ABSTRACT

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) and antibody-drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood-brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC.

PMID:37789330 | PMC:PMC10546716 | DOI:10.1186/s13058-023-01694-5

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PubMed articles on: Cardio-Oncology

Deep learning-assisted high-content screening identifies isoliquiritigenin as an inhibitor of DNA double-strand breaks for preventing doxorubicin-induced cardiotoxicity

Biol Direct. 2023 Oct 9;18(1):63. doi: 10.1186/s13062-023-00412-7.

ABSTRACT

BACKGROUND: Anthracyclines including doxorubicin are essential components of many cancer chemotherapy regimens, but their cardiotoxicity severely limits their use. New strategies for treating anthracycline-induced cardiotoxicity (AIC) are still needed. Anthracycline-induced DNA double-strand break (DSB) is the major cause of its cardiotoxicity. However, DSB-based drug screening for AIC has not been performed possibly due to the limited throughput of common assays for detecting DSB. To discover new therapeutic candidates for AIC, here we established a method to rapidly visualize and accurately evaluate the intranuclear anthracycline-induced DSB, and performed a screening for DSB inhibitors.

RESULTS: First, we constructed a cardiomyocyte cell line stably expressing EGFP-53BP1, in which the formation of EGFP-53BP1 foci faithfully marked the doxorubicin-induced DSB, providing a faster and visible approach to detecting DSB. To quantify the DSB, we used a deep learning-based image analysis method, which showed the better ability to distinguish different cell populations undergoing different treatments of doxorubicin or reference compounds, compared with the traditional threshold-based method. Subsequently, we applied the deep learning-assisted high-content screening method to 315 compounds and found three compounds (kaempferol, kaempferide, and isoliquiritigenin) that exert cardioprotective effects in vitro. Among them, the protective effect of isoliquiritigenin is accompanied by the up-regulation of HO-1, down-regulation of peroxynitrite and topo II, and the alleviation of doxorubicin-induced DSB and apoptosis. The results of animal experiments also showed that isoliquiritigenin maintained the myocardial tissue structure and cardiac function in vivo. Moreover, isoliquiritigenin did not affect the killing of HeLa and MDA-MB-436 cancer cells by doxorubicin and thus has the potential to be a lead compound to exert cardioprotective effects without affecting the antitumor effect of doxorubicin.

CONCLUSIONS: Our findings provided a new method for the drug discovery for AIC, which combines phenotypic screening with artificial intelligence. The results suggested that isoliquiritigenin as an inhibitor of DSB may be a promising drug candidate for AIC.

PMID:37807075 | PMC:PMC10561451 | DOI:10.1186/s13062-023-00412-7

04:16

PubMed articles on: Cardio-Oncology

Alterations in Left Atrial Strain in Breast Cancer Patients Immediately Post Anthracycline Exposure

Heart Lung Circ. 2023 Oct 6:S1443-9506(23)04291-9. doi: 10.1016/j.hlc.2023.06.864. Online ahead of print.

ABSTRACT

AIMS: With improved diagnosis and treatments, a greater percentage of breast cancer patients are achieving long-term survival. Consequently, long-term cardiotoxicity secondary to chemotherapy has become more prevalent, warranting improved cardiac surveillance. We evaluated changes in left atrial (LA) strain in breast cancer patients immediately post anthracycline (AC) therapy to assess its utility as a marker of diastolic dysfunction.

METHODS: This was a prospective cohort study of 128 consecutive human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who underwent transthoracic echocardiography prior to and immediately post AC treatment. Traditional left ventricular (LV) systolic and diastolic parameters and LA volumes were evaluated; additionally, LV global longitudinal strain (LV GLS) and LA phasic strain were measured.

RESULTS: All patients had normal LV ejection fraction (>53%) post AC, though LV GLS was significantly reduced. Peak E and é velocities were reduced post AC, with no change in LA volumes. LA reservoir strain (LASRES 34.8% vs 31.5%, p<0.001)CD 17.2% vs 14.4%, p<0.001)RES from baseline) (32%) compared to alteration in systolic function (≥15% reduction in LV GLS) (23%).

CONCLUSIONS: LA strain is a promising marker of early diastolic dysfunction. We demonstrate its potential utility in surveillance of breast cancer patients treated with AC.

PMID:37806911 | DOI:10.1016/j.hlc.2023.06.864

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PubMed articles on: Cardio-Oncology

Anthracycline‑induced delayed‑onset cardiac toxicity: A case report and literature review

Exp Ther Med. 2023 Sep 13;26(5):505. doi: 10.3892/etm.2023.12204. eCollection 2023 Nov.

ABSTRACT

Anthracyclic (ANT) drugs are widely used for patients with malignant tumors and can markedly prolong the disease-free survival rate of patients. As its clinical application becomes more common, information regarding serious cardiotoxicity as a result of ANT treatment is becoming understood. However, to the best of our knowledge, delayed-onset cardiotoxicity due to ANT use has not been studied sufficiently. The present report describes a 36-year-old male patient who presented to Guiqian International General Hospital (Guiyang, China) with a complaint of dyspnea in the last 10 days. Substantially elevated B-type natriuretic peptide levels and echocardiography showing enlargement of the entire heart, of the patient suggested that severe heart failure was the cause of his symptoms. However, the cause of this potential heart failure was not apparent until the patient was questioned about his cancer treatment history. Following consultation to evaluate the assessment of end-stage heart failure, currently only anti-heart failure treatment and symptomatic treatment can be provided. The present report describes this case and reviews the existing literature to provide a basis for the diagnosis and treatment of patients with delayed-onset heart failure following ANT treatment.

PMID:37822590 | PMC:PMC10562964 | DOI:10.3892/etm.2023.12204

04:16

PubMed articles on: Cardio-Oncology

Fabrication of blended nanofibrous cardiac patch transplanted with TGF-β3 and human umbilical cord MSCs-derived exosomes for potential cardiac regeneration after acute myocardial infarction

Nanomedicine. 2023 Oct 1;54:102708. doi: 10.1016/j.nano.2023.102708. Online ahead of print.

ABSTRACT

Acute myocardial infarction (AMI) is a common cardiovascular condition that progressively results in heart failure. In the present study, we have designed to load transforming growth factor beta 3 (TGF-β3) and cardio potential exosomes into the blended polycaprolactone/type I collagen (PCL/COL-1) nanofibrous patch (Exo@TGF-β3@NFs) and examined its feasibility for cardiac repair. The bioactivity of the developed NFs towards the migration and proliferation of human umbilical vein endothelial cells was determined using in vitro cell compatibility assays. Additionally, Exo@TGF-β3/NFs showed up-regulation of genes involved in angiogenesis and mesenchymal differentiations in vitro. The in vivo experiments performed 4 weeks after transplantation showed that the Exo@TGF-β3@NFs had a higher LV ejection fraction and fraction shortening functions. Subsequently, it has been determined that Exo@TGF-β3@NFs significantly reduced AMI size and fibrosis and increased scar thickness. The developed NFs approach will become a useful therapeutic approach for the treatment of AMI.

PMID:37788793 | DOI:10.1016/j.nano.2023.102708

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PubMed articles on: Cardio-Oncology

Editorial: Cancer treatment-related cardiovascular disease - real world data in cardio-oncology

Front Oncol. 2023 Sep 20;13:1277042. doi: 10.3389/fonc.2023.1277042. eCollection 2023.

NO ABSTRACT

PMID:37799461 | PMC:PMC10548460 | DOI:10.3389/fonc.2023.1277042

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PubMed articles on: Cardio-Oncology

A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy

Acta Pharmacol Sin. 2023 Oct 10. doi: 10.1038/s41401-023-01175-7. Online ahead of print.

ABSTRACT

Lysophosphatidic acid (LPA) is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug (NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor (LPAR2). In this study, we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury (enteropathy), another major complication of NSAID use. Wild-type (WT) and Lpar2 deficient (Lpar2-/-) mice were treated with a single, large dose (20 or 30 mg/kg, i.g.) of indomethacin (IND). The mice were euthanized at 6 or 24 h after IND treatment. We showed that IND-induced mucosal enteropathy and neutrophil recruitment occurred much earlier (at 6 h after IND treatment) in Lpar2-/- mice compared to WT mice, but the tissue levels of inflammatory mediators (IL-1β, TNF-α, inducible COX-2, CAMP) remained at much lower levels. Administration of a selective LPAR2 agonist DBIBB (1, 10 mg/kg, i.g., twice at 24 h and 30 min before IND treatment) dose-dependently reduced mucosal injury and neutrophil activation in enteropathy, but it also enhanced IND-induced elevation of several proinflammatory chemokines and cytokines. By assessing caspase-3 activation, we found significantly increased intestinal apoptosis in IND-treated Lpar2-/- mice, but it was attenuated after DBIBB administration, especially in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Finally, we showed that IND treatment reduced the plasma activity and expression of autotaxin (ATX), the main LPA-producing enzyme, and also reduced the intestinal expression of Lpar2 mRNA, which preceded the development of mucosal damage. We conclude that LPAR2 has a dual role in NSAID enteropathy, as it contributes to the maintenance of mucosal integrity after NSAID exposure, but also orchestrates the inflammatory responses associated with ulceration. Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy.

PMID:37816857 | DOI:10.1038/s41401-023-01175-7

04:16

PubMed articles on: Cardio-Oncology

Cardio-Oncology Rehabilitation for Cancer Survivors With High Cardiovascular Risk: A Randomized Clinical Trial

JAMA Cardiol. 2023 Oct 11:e233558. doi: 10.1001/jamacardio.2023.3558. Online ahead of print.

ABSTRACT

IMPORTANCE: Cardiovascular disease is a leading cause of morbidity in cancer survivors, which makes strategies aimed at mitigating cardiovascular risk a subject of major contemporary importance.

OBJECTIVE: To assess whether a center-based cardiac rehabilitation (CBCR) framework compared with usual care encompassing community-based exercise training (CBET) is superior for cardiorespiratory fitness improvement and cardiovascular risk factor control among cancer survivors with high cardiovascular risk.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, single-center, randomized clinical trial (CORE trial) included adult cancer survivors who had exposure to cardiotoxic cancer treatment and/or previous cardiovascular disease. Enrollment took place from March 1, 2021, to March 31, 2022. End points were assessed at baseline and after the 8-week intervention.

INTERVENTIONS: Participants were randomly assigned in a 1:1 ratio to 8 weeks of CBCR or CBET. The combined aerobic and resistance exercise sessions were performed twice a week.

MAIN OUTCOMES AND MEASURES: The powered primary efficacy measure was change in peak oxygen consumption (V̇o2) at 2 months. Secondary outcomes included handgrip maximal strength, functional performance, blood pressure (BP), body composition, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), lipid profile, plasma biomarker levels, physical activity (PA) levels, psychological distress, quality of life (QOL), and health literacy.

RESULTS: A total of 75 participants completed the study (mean [SD] age, 53.6 [12.3] years; 58 [77.3%] female), with 38 in the CBCR group and 37 in the CBET group. Participants in CBCR achieved a greater mean (SD) increase in peak V̇o2 than those in CBET (2.1 [2.8] mL/kg/min vs 0.8 [2.5] mL/kg/min), with a between-group mean difference of 1.3 mL/kg/min (95% CI, 0.1-2.6 mL/kg/min; P = .03). Compared with the CBET group, the CBCR group also attained a greater mean (SD) reduction in systolic BP (-12.3 [11.8] mm Hg vs -1.9 [12.9] mm Hg; P < .001), diastolic BP (-5.0 [5.7] mm Hg vs -0.5 [7.0] mm Hg; P = .003), and BMI (-1.2 [0.9] vs 0.2 [0.7]; P < .001) and greater mean (SD) improvements in PA levels (1035.2 [735.7] metabolic equivalents [METs]/min/wk vs 34.1 [424.4] METs/min/wk; P < .001), QOL (14.0 [10.0] points vs 0.4 [12.9] points; P < .001), and health literacy scores (2.7 [1.6] points vs 0.1 [1.4] points; P < .001). Exercise adherence was significantly higher in the CBCR group than in the CBET group (mean [SD] sessions completed, 90.3% [11.8%] vs 68.4% [22.1%]; P < .001).

CONCLUSION AND RELEVANCE: The CORE trial showed that a cardio-oncology rehabilitation model among cancer survivors with high cardiovascular risk was associated with greater improvements in peak V̇o2 compared with usual care encompassing an exercise intervention in a community setting. The CBCR also showed superior results in exercise adherence, cardiovascular risk factor control, QOL, and health literacy.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05132998.

PMID:37819656 | PMC:PMC10568446 | DOI:10.1001/jamacardio.2023.3558

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PubMed articles on: Cardio-Oncology

Multimodal Imaging of Cancer Therapy-Related Cardiac Dysfunction in Breast Cancer-A State-of-the-Art Review

J Clin Med. 2023 Sep 29;12(19):6295. doi: 10.3390/jcm12196295.