Page 12 - Laurens Bosman
P. 12

Sudden  cardiac  death  (SCD)  is  a  significant  public  health  issue  worldwide.  In  Western
              populations, SCD is reported to account for up to 15-20% of all deaths.   Especially in young
              individuals, such a sudden unexpected death is often associated with a devastating emotional
              and economic impact on family and society. In the Netherlands, every three days an individual
              below the age of 40 dies suddenly.  Characteristic of SCD in young individuals is that it is
              commonly caused by congenital disease, familial/genetic channelopathy, or familial/genetic
              cardiomyopathy. The subject of this thesis, arrhythmogenic right ventricular cardiomyopathy
              (ARVC), is one of these common causes of SCD in young individuals.

                   ARVC  is  a  familial  cardiomyopathy  characterized  by  fibrofatty  replacement  of
              predominantly  the  right  ventricular  myocardium.   The  prevalence  of  ARVC  is  estimated
              between 1 in 2000-5000, although as ARVC is thought to be underrecognized some claim the
              true prevalence to be closer to 1 in 1000.  The disease typically manifests in late adolescence
              or early adulthood, with possible first symptoms ranging from mild palpitations to SCD. In the
              majority of patients, a disease-causing variant is found in genes encoding the desmosome.
              Others may carry one of several non-desmosomal gene variants also associated with ARVC,
              and in the remaining cases no variants are found.  Most genetic variants show an autosomal
              dominant inheritance pattern, but with incomplete penetrance.  Besides the variety in genetic
              background,  the  phenotypic  disease  expression  and  risk  of  life-threatening  ventricular
              arrhythmias is also highly variable among individual ARVC patients. The cause of this high
              individual variation, even within the same family, is not well understood. Physical exercise is
              thought to  be  one  of  the  factors that  promote disease  progression,  but  the  nature  of this
              association needs to be further investigated. As a result of this individual variation, diagnosing
              patients with ARVC as well as estimating their risk of SCD is complex and challenging. The
              tools for providing personalized medicine to ARVC patients are still fairly limited. In Chapter
              2,  we  provide  a  detailed  description  and  discussion  of  the  current  state-of-the-art  in  our
              disease understanding, clinical diagnosis, risk prediction and treatment options.

                   As  there  is  no  cure for ARVC,  a  principle  aim  in  the  clinical  management  of  ARVC
              patients is prevention of SCD. The only proven therapy that prevents SCD in ARVC patients,
              the placement of an implantable cardioverter defibrillator (ICD), greatly depends on timely and
              accurate diagnosis and risk prediction. Hence, the challenges in diagnosis and risk prediction
              in ARVC have been an important topic of research in recent years. While progress has been
              made, many challenges still remain. Motivated by these clinical challenges, and inspired by
              the preceding work of many national and international researchers, I started my research
              career in 2016 focused to find potential solutions. In this thesis I present the results of my
              research on personalized medicine in ARVC.

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