Study on the underlying mechanism of Huachansu Capsule induced cardiotoxicity of normal rat by integrating transcriptomics, metabolomics and network toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Huachansu Capsule (HCSc) is a simple enteric-coated capsule refined from the skin of the dried toad, a traditional medicinal herb. It has been used clinically for many years to treat a variety of malignant tumors with remarkable efficacy. To date, a number of main components of HCSc have been reported to be cardiotoxic, but the specific mechanism of cardiotoxicity is still unknown. AIM OF THE STUDY: The aim of this study was to elucidate the possible cardiotoxic symptoms caused by high-doses of HCSc and to further reveal the complex mechanisms by which it causes cardiotoxicity. MATERIALS AND METHODS: UPLC-Q-Exactive Orbitrap MS and network toxicology were used to identify and predict the potential toxic components, related signaling pathways. Then, we used acute and sub-acute toxicity experiments to reveal the apparent phenomenon of HCSc-induced cardiotoxicity. Finally, we combined transcriptomics and metabolomics to elucidate the potential mechanism of action, and verified the putative mechanism by molecular docking, RT-qPCR, and Western blot. RESULTS: We found 8 toad bufadienolides components may be induced cardiac toxicity HCSc main toxic components. Through toxicity experiments, we found that high dose of HCSc could increase a variety of blood routine indexes, five cardiac enzymes, heart failure indexes (BNP), troponin (cTnI and cTnT), heart rate and the degree of heart tissue damage, while low-dose of HCSc had no such changes. In addition, by molecular docking, found that 8 kinds of main toxic components and cAMP, AMPK, IL1ß, mTOR all can be a very good combination, especially in the cAMP. Meanwhile, RT-qPCR and Western blot results showed that HCSc could induce cardiotoxicity by regulating a variety of heart-related differential genes and activating the cAMP signaling pathway. CONCLUSIONS: In this study, network toxicology, transcriptomics and metabolomics were used to elucidate the complex mechanism of possible cardiotoxicity induced by high-dose HCSc. Animal experiments, molecular docking, Western blot and RT-qPCR experiments were also used to verify the above mechanism. These findings will inform further mechanistic studies and provide theoretical support for its safe clinical application.

Cardiac Conduction System as an OAR in Radiation Therapy: Doses to SA/AV Nodes and Their Reduction.

Purpose: Despite advancements in radiation techniques, concerns persist regarding the adverse effects of radiation therapy, particularly cardiotoxicity or radiation-induced heart disease. Recently, arrhythmogenic toxicity has come to the forefront-the impact of radiation therapy on the cardiac conduction system. Our objective was to conduct a dosimetric study and subsequently investigate the feasibility of optimizing the sinoatrial (SA) and atrioventricular (AV) nodes as organs at risk (OARs) in proton radiation therapy for non-small cell lung cancer with N3 disease. Patients and Methods: Thirty-two non-small cell lung cancer patients with N3 disease undergoing proton radiation therapy were included. Sinoatrial and AV nodes, along with standard OARs, were delineated. Dosimetric analysis and optimization were performed using intensity-modulated proton therapy. Results: Patients surpassing a predefined SA node dose threshold underwent dose optimization. Proton radiation therapy with pencil beam scanning demonstrated a significant reduction in SA and AV node doses without compromising target volume coverage or significant shift in the dose to other monitored OARs. Conclusion: Dose reduction to the SA and AV nodes for pencil beam scanning is a relatively simple task, and the reduction can be very substantial. Larger cohort studies and diverse radiotherapeutic modalities are needed for further validation and refinement of dose constraints.

Expect the unexpected: fulminant myocardial cytotoxic Injury from Trabectedin.

BACKGROUND: Trabectedin (Tbt) is an alkylating agent prescribed for soft tissue sarcomas after treatment failure of first line agents. While cardiomyopathy can occur with Tbt treatment after anthracycline exposure, Tbt-induced fulminant myocardial cytotoxic injury in the setting of other systemic cytotoxicity associated with Tbt has not been reported. CASE PRESENTATION: 51-year-old female with hypertension, hyperlipidemia, metastatic leiomyosarcoma with progression of disease despite several lines of chemotherapy including doxorubicin-based therapy was started on Trabectedin (Tbt) 5 days prior to presentation with symptoms of fever, myalgias, arthralgias, and palpitations. She was admitted for management of rhabdomyolysis, acute kidney and liver injuries which were reportedly known to be associated with Tbt treatment. A baseline electrocardiogram (ECG) revealed sinus tachycardia with non-specific T-wave changes, and a transthoracic echocardiogram (TTE) was unremarkable. However, on day 3 of hospitalization, an episode of asymptomatic sustained monomorphic ventricular tachycardia with a heart rate of 150 beats per minute was captured on telemetry. A 12-lead ECG revealed new septal T-wave inversions. Labs revealed rising hs-TnI levels (peak at 37,933ng/L) and serum markers suggested multi-organ failure. Steroids were initiated given its role in treating multi-organ Tbt-induced toxicity. A cardiac MRI to rule out myocarditis and left heart catheterization to rule out obstructive coronary artery disease were forgone due to acute renal failure. A right heart catheterization with an endomyocardial biopsy was performed revealing normal cardiac filling pressures and indices. Pathology showed cytoplasmic vacuoles indicating drug-induced myocardial cytotoxicity. Serial echocardiograms revealed preserved biventricular function. The patient's clinical condition deteriorated with multi-organ failure despite maximal supportive care in the intensive care unit. She ultimately passed away, and an autopsy was declined. CONCLUSION: This is the first reported case of fulminant myocardial injury after initiation of Tbt with histologic evidence of drug-induced myocardial cytotoxicity. While it is unclear if anthracyclines potentiate Tbt cytotoxic injury as in this case, it is plausible; and that Tbt-induced cardiotoxicity ranges from subclinical to fulminant. Given increasing use of Tbt in refractory high-grade sarcomas, raising awareness of its toxicity profile will improve early detection and outcomes.

Serum Carnitine Concentrations and Cardiac Function in Pediatric, Adolescent and Young Adult Oncology Patients Receiving High-Dose Anthracyclines.

OBJECTIVE: Anthracycline chemotherapy agents have significant dose-dependent cardiotoxic effects. -Carnitine, a non-essential amino acid, is involved in long chain fatty acid oxidation, and carnitine deficiency can result in cardiomyopathy and cardiac arrhythmias. If administered concurrently with chemotherapy, carnitine supplementation could be a potential strategy to prevent cardiotoxicity. However, the association between serum carnitine concentrations and anthracycline cardiotoxicity during cancer treatment in the childhood, adolescent, and young adult (CAYA) age range has not been established. METHODS: This prospective pilot cohort study characterized changes in serum carnitine concentrations and cardiac function before, during, and approximately 1 year after large-dose anthracycline therapy in newly diagnosed CAYA cancer patients. RESULTS: Among 21 patients with a mean cumulative anthracycline dose exposure of 409 mg/m2 of -doxorubicin equivalents, left ventricular ejection fraction and relative wall thickness decreased, indicating an overall decline in cardiac function. A reversible decrease in serum carnitine concentrations was also observed. A non-statistically significant positive correlation was observed; for every 1 mmol/L decrease in serum carnitine concentration, there was a 0.09% decrease in LVEF (p = 0.2). CONCLUSIONS: These findings from this small pilot study suggest that there may be a relationship between serum carnitine concentrations and cardiac function after anthracycline therapy that should be evaluated in larger studies.

Evaluation of Cardiotoxicity of Cancer Chemotherapeutics Using Daphnia magna as a Preclinical Model.

One of the major concerns following cancer treatment is cardiotoxicity. Therefore, it is important to predict potential cardiotoxicity of cancer chemotherapeutics at the preclinical phase. Current models of cardiotoxicity testing involve either cell culture models or rodent models. We developed a simple invertebrate animal model for rapid screening of cardiotoxicity of cancer chemotherapeutics. Daphnia magna (water flea, a crustacean) has a transparent body and a large myogenic heart that can be easily monitored under a microscope. Using this model, we have previously described comparative cardiotoxicity of several kinase inhibitors that were approved for the treatment of multiple cancers. In this article, we describe the step-wise protocols for evaluating the heart rate and survival of D. magna with relevant information on troubleshooting. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Culturing and maintenance of D. magna Basic Protocol 2: Experimental design for evaluating heart rate of Daphnia Basic Protocol 3: Long-term effect on Daphnia survival upon drug exposure.

Cardio-Oncology and Heart Failure: A Scientific Statement from the Heart Failure Society of America.

Heart failure and cancer remain two of the leading causes of morbidity and mortality and the two disease entities are linked in a complex manner. Patients with cancer are at increased risk of cardiovascular complications related to the cancer therapies. The presence of cardiomyopathy or heart failure in a patient with new cancer diagnosis portends a high risk for adverse oncology and cardiovascular outcomes. With the rapid growth of cancer therapies, many of which interfere with cardiovascular homeostasis, heart failure practitioners need to be familiar with prevention, risk stratification, diagnosis, and management strategies in cardio-oncology. This Heart Failure Society of America statement addresses the complexities of heart failure care among patients with active cancer diagnosis and cancer survivors. Risk stratification, monitoring, and management of cardiotoxicity are presented across Stages A through D heart failure, with focused discussion on heart failure preserved ejection fraction and special populations such as survivors of childhood and young adulthood cancers. We provide an overview of the shared risk factors between cancer and heart failure, highlighting heart failure as a form of cardiotoxicity associated with many different cancer therapeutics. Finally, we discuss disparities in the care of patients with cancer and cardiac disease and present a framework for a multidisciplinary team approach and critical collaboration between heart failure, oncology, palliative care, pharmacy, and nursing teams in the management of these complex patients.

Cardiac events among a cohort of 17,389 patients receiving cancer chemotherapy: short and long term implications.

BACKGROUND: The association between cardiovascular disease and carcinogenesis is bidirectional and well-established. Furthermore, cancer treatment improves overall patient survival, potentially at the cost of incremental and fatal cardiovascular disease (CVD). AIM: To evaluate (a) In a real-world cohort, the proportion of patients offered cancer chemotherapy who have antecedent CVD (CVDA); (b) The rates of patient admission with subsequent development of CVD (CVDS) requiring hospital admission post assignment to chemotherapy; (c) The impact of CVDA and CVDS on mortality rates relative to those seen in patients without overt CVD (CVD-) and (d) The time course of mortality in CVD- versus CVDS patients. METHODS: Retrospective analysis was performed in deidentified linked health data sets. Correlates of mortality were evaluated by Cox proportional hazards evaluation. Relative and absolute time-variability of CVD as a primary cause of death were determined. RESULTS: Of the total 17,389 patients, there were 2,159 with CVDA. Over a median follow-up time of 4.6 years, CVDS admissions (n = 8,529) occurred more commonly in the presence of CVDA (70.0% vs. 46.1%, p < 0.001), and more than 50% of CVDS cases occurred in the first 12 months of follow-up. The 5-year mortality rates were 71.5% for CVDA, 64.7% for CVDS, and 40.8% for CVD- (p < 0.001). Development of CVDS was associated with a substantially increased risk of mortality in the next 12 months. The development of CVDs was also associated with an increased risk of cardiovascular, as against non-cardiovascular, mortality (7.1% vs. 1.6%, p < 0.001). CONCLUSIONS: Approximately 50% of patients assigned to cancer chemotherapy developed CVDS, heralding a particularly high risk of mortality over the next 12 months. Both CVDA and CVDS are associated with substantial increases in mortality rates relative to those in CVD- patients. This increased risk merits close individual monitoring.

Effects of Physical Activity on Cardiotoxicity and Cardio respiratory Function in Cancer Survivors Undergoing Chemotherapy: A Systematic Review and Meta-Analysis.

Introduction: Physical activity, as a promising complementary therapy, has shown considerable potential for reducing chemotherapy-related cardiotoxicity (CTRCT) and enhancing cardiorespiratory function (CRF). This study aimed to systematically assess the effects of physical activity on CTRCT and CRF in various cancer survivors receiving chemotherapy. Methods: A systematic review and meta-analysis was conducted. A literature search was conducted across 8 databases from inception to January 2024 and was limited to the English and Chinese languages. Statistical analysis was conducted using RevMan 5.3 and Stata 17.0 software. Results: Sixteen randomized controlled trials (RCTs) were included in the systematic review and 15 RCTs were included in the meta-analysis. Among various cancer survivors undergoing chemotherapy, physical activity markedly increased absolute oxygen uptake (VO2peak or VO2max; WMD = 292.99, 95% confidence interval [CI]:87.87 to 498.12, P = .005), with significant effects of subgroup analysis at 4 to 10 weeks (P = .02) or over 16 weeks (P < .01), moderate-to-high or high intensity training (both P < .0001), patients with breast cancer (P = .009) and reported CTRCT (P = .007); relative VO2peak or VO2max(WMD = 3.30, 95%CI: 2.02 to 4.58, P < .00001), with significant effects of subgroup analysis at 10 to 16 weeks or over 16 weeks, moderate-to-high or high intensity training, patients with breast cancer, with or without reported CTRCT and exercise during chemotherapy (all P < .01); E/A values (WMD = 0.11, 95%CI:0.03 to 0.18, P = .007) and flow-mediated dilatation (WMD = 2.71, 95%CI:1.49 to 3.94, P < .0001). Compared to the control group, physical activity had no significant improvement in E/e' values (P = .50), NT-proBNP (P = .12), hs-cTn (P = 3.83), left ventricular ejection fraction (WMD = 2.89, 95%CI: -3.28 to 9.06, P = .36) with non-significant effects being independent of exercise intensity or duration, with or without CTRCT and cancer types (all P > .05), and global longitudinal strain (WMD = 0.37, 95%CI: -0.20 to 0.94, P = .20) with non-significant effects being independent of exercise duration and cancer types(both P > .05). Conclusions: Physical activity may be an effective complementary therapy to improve CRF and CTRCT in various cancer survivors, particularly during medium to long duration and moderate-to-high and high intensity exercise with concurrent chemotherapy.

The effect of geraniol on nickel-induced embryotoxicity and cardiotoxicity in rats.

BACKGROUND: Nickel (Ni), commonly-used heavy metals in industrial activities, can lead to embryo and organ toxicity, especially cardiovascular damage. Geraniol (GER) has various beneficial effects such as anti-oxidant, anti-inflammatory, anti-tumor, anti-ulcer, anti-microbial, and neuroprotective activities. OBJECTIVE: The objective of this study was to investigate the effect of GER on Ni-induced embryotoxicity and cardiotoxicity in rats. METHODS: 40 mother Wistar rats were randomly divided into five groups: Control, GER 250, Ni, Ni + GER 100, and Ni + GER 250. On the 20th day of pregnancy, the animals were sacrificed and fetuses along with blood and tissue samples were collocated for morphological, serological, biochemical, and histopathologic analysis. RESULTS: Morphological assessments revealed GER's capacity to mitigate the incomplete ossification of fetal skeletons, indicating a potential safeguarding against the impact of Ni-induced embryotoxicity. Serological and biochemical analyses further affirm GER's role, with noteworthy reductions in cardiac injury markers, such as CRP, CKMB, CPK, LDH, and troponin, in response to GER administration, thereby suggesting its cardioprotective potential. Moreover, treatment with GER 250 could significantly reduce the level of MDA and increase the level of TAC compared to the Ni group. Histopathological examinations corroborated these findings, underscoring GER's ability to counteract cardiac injury and diminish structural damage in affected tissue. CONCLUSIONS: These multidimensional analyses indicate the protective prowess of GER against Ni-induced embryotoxic and cardiotoxic effects, shedding light on its potential therapeutic significance in combating adverse impacts stemming from Ni exposure.

Exploration of Specific Fluoroquinolone Interaction with SARS-CoV-2 Main Protease (Mpro) to Battle COVID-19: DFT, Molecular Docking, ADME and Cardiotoxicity Studies.

Herein, the pharmacokinetic profiles, binding interactions, and molecular properties of fluoroquinolone derivatives as prospective antiviral drugs are examined using a combination of docking, ADME, and DFT simulations. The effectiveness of the ligands is compared with the clinically tested and FDA-authorized medicine remdesivir. The findings demonstrated encouraging binding energies, indicating possible inhibitory effectiveness against SARS-CoV-2 Mpro. The fluoroquinolone derivatives also exhibit promising ADME characteristics, although compounds 5, 6, 9, 12-20 possess poor values, suggesting that oral administration may be possible. The potential of the selected compounds as SARS-CoV-2 Mpro inhibitors is thoroughly understood because of the integrated analysis of DFT, with compound 11 demonstrating the highest energy gap of 0.2604 eV of, docking with viral targets with docking scores of -7.9 to -5.9 kcal/mol, with compound 18 demonstrating the highest docking score, which is at the 13th position in energy difference in the DFT data. Their favorable electrical properties, robust binding interactions with viral targets, and attractive pharmacokinetic profiles boost their potential as prospective study subjects. These substances have the potential to be transformed into cutting-edge antiviral therapies that specifically target SARS-CoV-2 Mpro and related coronaviruses.

Isavuconazonium sulfate induces heart development defects in zebrafish larvae by upregulation of oxidative stress.

Environmental pollution remains a pressing global concern, with a substantial number of annual fatalities attributed to pollution-induced diseases. One emerging facet of environmental pollution is drug contamination, whereby pharmaceutical compounds can readily infiltrate water sources during manufacturing or utilization, subsequently being detected in various aquatic ecosystems. Some drugs have been detected in many watersheds at concentrations that can cause toxicity to aquatic organisms. Isavuconazonium sulfate (ISAV-SF), a prevalent antifungal medication, is no exception, warranting an exploration of its potential toxicity. However, limited research has been conducted in this domain. In this investigation, zebrafish were employed as a model organism to scrutinize the cardiotoxicity of ISAV-SF. Exposure of zebrafish embryos to concentrations of 0.5, 0.75, and 1 mg/L of ISAV-SF resulted in noteworthy cardiac developmental aberrations. These anomalies encompassed enlarged pericardial area, diminished heart rate, alterations in SV-BA distance, and the detachment of cardiomyocytes from the endocardium. Exposure to ISAV-SF caused disruption of the expression of genes related to cardiac development (gata4, klf2a, nkx2.5, vmhc, tbx2b), especially in the high concentration group. Moreover, the Notch signaling pathway was inhibited and oxidative stress levels were upregulated in all exposed groups. Remarkably, the administration of the antioxidant astaxanthin effectively mitigated oxidative stress levels, thus ameliorating heart developmental impairments. These results suggest that ISAV-SF may contribute to cardiac developmental defects by upregulating oxidative stress. This study serves as a pivotal reference for the utilization of ISAV-SF within the market, emphasizing the necessity to curtail its introduction into aquatic environments during production and consumption and to evaluate its repercussions on aquatic organisms.

Predictors of trastuzumab-induced cardiotoxicity among racially and ethnically diverse patients with HER2-positive breast cancer.

BACKGROUND: While trastuzumab has been shown to improve disease-free and overall survival in patients with HER2-positive breast cancer, it may also cause trastuzumab-induced cardiotoxicity (TIC). Although racial and ethnic minorities are at higher risk for cardiovascular disease (CVD) compared to non-Hispanic Whites (NHW), limited data exists on TIC incidence in diverse multi-ethnic populations. Our objective was to assess racial and ethnic differences in TIC and left ventricular ejection fraction (LVEF) recovery among patients with HER2-positive breast cancer. METHODS: We conducted a retrospective cohort study including patients diagnosed with stage I-III HER2-positive breast cancer between 2007 and 2022 who had received adjuvant trastuzumab. We analyzed associations between sociodemographic factors, tumor characteristics, treatment regimens, and CVD risk factors with the primary outcomes of TIC and LVEF recovery, using multivariable logistic regression models. TIC was defined as > 10% decrease in LVEF to an overall LVEF < 50%; LVEF recovery as a return to a LVEF > 50%. RESULTS: Among 496 evaluable patients, median age was 53 years (IQR: 45.0-62.0) with 36.6% NHW, 15.8% non-Hispanic Black (NHB), 27.8% Hispanic, and 19.8% Other. Fifty-three (10.6%) patients developed TIC, half of whom experienced LVEF recovery. Compared to NHW, NHB had a higher rate of TIC (9.3% vs. 17.7%, respectively) and lower rate of LVEF recovery (70.6% vs. 21.4%, respectively), however, race/ethnicity was not a significant predictor of TIC after adjusting for confounders. Increasing age, lower baseline LVEF, anthracycline use, and presence of hypertension or coronary artery disease were significantly associated with TIC in multivariable analysis. CONCLUSIONS: TIC was more common among NHB compared to NHW, however, Black race was not consistently associated with TIC after adjustment for CVD risk factors. This suggests that CVD comorbidities (e.g., hypertension) that more frequently affect racial and ethnic minorities and are modifiable may explain differences in TIC incidence and recovery.

Potential Player of Platelet in the Pathogenesis of Cardiotoxicity: Molecular Insight and Future Perspective.

Cancer patients may encounter the onset of cardiovascular disease due to tumor advancement or chemotherapy, commonly known as "cardiotoxicity." In this respect, the conventional chemotherapy treatment protocol involves a mixture of different medications. These medications can be detrimental to cardiac tissue, consequently exposing the patient to the possibility of irreversible cardiac injury. The enhancement of oxidative stress and inflammation is an important mechanism of chemotherapeutic agents for developing cardiotoxicity. Regarding their dual pro- and anti-inflammatory functions, platelets can significantly influence the progression or suppression of cardiotoxicity. Therefore, the expression of platelet activatory markers can serve as valuable prognostic indicators for cardiotoxicity. The primary objective of this study is to examine the significance of platelets in cardiotoxicity and explore potential strategies that could effectively target malignant cells while minimizing their cytotoxic impact, such as cardiotoxicity and thrombosis.

Potential mechanisms underlying podophyllotoxin-induced cardiotoxicity in male rats: toxicological evidence chain (TEC) concept.

Introduction: Podophyllotoxin (PPT) is a high-content and high-activity compound extracted from the traditional Chinese medicinal plant Dysosma versipellis (DV) which exhibits various biological activities. However, its severe toxicity limits its use. In clinical settings, patients with DV poisoning often experience adverse reactions when taking large doses in a short period. The heart is an important toxic target organ, so it is necessary to conduct 24-h acute cardiac toxicity studies on PPT to understand its underlying toxicity mechanism. Methods: Based on the concept of the toxicological evidence chain (TEC), we utilized targeted metabolomic and transcriptomic analyses to reveal the mechanism of the acute cardiotoxicity of PPT. The manifestation of toxicity in Sprague-Dawley rats, including changes in weight and behavior, served as Injury Phenotype Evidence (IPE). To determine Adverse Outcomes Evidence (AOE), the hearts of the rats were evaluated through histopathological examination and by measuring myocardial enzyme and cardiac injury markers levels. Additionally, transcriptome analysis, metabolome analysis, myocardial enzymes, and cardiac injury markers were integrated to obtain Toxic Event Evidence (TEE) using correlation analysis. Results: The experiment showed significant epistaxis, hypokinesia, and hunched posture in PPT group rats within 24 h after exposure to 120 mg/kg PPT. It is found that PPT induced cardiac injury in rats within 24 h, as evidenced by increased serum myocardial enzyme levels, elevated concentrations of cardiac injury biomarkers, and altered cardiac cell morphology, all indicating some degree of cardiac toxicity. Transcriptome analysis revealed that primary altered metabolic pathway was arachidonic acid metabolism after PPT exposure. Cyp2e1, Aldob were positively correlated with differential metabolites, while DHA showed positive correlation with differential genes Fmo2 and Timd2, as well as with heart injury markers BNP and Mb. Conclusion: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of PPT-induced acute cardiotoxicity, which involved oxidative stress, apoptosis, inflammatory response, and energy metabolism disorder.

The Risk and Reversibility of Osimertinib-related Cardiotoxicity in a Real-World Population.

INTRODUCTION: While osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, as the first-line therapy for metastatic non-small cell lung cancer (NSCLC) has shown significant survival benefits, concerns have arisen regarding its potential cardiotoxicity, particularly in real-world clinical settings. We aimed to investigate the incidence, risk factors, and reversibility of osimertinib-related cardiotoxicity. METHODS: We analyzed 1,126 NSCLC patients treated with osimertinib from May 2016 to April 2023 in two cancer centers. Osimertinib-related cardiotoxicity was defined as a composite of osimertinib-related cardiac dysfunction (ORCD), newly developed arrhythmia, and cardiac death. Total follow-up duration was 20.6 (10.8-35.2) months. RESULTS: The osimertinib was administered for a median of 12.4 months. The incidence of osimertinib-related cardiotoxicity was 4.7%. Advanced age (adjusted hazard ratio with 95% confidence interval; 1.07 [1.04-1.09], P < 0.001), a history of heart failure (HF; 3.35 [1.67-9.64], P = 0.025), atrial fibrillation (AF; 3.42 [1.27-9.22], P = 0.015), and baseline low left ventricle strain (0.87 [0.79-0.96], P = 0.005) were independently associated with development of cardiotoxicity. The recovery rate of ORCD was 82.4%, which did not differ between patients who discontinued medication and those who did not. CONCLUSION: In real-world practice, the incidence of osimertinib-related cardiotoxicity was 4.7%, including 3.4% for ORCD requiring cardiologic intervention, which is higher than previously reported. Given the long-term medication of osimertinib and increased mortality associated with cardiotoxicity, vigilant monitoring is crucial, especially in patients with advanced age, history of HF, AF, or decreased baseline LV strain.

Fasting: A Complex, Double-Edged Blade in the Battle Against Doxorubicin-Induced Cardiotoxicity.

In recent years, there has been a surge in the popularity of fasting as a method to enhance one's health and overall well-being. Fasting is a customary practice characterized by voluntary refraining from consuming food and beverages for a specified duration, ranging from a few hours to several days. The potential advantages of fasting, including enhanced insulin sensitivity, decreased inflammation, and better cellular repair mechanisms, have been well documented. However, the effects of fasting on cancer therapy have been the focus of recent scholarly investigations. Doxorubicin (Dox) is one of the most widely used chemotherapy medications for cancer treatment. Unfortunately, cardiotoxicity, which may lead to heart failure and other cardiovascular issues, has been linked to Dox usage. This study aims to comprehensively examine the possible advantages and disadvantages of fasting concerning Dox-induced cardiotoxicity. Researchers have investigated the potential benefits of fasting in lowering the risk of Dox-induced cardiac damage to solve this problem. Nevertheless, new studies indicate that prolonged alternate-day fasting may adversely affect the heart's capacity to manage the cardiotoxic properties of Dox. Though fasting may benefit overall health, it is essential to proceed cautiously and consider the potential risks in certain circumstances.

Cardiorespiratory Fitness in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis.

AIMS: Cardiovascular disease (CVD) is a leading cause of mortality in childhood cancer survivors (CCS) that may be related to the cardiotoxic effects of radiation or chemotherapy and concomitant reductions in cardiorespiratory fitness. Therefore, we sought to compare cardiorespiratory fitness (peak oxygen uptake, V̇O2peak) between CCS and age-matched non-cancer controls (CON). Secondary outcomes included hemodynamics and resting cardiac function. METHODS: Embase, Scopus, MEDLINE, CINAHL and SPORTDiscus databases were searched from inception to June 2023 for eligible studies. Cross-sectional studies with V̇O2peak measured in CCS and CON were included. Differences in outcomes and pooled estimates for each outcome were estimated from a fixed effects meta-analysis and between group differences were reported as a weighted mean difference (WMD). RESULTS: Of 2026 studies identified, 18 reported V̇O2peak (CCS: n=786, 44% female, mean age: 16-years, time post-therapy: 5.8 years; CON: n=1379, 50% female, mean age: 16-years). V̇O2peak was lower in CCS (WMD: -7.08mL/kg/min, 95% CI: -7.75 to -6.42, I2: 79%, n=2,165) with no difference for peak exercise heart rate (WMD: -1.4bpm, 95% CI: -3.0 to 0.2, I2: 63%, n=741). Resting left-ventricular ejection fraction (WMD: -1.61%, 95% CI: -2.60 to -0.62, I2.: 49%, n=222) and systolic blood pressure were lower (WMD: -3.8mmHg, 95% CI: -5.7 to -1.9, I2: 25%, n=184) while resting heart rate was higher in CCS (WMD: 4.9bpm; 95% CI: 1.8 to 7.9, I2: 55%, n=262). CONCLUSIONS: CCS have a marked reduction in cardiorespiratory fitness (7.1ml/kg/min lower than CON) that may have important prognostic implications for their future risk of CVD and mortality.

Childhood cancer survivors are at increased risk of developing cardiovascular disease, in particular, heart failure. This increased cardiovascular risk is partly due to cardiovascular damage from cancer treatment, but may also be due to reductions in cardiorespiratory fitness that accompany increased sedentary behavior prior to, during, or after cancer treatment. In this review, we assessed the degree of cardiorespiratory fitness impairment and cardiovascular function in childhood cancer survivors relative to their cancer-free peers. Key Findings:  Whilst traditional markers of cardiovascular function appear normal, childhood cancer survivors have a marked reduction in cardiorespiratory fitness that may increase their risk of heart failure and cardiovascular mortality.Measuring cardiorespiratory fitness alongside traditional cardiovascular risk markers may help to identify cancer survivors at increased risk of cardiovascular disease.

Protein overexpression by adeno-associated virus-based gene therapy products in cardiomyocytes induces endoplasmic reticulum stress and myocardial degeneration in mice.

Gene therapy (GT) products created using adeno-associated virus (AAV) vectors tend to exhibit toxicity via immune reactions, but other mechanisms of toxicity remain incompletely understood. We examined the cardiotoxicity of an overexpressed transgenic protein. Male C57BL/6J mice were treated with a single intravenous dose of product X, an AAV-based GT product, at 2.6 × 1013 vg/kg. Necropsies were performed at 24 h, 7 days, and 14 days after dosing. Pathological examination and gene expression analysis were performed on the heart. Histopathologically, hypertrophy and vacuolar degeneration of cardiomyocytes and fibrosis were observed 14 days after dosing. Immunohistochemistry for endoplasmic reticulum (ER) stress-related proteins revealed increased positive reactions for glucose-regulated protein 78 and C/EBPR homologous protein in cardiomyocytes 7 days after dosing, without histopathological abnormalities. Fourteen days after dosing, some cardiomyocytes showed positivity for PKR-like endoplasmic reticulum kinase and activating transcription factor 4 expression. Ultrastructurally, increases in the ER and cytosol were observed in cardiomyocytes 7 days after dosing, along with an increase in the number of Golgi apparatus compartments 14 days after dosing. The tissue concentration of the transgene product protein increased 7 days after dosing. Gene expression analysis showed upregulation of ER stress-related genes 7 days after dosing, suggesting activation of the PKR-like ER kinase pathway of the unfolded protein reaction (UPR). Thus, the cardiotoxicity induced by product X was considered to involve cell damage caused by the overexpression of the product protein accompanied by UPR. Marked UPR activation may also cause toxicity of AAV-based GT products.

Examining cardiac toxicity in HER2-positive breast cancer patients using trastuzumab and its influencing factors at Iran Hospital.

Trastuzumab is primarily utilized in the treatment of patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer. This study aimed to investigate the incidence of cardiac toxicity associated with trastuzumab in HER2-positive breast cancer patients at Iran Hospital in 2023, as well as the factors influencing this toxicity. In this cross-sectional study, 200 patients diagnosed with HER2-positive breast cancer and receiving trastuzumab were included. The criteria for heart failure in this study were defined as an ejection fraction (EF) of less than 50% or a decrease of greater than 10% in EF. Descriptive statistics, the chi-square statistical test, Fisher's exact test, and logistic regression analyses were employed to assess the variables. A p-value of less than 0.05 was deemed statistically significant. The mean age of the participants was 51.5 ± 2.5 years. The odds ratio (OR) for the variable of anthracyclines was 1.3 (95% CI: 1.2-1.4); for opium use, the OR was 2.7 (95% CI: 0.9-8.5); for diabetes, the OR was 2.7 (95% CI: 1.2-5.9); for ischemic heart disease, the OR was 3.5 (95% CI: 1.6-7.7); and for hypertension, the OR was 4.8 (95% CI: 2.1-10.7). The OR for obesity was 1.45 (95% CI: 1.01-2.18), and the OR for age was 1.10 (95% CI: 1.01-1.12). No statistically significant association was found between opium use and cardiotoxicity (p = 0.07). This research contributes to the identification of factors that may predict responses to anthracyclines and the potential for cardiotoxicities. Ultimately, this information could inform the development of more personalized treatment strategies.