Search

Background Fabry disease (FD) is a genetic disorder caused by defective α-galactosidase-A enzyme due to mutations in the GLA gene. A reliable diagnosis in classical FD males can be made by measuring the enzyme activity while diagnosing classical FD females and non-classical FD patients requires mutation analysis. Plasma globotriaosylsphingosine (Lyso-Gb3) has progressively gained more importance as a diagnostic biomarker for FD in recent years. Having another biomarker to complement plasma Lyso-Gb3 will increase the diagnostic accuracy in the era of mass screening, and also precision medicine. This study aims to highlight the clinical utility of the total concentration of urinary Lyso-Gb3 plus its analogues in diagnosing FD. Method Random urine samples collected from 42 FD patients and 48 healthy individuals. Lyso-Gb3 and its analogues were enriched by solid phase extraction and analysed by liquid chromatography tandem mass spectrometry. Results The total concentration of Lyso-Gb3 plus its analogues in classical FD male and female patients were 1124.4 ± 181.2 and 308.6 ± 78.6 pmol/mmol creat., respectively. The levels in non-classical FD male and female patients were 229.2 ± 169.4 and 314.4 ± 156.4 pmol/mmol creat., respectively. Urinary Lyso-Gb3 and its analogues were virtually undetectable in healthy volunteers making it 100% specific for FD diagnosis. For FD male and female patients, total concentration of urinary Lyso-Gb3 plus its analogue levels ≥0.25 pmol/mmol creat. yielded a diagnostic sensitivity and specificity of 100% (AUC = 1, p Conclusions Our study findings support that the total concentration of Lyso-Gb3 plus its analogues in urine is specific to FD and may provide extra diagnostic utility for both classical and non-classical FD patients.

Background Coronary microvascular dysfunction is prevalent in chronic kidney disease (CKD), and may contribute to the development of myocardial dysfunction in CKD. Coronary flow velocity reserve (CFVR) is a marker of coronary microvascular function and falls with increasing CKD stage. Living kidney donors have renal function consistent with early stage CKD and concern has been raised about their cardiovascular risk. No studies to date have investigated the presence of coronary microvascular dysfunction in living kidney donors. Methods 25 healthy controls and 23 living kidney donors were recruited and underwent assessment with transthoracic echocardiography, Doppler CFVR, myocardial contrast echocardiography and serum multiplex immunoassay panels. Results Doppler CFVR was significantly reduced in living kidney donors compared to controls (mean CFVR 3.4 ± 0.7 vs 3.8 ± 0.6, mean difference 0.4 95% confidence interval 0.03–0.8, p =.036). Quantitative myocardial contrast echocardiography showed a trend towards reduced coronary flow reserve in living kidney donors. Compared to controls, living kidney donors had higher serum high sensitivity C reactive peptide (hsCRP) and lower levels of uromodulin. Conclusions This is the first study of CFVR in living kidney donors. We have shown that the modest drop in estimated glomerular filtration rate in living kidney donors is associated with lower values of Doppler CFVR compared to controls, suggesting that isolated reductions in renal function may lead to altered microvascular function. The increase in hsCRP and reduction in uromodulin suggests that chronic subclinical inflammation may contribute to altered microvascular function in this population., Highlights • Coronary flow velocity reserve is reduced in living kidney donors compared to controls. • Markers of inflammation are elevated in living kidney donors. • Inflammation may cause coronary microvascular dysfunction in living kidney donors. • Living kidney donors need aggressive cardiovascular risk factor management.

Background Fabry disease (FD) is a treatable X-linked condition leading to progressive cardiac disease, arrhythmia and premature death. We aimed to increase awareness of the arrhythmogenicity of Fabry cardiomyopathy, by comparing device usage in patients with Fabry cardiomyopathy and sarcomeric HCM. All Fabry patients with an implantable cardioverter defibrillator (ICD) implanted in the UK over a 17 year period were included. A comparator group of HCM patients, with primary prevention ICD implantation, were captured from a regional registry database. Results Indications for ICD in FD varied with 72% implanted for primary prevention based on multiple potential risk factors. In FD and HCM primary prevention devices, arrhythmia occurred more frequently in FD over shorter follow-up (HR 4.2, p p = 0.002). Immediate shock therapy for sustained VT was also more common (HR 2.5, p p = 0.004, NSVT: HR 3.1, p Conclusion This study demonstrates arrhythmia burden and ICD usage in FD is high, suggesting that Fabry cardiomyopathy may be more ‘arrhythmogenic’ than previously thought. Existing risk models cannot be mutually applicable and further research is needed to provide clarity in managing Fabry patients with cardiac involvement.

Echocardiography plays an essential role in the diagnosis and assessment of cardiovascular disease. Measurements derived from echocardiography are also used to determine the severity of disease, its progression over time, and to aid in the choice of optimal therapy. It is therefore clinically important that echocardiographic measurements be reproducible, repeatable, and reliable. There are a variety of statistical tests available to assess these parameters, and in this article the authors summarize those available for use by echocardiographers to improve their clinical practice. Correlation coefficients, linear regression, Bland-Altman plots, and the coefficient of variation are explored, along with their limitations. The authors also provide an online tool for the easy calculation of these statistics in the clinical environment (www.birmingham.ac.uk/echo). Quantifying and enhancing the reproducibility of echocardiography has important potential to improve the value of echocardiography as the basis for good clinical decision-making.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects in secondary mitral regurgitation of: 1. Surgical mitral valve intervention and coronary artery bypass graft versus coronary artery bypass graft alone; and 2. Transcatheter mitral valve intervention and medical therapy versus medical therapy alone.

Background Mitral regurgitation (MR) is commonly observed following acute myocardial infarction (MI). Localised left ventricular (LV) remodelling in the region of papillary muscles together with impaired myocardial contractility promote MR. There is a paucity of long-term follow-up studies to determine whether the severity of MR observed post-MI, changes with time. Purpose This study retrospectively followed up patients with MR detected following acute MI (AMI) to investigate changes in MR severity with time and assess for pre-discharge predictors of MR regression or progression. Methods Clinical records of 1000 patients admitted with AMI between 2016 and 2017 to a single centre were retrospectively interrogated. One hundred and nine patients met the inclusion criteria of MR on pre-discharge transthoracic echocardiography (TTE) and follow-up TTE scans. Echocardiographic parameters were investigated to determine predictors of progression or regression at follow-up. Patients were divided according to those who had early follow-up TTE (within 1-year) and late follow-up TTE (beyond 1-year). Results Early follow-up TTE was performed in 73 patients at a median of 6 (IQR 3–9) months. Patients had a mean age of 69±13 years and were predominantly male 50/73 (68%). At baseline, relative MR severities were: 49/73 (67%) mild MR, 23/73 (32%) moderate MR and 1 (1%) severe MR. At follow-up, MR had completely resolved in 18/73 (23%) patients, while 39/73 (53%) had mild MR, 15/73 (21%) moderate MR and 1 (1%) severe MR. Compared to patients with no resolution of MR, those with completel resolution were younger (mean age 62±16 vs 72±11 years; p=0.015) but there were no other significant differences between the groups. Resolution at early follow-up did not significantly influence long-term mortality rates. Late follow-up TTE was performed in 69 patients at a median 2.4 (IQR 2–3.2) years. Pre-discharge, 49/69 (71%) patients had mild MR and 20/69 (29%) moderate MR. At follow-up, MR had completely resolved in 18/69 (26%), and amongst patients with persistent MR, proportion of severities were: 37/69 (54%) mild MR, 11/69 (16%) moderate MR and 3/69 (4%) severe MR. Patients with progression of mild MR were more likely to have lower left ventricular ejection fraction (LVEF: 47±15 vs 57±12%; p=0.010) and greater indexed left ventricular end-systolic volume (LVESVi: 37±23 vs 25±14 ml/m2; p Conclusion MR observed following AMI completely resolved in approximately one-quarter of patients at 6-month and 2-year follow-up. Progression of mild MR at long-term follow-up appears to be associated with increased mortality and is predicted by lower LVEF and greater LVESVi pre-discharge. Funding Acknowledgement Type of funding sources: None.

Background Annuloplasty failure caused by ring dehiscence can lead to trans-ring and para-ring mitral regurgitation (MR). Transcatheter treatments are available for patients at prohibitive risk of surgery. In patients unsuitable for edge-to-edge repair, valve-in-ring (ViR) transcatheter mitral valve (MV) implantation has been described to treat trans-ring or para-ring jets but not both concurrently. Case summary A 78-year-old male presented with severe MR due to dehiscence of a 34 mm Edwards Physio II mitral annuloplasty ring. Transoesophageal echocardiography showed two jets of regurgitation; trans-ring and para-ring. Repair was successfully undertaken with a ViR procedure (29 mm S3 Edwards Lifesciences). Discussion Patients with failure of MV annuloplasty with trans-ring and para-ring regurgitation can be safely and effectively treated by ViR transcatheter MV implantation.

Background: This European Neuroendocrine Tumor Society (ENETS) Expert Consensus document aims to provide practical guidance and standardization for echocardiography in the screening and follow-up of carcinoid heart disease (CHD) in patients with a neuroendocrine tumour (NET) and carcinoid syndrome. Methods: NET experts within the ENETS Carcinoid Heart Disease Task Force reviewed both general reporting guidelines and specialized scoring systems for transthoracic echocardiography (TTE) in CHD. Based on this review, a dedicated template report was designed by the multidisciplinary working group of cardiologists, oncologists, endocrinologists, gastroenterologists, surgeons and radiologists. Results: We propose a Synoptic Reporting of Echocardiography in Carcinoid Heart Disease which represents an agreed peer reviewed proforma to capture information at the time of referral and enable a detailed outcome of CHD assessment. This includes a systematic and detailed list of structures to evaluate data to capture at the time of reporting of TTE. Conclusions: Adherence to these reporting guidelines aims to promote homogeneous and detailed evaluation of CHD to secure accurate assessment and allow comparison of studies performed intra- and inter-individually. These guidelines could also facilitate CHD assessment as part of prospective clinical trials to enable standardization of the findings seen in response to therapy.

Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.

Data were collected on patients admitted to the Queen Elizabeth Hospital Birmingham with type-1 myocardial infarction during 2016 and 2017 inclusively, who were treated by percutaneous intervention and had pre-discharge transthoracic echocardiography. The data were obtained from prospectively maintained hospital databases and records. Echocardiography was performed and reported contemporaneously by accredited echocardiographers. The purpose was to understand the prevalence and characteristics of mitral regurgitation (MR) after acute MI, including patients with ST-elevation (STEMI) and non-ST elevation MI (NSTEMI). MR was observed in 294/1000 patients with the following relative severities: mild = 76%, moderate = 21%, severe = 3% [1]. MR was graded by multiparametric quantification including proximal isolvelocity surface area (PISA), vena contracta (VC), effective regurgitant orifice area (EROA) and regurgitant volume (RVol). Amongst all patients with MR (n=294), PISA was performed in 89/294 (30%), VC 75/294 (26%), EROA in 53/294 (18%) and RVol in 26/294 (9%). Amongst patients with moderate or severe MR (n=70), PISA was performed in 57/70 (81%), VC in 55/70 (79%), EROA in 46/70 (66%) and RVol in 25/70 (36%). Characteristics of MR following acute MI were also assessed including frequency of reported leaflet thickness (259/294 = 88%) and mitral annular calcification (102/294 = 35%). Furthermore, the effect of MI on pre-existing MR was investigated and patients with pre-existing MR who continue to have MR after acute MI were found to have progression of MR by one grade in approximately 25% of cases. Finally, using Cox proportional hazards univariate analysis, significant factors associated with mortality in patients with MR post-MI include age (HR 1.065; 95% CI 1.035-1.096; p

Hypertrophic cardiomyopathy (HCM) is common, inherited and characterised by unexplained thickening of the myocardium. The British Society of Echocardiography (BSE) has recently published a minimum dataset for transthoracic echocardiography detailing the core views needed for a standard echocardiogram. For patients with confirmed or suspected HCM, additional views and measurements are necessary. This guideline, therefore, supplements the minimum dataset and describes a tailored, stepwise approach to the echocardiographic examination, and echocardiography's position in the diagnostic pathway, before advising on the imaging of disease complications and invasive treatments.

Received 20th January 2021. Revised 26th January 2021. Accepted 26th January 2021. Journal Pre-proof online 1st February 2021.

Coronavirus disease 2019 (COVID-19) was initially regarded as a disease of the lungs, which manifests as an acute respiratory illness and pneumonia, although more recently cardiac complications have been well-characterised. Serological cardiac biomarkers have been used to define acute myocardial injury, with significant elevation of high-sensitivity cardiac troponin (hs-cTn) associated with poor prognosis. Accordingly, 20–25% patients with acute myocardial injury (as defined by an elevated hs-cTn greater than the 99th percentile) have clinical signs of heart failure and increased mortality. An important outstanding clinical question is how best to determine the extent and nature of cardiac involvement in COVID-19. Non-invasive cardiac imaging has a well-established role in assessing cardiac structure and function in a wide range of cardiac diseases. It offers the potential to differentiate between direct and indirect COVID-19 effects upon the heart, providing incremental diagnostic and prognostic utility beyond the information yielded by elevated cardiac biomarkers in isolation. This review will focus on the non-invasive imaging assessment of cardiac involvement in COVID-19.

Funding Acknowledgements Type of funding sources: None. BACKGROUND Clinical guidelines adopt LVEF cut-offs OBJECTIVES To determine whether myocardial fibrosis (MF) and grayzone fibrosis (GZF) on cardiovascular magnetic resonance (CMR) is associated with ventricular arrhythmias in patients with coronary artery disease (CAD) and a LVEF≥35%. METHODS In this retrospective study of CAD patients, GZF mass using the 3SD method (GZF3SD) and total fibrosis mass using the 2SD method (TF2SD) on CMR were assessed in relation to the primary, combined endpoint of SCD, ventricular tachycardia, ventricular fibrillation or resuscitated cardiac arrest. RESULTS Among 701 patients (age: 65.8 ± 12.3 yrs [mean ± SD]), 28 (3.99%) patients met the primary endpoint over 5.91 years (median; interquartile range 4.42-7.64). In competing risks analysis, a GZF3SD mass ≥ 5.0 g was strongly associated with the primary endpoint (subdistribution hazard ratio [sHR]: 17.4 [95% CI 6.64-45.5]); area under receiver operator characteristic curve [AUC]: 0.85, p < 0.001). A weaker association was observed for TF2SD mass ≥ 23 g (HR: 10.4 [95% CI 4.22-25.8]; AUC: 0.80, p < 0.001). The range of sHRs for GZF3SD mass (1 to 526.6) was wider than for TF2SD mass (1 to 37.6). CONCLUSIONS In CAD patients with a LVEF≥35%, GZF3SD mass was strongly associated with the arrhythmic endpoint. These findings hold promise for its use in identifying patients with CAD and a LVEF≥35% at risk of arrhythmic events. Abstract Figure.

Increased native myocardial T1 times in chronic kidney disease (CKD) may be due to diffuse interstitial myocardial fibrosis (DIF) or due to interstitial edema/inflammation. Concerns relating to nephrogenic systemic fibrosis with gadolinium-based contrast agents (GBCA) limit their use in end-stage kidney disease (ESKD) to measure extracellular volume (ECV) and characterise myocardial fibrosis. This study aimed to examine stability of myocardial T1 and T2 times before, and within 2 months after kidney transplantation; a time frame when volume status normalises but myocardial remodelling is unlikely to have occurred, and to compare these with ECV using GBCA after transplantation. Twenty-four patients with ESKD underwent serial cardiovascular magnetic resonance imaging, including T1 and T2 mapping. GBCA was administered on follow-up provided eGFR was >30 ml/min/1.73 m2. Eighteen age- and sex-matched controls were studied at one timepoint. ECV (ECV 28 ± 2% vs. 24 ± 2%, p = 0.001) and T2 times were higher in ESKD compared to controls. After transplantation, septal T1 times increased (MOLLI 985 ms ± 25 vs. 1002 ms ± 30, p = 0.014; ShMOLLI 974 ms ± 39 vs. 992 ms ± 33, p = 0.113), LV volumes reduced (LVEDvol indexed 79 ± 24 vs. 63 ± 20 ml/m2, p = 0.005) but LV mass was unchanged (LV mass index 89 g/m2 ± 38 to 83 g/m2 ± 23, p = 0.141). T2 times did not change after transplantation. Both ECV and myocardial T1 times are elevated in ESKD, supporting the theory that elevated T1 times are due to DIF, although a contribution from myocardial edema cannot be fully excluded. The lack of any fall in T1 or T2 times after transplantation suggests that myocardial T1 times are a stable measure of DIF in CKD., Highlights • ECV is elevated in ESKD suggesting the elevated myocardial T1 times observed are indicative of diffuse interstitial fibrosis. • The contribution of myocardial oedema towards elevated T1 times and ECV cannot be excluded in ESKD. • Native T1 times is a stable and reproducible biomarker of fibrosis.

Echocardiography plays a vital role in the follow-up of patients with replacement heart valves. However, there is considerable variation in international guidelines regarding the recommended time points after implantation at which routine echocardiography should be performed. The purpose of routine echocardiography is to detect early structural valve deterioration in biological valves to improve the timing of redo interventions. However, the risk of valve deterioration depends on many valve-related factors (valve design and patient prosthesis mismatch) and patient-related factors (age, diabetes, systemic hypertension, renal dysfunction and smoking). In this statement, the British Heart Valve Society and the British Society of Echocardiography suggest practical guidance. A plan should be made soon after implantation, but this may need to be modified for individual patients and as circumstances change. It is important that patients are managed in a multidisciplinary valve clinic.

Background: Quality assurance (QA) of echocardiographic studies is vital to ensure that clinicians can act on findings of high quality to deliver excellent patient care. To date, there is a paucity of published guidance on how to perform this QA. The British Society of Echocardiography (BSE) has previously produced an Echocardiography Quality Framework (EQF) to assist departments with their QA processes. This article expands on the EQF with a structured yet versatile approach on how to analyse echocardiographic departments to ensure high-quality standards are met. In addition, a process is detailed for departments that are seeking to demonstrate to external bodies adherence to a robust QA process. Methods: The EQF consists of four domains. These include assessment of Echo Quality (including study acquisition and report generation); Reproducibility & Consistency (including analysis of individual variability when compared to the group and focused clinical audit), Education & Training (for all providers and service users) and Customer & Staff Satisfaction (of both service users and patients/their carers). Examples of what could be done in each of these areas are presented. Furthermore, evidence of participation in each domain is categorised against a red, amber or green rating: with an amber or green rating signifying that a quantifiable level of engagement in that aspect of QA has been achieved. Conclusion: The proposed EQF is a powerful tool that focuses the limited time available for departmental QA on areas of practice where a change in patient experience or outcome is most likely to occur.

Mitral regurgitation (MR) following acute myocardial infarction (AMI) worsens prognosis and reports of prevalence vary significantly. The objective was to determine prevalence, risk factors, and outcomes related to MR following AMI. We identified 1000 consecutive patients admitted with AMI in 2016/17 treated by percutaneous coronary intervention with pre-discharge transthoracic echocardiography. MR was observed in 294 of 1000 (29%), graded as mild (n = 224 [76%]), moderate (n = 61 [21%]) and severe (n = 9 [3%]). Compared with patients without MR, patients with MR were older (70 ± 12 vs 63 ± 13 years; p0.001), with worse left ventricular ejection fraction (LVEF) (52 ± 15% vs 55 ± 11%; p0.001) and creatinine clearance (69 ± 33 ml/min vs 90 ± 39 ml/min; p0.001). They also had higher rates of hypertension (64% vs 55%; p = 0.012), heart failure (3.4% vs 1.1%; p = 0.014), previous MI (28% vs 20%; p = 0.005) and severe flow-limitation in the circumflex (50% vs 33%; p0.001) or right coronary artery (51% vs 42%; p = 0.014). Prevalence and severity of MR were unaffected by AMI subtype. Revascularization later than 72 hours from symptom-onset was associated with increased likelihood of MR (33% vs 25%; p = 0.036) in patients with non-ST elevation myocardial infarction (NSTEMI). After a mean of 3.2 years, 56 of 288 (19%) patients with untreated MR died. Age and LVEF independently predicted mortality. The presence of even mild MR was associated with increased mortality (p = 0.029), despite accounting for confounders. In conclusion, MR is observed in over one-quarter of patients after AMI and associated with lower survival, even when mild. Prevalence and severity are independent of MI subtype, but MR was more common with delayed revascularization following NSTEMI.

BackgroundDegenerative aortic stenosis (AS), the most common valvular heart disease in the Western world, is often diagnosed late when the mortality risk becomes substantial. We determined the feasibility of AS screening during influenza vaccination at general practitioner (GP) surgeries in the UK.MethodsConsecutive subjects aged >65 years presenting to a GP for influenza vaccination underwent heart auscultation and 2D echocardiography (V-scan). Based on these findings, a patient management strategy was determined (referral to cardiologist, review within own practice or no follow-up measures) and status at 3 months was determined.Results167 patients were enrolled with a mean age of 75 years. On auscultation, a heart murmur was detected in 30 of 167 (18%) patients (6 subjects with an AS-specific and 24 with a non-specific murmur). 75.2% of those with no murmur had a negative V-scan finding. Conversely, 16 of 30 (53%) patients with any murmur had an abnormal V-scan finding that was largely related to the aortic valve. Using clinical auscultation and V-scan screening, a decision not to pursue follow-up measures was taken in 147 (88%) cases, whereas 18 (10.8%) subjects were referred onward; with 5 of 18 (27.8%) and 3 of 18 (16.7%) being diagnosed with mild and moderate AS.ConclusionsOur pilot study confirms feasibility of valvular heart disease screening in the elderly in a primary care setting. Using simple and inexpensive diagnostic measures and 7.3 million UK inhabitants undergoing influenza vaccination, nationwide screening could potentially identify 130 000 patients with moderate AS and a significant number of patients with severe AS.

Importance: There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure. Objective: To compare low-dose digoxin with bisoprolol (a β-blocker). Design, Setting, and Participants: Randomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019. Interventions: Digoxin (n = 80; dose range, 62.5-250 μg/d; mean dose, 161 μg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d). Main Outcomes and Measures: The primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting. Results: Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, −1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, −2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P Conclusions and Relevance: Among patients with permanent atrial fibrillation and symptoms of heart failure treated with low-dose digoxin or bisoprolol, there was no statistically significant difference in quality of life at 6 months. These findings support potentially basing decisions about treatment on other end points.

ObjectiveApproximately 3.4% of adults aged >75 years suffer from aortic stenosis (AS). Guideline indications for aortic valve replacement (AVR) distinguish between patients with symptomatic and asymptomatic severe AS. The present analysis aims to assess contemporary practice in the treatment of severe AS across Europe and identify characteristics associated with treatment decisions, namely denial of AVR in symptomatic patients and assignment of asymptomatic patients to AVR.MethodsParticipants of the prospective, multinational IMPULSE database of patients with severe AS were grouped according to AS symptoms, and stratified into subgroups based on assignment to/denial of AVR.ResultsOf 1608 symptomatic patients, 23.8% did not undergo AVR and underwent medical treatment. Denial was independently associated with multiple factors, including severe frailty (p=0.024); mitral (p=0.002) or tricuspid (p=0.004) regurgitation grade III/IV, and the presence of renal impairment (p=0.017). Of 392 asymptomatic patients, 86.5% had no prespecified indication for AVR. Regardless, 36.3% were assigned to valve replacement. Those with an indexed aortic valve area (AVA; p=0.045) or left ventricular ejection fraction (LVEF; pConclusionsThere may be considerable discrepancies between guideline-based recommendations and clinical practice decision-making in the treatment of AS. It appears that guidelines may not fully capture the complete clinical spectrum of patients with AS. Thus, there is a need to find ways to increase their acceptance and the rate of adoption.

Valvular heart disease (VHD) is a chronic progressive condition with an increasing prevalence in the Western world due to aging populations. VHD is often diagnosed at a late stage when patients are symptomatic and the outcomes of therapy, including valve replacement, may be sub-optimal due the development of secondary complications, including left ventricular (LV) dysfunction. The clinical application of artificial intelligence (AI), including machine learning (ML), has promise in supporting not only early and more timely diagnosis, but also hastening patient referral and ensuring optimal treatment of VHD. As physician auscultation lacks accuracy in diagnosis of significant VHD, computer-aided auscultation (CAA) with the help of a commercially available digital stethoscopes improves the detection and classification of heart murmurs. Although used little in current clinical practice, CAA can screen large populations at low cost with high accuracy for VHD and faciliate appropriate patient referral. Echocardiography remains the next step in assessment and planning management and AI is delivering major changes in speeding training, improving image quality by pattern recognition and image sorting, as well as automated measurement of multiple variables, thereby improving accuracy. Furthermore, AI then has the potential to hasten patient disposal, by automated alerts for red-flag findings, as well as decision support in dealing with results. In management, there is great potential in ML-enabled tools to support comprehensive disease monitoring and individualized treatment decisions. Using data from multiple sources, including demographic and clinical risk data to image variables and electronic reports from electronic medical records, specific patient phenotypes may be identified that are associated with greater risk or modeled to the estimate trajectory of VHD progression. Finally, AI algorithms are of proven value in planning intervention, facilitating transcatheter valve replacement by automated measurements of anatomical dimensions derived from imaging data to improve valve selection, valve size and method of delivery.

Funding Acknowledgements Type of funding sources: None. Background Staging of Fabry disease (FD) cardiomyopathy uses multiparametric cardiac MRI. Advanced disease is characterized by left ventricular hypertrophy (LVH), myocardial inflammation/oedema (high native T2 mapping) and/or fibrosis (late gadolinium enhancement, LGE). Pre-LVH involvement has been described and includes myocardial sphingolipid storage (low native T1 mapping), impaired LV global longitudinal strain (GLS) and microvascular disease/dysfunction (low stress myocardial blood flow, MBF, in perfusion mapping). We aimed to define (1) the early myocardial phenotype prior to T1 lowering/pre-storage and (2) the stages of cardiac involvement in FD. Methods FD patients and age, sex and heart rate matched healthy controls underwent same-day ECG with advanced analysis and multiparametric CMR (cines, GLS, pre-contrast T1 and T2 mapping, adenosine stress perfusion mapping [for MBF] and LGE). Results 114 Fabry patients (46 ± 13 years, 61% female, 37% [n = 72] had LVH) and 76 controls (49 ± 15 years, 50% female) were included. FD with vs without LVH in brief and as expected, FD with LVH had significantly (p FD pre-LVH low T1 vs pre-LVH normal T1: low T1 patients (32/72, 44%) had higher LV mass index (67 ± 14 vs 59 ± 10g/m2, P = 0.011), maximum Q wave amplitude (2[1-2] vs 1[1-2]mm, P FD pre-LVH normal T1 vs healthy controls: normal T1 pre-LVH Fabry patients (40/72, 56%) had reduced GLS (-18 ± 2 vs -20 ± 2%, P Conclusion Prior staging of Fabry cardiomyopathy included a pre-LVH stage (accumulation/storage) and two LVH stages (hypertrophy and inflammation; fibrosis and impairment). Here we define an even earlier stage, pre-LVH pre-detectable storage, defined by microvascular dysfunction, impaired GLS and altered atrial depolarization and ventricular repolarization intervals (see Figure). Abstract Figure. Proposed stages of cardiac involvement

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): (1) University Hospitals Birmingham Charity (2) Metchley Park Medical Society Introduction Coronary microvascular dysfunction (CMD) is common among patients with end-stage renal disease (ESRD) and confers poor prognosis. Coronary flow velocity reserve (CFVR) is a marker of coronary microvascular function and can be reliably measured using Doppler echocardiography. Reduced CFVR in ESRD has been attributed to factors such as hypertension and left ventricular hypertrophy (LVH). Anaemia is prevalent in ESRD but the association between haemoglobin and CFVR in ESRD has not been studied. Purpose To assess if CFVR is related to haemoglobin among patients with ESRD. Methods 22 subjects with ESRD and awaiting kidney transplant (8 pre-dialysis and 14 on peritoneal dialysis) were studied with adenosine myocardial contrast echocardiography, Doppler CFVR assessment and serum multiplex immunoassay analysis. Individuals with diabetes, uncontrolled hypertension or ischaemic heart disease were excluded. Results 7/22 (32%) of subjects had CMD (defined as CFVR CFVR was significantly lower in subjects with CMD (1.6 ± 0.2 vs 3.2 ± 0.9, p Conclusions Among our cohort of ESRD patients awaiting kidney transplant, there was a high prevalence of CMD despite well controlled blood pressure and no significant LVH. Subjects with CMD had significantly lower haemoglobin than subjects without CMD. Reduced haemoglobin causes impaired oxygen carrying capacity to the myocardium, which may lead to microvascular ischaemia and adverse microvascular remodelling, causing CMD. Thus, anaemia may be a potentially correctible driver of CMD in ESRD. This association needs to be confirmed in larger studies. Abstract Figure 1

Objectives To enhance adherence to cardiac rehabilitation (CR), a patient education programme called ‘learning and coping’ (LC-programme) was implemented in three hospitals in Denmark. The aim of this study was to investigate the cost–utility of the LC-programme compared with the standard CR-programme. Methods 825 patients with ischaemic heart disease or heart failure were randomised to the LC-programme or the standard CR-programme and were followed for 3 years. A societal cost perspective was applied and quality-adjusted life years (QALY) were based on SF-6D measurements. Multiple imputation technique was used to handle missing data on the SF-6D. The statistical analyses were based on means and bootstrapped SEs. Regression framework was employed to estimate the net benefit and to illustrate cost-effectiveness acceptability curves. Results No statistically significant differences were found between the two programmes in total societal costs (4353 Euros; 95% CI –3828 to 12 533) or in QALY (–0.006; 95% CI –0.053 to 0.042). At a threshold of 40 000 Euros, the LC-programme was found to be cost-effective at 15% probability; however, for patients with heart failure, due to increased cost savings, the probability of cost-effectiveness increased to 91%. Conclusions While the LC-programme did not appear to be cost-effective in CR, important heterogeneity was noted for subgroups of patients. The LC-programme was demonstrated to increase adherence to the rehabilitation programme and to be cost-effective among patients with heart failure. However, further research is needed to study the dynamic value of heterogeneity due to the small sample size in this subgroup.

BackgroundContemporary data regarding the impact of comorbidities on the clinical presentation and management of patients with severe aortic stenosis (AS) are scarce.MethodsProspective registry of severe patients with AS across 23 centres in nine European countries.ResultsOf the 2171 patients, chronic kidney disease (CKD 27.3%), left ventricular ejection fraction (LVEF) ConclusionsComorbidities in severe patients with AS affect the presentation and management of patients with severe AS. TAVI was offered more often than SAVR and performed within a shorter time period.

Background Myocardial fibrosis occurs in end-stage heart failure secondary to mitral regurgitation (MR), but it is not known whether this is present before onset of symptoms or myocardial dysfunction. This study aimed to characterise myocardial fibrosis in chronic severe primary MR on histology, compare this to tissue characterisation on cardiovascular magnetic resonance (CMR) imaging, and investigate associations with symptoms, left ventricular (LV) function, and exercise capacity. Methods Patients with class I or IIa indications for surgery underwent CMR and cardiopulmonary exercise testing. LV biopsies were taken at surgery and the extent of fibrosis was quantified on histology using collagen volume fraction (CVFmean) compared to autopsy controls without cardiac pathology. Results 120 consecutive patients (64 ± 13 years; 71% male) were recruited; 105 patients underwent MV repair while 15 chose conservative management. LV biopsies were obtained in 86 patients (234 biopsy samples in total). MR patients had more fibrosis compared to 8 autopsy controls (median: 14.6% [interquartile range 7.4–20.3] vs. 3.3% [2.6–6.1], P mean 13.6% [6.3–18.8], P mean 15.7% [9.9–23.1] (P = 0.083). Fibrosis was patchy across biopsy sites (intraclass correlation 0.23, 95% CI 0.08–0.39, P = 0.001). No significant relationships were identified between CVFmean and CMR tissue characterisation [native T1, extracellular volume (ECV) or late gadolinium enhancement] or measures of LV function [LV ejection fraction (LVEF), global longitudinal strain (GLS)]. Although the range of ECV was small (27.3 ± 3.2%), ECV correlated with multiple measures of LV function (LVEF: Rho = − 0.22, P = 0.029, GLS: Rho = 0.29, P = 0.003), as well as NTproBNP (Rho = 0.54, P 2max: R = − 0.22, P = 0.030). Conclusions Patients with chronic primary MR have increased fibrosis before the onset of symptoms. Due to the patchy nature of fibrosis, CMR derived ECV may be a better marker of global myocardial status. Clinical trial registration Mitral FINDER study; Clinical Trials NCT02355418, Registered 4 February 2015, https://clinicaltrials.gov/ct2/show/NCT02355418

Introduction: The mechanisms linking obesity to increased mortality in patients with coronavirus-disease 2019 (COVID-19) are unclear. Hypothesis: We hypothesised that obesity would be associated with adverse right ventricular (RV) remodelling and function which might be further exacerbated by COVID-19 associated increases in RV afterload/demand. Methods: We used echocardiography and computed tomography to establish links between RV dimensions and function and bodyweight in patients with severe COVID-19. In obese and non-obese participants without COVID-19, we used cardiovascular magnetic resonance to define the effects of obesity upon RV volumes, energetics, systolic function and stress reserve. Results: In patients with severe COVID-19, increasing bodyweight was associated with disproportionate RV dilatation (n=26, echocardiography, R=0.42, P=0.03, CT n=34, R=0.23, P=0.004) and impairment of RV systolic function (fractional area change (FAC) R=-0.45, P=0.04); obesity (BMI >30kg/m2) was associated with a 32% reduction in RV FAC (P=0.03). Similar associations were seen in a validation cohort (n=91, all P2 ) was associated with RV remodelling, impaired cardiac energetics (PCr/ATP ratio 23% lower, P2 , n=27) had impaired RV diastolic filling rate at rest (P Conclusions: Increasing body weight is associated with both significant alterations in RV volumes, systolic function and stress responses which are mitigated with weight loss and also with disproportionate RV dilatation and dysfunction in severe COVID-19. RV dysfunction is a modifiable mechanism which might link obesity to adverse outcomes in patients with COVID-19 and other disorders stressing the right heart.

Background Cardiac involvement of Fabry disease (FD) includes left ventricular hypertrophy (LVH), inflammation, arrhythmia and sudden death. There are limited data regarding potential risk predictors and no definitive criteria exist to guide implantation of cardiac devices for primary prevention. Despite phenotypic similarities between FD and hypertrophic cardiomyopathy (HCM), FD is specifically excluded from the ESC sudden cardiac death risk prediction tool used for HCM. Purpose To evaluate differences in device implantation and arrhythmic burden between advanced Fabry cardiomyopathy and HCM. Methods This multi-centre, retrospective study including genetically confirmed FD and age/gender-matched HCM patients all of whom had an implantable cardioverter defibrillator (ICD). Data was collected prior to device implantation on disease characteristics, biomarkers and CMR imaging. Arrhythmia burden and changes in therapy were captured following implantation. Results Of the UK FD population under follow-up, 50/880 had an ICD implanted (80% males, 51% non-classical mutation, mean age at device implantation 57±12 years). A comparator group included 64 age- and gender-matched HCM patients (67% males, mean age at implant 46±39 years). Baseline LV mass was greater in FD (291±97g/m2 vs 218±78g/m2, p=0.012). FD patients had higher troponin (95 vs 19ng/l, p Indications for ICD insertion in FD included: presumed HCM dual pathology 14%, symptomatic NSVT 18%, asymptomatic NSVT 24%, co-existing long QT 2%, CRT-D 14%, no clear indication (primary prevention in the presence of multiple potential arrhythmic risk factors) 28%. All HCM patients were risk stratified and underwent device implantation based on an estimated 5-year SCD risk >4%. All FD patients had a SCD risk >4% using this risk calculator. Arrhythmia were more common in FD over shorter follow-up (37/50, 74% over 4.3±3.0 years vs 28/64 in HCM, 44% over 6.5±2.9 years, p=0.001). Notably, VT requiring anti-tachycardia pacing (ATP) +/− defibrillation therapy from the ICD was more frequent (FD: 14/50, 28% vs HCM: 8/64, 12%, p=0.055), as was immediate shock therapy for sustained VT (p=0.009, figure panel B). FD patients with arrhythmia were often older, had greater LV mass, a larger left atrium and a broader QRS duration. These clinical features tended to occur more frequently in FD than in the HCM group. Conclusion This study has shown that delivery of device therapy in Fabry cardiomyopathy is higher than in HCM. Despite similar rates of asymptomatic NSVT, a higher rate of ventricular arrhythmia requiring ATP/defibrillation therapy occurred in FD. Although both FD and HCM had similar risk percentages according to the ESC calculator, active troponitis in FD was double that of HCM. Funding Acknowledgement Type of funding source: None

Introduction Echocardiography is essential for the management of patients with atrial fibrillation (AF), but current methods are time consuming and lack any evidence of reproducibility. Purpose To compare conventional averaging of consecutive beats with an index beat approach, where systolic and diastolic measurements are taken once after two prior beats with a similar RR interval (not more than 60 ms difference). Methods Transthoracic echocardiography was performed using a standardized and blinded protocol in patients enrolled into the RAte control Therapy Evaluation in permanent AF randomised controlled trial (RATE-AF; NCT02391337). AF was confirmed in all patients with a preceding 12-lead ECG. A minimum of 30-beat loops were recorded. Left ventricular function was determined using the recommended averaging of 5 and 10 beats and using the index beat method, with observers blinded to clinical details. Complete loops were used to calculate the within-beat coefficient of variation (CV) and intraclass correlation coefficient (ICC) for Simpson's biplane left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and filling pressure (E/e'). Results 160 patients (median age 75 years (IQR 69–82); 46% female) were included, with median heart rate 100 beats/min (IQR 86–112). For LVEF, the index beat had the lowest CV of 32% compared to 51% for 5 consecutive beats and 53% for 10 consecutive beats (p Conclusion Index beat determination of left ventricular function improves reproducibility, saves time and does not compromise validity compared to conventional quantification in patients with heart failure and AF. After independent validation, the index beat method should be adopted into routine clinical practice. Comparison for measurement of E/e' Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institute of Health Research UK

Background Previous studies of the incidence and severity of mitral regurgitation (MR) following acute myocardial infarction (MI) were limited by the study population (ST-elevation MI only), by diagnostic methods (lack of multiparametric quantification), or by the time-frame of study (late assessment post-MI). The true incidence of ischaemic MR (IMR) immediately following type 1 MI [non-ST-elevation (NSTEMI) and ST-elevation (STEMI)] patients in the modern era of universal early revascularisation remains unclear. Since even mild IMR confers a poor prognosis, factors which promote or protect against the development of MR require further evaluation. Purpose To determine the incidence, clinical and angiographic characteristics of patients with IMR following type 1 MI treated with PCI. Methods This was a single-centre study of 1000 consecutive, prospectively recruited patients admitted to the Queen Elizabeth Hospital Birmingham with type 1 MI who underwent PCI. Early inpatient transthoracic echocardiography (TTE) was performed by accredited echocardiographers using standard multiparametric quantification. Results MR was observed in 294/1000 patients (29.4%) post-MI, graded as mild (76%), moderate (21%) and severe (3%). Median time from symptom onset to PCI was 1 day (IQR 0–4) and to TTE 2 days (IQR 1–3). Compared to patients without MR (MR-), those with MR (MR+) were older (73±12 years vs 66±13 years; p MR+ patients were more likely to have severe disease in the left circumflex (LCx) (50% vs 33%; p Incidence of MR was equal (29%) amongst STEMI (126/431) and NSTEMI (168/569) patients. While the time to revascularisation did not affect the prevalence of MR following STEMI (linear regression analysis of door-to-balloon time in MR+ and MR- patients p=0.843), NSTEMI patients were more likely to develop MR if revascularisation was delayed (linear regression analysis of symptom onset to PCI time MR+ vs MR- p=0.061). Conclusion Almost 1/3 of patients with type 1 MI undergoing revascularisation have MR evident on pre-discharge TTE. Factors promoting MR include older age, male sex, HTN, HF, larger non-LAD territory infarct, and depressed LVEF. The incidence of MR following STEMIs and NSTEMIs is equal. Earlier revascularisation is unlikely to reduce MR in STEMI patients but may improve MR prevalence following NSTEMI. Funding Acknowledgement Type of funding source: None

Background Cardiac involvement in Fabry Disease (FD) occurs prior to left ventricular hypertrophy (LVH) and is characterized by low myocardial native T1 with storage reflected by cardiovascular magnetic resonance (CMR) and ECG changes. Objectives We hypothesize that a pre-storage myocardial phenotype might occur even earlier, prior to T1 lowering. Methods FD patients and age, sex and heart rate matched healthy controls underwent same-day ECG with advanced analysis and multiparametric CMR (cines, global longitudinal strain [GLS], T1 and T2 mapping, stress perfusion [myocardial blood flow, MBF] and late gadolinium enhancement [LGE]). Results 114 Fabry patients (46±13 years, 61% female) and 76 controls (49±15 years, 50% female) were included. In pre-LVH FD (n=72, 63%), a low T1 (n=32/72, 44%) was associated with a constellation of ECG and functional abnormalities compared to normal T1 FD patients and controls. However, pre-LVH FD with normal T1 (n=40/72, 56%) also had abnormalities compared to controls: reduced GLS (−18±2 vs −20±2%, P Conclusions FD has a measurable myocardial phenotype pre-LVH and pre-detectable myocyte storage with microvascular dysfunction, subtly impaired GLS and altered atrial depolarization and ventricular repolarization intervals. Proposed stages of cardiac involvement Funding Acknowledgement Type of funding source: None

Background Carcinoid heart disease (CHD) often complicates neuroendocrine tumours (NET). The prognosis of CHD without intervention is poor; 3 year survival is estimated at 31%. Surgical valve replacement is the only treatment for CHD, but is associated with high 30-day mortality (10–15%). Purpose The aim is to identify pre-operative transthoracic echocardiogram (PTTE) findings that could determine which patients have a high likelihood of post-surgical mortality at 1 year. Methods This retrospective observational cohort study recruited 88 patients with a confirmed diagnosis of CHD between 2005–19 at University Hospital Birmingham; 49 (56%) of these were treated surgically. Indications for surgery: stable NET, symptomatic severe valvular dysfunction, progressive RV dilatation or RV dysfunction, no significant comorbidities. All patients underwent a standard PTTE. PTTE parameters assessed: right ventricular (RV) size, RV function (qualitative), TAPSE, RV fractional area change, RV S wave velocity, left ventricular (LV) size, LV ejection fraction and valve velocities. Surgery was performed by a single surgical team with bioprosthetic valve replacements. Results Patients were followed up for a median of 15 months (IQR: 6–59) after surgery, during which time there were 33 deaths, giving a median survival time of 30 months (IQR: 7–85). Increasingly severe RV dilatation was significantly associated with shorter survival (p=0.032). The estimated survival rate at three years was 67% in those with normal RV size, compared to 24% in the severe RV group (Figure 1). RV basal diameter was assessed used ROC curve analysis for the outcome of one year survival and returned an area under the curve of 0.66 (SE=0.10). Youden's index identified RV diameter >4.8cm to be the optimal cut-off for identifying high-risk patients. One year mortality rates were 26% (7/27) vs. 75% (9/12) in those with RV basal diameter of ≤4.8 vs. >4.8cm (p=0.006). Conclusion A pre-operative right ventricular basal diameter >4.8cm is associated with a near three-fold increase in post-operative mortality at one year. These findings highlight the importance of regular imaging in order to optimise the timing of surgery in patients with CHD. Figure 1. Kaplan-Meier curve of post-op survival Funding Acknowledgement Type of funding source: None

Chronic primary mitral regurgitation (MR) exposes the left ventricle (LV) to volume overload and is associated with evidence of fibrosis on non-invasive imaging. It is not known whether fibrosis predicts outcome from surgery. This study aimed to 1) quantify myocardial fibrosis on histology and non-invasive imaging, 2) investigate any association between fibrosis and LV size and function, 3) determine the impact of fibrosis on post-operative outcome. Methods In a prospective observational multicentre study, 105 patients with severe MR (N=65/32/8 NYHA Class I/II/III respectively; mean age 63.1±13.4 years; male 73%; VO2max 91.2±22.4%) had multiparametric cardiac magnetic resonance (CMR), symptom assessment (Minnesota Living with Heart Failure Questionnaire (MLHFQ)) and cardiopulmonary exercise testing before and at 9 months following repair. Patients consented for up to 3 intraoperative LV biopsies for histological collagen volume fraction (CVF) quantification. Results 234 LV biopsies were feasible from 86 patients with median CVF of 14.6% [IQR 7.4–20.3]. Fibrosis was present even in NYHA Class I patients (13.6% [6.3–18.8]), and was significantly higher than the 3.3% [2.6–6.1] obtained from 8 autopsy controls without cardiac disease (P Pre-operatively, there was no relationship between CVF and LV size, systolic function, ECV, late gadolinium enhancement, although it did correlate with MLHFQ (R=0.23, P=0.034). Conversely, ECV (27.4±3.3%) correlated with systolic (LVEF Rho=−0.22, P=0.029; LVESVi Rho=0.22, P=0.025, GCS Rho=0.31, P=0.002) and diastolic function (E/e' R=0.25, P=0.022), exercise capacity (%VO2max R=−0.22, P=0.030), with borderline correlation to MLHFQ (R=0.19, P=0.058). Post-operatively, although LVEF remained normal (defined as >50%) in all but 6 patients (LVEF pre 69.1±8.0 vs post 63.3±8.3%, P Conclusions Myocardial fibrosis is present in primary MR, before the onset of symptoms. Due to its patchy nature, ECV but not fibrosis on histology is a better marker of pre-operative myocardial function and symptom status. Despite ECV reduction following successful MR surgery, symptomatic patients fail to regain exercise fitness and symptom-free status – providing further support for the benefits of early surgery. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

Background Ischaemic mitral regurgitation (IMR) confers a poor prognosis. Transcatheter intervention may improve survival but benefit is likely to depend on severity of IMR relative to LV remodelling following myocardial infarction (MI). In theory, those with “discordant” IMR (significant regurgitant volume without severe LV dilatation or impairment), are expected to benefit most from mitral intervention. While subcategorization may help to inform treatment, there are no data on post-MI patients in this respect. Purpose To determine the incidence of discordant & concordant IMR categorised on echocardiography post-MI and impact on outcomes. Methods 1000 consecutive patients admitted to our hospital with myocardial infarction who underwent coronary angioplasty were included. Early inpatient TTE was performed by accredited echocardiographers using standard multiparametric quantification. Using TTE parameters, 4 subgroups were identified (figure) according to the degree of MR relative to LV remodelling. Thresholds were based on European guidelines (± 2SD from normal) and median value among survivors for vena contracta (VC): – LVEF: 52% (♂), 54% (♀) – Indexed LV end diastolic volume (LVEDVi): 74ml/m2 (♂), 61ml/m2 (♀) – Effective regurgitant orifice area (EROA) ≥0.2cm2 – Regurgitant volume (RVol) ≥30ml – VC ≥0.5cm Results MR was seen in 294/1000 patients (29.4%) with a severity of mild (76%), moderate (21%) and severe (3%). Concordant and discordant IMR were each seen in 16/294 (5%) of IMR patients post-MI. After a mean follow up of 3.2 years, IMR patients had a 3% rate of heart failure (HF) within 1 year and 19% mortality. Non-survivors had significantly worse IMR (PISA 0.65±0.25cm vs 0.54±0.19cm; p=0.033; VC 0.63±0.25cm vs 0.49±0.18cm; p=0.014), worse LV function (LVEF 44±17% vs 51±13%; p Conclusion 1) Significant predictors of mortality in IMR include LA dilatation and decline in LVEF, but not LV dilatation. 2) Although discordant severe IMR is uncommon following MI, mortality if left untreated remains high. Attention should be paid to early selection of this cohort for intervention. Funding Acknowledgement Type of funding source: None

Background Controversy exists as to whether low-dose cabergoline is associated with clinically significant valvulopathy. Few studies examine hard cardiac endpoint data, most relying on echocardiographic findings. Objectives To determine the prevalence of valve surgery or heart failure in patients taking cabergoline for prolactinoma against a matched nonexposed population. Design Population-based cohort study based on North East London primary care records. Methods Data were drawn from ~1.5 million patients’ primary care records. We identified 646 patients taking cabergoline for >6 months for prolactinoma. These were matched to up to 5 control individuals matched for age, gender, ethnicity, location, diabetes, hypertension, ischemic heart disease, and smoking status. Cumulative doses/durations of treatment were calculated. Cardiac endpoints were defined as cardiac valve surgery or heart failure diagnosis (either diagnostic code or prescription code for associated medications). Results A total of 18 (2.8%) cabergoline-treated patients and 62 (2.33%) controls reached a cardiac endpoint. Median cumulative cabergoline dose was 56 mg (interquartile range [IQR] 27-123). Median treatment duration was 27 months (IQR 15-46). Median weekly dose was 2.1 mg. Neither univariate nor multivariate analysis demonstrated a significant association between cabergoline treatment at any cumulative dosage/duration and an increased incidence of cardiac endpoints. In a matched analysis, the relative risk for cardiac complications in the cabergoline-treated group was 0.78 (95% CI, 0.41-1.48; P = 0.446). Reanalysis of echocardiograms for 6/18 affected cabergoline-treated patients showed no evidence of ergot-derived drug valvulopathy. Conclusions The data did not support an association between clinically significant valvulopathy and low-dose cabergoline treatment and provide further evidence for a reduction in frequency of surveillance echocardiography.

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinaemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative adipose tissue failure in monogenic obese cohort; a finding supported by observations in a novel conditional mouse model (Almsflin/flin) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model (Almsflin/flin;Adipo-Cre+/-) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative adipose tissue failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte driven insulin resistance may assist development of adipose tissue targeted therapeutic strategies for diabetes.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

BackgroundAn investigation into differences in the management and treatment of severe aortic stenosis (AS) between Germany, France and the UK may allow benchmarking of the different healthcare systems and identification of levers for improvement.MethodsPatients with a diagnosis of severe AS under management at centres within the IMPULSE and IMPULSE enhanced registries were eligible.ResultsData were collected from 2052 patients (795 Germany; 542 France; 715 UK). Patients in Germany were older (79.8 years), often symptomatic (89.5%) and female (49.8%) and had a lower EF (53.8%) than patients in France and UK. Comorbidities were more common and they had a higher mean Euroscore II.Aortic valve replacement (AVR) was planned within 3 months in 70.2%. This was higher (pFrance> UK; pSymptomatic patients were scheduled for an AVR in 79.4% (Germany> France> UK; pConclusionPatients in Germany had more advanced disease. The rate of intervention within 3 months after diagnosis was startlingly low in the UK. Asymptomatic patients without a formal indication often underwent an intervention in Germany and France.

Learning objectives Valvular heart disease (VHD) affects 1 in 50 of the general population and 1 in 3 of the over 65s, and is associated with increased morbidity and premature mortality.1 Among adults presenting to hospital with severe VHD, mitral regurgitation (MR: 21.3%) is the second and aortic regurgitation (AR: 5.3%) is the third most common valve lesion after aortic stenosis (41.2%).2 The predominance of MR above AR is also found in community-based studies, although it is much more common to find mild and moderate VHDs than severe disease in the general population.1 VHD of all types is more common with advancing age, and given the steady rise of life expectancy in the Western world, the frequency of patients presenting with MR and AR is increasing. Despite clear evidence of benefit from surgery when performed in a timely fashion, many patients undergo operation late in the course of disease, with more advanced symptoms and higher rates of heart failure and ventricular dysfunction.2 There is a long latent period in the majority of patients with either MR or AR, and timely diagnosis, careful monitoring and early referral remain critical to care. The severity of regurgitation through the MV and AV is governed by the Gorlin formula, which states that flow through an orifice varies by the square root of the pressure gradient across the orifice, the duration of flow and a discharge coefficient.3 Therefore, the main determinants …

Background Ischaemic mitral regurgitation (IMR) is associated with left atrial (LA) dilatation. In patients with primary MR, LA enlargement is an independent predictor of mortality following medical management and mitral valve surgery. The prognostic significance of LA dilatation in IMR post-myocardial infarction (MI) has not been studied. Purpose To determine the impact of LA dilatation on mortality in patients with IMR. Methods 1000 consecutive patients admitted to the Queen Elizabeth Hospital Birmingham with MI who underwent percutaneous coronary intervention were included. Early inpatient TTE was performed within 24-48 hours by accredited echocardiographers using standard multiparametric quantification of IMR, including proximal isovelocity surface area (PISA), effective regurgitant orifice (EROA), vena contracta (VC), and regurgitant volume (RVol). LA size was measured by the recommended biplane method for calculation of LA volume and indexed to body surface area (Mosteller). Analysis was performed on patients with indexed LA volume (LAVi) above and below 34ml/m2 (defined as the upper limit of normal in European Cardiovascular Imaging guidelines). Results MR was observed in 294/1000 patients (29.4%) post-MI, graded as mild (76%), moderate (21%) and severe (3%). A total of 275/294 (94%) had complete chamber volume data. LA dilatation (LAVi > 34ml/m2) was seen in 124 (45%) patients while 151/275 (55%) had normal LA volume (LAVi Although patients with LAVi > 34ml/m2 were older (76+/-11 years vs 70+/-12; p 34ml/m2 accounted for 60% of this mortality. Conclusion IMR patients with LA dilatation have significantly higher mortality than those with normal LA volume. Those with LAVi > 34ml/m2 account for 60% of all IMR mortality, despite fewer ST elevation infarcts and smaller troponin rise. Future studies of intervention for IMR should consider LA dilatation as a potential marker of outcome. Conflict of Interest None

Introduction Patients with repaired tetralogy of Fallot (RTOF) develop chronic pulmonary regurgitation and require monitoring for right ventricular dilatation. Pulmonary valve replacement can prevent irreversible right ventricular (RV) dilatation and dysfunction and cardiac magnetic resonance (CMR) is used to facilitate its optimal timing. There are however, different techniques published for measuring RV volumes. We sought to determine whether the choice of myocardial contouring technique affects preoperative RV volumetric thresholds for intervention. Methods Consecutive patients (n = 24, age 25.2±15.5 years, 42% male) with RTOF were identified retrospectively, having undergone CMR for clinical surveillance at a Level 1 ACHD surgical referral centre. Volumetric analysis was made by two experienced, independent observers blinded to clinical status. Right ventricular volumes were measured using three contouring techniques: 1) smooth, where the trabeculae were counted as part of the blood volume; 2) detailed, using semi-automated thresholding; 3) detailed, with manual contours. For 2) and 3), trabeculae and sub-valvar apparatus were counted as part of the myocardium. Inter-observer variability (F.L. & C.M.) was assessed blinded in 5 randomly selected patients. Results Right ventricular end-diastolic volume (EDV) was largest for smooth contours compared with thresholding and manual (table), as was end-systolic volume (ESV) (p Conclusions Smooth right ventricular contouring in RTOF creates larger RV volumes than detailed and may result in differences in management strategy. Smooth contouring is more reproducible than detailed methods using thresholding. Manual contouring was the least reproducible in this series. Our results are similar to studies of left ventricular contouring demonstrating larger volumes using smooth compared with detailed methods. The difference in right ventricular volume is accentuated in RTOF due to increased RV trabeculation. Consensus on contouring techniques in RTOF is vital to ensure standardisation of care. Conflict of Interest None

Introduction Echocardiography is essential for the management of patients with atrial fibrillation (AF), but current methods are time consuming and lack any evidence of reproducibility. Purpose To compare conventional averaging of consecutive beats with an index beat approach, where systolic and diastolic measurements are taken once after two prior beats with a similar RR interval (not more than 60 ms difference). Methods Transthoracic echocardiography was performed using a standardized and blinded protocol in patients enrolled into the RAte control Therapy Evaluation in permanent AF randomised controlled trial (RATE-AF; NCT02391337). AF was confirmed in all patients with a preceding 12-lead ECG. A minimum of 30-beat loops were recorded. Left ventricular function was determined using the recommended averaging of 5 and 10 beats and using the index beat method, with observers blinded to clinical details. Complete loops were used to calculate the within-beat coefficient of variation (CV) and intraclass correlation coefficient (ICC) for Simpson’s biplane left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and filling pressure (E/e’). Results 160 patients (median age 75 years (IQR 69-82); 46% female) were included, with median heart rate 100 beats/min (IQR 86-112). For LVEF, the index beat had the lowest CV of 32% compared to 51% for 5 consecutive beats and 53% for 10 consecutive beats (p Conclusion Index beat determination of left ventricular function improves reproducibility, saves time and does not compromise validity compared to conventional quantification in patients with heart failure and AF. After independent validation, the index beat method should be adopted into routine clinical practice. Conflict of Interest Nothing to declare

Chronic primary mitral regurgitation (MR) exposes the left ventricle (LV) to volume overload and is associated with evidence of fibrosis on non-invasive imaging. It is not known whether fibrosis predicts outcome from surgery. This study aimed to 1) quantify myocardial fibrosis on histology and non-invasive imaging, 2) investigate any association between fibrosis and LV size and function, 3) determine the impact of fibrosis on post-operative outcome. Methods In a prospective observational multicentre study, 105 patients with severe MR (N=65/32/8 NYHA Class I/II/III respectively; mean age 63.1±13.4years; male 73%; VO2max 91.2±22.4%) had multiparametric cardiac magnetic resonance (CMR), symptom assessment (Minnesota Living with Heart Failure Questionnaire (MLHFQ)) and cardiopulmonary exercise testing before and at 6-9 months following repair. Patients consented for up to 3 intraoperative LV biopsies for histological collagen volume fraction (CVF) quantification. Results 234 LV biopsies were collected from 86 patients with median CVF of 14.6%[IQR 7.4-20.3]. Fibrosis was present even in NYHA Class I patients (13.6%[6.3-18.8]), and was significantly higher than the 3.3%[2.6-6.1] obtained from 8 autopsy controls without cardiac disease (P Pre-operatively, there was no relationship between CVF and LV size, systolic function, ECV, late gadolinium enhancement, although CVF did correlate with MLHFQ (R=0.23, P=0.034). Conversely, ECV correlated with systolic (LVEF Rho=-0.22, P=0.029; LVESVi Rho 0.22, P=0.025, GCS Rho=0.31, P=0.002) and diastolic function (E/e’ R=0.25, P=0.022), exercise capacity (%VO2max R=-0.22, P=0.030), with borderline correlation to MLHFQ (R=0.19, P=0.058). Following surgery, although LVEF remained >50% in all but 6 patients (LVEF pre 69.1±8.0 vs post 63.3±8.3%, P Conclusions Myocardial fibrosis is present in primary MR, before the onset of symptoms. Due to its patchy nature, ECV but not fibrosis on histology is a better marker of pre-operative myocardial function and symptom status. Despite ECV reduction following successful MR surgery, symptomatic patients fail to regain exercise fitness and symptom-free status – providing further support for the benefits of early surgery. Conflict of Interest None