array, and chemokine/cytokine array.
The researchers discovered that p38β mitogen-activated protein kinase plays a crucial role in protecting female mice against DOX-induced cardiac injury. Interestingly, male mice exhibited a different activation pattern in their intracellular signaling pathways, and deleting p38α had a mild cardioprotective effects.
These findings shed light on the importance of understanding gender-specific differences in heart health and provide a potential target for future cancer therapies.
Cyclophosphamide (CYC) is another chemotherapeutic agent mainly used to treat breast cancer, lung cancer, leukemia, lymphoma and myeloma.
A study conducted by Nancy S. Younis6 at King Faisal University, shown that Wistar rats treated with a natural compound called β-caryophyllene (BCP) after Cyclophosphamide exposure experienced enhanced antioxidative capacity, reduced inflammation and apoptosis responses, and improved cardiac markers.
Using the ecgTUNNEL platform, uninterrupted ECG recordings were obtained and analyzed using ECG analyzer software. The changes in P-R, R-R, Q-T, R wave amplitude, and heart rate HR (beat/min) were determined using IOX software. CYC administration caused numerous ECG abnormalities, including an increase in P-R, R-R, Q-T intervals, as well as a decrease in the R-wave amplitude and heart rate, thus revealing abnormal cardiac function. The researchers showed that BCP can shield protect cardiac tissues against CYC-induced cardiotoxicity by intensifying antioxidant enzyme activity and mitigating inflammation. This shielding manifested itself in improved cardiac activity, as reflected in the electrophysiology outcomes in a dose-dependent manner:
Figure 2: Effects of treatment with β-caryophyllene (BCP) for 14 days on cyclophosphamide (CYC) induced cardiac in body weights and heart to body weights ratio in rat. Younis, Nancy S. 2022. “β-Caryophyllene Ameliorates Cyclophosphamide Induced Cardiac Injury: The Association of TLR4/NFκB and Nrf2/HO1/NQO1 Pathways” Journal of Cardiovascular Development and Disease 9, no. 5: 133. https://doi.org/10.3390/jcdd9050133
Figure 3: Effects of treatment with β-caryophyllene (BCP) for 14 days on cyclophosphamide (CYC) induced cardiac injury on ECG traces. Younis, Nancy S. 2022. “β-Caryophyllene Ameliorates Cyclophosphamide Induced Cardiac Injury: The Association of TLR4/NFκB and Nrf2/HO1/NQO1 Pathways” Journal of Cardiovascular Development and Disease 9, no. 5: 133. https://doi.org/10.3390/jcdd9050133
This research not only offers hope for long-term health of patients battling cancer but also highlights the potential of natural compounds in improving the safety and efficacy of cancer treatments.
Cardiotoxicity is frequently seen in cancer patients who have received a therapy. However, the potential effect of cancer itself on cardiac function have yet to be fully explored.
Ana Gams et al investigated the cardiac function in mice with pancreatic and liver cancers, by recording electrocardiograms in conscious subjects using non‐invasive emka TECHNOLOGIES ecgTUNNEL7.
Monitoring mouse ECGs demonstrated a potential correlation between tumor burden and Heart Rate Variability, particularly in female mice. This study revealed intriguing sex-specific disparities in cancer-related Heart Rate modulation, as female mice exhibit a lower median Heart Rate and higher Heart Rate Variability (HRV). These findings strongly suggest that HRV could potentially serve as a valuable cancer biomarker, although the influence of sex differences must be taken into consideration.
5. Anthracycline cardiotoxicity is exacerbated by global p38β genetic ablation in a sexually dimorphic manner but unaltered by cardiomyocyte-specific p38α loss. Sharon A. George et al. American Physiology Society. 2023
7. Gams A, Nevarez A, Perkail S, Venegas A, George SA, Efimova T, Efimov IR. Evidence of sex differences in cancer-related cardiac complications in mouse models of pancreatic and liver cancer. Physiol Rep. 2023 Apr.
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