ABSTRACT

Methylimidazolium ionic liquids (MILs) are solvent chemicals used in industry. Recent work suggests that MILs are beginning to contaminate the environment and lead to exposure in the general population. In this study, the potential for MILs to cause cardiac toxicity has been examined. The effects of 5 chloride MIL salts possessing increasing alkyl chain lengths (2 C, EMI; 4 C, BMI; 6 C; HMI, 8 C, M8OI; 10 C, DMI) on rat neonatal cardiomyocyte beat rate, beat amplitude and cell survival were initially examined. Increasing alkyl chain length resulted in increasing adverse effects, with effects seen at 10-5 M at all endpoints with M8OI and DMI, the lowest concentration tested. A limited sub-acute toxicity study in rats identified potential cardiotoxic effects with longer chain MILs (HMI, M8OI and DMI) based on clinical chemistry. A 5 month oral/drinking water study with these MILs confirmed cardiotoxicity based on histopathology and clinical chemistry endpoints. Since previous studies in mice did not identify the heart as a target organ, the likely cause of the species difference was investigated. qRT-PCR and Western blotting identified a marked higher expression of p-glycoprotein-3 (also known as ABCB4 or MDR2) and the breast cancer related protein transporter BCRP (also known as ABCG2) in mouse, compared to rat heart. Addition of the BCRP inhibitor Ko143 - but not the p-glycoproteins inhibitor cyclosporin A - increased mouse cardiomyocyte HL-1 cell sensitivity to longer chain MILs to a limited extent. MILs therefore have a potential for cardiotoxicity in rats. Mice may be less sensitive to cardiotoxicity from MILs due in part, to increased excretion via higher levels of cardiac BCRP expression and/or function. MILs alone, therefore may represent a hazard in man in the future, particularly if use levels increase. The impact that MILs exposure has on sensitivity to cardiotoxic drugs, heart disease and other chronic diseases is unknown.

PMID:37272551 | DOI:10.1016/j.ecoenv.2022.114439

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PubMed articles on: Cardio-Oncology

Monocyte-to-lymphocyte ratio as predictor of cancer therapy-related cardiotoxicity in patients with breast cancer: a pilot cohort study

Breast Cancer Res Treat. 2023 Jun 5. doi: 10.1007/s10549-023-06979-z. Online ahead of print.

ABSTRACT

BACKGROUND: Elevated pre-treatment baseline inflammation has been associated with cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer. Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and systemic immune-inflammation index (NLR × platelets) have emerged in clinical context as markers of disease-related inflammation.

OBJECTIVES: To evaluate development of CTRCD according to pre-treatment blood inflammatory biomarkers in patients with breast cancer.

METHODS: Pilot cohort study including consecutive female patients ≥ 18 years with HER2-positive early breast cancer who consulted at the institution's breast oncology outpatient clinic between march/2019 and march/2022. CTRCD: absolute reduction in LVEF > 10% to below 53% (2D-echocardiogram). Survival analysis was performed using Kaplan-Meier curves, compared by the log-rank test, and discrimination ability was evaluated through AUC-ROC.

RESULTS: Forty-nine patients (53.3 ± 13.3 y) were included and followed-up for a median of 13.2 months. CTRCD was observed in 6 (12.2%) patients. Patients with high blood inflammatory biomarkers had lower CTRCD-free survival (P < 0.050 for all). MLR showed statistically significant AUC (0.802; P = 0.017). CTRCD was observed in 27.8% of patients with high MLR versus 3.2% with low MLR (P = 0.020); negative predictive value was 96.8% (95%CI 83.3-99.4%).

CONCLUSION: In patients with breast cancer, elevated pre-treatment inflammatory markers were associated with increased risk of cardiotoxicity. Among these markers, MLR had good discriminatory performance and high negative predictive value. The incorporation of MLR might improve risk evaluation and selection of patients for follow-up during cancer therapy.

PMID:37273150 | DOI:10.1007/s10549-023-06979-z

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PubMed articles on: Cardio-Oncology

Finally Getting to the Heart of the Matter: Imaging Multiorgan Treatment Response in AL Amyloidosis

JACC Cardiovasc Imaging. 2023 May 5:S1936-878X(23)00190-0. doi: 10.1016/j.jcmg.2023.03.022. Online ahead of print.

NO ABSTRACT

PMID:37269271 | DOI:10.1016/j.jcmg.2023.03.022

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PubMed articles on: Cardio-Oncology

Long COVID syndrome after SARS-CoV-2 survival in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Pulm Circ. 2023 May 31;13(2):e12244. doi: 10.1002/pul2.12244. eCollection 2023 Apr.

ABSTRACT

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients have a more severe COVID-19 course than the general population. Many patients report different persistent symptoms after SARS-CoV-2 infection. The aim of our study is to analyze the prevalence of long COVID-19 symptoms and assess if COVID-19 affects pulmonary hypertension (PH) prognosis. PAH/CTEPH patients who survived COVID-19 for at least 3 months before visiting the PH centers were included in the study. The patients were assessed for symptoms in acute phase of SARS-CoV-2 infection and persisting in follow-up visit, WHO functional class, 6-min walk distance, NT-proBNP concentration. The COMPERA 2.0 model was used to calculate 1-year risk of death due to PH at baseline and at follow-up. Sixty-nine patients-54 (77.3%) with PAH and 15 (21.7%) with CTEPH, 68% women, with a median age of 47.5 years (IQR 37-68)-were enrolled in the study. About 17.1% of patients were hospitalized due to COVID-19 but none in an ICU. At follow-up (median: 155 days after onset of SARS-CoV-2 symptoms), 62% of patients reported at least 1 COVID-19-related symptom and 20% at least 5 symptoms. The most frequently reported symptoms were: fatigue (30%), joint pain (23%), muscle pain (17%), nasal congestion (17%), anosmia (13%), insomnia (13%), and dyspnea (12%). Seventy-two percent of PH patients had a low or intermediate-low risk of 1-year death due to PH at baseline, and 68% after COVID-19 at follow-up. Over 60% of PAH/CTEPH patients who survived COVID-19 suffered from long COVID-19 syndrome, but the calculated 1-year risk of death due to PH did not change significantly after surviving mild or moderate COVID-19.

PMID:37266140 | PMC:PMC10232226 | DOI:10.1002/pul2.12244

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PubMed articles on: Cardio-Oncology

An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis

Circ Res. 2023 Jun 2. doi: 10.1161/CIRCRESAHA.122.322017. Online ahead of print.

ABSTRACT

BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis.

METHODS: A ERK5 S496A (dephosphorylation mimic) KI (knock in) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and WT (wild type) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis.

RESULTS: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors.

CONCLUSIONS: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

PMID:37264926 | DOI:10.1161/CIRCRESAHA.122.322017

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PubMed articles on: Cardio-Oncology

Vascular Inflammation, Cancer, and Cardiovascular Diseases

Curr Oncol Rep. 2023 Jun 1. doi: 10.1007/s11912-023-01426-0. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Cancer and cardiovascular disease are among the leading causes of morbidity and mortality in the USA. Cancer and cardiovascular disease have inflammatory underpinnings that have been associated with both the development and progression of these disease states.

RECENT FINDINGS: Inflammatory signaling has been found to be a critical event in both cardiovascular disease and cancer formation and progression. Further, many chemotherapeutic agents potentiate inflammation exacerbating existing cardiovascular disease or leading to its presence. The exact mechanisms of these interactions remain poorly understood. The proinflammatory milieu observed in both cancer and cardiovascular disease likely plays an important role in the development and potentiation of both conditions. Further evaluation of this relationship will be critical in the development of new diagnostic and therapeutic modalities.

PMID:37261651 | DOI:10.1007/s11912-023-01426-0

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PubMed articles on: Cardio-Oncology

Mediastinal gray zone lymphoma in a pregnant woman presenting with cardiac tamponade

Cardiooncology. 2023 May 31;9(1):27. doi: 10.1186/s40959-023-00173-2.

ABSTRACT

BACKGROUND: Mediastinal gray zone lymphoma is a newly recognized rare B cell neoplasm, which is challenging in diagnosis and treatment.

CASE PRESENTATION: In the current study, we aimed to report a 25-year-old pregnant woman at 25 weeks of gestation who presented with chronic cough and progressive shortness of breath, hypotension, tachycardia, and tachypnea. A large circumferential pericardial effusion with compressive effect on the right atrium and right ventricle and a large extracardiac mass with external pressure to mediastinal structures were seen on trans thoracic echocardiography. The emergency pericardiocentesis was performed with the diagnosis of cardiac tamponade. Also, CMR revealed a huge heterogeneous anterior mediastinal mass, and the pathology and the immunohistochemistry of the mass biopsy revealed gray zone lymphoma with positive CD3, CD20, CD30, CD45, PAX5, and negative CD15 expression. Three courses of chemotherapy with the CHOP regimen were performed with an acceptable response every three weeks before delivery. A caesarian section was performed at 37 weeks without any problem for the patient and fetus, and chemotherapy will be started three weeks after delivery.

CONCLUSION: Cardiac tamponade as an emergency condition occurred in this pregnant patient by malignant pericardial effusion and mediastinal mass pressure. Accurate diagnosis and on time interventions caused a significant improvement and a successful delivery.

PMID:37259152 | PMC:PMC10230740 | DOI:10.1186/s40959-023-00173-2

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PubMed articles on: Cardio-Oncology

Gefitinib Increases the Incidence of QT Prolongation in Patients with Non-Small Cell Lung Cancer

Int Heart J. 2023;64(3):365-373. doi: 10.1536/ihj.22-583.

ABSTRACT

Gefitinib (GEF) may increase the risk of corrected QT prolongation (QTc). We aimed to evaluate whether gefitinib increases the risk of corrected QT interval (QTc) prolongation and analyze the associated risk factors.A total of 122 cases of advanced EGFR-mutated non-small cell lung cancer (NSCLC) who received gefitinib therapy from January 2015 to December 2020 were evaluated. The results of at least two resting 12-lead electrocardiogram before and after gefitinib treatment were obtained. The Bazett and Fridericia formulas were used to calculate the QTc interval, and the changes of QTc interval values before and after treatment were evaluated. The correlation between gefitinib and QTc interval prolongation and related risk factors were analyzed.After gefitinib-targeted therapy, 23 patients (18.9%) had a prolonged QTc interval, which increased from a mean of 446 ± 25 ms at baseline to 478 ± 18 ms (P < 0.001). Three of the patients met criteria for Grade 3 QTc prolongation in the common term V5.0 for clinical adverse events. Univariate analysis showed that age (ORR, 1.054; 95% confidence interval [CI], 1.003-1.107; P = 0.038), history of hypertension (ORR, 3.409; 95% CI, 1.334-8.713; P = 0.01), CCB medication history (ORR, 0.259; 95% CI, 0.094-0.712; P = 0.009), history of lung cancer surgery (ORR, 0.231; 95% CI, 0.064-0.829; P = 0.025), and baseline QT interval (ORR, 0.978; 95% CI, 0.964-0.993; P = 0.004) were important predictors of QTc interval prolongation in patients treated with gefitinib. The results of multivariate analysis showed that the history of lung cancer surgery and the baseline QT interval were important factors affecting QTc interval prolongation in patients treated with gefitinib.Gefitinib increases the risk of QTc prolongation in NSCLC patients, which may be more pronounced in patients with advanced age, hypertension, CCB therapy, lung cancer surgery, and a long QT interval at baseline.

PMID:37258113 | DOI:10.1536/ihj.22-583

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PubMed articles on: Cardio-Oncology

Prognosis of immune checkpoint inhibitors-induced myocarditis: a case series

J Immunother Cancer. 2023 May;11(5):e004792. doi: 10.1136/jitc-2022-004792.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune-related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening.

METHODS: We conducted a multicenter cross-sectional retrospective study with the aim of better characterizing ICI-related myocarditis. Myocarditis diagnosis was based on the recent consensus statement of the International Cardio-Oncology Society.

RESULTS: Twenty-nine patients were identified, from six different referral centers. Most patients (55%) were treated using anti-programmed-death 1, rather than ICI combination (35%) or anti-programmed-death-ligand 1 (10%). Transthoracic echocardiography was abnormal in 52% of them, and cardiac magnetic resonance showed abnormal features in 14/24 patients (58%). Eleven patients (38%) were classified as severe. Compared with other patients, they had more frequently pre-existing systemic autoimmune disease (45% vs 6%, p=0.018), higher troponin level on admission (42-fold the upper limit vs 3.55-fold, p=0.001), and exhibited anti-acetylcholine receptor autoantibodies (p=0.001). Seven patients (24%) had myocarditis-related death, and eight more patients died from cancer progression during follow-up. Twenty-eight patients received glucocorticoids, 10 underwent plasma exchanges, 8 received intravenous immunoglobulins, and 5 other immunosuppressants. ICI rechallenge was performed in six patients, with only one myocarditis relapse.

DISCUSSION: The management of ICI-related myocarditis may be challenging and requires a multidisciplinary approach. Prognostic features are herein described and may help to allow ICI rechallenge for some patients with smoldering presentation, after an accurate evaluation of benefit-risk balance.

PMID:37258037 | DOI:10.1136/jitc-2022-004792

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PubMed articles on: Cardio-Oncology

Morbidity and mortality of patients with diabetic neuropathy treated with pathogenetically oriented alpha-lipoic acid versus symptomatic pharmacotherapies - a nationwide database analysis from Hungary

Diabetes Res Clin Pract. 2023 May 29:110734. doi: 10.1016/j.diabres.2023.110734. Online ahead of print.

ABSTRACT

AIMS: Diabetic neuropathy is associated with increased risk of morbidity and all-cause mortality. It is unclear whether these outcomes differ in patients with diabetic neuropathy treated with pathogenetically oriented vs symptomatic pharmacotherapies.

METHODS: We performed a retrospective (2009-2019) database analysis of patients treated with pathogenetically oriented alpha-lipoic acid (ALA) or symptomatic pharmacotherapies for diabetic neuropathy. We investigated clinical outcomes in propensity score matched patients in Hungary. Changes in hazard ratios and annualized event rates were assessed and sensitivity analyses performed.

RESULTS: Hazard ratios favored treatment with ALA vs symptomatic pharmacotherapies regarding acute myocardial infarction (HR 0.73, 95%CI: 0.60-0.89, p = 0.0016), stroke (HR 0.71, 95%CI: 0.62-0.82, p<0.0001),<0.0001),<0.0001),

CONCLUSIONS: This retrospective database analysis revealed a lower occurrence of cardio- and cerebrovascular morbidity, cancer events and all-cause mortality in patients with diabetic neuropathy treated with pathogenetically oriented ALA vs symptomatic pharmacotherapies. This hypothesis-generating result requires further investigations.

PMID:37257759 | DOI:10.1016/j.diabres.2023.110734

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PubMed articles on: Cancer & VTE/PE

Comparison of long-term complications in cancer patients with incidental and acute symptomatic venous thromboembolism

Front Cardiovasc Med. 2023 May 19;10:1118385. doi: 10.3389/fcvm.2023.1118385. eCollection 2023.