Abstract Introduction People with heart failure (HF) usually have multiple comorbidities and these confer adverse prognosis. The chronology of comorbidity development in relation to HF has not been investigated, which hinders development of preventative strategies. Purpose We aimed to define the chronology of comorbidity diagnoses in relation to HF diagnosis and hypothesised that HF is preceded by most of its comorbidities. Methods We used UK Biobank data to identify 21,127 people with HF diagnosis at any stage before or after recruitment. Comorbidities were defined using primary care records, and were not included if self-reported or their date of diagnosis unknown. Comorbidities were selected based on methods of Conrad et al. (Lancet 2018; 391(10120): 572-580), and defined using CALIBER or UK Biobank criteria. We investigated the time between first diagnosis of HF and first diagnosis of 15 common comorbidities, including after stratification by sex and age at HF diagnosis. Analysis was conducted using RStudio. Results For all studied comorbidities, except dementia, at least half of diagnoses predated or developed synchronously with HF. For myocardial infarction, obesity, cancer, atrial fibrillation, hypertension, diabetes and depression, at least three quarters of diagnoses predated or developed synchronously with HF. The median time between comorbidity and HF diagnoses varied substantially between comorbidities, ranging from depression preceding HF by 10.7 years to dementia proceeding HF by 0.7 years. The interquartile range of time between comorbidity and HF diagnoses varied substantially, ranging from 2.4 years for myocardial infarction to 15.2 years for depression, indicating most cases of the former develop in a narrow window (usually prior to HF diagnosis). All comorbidities presented earlier in women, with this being most marked for cancer (median time between cancer and HF -2.6 years for men and -7.1 years for women). As the age of HF diagnosis increased, the time spent with all studied comorbidities also increased. Indeed, in HF diagnosed before the age of 60, a majority of comorbidity diagnoses (except for depression) occurred after HF. Conclusion HF most often develops late in the process of comorbidity accrual, although this pattern is reversed in people developing HF at younger ages. Sex differences are also notable, with women developing comorbidities earlier in relation to their HF diagnosis. Understanding the chronology of comorbidity development may help to guide strategies to prevent multimorbidity, which are likely to require a personalised approach. For people with established HF, our data also emphasise the importance of holistic care that accounts for complex multimorbidity.Figure 1

AbstractAimsLeft ventricular (LV) thrombus is increasingly detected in patients with and without ischaemic heart disease due to the increased availability of cardiac magnetic resonance imaging. Risk factors include anterior ST elevation myocardial infarction, delayed reperfusion therapy, and non‐ischaemic cardiomyopathy with severe LV systolic dysfunction. We aimed to report the characteristics and outcomes of patients with LV thrombus treated with either vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) with a view to describing differences in efficacy, specifically, subsequent thromboembolic events, thrombus resolution, and also side effects of therapy including clinically significant bleeding.Methods and resultsWe conducted a retrospective, observational cohort study of patients diagnosed with LV thrombus between 1 December 2012 and 30 June 2018 and treated with either DOAC or VKA. We recorded patient demographics, past medical history, prescribed medications, and baseline investigations. The primary outcomes were rates of thromboembolism and clinically significant bleeding, with secondary outcomes of thrombus resolution on repeat cardiac imaging, repeat hospitalization, and all‐cause mortality. During the study period, 84 patients were diagnosed with and managed for LV thrombus. Of these, 62 received VKA and 22 DOAC including 13 prescribed rivaroxaban, eight apixaban, and one dabigatran. Most patients 75 (89%) were male with an average age of 62 ± 14 years. Ischaemic heart disease was the cause of LV impairment in 73 (87%) patients. Baseline characteristics were similar between groups at baseline. Most n = 55 (65%) were co‐prescribed a single antiplatelet agent and 32 (38%) received dual‐antiplatelet therapy. During an average follow‐up of 3.0 ± 1.4 years, there were no statistically significant differences between VKA and DOAC in rates of stroke (2% vs. 0%, P = 0.55), other thromboemboli (2% vs. 0%, P = 0.55), or clinically significant bleeding (10% vs. 0%, P = 0.13). The average interval to cardiac imaging follow‐up was 233 ± 251 days and was not different between groups (P = 0.83), and there was no difference in the rate of resolution of thrombus (76% vs. 65% P = 0.33). Rehospitalization (50% vs. 45%: P = 0.53) and all‐cause mortality (10% vs. 14%; P = 0.61) were also similar.ConclusionsOur data suggest that DOACs are likely to be at least as effective and safe as VKA for stroke prevention in patients with LV thrombus and, despite their lack of a licence for this indication, are therefore likely to represent a reasonable and more convenient option for this setting. The optimal timing and type of anticoagulation for LV thrombus, as well as the role of screening for high‐risk patients, should be tested in prospective, randomized trials.

Background: Three-dimensional speckle-tracking echocardiography (3D-STE) is believed to be influenced by image quality, although quantitative evidence on this is limited. A previous evaluation indicated that sub-optimal image quality introduces a systematic bias in 3D-STE derived left ventricular (LV) deformation indices1, 2. Therefore, we aimed to quantify the extent of bias in proportion to impairment in image quality. Methods: This was a prospective experimental study. 18 healthy participants (age 31 ± 6 years, 83.3 % men) with good echocardiographic windows underwent 3D echocardiography (3DE). To impair the quality of the 3DE images of the LV in a reproducible and graded manner, a sheet of ultrasound-attenuating material, neoprene rubber, of three different thicknesses (2, 3 and 4 mm) was used to mimic mild, moderate and severe impairment in image quality respectively. 4 gated LV 3DE full-volume data-sets (including the optimal quality reference) were acquired per participant. All acquisitions were free of stitching artefacts and similar frame rates were maintained throughout. LV volumetric, and global and segmental LV deformation indices were measured. Mixed linear modelling was used to estimate the extent of bias. Results: There was a systematic bias in all global and segmental LV strains, and LV rotational indices. quality Conclusions: Abstract 2: First-phase ejection fraction is a powerful predictor of adverse events in asymptomatic patients with aortic stenosis preserved total ejection fraction Objectives First-phase ejection fraction (EF1), the ejection fraction up to the time of maximal ventricular contraction may be more sensitive than existing markers in detecting early systolic dysfunction. We examined the prognostic value of EF1 in patients with aortic stenosis (AS), a condition in which left ventricular dysfunction as measured by conventional indices is an indication for valve replacement. Methods Abstract 3: Improved Aortic Dimension Assessment With Specialist Echocardiography Clinics: A Quality Improvement Study. Background: Aortopathy is a common clinical problem. Guidelines recommend the use of double-oblique short axis imaging (CT/MRI) for significant aortic dilatation. Echocardiography is more readily available and cost effective. However accuracy and reproducibility is affected by operator variability. Good correlation between imaging techniques is vital for patient management, and may reduce health care expense and ionizing radiation. Objectives: We investigated the effect of dedicated specialist valve/aortopathy echocardiography clinics on accuracy of measurements and correlation with CT/MRI, compared to routine echocardiography performed outside these clinics. We hypothesized that a dedicated specialist based clinics would yield a better correlation with CT/MRI. Methods: 30 patients undergoing echocardiography in a specialist clinic for aortopathy, who also had correlative imaging with CT/MRI were retrospectively analysed. Aortic measurements were obtained using the inner edge to inner edge in end diastole method. Correlative imaging was compared for the aortic root (aortic annulus, sinus of valsalva, sinotubular junction) and ascending aortic measurements. A similar cohort of 25 patients outside specialist echocardiography clinic was used for comparison. Results: Patient Abstract 5: Introduction: BSE guidelines to assess the probability of pulmonary hypertension (PH) have been recently published. We present a contemporary dataset of patients attending a regional service for evaluation of PH. We audit BSE guidelines and highlight areas for potential development. Methods: 174 patients attending from August 2017 for PH assessment had echo and right heart catheter (RHC) data analysed from the RUH PH registry. Results: Of the 174 patients, 142 (82%) were diagnosed as having PH at RHC (mean RHC mPAP 44.4mmHg). Of those with RHC PH (n=142), 92 (65%) had high probability of PH based on echo assessment, 33 (23%) had intermediate echo probability of PH whilst 17 (12%) had low echo probability of PH (Figures 5 & 6). Only 2 patients with a high echo probability of PH (2%) had no RHC PH.

Patients with myocardial infarction (MI) are at risk of developing left ventricular systolic dysfunction (LVSD), with implications for quality of life, driving and mortality related to heart failure and sudden death. Current UK and European guidelines recommend inpatient echocardiography after MI, to identify those with severe LVSD. This guides early secondary prevention and consideration of prophylactic implantable cardioverterdefibrillator (ICD) therapy if severe LVSD is sustained after 6 weeks.

Abstract Introduction Cardiac resynchronisation therapy (CRT) is a routine treatment for heart failure with reduced ejection fraction and conduction delay to improve symptoms and prognosis. Technological advancements both in cardiac magnetic resonance (CMR) and devices (MRI-conditional modes) now enable investigation of the haemodynamic response to CRT over a range of heart rates. Methods Patients with a CRT-D device were enrolled from heart failure clinics at a single tertiary centre. A complete device system assessment and baseline device check was conducted to ensure MRI compatibility and suitability. Left ventricular (LV) volumes and systolic blood pressure were measured at baseline and heart rates of 75, 90, 100, 115, 125, and 140 bpm (randomised order) with CRT active and intrinsic conduction (AOO). MRI conditional mode parameters were replicated through standard parameter modification to ensure biventricular pacing during CRT active scans. All scans were conducted using a 3.0 T Siemens Prisma MRI scanner with analysis on commercially available software. Contractility was derived from the systolic blood pressure and left ventricular end systolic volume. A post scan device and lead assessment was conducted to assess for scanning safety. Results Scanning was conducted in 22 patients (safety cohort). Post scan battery voltage reduced by 2.9±1.0%. Mean change in atrial, right ventricular and left ventricular lead impedance was 0.5±0.06%, 3.0±0.04% and −1.7±0.05% respectively. Mean change in atrial, right ventricular and left ventricular pacing threshold was 0.0±0.3%, 8.3±0.3% and 5.6±0.3%. No patient experienced symptoms related to scanning or device failure. Preliminary data for patients with CRT on and off have been analysed (paired analysis cohort, n=8, 6 men). Mean age was 71.1±8.2, aetiology was primarily ischaemic (62.5%) with the remainder dilated cardiomyopathy. The mean LV ejection fraction at baseline was 29.4±12.9%. Biventricular pacing led to acute improvements in ejection fraction (p=0.005), left ventricular cardiac output (p<0.0001) and contractility (p=0.05) over the entire range of heart rates studied. We also noted an improvement in the force frequency relationship during biventricular pacing with a higher peak contractility (p=0.05), a higher heart rate at which this occurred (HR=130) and a generally up sloping relationship when compared with intrinsic conduction. Conclusion We have demonstrated for the first time, the mechanistic improvements in cardiac contractility consequent to CRT using CMR and also that MRI scans of conditional devices can be safe with CRT active. Acknowledgement/Funding Dr A Koshy is conducting a PhD supported by grant from Medtronic. Dr Klaus Witte has received honoraria from Medtronic

Abstract Background Low cardiorespiratory fitness, defined by reduced maximal oxygen consumption (VO2), is a predictor of mortality in patients without chronic disease. However, the relation between ventilatory efficiency (as measured by the slope of the relation between ventilation (VE) and carbon dioxide production (VCO2)) and all-cause mortality is unknown. Purpose To assess the relation between variables derived from cardiopulmonary exercise testing and long-term survival in normal subjects Method We recruited 145 healthy subjects, with no history of chronic disease (57% male, mean age 63±12) from primary care at random. All participants underwent cardiopulmonary exercise testing at baseline. Participants were followed for 15.5±3.5 years. The primary end-point was all-cause mortality. Cox-proportional hazard models were used to assess the relationship between measures of exercise performance and outcome. Hazard ratios (HR) are reported with 95% confidence intervals (CI). Results During follow up, 34 participants (23.4%) died. On univariable analysis, VE/VCO2 slope, peak VO2, respiratory exchange ratio at peak exercise, peak heart rate and 6-minute walk test distance were significant predictors of all-cause mortality (table 1). However, only VE/VCO2 slope (HR per unit increase: 1.13, 95% CI: 1.00–1.28, P=0.043) and peak heart rate (HR per 10 unit increase: 0.73, 95% CI: 0.57–0.93, P=0.010) were independent predictors of all-cause mortality on multivariable analysis. Table 1. Cox regression analysis (univariable and multivariable) for cardiopulmonary exercise testing measures and all-cause mortality HR Presentation Univariable analysis Multivariable analysis HR 95% CI p value HR 95% CI p value Peak VO2 (ml/kg/min) Per unit increase 0.90 0.86–0.95 <0.001 0.94 0.86–1.03 0.214 VE/VCO2 slope Per unit increase 1.08 1.01–1.17 0.049 1.13 1.00–1.28 0.043 Exercise RER Per 0.1 unit increase 0.46 0.31–0.67 <0.001 0.72 0.45–1.17 0.185 Peak heart rate (bpm) Per 10 unit increase 0.73 0.65–0.81 <0.001 0.73 0.57–0.93 0.010 6MWT (metre) Per 25 unit increase 0.92 0.86–0.98 0.009 1.02 0.86–1.17 0.789 Peak systolic BP (mmHg) Per 10 unit increase 1.13 0.98–1.31 0.101 – – – Multivariable analysis is adjusted for age, body mass index, sex, smoking, resting systolic blood pressure and forced vital capacity. Abbreviations: 6MWT, 6-minute walk test; CI, confidence interval; HR, hazard ratio; RER, respiratory exchange ratio. Conclusions Raised VE/VCO2 slope is an independent predictor of all-cause mortality in healthy patients with no history of chronic disease.

Background: In the PIONEER-HF study, in-hospital initiation of sacubitril/valsartan (S/V) versus enalapril in patients with heart failure (HF) and reduced ejection fraction (HFrEF), stabilised after acute decompensation, was associated with superior reduction of NT-proBNP, irrespective of prior use of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Methods: In TRANSITION (NCT02661217), 1002 patients with HFrEF, hospitalised for acute decompensated HF after haemodynamic stabilisation, were randomised 1:1 and initiated open-label S/V either pre- or post-discharge (1–14 days). Primary endpoint was the proportion of patients achieving the target dose (97/103 mg, bid) at 10 weeks post-randomisation. Endpoints, adverse events (AEs) and serious AEs (SAEs) were compared by ACEi/ARB status in the combined pre- and post-discharge arms. Results: ACEi/ARB-naïve group [326 (32.9%)] had lower systolic blood pressure, serum creatinine, higher heart rate, and more often had non-ischaemic HF aetiology. Similar proportions of ACEi/ARB-naïve and non-naïve patients achieved the target dose of S/V (48.3% vs 47.9%, RRR 1.01 [0.88–1.16]) (Figure) and 88% patients from both groups were maintained on any S/V dose at Week 10. The rate of permanent discontinuation of S/V due to AEs was low and comparable. Overall incidence of AEs was 65.3% in ACEi/ARB-naïve and 68.3% in non-naïve patients (RRR 0.96 [0.87–1.05]) and incidence of SAEs was 16.3% and 19.4% respectively (RRR 0.83 [0.63–1.12]) (Table). Conclusion: In hospitalised patients with HFrEF naïve to ACEi/ARB, S/V can be safely initiated pre-discharge or shortly after discharge, and up-titration is well tolerated.

Background: Initiation of sacubitril/valsartan (S/V) in hospitalised patients with heart failure (HF) with reduced ejection fraction (HFrEF), stabilised after admission due to decompensated HF (ADHF), was associated with superior NT-proBNP reduction compared to enalapril in the PIONEER-HF study. Treatment effect was similar in patients with and without a prior diagnosis of HFrEF. Methods: In TRANSITION (NCT02661217), 1002 patients with HFrEF, hospitalised for ADHF, after haemodynamic stabilisation, were randomised 1:1 to start open-label S/V either pre- or post-discharge (1–14 days). Primary endpoint was the proportion of patients achieving the target dose (97/103 mg bid) at 10 weeks post-randomisation. Endpoints, adverse events (AEs) and serious AEs (SAEs) were compared by HF history status in the combined pre- and post-discharge arms. Results: 286 patients had de novo HFrEF and 705 had a prior diagnosis of HFrEF. At baseline, de novo HF patients were younger, had lower systolic BP, serum creatinine, and hs-TnT levels; and higher pulse rate and, eGFR; more non-ischaemic HF, and fewer had comorbidities. More de novo HF patients achieved the target dose versus subjects with a prior diagnosis of HF (56.0% vs 44.8%, RRR1.30 [1.12–1.52]) and 90% were able to achieve and maintain any dose (Figure). The number of SAEs and treatment interruptions due to AEs was lower in patients with de novo HFrEF (Table). Conclusions: Patients with de novo HFrEF can be safely initiated on S/V and are more likely to achieve the target dose and maintain treatment by Week 10, compared to patients with a previous diagnosis of HFrEF.

Objectives: Mitochondrial permeability transition pore (mPTP) opening plays a crucial contributory role in cell death during ischemia-reperfusion. Cyclosporine A (CsA) is an inhibitor of mPTP opening. The present study aimed to establish whether the addition of CsA reduces ischemia-reperfusion injury (IRI) after elective cardiac arrest.

Background: Two aldosterone inhibitors are currently licensed for heart failure (HF) in the UK: spironolactone and eplerenone. Recent clinical guidelines recommend eplerenone after an acute myocardial infarction (MI) for patients with symptoms and/or signs of HF and left ventricular dysfunction.Objectives: The primary objective was to evaluate relative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone in patients with postMI HF and explore the possibility of conducting an indirect comparison of spironolactone and eplerenone. A second objective was to undertake value-of-information (VOI) analyses to determine the need for further research to identify research questions critical to decision-making and to help inform the design of future studies.Data sources: Relevant databases including MEDLINE, EMBASE and CENTRAL were searched between September and December 2008. Randomised controlled trials (RCTs) of spironolactone, eplerenone, canrenone or potassium canrenoate were included if conducted in a postMI HF population. Trials of general HF patients with a subgroup of postMI HF patients were considered if they had at least 100 ischaemic participants per arm and the authors provided subgroup data when contacted. Adverse events summary data were sought from recognised reference sources and RCTs or observational studies in any population that recruited more than 100 participants.Review methods: The comparative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone was derived using Bayesian meta-regression drawing on a wider 'network' of aldosterone trials to those considered in the main clinical effectiveness review. An alternative scenario was also considered assuming a 'class effect' for the aldosterone antagonists in terms of major clinical events, but allowing for potential differences in side effect profiles. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) where appropriate. Uncertainty in cost-effectiveness results was also presented and used to inform future research priorities using VOI analyses based on expected value of perfect information (EVPI).A probabilistic decision analytic model was developed to estimate cost-effectiveness of spironolactone, eplerenone and standard care for management of postMI HF, provide estimates relevant to the NHS and explore alternative approaches to an indirect comparison between spironolactone and eplerenone. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the NHS persepctive. In the base-case analysis, 2-year treatment duration was assumed, consistent with the follow-up in the main RCTs. Other scenarios were explored to examine the robustness of alternative assumptions including impact of different treatment durations.Results: Searches yielded five RCTs: two spironolactone trials of poor methodological quality and three trials of which only one (of eplerenone) specifically examined postMI HF (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, EPHESUS). One trial of spironolactone (Randomised Aldactone Evaluation Study, RALES) and one of canrenone (Antiremodelling Effect of Aldosterone receptors blockade with canrenone In mild Chronic Heart Failure, AREA IN-CHF) comprised general HF, but data were available for an ischaemic subgroup. Structural similarity of spironolactone and eplerenone suggests that they may be interchangeable, but formal indirect comparison between the three trials was severely limited by trial differences. Relative safety data were limited from RCTs and observational sources. Hyperkalaemia rates varied, but were generally higher than for placebo; data were insufficient to assess discontinuation because of hyperkalaemia. Gynaecomastia rates were higher with spironolactone. Adverse event data were sparse. Systematic review of economic evidence identified three main published studies but none used a UK perspective or attempted to compare cost-effectiveness in postMI HF. The new decision model indicated that eplerenone was the most cost-effective strategy for postMI HF (ICER of eplerenone compared with standard care was 4457 pound per QALY, increasing to 7893 pound per QALY if treatment continued over the patient's lifetime); in neither scenario did spironolactone appear cost-effective. The ICER of eplerenone was consistently under the 20,000-30,000 pound per QALY threshold used to establish value for money in the NHS. Uncertainty resulted in EVPI estimates between 820M pound (base-case) and 1265M pound (lifetime treatment duration scenario). When class effect for mortality and hospitalisations was assumed spironolactone emerged as the most cost-effective treatment and EVPI estimates were negligible. If class effect is considered more plausible than the results of the evidence synthesis model then there would be limited value in additional research.Limitations: Exchangeability between trials was poor and there was a lack of robust data in RCTs.Conclusions: Only two good-quality trials of aldosterone inhibitors in the postMI HF population were found, but lack of exchangeability with respect to study populations, meant that a comparison between these drugs could not be done. It consistently emerged that, compared with usual care, use of an aldosterone antagonist appears to be a highly cost-effective strategy for the management of postMI HF patients in the NHS. An adequately powered, well-conducted RCT that directly compares spironolactone and eplerenone is required to provide more robust evidence on the optimal management of postMI HF patients.