The circadian timing system is highly integrated with the sleep-wake regulation system. This thesis focuses on how different pharmacological treatments influence the sleep regulation system and the... Show moreThe circadian timing system is highly integrated with the sleep-wake regulation system. This thesis focuses on how different pharmacological treatments influence the sleep regulation system and the circadian timing rhythm in two murine models. In the first animal model, which is presented in Chapter 2 and 3, we implanted EEG/EMG electrodes in freely moving Brown Norway rats. We chose this rat strain because it is pigmented and therefore a more representative model than the more mainstream rat strains which are usually albino rats. This study aimed to investigate the effect of caffeine, sleep deprivation and ketamine on sleep and circadian-controlled activity under constant darkness. In the second animal model, which is presented in Chapter 4 and 5, we implanted EEG/EMG or Multi-unit electrodes in chemotherapy-induced fatigue mice. All the results from this thesis and future perspectives were discussed in Chapter 6. We are able to see how disruption of sleep and the circadian clock adversely affect health and may contribute to many diseases in modern society. In this thesis, these studies provide a better understanding of these drugs influence the circadian timing system and sleep-wake regulation and maybe new treatment approaches for antidepressant therapy and cancer related fatigue. Show less
Heemelaar, J.C.; Heemelaar, S.; Hertel, S.N.; Jukema, J.W.; Sueters, M.; Louwerens, M.; Antoni, M.L. 2023
Background: Childhood cancer survivors (CCS) are at increased risk of cardiomyopathy during pregnancy if they have prior cardiotoxic exposure. Currently, there is no consensus on the necessity,... Show moreBackground: Childhood cancer survivors (CCS) are at increased risk of cardiomyopathy during pregnancy if they have prior cardiotoxic exposure. Currently, there is no consensus on the necessity, timing and modality of cardiac monitoring during and after pregnancy. Therefore, we examined cardiac function using contemporary echocardiographic parameters during pregnancy in CCS with cardiotoxic treatment exposure, and we observed obstetric outcomes in CCS, including in women without previous cardiotoxic treatment exposure. Method: A single-center retrospective cohort study was conducted among 39 women enrolled in our institution's cancer survivorship outpatient clinic. Information on potential cardiotoxic exposure in childhood, cancer diagnosis and outcomes of all pregnancies were collected through interviews and review of health records. Echocardiographic exams before and during pregnancy were retrospectively analyzed for left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) if available. The primary outcomes were (i) left ventricular dysfunction (LVD) during pregnancy, defined as LVEF < 50% or a decline of >= 10% in LVEF below normal (< 54%), and (ii) symptomatic heart failure (HF). Rate of obstetric and fetal complications was compared to the general population through the national perinatal registry (PERINED). Results: All pregnancies (91) of 39 women were included in this study. The most common malignancy was leukemia (N = 17, 43.6%). In 22 patients, echocardiograms were retrospectively analyzed. LVEFbaseline was 55.4 +/- 1.2% and pre-existing subnormal LVEF was common (7/22, 31.8/%). The minimum value of LVEF during pregnancy was 3.8% lower than baseline (p = 0.002). LVD occurred in 9/22 (40.9%) patients and HF was not observed. When GLS was normal at baseline (< -18.0%; N = 12), none of the women developed LVD. Nine of out ten women with abnormal GLS at baseline developed LVD later in pregnancy. In our cohort, the obstetric outcomes seemed comparable with the general population unless patients underwent abdominal irradiation (N = 5), where high rates of preterm birth (only 5/18 born at term) and miscarriage (6/18 pregnancies) were observed. Conclusion: Our study suggests that women with prior cardiotoxic treatment have a low risk of LVD during pregnancy if GLS at baseline was normal. Pregnancy outcomes are similar to the healthy population except when patients underwent abdominal irradiation. Show less
Background Cardiotoxicity presenting as cardiomyopathy is a common side effect in cancer treatment especially with anthracyclines. The role of genetic predisposition is still being investigated... Show moreBackground Cardiotoxicity presenting as cardiomyopathy is a common side effect in cancer treatment especially with anthracyclines. The role of genetic predisposition is still being investigated.Case summary Four unrelated patients with a familial burden for cardiac disease, who developed cardiomyopathy after anthracycline treatment are presented. Case 1 received chemotherapy for breast cancer and developed a dilated left ventricle just after treatment. Her father had died unexpectedly while being screened for heart transplant. Case 2 was known with a family history of sudden cardiac death prior to her breast cancer diagnosis. She received anthracycline-containing chemotherapy treatment twice in 5 years due to recurrence of breast cancer. During that period, two brothers developed a cardiomyopathy. Eighteen years later, a genetic predisposition for cardiomyopathy was ascertained and at screening an asymptomatic non-ischaemic cardiomyopathy was established. Case 3 was diagnosed with a dilated cardiomyopathy 1 year after chemotherapy treatment for breast cancer. Her mother had developed a dilated cardiomyopathy several years before. Case 4 received chemotherapy treatment for Non-Hodgkin's lymphoma and developed dilated cardiomyopathy 1 year later. His brother died from congestive heart failure which he developed after chemotherapy for Non-Hodgkin's lymphoma and a grandmother had died suddenly during child delivery. In all four cases, genetic screening showed (likely) pathogenic variants in cardiomyopathy-associated genes.Discussion Current guidelines recommend cardiac evaluation in cancer patients receiving chemotherapy based on the presence of cardiovascular risk factors at the start of treatment. This series emphasizes the importance of including a thorough family history in this process. Show less
The anthracycline drug doxorubicin, is one of the most used chemotherapeutic drugs, with over one million patients treated every year. However, the exact molecular mechanism by which this drug kill... Show moreThe anthracycline drug doxorubicin, is one of the most used chemotherapeutic drugs, with over one million patients treated every year. However, the exact molecular mechanism by which this drug kill tumor cells remain unclear. In addition, treatment with anthracyclines coincides with severe adverse effects such as cardiotoxicity, secondary tumor formation and gonadotoxicity. Understanding how these highly effective anticancer drugs function and why they cause these severe toxicities would have tremendous impact on cancer treatment and the quality of life of cancer survivors. Therefore, even today, studying old anticancer drugs has high therapeutic potential and opens new exciting paths to improve currently available treatment options. Show less
Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac... Show moreSerum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients. The Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the Cardio-Oncology Council of the ESC have evaluated the current evidence for the role of cardiovascular biomarkers in cancer patients before, during and after cardiotoxic cancer therapies. The characteristics of the main two biomarkers troponin and natriuretic peptides are discussed, the link to the mechanisms of cardiovascular toxicity, and the evidence for their clinical use in surveillance during and after anthracycline chemotherapy, trastuzumab and HER2-targeted therapies, vascular endothelial growth factor inhibitors, proteasome inhibitors, immune checkpoint inhibitors, cyclophosphamide and radiotherapy. Novel surveillance clinical pathways integrating cardiac biomarkers for cancer patients receiving anthracycline chemotherapy or trastuzumab biomarkers are presented and future direction in cardio-oncology biomarker research is discussed. Show less
