NIHR Barts Cardiovascular Biomedical Research Unit

RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQ helicases plays critical roles in genome maintenance and stability, and the RecQ protein family members are often referred to as guardians of the genome. The importance of these proteins in cellular homeostasis is underscored by the fact that defects in BLM, WRN, and RECQL4 are linked to distinct heritable human disease syndromes. Each human RecQ helicase has a unique set of protein-interacting partners, and these interactions dictate its specialized functions in genome maintenance, including DNA repair, recombination, replication, and transcription. Human RecQ helicases also interact with each other, and these interactions have significant impact on enzyme function. Future research goals in this field include a better understanding of the division of labor among the human RecQ helicases and learning how human RecQ helicases collaborate and cooperate to enhance genome stability.

The phenotype and outcome of severe pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is described in small numbers, and predictors of survival are unknown. Data was retrieved for 101 consecutive, treatment-naïve cases of pulmonary hypertension in COPD. Mean ± SD follow-up was 2.3 ± 1.9 years. 59 patients with COPD and severe pulmonary hypertension, defined by catheter mean pulmonary artery pressure ≥40 mmHg, had significantly lower carbon monoxide diffusion, less severe airflow obstruction but not significantly different emphysema scores on computed tomography compared to 42 patients with mild-moderate pulmonary hypertension. 1- and 3-year survival for severe pulmonary hypertension, at 70% and 33%, respectively, was inferior to 83% and 55%, respectively, for mild-moderate pulmonary hypertension. Mixed venous oxygen saturation, carbon monoxide diffusion, World Health Organization functional class and age, but not severity of airflow obstruction, were independent predictors of outcome. Compassionate treatment with targeted therapies in 43 patients with severe pulmonary hypertension was not associated with a survival benefit, although improvement in functional class and/or fall in pulmonary vascular resistance >20% following treatment identified patients with improved survival. Standard prognostic markers in COPD have limited value in patients with pulmonary hypertension. This study identifies variables that predict outcome in this phenotype. Despite poor prognosis, our data suggest that further evaluation of targeted therapies is warranted.

Cannabis use is considered a contributory cause of schizophrenia and psychotic illness. However, only a small proportion of cannabis users develop psychosis. This can partly be explained by the amount and duration of the consumption of cannabis and by its strength but also by the age at which individuals are first exposed to cannabis. Genetic factors, in particular, are likely to play a role in the short- and the long-term effects cannabis may have on psychosis outcome. This review will therefore consider the interplay between genes and exposure to cannabis in the development of psychotic symptoms and schizophrenia. Studies using genetic, epidemiological, experimental, and observational techniques will be discussed to investigate gene-environment correlation gene-environment interaction, and higher order interactions within the cannabis-psychosis association. Evidence suggests that mechanisms of gene-environment interaction are likely to underlie the association between cannabis and psychosis. In this respect, multiple variations within multiple genes--rather than single genetic polymorphisms--together with other environmental factors (eg, stress) may interact with cannabis to increase the risk of psychosis. Further research on these higher order interactions is needed to better understand the biological pathway by which cannabis use, in some individuals, may cause psychosis in the short- and long term.

OBJECTIVE: Pregnancy in women with pulmonary hypertension (PH) is reported to carry a maternal mortality rate of 30-56%. We report our experience of the management of pregnancies using a strategy of early introduction of targeted pulmonary vascular therapy and early planned delivery under regional anaesthesia. DESIGN: Retrospective observational study. SETTING: Specialist quaternary referral pulmonary vascular unit. POPULATION: Nine women with PH who chose to proceed with ten pregnancies. METHODS: A retrospective review of the management of all women who chose to continue with their pregnancy in our unit during 2002-2009. MAIN OUTCOME MEASURES: Maternal and fetal survival. RESULTS: All women commenced nebulised targeted therapy at 8-34 weeks of gestation. Four women required additional treatment or conversion to intravenous prostanoid therapy. All women were delivered between 26 and 37 weeks of gestation. Delivery was by planned caesarean section in nine cases. All women received regional anaesthesia and were monitored during the peripartum period in a critical care setting. There was no maternal mortality during pregnancy and all infants were free from congenital abnormalities. One woman died 4 weeks after delivery following patient-initiated discontinuation of therapy. All remaining women and infants were alive after a median of 3.2 years (range, 0.8-6.5 years) of follow-up. CONCLUSION: Although the risk of mortality in pregnant women with PH remains significant, we describe improved outcomes in fully counselled women who chose to continue with pregnancy and were managed with a tailored multiprofessional approach involving early introduction of targeted therapy, early planned delivery and regional anaesthetic techniques.

Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

Lamins A and C are intermediate filament nuclear envelope proteins encoded by the LMNA gene. Mutations in LMNA cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an LMNA mutation may be quite high. Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for LMNA , alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated. Genotyping and family screening are clinically important both to confirm and to exclude LMNA mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our LMNA knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

OBJECTIVES: The aim of this double-blind, randomized, sham-controlled study was to verify the blood pressure (BP)-lowering efficacy of externally delivered focused ultrasound for renal denervation (RDN). BACKGROUND: Nonrandomized, first proof-of-concept study and experimental evidence suggested that noninvasive techniques of RDN emerged as an alternative approach of RDN to invasive technologies. METHODS: WAVE IV, an international, randomized (1 : 1) sham-controlled, double-blind prospective clinical study, was prematurely stopped. Patients were enrolled if office BP was at least 160 mmHg and 24-h ambulatory BP was at least 135 mmHg, while taking three or more antihypertensive medications. The treatment consisted of bilateral RDN using therapeutic levels of ultrasound energy and the sham consisted of bilateral application of diagnostic levels of ultrasound energy. RESULTS: In the 81 treated patients neither changes in office BP at 12 and 24 weeks, nor changes in 24-h ambulatory BP at 24-week follow-up visit differed between the two groups significantly. Of note, no safety signal was observed. Adherence analysis disclosed full adherence in 77% at baseline and 82% at 6 months' follow-up visit. Post hoc analysis revealed that stricter criteria for stabilization of BP at baseline were associated with a numerically greater change in 24-h ambulatory BP in the RDN group than in the sham group. CONCLUSION: Our data did not prove that antihypertensive efficacy of the externally delivered focused ultrasound for RDN was greater than the sham effect. Stabilization of BP at baseline was identified as an important determinant of BP changes.

AIM: To explore the knowledge of chronic orofacial pain within general dental practitioners (GDPs) and dental specialists. METHODS: Following a recent national survey of GDPs and specialists on the diagnosis of facial pain, all those who responded were asked to answer four multiple-choice questions on chronic orofacial pain as part of a continuing professional development exercise. The questions were formulated using a review of the literature and consultation with a facial pain expert and were administered by post. RESULTS: Of the 380 subjects who completed the original survey, 212 (56%) returned completed multiple-choice questionnaires. Specialists correctly answered significantly more questions than GDPs (P<0.001). The majority of specialists-49/83 (59%)-obtained a score of three or more, compared to 39/129 (30%) GDPs. This was due to variation in answering one question. Significantly more specialists--50 (60%)--correctly selected trigeminal neuralgia (TN) as a condition that is not associated with COFP, whereas only 41 (32%) GDPs chose this answer. Both specialists and GDPs grossly underestimated the prevalence of COFP in secondary care clinics. CONCLUSIONS: The results suggest that specialists and GDPs may have sufficient knowledge to make an appropriate diagnosis of COFP, but they also highlight the knowledge gaps and perhaps the need for more extensive inclusion of COFP in the dental undergraduate curriculum.

OBJECTIVE: To investigate the association of volume of total hip arthroplasty (THA) between consultants and within the same consultant in the previous year and the hazard of revision using multilevel survival models. DESIGN: Prospective cohort study using data from a national joint replacement register. SETTING: Elective THA across all private and public centres in England and Wales between April 2003 and February 2017. PARTICIPANTS: Patients aged 50 years or more undergoing THA for osteoarthritis. INTERVENTION: The volume of THA conducted in the preceding 365 days to the index procedure. MAIN OUTCOME AND MEASURE: Revision surgery (excision, addition or replacement) of a primary THA. RESULTS: Of the 579 858 patients undergoing primary THA (mean baseline age 69.8 years (SD 10.2)), 61.1% were women. Multilevel survival found differing results for between and within-consultant effects. There was a strong volume-revision association between consultants, with a near-linear 43.3% (95% CI 29.1% to 57.4%) reduction of the risk of revision comparing consultants with volumes between 1 and 200 procedures annually. Changes in individual surgeons (within-consultant) case volume showed no evidence of an association with revision. CONCLUSION: Separation of between-consultant and within-consultant effects of surgical volume reveals how volume contributes to the risk of revision after THA. The lack of association within-consultants suggests that individual changes to consultant volume alone will have little effect on outcomes following THA.These novel findings provide strong evidence supporting the practice of specialisation of hip arthroplasty. It does not support the practice of low-volume consultants increasing their personal volume as it is unlikely their results would improve if this is the only change. Limiting the exposure of patients to consultants with low volumes of THA and greater utilisation of centres with higher volume surgeons with better outcomes may be beneficial to patients.

OBJECTIVE: To test the hypothesis that imaging signs of 'brain frailty' and acute ischaemia predict clinical outcomes and symptomatic intracranial haemorrhage (sICH) after thrombolysis for acute ischaemic stroke (AIS) in the alteplase dose arm of ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED). METHODS: Blinded assessors coded baseline images for acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions; and hyperattenuated arteries) and pre-existing changes (atrophy, leucoaraiosis and old ischaemic lesions). Logistic regression models assessed associations between imaging features and death at 7 and 90 days; good recovery (modified Rankin Scale scores 0-2 at 90 days) and sICH. Data are reported with adjusted ORs and 95% CIs. RESULTS: 2916 patients (67±13 years, National Institutes of Health Stroke Scale 8 (5-14)) were included. Visible ischaemic lesions, severe hypoattenuation, large ischaemic lesion, swelling and hyperattenuated arteries were associated with 7-day death (OR (95% CI): 1.52 (1.06 to 2.18); 1.51 (1.01 to 2.18); 2.67 (1.52 to 4.71); 1.49 (1.03 to 2.14) and 2.17 (1.48 to 3.18)) and inversely with good outcome. Severe atrophy was inversely associated with 7-day death (0.52 (0.29 to 0.96)). Atrophy (1.52 (1.08 to 2.15)) and severe leucoaraiosis (1.74 (1.20 to 2.54)) were associated with 90-day death. Hyperattenuated arteries were associated with sICH (1.71 (1.01 to 2.89)). No imaging features modified the effect of alteplase dose. CONCLUSIONS: Non-expert-defined brain imaging signs of brain frailty and acute ischaemia contribute to the prognosis of thrombolysis-treated AIS patients for sICH and mortality. However, these imaging features showed no interaction with alteplase dose.

Metabolomic data can potentially enable accurate, non-invasive and low-cost prediction of coronary artery disease. Regression-based analytical approaches however might fail to fully account for interactions between metabolites, rely on a priori selected input features and thus might suffer from poorer accuracy. Supervised machine learning methods can potentially be used in order to fully exploit the dimensionality and richness of the data. In this paper, we systematically implement and evaluate a set of supervised learning methods (L1 regression, random forest classifier) and compare them to traditional regression-based approaches for disease prediction using metabolomic data.

OBJECTIVE: To determine whether the use of unique customized spectacles provided with modified side arms may be helpful in reducing benign essential blepharospasm (BEB) in patients describing periocular sensory tricks (ST). METHODS: A prospective descriptive study of patients with BEB with positive periocular or temporal region ST phenomenon response under the care of the Botox Clinic at Moorfields Eye Hospital, London, UK. Nine consecutive patients with BEB describing ST were recruited, and the disease frequency and severity were assessed with the Jankovic Rating Scale (JRS) and the Blepharospasm Disability Index (BSDI) before and after the use of the sensory trick frames (STF). RESULTS: A reduction in the score was noted in both severity (p = 0.0115) and frequency patterns (p = 0.0117) in the JRS in patients using the STF. A significant reduction of the BSDI score was also observed (p = 0.0314). CONCLUSION: All the patients selected and fitted with the STF had a reduction in spasms and related symptoms. This new device may be helpful in some selected BEB patients who previously responded positively to periocular pressure alleviating maneuvers.

Background: Women are underrepresented in leading medical positions and academia. The gender-gap in authorship of congenital heart disease (CHD) publications remains unknown. As determinants of gender equity in this field are poorly characterised, we aimed to quantify and characterise publications in CHD and to assess factors associated with female representation in research. Methods and results: We identified 35 118 CHD publications between 2006 and 2015 for which author gender could be ascertained. Overall, 25.0% of all authors were female. Women accounted for 30.2% and 20.8% of all first and senior authorship positions with great geographic heterogeneity. While globally female first and senior authorship increased by 0.8% and 0.6%/year, some geographic regions showed no improvement in gender representation. Significant predictors of female first authorship on logistic regression analysis were country gross domestic product, human development index, gender inequality index and a female senior author (p<0.0001 for all). Publications with a female lead author tended to be published in journals with a higher impact factor (IF) and to attract more citations compared with those with a male author. Mixed gender authorship was associated with higher IF and number of citations. Women were less disadvantaged when the analysis was confined to original research. Conclusions: While modest improvement in female authorship over time was noted, women remain underrepresented in contemporary academic CHD. Manuscripts with mixed gender authorship had higher IF and more citations. The main predictor of female first authorship was a female senior author. These data should inform policy recommendations regarding gender parity.

PBM and AT are supported by the NIHR&#13;\nCardiovascular Biomedical Research Centre and the&#13;\nMedical Research Council: MR/N025083/1.

<h3>Introduction</h3> The common heritable condition of Bicuspid Aortic Valve (BAV) is phenotypically heterogeneous, with valve dysfunction and aortopathy the major complications. We report overrepresentation of rare, likely pathogenic variants in target genes in a large cohort of 176 patients with BAV. We also describe a more severe aortic phenotype in patients with more than one known or likely pathogenic variant, supporting a multi-hit hypothesis for development of complications of BAV. <h3>Methods</h3> We recruited 176 patients with BAV without known syndromic basis from two large tertiary referral centres. Phenotyping was performed with routine clinical MRI and/or echocardiography. We identified 63 genes of interest with known or suspected links to BAV or to aortic /aortic valve (AV) pathology. We used genomic DNA from our patients for NGS of these target genes. Control populations were provided by the Exome Variant Server (EVS; 6503 samples) and 1000 genomes project. We analysed called variants <i>in silico </i>, usingSIFT, Polyphen2, Grantham scoring and phastCONS, and categorised variants into the following groups based on likely pathogenicity using a combination of <i>in silico </i> tools: known links with disease, likely, possible, and unlikely pathogenicity. <h3>Results</h3> 10 patients (5.7% of our cohort) had variants previously associated with aortic or AV pathology or with abnormalities of smooth muscle function; 3 in GATA5, 2 in FBN1, 2 in MYH11, 1 in NOTCH1 and 1 in COL3A1. <i>In silico </i> analysis identified 45 further instances of 31 likely pathogenic, rare variants in 33 patients (a further 19% of our cohort), in 11 different genes: GATA5 (see Table 1), NOTCH1 (see Figure 1), MYH11, PLOD3, FBN1, MMP9, NKX2–5, JAG1, ACE, ENG, PDIA2 and KCNJ2. The combined prevalence of these known or likely pathogenic variants in our cohort was significantly greater than in the EVS control populations (p &lt; 0.0001). 10 patients had known or likely pathogenic variants in more than one gene of interest. These 10 patients had a significantly higher prevalence of significant aortopathy and/or coarctation of the aorta than the rest of our cohort (6/10 vs 20/176; p = 0.0006). <h3>Conclusions</h3> We identified known or likely pathogenic genetic variants in nearly a quarter of our BAV cohort. Some of these (eg the c.698T &gt;C variant in GATA5) may be common polymorphisms, wrongly classified by <i>in silico </i> tools. However, many are undoubtedly genuine determinants of phenotype, as evidenced by their overrepresentation in our cohort, and the finding of a more severe aortic phenotype in patients with more than one presumed pathogenic variant. Further research, including our own control population and family studies, is planned. This is also the first study, to our knowledge, to correlate BAV aortopathy with more complex genotypes, and lends support to a multi-hit genetic hypothesis for development of aortic complications of BAV.

Objective: The aim of this double blind randomized sham-controlled study was to verify the blood pressure (BP) lowering efficacy of externally delivered focussed ultrasound for renal denervation (RDN). Design and method: The WAVE IV study was an international, randomized (1:1), sham-controlled, double blind prospective clinical study carried out in 13 institutions. Patients (18–80 years of age) had true treatment resistant hypertension with office BP > = 160 mmHg whilst taking 3 or more antihypertensive medications. The treatment consisted of bilateral RDN using therapeutic levels of ultrasound energy and the sham consisted of bilateral application of diagnostic levels of ultrasound energy. The primary objective was change in office BP and secondary objective change in 24-hour ambulatory BP at 24 week follow-up visit. Results: An interim analysis showing lack of evidence of antihypertensive efficacy by the externally delivered focused ultrasound in the RDN group over the sham group prompted termination of the trial. Out of 239 screened patients, 81 were treated. Neither changes in office BP at 24 weeks (sham: −18.9 ± 14 vs RDN: −13.2 ± 20 mmHg, p = 0.133), nor changes in 24-hour ambulatory BP at 24 week follow-up visit (sham: −5.90 ± 15 vs RDN: −7.11 ± 13 mmHg, p = 0.770) differed between the two groups significantly. Of note, no safety signal was observed. Medication changes were less than 15% throughout the first follow-up period of 24 weeks. In a subset urinary toxicological analysis disclosed full adherence in 77% at baseline and 82% at 6 months. Post hoc analysis revealed that stricter criteria for stabilisation of BP at baseline were associated with a numerically greater change in 24-hour ambulatory BP in the RDN group than in the sham group. Systolic BP changes were numerically greater in patients with pulse pressure < 65 compared to those with pulse pressure > = 65 mmHg. Conclusions: Our data did not prove that antihypertensive efficacy of the externally delivered focused ultrasound for RDN was greater than the sham effect. Post-hoc analysis suggested that the predominance of treatment resistant hypertensive patients with stiff arteries, and less stringent stabilisation of baseline BP may have hampered our trial.

Background: Children undergoing bone marrow transplant (BMT) are at risk of developing malnutrition. A feeding tube becomes a requirement for most children to meet their nutritional and medication requirements. Two tubes are typically used: nasogastric tube (NGT) or gastrostomy. At the UK center where this study took place, parents are offered a choice between these tubes. Objective: This qualitative data collection in a mixed methods study explored why parents choose either tube and their experiences of using it. Methods: Parents participated in 2 semistructured interviews. First, on admission to explore why they chose either tube. Second, 1–2 months postdischarge to explore their experience of using the tube. Interviews took place over 18 months. Transcripts were thematically analyzed. Results: Sixteen parents whose child had an NGT, 17 a gastrostomy, were interviewed. Choice was experienced across a continuum of difficulty and freedom. Many parents deferred to the expertise of professionals; others felt they were the experts in their child. Influential factors in decision-making included expected duration of need, the child’s age and activity, cosmetic differences, balancing gastrostomy surgery against NGT dislodgement, lay advice, healthcare professionals’ recommendations and prior tube feeding experiences. Conclusions: Parents valued choice appreciating 1 feeding tube might not suit every child. Implications for Practice: Choice of a gastrostomy or NGT should be offered to children prior to BMT. What is Foundational: Parents navigate a complex decision-making process when choosing a feeding tube for their child. Healthcare professionals can facilitate informed decision-making through collaborative discussions, inclusion of peer support, and provision of balanced information.

Introduction Patients with dysglycaemia at the time of ST-elevation myocardial infarction (STEMI) have a worse prognosis. The reasons for this are not entirely clear. Admission hyperglycaemia has been associated with larger infarct size. Table 1 Age (years) 60.77±11.75 (89% male sex) Reperfusion therapy PPCI: 45 (80%)/thrombolysis 11 (20%) Time to reperfusion (minutes) 194.16±121.12 Multivessel disease 22/56 (39%) LAD culprit 25/56 (45%) Percentage ECG resolution 62%±34% (median 67%) Glucose (mmol/l) 7.97±2.54 (median 7.7, IQR 2.10) HbA1c (%) 6.67±1.07 (median 5.9, IQR 0.4) Infarct size % 23.08±12.97 Myocardial Salvage Index % 53.71±26.41 The aims of this study were to examine the relation of acute and chronic glycaemic state to myocardial scar and salvage characteristics in patients with reperfused ST-elevation myocardial infarction. Methods Fifty-six patients treated for first ST-elevation myocardial infarction (STEMI) without a pre-existing diagnosis of Diabetes mellitus were prospectively enrolled between January and December 2010. Glycosylated haemoglobin (HbA1c) and glucose levels were sampled on admission to the emergency cardiac ward. Patients underwent cardiac magnetic resonance (CMR) examination during the index admission (median day 2 for CMR, IQR 2 days), with assessment of area-at-risk (STIRs), Infarct size (IS%), late microvascular obstruction (MVO%), and left ventricular function. Population characteristics are presented in table 1. There were no significant differences between patients receiving Primary Percutaneous Coronary Intervention (PPCI) or thrombolysis, so these were grouped for analysis. Patients were dichotomised into groups above and below the median both for admission glucose level and separately for HbA1c level before comparison between groups using Independent samples t test. Spearman's rank correlation was used to compare non-parametric data. Correlations with a p&lt;0.1 were entered into a multivariate linear regression model. Results When patients were dichotomised into glucose levels below (&lt;7.8 mmol/l) and above the median (¡Ý7.8 mmol/l), the supra-median group were significantly older (64.7 years vs 57.1 years, p=0.018) and had greater Infarct size (28.33% vs 18.46%, p=0.007). Dichotomising patients by HbA1c into levels below the median (&lt;5.9%) and above the median (¡Ý5.9%), the supra-median group had significantly greater glucose levels (8.8 mmol/l vs 7.1 mmol/l, p=0.011), less ST-segment resolution (51.6% vs 75.5%, p=0.007), greater MVO% (2.77% vs 1.11%, p=0.049), greater intra-myocardial haemorrhage (IMH%) (1.96% vs 0.61%, p=−0.015), and lower myocardial salvage index (MSI%) (43.30% vs 65.15%, p=0.003). Correlations between infarct characteristics and admission glucose and HbA1c are shown in table 2. Admission glucose correlated significantly with age and IS%, while HbA1c correlated significantly with time to reperfusion and MSI%. On multivariate linear regression analysis however, glucose was not a predictor of IS% (R=0.549, R2=0.302, Age t=3.441, p=0.001, time to reperfusion t=2.708, p=0.009, glucose- not significant), and HbA1c was not a predictor of MSI% (R=0.453, R2=0.206, age t=−2.529, p=0.015, time to reperfusion t=−2.237, p=0.030, HbA1c-not significant). Table 2 Admission glucose HbA1c Percentage ECG resolution R=−0.393, p=0.003 R=−0.352, p=0.010 Time to reperfusion R=0.185, p=0.177 R=0.334, p=0.015 Age R=0.361, p=0.007 R=0.184, p=0.188 Infarct size % R=0.296, p=0.028 R=0.152, p=0.277 Microvascular obstruction % R=0.259, p=0.056 R=0.199, p=0.152 Intramyocardial haemorrhage % R=0.187, p=0.176 R=0.292, p=0.036 Area-at-risk (oedema) % R=0.128, p=0.358 R=−0.176, p=0.213 Myocardial Salvage Index % R=−0.187, p=0.176 R=−0.399, p=0.003 Conclusions/implications

https://osf.io/preprints/osf/yvm5h_v2

<title>Abstract</title> Unilateral aldosterone-producing adrenal adenomas (APAs) are the potentially curable cause of 5% of all cases of hypertension. At present surgical removal of a whole gland is the only approved option for achieving cure, with uncertain long-term outcomes. Endoscopic ultrasound-guided trans-gastric radiofrequency ablation (EUS-RFA) offers a less invasive alternative to total adrenalectomy for the treatment of left-sided APAs. We aimed to determine whether EUS-RFA of APAs is safe and evaluate its likelihood of success in curing primary aldosteronism. We conducted a multi-centre feasibility study of EUS-RFA as a nonsurgical, adrenal-sparing treatment for left-sided APAs. The primary endpoint was safety, judged by the occurrence of pre-specified major hazards (intestinal haemorrhage, infarction or viscus perforation); and the secondary endpoints were biochemical and clinical efficacy (Primary Aldosterone Surgical Outcome (PASO) criteria). 28 participants (21 male, 7 female, mean age 57.7 +/- 10.3 years; 16 White, 11 Black, 1 Asian), underwent 35 ablations on one (n=21) or two (n=7) occasions. None of the pre-specified major hazards occurred. There were 21 biochemical and 12 clinical successes. These were complete in 16 and 4 participants, respectively, associated with &gt;75% eradication of the APA, judged by molecular imaging. EUS-guided trans-gastric RFA is a safe alternative to total adrenalectomy for the treatment of left-sided APAs and can lead to complete PASO success when most of the APA is ablated.