The transient hyperaemic response (THR) is a novel way of assessing vascular reactivity that measures vasodilatory responses after 10-20 second periods of ischaemia. Previous studies have combined the THR test with measurements of microcirculatory perfusion using laser Doppler flowmetry in the of forearm skin of healthy volunteers. A database of over 1000 measurements in over 100 subjects was analysed to further establish the inter- and intra-individual variability of THR measurements. THR measurements of skin vascular reactivity were performed in laboratory experiments designed to explore the practicality of the test when investigating vascular reactivity in critical illness. Positive end-expiratory pressure caused fluctuations in skin perfusion but did not alter the THR. Both perfusion and THR could be manipulated by the iontophoresis of several drugs used in critical care, but the possibility of carrier solutions causing vasodilatory effects could not be ruled out. Norepinephrine was successfully iontophoresed into forearm skin and caused vasoconstriction which partially reversed the decreased THR caused by localised heating. A pilot study of cutaneous THR measurements in patients with evidence of systemic inflammation demonstrated decreases in vascular reactivity compared with the database of healthy volunteers, but the test was found to be less robust within intensive care than was anticipated. A retrospective analysis was performed of patients admitted to intensive care following a planned operation, or presumed to have sepsis, in order to evaluate the effects of prior administration of statins and other potentially vasoactive drugs. Previous research demonstrated associations between statin usage and improved outcome in bacteraemic patients. This analysis identified no benefit from prior statin usage. One hypothesis generated by this research was that the pleiotropic effects of different statins were not class effects. Further research designed to evaluate the effects of different statins on skin microvascular reactivity using the transient hyperaemic response is planned.

Previously, acyl derivatives of CoA were shown to antagonise human native and recombinant P2Y1 purine receptors. The main aim of this thesis was to study the effect of these endogenous nucleotide derivatives at endogenous P2Y1 receptors in blood vessels. Using isometric tension recordings, CoA, acetyl-CoA and palmitoyl-CoA (PaCoA) appeared to show selectivity for P2Y1 receptors (over P2Y2 and adenosine receptors) in the rat isolated thoracic aorta, with PaCoA being the most potent of the CoA derivatives used. In porcine isolated mesenteric arteries (PMA) and porcine isolated coronary arteries (PCA), isometric tension recordings indicated that ADP mediated endothelium-dependent and endothelium-independent relaxations, respectively. Relaxations in PMA were blocked by the P2Y1 receptor antagonist MRS2500 and PaCoA, whilst these were ineffective against ADP relaxations in the PCA. A FlexStation was used to monitor calcium responses in native HEK293 cells expressing P2Y1 and P2Y2 receptors using ADP and UTP, respectively. Responses to UTP were not significantly altered in the presence of PaCoA. In contrast, ADP-evoked responses were significantly inhibited in the presence of either MRS2500 or PaCoA. These data raise the possibility of an endogenous selective antagonism of P2Y1 receptors via CoA compounds, irrespective of species or cellular environment. Nicotinamide adenine dinucleotide (NAD) is an intracellular nucleotide which has been identified as an agonist at P2Y1, P2Y11, P2X and adenosine receptors. NAD evoked endothelium-independent concentration-dependent contractions of the pre-contracted PMA, which were unaltered in the presence of PaCoA. In contrast, αβ-methylene ATP (a desensitizing P2X receptor agonist) significantly reduced these responses suggesting the involvement of P2X1-like receptors. In both RTA and PCA, NAD evoked endothelium-independent concentration-dependent relaxations of the pre-contracted vessels, which were attenuated by SCH58261, but not PaCoA, which suggests the involvement of smooth muscle A2A receptors. These results together emphasise the possibility of a tissue and receptor-specific role of NAD as an endogenous extracellular nucleotide in purinergic signalling.

Congenital heart defects are responsible for more neonatal deaths than any other birth defect. Although genetic and environmental factors play an important role, either separately or in combination (multifactorial), still the cause in most cases remains unknown. Changing life styles, e.g. exposure of the mother to excessive alcohol, nicotine in tobacco smoke, easily available traditional and, over the counter medicines and environmental contaminants could be possible causes of congenital malformations. Maternal diseases like diabetes mellitus are also one of the etiological factors for developmental defects. Several developmental genes, for instance connexin 43; one of the key proteins involved in cardiovascular development, and endothelin 1; another important gene required in many developmental processes, could be responsible for developmental anomalies of the heart. Supplementation with micronutrients such as folic acid and Vitamin C during the periconceptional period has been shown to prevent some neural tube and congenital heart defects. This study was aimed at evaluating the adverse effects of ethanol, retinoic acid, nicotine, cadmium chloride, sodium fluoride, ginseng and diabetic conditions on chick cardiomyocytes cultured in the micromass system, and examining the potential protective effects of folic acid and vitamin C. Also teratogenic effects of some of the teratogens, ethanol, nicotine, retinoic acid and diabetic conditions, were examined using in ovo culture. Hearts were dissected from 5 day old White Leghorn chick embryos and the cells were isolated and cultured. They were exposed to different concentrations of test chemicals. Folic acid and vitamin C were added to see any protective effects. Cell viability was assessed using the resazurin reduction assay and the kenacid blue assay was performed for determining cell number. For in ovo culture, day 3 chick embryos were injected with ethanol, nicotine, retinoic acid or diabetic molecules or a combination of teratogenic chemicals and vitamins (folic acid and vitamin C). Immunohistochemistry and western blotting were employed to detect the expression of connexin 43 and endothelin 1. Results of micromass culture revealed that ethanol, retinoic acid, nicotine, cadmium chloride and diabetic conditions dramatically reduced cellular differentiation, cell viability and protein content in a dose dependant manner. However, vitamin C (100µM) and folic acid (1mM) administered concurrently with these chemicals, except for cadmium chloride, could significantly improve all parameters such that the values were comparable with the control. Nicotine had no effect on cell viability and protein content, but cell beating was significantly affected. This effect was reversed by the addition of Vitamin C and folic acid. Results of in ovo culture showed that ethanol and diabetic conditions caused gross and histological malformations in chick embryos. However their effects were abrogated with supplemental folic acid and vitamin C. Immunohistochemical and western blotting results demonstrated a decreased expression of Cx43 and endothelin 1 in ethanol, retinoic acid, nicotine and diabetic condition treated cells while addition of vitamins restored their expression so they were comparable to controls. It may be that environmentally induced teratogenic effects on heart development could be prevented by supplementation with Vitamin C and folic acid during pregnancy.

Human pluripotent stem cell (hPSC) derived cardiomyocytes can provide robust in vitro models for pharmaceutical drug screening and modelling cardiac disease. To fully realise these potentials, hPSC-cardiomyocytes must be reproducibly cultured to a more mature state than has thus far been achieved. Defined and well controlled culture conditions underpin the ability to derive hPSC-cardiomyocytes of consistent quality. These include cell source, culture medium and substrate. This thesis is concerned with the latter; culture substrates are currently biological in nature creating inherent variability in culture conditions. There is limited knowledge on the interaction between cardiomyocytes and synthetic, non-biological substrates making rational design of materials impractical. To aid discovery of novel culture substrates, 115 polyacrylate and polyacrylamide substrates were microarrayed and investigated using a parallel screening approach. The use of polyacrylates and polyacrylamides as biomaterials has been demonstrated previously, including contact lenses, bone cements and hydrogels to support cells. The diverse chemistry exhibited across the range of polymers enables modelling of structure-activity relationships between substrate chemistry and cardiomyocyte behaviour. Cardiomyocytes derived from human embryonic stem cells (hESC) were cultured on the microarrays in the presence and absence of serum. Attachment density (nuclei count via DAPI staining) and cardiomyocyte spread (surface area using sarcomeric α-actinin immunostaining) on each substrate was acquired by automated fluorescence microscopy and image analysis software. From this primary screen, 70 % of polymers were found to support cardiomyocytes adhesion in serum conditioned arrays, BM34 (fufuryl methacrylate) supported the highest relative cell density (0.59 ±0.28) and also the largest cell size (1364 ±937 µm2), which was comparable to gelatin control. In serum free conditions, only 10 % of polymers supported cardiomyocyte attachment. The highest relative cell density was on AM38 (Dimethylamino-propyl acrylate) and largest cell size on BM49 (Tert-butylamino-ethyl methacrylate), 274 ±75 µm2, which was significantly lower than cell density and cell area (2019 ±596 µm2) on gelatin control. To investigate if synergy exists between polymers that enable adhesion in serum free conditions and those that support larger cell areas in serum conditioned arrays, 24 polymers were mixed pair-wise to form second generation microarrays comprising of 576 co-polymers. This diverse library enabled unique combinations of chemical moieties to be explored and co-polymers were found to have a greater proportion (74 %) that supported cardiomyocyte attachment in serum free conditions, largest average cell size was now 1089 ±260 µm2 on BM80/AM64 (Methacryloyloxy)ethyl acetoacetate/ Hexadecafluoro-9-(trifluoromethyl)decyl acrylate). Five co-polymers were chosen to perform more detailed characterisation of cardiomyocytes cultured on them for 5 and 25 days. Electrophysiological profiling and quantification of myofibril organisation identified co-polymers AD17/BM54 (Hexanediol ethoxylate diacrylate/ Ethoxyethyl methacrylate) and BM80/AD17 to be comparable to control gelatin. Partial least squares multivariate regression analysis correlated chemical species from the polymeric substrate, identified using time of flight secondary ion mass spectrometry, with cardiomyocyte response and identified moieties beneficial or detrimental for cardiomyocyte adhesion and cell area. This may aid rational design of tailor-made non-biological substrates for cell culture. In summary, the parallel screening of co-polymers of acrylates and acrylamides has been the first step in a discovery process of lead materials capable of progressing the culture of cardiomyocytes in more reproducible, economical and defined conditions. Only five substrates were analysed in detail, leaving a large library of co-polymers worthy of further investigation, including the physical properties of the polymers that need to be considered for practical use of the polymers in culture.

Hypertrophic cardiomyopathy (HCM) is a prevalent genetic cardiovascular disease affecting 1:500 individuals whose cardiac function is deteriorated due to thickening of the left ventricle of the heart, mostly owing to mutations in sarcomeric genes. Modeling HCM in vitro using human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) offers promise to further investigate the disease mechanisms, towards the development of effective drugs. Herein, nickase CRISPR/Cas9 genome editing technology was harnessed to introduce the R453C pathological mutation in the MYH7 sarcomeric gene, in three healthy hPSC lines. Monoclonal hPSC lines generated displayed the mutation in one or both alleles, as confirmed by PCR-genotyping and Sanger sequencing. A monolayer cardiac differentiation protocol was applied to the generated hPSC lines, resulting in >90% cardiomyocyte purities, and expression of mutant allele(s) of the MYH7 gene was analysed by RT-PCR. High-content imaging analysis showed that mutant hPSC-CMs displayed higher expression of hypertrophic marker Brain Natriuretic Peptide (BNP), in comparison to isogenic controls. BNP expression was maximised by treatment with hypertrophic inducer Endothelin-1 and rescued by its antagonist Bosentan. Flow cytometry analysis revealed a mild increase in cell volume of mutant cardiomyocytes relative to their wild-type controls. Functional evaluation of gene-edited lines exposed higher mitochondrial respiration rates relative to the isogenic controls, with the same mitochondrial content, resulting in a trend towards oxidative stress. Further genome engineering to incorporate a calcium indicator in R453C-MYH7 lines enabled confocal line analysis of calcium transients. MYH7-mutant hPSC-CMs exhibited higher frequency of irregular events in comparison to the healthy control, faster calcium kinetics, and higher resting cytosolic calcium concentration. Integration of hPSC-CMs in Engineered Heart Tissues (EHTs) and subsequent analysis of contractile force showed that mutant lines had a hypo-contractile and negative clinotropic phenotype relative to their isogenic controls. Moreover, R453C-MYH7 hEHTs showed a more pronounced negative force-frequency relationship in comparison with the healthy lines. These phenotypes were not rescued by treatment with cardiac myosin activator Omecamtiv Mecarbil, suggesting that targeting other mechanisms indirectly related with the contractile apparatus may be a preferred route to attenuate the observed pathological changes. Finally, transcriptomic analysis of gene-edited lines showed up-regulation of genes associated with fetal gene program, hypertrophy, fibrosis, apoptosis and autophagy, indicating potential molecular mechanisms associated with the observed phenotypes and HCM progression. Overall, hPSC-CMs bearing the R453C-MYH7 mutation exhibit the main molecular and functional hallmarks of HCM, providing a physiologically-relevant platform that enables further dissection of disease mechanisms and promotes pharmacological intervention.

Non-ischaemic right ventricular dysfunction and cardiac failure is a source of considerable morbidity in children with congenital heart disease. Despite an increasing body of evidence suggesting that the intrinsic regenerative capacity of the heart can be encouraged by stimulation of resident cardiac stem cells or the transplantation of extracardiac progenitor cells, cell transplantation has not previously been studied in the paediatric setting where enhancing the function of the ventricle in response to supraphysiological workloads might be beneficial. Firstly I studied extra-cellular matrix composition, myocyte homeostasis and gene expression in right ventricular biopsies obtained from patients with Hypoplastic Left Heart Syndrome (HLHS) undergoing neonatal surgical palliation and from patients undergoing neonatal truncus arteriosus repair in order to investigate potential differences in the myocardial substrate which could have implications for adaptive growth potential and haemodynamic performance in HLHS. Simultaneous to these activities, I collected, isolated and analysed umbilical cord blood stem cells from children born with either structurally-normal hearts or HLHS to investigate whether such cell populations might be useful in cardiac augmentation. We then transplanted human cord blood stem cells from normal cord blood donors into an immunosuppressed neonatal sheep model of right ventricular training, taking load-independent functional measurements at baseline and again after one month. Transplanted human cells were detected in the myocardium, spleen, kidney and bone marrow up to 6 weeks after transplantation. Human cells expressed the haematopoietic marker CD45 and in the bone marrow and spleen, also the mature B cell marker CD23. Significant functional improvements were seen in the group receiving human cord blood stem cells compared to placebo. Data demonstrated that lineage negative-enriched cord blood stem cells engraft and adopt traditional haematopoietic cell fates in both myocardium as well as natural niches such as bone marrow and spleen.

Prospective, randomised controlled trials were performed to investigate the benefits of cardiac rehabilitation in two selected patient groups. One group comprised patients in the early stage of recovery after an uncomplicated myocardial infarction. The other consisted of patients with stable chronic heart failure, who are usually excluded from exercise programmes. The reliability and validity of a new method of measuring ambulatory activity was determined. The rehabilitation programme for the post myocardial infarction patients lasted six weeks and contained education and exercise components. Three groups were recruited; a control group, a group who only undertook the education sessions and a group who also participated in a training programme. Comparison of changes in psycho-social parameters and physiological function were made between the groups after completing the programme and three months later. The education + exercise group showed significantly greater improvements (p<0.05) in anxiety, ambulatory activity and rehabilitation status compared to the other groups. Indications of predominantly peripheral adaptation to training were observed, but no significant differences in physiological function were found between the three groups. The education only group did not show any significant differences to the control group in any areas. A crossover-design was used in the chronic heart failure study. This comprised a control and exercise period, each lasting two months. Assessments of psycho-social parameters and physiological function were made at monthly intervals. Exercise training produced significant improvements in depression, quality of life and ambulatory activity. Both central and peripheral adaptations to training were observed, with significant benefits in peak cardiac index, oxygen uptake and resting heart rate. Improvements in ventilator efficiency were also noted.

Background Essential hypertension remains a major risk factor for coronary heart disease (CHO) and stroke, and its prevalence is greater, more severe, occurs earlier, and is less well controlled among black individuals than among white individuals, at all ages after young adult hood (Comoni-Huntley et al, 1989). In Caucasians, studies have shown that β2-adrenoceptor polymorphism accounts for the variability in the vascular responsiveness to the agonist isoprenaline (Cockcroft et al, 1994 and Lang et al, 1995). Individuals homozygous for Gln 27 β2-adrenoceptor showed reduced responses due to chronic down regulation of β2-adrenoceptor in the vasculature. Therefore, variability in response to isoprenaline was determined by β2-adrenoceptor gene polymorphism. Aim and Objectives This study investigated whether there is a relationship between the ArglGly16 and Gln/Glu 27 β2-adrenoceptor polymorphisms by examining whether the incidence of occurrence is prevalent in African Trinidadians. In addition, comparison data of vascular responses with arterial compliance using pulse wave analysis (PWA) was correlated. The study aimed to give evidence if these polymorphisms contributed fully or in part, to determine the disease severity, or response to therapy in hypertensive individuals. It also aimed to prove that PWA is a reliable and therapeutic tool, in diagnosing and treating blood pressure, as reliance on brachial artery recording of blood pressure, alone, is becoming a poor indicator and predictor of risk. Methods The study genotyped 408 African Trinidadian subjects for the β2-adrenoceptor polymorphism and used the technique of applanation tonometry to analyse the central pulse wave, generating information on arterial compliance, left ventricular function and coronary perfusion. Blood pressure was measured in triplicate using a semiautomatic blood pressure meter after 15 minutes of supine rest and bloods lipids assessed using a validated portable lipid cartridge. This was achieved by subjects attending a nurse-led cardiovascular risk clinic. Results There is no significant association between the Arg-Glyl6 polymorphism and the Gln-Glu27 polymorphism and hypertension in African Trinidadians. Interestingly, the appearance of the Glu27 polymorphism was very uncommon in African Trinidadians and this is constant with findings by Candy et al, 2000. Conclusion There is no difference in the frequency of β2-polymorphisms between normotensive and hypertensive African Trinidadians, and are unlikely to be a contributing factor for essential hypertension. Therefore, hypertension would indicate that it is polygenic with complex gene to gene and gene environmental interactions, through multiple, indirect and intermediate phenotypes and interactions.

Background: Screening for atrial fibrillation (AF) has been recommended but is yet to be implemented in clinical practice. However, the most effective approaches for screening are not known and it is unclear if screening could feasibly be implemented in primary care. Aims and methods The overall aims were to determine how AF screening might feasibly and effectively be introduced into primary care in the United Kingdom (UK). Objectives were: 1) to determine the range and accuracies of methods for detecting pulse irregularities attributable to AF, 2) to determine the range and accuracies of methods for diagnosing AF using 12-lead electrocardiograms (ECGs) and 3) to investigate the feasibility and opinions of healthcare professionals (HCPs) in primary care about implementing AF screening. Three studies were undertaken: 1) a systematic review and meta-analysis of the diagnostic accuracy of methods for detecting pulse irregularities caused by AF, 2) a systematic review and meta-analysis of the diagnostic accuracy of methods for diagnosing AF using 12-lead ECG and 3) a survey of HCPs in primary care about screening implementation. Results: Study 1: Blood pressure monitors (BPMs) and non-12-lead ECGs had the greatest accuracy for detecting pulse irregularities attributable to AF [BPM: sensitivity 0.98 (95% CI 0.92-1.00), specificity 0.92 (95% CI 0.88-0.95), positive likelihood ratio (PLR) 12.1 (95% C.I 8.2-17.8) and negative likelihood ratio (NLR) 0.02 (95% C.I 0.00-0.09); non-12-lead ECG: sensitivity 0.91 (95% CI 0.86-0.94), specificity 0.95 (95% CI 0.92-0.97), PLR 20.1 (95% C.I 12-33.7), NLR 0.09 (95% C.I 0.06 to 0.14); there were similar findings for smart-phone applications although these studies were small in size. The sensitivity and specificity of pulse palpation were 0.92 (95% CI 0.85-0.96) and 0.82 (95% CI 0.76-0.88), respectively (PLR 5.2 (95% C.I 3.8-7.2), NLR 0.1 (0.05-0.18)]. Study 2: The sensitivity and specificity of automated software were 0.89 (95% CI 0.82-0.93) and 0.99 (95% CI 0.99-0.99), respectively; PLR 96.6 (95% C.I 64.2-145.6); NLR 0.11 (95% C.I 0.07-0.18). ECG interpretation by any HCPs had a similar sensitivity for diagnosing AF as automated software but a lower specificity [sensitivity 0.92 (95% CI 0.81-0.97), specificity 0.93 (95% CI 0.76-0.98), PLR 13.9 (95% C.I 3.5-55.3), NLR 0.09 (95% C.I 0.03-0.22). Sub-group analyses of primary care professionals found greater specificity for General Practitioners (GPs) than nurses [GPs: sensitivity 0.91 (95% C.I 0.68-1.00); specificity 0.96 (95% C.I 0.89-1.00). Nurses: sensitivity 0.88 (95% C.I 0.63-1.00); specificity 0.85 (95% C.I 0.83-0.87)]. Study 3: 39/48 (81%) practices had an ECG machine and diagnosed AF in-house. Fewer non-GP HCPs reported having excellent knowledge about ECG interpretation, diagnosing and treating AF than GPs [Proportion (95% CI): ECG interpretation = GPs: 5.9 (2.8-12.0); healthcare assistants (HCAs): 0; nurses: 2.0 (0.3-13.9); Nurse practitioners (NPs): 11.8 (3.0-36.4). Diagnosing AF = GPs: 26.3 (17.8-37.0); HCAs: 0; nurses: 2.0 (0.3-12.9); NPs: 11.8 (2.7-38.8). Treating AF = GPs: 16.9 (9.9-27.4); HCAs: 0; nurses: 0; NPs: 5.9 (0.8-34.0)]. A greater proportion of non-GP HCPs reported they would benefit from ECG training specifically for AF diagnosis than GPs [proportion (95% CI) GPs: 11.9% (6.8-20.0); HCAs: 37.0% (21.7-55.5); nurses: 44.0% (30.0-59.0); NPs 41.2% (21.9-63.7)]. Barriers included time, workload and capacity to undertake screening activities, although training to diagnose and manage AF was a required facilitator. Conclusions: BPMs and non-12-lead ECG were most accurate for detecting pulse irregularities caused by AF. Automated ECG-interpreting software most accurately excluded AF, although its ability to diagnose this was similar to all other HCP groups. Within primary care, the specificity of AF diagnosis was greater for GPs than nurses. Inner-city general practices were found to have adequate access to resources for AF screening. Non-GP HCPs would like to up-skill in the diagnosis and management of AF and they may have a role in future AF screening. However, organisational barriers, such as lack of time, staff and capacity, should be overcome for AF screening to be feasibly implemented within primary care.

Background: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited genetic disorder of blood vessel development characterised by mucocutaneous telangiectasia and arteriovenous malformations (AVMs). There are no recent epidemiological studies of the prevalence of HHT in the UK, and no population-based studies investigating the burden of disease complications and mortality in this country. Some of the most devastating complications of HHT such as stroke and cerebral abscess arise as a result of AVMs developing in the pulmonary circulation. Current evidence for the management of pulmonary AVMs using percutaneous embolisation derives from relatively small cohorts published by specialist centres worldwide. No studies have attempted to pool this published literature to summarise the complication rates and efficacy of embolisation. Additionally, there is uncertainty as to whether the apparent low mortality associated with treatment of PAVMs (published in the worldwide literature) is also replicated in the experiences of UK centres currently undertaking the procedure. Methodology: This research project used large-scale, representative primary care (The Health Improvement Network - THIN) and secondary care (Health Episode Statistics - HES) databases to investigate the prevalence, comorbidities and mortality related to HHT, and the mortality related to treatment for pulmonary AVMs. We further used epidemiological methods to summarise the worldwide published literature regarding the safety and efficacy of percutaneous embolisation as a treatment for pulmonary AVMs. The specific questions addressed in the studies were; 1. What is the current UK prevalence of HHT and how does this vary with respect to sociodemographic factors? Using a primary care database (THIN), prevalence rates and adjusted prevalence rate ratios were calculated for HHT and pulmonary AVMs stratified for age group, sex, calendar year, socioeconomic status and geographical location. 2. What are the significant complications and comorbidities associated with HHT? A case-control study using THIN examined the common complications associated with a diagnosis of HHT and looked at commoner cardiovascular and malignant comorbidities that may be associated with a diagnosis of HHT. 3. What is the mortality related to HHT in the UK? A case-control study in THIN compared mortality between over 600 cases of HHT with age, sex and primary care practice matched controls, analysing mortality trends by age, sex and socioeconomic status. 4. What is the safety and effectiveness of percutaneous embolisation as a treatment for pulmonary arteriovenous malformations? A systematic review and meta-analysis of published studies worldwide looking at safety and effectiveness of embolisation was undertaken. 5. What are the current mortality trends in England for patients undergoing percutaneous embolisation for treatment of pulmonary arteriovenous malformations? Using an extract from the HES database linked to Office for National Statistics death data we investigated mortality associated with embolisation for arteriovenous malformation in England over a 15 year period. Results: 1. The minimum prevalence of diagnosed HHT in the UK was calculated to be 1 in 9,400, with the disease more commonly diagnosed in the female sex, those from older age groups, those from higher socioeconomic groups and patients from certain geographical areas of the UK. 2. A variety of haemorrhagic and neurological complications were commoner in HHT than matched controls including stroke (odds ratio (OR) 1.81) , cerebral abscess (OR 30), epistaxis (OR 11.6) and gastrointestinal haemorrhage (OR 6.08). The odds of cardiac failure (OR 2.36) and colon cancer (OR 2.76) were significantly higher in those with HHT when compared to controls. 3. The hazard ratio for death in HHT cases was twice as high as their matched controls. The median age at death in HHT cases was three years younger than their matched controls. 4. Percutaneous embolisation appears to be a safe procedure for embolisation of pulmonary arteriovenous malformations with a major complication in less than 1% of procedures undertaken. It is effective in 84% of patients who undergo embolisation, or in 90% of lesions treated. 5. The mortality associated with percutaneous embolisation between 1997 and 2011 in England is very low and may be zero. Conclusions: HHT has a UK prevalence in line with that described in studies from other countries worldwide, though as this prevalence is only in those with diagnosed disease, the true prevalence is likely to be significantly higher. HHT is associated with significant haemorrhagic and neurological complications and HHT cases have a higher mortality than their matched controls. Percutaneous embolization appears to be a safe and effective treatment for pulmonary AVMs worldwide and is associated with a very low mortality in England.