34 research outputs found
Congenital Aortic Stenosis and Aneurysms
Due to improvements in pediatric cardio-thoracic surgery, anesthesia and diagnostics over the past
decades, the number of adult patients with congenital heart disease (CHD) is growing. This causes
an increasing demand in clinical practice for insight in long term outcome in both non-operated and
operated adult CHD patients. Furthermore, knowledge about etiology and genetics of CHD is rapidly
expanding. Every day new genes and syndromes are identified.
In order to grasp the exact nature of the pathologies described in this thesis, the epidemiology of
CHD and the functional anatomy of the left ventricular outflow tract and aorta will first be delineated.
Thereafter, the congenital aortic disorders investigated in this thesis will be introduced individually.
Finally, the aim and outline of this thesis will be presented
VentricularâVascular Coupling in Marfan and NonâMarfan Aortopathies
Background: Marfan syndrome (MFS) and familial nonâsyndromal thoracic aortic
aneurysm and dissection (nsâTAAD) are genetic aortopathies causing aortic
dilatation with increased aortic stiffness. Left ventricular (LV)
contractility and ventricularâvascular coupling index (VVI) were compared
between MFS and nsâTAAD and determinants of VVI were investigated. Methods and
Results: Patients with MFS (M 57, F 47) and nsâTAAD (M 72, F 39) were studied
by echocardiography and compared with controls (M 77, F 71). Aortic geometry,
hemodynamics, LV work, LV contractility (endâsystolic elastance [Ees]), and
VVI were documented. Aortic sinuses were equally dilated in MFS (19.7±2.4) and
nsâTAAD (19.8±1.8) compared to controls (16.2±1.4 mm·mâ2, P<0.001). Aortic
stiffness index was increased in MFS (9.7±5.1) and nsâTAAD (10.8±4.7) versus
controls (5.4±2.0, P<0.01); LV stroke work was unchanged in MFS (436±74)
compared to controls (435±60) but increased in nsâTAAD (492±109 mJ·mâ2
P<0.01). The LV Ees was reduced in MFS (1.32±0.19) compared to controls
(1.65±0.29 mm Hg·mLâ1, P<0.01) but increased in nsâTAAD (1.83±0.30, P<0.01)
and VVI was abnormal in MFS (0.71±0.11) compared to controls (0.62±0.07,
P<0.01) and nsâTAAD (0.62±0.09). Treatment with ÎČâblockers was associated with
partial normalization of VVI in MFS. A VVI â„0.8 was associated with increased
risk of death and heart failure in MFS. Conclusions: Left ventricular
contractility and ventricularâvascular coupling are abnormal in MFS but
preserved in nsâTAAD, and are independent of aortic stiffness, consistent with
intrinsic impairment of myocardial contractility in MFS
Psychological well-being in patients with aneurysms-osteoarthritis syndrome
Aneurysms-osteoarthritis syndrome (AOS) is characterized by arterial aneurysms and dissection in combination with early-onset osteoarthritis, which can impact quality of life. We describe the subjective quality of life and investigate anxiety and depression in 28 AOS patients aged 15â73 years. Three questionnaires were used: 36-Item Short Form Survey (SF-36), hospital anxiety and depression scale (HADS) and Rotterdam disease specific questionnaire. Results of the SF-36 and HADS were compared to a reference Dutch cohort and the SF-36 questionnaire also to patients with Marfan syndrome. Compared to the general population, AOS patients scored significantly lower on the following SF-36 domains: physical functioning, vitality, social functioning, bodily pain, and general health. Physical functioning was also lower than in Marfan patients. Patients with AOS scored higher on the HADS depression scale, while anxiety did not show a significant difference compared to the general population. No difference in SF-36 and HADS domain scores were found between patient with and without orthopaedic symptoms and patients with or without previous aortic surgery. Additionally, we found that patients' worries for their future and heredity o
Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1
Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers
Aneurysms-osteoarthritis syndrome : SMAD3 gene mutations /
"[This book] is a first-of-its-kind compilation of the genetic discovery, research, and care associated with AOS. With the field of genetically triggered aortopathies growing, this important reference will compile the newest discoveries in this field, allowing cardiologists, cardio-thoracic surgeons, clinical geneticists, vascular surgeons, orthopedic surgeons, and researchers to gain the knowledge they need without having to gather the data from various sources.Coverage includes genotype and phenotype correlations, the functional role of SMAD3, and insights into the role of TGFbeta signaling in aortic disease. The book will increase knowledge about AOS, providing awareness and better patient care for this aggressive disease." -- from website publisherIncludes bibliographical references and index.Online resource, title from PDF title page (EBSCO, viewed October 23, 2016)."[This book] is a first-of-its-kind compilation of the genetic discovery, research, and care associated with AOS. With the field of genetically triggered aortopathies growing, this important reference will compile the newest discoveries in this field, allowing cardiologists, cardio-thoracic surgeons, clinical geneticists, vascular surgeons, orthopedic surgeons, and researchers to gain the knowledge they need without having to gather the data from various sources.Coverage includes genotype and phenotype correlations, the functional role of SMAD3, and insights into the role of TGFbeta signaling in aortic disease. The book will increase knowledge about AOS, providing awareness and better patient care for this aggressive disease." -- from website publisherChapter 1 - Genetics of Aneurysms-Osteoarthritis Syndrome -- Chapter 2 - Cardiovascular Phenotype of Aneurysms-Osteoarthritis Syndrome -- Chapter 3 - Systemic Features of Aneurysms-Osteoarthritis Syndrome -- Chapter 4 - Differential Diagnosis in Heritable Thoracic Aortic Diseases -- Chapter 4a - Marfan Syndrome -- Chapter 4b - Loeys-Dietz Syndrome -- Chapter 4c - Ehlers-Danlos Syndrome -- Chapter 4d - Bicuspid Aortic Valve -- Chapter 4e - Turner Syndrome -- Chapter 5 - Cardiovascular Imaging in Aneurysm-Osteoarthritis Syndrome -- Chapter 6 - Treatment Options -- Chapter 6a - Optimal Cardiovascular Medical Treatment -- Chapter 6b - Cardiothoracic Surgical Experience -- Chapter 6c - Vascular Interventions and Surgical Experience -- Chapter 6d - Orthopedic Evaluation and Treatment Options -- Chapter 6e - Genetic Counseling -- Chapter 6f - Approach to Clinical ManagementElsevie
Pulmonary stenosis: Update on diagnosis and therapeutic options
Pulmonary stenosis (PS) accounts for approximately
8% of all congenital heart defects.1 Valvular PS is
usually an isolated defect, but it can be associated
with other congenital heart defects, such as atrial
septal defect (ASD), ventricular septal defect
(VSD), and persistent ductus arteriosus. Combined
valvular and infundibular PS can be part of tetralogy
of Fallot (ToF).
The clinical presentation of PS may vary from
critical stenosis in the newborn, to asymptomatic
mild stenosis without need for therapy throughout
life. The need for treatment of critical PS in the
newborn is obvious, but the optimal timing, type
of treatment, and follow-up strategy for the asymptomatic
patient is less well defined