Fetal Tachyarrhythmia - Part II: Treatment

The decision to initiate pharmacological intervention in case of fetal tachycardia depends on several factors and must be weighed against possible maternal and/or fetal adverse effects inherent to the use of antiarrhythmics. First, the seriousness of the fetal condition must be recognized. Many studies have shown that in case of fetal tachycardia, there is a significant predisposition to congestive heart failure and subsequent development of fetal hydrops and even sudden cardiac death1,2,3 Secondly, predictors of congestive heart failure have been suggested in several studies, such as the percentage of time that the tachycardia is present, the gestational age at which the tachycardia occurs4, the ventricular rate5 and the site of origin of the tachycardia6. However, the sensitivity of these predictors is low and they are therefore clinically not very useful. In addition, hemodynamic compromise may occur in less than 24 - 48 hours as has been shown in the fetal lamb7 and in tachycardic fetuses8,9. On the other hand, spontaneous resolution of the tachycardia has also been described10. Thirdly, transplacental management of fetuses with tricuspid regurgitation11, congestive heart failure or fetal hydrops is difficult12,13, probably as a result of limited transplacental transfer of the antiarrhythmic drug14,15. In case of fetal hydrops, conversion rates are decreased and time to conversion is increased13. Treatment of sustained fetal tachycardia is therefore to be preferred above expectant management, although some centers oppose this regimen and suggest that in cases with (intermittent) fetal SVT not complicated by congestive heart failure or fetal hydrops, conservative management and close surveillance might be a reasonable alternative16,17,18

Fetal Tachyarrhythmia - Part I: Diagnosis

Fetal tachycardia, first recognized in 1930 by Hyman et al1, is a condition occurring in approximately 0.4-0.6% of all pregnancies2. A subset of these cases with more sustained periods of tachycardia is clinically relevant. The necessity of therapeutic intervention in this condition is still a matter of discussion focused on the natural history of the disease. The spectrum of opinions varies from non-intervention3,4,5 based on a number of cases in which the tachycardia subsided spontaneously6, to aggressive pharmacotherapeutic intervention7,8 based on reports of deterioration of the fetal condition ultimately ending in significant neurological morbidity9,10,11, or fetal demise12,13,14. Prenatal treatment through indirect, maternally administered drug therapy seems to be the preference of most centers15,16,17,18,19,20,21. This matter will be discussed further in Fetal Tachyarrhythmia, Part II, Treatment

Receiving and providing informal care:Does context matter?

Boer, A.H. de [Promotor]Woittiez, I.B. [Copromotor

Immunohistochemical and molecular studies on the pathogenesis of pheochromocytomas and paragangliomas

Abstract In the last decades major progress has been made in discovering genes implicated in the syndromic occurrence of pheochromocytomas (PCC) and paragangliomas (PGL). It’s now well established that about 35% of all PCC/PGL are due to germline mutations in one of the genes: RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, PHD2, HIF2A, KIF1B, and FH. In addition, somatic mutations in RET, VHL, NF1, and HIF2A can also be detected in a subset of sporadic PCC/PGL. However, the pathogenesis of sporadic PCC and PGL is currently poorly understood. This issue has been investigated in the first part of this thesis (Chapters 2 and 3) by a candidate gene approach. SDHB and SDHA immunohistochemistry (IHC) is a valuable tool to identify PCC/PGL patients with mutations in one of the succinate dehydrogenase (SDH) genes. In the second part of this thesis we validated the reproducibility of this assessment method. Moreover, we determined if SDHA IHC could be a valuable tool to guide genetic testing in another tumor type from the SDH-associated tumor spectrum: gastrointestinal stromal tumors. In addition, we searched for new tools to validate SDH mutations. A major problem in PCC management remains the lack of predictive markers for malignancy and the lack of curative treatment options for progressive disease. In the last part of this thesis we focused on activation of intracellular pathways that could be targets for therapy and on validation of a prognostic tool for the distinction between benign and malignant PCC