Genetics and genomics of aortic form and function

The thoracic aorta is a dynamic organ which adapts and remodels throughout life. Thoracic aortic size, shape and function are important contributors to both cardiovascular health and disease and risk of aortic disease. A complex interaction of environmental, genetic and haemodynamic factors is mediated by cells of the aortic wall. This thesis presents aortic phenotyping, genotyping and genome-wide associations of aortic traits in a large healthy cohort of 1218 volunteers. This is the largest study to report normal parameters for healthy thoracic aortic size, shape and function derived from cardiovascular magnetic resonance imaging. Anthropometric and cardiovascular risk factors such as age, gender, body fat mass and lipid profile are identified as significant determinants of aortic phenotype. The work suggests that cardiovascular risk factors could impair normal adaptive aortic remodelling with age. Genome-wide association studies of aortic dimensions and function identify new common variants, genes and pathways which could be important in aortic biology and cardiovascular risk. These include genes involved in cardiovascular development (eg PCDH7 and SON associated with aortic root diameter), autonomic cardiovascular responses (eg GABA receptor genes associated with aortic root diameter), fibrosis (eg ACTC1, AGTR1 associated with ascending aortic distensibility, BAMBI and MYOD associated with descending aortic distensibility) and obesity (eg ARID5B and IRX3 associated with aortic pulse wave velocity and ascending aortic area respectively). Multiple regulatory pathways including TGF-ß and IGF signalling (IGF1R, IGF2R), are identified which are associated with aortic dimensions and function. Joint trait analysis of aortic root dimensions identifies a new genome-wide significant association with TENM4, a key driver of early mesodermal development, and suggestive association with PTN, which is functionally related and plays a key role in angiogenesis. The primary analyses are complemented by exploratory assessment of rare genetic variation in bicuspid aortic valve (BAV) using panel sequencing in 177 patients. Rare variants might cause, or modify phenotype in BAV, but the clinical utility of panel sequencing remains poor. A further complementary study investigates the interaction of haemodynamics with aortic cellular phenotype, using microarray assessment of aortic endothelial cell transcriptomic response to shear stress pattern. Several genes of interest in atherosclerosis and aortic disease are differentially expressed with shear stress pattern, such as FABP4, ANGPT2, FILIP1, KIT, DCHS1, TGFBR3 and LOX. This work yields new insights into aortic phenotype, identifies key loci which might determine aortic traits and explores the complex interdependence of genetics, haemodynamics and environmental variables in aortic biology.Open Acces

Bicuspid aortic valve and associated aortopathy: a combined biomechanics, histological and genetic analysis

Bicuspid aortic valve (BAV) is the most common inborn heart defect and a continuum of a disease process affecting the aortic valve and the thoracic aorta with an increased risk of thoracic aortic aneurysm (TAA) formation and dissection. Aortic dilatation may be related to haemodynamic perturbations or intrinsic wall abnormalities. The aim of this thesis was to investigate the relative contribution of these parameters to BAV aortopathy via integrated analyses. Distribution of circumferential stress in the aorta of BAV patients planned to undergo surgery was analysed using computed tomography imaging and computational modelling. During surgery, aortic biopsies were taken from discrete areas and examined for histological abnormalities. Maximal mechanical stress occurred in the medial ascending aorta in the majority of cases with integrated analyses exhibiting a positive correlation between aortic fibrosis and mechanical stress, both in the root and the ascending aorta. The degree of histological abnormalities and transforming growth factor beta (TGFβ) activation was also assessed in collected tissue biopsies. Patients with either root dilatation and/or predominant regurgitant valve disease had greater levels of medial wall degeneration in their ascending aorta whereas enhanced TGFβ signalling was present in aneurysmal but also, non-dilated BAV aortic segments, pointing to a genetic trigger. Copy number variation (CNV) analyses in a larger BAV cohort revealed a large heterozygous deletion in the angiotensin converting enzyme (ACE) gene and targeted next-generation sequencing revealed previously reported variants in NOTCH1, COL3A1, and APOE genes with additional discovery of a large number of likely pathogenic variants in genes related to BAV formation and aortopathy. In conclusion, different BAV aortic phenotypes were recognised and further analysed. The presence of multiple likely pathogenic variants in sequenced patients suggests a polygenic nature of BAV disease which, in conjuction with local haemodynamic perturbations, supports a mutlifactorial origin of BAV aortopathy.Open Acces

Aortic “Disease-in-a-Dish”: Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling

Thoracic aortic diseases, whether sporadic or due to a genetic disorder such as Marfan syndrome, lack effective medical therapies, with limited translation of treatments that are highly successful in mouse models into the clinic. Patient-derived induced pluripotent stem cells (iPSCs) offer the opportunity to establish new human models of aortic diseases. Here we review the power and potential of these systems to identify cellular and molecular mechanisms underlying disease and discuss recent advances, such as gene editing, and smooth muscle cell embryonic lineage. In particular, we discuss the practical aspects of vascular smooth muscle cell derivation and characterization, and provide our personal insights into the challenges and limitations of this approach. Future applications, such as genotype-phenotype association, drug screening, and precision medicine are discussed. We propose that iPSC-derived aortic disease models could guide future clinical trials via “clinical-trials-in-a-dish”, thus paving the way for new and improved therapies for patients

A multiscale computational model of arterial growth and remodeling including Notch signaling

Blood vessels grow and remodel in response to mechanical stimuli. Many computational models capture this process phenomenologically, by assuming stress homeostasis, but this approach cannot unravel the underlying cellular mechanisms. Mechano-sensitive Notch signaling is well-known to be key in vascular development and homeostasis. Here, we present a multiscale framework coupling a constrained mixture model, capturing the mechanics and turnover of arterial constituents, to a cell-cell signaling model, describing Notch signaling dynamics among vascular smooth muscle cells (SMCs) as influenced by mechanical stimuli. Tissue turnover was regulated by both Notch activity, informed by in vitro data, and a phenomenological contribution, accounting for mechanisms other than Notch. This novel framework predicted changes in wall thickness and arterial composition in response to hypertension similar to previous in vivo data. The simulations suggested that Notch contributes to arterial growth in hypertension mainly by promoting SMC proliferation, while other mechanisms are needed to fully capture remodeling. The results also indicated that interventions to Notch, such as external Jagged ligands, can alter both the geometry and composition of hypertensive vessels, especially in the short term. Overall, our model enables a deeper analysis of the role of Notch and Notch interventions in arterial growth and remodeling and could be adopted to investigate therapeutic strategies and optimize vascular regeneration protocols.</p

The role of mathematical models in designing mechanopharmacological therapies for asthma

Healthy lung function depends on a complex system of interactions which regulate the mechanical and biochemical environment of individual cells to the whole organ. Perturbations from these regulated processes give rise to significant lung dysfunction such as chronic inflammation, airway hyperresponsiveness and airway remodelling characteristic of asthma. Importantly, there is ongoing mechanobiological feedback where mechanical factors including airway stiffness and oscillatory loading have considerable influence over cell behavior. The recently proposed area of mechanophar-macology recognises these interactions and aims to highlight the need to consider mechanobiology when identifying and assessing pharmacological targets. However, these multiscale interactions can be difficult to study experimentally due to the need for measurements across a wide range of spatial and temporal scales. On the other hand, integrative multiscale mathematical models have begun to show success in simulating the interactions between different mechanobiological mechanisms or cell/tissue-types across multiple scales. When appropriately informed by experimental data, these models have the potential to serve as extremely useful predictive tools, where physical mechanisms and emergent behaviours can be probed or hypothesised and, more importantly, exploited to propose new mechanopharmacological therapies for asthma and other respiratory diseases. In this review, we first demonstrate via an exemplar, how a multiscale mathematical model of acute bron-choconstriction in an airway could be exploited to propose new mechanopharmacological therapies. We then review current mathematical modelling approaches in respiratory disease and highlight hypotheses generated by such models that could have significant implications for therapies in asthma, but that have not yet been the subject of experimental attention or investigation. Finally we highlight modelling approaches that have shown promise in other biological systems that could be brought to bear in developing mathematical models for optimisation of mechanopharmacolog-ical therapies in asthma, with discussion of how they could complement and accelerate current experimental approaches

Blood

This book examines both the fluid and cellular components of blood. After the introductory section, the second section presents updates on various topics in hemodynamics. Chapters in this section discuss anemia, 4D flow MRI in cardiology, cardiovascular complications of robot-assisted laparoscopic pelvic surgery, altered perfusion in multiple sclerosis, and hemodynamic laminar shear stress in oxidative homeostasis. The third section focuses on thalassemia with chapters on diagnosis and screening for thalassemia, high blood pressure in beta-thalassemia, and hepatitis C infection in thalassemia patients

New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas

This book includes 17 papers published in the Special Issue/Article Collectoin “New Insights in the Genetics and Genomics of adrenocortical tumors and pheochromocytomas” including an editorial, 10 research papers and six review articles. Adrenal tumors represent a hot topic in contemporary endocrine oncology. Significant advancements in the genetics of genomics of these tumors have been made in recent years, and these articles give a useful and comprehensive overview of these issues. Questions regarding molecular pathogenesis, diagnosis (biomarkers) and even treatment are discussed in the papers written by international leaders of the field. Manuscripts are focused on three main topics: i. primary aldosteronism (the most common cause of secondary endocrine hypertension), ii. adrenocortical cancer and iii. pheochromocytoma/paraganglioma, which are the tumors with the highest heritability in humans. The book is edited by Prof. Peter Igaz (Department of Endocrinology, Faculty of Medicine, Semmelweis University)

The use of next generation sequencing in rare disease

Introduction: High throughput next generation sequencing (NGS) strategies such as whole exome sequencing (WES) are frequently used in medical research to identify the molecular cause of Mendelian genetic disease. WES, or clinical exome sequencing strategies are now being adopted into clinical genetics practice. This study focuses on the application of WES for genetic diagnosis in a group of mainly consanguineous families with rare phenotypes for which an autosomal recessively inherited disease was suspected but the molecular basis was unknown. Materials and methods: Families were recruited retrospectively from a previous research cohort (the National Autozygosity Mapping study) and prospectively from the Birmingham Women’s and Children’s NHS Foundation Trust. WES was subsequently performed. Results: 35 families with rare genetic disorders were studied by WES (in 9 families a single individual underwent sequencing). After bioinformatics analysis of WES data and detailed reassessment of the phenotype a molecular genetic diagnosis was reached in 15 families (42.9%). Conclusion: WES is an effective strategy for identifying the molecular basis of recessively inherited disorders in consanguineous families. The combination of WES with detailed phenotyping significantly improved variant interpretation and diagnostic yield over WES alone

Abstracts from the 50th European Society of Human Genetics Conference: Posters

International audienc