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Aims: Patients visiting the emergency department (ED) or hospitalized for heart failure (HF) are at increased risk for subsequent adverse outcomes, however effective risk stratification remains challenging. We utilized a machine-learning (ML)-based approach to identify HF patients at risk of adverse outcomes after an ED visit or hospitalization using a large regional administrative healthcare data system., Methods and Results: Patients visiting the ED or hospitalized with HF between 2002-2016 in Alberta, Canada were included. Outcomes of interest were 30-day and 1-year HF-related ED visits, HF hospital readmission or all-cause mortality. We applied a feature extraction method using deep feature synthesis from multiple sources of health data and compared performance of a gradient boosting algorithm (CatBoost) with logistic regression modelling. The area under receiver operating characteristic curve (AUC-ROC) was used to assess model performance. We included 50,630 patients with 93,552 HF ED visits/hospitalizations. At 30-day follow-up in the holdout validation cohort, the AUC-ROC for the combined endpoint of HF ED visit, HF hospital readmission or death for the Catboost and logistic regression models was 74.16 (73.18-75.11) versus 62.25 (61.25-63.18), respectively. At 1-year follow-up corresponding values were 76.80 (76.1-77.47) versus 69.52 (68.77-70.26), respectively. AUC-ROC values for the endpoint of all-cause death alone at 30-days and 1-year follow-up were 83.21 (81.83-84.41) versus 69.53 (67.98-71.18), and 85.73 (85.14-86.29) versus 69.40 (68.57-70.26), for the CatBoost and logistic regression models, respectively., Conclusions: ML-based modelling with deep feature synthesis provided superior risk stratification for HF patients at 30-days and 1-year follow-up after an ED visit or hospitalization using data from a large administrative regional healthcare system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Tafamidis is a costly therapy that improves outcomes for patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM), although significant knowledge gaps exist for predicting longer-term response to treatment. The purpose of this study was to examine baseline predictors of adverse outcomes and their association with tafamidis treatment in comparison with those untreated in a clinical cohort from a Canadian ATTR-CM referral center. Methods: Patients with a confirmed diagnosis of ATTR-CM were included. Multivariable modeling was used to identify baseline variables associated with the primary outcome of all-cause mortality and secondary outcomes of cardiovascular mortality or hospitalization. Cox proportional hazard and competing risk analyses were used, with tafamidis modeled as a time-varying covariate. Results: In total, 139 ATTR-CM patients were included, with a median age of 80.9 years [74.3-86.6 years], from 2011 to 2022. The mean follow-up was 2.9 ± 1.8 years. Eighty (55%) patients were treated with tafamidis. All-cause mortality and cardiovascular mortality alone were associated with the following baseline variables: age, clinical frailty scale, systolic blood pressure, renal function, and right ventricular size and function (all p < 0.05), with no identified interactions with tafamidis treatment. Only baseline renal function was associated with cardiovascular hospitalization ( p < 0.05). Conclusion: Important baseline variables associated with adverse ATTR-CM disease outcomes included renal function, systolic blood pressure, frailty, and right ventricular size and function. The risk factors were independent of treatment with tafamidis. These findings may help improve risk stratification for determining eligibility for ATTR-CM therapies.

Background: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients., Methods and Results: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51)., Conclusions: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients., Competing Interests: Declaration of Competing Interest K.F.D. has received financial support to attend educational meetings from Cytokinetics during the conduct of the study, personal fees from AstraZeneca, consulting fees from Us2.ai and research grants to his institution from AstraZeneca and Boehringer Ingelheim outside the submitted work. J.J.V.M. has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). R.D. has received research grants and other payment or honoraria from Amgen. G.M.F. has received grant funding to his institution from American Heart Association, Amgen, Bayer, Bristol Myers Squibb, CSL-Behring, Cytokinetics, Merck, Myokardia, and National Institutes of Health; has received consulting fees from Abbott, American Regent, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, Cytokinetics, Medtronic, Myovant, Novartis, Reprieve, Sequana, Windtree Therapeutics, and WhiteSwell; and has participated on Data Safety Monitoring boards or advisory boards for EBR Systems, LivaNova, Medtronic, Siemens, Rocket Pharma, and V-Wave. M.M. has received funding to his institution from Amgen and Cytokinetics as participant to the Executive Committee during the trial and for patients’ enrolment; has received consulting fees for participation to advisory boards from AstraZeneca, Bayer, and Boehringer Ingelheim; has received personal fees as member of Executive or Data Monitoring Committees of sponsored clinical trials from LivaNova and Vifor Pharma; has received speaker fees from Abbott Vascular and Edwards Therapeutics for speeches at sponsored meetings; and has participated on Data Safety Monitoring boards for Actelion. S.D.S. has received grant funding to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis Pharmaceuticals, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has received consulting fees from Abbott, Action, Akros, Alnylam, American Regent, Amgen, Anacardio, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior, Cardurion, CellProthera, Corvia, Cytokinetics, Daiichi Sankyo, Dinaqor, GlaxoSmithKline, Janssen, Lexicon, Lilly, Merck, Moderna, Myokardia, Novartis, Puretech Health, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta, Tenaya, Theracos, and Tremeau. K.F.A. has received research grants from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals Inc., Eli Lilly USA, LivaNova USA, Merck, Novartis, and Otsuka; acted as a consultant to Amgen, Cytokinetics, Inc., Novartis, Roche Diagnostics, Relypsa, and Windtree Therapeutics. M.B. has received funds from the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and personal fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, ReCor, Servier, Vifor Pharma, and Boehringer Ingelheim. A.R.G. reports consulting fees for clinical trials from Amgen, Novartis, KOWA, and Bayer outside the submitted work; personal payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk outside the submitted work; support for attending meetings and/or travel from Pfizer, AstraZeneca, and Boehringer Ingelheim; and leadership or fiduciary role as President, Bulgarian Society of Cardiology 2020-22. J.G.H. has received grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, and Pfizer; has received personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, and Pfizer; and is Co-Chair of the Heart Failure Pathway Group of the Province of Alberta, Heart Failure lead at University of Calgary, and in the Canadian Cardiovascular Society Guidelines and Development Committees. M.L. has received grant funding and personal fees from Amgen; has received honoraria from Novartis; and has served as the New Zealand Chairperson for Cardiac Society Australia and New Zealand. P.P. has received research grants to his institution from Amgen and Vifor Pharma; and has received consulting fees or honoraria from Abbott Vascular, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Cibiem, Coridea, Impulse Dynamics, Novartis, Pfizer, Renal Guard Solutions, Servier, and Vifor Pharma. M.B.Y. reports funding to his institution from Amgen, Bayer, Novartis, and Dalcor Pharmaceuticals outside the submitted work. F.Z. reports consulting fees from Cardior, Cereno pharmaceutical, Cellprothera, Owkin, Novo Nordisk, Vifor, and Fresenius; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer and Bayer; payment for expert testimony from Cardiorentis; stock or stock options in Cereno pharmaceutical; and steering committee personal fees from Applied Therapeutics, Amgen, Bayer, Boehringer, CVRx, Novartis, and Merck. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. Z.M.M. has no conflicts of interest to disclose. S.A.A. is an employee and shareholder of Amgen. P.H.D., S.B.H., S.K., and F.I.M. are employees and shareholders of Cytokinetics. J.R.T. has received personal fees as Chairperson of the GALACTIC-HF Executive Committee from Amgen and Cytokinetics; has received personal fees for research contracts and/or consulting fees from 3ive Labs, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; has served as Secretary and Treasurer of Heart Failure Society of America; and is currently President-Elect of the Heart Failure Society of America. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Systemic sclerosis (SSc) is associated with esophageal dysmotility. Autologous hematopoietic cell transplantation (HCT) results in improvement of skin tightness and lung function. Whether esophageal motility improves after HCT is unknown., Methods: Esophageal motility was studied using high-resolution esophageal manometry in 21 SSc patients before and at multiple time points after autologous HCT. Median posttransplant follow-up was 2 years (range, 6 months to 5 years)., Results: Prior to HCT, all 21 patients had abnormal motility-10 (48%) had unmeasurable and 11 (52%) had measurable peristalsis. Manometric diagnosis in the former 10 patients was "absent contractility" and in the latter 11 patients "ineffective esophageal motility (IEM)." After HCT, among the 10 patients with absent contractility, 9 continued to have absent contractility and one demonstrated weak measurable peristalsis. Of the 11 patients with IEM, 5 experienced SSc relapse, and 2 out of these 5 patients developed absent contractility. Among the 6 non-relapsed patients, 4 continued to have IEM, and 2 developed normal motility., Conclusions: HCT appears to have no beneficial effect on motility in patients with unmeasurable peristalsis. In patients with measurable peristalsis, HCT appears to stabilize and in some normalize motility, unless relapse occurs. Key Points • In patients with systemic sclerosis, esophageal dysmotility is a significant contributor to morbidity and so far, there has been no data describing the effects of hematopoietic cell transplantation on esophageal motility. • Our work demonstrated that in patients with systemic sclerosis and unmeasurable esophageal peristalsis prehematopoietic cell transplantation, there was no measurable beneficial effect of transplantation on esophageal motility. • In patients with systemic sclerosis and measurable peristalsis prehematopoietic cell transplantation, esophageal motility stabilized, except in relapsed patients., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Left ventricular (LV) circumferential and longitudinal strain provide important insight into LV mechanics and function, each contributing to volumetric changes throughout the cardiac cycle. We sought to explore this strain-volume relationship in more detail, by mathematically integrating circumferential and longitudinal strain and strain rate to predict LV volume and volumetric rates of change., Methods: Cardiac magnetic resonance (CMR) imaging from 229 participants from the Alberta HEART Study (46 healthy controls, 77 individuals at risk for developing heart failure [HF], 70 patients with diagnosed HF with preserved ejection fraction [HFpEF], and 36 patients with diagnosed HF with reduced ejection fraction [HFrEF]) were evaluated. LV volume was assessed by the method of disks and strain/strain rate were assessed by CMR feature tracking., Results: Integrating endocardial circumferential and longitudinal strain provided a close approximation of LV ejection fraction (EF Strain ), when compared to gold-standard volumetric assessment (EF Volume : r = 0.94, P < 0.0001). Likewise, integrating circumferential and longitudinal strain rate provided a close approximation of peak ejection and peak filling rates (PER Strain and PFR Strain , respectively) compared to their gold-standard volume-time equivalents (PER Volume , r = 0.73, P < 0.0001 and PFR Volume , r = 0.78, P < 0.0001, respectively). Moreover, each integrated strain measure differentiated patients across the HF continuum (all P < 0.01), with the HFrEF group having worse EF Strain , PER Strain , and PFR Strain compared to all other groups, and HFpEF having less favorable EF Strain and PFR Strain compared to both at-risk and control groups., Conclusions: The data herein establish the theoretical framework for integrating discrete strain components into volumetric measurements across the cardiac cycle, and highlight the potential benefit of this approach for differentiating patients along the heart failure continuum., (© 2023. Society for Cardiovascular Magnetic Resonance.)

Background: Preclinical and observational studies suggest that the gut microbiome plays a role in the pathogenesis of heart failure (HF); the gut microbiome may be modified by fermentable dietary fibre (FDF). The Need for F ib e r A ddition in S ymp t omatic H eart F ailure (FEAST-HF) trial evaluated feasibility of recruitment and supplementation with FDF in HF and whether FDF (acacia), compared to control, reduced the level of N-terminal pro-b-type natriuretic peptide (NT-proBNP) and growth stimulation expressed gene 2 (ST2), and produced changes in the gut microbiome., Methods: Participants were randomly allocated 1:1:1 to either of the intervention arms (5 g/d or 10 g/d acacia) or to the control arm (10 g/d microcrystalline cellulose (MCC; nonfermentable active control). Adherence and tolerance were assessed, and clinical events were monitored for safety. All outcomes (NT-proBNP, ST2, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire scores, 6-minute walk test score, gut microbiome) were measured at baseline, and at 6 and 12 weeks., Results: Between September 13, 2018 and December 16, 2021, 51 patients were randomly allocated to either MCC (n = 18), acacia 5 g daily (n = 13), or acacia 10 g daily (n = 18). No differences occurred between either dose of acacia and MCC in NT-proBNP level, ST2, New York Heart Association class, or questionnaire scores over 12 weeks. Dietary treatment arms had a negligible impact on microbial communities. No safety, tolerability, or adherence issues were observed., Conclusions: Dietary supplementation with acacia gum was both safe and well tolerated in ambulatory patients with HF; however, it did not change NT-proBNP level, ST2, or the composition of the gut microbiome.ClinicalTrials.gov: NCT03409926., (© 2023 The Authors.)

Background: Pulmonary hypertension is common among patients with heart failure (HF). Right ventricular systolic pressure (RVSP) is frequently used to assess its presence and severity. Although RVSP has been associated with adverse outcomes, the importance of serial measurements has not been studied. We evaluated associations between serial RVSP measurements and cardiovascular events in patients with HF., Methods: Patients with HF and 2 echocardiograms performed ≥ 6 months apart were included. RVSP was categorized, using the second echocardiogram, as follows: normal (< 40 mm Hg); severely elevated (≥ 60 mm Hg); moderately elevated (50-59 mm Hg); or mildly elevated (40-49 mm Hg). Patients also were classified according to change in RVSP categories between echocardiograms. The primary outcome was time to HF hospitalization (HFH) or all-cause mortality (ACM) after the second echocardiogram., Results: In total, 4319 patients were included (median age: 78 years; 52.1% female). During a median follow-up period of 19.4 months, HFH/ACM occurred in 2714 patients (62.8%). In multivariable analysis, baseline RSVP that was mildly elevated (1069 patients, hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.12-1.54), moderately elevated (797 patients, HR 1.54, 95% CI 1.30-1.82), or severely elevated (837 patients, HR 1.92, 95% CI 1.60-2.31) was independently associated with HFH/ACM. Additionally, improving RVSP was associated with increased HFH/ACM in both categorical (HR 1.16, 95% CI 1.01-1.33) and continuous analyses., Conclusions: RVSP measurements identify patients at increased risk who may require more-aggressive monitoring and medical therapy. Our study raises the hypothesis that, in addition to the absolute value of RVSP, improving RVSP category may identify higher-risk patients, but further study is needed to elucidate the underlying reasons., (© 2023 The Authors.)

Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) patients are often older and may be at risk for obstructive epicardial coronary artery disease (oeCAD). While ATTR-CM may cause small vessel coronary disease, the prevalence and clinical significance of oeCAD is not well described., Methods and Results: The prevalence and incidence of oeCAD and its association with all-cause mortality and hospitalization among 133 ATTR-CM patients with ≥ 1-year follow-up was evaluated. The mean age was 78 ± 9 years, 119 (89%) were male, 116 (87%) had wild-type and 17 (13%) had hereditary subtypes. Seventy-two (54%) patients underwent oeCAD investigations, with 30 (42%) receiving a positive diagnosis. Among patients with a positive oeCAD diagnosis, 23 (77%) were diagnosed prior to ATTR-CM diagnosis, 6 (20%) at the time of ATTR-CM diagnosis, and 1 (3%) after ATTR-CM diagnosis. Baseline characteristics between patients with and without oeCAD were similar. Among patients with oeCAD, only 2 (7%) required additional investigations, intervention or hospitalization after ATTR-CM diagnosis. After a median follow-up of 27 months there were 37 (28%) deaths in the study population, including 5 patients with oeCAD (17%). Fifty-six (42%) patients in the study population required hospitalization, including 10 patients with oeCAD (33%). There was no significant difference in the rates of death or hospitalization among ATTR-CM patients with and without oeCAD, and oeCAD was not significantly associated with either outcome by univariable regression analysis., Conclusions: While oeCAD is prevalent in ATTR-CM patients, this diagnosis is frequently known at time of ATTR-CM diagnosis and characteristics are similar to patients without oeCAD., (© 2023. The Author(s).)

Aims: To compare the cost-effectiveness of immediate and 12-month delayed initiation of dapagliflozin treatment in patients with a history of hospitalization for heart failure (HHF) from the UK, Canadian, German, and Spanish healthcare perspectives., Methods and Results: A cost-utility analysis was conducted using a decision-analytic Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire scores, type 2 diabetes mellitus status and incidence of heart failure (HF) events. Patient-level data for patients with prior HHF from the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial were used to inform the model inputs on clinical events and utility values. Healthcare costs were sourced from the relevant national reference databases and the published literature. Compared to standard therapy, immediate initiation of dapagliflozin decreased HHF (187 events), urgent HF visits (32 events) and cardiovascular mortality (18 events). Standard therapy was associated with lifetime costs of £13 224 and 4.02 quality-adjusted life years (QALYs). Twelve-month delayed initiation of dapagliflozin was associated with total discounted lifetime costs and QALYs of £16 660 and 4.61, respectively, compared to £16 912 and 4.66, respectively, for immediate initiation. Compared to standard therapy, immediate and 12-month delayed initiation of dapagliflozin yielded an incremental cost-effectiveness ratio (ICER) of £5779 and £5821, respectively. Compared to 12-month delayed initiation, immediate initiation of dapagliflozin had an ICER of £5263. Results were similar from the Canadian, German, and Spanish healthcare perspectives., Conclusion: Both immediate and 12-month delayed initiation of dapagliflozin are cost-effective. However, immediate initiation provides greater clinical benefits, with almost 10% additional QALYs gain, compared to 12-month delayed initiation of dapagliflozin and should be considered standard of care., (© 2023 Health Economics and Outcomes Research, AstraZeneca and The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF)., Methods and Results: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo., Conclusion: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values., Competing Interests: Conflict of interest: M.M. has received funding to his institution from Amgen and Cytokinetics as participant to the Executive Committee during the trial and for patients’ enrolment; has received consulting fees for participation to advisory boards from AstraZeneca, Bayer, and Boehringer Ingelheim; has received personal fees as member of Executive or Data Monitoring Committees of sponsored clinical trials from LivaNova and Vifor Pharma; has received speaker fees from Abbott Vascular and Edwards Therapeutics for speeches at sponsored meetings; and has participated on Data Safety Monitoring boards for Actelion. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. R.D. has received research grants and other payment or honoraria from Amgen. G.M.F. has received grant funding to his institution from American Heart Association, Amgen, Bayer, Bristol Myers Squibb, CSL-Behring, Cytokinetics, Merck, Myokardia, and National Institutes of Health; has received consulting fees from Abbott, American Regent, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, Cytokinetics, Medtronic, Myovant, Novartis, Reprieve, Sequana, Windtree Therapeutics, and WhiteSwell; and has participated on Data Safety Monitoring boards or advisory boards for EBR Systems, LivaNova, Medtronic, Siemens, Rocket Pharma, and V-Wave. J.J.V.M. has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received personal fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, Sun Pharmaceuticals, and The Corpus; and has received funding paid to his institution for activities related to trials or other activities from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, DalCor, GlaxoSmithKline, Ionis Pharmaceuticals, KBP Biosciences, Novartis, and Theracos. S.D.S. has received grant funding to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis Pharmaceuticals, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has received consulting fees from Abbott, Action, Akros, Alnylam, American Regent, Amgen, Anacardio, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior, Cardurion, CellProthera, Corvia, Cytokinetics, Daiichi Sankyo, Dinaqor, GlaxoSmithKline, Janssen, Lexicon, Lilly, Merck, Moderna, Myokardia, Novartis, Puretech Health, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta, Tenaya, Theracos, and Tremeau. D.B. has received research grants from Abbott, Bayer, Boehringer Ingelheim, Novartis, Pfizer, SOBI, and Zoll; has received consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, SOBI, and Zoll; has received speaker fees or honoraria and support for attending meetings and/or travels from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Ionis Pharmaceuticals, MSD, Novartis, Pfizer, SOBI, and Zoll; and is in the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function. J.C.F. has served on the Board of Directors for the Heart Failure Society of America. C.F. has received personal fees for consulting from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Servier, and Vifor Pharma; has received honoraria for lectures and educational events from AstraZeneca, Bayer, Boehringer Ingelheim, Servier, and Vifor Pharma; has received honoraria for lectures from Novartis; has received support for attending meetings and/or travel from Bayer, Servier, and Vifor Pharma; has participated on advisory boards for Bayer, Boehringer Ingelheim, Novartis, and Vifor Pharma; and has received grants for medical writing from Merck Serono and Roche. E.G. has received consulting fees from AOP Orphan Pharmaceuticals, Bayer, Boehringer Ingelheim, Novartis, and Servier; has received personal fees from Bayer, Boehringer Ingelheim, Janssen Pharmaceuticals, Novartis, Pfizer, and Servier; and is the President of the Slovak Society of Cardiology. J.G.H. has received grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, and Pfizer; has received personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, and Pfizer; and is Co-Chair of the Heart Failure Pathway Group of the Province of Alberta, Heart Failure lead at University of Calgary, and in the Canadian Cardiovascular Society Guidelines and Development Committees. J.L. has received research agreements from Amgen during the conduct of the study through the National Center for Cardiovascular Diseases. E.O. has received support to her institution (Montreal Heart Institute) for being local Principal Investigator and member of the Steering Committee of the GALACTIC-HF trial from Amgen and Cytokinetics; has received grant funding to her institution (Montreal Heart Institute) for clinical trials from AstraZeneca, American Regent, Cardurion, and Canadian Institutes of Health Research (CIHR); has received consulting fees from AstraZeneca, Bayer, Cytokinetics, Boehringer Ingelheim, Eli Lilly, and Janssen; has received speaker fees or other honoraria from AstraZeneca, Bayer, and Boehringer Ingelheim; and has participated on Data Safety Monitoring boards or advisory boards for Bayer, Boehringer Ingelheim, and the independent COLpEF trial. S.A.A. is an employee and shareholder of Amgen. S.B.H., S.K., and F.I.M. are employees and shareholders of Cytokinetics. J.R.T. has received personal fees as Chairperson of the GALACTIC-HF Executive Committee from Amgen and Cytokinetics; has received personal fees for research contracts and/or consulting fees from 3ive Labs, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; has served as Secretary and Treasurer of Heart Failure Society of America; and is currently President-Elect of the Heart Failure Society of America. The other authors have no conflicts of interest to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Systemic sclerosis (SSc) is an autoimmune, multi-organ, connective tissue disease associated with significant morbidity and mortality. Conventional immunosuppressive therapies demonstrate limited efficacy. Autologous hematopoietic stem cell transplantation (HCT) is more efficacious but carries associated risks, including treatment-related mortality. Here, we review HCT as a treatment for SSc, its efficacy and toxicity in comparison to conventional therapies, and the proposed mechanisms of action. Furthermore, we discuss the importance of and recent developments in patient selection. Finally, we highlight the knowledge gaps and future work required to further improve patient outcomes.

Introduction: Heart failure (HF), and especially HF with preserved ejection fraction (HFpEF), remains a challenging condition to define. The heterogenous nature of this population may be related to a variety of underlying etiologies interacting myocardial dysfunction., Method: Alberta HEART study was a prospective, observational cohort that enrolled participants along the spectrum of heart failure including: healthy controls, people at risk of HF, and patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF). We aimed to explore phenotypes of patients with HF and at-risk of developing HF. Utilising 27 detailed clinical, echocardiographic and biomarker variables, latent class analysis with and without multiple imputation was undertaken to identify distinct clinical phenotypes., Results: Of 621 participants, 191 (30.8%) and 169 (27.2%) were adjudicated by cardiologists to have HFpEF and HFrEF respectively. In the overall cohort, latent class analysis identified four distinct phenotypes. Phenotype A (n=152, 24.5%) was a healthy and low risk group. Phenotype B (n=129, 20.8%) demonstrated increased left ventricular mass and end-diastolic volumes, with elevated natriuretic peptides and clinical features of congestion. Phenotype C (n=128, 20.6%) was primarily characterised by obesity (80%) and normal indexed cardiac chamber sizes, low natriuretic peptide levels and minimal features of congestion.  Phenotype D (n=212, 34.1%) consisted of elderly patients with clinical features of congestions. Phenotypes B and D demonstrated the highest risk of mortality and hospitalization over a median follow-up of 3.7 years., Conclusion: Phenotypes with congestive features demonstrated increased risk profiles. Heart failure is a heterogenous classification which requires further work to appropriately categorise patients based on the underlying etiology or mechanism of impairment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Heart failure with mildly reduced ejection fraction (HFmrEF) is associated with a favourable prognosis compared with heart failure (HF) with reduced ejection fraction (EF). We assessed whether left ventricular ejection fraction (LVEF) trajectory can be used to identify groups of patients with HFmrEF who have different clinical outcomes in a large retrospective study of patients with serial imaging., Methods and Results: Patients with HF and ≥2 echocardiograms performed ≥6 months apart were included if the LVEF measured 40-49% on the second study. Patients were classified as HFmrEF-Increasing if LVEF had increased ≥10% (n = 450), HFmrEF-Decreasing if LVEF had decreased ≥10% (n = 512), or HFmrEF-Stable if they did not meet other criteria (n = 389). The primary outcome was all-cause mortality or cardiovascular hospitalization after the second echocardiogram. Associations with time to first event were assessed with multivariable Cox analyses adjusted for age, co-morbidities, and medications. In total, 1351 patients with HFmrEF (median age 74, 64.2% male) were included with 28.8% exhibiting stable LVEF. During median follow-up of 15.3 months, the composite outcome occurred in 811 patients. During follow-up, patients with HFmrEF-Increasing were less likely to experience the primary outcome [adjusted hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.60-0.88, P < 0.001] compared with HFmrEF-Stable. Patients with HFmrEF-Decreasing were more likely to experience the composite outcome in unadjusted analyses (unadjusted HR 1.19, 95% CI 1.01-1.40, P = 0.040) but not adjusted analyses (adjusted HR 1.16, 95% CI 0.98-1.37, P = 0.092). Associations with death or HF hospitalizations were similar (HFmrEF-Increasing: adjusted HR 0.72, 95% CI 0.59-0.88, P = 0.005; HFmrEF-Decreasing: adjusted HR 1.20, 95% CI 1.01-1.44, P = 0.044). Patients with HFmrEF-Decreasing had a similar risk of the composite outcome as patients with HF with reduced EF (adjusted HR 1.03, 95% CI 0.89-1.20, P = 0.670). Patients with HFmrEF-Increasing were less likely to experience the composite outcome compared with patients with HF with preserved EF (adjusted HR 0.73, 95% CI 0.62-0.87, P < 0.001)., Conclusions: Amongst patients with HFmrEF, those exhibiting positive LVEF trajectory were less likely to experience adverse outcomes after correcting for important confounders including medical therapy. Categorizing HFmrEF patients based on LVEF trajectory provides meaningful clinical information and may assist clinicians with management decisions., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Among patients with heart failure (HF) and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on new-onset AF., Methods and Results: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had 'any AF' (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.62-0.92 and 0.74, 95% CI 0.62-0.88, respectively; p for interaction = 0.88]. Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new-onset AF compared with placebo (HR 0.86, 95% CI 0.60-1.22). However, patients with new-onset AF had a 5 to 6-fold higher risk of adverse outcomes when compared to those without incident AF., Conclusions: Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all-cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new-onset AF., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Importance: Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies., Objective: To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial., Design, Setting, and Participants: The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months., Interventions: Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo., Main Outcomes and Measures: The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability., Results: Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo., Conclusions and Relevance: In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited., Trial Registration: ClinicalTrials.gov Identifier: NCT02929329.

Objectives: This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure)., Background: Black patients may respond differently to certain treatments for HFrEF than White patients., Methods: Patients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death., Results: Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients., Conclusions: Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)., Competing Interests: Funding Support and Author Disclosures DAPA-HF was funded by AstraZeneca. Dr McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant (RE/18/6/34217). Dr Docherty’s employer (University of Glasgow) has been remunerated by AstraZeneca for involvement in the DAPA-HF trial; and he has also received speaker fees from AstraZeneca and Eli Lilly. Dr Ogunniyi has received research grants from AstraZeneca, Boehringer Ingelheim, and Zoll and Advisory Board fees from Pfizer. Dr Desai has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. Dr Diez has received personal fees from AstraZeneca. Dr Howlett has received research grants from University Hospital Foundation, Pfizer, and Novartis; consulting fees from AstraZeneca, Bayer, Novartis, Merck, Janssen, Otsuka, Servier, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Akcea, Alnylam, and Pfizer; speaker fees from AstraZeneca, Bayer, Novartis, Merck, Janssen, Servier, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Pfizer; and has participated on a Data Safety Monitoring Board or Advisory Board for Novartis, AstraZeneca, and Medtronic. Dr Nicolau has received research grants and personal fees from Vifor Pharma (National Lead Investigator [NLI]/Steering Committee [SC] member for AFFIRM); research grants from AstraZeneca (NLI), Bayer (Principal Investigator [PI] Compass), Esperion and CLS Behring (NLI/SC member), DalCor (NLI), Janssen (NLI/SC member), Novartis (PI, consultant), Novo Nordisk (PI), and Sanofi (NLI, PI, Advisory Board); and personal fees from Amgen (consultant), Bayer, Daiichi-Sankyo (speaker), Novartis, Sanofi, and Servier (speaker, Advisory Board). Dr O’Meara or her institution has received financial support for clinical trials from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis; has served as a consultant or speaker for Amgen, Boehringer Ingelheim, Novartis, and AstraZeneca. Dr Verma has received personal fees from AstraZeneca, Sun Pharmaceuticals, and Toronto Knowledge Translation Working Group during the conduct of the study; grants and personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Merck; grants from Bristol Myers Squibb; and personal fees from Eli Lilly, Janssen, Novartis, Novo Nordisk, and Sanofi. Dr Inzucchi has received personal fees and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Sanofi/Lexicon, Merck, VTV Therapeutics, and Abbott/Alere; and personal fees from AstraZeneca and Zafgen. Dr Køber has received financial from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. Dr Kosiborod has received personal fees from AstraZeneca and Vifor Pharma; grants, personal fees, and other from AstraZeneca; grants and personal fees from Boehringer Ingelheim; and personal fees from Sanofi, Amgen, Novo Nordisk, Merck (Diabetes), Janssen, Bayer, Applied Therapeutics, and Eli Lilly. Dr Lindholm is an employee of AstraZeneca. Dr Martinez has received personal fees from AstraZeneca. Dr Bengtsson is an employee of AstraZeneca. Dr Ponikowski has received personal fees and other from AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb, Cibiem, Novartis, and RenalGuard; personal fees from Pfizer, Servier, Respicardia, and Berlin-Chemie; financial support from Amgen; and grants, personal fees, and other from Vifor Pharma. Dr Sabatine has received grants from Bayer, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; and personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, Dal-Cor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche, and Zora Biosciences. Dr Sjöstrand is an employee of AstraZeneca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. Dr Langkilde is an employee of AstraZeneca. Dr Jhund’s employer (University of Glasgow) has been remunerated by AstraZeneca for involvement in the DAPA-HF and DELIVER trials; has received speaker and Advisory Board fees from Novartis; and Advisory Board fees and grants from Boehringer Ingelheim. Dr McMurray’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF, DELIVER, and DETERMINE trials as well as Amgen, Boehringer Ingelheim, Cytokinetics, DalCor, GlaxoSmithKline, Pfizer, Theracos, and Novartis; has received other support from Bayer, Bristol Myers Squibb, Cardurion, KBP Biosciences, Ionis, and Alnylam; has received speaker fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus; and is director of Global Clinical Trial Partners Ltd., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Surveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome., Methods and Results: A prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow-up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan-Meier analyses compared to those with no remodelling, log-rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction., Conclusions: Cardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long-term outcomes whereas change in left ventricular ejection fraction did not., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The advent of newly available medical therapies for heart failure with reduced ejection fraction (HFrEF) has resulted in many potential therapeutic combinations, increasing treatment complexity. Publication of expert consensus guidelines and initiatives aimed to improve implementation of treatment has emphasized sequential stepwise initiation and titration of medical therapy, which is labour intensive. Data taken from heart failure registries show suboptimal use of medications, prolonged titration times, and consequently little change in dose intensity, all of which indicate therapeutic inertia. Recently published evidence indicates that 4 medication classes-renin-angiotensin-neprilysin inhibitors, β-blockers, mineralocorticoid antagonists, and sodium-glucose cotransporter inhibitors-which we refer to as Foundational Therapy, confer rapid and robust reduction in both morbidity and mortality in most patients with HFrEF and that they work in additive fashion. Additional morbidity and mortality may be observed following addition of several personalized therapies in specific subgroups of patients. In this review, we discuss mechanisms of action of these therapies and propose a framework for their implementation, based on several principles. These include the critical importance of rapid initiation of all 4 Foundational Therapies followed by their titration to target doses, emphasis on multiple simultaneous drug changes with each patient encounter, attention to patient-specific factors in choice of medication class, leveraging inpatient care, use of the entire health care team, and alternative (ie, virtual visits) modes of care. We have incorporated these principles into a Cluster Scheme designed to facilitate timely and optimal medical treatment for patients with HFrEF., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF)., Methods and Results: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported., Conclusion: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown., Methods: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes., Results: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups., Conclusions: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.)., (Copyright © 2020 Massachusetts Medical Society.)

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials., Methods and Results: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m 2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594)., Conclusions: GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The aim of this study is to determine factors associated with long-term recovery of left ventricular ejection fraction (LVEF) in patients with heart failure with reduced EF (HFrEF) and if further recovery also occurs in this group., Methods and Results: Among 621 participants enrolled in the Alberta Heart Failure Etiology and Analysis Team (HEART) Study, 316 with Stage C HF underwent comprehensive imaging and biomarker testing at enrolment and at 1-year follow up. Using pre-enrolment data, HF with recovered EF (HFrecEF) was defined as an absolute improvement ≥5% in LVEF from the prior lowest LVEF value, with a final LVEF value > 35% at or prior to study baseline. Participants with all LVEF > 40% were included for comparison. Hospitalization-free survival to 5 years was performed. The median cohort age was 66 years, and time from diagnosis was 4 years; 82% were male patients. Of the 316 patients, 95 (30%) patients had HFrecEF and 56 (18%) patients pHFrEF. On multivariate analysis, only shorter duration of HF was predictive of HFrecEF status. Over 1 year, LVEF increased in the HFrecEF group 4.0% (0.15-7.90, P = 0.042) as compared with persistent HFrEF, who in turn demonstrated higher baseline serum high sensitivity Troponin-T with further increase at follow up 0.55(0.33-0.86, P = 0.011). No change in any parameter in the HFpEF/HFmrEF group at follow up was observed., Conclusions: Patients with HFrecEF demonstrate evidence of additional late improvement in LVEF and unchanged troponin levels, in contrast to those with persistent HFrEF, where LVEF does not improve and serum troponin rises over time. These data help to inform mechanisms relating to late LV remodelling., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)., Methods and Results: Key inclusion criteria were: New York Heart Association Class II-IV, left ventricular ejection fraction ≤ 40%, elevated N-terminal pro-B-type natriuretic peptide level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening heart failure or cardiovascular death. The efficacy and safety of dapagliflozin were examined using SBP as both a categorical and continuous variable. A total of 1205 patients had a baseline SBP <110 mmHg; 981 ≥ 110 < 120; 1149 ≥ 120 < 130; and 1409 ≥ 130 mmHg. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was -2.54 (-3.33 to -1.76) mmHg (P < 0.001), with a smaller between-treatment difference in patients in the lowest compared to highest SBP category. Patients in the lowest SBP category had a much higher rate (per 100 person-years) of the primary outcome [20.6, 95% confidence interval (95% CI) 17.6-24.2] than those in the highest SBP category (13.8, 11.7-16.4). The benefit and safety of dapagliflozin was consistent across the range of SBP; hazard ratio (95% CI) in each SBP group, lowest to highest: 0.76 (0.60-0.97), 0.76 (0.57-1.02), 0.81 (0.61-1.08), and 0.67 (0.51-0.87), P interaction = 0.78. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined., Conclusion: Dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF., Clinical Trial Registration: ClinicalTrials.gov NCT03036124., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo., Methods: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms., Results: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively ( P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization., Conclusions: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Aims: In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether this benefit was consistent in relation to background HF therapy., Methods and Results: In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n = 4744) were treated with a diuretic (84%), renin-angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 [95% confidence interval (CI) 0.65-0.85] for the primary composite endpoint (P < 0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61-0.86) compared with 0.77 (95% CI 0.63-0.94) in those not on all three of these treatments (P-interaction 0.64)., Conclusion: The benefit of dapagliflozin was consistent regardless of background therapy for HF., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Quality improvement initiatives improve health care delivery but may be resource intensive and disrupt clinical care. An embedded heart failure order set (HFOS) within a computerized physician order-entry system may mitigate these concerns., Methods: An HFOS, based on proven interventions, was implemented within an existing computerized physician order-entry system in all adult acute-care hospitals in a single Canadian metropolitan city and interrogated between January 1, 2013 and December 31, 2015. The composite of repeat hospitalization or death within 30 days of hospital discharge and hospital length of stay were reported., Results: In total, 8969 patients were included with mean age 75.6 ± 13.5 years; 4673 (52.1%) were male. The HFOS was used in 731 (8.2%) patients. After analysis of 724 pairs of propensity-score matched cohorts, patients with HFOS use experienced a lower median length of stay (8.6 vs 9.4 days, P  = 0.016) and a trend toward lower composite repeat hospitalization or death (14.5% vs 17.7%, P  = 0.115, hazard ratio 0.79 (0.60-1.05). Patients with HFOS use were more likely to undergo a test for left ventricular ejection fraction (88.6% vs 76.7%, P < 0.001, and to be referred to a heart failure clinic (48.5% vs 6.3%), with similar rates of discharge prescription of beta-blockers (88.7% vs 86.3) and angiotensin-converting enzyme inhibitors (87.4% vs 89.0%)., Conclusions: Use of a designated HFOS within a computerized physician order-entry system is associated with shorter hospital length of stay without increase in deaths or readmissions. These findings should be confirmed in a prospective controlled trial., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Background: Angiotensin receptor neprilysin inhibitor (ARNi) therapy improves clinical outcomes in patients with heart failure and reduced left ventricular ejection fraction. However, ARNi therapy uptake remains modest, potentially in part due to perceived cost considerations of early transition from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy., Methods: We constructed a decision-analytic Markov model to assess cost-effectiveness of 3 different ARNi initiation strategies according to timing of initiation: (1) de novo , or immediate initiation at baseline, (2) Early or after 3 months, or (3) Late, or after 9 months. Initiation strategies were compared with (4) current care, with utilization of ARNi derived from a large observational database. Total costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) were estimated over a 5-year time horizon in the base case analysis., Results: Current care was associated with the lowest total cost (CAD$26,664) and accrued benefit (3.28 QALYs). The de novo strategy yielded an ICER of $34,727 per QALY gained, whereas Early and Late initiation strategies yielded a less favourable ICER per QALY gained of $35,871 and $40,234, respectively. The model was most sensitive to the cost of ARNi therapy., Conclusion: A strategy of de novo ARNi initiation is economically attractive and becomes less favourable as the delay of initiation increases. Our results suggest that ARNi therapy should be initiated as soon as possible for patients with heart failure and reduced left ventricular ejection fraction., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

This joint Canadian Heart Failure Society and the CCS Heart Failure guidelines report has been developed to provide a pan-Canadian snapshot of the current state of clinic-based ambulatory heart failure (HF) care in Canada with specific reference to elements and processes of care associated with quality and high performing health systems. It includes the viewpoints of persons with lived experience, patient care providers, and administrators. It is imperative to build on the themes identified in this survey, through engaging all health care professionals, to develop integrated and shared care models that will allow better patient outcomes. Several patient and organizational barriers to care were identified in this survey, which must inform the development of regional care models and pragmatic solutions to improve transitions for this patient population. Unfortunately, we were unsuccessful in incorporating the perspectives of primary care providers and internal medicine specialists who provide the majority of HF care in Canada, which in turn limits our ability to comment on strategies for capacity building outside the HF clinic setting. These considerations must be taken into account when interpreting our findings. Engaging all HF care providers, to build on the themes identified in this survey, will be an important next step in developing integrated and shared care models known to improve patient outcomes., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Cardiac amyloidosis is an under-recognized and potentially fatal cause of heart failure and other cardiovascular manifestations. It is caused by deposition of misfolded precursor proteins as fibrillary amyloid deposits in cardiac tissues. The two primary subtypes of systemic amyloidosis causing cardiac involvement are immunoglobulin light chain (AL), a plasma cell dyscrasia, and transthyretin (ATTR), itself subdivided into a hereditary subtype caused by a gene mutation of the ATTR protein, and an age-related wild type, which occurs in the absence of a gene mutation. Clinical recognition requires a high index of suspicion, inclusive of the extracardiac manifestations of both subtypes. Diagnostic workup includes screening for serum and/or urine monoclonal protein suggestive of immunoglobulin light chains, along with serum cardiac biomarker measurement and performance of cardiac imaging for findings consistent with amyloid infiltration. Modern cardiac imaging techniques, including the use of nuclear scintigraphy with bone-seeking radiotracer to noninvasively diagnose ATTR cardiac amyloidosis, have reduced reliance on the gold standard endomyocardial biopsy. Disease-modifying therapeutic approaches have evolved significantly, particularly for ATTR, and pharmacologic therapies that slow or halt disease progression are becoming available. This Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement provides evidence-based recommendations that support the early recognition and optimal diagnostic approach and management strategies for patients with cardiac amyloidosis. This includes recommendations for the symptomatic management of heart failure and other cardiovascular complications such as arrhythmia, risk stratification, follow-up surveillance, use of ATTR disease-modifying therapies, and optimal clinical care settings for patients with this complex multisystem disease., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Right heart function is an important prognostic determinant in cardiac amyloidosis. In this study we characterized serial changes in right and left heart function and evaluated their prognostic significance., Methods: Cardiac amyloidosis patients with baseline and follow-up echocardiograms were included. Right and left heart function measured at baseline, 1 year, and most recent follow-up were compared and correlated with all-cause mortality or cardiovascular hospitalization., Results: Ninety-three patients were included; 36 (39%) with light chain amyloidosis and 57 (61%) with transthyretin amyloidosis. Among measures of right heart function for the study population and light chain and transthyretin amyloidosis subtypes, only absolute right ventricular (RV) free wall longitudinal strain (FWLS) changed significantly from baseline to 1 year and most recent follow-up echocardiogram. After a median of 26 months (range, 14-35 months), 21 (22%) patients died and 17 (18%) had a cardiovascular hospitalization. Baseline RV FWLS was significantly associated with the primary endpoint (hazard ratio, 1.2 per % change; 95% confidence interval, 0.8-2.6; P < 0.01), whereas change from baseline to 1 year was not for any measure of right heart function. Baseline left ventricular (LV) global longitudinal strain (GLS) and 1 year change were significantly associated with the primary end point. Change in RV FWLS at 1 year was significantly correlated with baseline LV GLS (r = 0.68; P = 0.01) and change at 1 year follow-up (r = 0.72; P < 0.01)., Conclusions: In cardiac amyloidosis patients, baseline RV FWLS was associated with adverse outcomes whereas changes at follow-up was not. Change in RV FWLS was significantly correlated with baseline and follow-up change in LV GLS, possibly reflecting progressive biventricular amyloid deposition., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes., Methods: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death., Results: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups., Conclusions: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.)., (Copyright © 2019 Massachusetts Medical Society.)

Objectives: The authors investigated the impact of coronary artery bypass grafting (CABG) on first and recurrent hospitalization in this population., Background: In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, CABG reduced all-cause death and hospitalization in patients with and ischemic cardiomyopathy and left ventricular ejection fraction <35%., Methods: A total of 1,212 patients were randomized (610 to CABG + optimal medical therapy [CABG] and 602 to optimal medical therapy alone [MED] alone) and followed for a median of 9.8 years. All-cause and cause-specific hospitalizations were analyzed as time-to-first-event and as recurrent event analysis., Results: Of the 1,212 patients, 757 died (62.4%) and 732 (60.4%) were hospitalized at least once, for a total of 2,549 total all-cause hospitalizations. Most hospitalizations (66.2%) were for cardiovascular causes, of which approximately one-half (907 or 52.9%) were for heart failure. More than 70% of all hospitalizations (1,817 or 71.3%) were recurrent events. The CABG group experienced fewer all-cause hospitalizations in the time-to-first-event (349 CABG vs. 383 MED, adjusted hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.74 to 0.98; p = 0.03) and in recurrent event analyses (1,199 CABG vs. 1,350 MED, HR: 0.78, 95% CI: 0.65 to 0.94; p < 0.001). This was driven by fewer total cardiovascular (CV) hospitalizations (744 vs. 968; p < 0.001, adjusted HR: 0.66, 95% CI: 0.55 to 0.81; p = 0.001), the majority of which were due to HF (395 vs. 512; p < 0.001, adjusted HR: 0.68, 95% CI: 0.52-0.89; p = 0.005). We did not observe a difference in non-CV events., Conclusions: CABG reduces all-cause, CV, and HF hospitalizations in time-to-first-event and recurrent event analyses. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595)., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Aims: Ivabradine is a selective sinus node inhibitor indicated in patients with symptomatic chronic heart failure on stable guideline-recommended heart failure therapy including appropriate doses of beta-blockers. The use in cardiogenic shock remains off label and has been considered a contraindication due to the theoretical risk of attenuating compensatory tachycardia. Tachycardia, especially in the context of inotropic therapy, may be deleterious, resulting in increased myocardial oxygen consumption and reduction in diastolic filling. As ivabradine does not have negative inotropic action, it may present a potential means to manage tachycardia in cardiogenic shock. We present a case series of four patients with cardiogenic shock started on ivabradine who were unable to tolerate beta-blockers., Methods and Results: Five patients identified with cardiogenic shock defined as a severe reduction in cardiac index (<2.0 L/min/m 2 ) and elevated filling pressures on inotropic therapy were started on ivabradine in patients with sinus tachycardia [heart rate (HR) >100] who were intolerant to beta-blockers. Each patient had a cardiac magnetic resonance imaging, echocardiogram, and coronary angiogram for determination of aetiology. Invasive haemodynamics via pulmonary artery catheterization were measured during initiation and titration of ivabradine (baseline, 6, 12, 24, and 48 h after ivabradine administration) with continuous telemetry monitoring for any dysrhythmia or bradyarrhythmias. All patients tolerated ivabradine initiation, and at 24 h, an observed decrease in HR (106 ± 6.8 vs. 91.6 ± 6.4 b.p.m., P = 0.04), pulmonary arterial occlusion pressure (30.4 ± 4.8 vs. 24 ± 5.1 mmHg, P = 0.04), and right atrial pressure (16.8 ± 6.2 vs. 9 ± 4.3 mmHg, P = 0.0002). An improvement was observed in mixed venous oxygen saturation (SvO 2 ) (51 ± 8.8 vs. 64.8 ± 5.3%, P < 0.04), stroke volume (37.2 ± 7.6 vs. 49.2 ± 12.9 mL, P < 0.04), and right and left ventricular stroke work index (Table 1). No significant changes were observed with mean arterial pressure (73.4 ± 7.5 vs. 75.8 ± 5.0 mmHg, P = 0.81) and thermodilution-derived cardiac index (1.7 ± 0.2 vs. 2.5 ± 0.7 L/min/m 2 , P = 0.58). Inotropic support was weaned successfully in three of five patients (88 ± 30 h) with subsequent titration of beta-blocker therapy. Two patients improved clinically but ultimately required left ventricular assist device implantation. All patients were discharged alive from hospital at 17 ± 7.9 days following ivabradine initiation., Conclusions: In our small non-randomized series of patients in cardiogenic shock, ivabradine was safely used to reduce HR in patients previously intolerant of beta-blockade. There are limited data surrounding the use of ivabradine in cardiogenic shock, and future studies should be undertaken to determine the optimal HR in humans with cardiogenic shock and whether systematic limitation of peak HR may improve outcomes., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)