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Background/Aims Cardiovascular disease (CVD) is well-recognised in giant cell arteritis (GCA) and thoracic aortic aneurysms (TAAs) are a late complication. Although the British Society for Rheumatology acknowledge the increased risk of CVD and TAAs, guidance for the management of GCA does not recommend antithrombotic agents or vascular screening due to lack of evidence. Positron emission topography (PET-CT) is commonly used for evaluation of large vessel vasculitis (LVV) in GCA. Although not routinely reported, additional measurements including aortic calibre and presence of coronary and aortic calcification can be assessed. LVV is known to be a risk factor for TAA. Therefore, this cohort represents an enriched population to evaluate for cardiovascular abnormalities. Our aims were to: estimate the prevalence of CV abnormalities on PET-CT scans in GCA; develop a standard operating procedure of CV parameters to improve the management of cardiovascular complications in conjunction with radiology and cardiology. Methods A retrospective review of PET-CT scans in GCA patients between 2016-2022 was undertaken. We determined the prevalence of CV abnormalities. Maximum diameter of the thoracic aorta and the presence of coronary and aortic calcification were reviewed by a PET-CT radiologist. Clinical characteristics and CV risk factors were evaluated. A standardised reporting protocol was developed for GCA PET-CT scans. A local guideline for the management of CV abnormalities was formulated. Results Fifty-two consecutive patients with GCA who had undergone PET-CT were identified. Most were female (40/51; 80%). Median age at diagnosis was 71 years (interquartile range [IQR] 63-75). Median time from GCA diagnosis to PET-CT scan was 20 months (IQR 4-38). Nine patients were diagnosed with GCA by PET-CT scan. Most GCA patients (32/51; 63%) were known to have CVRFs. 17/32 (53%) took an antithrombotic and/or anticoagulant, and 10/32 (31%) had a lipid lowering therapy. Original PET-CT scans reported coronary artery and/or aortic calcification in 6/51 (12%) GCA patients. Re-examination of PET-CT scans found coronary artery calcification in 38/51 (74%) and aortic calcification in 14/51 (27%) of all GCA patients. Coronary artery calcification was found in 27/32 (84%) of GCA patients known to have CVRFs, and 12/32 (38%) had evidence of aortic calcification. For GCA patients without CVRFs, 11/19 (58%) had evidence of coronary artery calcification and 2/19 (10%) had aortic calcification. Conclusion We observed a significant burden of cardiovascular abnormalities on PET-CT in GCA patients. Ten percent of patients with aortic dilation required follow up. A significant proportion of those with coronary calcification were not on primary prevention therapy. Importantly, 58% of patients without known CV risk factors were found to have coronary artery calcification. Given the burden of abnormalities identified we have now instituted a standardised reporting policy on CV abnormalities on PET-CT for GCA indications. Local policies have been developed for the management of thoracic aneurysms in GCA. Disclosure B. Mulhearn: None. J. Ellis: None. R. Foley: None. S. Gunawardana: None. R. Wickramarachchi: None. J. Rodrigues: None. O. Watkinson: None. S. Tansley: None. R. Graham: None. S. Skeoch: None.

BackgroundTwo recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes.MethodsIn this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex.Results387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, PConclusionsTreatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Aims Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity. Methods and results In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post-operatively from 71.9 ± 39.6 mmHg to 13.4 ± 18.5 mmHg (P 1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (>30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P 30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years. Conclusion Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients.

Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden. The ERIC-PPCI trial was funded by a British Heart Foundation clinical study grant (grant number CS/14/3/31002) and a University College London Hospitals/University College London Biomedical Research Centre clinical research grant. The CONDI-2 trial was funded by Danish Innovation Foundation grants (grant numbers 11-108354 and 11-115818), Novo Nordisk Foundation (grant number NNF13OC0007447), and TrygFonden (grant number 109624). DJH was supported by the British Heart Foundation (grant number FS/10/039/28270), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the Duke-National University Singapore Medical School, the Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (grant number NMRC/CSA-SI/0011/2017) and its Collaborative Centre Grant scheme (grant number NMRC/CGAug16C006), and the Singapore Ministry of Education Academic Research Fund Tier 2 (grant number MOE2016-T2-2-021). HEB was supported by the Novo Nordisk Foundation (grant numbers NNF14OC0013337, NNF15OC0016674). RKK is supported by the Oxford NIHR Biomedical Centre. The research was also supported by the NIHR infrastructure at Leeds. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. This article is based on the work of COST Action EU-CARDIOPROTECTION (CA16225) and supported by COST (European Cooperation in Science and Technology). We thank all study personnel for their invaluable assistance. Sí

Cardiovascular involvement is a recognised feature of more than 50 different inherited disorders of metebolism. Most frequently cardiovascular disease associated with inherited disorders of metabolism presents as part of multisystem disease, but on occasion it may be the most significant (e.g., Infantile Pompe disease, Danon disease) or only (e.g., Fabry disease, Glycogen storage disease XV) presenting feature, and a high index of suspicion is needed to reach the correct diagnosis. Diagnosis is important because many of these disorders (partly) respond to treatments such as dietary modification, co-factor administration, enzyme replacement therapy, or haematopoietic stem cell transplantation.

Background This report studies the early and medium-term clinical and echocardiographic outcomes of the Alfieri edge-to-edge mitral valve repair, as adjunctive therapy, to prevent and treat systolic anterior motion (SAM) at the time of septal myectomy (SM) for left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. Methods From 2009-2015, 11 consecutive patients had a trans-atrial Alfieri repair, to prevent (n = 7) or treat (n = 4) SAM at the time of SM. Results No patients were lost to follow-up. There were no perioperative or late deaths. Pre-bypass, the mean left ventricular outflow tract gradient, measured directly by simultaneous needle insertion, was 40.7 ± 19.9 mmHg at rest and 115.8 ± 30.4 mmHg on provocation with Isoproterenol, which reduced after SM and Alfieri repair and discontinuation of bypass, to a mean gradient of 8.3 ± 9.8 mmHg at rest and 25.8 ± 9.2 mmHg on provocation. One patient who required mitral valve replacement on day 4, was hospitalized at 2.7 years with heart failure requiring diuresis and remains well at 6 years. One patient developed postoperative atrial fibrillation. There were no other early or late complications. At a median follow-up of 6.6 years (international quartile range 1.2-7.4), clinical and echocardiographic data demonstrated maintained improvement in mean New York Heart Association class from 2.6 ± 0.9 preoperatively to 1.7 ± 0.4 and reduction in mean grade of mitral regurgitation from 2.7 ± 0.8 preoperatively to 0.7 ± 0.6. Conclusions The Alfieri repair, as adjunctive therapy, for the prevention or treatment of SAM at the time of SM demonstrates satisfactory early and medium-term clinical and echocardiographic outcomes supporting the ongoing utility of this approach.

Background Left ventricular outflow tract obstruction (LVOTO) causes exertional symptoms in two thirds of patients with hypertrophic cardiomyopathy (HCM). Consensus guidelines recommend surgical intervention in patients with drug refractory symptoms. The primary aim of this study was to perform a systematic review and meta-analysis to determine morbidity and mortality after surgery. Methods Study Selection: Studies reporting outcomes following surgical intervention for symptomatic LVOTO in HCM. Data Extraction: Articles from searching two scientific databases (PubMed and Web of Science) were reviewed and data were extracted by two investigators. Meta-analysis of data was performed with heterogeneity assessed using I2 statistic. Results 85 studies were included in the systematic review and 35 studies in the meta-analysis. Contemporary early ( 30 days) mortality following septal myectomy were 1.4% (CI 0.8, 2.4) I2 9.0%, p = 0.36 and 0.7% (CI 0.3, 1.2) I2 70.7%, p Conclusions Contemporary surgical management of LVOTO is associated with low operative mortality rates but further studies are needed to investigate the impact of surgical therapy on non-fatal early and late complications.

Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity.In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post-operatively from 71.9 ± 39.6 mmHg to 13.4 ± 18.5 mmHg (P 0.05). Overall, 72.4% of patients improved by1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P 0.05). Long-term (30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years.Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients.

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR 90. In addition, men with classical disease and a baseline eGFR 60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.

Importance Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro–brain natriuretic peptide level, and troponin T level. Results Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, −2.58 to −0.11 mL/kg per minute;P = .03) in the intervention group after 3 months. Conclusions and Relevance In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration ClinicalTrials.gov identifier:NCT01696370

Sudden cardiac death (SCD) is a tragic outcome in hypertrophic cardiomyopathy, but it occurs at a low frequency overall and is challenging to predict accurately. Many important predictors of SCD have emerged over the past 50 years, one of which is a family history of SCD. The available data are limited by their retrospective nature and variability in the definition of family history across studies. We advocate a novel model of risk stratification in which no individual predictor has primacy; rather the overall clinical picture of the patient is used to determine their SCD risk.

The distribution of inhibitory and excitatory synapses on neocortical neurons is at odds with a simple view that cortical functioning can persist by maintaining a balance between inhibitory and excitatory drives. Pyramidal cells can potentially be shut down by very powerful proximal inhibitory synapses, despite these accounting for perhaps less than 1% of their total number of synaptic inputs. Interneurons in contrast are dominated by excitatory inputs. These may be powerful enough to effect an apparent depolarizing block at the soma. In this extreme case though, models suggest that action potentials are generated down the axon, and the cells behave like integrate-and-fire neurons. We discuss possible network implications of these modelling studies.

The activity of pyramidal cells is controlled by two opposing forces: synaptic inhibition and synaptic excitation. Interestingly, these synaptic inputs are not distributed evenly across the dendritic trees of cortical pyramidal cells. Excitatory synapses are densely packed along only the more peripheral dendrites, but are absent from the proximal stems and the soma. In contrast, inhibitory synapses are located throughout the dendritic tree, the soma, and the axon initial segment. Thus both excitatory and inhibitory inputs exist on the peripheral dendritic tree, while the proximal segments only receive inhibition. The functional consequences of this uneven organization remain unclear. We used both optogenetics and dynamic patch clamp techniques to simulate excitatory synaptic conductances in pyramidal cells, and then assessed how their firing output is modulated by gamma-amino-butyric acid type A (GABAA) receptor activation at different regions of the somatodendritic axis. We report here that activation of GABAA receptor on the same dendritic compartment as excitatory inputs causes a rightwards shift in the function relating firing rate to excitatory conductance (the input–output function). In contrast, GABAA receptor activation proximal to the soma causes both a rightwards shift and also a reduction in the maximal firing rate. The experimental data are well reproduced in a simple, four compartmental model of a neuron with inhibition either on the same compartment, or proximal, to the excitatory drive.

Introduction Hypertrophic cardiomyopathy (HCM) is a genetic disorder with significant variability in its clinical phenotype. Most major studies in HCM to date have been largely based on Caucasian patients, but there are some indications that racial background may have an important effect on the disease course. In other areas (such as athletes and hypertensive patients) black patients have been shown to be significantly different to white patients in terms of ECG and echocardiographic appearances. In this study we have used a large single centre population to determine the effect of racial group on baseline phenotype and clinical outcomes in HCM. Methods The case records of sequential patients with hypertrophic cardiomyopathy referred to our cardiomyopathy clinic were reviewed. Patients were asked to identify their racial group using the standard Office of National Statistics classification. Patients who identified themselves as mixed race were excluded. Patients underwent comprehensive cardiac assessment at their baseline visit, and were followed up regularly, for a mean of 7 years. Results Records were available for 2248 patients (95 Black/African/Caribbean/Black British (B), 216 Asian/Asian British (A), 1937 White (W)). Asian patients were more likely to be male (W 66%, B 66%, A 78%, p At baseline assessment, there were differences in the morphological pattern of left ventricular hypertrophy on echo, with more B patients having apical and concentric distributions of hypertrophy, while W and A patients mostly displayed asymmetric septal hypertrophy (p During follow-up, there were significant differences between ethnic groups in a combined end-point of mortality and cardiac transplant (Annual rates W 1.4%, B 1.7%, A 0.6%, p 0.02), but there were no significant differences in a secondary combined end-point of sudden cardiac death, aborted sudden death, and appropriate ICD therapy (Annual rates W 0.4%, B 0.4%, A 0.2%, p 0.4). W patients were significantly more likely to receive a pacemaker (Annual rates W 1.8%, B 0.9%, A 0.8%, p Conclusions In this large single centre study of hypertrophic cardiomyopathy, there were significant differences between racial groups in terms of their clinical phenotype at presentation and their long term outcomes. Further work is required to try and understand the different genetic and social factors which lead to these different disease patterns.

We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels. Electronic supplementary material The online version of this article (doi:10.1007/s10545-016-9978-1) contains supplementary material, which is available to authorized users.