ABSTRACT

BACKGROUND Cardiotoxicity from radiotherapy and anti-cancer therapies have been reported in patients with breast cancer. This study aimed to investigate the early echocardiography and ECG changes following radiotherapy in 68 patients ages 30-78 years with stages II-III HER2-positive breast cancer treated with anthracycline-based chemotherapy with or without trastuzumab-based therapy from 2015 to 2021. MATERIAL AND METHODS We analyzed data of 68 breast cancer patients aged 30-78 years, predominantly in AJCC stages II-III (61) and HER2-positive (58), treated and monitored from 2015 to 2021. Cardiac function was assessed using echo- and electrocardiography. We employed univariate logistic models to gauge associations between pre-existing cardiac conditions, treatment modalities, and changes in cardiac function. RESULTS A decrease in the left ventricle ejection fraction (EF) by >5% was associated with heart doses >49.3 Gy and with maximum and average doses to the left anterior descending artery (LAD) exceeding 46.9 Gy and 32.7 Gy, respectively. An EF drop of ≥10% was correlated with anti-HER2 therapy, pre-existing ECG changes, and the onset of conditions in the left ventricle, major vessels, and valves. Conditions were exacerbated in patients with prior echocardiographic abnormalities, while some emerged concurrent with the EF decline. CONCLUSIONS This research emphasizes the importance of personalized heart monitoring and care for breast cancer patients undergoing multimodal therapies. Significant and potentially irreversible EF declines can result from radiation and anti-HER2 treatments.

PMID:37772333 | DOI:10.12659/MSM.941754

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PubMed articles on: Cardio-Oncology

Sheng-Mai-Yin inhibits doxorubicin-induced ferroptosis and cardiotoxicity through regulation of Hmox1

Aging (Albany NY). 2023 Sep 28;15. doi: 10.18632/aging.205062. Online ahead of print.

ABSTRACT

Doxorubicin (DOX) is a potent chemotherapeutic drug used for treating various cancers. However, its clinical use is limited due to its severe cardiotoxicity, which often results in high mortality rates. Sheng-Mai-Yin (SMY), a Traditional Chinese medicine (TCM) prescription, has been reported to exert a cardioprotective effect in various cardiovascular diseases, including DOX-induced cardiotoxicity (DIC). This study aimed to provide novel insights into the underlying cardioprotective mechanism of SMY. SMY, composed of Codonopsis pilosula (Franch.), Ophiopogon japonicus (Thunb.), and Schisandra chinensis (Turcz.) at a ratio of 3:2:1, was intragastrically administered to male C57BL/6 mice for five days prior to the intraperitoneal injection of mitoTEMPO. One day later, DOX was intraperitoneally injected. Hematoxylin-eosin staining and Sirius red staining were carried out to estimate the pharmacological effect of SMY on cardiotoxicity. Mitochondrial function and ferroptosis biomarkers were also examined. AAV was utilized to overexpress Hmox1 to confirm whether Hmox1-mediated ferroptosis is associated with the cardioprotective effect of SMY on DOX-induced cardiotoxicity. The findings revealed that SMY therapy reduced the number of damaged cardiomyocytes. SMY therapy also reversed the inductions of cardiac MDA, serum MDA, LDH, and CK-MB contents, which dramatically decreased nonheme iron levels. In the meantime, SMY corrected the changes to ferroptosis indices brought on by DOX stimulation. Additionally, Hmox1 overexpression prevented SMY's ability to reverse cardiotoxicity. Our results showed that SMY effectively restrained lipid oxidation, reduced iron overload, and inhibited DOX-induced ferroptosis and cardiotoxicity, possibly via the mediation of Hmox1.

PMID:37770231 | DOI:10.18632/aging.205062

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PubMed articles on: Cardio-Oncology

Osthole protects H9c2 cardiomyocytes against trastuzumab-induced damage by enhancing autophagy through the p38MAPK/mTOR signaling pathway

Toxicol In Vitro. 2023 Sep 26:105704. doi: 10.1016/j.tiv.2023.105704. Online ahead of print.

ABSTRACT

Trastuzumab (TRZ) is a novel targeted anti-tumor agent that significantly improve the survival of patients with human epidermal growth factor receptor (HER2) positive breast cancer. However, its clinical application is limited due to the side effects of cardiotoxicity. Osthol (OST), a coumarin derivative isolated from Cnidium monnieri (L.) Cusson, has previously demonstrated cardioprotective effects. The aim of this study was to observe the protective effect of OST on TRZ-induced cardiomyocytes damage and to explore its potential mechanism. The results showed that OST pretreatment could significantly inhibit TRZ-induced cardiomyocytes damage, and markedly increase the ratio of LC3II/I and Beclin-1 protein expression, and reduce the protein expression of p62. OST pretreatment significantly attenuated oxidative stress and apoptosis induced by TRZ, as evidenced by reducing intracellular ROS level, Bax/Bcl-2 ratio, and Caspase-3 protein expression. Additionally, OST markedly increased the phosphorylation level of p38MAPK and decreased mTOR phosphorylation level. However, the effects of OST on enhancing autophagy, reducing oxidative stress, apoptosis and the phosphorylation level of mTOR were reversed after the addition of 3-MA or SB203580. Molecular docking results indicated that OST exerted a good binding ability with p38MAPK protein. Our findings suggested that OST could protect TRZ-induced cardiomyocytes damage by enhancing autophagy via the p38MAPK/mTOR signaling pathway.

PMID:37769856 | DOI:10.1016/j.tiv.2023.105704

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PubMed articles on: Cardio-Oncology

Hormone therapy, cardio-metabolic profile, and cardiotoxicity. Still a dark side of cardio-oncology - Part 2: Prostate cancer

G Ital Cardiol (Rome). 2023 Oct;24(10):781-791. doi: 10.1714/4100.40978.

ABSTRACT

Hormone therapies (HTs) with anti-androgenic properties are a cornerstone for the treatment of prostate cancer (PC) and have significantly improved the survival of patients, though exposing them to a higher risk of cardiovascular diseases (CVDs), which represent a major cause of morbidity and mortality. This occurs due to the high average age of patients undergoing HT for PC, an age group in which CVDs have a high prevalence and incidence, and due to the type and duration of HTs that are increasingly effective but at the same time more aggressive towards cardiovascular health. Recent evidence from the real world suggests, however, that the cardiometabolic risk is widely underestimated and undertreated with significant impact also on the oncological prognosis. In the light of the results of the PRONOUNCE study, in this review it is emphasized the need for a multidisciplinary management of patients with PC who are candidate for or treated with HT by implementing a personalized treatment program in accordance with the current European guidelines on CVD prevention.

PMID:37767830 | DOI:10.1714/4100.40978

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PubMed articles on: Cardio-Oncology

Cardiac safety assessment of a novel recombinant bispecific antibody targeting the ether-à-go-go related gene 1 (hERG1)-β1 integrin macromolecular complex

Front Pharmacol. 2023 Sep 12;14:1237431. doi: 10.3389/fphar.2023.1237431. eCollection 2023.

ABSTRACT

Introduction: In the last decades, mounting evidence has pointed out the human ether-á-go-go-related gene (hERG1) potassium channel as a novel biomarker in human cancers. However, hERG1 sustains the cardiac repolarizing current IKr and its blockade can induce a prolonged QT interval at the ECG, which increases the risk of life-threatening arrhythmias. This represents a major hindrance for targeting hERG1 for antineoplastic therapeutic purposes. Based on our discovery that hERG1 resides in a macromolecular complex with the β1 subunit of integrin adhesion receptors only in tumors, and not in the heart, we generated (and patented WO2019/015936) a novel engineered, single chain, bispecific antibody in the format of a diabody (scDb-hERG1-β1). This antibody has been proven to target with high affinity the hERG1/β1 integrin complex and to exert a good antineoplastic activity in preclinical mouse models. Methods: In the present study, we evaluated the cardiac safety of the scDb-hERG1-β1, determining the action potential duration (APD) of human cardiomyocytes, either atrial (from valve-disease patients) or ventricular (from aortic stenosis patients). Cardiac cells were incubated in vitro with i) the scDb-hERG1-β1, ii) the full length anti-hERG1 monoclonal antibody (mAb-hERG1) and iii) its single chain Fragment variable derivative (scFv-hERG1), from which the scDb-hERG1-β1 was assembled. All the tests were performed before and after treatment with the specific hERG1 blocker E4031. In addition, we have performed preliminary experiments, analyzing the effects of the scDb-hERG1/β1 in vivo measuring the QT interval length of the surface ECG after its injection intravenously in farm-pigs. Results: The scDb-hERG1-β1 did not produce any lengthening of APD compared to control (vehicle) conditions, either in atrial or ventricular cardiomyocytes, whereas both the hERG1-mAb and the scFv-hERG1 produced a significant APD prolongation. The addition of E4031 further prolonged APD. The scDb-hERG1-β1 did not produce any alterations of the QT (and QTc) interval values, once injected intravenously in farm pigs. Discussion: Overall, the above evidences plead for the cardiac safety of the scDb-hERG1-β1, suggesting that an application of this antibody for anti-cancer therapy will be untainted by cardiotoxicity.

PMID:37767396 | PMC:PMC10520717 | DOI:10.3389/fphar.2023.1237431

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PubMed articles on: Cardio-Oncology

Usefulness of Longitudinal Strain to Assess Cancer Therapy-Related Cardiac Dysfunction and Immune Checkpoint Inhibitor-Induced Myocarditis

Pharmaceuticals (Basel). 2023 Sep 14;16(9):1297. doi: 10.3390/ph16091297.

ABSTRACT

Longitudinal strain (LS) measured by echocardiography has been reported to be useful not only for the diagnosis and risk stratification of various cardiac diseases, but also in cardio-oncology. Most previous studies have been conducted on patients undergoing treatment with anthracyclines and human epidermal growth factor receptor 2-targeted therapies. Existing guidelines recommend that global LS (GLS) should be measured before and after the administration of cancer drugs. This recommendation is based on many reports showing that a decline in GLS is indicative of early or mild cancer therapy-related cardiac dysfunction. The main purpose of this article is to provide insight into the importance of LS in patients undergoing cancer treatment and highlight the role of LS evaluation in patients undergoing immune checkpoint inhibitor (ICI) treatment, which is being used with increasing frequency. Among cancer drug therapies, immune checkpoint inhibitors (ICIs) have an important place in cancer treatment and are used for the treatment of many types of cancer. Although the efficacy of ICIs in cancer treatment has been reported, immune-related adverse events (irAEs) have also been reported. Among these irAEs, cardiovascular complications, although rare, are recognized as important adverse events that may result in ICI treatment discontinuation. Myocarditis is one severe adverse event associated with ICIs, and it is important to standardize diagnostic and therapeutic approaches to it. Several studies have reported a relationship between LS and cardiac complications associated with ICIs which may contribute to the early diagnosis of ICI-induced cardiac complications.

PMID:37765105 | PMC:PMC10535915 | DOI:10.3390/ph16091297

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PubMed articles on: Cardio-Oncology

Hyperhomocysteinaemia Promotes Doxorubicin-Induced Cardiotoxicity in Mice

Pharmaceuticals (Basel). 2023 Aug 28;16(9):1212. doi: 10.3390/ph16091212.

ABSTRACT

Doxorubicin, a widely used chemotherapeutic drug in clinical oncology, causes a series of cardiac side effects referred to as doxorubicin-induced cardiotoxicity. Hyperhomocysteinaemia is an independent risk factor for multiple cardiovascular diseases. However, whether hyperhomocysteinaemia contributes to doxorubicin-induced cardiotoxicity is currently unknown. In this study, we explored the pathogenic effects of hyperhomocysteinaemia induced by dietary methionine supplementation (2% wt/wt in rodent chow) in a mouse model of doxorubicin-induced cardiotoxicity. Our data showed that methionine supplementation doubled serum homocysteine levels, inducing mild hyperhomocysteinaemia. Doxorubicin at a cumulative dosage of 25 mg/kg body weight led to significant weight loss and severe cardiac dysfunction, which were further exacerbated by methionine-induced mild hyperhomocysteinaemia. Doxorubicin-induced cardiac atrophy, cytoplasmic vacuolisation, myofibrillar disarray and loss, as well as cardiac fibrosis, were also exacerbated by methionine-induced mild hyperhomocysteinaemia. Additional folic acid supplementation (0.006% wt/wt) prevented methionine-induced hyperhomocysteinaemia and inhibited hyperhomocysteinaemia-aggravated cardiac dysfunction and cardiomyopathy. In particular, hyperhomocysteinaemia increased both serum and cardiac oxidative stress, which could all be inhibited by folic acid supplementation. Therefore, we demonstrated for the first time that hyperhomocysteinaemia could exacerbate doxorubicin-induced cardiotoxicity in mice, and the pathogenic effects of hyperhomocysteinaemia might at least partially correlate with increased oxidative stress and could be prevented by folic acid supplementation. Our study provides preliminary experimental evidence for the assessment of hyperhomocysteinaemia as a potential risk factor for chemotherapy-induced cardiotoxicity in cancer patients.

PMID:37765020 | PMC:PMC10534320 | DOI:10.3390/ph16091212

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PubMed articles on: Cardio-Oncology

Creatine and Resistance Training: A Combined Approach to Attenuate Doxorubicin-Induced Cardiotoxicity

Nutrients. 2023 Sep 19;15(18):4048. doi: 10.3390/nu15184048.