One of the main challenges in the clinical management of patients with monogenic cardiac disease patients is the clinical heterogeneity in disease severity. Clinical manifestation of congenital... Show moreOne of the main challenges in the clinical management of patients with monogenic cardiac disease patients is the clinical heterogeneity in disease severity. Clinical manifestation of congenital long QT syndrome type 2 (LQT2) can range from the absence of symptoms to life-threatening arrhythmia episodes. Insight into the genetic etiology could advance clinical-decision making and guide the development of tailored medicine strategies. The focus of this thesis was twofold, 1) to validate technical procedures to store hiPSC-CMs and 2) to investigate genetic variant pathogenicity and unravel variable disease expressivity in genetically-matched hiPSC-CM models with LQT2-associated variants. First we established cryopreservation as an opportune method to store hiPSC-CMs with molecular and functional characteristics being retained after thaw and recovery. Second, we demonstrate the potential of hiPSC-CMs to reveal the inherent severity of KCNH2 mutations when using genetically-matched lines with KCNH2 mutations either located in different regions of the affected cardiac ion channel, in conjunction with a common single nucleotide, or a compound heterozygous mutation. Show less
Zandstra, T.; Kies, P.; Maan, A.; Man, S.C.; Bootsma, M.; Vliegen, H.; ... ; Jongbloed, M. 2020
Background: Patients with a systemic right ventricle are prone to develop heart failure. Abnormal heart rate variability (HRV), a measure of autonomic dysfunction, is associated with morbidity and... Show moreBackground: Patients with a systemic right ventricle are prone to develop heart failure. Abnormal heart rate variability (HRV), a measure of autonomic dysfunction, is associated with morbidity and mortality in patients with left ventricular failure. The association between HRV and supraventricular arrhythmias (SVTs), which are associated with adverse events in this population, was assessed.Methods: 24-Hour Holter recordings of patients with a systemic right ventricle and healthy controls were analysed in a retrospective cohort study. HRV was calculated and compared between groups. Correlation coefficients were determined for HRV variables and clinical characteristics. The relation between HRV and SVTs was investigated with linear regression.Results: The patient group included 29 patients (69%) late after Mustard or Senning correction for transposition of the great arteries, and 13 patients with congenitally corrected transposition of the great arteries (31%). The control group included 38 subjects. HRV was significantly lower in patients compared with controls. In the patient group, lower SDANN (standard deviation of the average NN intervals calculated over 5-minute intervals) was independently associated with a higher number of supraventricular arrhythmias (95% CI -0.03 to -0.0004, p = 0.045). In exploratory correlation analysis, several HRV variables correlated with echocardiographic systemic right ventricular function (rho = 0.36, p = 0.02 for SDANN), and exercise capacity (rho = 0.39, p = 0.05 for SDANN).Conclusion: In patients with a systemic right ventricle, HRV is lower compared with controls and (SDANN) is independently associated with supraventricular arrhythmias. Show less
Skeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of... Show moreSkeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of effective treatments has proven to be challenging. This is because of the limited suitability of existing experimental models for acquiring a thorough understanding of the mechanisms underlying skeletal and cardiac muscle diseases and the lack of efficiency and specificity of many of the currently available therapeutic interventions. Therefore, the aim of this thesis was to establish and use dedicated cellular models in combination with genetic interventions to study the biology of skeletal and cardiac muscles in healthy and diseased states and thereby identify potential targets for future therapeutic interventions. The experiments described in this thesis indeed emphasized the importance of cellular models for (i) elucidating the mechanisms underlying skeletal and cardiac muscle diseases and (ii) identification of novel therapeutic targets. This thesis also underlined the usefulness of viral vector-mediated gene transfer technology for development of biological assays and the evaluation of therapeutic targets. In conclusion, application of in vitro models in combination with genetic interventions can improve our understanding of skeletal and cardiac muscle diseases and aid development of new therapies for these disorders. Show less
