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Aims No therapy has shown to reduce the risk of hospitalization for heart failure across the entire range of ejection fractions seen in clinical practice. We assessed the influence of ejection fraction on the effect of the sodium–glucose cotransporter 2 inhibitor empagliflozin on heart failure outcomes. Methods and results A pooled analysis was performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials (9718 patients; 4860 empagliflozin and 4858 placebo), and patients were grouped based on ejection fraction: Conclusion The magnitude of the effect of empagliflozin on heart failure outcomes was clinically meaningful and similar in patients with ejection fractions Key Question How does ejection fraction influence the effects of empagliflozin in patients with heart failure and either a reduced or a preserved ejection fraction? Key Finding The magnitude of the effect of empagliflozin on heart failure outcomes and health status was similar in patients with ejection fractions Take Home Message The consistency of the response in patients with ejection fractions of

Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans., Graphical Abstract An in-depth review of existing pre-clinical HFpEF mouse models with validation of their translational value using the HFA-PEFF and H2FPEF scores.

Aims The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial. Methods and results Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%. Conclusions There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events., Graphical Abstract Effect of empagliflozin by region and race in EMPEROR-Reduced. Inclusion of outpatient events in the extended composite endpoint attenuated the between-region differences in the effect of empagliflozin seen in the primary outcome of EMPEROR-Reduced.

Aim The aim of this study was to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicentre, international, effectiveness study. Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. Methods and results From July 2016 to November 2020, we enrolled 3574 all-comers (age 65 ± 11 years, 2070 males, 58%; ejection fraction 60 ± 10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent clinically indicated ABCDE-SE. The employed stress modality was exercise (n = 952, with semi-supine bike, n = 887, or treadmill, n = 65 with adenosine for step D) or pharmacological stress (n = 2622, with vasodilator, n = 2151; or dobutamine, n = 471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only endpoint. Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D, and 37% for E steps. During a median follow-up of 21 months (interquartile range: 13–36), 73 deaths occurred. Global X2 was 49.5 considering clinical variables, 50.7 after step A only (P = NS (not significant)) and 80.6 after B–E steps (P, Graphical Abstract This study recruited 3,574 patients from 13 stress echo laboratories of 5 countries and shows the prognostic value of the new state-of-the art cardiac functional testing with stress echo ABCDE protocol: Step A for regional wall motion abnormalities; step B for B-lines obtained with 4-site simplified scan and lung ultrasound; step C for contractile reserve with volumetric echocardiography; step D for Doppler-based assessment of coronary flow reserve in mid-distal left anterior descending coronary artery; step E for EKG-based heart rate reserve.

Aims The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results In a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, ‘other’ ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group [hazard ratio 0.79 (95% confidence interval 0.63–0.99), P = 0.037], and the effect was consistent across each of the components of the composite outcome. Conclusions Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF. Clinical trial registration ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).

Aims Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF. Methods and results Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF Conclusions Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force–frequency relationship.

Objective The aim of this study was to assess the impact of sex on the management and outcome of patients according to aortic stenosis (AS) severity. Introduction Sex differences in the management and outcome of AS are poorly understood. Methods Doppler echocardiography data of patients with at least mild-to-moderate AS [aortic valve area (AVA) ≤1.5 cm2 and peak jet velocity (VPeak) ≥2.5 m/s or mean gradient (MG) ≥25 mmHg] were prospectively collected between 2005 and 2015 and retrospectively analysed. Patients with reduced left ventricular ejection fraction (mild were excluded. Results Among 3632 patients, 42% were women. The mean indexed AVA (0.48 ± 0.17 cm2/m2), VPeak (3.74 ± 0.88 m/s), and MG (35.1 ± 18.2 mmHg) did not differ between sexes (all P ≥ 0.18). Women were older (72.9 ± 13.0 vs. 70.1 ± 11.8 years) and had more hypertension (75% vs. 70%; P = 0.0005) and less coronary artery disease (38% vs. 55%, P < 0.0001) compared to men. After inverse-propensity weighting (IPW), female sex was associated with higher mortality (IPW-HR: 1.91 [1.14–3.22]; P = 0.01) and less referral to valve intervention (competitive model IPW-HR: 0.88 [0.82–0.96]; P = 0.007) in the whole cohort. This excess mortality in women was blunted in concordant non-severe AS initially treated conservatively (IPW-HR = 1.03 [0.63–1.68]; P = 0.88) or in concordant severe AS initially treated by valve intervention (IPW-HR = 1.25 [0.71–2.21]; P = 0.43). Interestingly, the excess mortality in women was observed in discordant low-gradient AS patients (IPW-HR = 2.17 [1.19–3.95]; P = 0.01) where women were less referred to valve intervention (IPW-Sub-HR: 0.83 [0.73–0.95]; P = 0.009). Conclusion In this large series of patients, despite similar baseline hemodynamic AS severity, women were less referred to AVR and had higher mortality. This seemed mostly to occur in the patient subset with discordant markers of AS severity (i.e. low-gradient AS) where women were less referred to AVR.

Aims Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial. Methods and results Body mass index was analysed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Body mass index ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (standard deviation ± 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); Class I obesity 1574 (25.2%); Class II obesity 798 (12.8%); and Class III obesity 415 (6.6%). Compared with placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval): 0.89 (0.69–1.15), 0.87 (0.70–1.08), 0.74 (0.58–0.93), 0.78 (0.57–1.08), and 0.72 (0.47–1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (−1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (−0.1, 3.8), 2.7 (−0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: –0.88 (−1.28, –0.47), –0.65 (−1.04, –0.26), –1.42 (−1.89, –0.94), –1.17 (−1.94, –0.40), and –2.50 (−4.4, –0.64) kg (P-interaction = 0.002). Conclusions Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared with those without, and has the additional benefit of causing modest weight loss.

Background Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients. Methods and results One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms). Conclusions During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

Aims We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction. Methods and results The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P Conclusion The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

Aims The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups. Methods and results We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping. Conclusion The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach., Graphical Abstract

Aims In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction. Methods and results Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68–1.02), HR 0.74 (0.58–0.94), and HR 0.61 (0.46–0.82) for, Graphical abstract

Aims Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF. Methods and results We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6–8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4–0.6, P Conclusion The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.

The measurement of left ventricular ejection fraction (LVEF) is a ubiquitous component of imaging studies used to evaluate patients with cardiac conditions and acts as an arbiter for many management decisions. This follows early trials investigating heart failure therapies which used a binary LVEF cut-off to select patients with the worst prognosis, who may gain the most benefit. Forty years on, the cardiac disease landscape has changed. Left ventricular ejection fraction is now a poor indicator of prognosis for many heart failure patients; specifically, for the half of patients with heart failure and truly preserved ejection fraction (HF-PEF). It is also recognized that LVEF may remain normal amongst patients with valvular heart disease who have significant myocardial dysfunction. This emphasizes the importance of the interaction between LVEF and left ventricular geometry. Guidelines based on LVEF may therefore miss a proportion of patients who would benefit from early intervention to prevent further myocardial decompensation and future adverse outcomes. The assessment of myocardial strain, or intrinsic deformation, holds promise to improve these issues. The measurement of global longitudinal strain (GLS) has consistently been shown to improve the risk stratification of patients with heart failure and identify patients with valvular heart disease who have myocardial decompensation despite preserved LVEF and an increased risk of adverse outcomes. To complete the integration of GLS into routine clinical practice, further studies are required to confirm that such approaches improve therapy selection and accordingly, the outcome for patients.

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Aims Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. Methods and results We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. Conclusion Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. Trial registration Clinicaltrials.gov identifier: NCT01458405.

Aims The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy. Methods and results We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537–0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class Conclusion In contemporary ICM/DCM patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a 27% lower mortality after adjustment. There appear to be patients with less survival advantage, such as older patients or diabetics.

Secondary mitral regurgitation and secondary tricuspid regurgitation due to heart failure (HF) remain challenging in almost every aspect: increasing prevalence, poor prognosis, notoriously elusive in diagnosis, and complexity of therapeutic management. Recently, defined HF subgroups according to three ejection fraction (EF) ranges (reduced, mid-range, and preserved) have stimulated a structured understanding of the HF syndrome but the role of secondary valve regurgitation (SVR) across the spectrum of EF remains undefined. This review expands this structured understanding by consolidating the underlying phenotype of myocardial impairment with each type of SVR. Specifically, the current understanding, epidemiological considerations, impact, public health burden, mechanisms, and treatment options of SVR are discussed separately for each lesion across the HF spectrum. Furthermore, this review identifies important gaps in knowledge, future directions for research, and provides potential solutions for diagnosis and treatment. Mastering the challenge of SVR requires a multidisciplinary collaborative effort, both, in clinical practice and scientific approach to optimize patient outcomes.

Aims The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin–angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF). Methods and results We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45–0.65] for the recurrent primary endpoint compared with putative placebo (P Conclusion This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.

Background We previously showed that angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) were associated with heart failure with recovered ejection fraction (HFrecEF) in patients with dilated cardiomyopathy (DCM). However, the different effects of these drugs on cardiac reverse remodeling have not been fully elucidated. The aim of this study was to assess comparative effectiveness of ACEi versus ARB on recovery of left ventricular ejection fraction (LVEF) among patients with DCM. Methods We analyzed the clinical personal records of DCM, a national database of Japanese Ministry of Health, Labour and Welfare, from 2003 to 2014. Patients with LVEF Results Out of 4,618 eligible patients, 2,238 patients received ACEi and 2,380 patients received ARB. Propensity score matching yielded 1,341 pairs. Mean age was 56.0 years and 2,041 (76.1%) was male. Mean LVEF was 27.6%, and median duration of HF was 1 year. The primary outcome was observed more frequently in ARB group than in ACEi group (59.8% vs. 54.1%; odds ratio [OR] 1.26; 95% confidence interval [CI] 1.08–1.47; P=0.003). The change in LVEF from baseline to 3 years of follow-up was greater in ARB group than in ACEi group (15.8±0.4 vs. 14.0±0.4%, P=0.002). In the ACEi group, 946 patients (70.6%) continued to receive ACEi at 3 years of follow-up, while 1,088 patients (81.3%) continued to receive ARB in the ARB group. Per-protocol analysis consistently showed that ARB increased the prevalence of HFrecEF (62.0% vs. 54.0%; OR 1.39; 95% CI 1.17–1.66; P Conclusions The use of ARB was associated with HFrecEF more frequently than ACEi among patients with DCM and reduced LVEF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Health Sciences Research Grants from the Japanese Ministry of Health, Labour and Welfare (Comprehensive Research on Cardiovascular Diseases)Japan Agency for Medical Research and Development (AMED) grant

Background An increasing number of patients living with chronic ischemic cardiomyopathy (ICM) are potential candidates for cell therapy, including adipose tissue-derived mesenchymal stromal cells (ASC). However, proper assessment of clinical effects in relation to cellular effector mechanisms, such as angiogenesis, is currently lacking. Purpose To investigate the prognostic value of assessing angiogenesis non-invasively using novel PET imaging in terms of functional outcome after cell therapy in a homologous animal model of ICM. Methods Myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery. Four weeks after infarction, the rats were scanned with [18F]-FDG and echocardiography, and based on left ventricular ejection fraction (LVEF) and infarct size randomized to allogeneic ASC treatment (n=14) or saline (n=9). Animals were treated using echo-guided trans-thoracic intramyocardial injections. Follow-up echocardiography was performed four weeks after treatment. Angiogenesis was assessed non-invasively using the [68Ga]-NODAGA-E[(cRGDyK)]2 (RGD) PET-tracer before treatment and two weeks after the treatment (Figure). The output was RGD-uptake by maximum standardized uptake value (SUVmax). Results RGD-uptake in the infarct area significantly decreased in the saline group (p=0.04), while this decline was not significant in the ASC group (p=0.58). There was no effect on LVEF of the cell therapy in this study (p=0.70). When the rats were grouped by RGD-uptake post treatment, the high RGD-uptake group (n=8) improved LVEF compared to the rats with medium or low RGD-uptake (n=15, p=0.04) irrespective of the treatment. This could indicate that non-invasive detection of a high degree of myocardial angiogenesis measured using RGD is predictive of improvement in cardiac pump function in ICM. Conclusions Following injection of ASC or saline, a high RGD-uptake precluded improvement in pump function. This is the first evidence of how uptake of the novel RGD tracer relates to changes in pump function in ICM and the results could affect the design of future clinical trials using regenerative therapy for ICM patients. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Aase and Ejnar Danielsens FondDoctor Sofus Carl Emil Friis and wife Olga Doris Friis' Scholarship Study design, RGD-uptake, and results

Background/Introduction Atrial fibrillation (AF) is a common heart rhythm disturbance, associated with an increased risk of stroke, hospital admissions and mortality, especially in patients with reduced ejection fraction. Among the oldest medications used for heart-rate control is digitalis, but largely due to observational studies showing an increased risk of death it has fallen out of favour. Recently newer clinical trials reported that the treatment with digitalis in permanent AF might be superior to beta blocker therapy in regard to functional status and symptom burden. Given this diverging results we attempt to analysis a large cohort of patients facilitating a propensity score matching algorithm. Purpose To assess the associations of digitalis treatment with mortality in patients with increased cardiovascular risk. Methods Patients were derived from a large cohort study including participants from a tertiary care centre who were referred to coronary angiography. The propensity score matching is based on a predefined list of variables, with digitalis as treatment. Matching strategy is nearest neighbour matching and to prove consistency, radius matching (radius = 0.1). For survival analysis we used a Cox proportional hazard regression comparing patients with and without digitalis for all-cause mortality. The analysis is conducted using STATA 13 MP. All patients provided written informed consent and the study was approved by the ethics committee. Results A total of 2457 patients (median age: 63.5 [IQR = 56.3–70.6] years, 30.1% women) referred to coronary angiography, with a median follow up of 9.9 (IQR = 8.5–10.7) years were included. The matching process and the resulting propensity score fulfilled all statistical assumptions and resulted in a balanced cohort. The risk for all-cause mortality was higher among propensity score matched participants not treated with digitalis compared to patients on treatment (n=514) HR 3.03 (95% CI 2.5 to 3.7). Total mortality in patients with AF on digitalis after a median follow-up of 9.9 years was 27.6%. At baseline, only 42.4% of patients with AF were on oral anticoagulation. Conclusions In the present cohort treatment with digitalis was associated with a lower risk of all-cause mortality after long-term follow-up. The patient population has a clinically significant 10-year mortality risk. The results may not apply to other cohorts but may help inform future clinical trials. Funding Acknowledgement Type of funding sources: None.

Background Right Ventricular (RV) dysfunction and pulmonary hypertension (PH) are two very likely acute and long term targets of COVID-19 pneumonia, with a potential prognostic implications. Purpose To determine the COVID-19 pneumonia effects on the right ventricular to pulmonary circulation coupling through bedside echocardiography and extend its implications to prognostic assessment. Methods Single-centre study including consecutive subjects hospitalized for COVID-19 pneumonia who underwent a clinical indicated echocardiogram between March 2020 and December 2020. Extensive analysis of cardiac function was performed offline by an operator blinded to clinical data, laboratory findings and CT scans. Results 133 patients were enrolled (mean age 69±12 years, 57% men), 38% of whom already had cardiac disease in their medical history. In-hospital mortality was 26% (35 pts), during a mean hospital stay of 26±16 days. Non survivors had higher pulmonary artery systolic pressure (PASP) and worse RV function, assessed with both standard parameters (i.e. TAPSE) and with the novel speckle tracking analysis by RV-Global Longitudinal Strain (RV-GLS) and RV-Free Wall Longitudinal Strain (RV-FWLS). The combination of these two variables in TAPSE/PASP ratio allows assessment of RV to pulmonary circulation (Pc) coupling and was strongly associated with in-hospital death (HR 0.73, 95% CI 0.59–0.89, p=0.003) and patients with TAPSE/PASP Conclusions Either PH and RV dysfunction predict in-hospital mortality in patients with COVID-19 pneumonia. The assessment of RV to Pc coupling, however, better describes the adaptive RV response to increased PASP and gives additional prognostic information in a population with a relevant prevalence of comorbidities. Funding Acknowledgement Type of funding sources: None.

Background In patients with dilated cardiomyopathy (DCM), the patients could be symptomatic or presented with recurrent fluid overload, syncope or sudden cardiac death (SCD) while the coronary arteries were patent. The aim of our study was to use the coronary flow abnormalities to stratify the high risk symptomatic versus the low risk asymptomatic patient with DCM. Methods Consecutive patients with DCM were enrolled. Twenty patients with normal ejection fraction (EF) without coronary artery disease served as control. The study patients were checked for symptoms (fluid overload, syncope, SCD) and re-admission. All patients underwent a new coronary angiographic technique with injection of contrast until all the coronary arteries were completely filled. As the injection of contrast stopped, the blood in white color moved in and the blood movement could be clearly observed. The angiogram was recorded from the entry of blood flow until all the contrast was cleared. During the review, the investigators downloaded, selected the angiogram from the electronic medical record, tapped on the Key Image and used the Up and Down arrow to move the images, frame-by-frame. Each frame represented a 0.06-second recording. The duration of the arterial phase was calculated starting the time when the blood entered the ostium of the index artery until all the contrast disappeared from the distal vasculature. At the same time, an AI program was trained to measure the length of the arterial phase by Machine learning, supervised and unsupervised Deep Learning and Convoluted Neural Networks. (Figure 1) The AI programs compared the time when the arteries were full with contrast until there was no contrast left in the distal vasculature. (Figure 2) Results One hundred patients with DCM were consecutively enrolled. Twenty patients served as control. In the control group with normal flow and EF, the duration of the arterial phase was 24–30 frames (1.44 to 2 seconds). In the study group, seventy patients had extremely prolonged arterial phase (average of 120 frames or >8 seconds (p Conclusions In patients with DCM, the extreme prolonged arterial phase caused ischemia in the myocardium even there was no coronary artery disease. This ischemic burden triggered recurrent ventricular dysfunction, arrhythmia, syncope and SCD. The patients with normal arterial phase became asymptomatic after optimal medical treatment. With these results, more effective prevention and management could be achieved for high risk symptomatic patients with high mortality and readmissions. Funding Acknowledgement Type of funding sources: None. U Net architectureArterial Phase

Background For cardiac resynchronization therapy (CRT), patients with chronic heart failure (HF) and wide (>150msec) QRS duration (QRSd) received class I/A indication. However, its beneficial effect seemed to be limited for those with mid- (120–150msec) QRSd. Recent studies demonstrated that QRSd normalized to left ventricular end-diastolic volume (QRSd/ LVEDV) improved prediction of clinical outcome in patients with CRT. Therefore, we sought to investigate predictive value of QRSd/LVEDV for responding to CRT in patients with mid-QRSd. Methods This was retrospective multi-center observational cohort study. A total 506 consecutive patients who underwent CRT implantation in Tohoku University Hospital and National Cerebral and Cardiovascular Center were evaluated. Exclusion criteria were QRSd less than 120ms, upgrade procedures from other implanted non-CRT devices and bradycardia requiring pacing. We evaluated clinical variables, data of electrocardiogram and transthoracic echocardiography at baseline and 6 months after CRT implantation. Primary endpoint was a HF hospitalization after CRT implantation. Distribution of free from HF hospitalization during follow-up was calculated using Kaplan-Meier curves, and the effects of covariate on the time to endpoint were investigated using a Cox proportional hazards model. Results After 199 patients were excluded based on exclusion criterion, remaining 307 patients were included for the analysis. Mean age was 62±14 [SD] years, and 238 (77%) were male. Mean LVEF and LVEDV were 25±9% and 234±82ml, respectively, and 24% of patients had ischemic etiology of HF. During the median 948 days of follow-up, CRT patients with mid QRSd (n=126; 136±10msec), as compared with those with wide QRSd (n=181; 174±17msec), tended to have higher incidence of HF hospitalization (Wilcoxon p=0.03). Multivariate analysis showed that QRSd and QRSd/LVEDV were significant predictors for HF hospitalization in CRT patients with mid QRSd, and cut-off values (137msec of QRSd and 0.65 of QRSd/LVEDV), which was calculated by receiver operative curve analysis, was used for risk stratification. QRSd Conclusion The present study demonstrates that QRSd normalized to left ventricular end-diastolic volume (QRSd/ LVEDV) could be clinical value in predicting outcome in CRT patients with mid-QRSd. These findings indicate normalized QRSd reflects myocardial conduction properties and contribute to risk stratification. Funding Acknowledgement Type of funding sources: None.

Background The common method of assessing left ventricle (LV) volumes and ejection fraction (EF) is hand-tracing Biplane Simpson method. Alternatively, ultrasound vendors offer different semi-automated LV endocardial border detection software with anatomical intelligence to assess LV volumes and EF. By using speckle-tracking technique, this software tracks the LV endocardium throughout the cardiac cycle and computes the LV volumes in every image frame using the disk summation method from which a volume-curve is generated, and the EF is calculated using the maximum and minimum volumes obtained. Data on the performance of this method in comparison with the hand-tracing Biplane Simpson method in daily clinical practice is scarce. Purpose To determine the accuracy of LV volumes and EF using semi-automated LV endocardial detection tracing, and to compare the reproducibility of this method with the hand-tracing Biplane Simpson method, among operators with varying level of experience in echocardiography. Methods This was a single center retrospective observational study, conducted in year 2020. 127 patients, aged >18 years, who underwent clinically indicated transthoracic echocardiography were recruited. The echocardiographic images were analyzed independently in a blinded fashion by 3 operators – a sonographer, a fellow-in-training and a cardiologist specialized in echocardiography. The LV volumes and EF were first measured using hand-tracing Biplane Simpson method, then repeated using semi-automated tracing at a different time and the operator were blinded to the initial hand-tracing measurements. Results The mean age of patients was 50±16 years, 35.4% were male, mean body surface area was 1.62±0.18m2, 92.1% were in sinus rhythm, and 61.4% had good acoustic window. Table 1 shows the LV end-diastolic volume (EDV), end-systolic volume (ESV) and EF, measured using different method, by the 3 operators. There were excellent correlation and agreement between semi-automated tracing measurements and hand-tracing measurements of LV EDV (r=0.985, LOA [mean ± 1.96 SD] 16.9 ml, ICC 0.991), ESV (r=0.990, LOA 12.7 ml, ICC 0.994) and EF (r=0.962, LOA 7.43%, ICC 0.967) by experienced cardiologist. The limit of agreement (LOA) between cardiologist and sonographer for semi-automated tracing measurement of LV EDV, ESV and EF were 29.13 ml, 19.74 ml and 9.25% respectively, which was comparable with that of hand-tracing measurement. The agreement between cardiologist and fellow-in-training for semi-automated tracing measurement of LV volumes and EF was slightly better than hand-tracing method, with a LOA of 25.60 ml, 17.48 ml and 7.08%, for EDV, ESV and EF respectively (Table 2). Conclusion In daily clinical practice, measurement of LV volumes and EF using semi-automated LV endocardial tracing method is accurate and demonstrates comparable reproducibility with hand-tracing Biplane Simpson method among operators with different level of experience in echocardiography. Funding Acknowledgement Type of funding sources: None.

Background Oral beta-blockers have beneficial effect on long-term mortality in high-risk as low left ventricular ejection fraction (LVEF) patients with MI, but the effect and duration of use of Beta-blockers in post-AMI patients with preserved LVEF is still unknown. Methods We performed a systematic search in Cochrane library, Embase, Medline, Pubmed, Scopus, Web of Science, clinical trial registries, and for eligible studies (26,431 patients). Data for outcomes were pooled as Hazard ratios (HRs), with 95% confidence interval, using RevMan software for windows. Results The pooled effect-estimate showed significant decrease in all cause mortality in beta-blocker group (HR 0.71, 95% CI 0.62–0.82). A subgroup analysis regarding duration of use of BB (≤1 year or >1 year), age (≤65 or ≥65),sex, use of CCB, presence of HTN or DM, and LVEF (≥50 or ≥40) was done. No significant subgroup differences were detected: duration of use of BB (p=0.32), age (p=0.23), sex (p=0.84), CCBs (p=0.28), HTN (p=0.32), DM (p=0.92),and LVEF (p=0.06). No significant differences between bet-blocker vs. no beta-blockers in terms of cardiac death (HR 0.69, 95% CI 0.33–1.46), re-infarction (HR1.00, 95% CI 0.68–1.48), re-hospitalization (HR1.08, 95% CI 0.32–3.68), and revascularization (HR 0.94, 95% CI 0.76–1.16). Conclusion Beta-blockers might reduce mortality of post-AMI patients with preserved LVEF, but failed to prevent cardiac events. The upcoming trials (REBOOT, BETAMI, DANBLOCK, and ABYSS) will define the use of Beta-blockers in post AMI patients with preserved Left ventricular ejection fraction. Funding Acknowledgement Type of funding sources: None.

Background In heart failure with reduced ejection fraction (HFrEF), uptitration of neurohormonal antagonists to trial-proven doses shown to reduce mortality is challenging and seldomly achieved in clinical practice. A major reason for underdosing of these agents is the lack of a clear description of what constitutes an acceptable standard of care in HFrEF. To address this limitation, a novel framework for describing the physician adherence to evidence-based treatment was recently proposed. The aim of our study was to evaluate and validate the proposed framework in a real-world population of patients with HFrEF. Methods A cohort of patients with HFrEF, defined as left ventricular ejection fraction (LVEF) Results A total of 408 patients (mean age 68±12 years, 78% male, 63% ischemic etiology) were included. The median LVEF was 31% (IQR 25–36) and most patients were in NYHA class II or III [210 (51.5%) and 163 (40%), respectively]. Medical therapy is described in Table 1. During a median follow-up of 3.3 years (IQR 1.4–5.6), 210 patients died. On univariable analysis, achieving Status I of beta-blocker (BB) therapy (HR: 0.50; 95% CI: 0.32–0.81; P=0.004) or ACEi/ARB (HR: 0.56; 95% CI: 0.36–0.86; P=0.012) was associated with reduced all-cause mortality. The mortality of patients in Status II of BB or ACEi/ARB was similar to the mortality of those not receiving the drug (HR for BB: 0.90; 95% CI: 0.53–1.52; P=0.69 and HR for ACEi/ARB: 0.71; 95% CI: 0.42–1.18; P=0.182) – figure 1. Achieving Status I of BB remained independently associated with reduced mortality after adjustment for several clinical and echocardiographic confounders (n=13) (adjusted HR: 0.59; 95% CI: 0.35–0.98; P=0.041). Conclusions In this real-world population of patients with HFrEF, the vast majority of patients were in Status I of BB and ACEi/ARB therapy. Achieving Status I of BB therapy seems to be associated with reduced mortality, even after adjustment for several markers of disease severity, highlighting the need for uptitration of medical therapy to maximal tolerated doses according to trial-proven regimens. Funding Acknowledgement Type of funding sources: None.

Introduction Modern pharmacological treatment of heart failure with reduced ejection fraction (HFrEF) dramatically improves its prognosis. However, the increasingly complexity and associated costs might threat their effective uptake in clinical practice. We aimed to study the pill burden and out-of-pocket costs of cardiovascular drug therapy of a contemporary cohort of HFrEF patients. Methods We performed a retrospective, cross-sectional, single-center study on a convenience sample of 100 consecutive HFrEF patients assessed at our HF outpatient clinic (January-June 2020). The pill burden was assessed by the number of prescribed different cardiovascular drugs and pills per day. The out-of-pocket (OOP) costs were defined using the total patients co-payment of cardiovascular medications per month of treatment, taken in account the exemptions provided by the Portuguese National Health System (NHS). The included drug classes were antiplatelets, anticoagulants, statins, HF drugs (Beta-blockers [BB], angiotensin-converting enzyme inhibitors [ACEi]/ angiotensin receptor blockers [ARBs]/ angiotensin receptor-neprilysin inhibition [ARNI], mineralocorticoid antagonists [MRA], sodium glucose cotransport inhibitors [iSGLT2], digoxin, loop diuretic) and antiarrhythmics. Results The mean age was 62±12 years and only 24% were female. The etiology of HF was ischemic in 42% of the patients, 86% were in NYHA II class and 5% in NYHA III-IV. The mean LVEF was 34±5% and the median NT-proBNP was 482 pg/mL [172–1120]. 92% of patients were on BB, 67% on ACEI/ARBs, 25% on ARNI, 81% on MRA and 30% on iSGLT2. The use of implantable cardioverter-defibrillators was 38% and 20% of patients were resynchronized. The number of cardiovascular (CV) drugs per day was 5.4±1.6 per patient and the number of CV pills per day was 6.6±2. Most patients (65%) had low income and had the maximal exemption on medication costs provided by NHS. Overall, the mean OOP costs was €16.1 per month of treatment and the mean OOP costs for patients exempted and not exempted was €12.9 and €22.3, respectively. The mean OOP costs of evidence-based HF-modifying drugs (BB, ACEI/ARBs, ARNI, MRA, iSGLT2) was €10.1 and the mean OOP costs of evidence-based HF-modifying drugs for patients exempted and not exempted were €7.9 and €14.2, respectively. However, for patients on ARNI the mean OOP costs was almost 3 times higher (€33.6). Conclusions In this optimally treated contemporary cohort of HFrEF, the pill burden due to cardiovascular therapy only is high (7 pills/day). With the exception of patients on ARNI, the overall OOP costs of HF-modifying prognostic drugs are low. Funding Acknowledgement Type of funding sources: None.

Background Following the PARADIGM trial, some studies have identified cardiac remodeling as major background for hard end point benefits of Sacubitril/Valsartan (S/V), but few adopted a well described definition in the literature. Purpose We aimed at a comprehensive evaluation of the effects of S/V on echo-derived measures of cardiac remodeling along with clinical and laboratory data over a medium-term follow-up pointing to a real-world HFrEF population. Methods This is a prospective observational study of HFrEF patients on optimal medical therapy (OMT) initiated with S/V at Heart Failure Clinic of our institute (January 2017-January 2020). In 62 HFrEF, echocardiographic, laboratory and clinical data were collected at baseline and over 10 (Q1-Q3 8–13) months after S/V initiation. Mean age was 68±12 years, 79% men. Left ventricular reverse remodeling (LVRR) was defined as: 1) an absolute increase in LVEF ≥10 points or a LVEF ≥50% at follow-up and 2) a relative decrease in indexed left ventricular end-diastolic diameter of at least 10% or an indexed left ventricular end-diastolic diameter ≤33 mm/m2. Results Compared to baseline, S/V promoted a significant improvement of LV ejection fraction (LVEF, from 30% to 37%; p Conclusions Our data point to a remarkable medium-term reverse remodeling effect by S/V in HFrEF. Findings reinforce the concept that the main benefits of S/V on hard end-points are mediated by its cardiac-related effects. Both a left and right reverse remodeling occur in HFrEF patients who start S/V in the most adaptable phase of the disease supporting an early administration. Funding Acknowledgement Type of funding sources: None.

Introduction The incidence of acute cardiac injury in COVID-19 patients is frequently subclinical and can be identified by cardiac magnetic resonance imaging. Left ventricular global longitudinal strain (LV-GLS) using two-dimensional speckle-tracking echocardiography (2D-STE) provides an accurate validated method for early detection of subclinical myocardial dysfunction. So far, long-term cardiovascular complications of COVID-19 are undetermined therefore several validated methods should be used for early diagnosis and intervention in those patients. Purpose The aim of this work was to describe GLS as an indicator of myocardial injury in a case series of non-hospitalized COVID-19 patients complaining of persistent dyspnea after resolution of COVID-19 infection. Methods A total number of 18 patients who were diagnosed with COVID-19 and were not indicated for hospital admission due to mild symptoms presenting with residual persistent dyspnea following COVID-19 infection resolution. Through clinical examination and standard 2D transthoracic echocardiography with STE emphasizing on LV-GLS was performed using Philips Epic - Qlab 10 software. Results The mean age of the included patients was 37.44±6.33 years, the mean time from COVID-19 diagnosis was 48.1±15.45 days, all patients (100%) had persistent dyspnea grade II. The mean left ventricular ejection fraction (LVEF) was 62.9±3.46% while the mean LV-GLS was −15.55±2.16%. Clinical and echocardiographic data is presented in Table 1. Conclusion In a case series of non-hospitalized COVID-19 survivors who complained of persistent dyspnea, GLS was low in comparison to the normally reported values of LV-GLS although they had normal LVEF indicating the persistence of myocardial injury even in mild cases of COVID-19 long after infection resolution. Further close follow-up of even mild and moderate COVID-19 survivors is certainly required to detect long-term cardiovascular sequelae. 2D STE with LV-GLS can be used as a readily available validated technique to detect early or persistent myocardial dysfunction succeeding COVID-19 infection. Funding Acknowledgement Type of funding sources: None.

Introduction Global longitudinal strain (GLS) is considered a more sensitive marker of systolic dysfunction than other measures commonly used in clinical practice, such as left ventricle ejection fraction (EF). Our objective was to evaluate the impact of reduced GLS in death and cardiovascular events in patients hospitalized due to heart failure with mid-range or preserved ejection fraction, with previous history of acute myocardial infarction. Methods A retrospective analysis of 170 patients admitted to a Cardiology ward due to acute heart failure (AHF) was performed. Patients with reduced EF (Simpson biplane method - EF Results A total of 127 patients were included. Mean patient age was 64 (±14) years; 72% were men. 48% of patients had history of ST elevation AMI. Mean EF was 54% (±8) and mean GLS was −14.3 (±3.8). Rates of 12MM and 12CV M were 14.2% and 19.3%, respectively. A statistically significant association between 12MM and 12MCV was found in univariate analysis for GLS (p0.05). However, when considering a severely compromised GLS ( Conclusion GLS is an independent predictor of 12MM and 12CVM in patients hospitalized due to AHF, with an EF ≥40% and previous history of acute myocardial infarction. In the subgroup of patients with heart failure with mid-range EF, a severely compromised GLS ( Funding Acknowledgement Type of funding sources: None.

Introduction The specific risk factors for left ventricular thrombus (LVT) formation on transthoracic echocardiography (TTE) independent of age, sex, and left ventricular ejection fraction (LVEF) remain uncertain. Purpose To conduct a propensity-matched case control study of LVT. Methods We queried structured TTE report data from 113,673 patients at our institution to identify individuals with LVT on TTE, 2000–2011. Cases were matched 1:1 with controls on age, sex, LVEF, inpatient/outpatient status, image quality, test year, blood pressure, heart rate, height, and weight. using propensity scores. Risk factors for LVT formation were determined using medical chart review. Results Over 12 years, we identified 132 patients with LVT and 132 matched controls (mean age 62.0±16.1 years, 73.1% male, mean LVEF 27.0% ± 16.0%). Cases were similar to controls across all matched variables except height (cases vs. controls, mean height 172.2±8.8 vs. 174.8±9.3 cm, p=0.03). Compared with controls, TTEs for cases were more frequently performed for the indications of myocardial infarction (MI; 28.0% vs. 9.9%, p0.05 for all). Of those with LVT, 54 (40.9%) had LVT resolution over a median of 4.4 (0.9 to 13.6) months. Conclusions In this single center, propensity-matched case-control study of individuals with LVT on TTE, a history of peripheral arterial disease was associated with a 4.3-fold increased odds of LVT formation independent of age, sex, LVEF, history of MI, stroke, or PCI. Of those with LVT, anticoagulation was used on presentation in 22.0%. Nearly half had LVT resolution within 4.4 months. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The project was funded by a grant from the National, Heart, Lung, and Blood Institute (1K23HL144907 - Strom).

Introduction The recent advances in the treatment for heart failure with reduced ejection fraction (HFrEF) have been remarkable, while no therapy has convincingly improved the prognosis in HF patients with preserved (HFpEF) and mid-range (HFmrEF) ejection fraction. Frequent decompensations of HF lead to progressive deterioration of cardiac and renal function, and quality of life. Hence, prior studies have reported that the mortality of HFrEF patients increases as hospitalization for HF repeats. However, it is still unclear whether this trend applies for HFpEF and HFmrEF patients. Purpose We aimed to compare the prognostic impact of re-hospitalization due to HF on cardiovascular death (CVD) among HFrEF, HFmrEF and HFpEF patients. Methods This observational study included 1,930 consecutive patients who were hospitalized for worsening of HF and discharged alive. Of them, patients who have never or have not been hospitalized for HF at least last 2 years, were finally analyzed. Patients were consisted of the population with HFrEF (EF50%, n=291). Patients in each EF-classified population were divide into 2 subgroups based on whether patients were re-hospitalized for HF during the observational period, respectively. The primary endpoint of this study was CVD. Results During the observation period, Kaplan-Meier analysis showed that patients who were re-hospitalized for HF had higher event rate of CVD in HFrEF group (Log-rank p=0.008, Figure). Even after adjusting with multivariate covariates including age, sex, EF, brain natriuretic peptide and estimated glomerular filtration rate, re-hospitalization for HF was an independent predictor for CVD in HFrEF group (HR: 1.95, 95% CI: 1.11–2.86, p=0.029). However, in HFmrEF group and HFpEF group, there was no significant difference in the rates of CVD between 2 subgroups divided whether patients were re-hospitalized for HF or not (p=0.91, p=0.34, respectively). Conclusion Re-hospitalization for HF affected the CVD rate in HFrEF group, but not in HFmrEF and HFpEF groups. The prevention of re-hospitalization for HF is important particularly in HFrEF patients in order to improve cardiovascular mortality. Funding Acknowledgement Type of funding sources: None.