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

02:05

PubMed articles on: Cardio-Oncology

When helping hurts: restricting cardiotoxicity of cancer therapeutics with accurate cardiovascular risk assessment works!

Eur J Prev Cardiol. 2023 Sep 25:zwad273. doi: 10.1093/eurjpc/zwad273. Online ahead of print.

NO ABSTRACT

PMID:37747453 | DOI:10.1093/eurjpc/zwad273

02:05

PubMed articles on: Cardio-Oncology

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer: The CVSS Study

J Am Heart Assoc. 2023 Oct 3;12(19):e030020. doi: 10.1161/JAHA.123.030020. Epub 2023 Sep 26.

ABSTRACT

Background The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. Methods and Results A total of 1002 CCSs (age range, 23-48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age- and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4-2.8) for HF stage A and 4.6 (95% CI, 4.1-5.1) for the composite of HF stage B to D in an age- and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (β, -4.30 [95% CI, -5.70 to -2.80]), soft tissue sarcoma (β, -1.60 [95% CI, -2.90 to -0.30]), and renal tumors (β, -1.60 [95% CI, -2.80 to -0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. Conclusions The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.

PMID:37750584 | DOI:10.1161/JAHA.123.030020

02:05

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

02:05

PubMed articles on: Cardio-Oncology

Aortic Valve Stenosis and Cancer: Problems of Management

J Clin Med. 2023 Sep 6;12(18):5804. doi: 10.3390/jcm12185804.