Loeys-Dietz syndrome: A possible solution for Akhenaten’s and his family’s mystery syndrome

The presence of a familial disease among royal members of 18th dynasty of the new kingdom who ruled in Egypt from the mid-16th to the early 11th centuries BC has been established, largely prompted by the bizarre body shape of Akhenaten (the iconoclastic pharaoh of this dynasty) and his family, as demonstrated in statues and artwork. It had been thought previously that this was an expression of a revolutionised artistic style that followed radical reforms by Akhenaten of Egyptian society, but recent studies on mummies confirmed the presence of a constellation of corresponding pathologies. Several illnesses have been suggested to solve this enigma; we propose Loeys-Dietz syndrome as a probable diagnosis for this genetic affliction within the royal family

Angiotensin II blockade and aortic-root dilation in Marfan's syndrome

Background: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor (beta) (TGF-(beta)) that can be mitigated by treatment with TGF-(beta) antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. Methods: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. Results: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. Conclusions: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial

Replacing vascular corrosion casting by in-vivo micro-CT imaging for building 3D cardiovascular models in mice

The purpose of this study was to investigate if in vivo micro-computed tomography (CT) is a reliable alternative to micro-CT scanning of a vascular corrosion cast. This would allow one to study the early development of cardiovascular diseases. Datasets using both modalities were acquired, segmented, and used to generate a 3D geometrical model from nine mice. As blood pool contrast agent, Fenestra VC-131 was used. Batson's No. 17 was used as casting agent. Computational fluid dynamics simulations were performed on both datasets to quantify the difference in wall shear stress (WSS). Aortic arch diameters show 30% to 40% difference between the Fenestra VC-131 and the casted dataset. The aortic arch bifurcation angles show less than 20% difference between both datasets. Numerically computed WSS showed a 28% difference between both datasets. Our results indicate that in vivo micro-CT imaging can provide an excellent alternative for vascular corrosion casting. This enables follow-up studies

iPSC-cardiomyocyte models of Brugada syndrome : achievements, challenges and future perspectives

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias

Intermittent Brugada syndrome in an anorexic adolescent girl

AbstractWe report an anorexic adolescent girl with an intermittent Brugada syndrome. A 14-year-old anorexic girl with a body mass index (BMI) of 13.15kg/m2 was admitted in the acute state of the disease with an ST elevation in V1 and V2, suggestive of Brugada syndrome. After 1 month of re-feeding, a control electrograph (ECG) was normal, but after an 8-month follow-up control with a nearly normal BMI, the ECG was again suggestive of Brugada syndrome. A genetic analysis of the gene SNC5A established a genetic change (p Leu 1582 pro), which provides the final explanation for the Brugada syndrome. Every rhythm problem in the acute state or during the re-feeding procedure deserves a strict follow-up to distinguish iatrogenic from heritable rhythm problems.<Learning objective: (i) We report the first case of a patient with anorexia nervosa with an intermittent Brugada syndrome. (ii) Moderate hypothermia can decrease the depolarization of pacemaker cells and cause ST-segment changes. (iii) Every rhythm problem in the acute state or during the re-feeding procedure deserves a strict follow-up to distinguish iatrogenic from heritable rhythm problems. (iv) A genetic analysis can make the distinction and is necessary to give advice for the future lifestyle of the patient.

Absence of cardiovascular manifestations in a haploinsufficient TGFBR1 mouse model

Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor beta (TGF beta)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGF beta receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGF beta signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno) histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS