Late cardiovascular and neurological complications in Hodgkin lymphoma survivors

This thesis focuses on the early detection of cardiovascular and neurological abnormalities in Hodgkin Lymphoma Survivors (HLS) in a population of 82 patients and 40 controls and in a cross-sectional setting. Several screening test were performed for the assessment of these late effects of treatment. Arterial stiffness has been previously shown to be an early marker of cardiovascular disease (CVD) and a surrogate marker for cardiovascular mortality in several high risk populations. In the studied population two different parameters of arterial stiffness were measured: the carotid-femoral pulse wave velocity (PWVcf) and the common carotid artery (CCA) distensibility coefficient (DC). It is shown for the first time that arterial stiffness is associated with radiotherapy in HLS. Arterial stiffness was most increased in HLS irradiated at older age (above 35-40 years). We hypothesise that the pathophysiology of arterial stiffening after radiotherapy is multifactorial. First, arterial stiffening can be a consequence of nitric oxide (NO)- and prostacyclin-mediated endothelial dysfunction which was shown to occur early and probably still is present years after radiotherapy. Furthermore, atherosclerotic lesions of the arterial wall can contribute to the stiffening of arteries. Preclinical atherosclerotic disease was evaluated by evaluating Intima media thickness (IMT) and the occurrence of plaque at the CCA and Coronary artery calcium (CAC)-score. All these three indicators demonstrate an association between radiotherapy and atherosclerotic disease. Atherosclerosis was most prevalent when HLS were followed for 10-15 years or more form radiotherapy. This is consistent with findings from studies describing symptomatic CVD, suggesting that radiotherapy has a prolonged effect on atherosclerosis. When screening for valvular disease, we found that nearly half of all patients had mild, moderate or severe valve abnormalities. Valvular disease was more prevalent in HLS treated with mediastinal radiotherapy (61.2 %) when compared to HLS treated without mediastinal radiotherapy (31%). Furthermore, the prevalence of valvular disease increased with time after radiotherapy. For the first time a study was performed that systematically looked into the burden and pathophysiological mechanism of radiation-induced muscular damage. Based on clinical findings, results of muscle ultrasound and needle electromyography of muscles situated within and outside the radiation field, we conclude that damage is most likely caused by an extrinsic factor such as progressive microvascular fibrosis. When considering a vascular injury as the primary cause of myogenic damage, we suggest training of the affected muscles, starting soon after radiotherapy to promote increased vascularisation of the muscles by forming collateral vessels. After considering the results of these screening tests, we recommend a comprehensive screening programme of HLS for the timely detection of cardiovascular damage.