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Aims: The relationship between body mass index (BMI) and clinical outcomes in patients with cardiovascular disease, including acute heart failure (AHF) and acute myocardial infarction (AMI), remains debated. This study investigates the association between BMI and clinical outcomes within the PARADISE-MI cohort, while also evaluating the impact of angiotensin receptor-neprilysin inhibitor (ARNI) versus angiotensin-converting enzyme inhibitor (ACE-I) treatment on this relationship., Methods and Results: The analysis included 5589 patients from the PARADISE-MI study with available baseline BMI data. The cohort comprised patients with AMI and pulmonary congestion and/or left ventricular ejection fraction ≤40%. Patients were categorized into six World Health Organization BMI subgroups. The primary outcome of interest was the composite endpoint of cardiovascular death, heart failure (HF)-associated hospitalization, and outpatient symptomatic HF episodes. The mean baseline BMI of the cohort was 28.1 ± 5.0 kg/m 2 . The lowest rate of the primary composite endpoint (6.2/100 patient-years) was observed in overweight patients (BMI 25-29.9 kg/m 2 ), while the highest rates were found in the lowest and highest BMI subgroups (8.4/100 patient-years for BMI <18.5 kg/m 2 and 9.7/100 patient-years for BMI >40 kg/m 2 ). There was no significant interaction between BMI and the treatment effect of ARNI versus ACE-I on the primary composite outcome (p = 0.73). Additionally, no significant differences in the incidence of adverse events or serious adverse events were noted across the BMI subgroups., Conclusions: In AMI with AHF patients, the relationship between BMI and the primary composite outcome is non-linear, with the lowest event rates observed in overweight individuals. Outcomes and safety profiles for ARNI and ACE-I treatments were similar across BMI subgroups., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are standard-of-care treatment in heart failure (HF). The risk of ketosis in patients with HF is unclear, especially during hospitalisation., Aim: We aimed to evaluate the normal ketone concentration range in HF patients., Method: We performed a cross-sectional study of inpatients with acutely decompensated HF and outpatients with stable HF. Ketone concentrations were measured and analysed based on SGLT2i use. Baseline demographic data (age, gender, body mass index [BMI]), time since last meal, HF type, type 2 diabetes status, insulin use, and blood parameters (creatinine, glycosylated haemoglobin A1c [HbA1c] and N-terminal pro-B-type natriuretic peptide) were collected from patients or medical records. The primary outcome was capillary blood ketone concentration in patients with acute decompensated HF and stable chronic HF stratified by SGLT2i use. Multivariate regression was also performed using ketones as the outcome variable, with age, gender, BMI, glucose levels, HbA1c, time since last meal and presence of insulin therapy as predictor variables., Results: A total of 20 individuals with decompensated HF (n=5 SGLT2i treated) and 47 with stable chronic HF (n=22 SGLT2i treated) were recruited. Median ketone concentrations were similar in all groups irrespective of SGLT2i use and the presence of acute decompensation (0.1 mmol/L, biggest interquartile range 0.2 mmol/L, p=0.49). Apart from time from last meal, multivariate regression analysis showed no association of ketone concentration with SGLT2i use, age, gender, BMI, type 2 diabetes status, insulin use and blood glucose level., Conclusions: Ketone concentrations were low in individuals with HF regardless of SGLT2i use or the presence of acute decompensation., Competing Interests: Conflicts of Interest M.M.U. has previously received research grants for other research from AstraZeneca. N.S. has previously received speaker honoraria from Novartis. J.H.H. has previously received speaker honoraria from Novartis and Bayer. C.M.B. has previously received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Novartis and Pfizer. C.G.D.P. has previously received research funding for other research from AstraZeneca and Novartis, as well as consulting fees and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Novartis, Vifor and Roche. J.Y.T., L.A.E., J.M.I., H.T.N., and T.R.J.T. do not have any known disclosures or conflicts of interest., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Aims: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM., Methods and Results: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported., Conclusions: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome., Methods: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome., Results: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes., Conclusions: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931., Competing Interests: Disclosures Dr Harrington receives salary support from T32 training grant T32HL069749. Dr Mentz received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr Rockhold receives research support from the National Institutes of Health (NIH), PCORI, Bristol Myers Squibb, AstraZeneca, American Regent, Gates Foundation, and Eidos; consulting for Janssen, Clover, Doctor Evidence, and Intercept; data safety monitoring board for Lilly, AstraZeneca, Merck, Gilead, Novartis, Icosavax, Sanofi, UCB, Amgen, Biogen, Bristol Myers Squibb, Pulmocide, Alkermes, and Diurnal; nonprofit chairman of the board (unpaid) for the Frontier Science Foundation; and stock/stock options from GlaxoSmithKline, Clover, Athira, Doctor Evidence, Datavant, Spencer Health Solutions, and Adaptic Health. Dr Wong received research support and honoraria from American Regent, AstraZeneca, Novartis, Pfizer, and Vifor. Dr Troughton received research support and honoraria from American Regent, Bayer, Merck, and Roche Diagnostics. Dr De Pasquale received consultant fees or honoraria from American Regent, AstraZeneca, Bayer, Biotronic, Boehringer Ingelheim, Lilly, Novartis, Otsuka, Roche Servier, St Jude, and Vifor and research support from AstraZeneca and Novartis. Dr O’Meara received research support from the Canadian Heart Function Alliance, the TIMI Group, American Regent, Cardurion, and AstraZeneca for work as a steering committee member; Cardurion (paid to her institution); and consulting and speaking fees from AstraZeneca, Boehringer Ingelheim, Bayer, Eli Lilly, and Janssen. J.A. Ezekowitz reports research grants or consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Lewis reports research funding from the NIH, the American Heart Association, Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, SoniVie, and NXT. Dr Lewis received honoraria as an advisory board member for American Regent and as an advisory board member for Pfizer, Merck, Boehringer Ingelheim, NXT, American Regent, Cyclerion, Cytokinetics, and Amgen outside of the subject content of the current study. Dr Lewis receives royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Hernandez reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Novartis, and Verily and consulting from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squib, Myokardia, and Novo Nordisk. Dr Butler reports serving as a consultant to Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin Cures, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Occlutech, Relypsa, Roche, Sanofi, SC Pharma, V-Wave Ltd, and Vifor. R. Adamczyk and Drs Storie and Blackman are employees of American Regent. The other authors report no conflicts.

Background: Prior clinical trials have investigated intravenous iron in patients with heart failure (HF) and iron deficiency, but the safety and efficacy of this therapy remains unclear., Methods: We report the baseline demographics and clinical characteristics of patients enrolled in the HEART-FID study and compare HEART-FID participants with patients within other contemporary clinical trials of patients with HF with reduced ejection fraction (HFrEF), including other intravenous iron trials., Results: In the 3,065 participants randomized in HEART-FID, median (IQR) age was 69.7 (62.0-76.5) years, 1,037 (33.8%) were female, 322 (10.5%) were Black, median ejection fraction was 32% (25%-37%), 1,837 (60.0%) had ischemic etiology, and baseline median NT-proBNP was 1,462 (721-2,966) pg/mL. Median baseline hemoglobin was 12.6 (11.6-13.6) g/dL, and median 6-minute walk test distance was 272 (196-350) m, similar to prior intravenous iron HFrEF trials. Common comorbidities included atrial fibrillation/flutter (43.7%), and type 2 diabetes (45.2%). Compared with several recent HFrEF trials, patients enrolled in HEART-FID had similar baseline demographics and clinical characteristics, though a greater proportion of women and Black participants were recruited in HEART-FID. In HEART-FID, HFrEF therapy included a beta-blocker in 92.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (ARNI) in 86.1% (with 29.7% ARNI), and a mineralocorticoid antagonist (MRA) in 55.6%., Conclusions: Patients enrolled in HEART-FID were similar to those enrolled in other contemporary HFrEF trials and registries, including trials of intravenous iron in HFrEF. However, the HEART-FID cohort is substantially larger and more racially diverse than prior trials of intravenous iron in HFrEF., Trial Registration: ClinicalTrials.gov (NCT03037931)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Recent clinical trials have demonstrated that sodium-glucose cotransporter 2 inhibitors (SGLT2i), which were previously only indicated in treatment of type 2 diabetes mellitus (T2DM), can markedly reduce heart failure hospitalisation (HFH), with less striking potential reductions in acute coronary syndromes and cardiac arrhythmias. To evaluate the impact of SGLT2i on cardiovascular outcomes in real-world practice, we performed a retrospective cohort analysis on South Australian (SA) data., Methods: A total of 842 individuals with T2DM receiving SGLT2i were identified from SA public hospitals between 2011 and 2019. Episodes of care were temporally matched with those of 3,128 individuals with T2DM not receiving SGLT2i (control). Baseline characteristics were adjusted using inverse probability treatment weighting. The incidence of cardiovascular events at 12 and 24 months was evaluated using coded (International Classification of Diseases, Tenth Revision, Australian Modification [ICD-10-AM]) data., Results: The primary outcome of HFH was lower with SGLT2i use at 12 months (adjusted hazard ratio [HR adj ] 0.44; 95% confidence interval [CI] 0.29-0.68; p<0.001) and 24 months. There were also lower hospitalisations due to acute myocardial infarction (HR adj 0.42; 95% CI 0.21-0.85; p=0.015) and atrial or ventricular arrhythmias (HR adj 0.29; 95% CI 0.14-0.59; p=0.001), with no difference observed in hospitalisation due to ischaemic cerebrovascular events. There was no difference in all-cause mortality at 12 months but interestingly a higher rate at 24 months (HR adj 2.08; 95% CI 1.59-2.72; p<0.001). Despite this, similar reductions in cardiovascular outcomes were observed at 24 months., Conclusion: Use of SGLT2i in patients with T2DM in SA was associated with reductions in cardiovascular events even before their recent Pharmaceutical Benefits Scheme (PBS) listing for heart failure. Furthermore, this analysis supports that SGLT2i play a role not only in HFH reduction but also in reducing coronary and tachyarrhythmic events. This real-world evidence supports the use of SGLT2i as broadly protective cardiovascular drugs., Competing Interests: Conflicts of Interest D.P.C. received institutional research funding from AstraZeneca. K.L. is involved in institutional research grants funded by AstraZeneca. E.S.G. was previously involved in institutional research grants funded by Bayer. C.G.D.P. reports research funding from AstraZeneca and Novartis, and consulting fees or speaker honoraria for AstraZeneca, Novartis, CSL Vifor, Boehringer Ingelheim, Bayer, Eli Lilly, and Roche Diagnostics. The remaining authors have no funding sources to report., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed., Methods: In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every 6 months as needed on the basis of iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at 0.01., Results: We enrolled 3065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon-Mann-Whitney P = 0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group)., Conclusions: Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. (Funded by American Regent, a Daiichi Sankyo Group company; HEART-FID ClinicalTrials.gov number, NCT03037931.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Dyspnea, the cardinal manifestation of chronic heart failure (CHF), may reflect both pulmonary oedema and pulmonary remodeling resulting in tissue stiffening. Emerging evidence suggests that predominance of distinct phenotypes of alveolar and recruited macrophages, designated M1 and M2, may regulate the course of inflammatory tissue repair and remodeling in the lung., Methods: In a CHF rat model, we found fibrotic reinforcement of the extracellular matrix with an increase in monocyte chemotactic protein (MCP)-1/CCL2 in bronchoalveolar lavage (BAL), corresponding to a 3-fold increase in recruited macrophages. In this clinical cross sectional study, we aimed to examine potential mediators of leukocyte activation and lung infiltration in parallel BAL and blood from CHF patients compared to non-CHF controls., Results: Mini-BAL and peripheral blood samples were obtained from hospitalized CHF, acute decompensated CHF and non-CHF patients. CHF patients and decompensated CHF patients demonstrated increases from non-CHF patients in BAL MCP-1, as well as the M2 macrophage cytokines interleukin-10 and transforming growth factor-β. BAL and plasma MCP-1 were significantly correlated; however, MCP-1 was 20-fold higher in epithelial lining fluid in BAL, indicative of an alveolar chemotactic gradient. An increase in transglutaminase 2 positive M2 macrophages in parallel with a decrease in the MCP-1 receptor, CC chemokine receptor 2 (CCR2), was apparent in BAL cells of CHF patients compared to non-CHF., Conclusion: These data suggest a pathway of MCP-1 mediated M2 macrophage prevalence in the lungs of CHF patients which may contribute to pulmonary fibrotic remodeling and consequent increased severity of dyspnea., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carmine De Pasquale reports financial support was provided by Pfizer Australia Pty Ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI., Methods: We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization., Results: Patients were randomly assigned at a median of 4.4 [3.0-5.8] days after index AMI (ST-segment-elevation myocardial infarction 76%, non-ST-segment-elevation myocardial infarction 24%), by which time 89% of patients had undergone coronary reperfusion. Compared with ramipril, sacubitril/valsartan decreased the risk of coronary outcomes (hazard ratio, 0.86 [95% CI, 0.74-0.99], P =0.04) over a median follow-up of 22 months. Rates of the components of the composite outcomes were lower in patients on sacubitril/valsartan but were not individually significantly different., Conclusions: In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02924727.

Objective: Frailty is common in the aortic stenosis (AS) population and impacts outcomes after both transcatheter and surgical aortic valve replacement (TAVR and sAVR, respectively). Frailty can significantly impact the decision regarding the suitability of a patient for aortic valve intervention, with frail patients often excluded. Since many frailty tools use indicators which may be influenced by AS itself, some of which are subjectively symptom driven, we sought to determine the impact of intervention on frailty scores., Methods: A prospective, observational cohort study included patients being assessed for aortic valve (AV) intervention with either TAVR or sAVR due to severe aortic stenosis. Patients were assessed for symptoms at baseline, and 1- and 6-months post intervention subjectively, using the New York Heart Association (NYHA) class and the Kansas City Cardiomyopathy Questionnaire (KCCQ), and objectively, using a 6-minute walk test (6MWT). These were compared with frailty at baseline and final review using the Fried Frailty Scale (FFS)., Results and Conclusions: Sixty-six (66) patients completed pre- and post-intervention reviews. The mean FFS score was significantly lower, indicating less frailty, at 6 months relative to pre procedure (1.18 vs 1.73, p=0.002). This correlated with the change in symptoms (p<0.001). Between intervention groups, the final mean FFS of both groups decreased significantly, with TAVR to 1.33 (p=0.030) and sAVR to 0.8 (p=0.015). There was no difference in the degree of improvement between interventions (p=0.517). Aortic valve intervention improves frailty scores in both TAVR and sAVR treated patients., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Introduction: Experienced echocardiographers can quickly glean diagnostic information from limited echocardiographic views. The use of limited cardiac ultrasound, particularly as a screening tool, is increasing. During the COVID-19 pandemic, limited cardiac ultrasound has the major advantage of reducing exposure time between sonographer and patient. The sensitivity and negative predictive value of a "screening" echocardiogram with highly limited views is uncertain., Aim/method: We examined the accuracy of limited echocardiography in 203 consecutive, de novo studies. We used six images: parasternal long axis, with colour Doppler over the mitral valve, and aortic valve, and apical four-chamber with colour Doppler over the mitral valve, and tricuspid valve. We compared the interpretation of 12 subjects with the final echocardiogram report, (gold standard). The subjects comprised four experienced echocardiography-specialised cardiologists, four experienced cardiologists with non-imaging subspecialty interests, and four senior cardiac sonographers. Studies were graded as: (1) normal or (2) needs full study (due to inadequate images or abnormality detected). Sensitivity, specificity, negative predictive value, positive predictive value and accuracy are reported., Results: Forty-one per cent (41%) of studies were normal by the gold standard report. Overall, a screening echocardiogram had a sensitivity of 71.2%, specificity of 57.1% to detect an abnormal echocardiogram, negative predictive value 58.4%, positive predictive value of 70.2%, and accuracy of 65.4%. When inadequate images were excluded, overall accuracy was nearly identical at 64.6%. The overall accuracy between the three groups of interpreters was similar: 66.5% (95% CI 63.1-69.7) for echocardiography-specialised cardiologists, 65.3% (95% CI 61.9-68.5) for non-echocardiography specialised cardiologists, and 64.4% (95% CI 61.0-67.7) for sonographers. These groups are all highly experienced practitioners. There was no difference in sensitivity or specificity comparing echocardiography-specialised cardiologists with cardiologists of other subspecialty experience. Comparing cardiologists to sonographers, cardiologists had lower sensitivity (echocardiography specialists 67.6%, 95% CI 63.2-71.8, non-echocardiography specialists 62.0%, 95% CI 57.4-66.4) compared to sonographers (84.0% [95% CI 80.4-87.2, p<0.05]), but cardiologists had higher specificities (64.9% [95% CI 59.5-70.0] for the echocardiography specialists, and 69.9% [95% CI 64.7-74.8] for non echocardiography specialists), compared to 36.6% (95% CI 31.4-42.0, p<0.05) for the sonographer group. When looking at only the studies considered to be interpretable, cardiologists had higher positive predictive value (echocardiography specialists 73.7%, 95% CI 69.0-78.1, non echocardiography specialists 74.1%, 95% CI 68.8-79.9), as compared to sonographers (64.3%, 95% CI 59.8-68.5%)., Conclusions: Limited cardiac ultrasound as a screening tool for a normal heart had a sensitivity of only 71%, when performed and interpreted by experienced personnel, raising questions regarding the safety of this practice. Caution is especially recommended in extrapolating its use to non-specialised settings., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Background: Sodium glucose cotransporter-2 (SGLT2) inhibitors have significant heart failure and renoprotective benefits with a wide spectrum of unfamiliar and potentially serious adverse effects. Limited understanding of the risk-benefit profile of SGLT2 inhibitor treatment may result in under utilisation by prescribers and patients., Methods: Data from recent seminal randomized, placebo-controlled, outcome trials for multiple SGLT2 inhibitors were incorporated. Trial populations were sub-classified into high cardiovascular risk T2DM, HFrEF, and CKD. Efficacy outcomes of heart failure hospitalisation (HFH), cardiovascular (CV) mortality, total mortality, and prevention of renal deterioration were examined. Safety outcomes included were major hypoglycaemia, diabetic ketoacidosis (DKA), urinary tract infections (UTI), mycotic genital infections (MGI), hypotension, amputations and fractures. Absolute risk reduction/increase were used to calculate number needed to treat/harm., Results: Trial data comprised 71,545 patients, of which 53,144 were high risk T2DM, 9696 HFrEF and 8705 CKD. For HFrEF, NNT for HFH was 18, CV mortality 93, total mortality 76, prevention of renal deterioration 143 and prevention of DKA 6224. NNH for UTI was 557, MGI 356, hypotension 120, hypoglycaemia 574, amputations 707 and fractures 858. For CKD, NNT for HFH was 116, CV mortality 245, total mortality 138, and prevention of renal deterioration was 63. NNH for DKA was 1458, UTI 309, MGI 291, hypotension 165, hypoglycaemia 374, amputations 4450 and fractures 696. In the T2DM cohort, NNT for HFH was 139, CV mortality 851, total mortality 601 and prevention of renal deterioration 558. NNH DKA was 1525, UTI 239, MGI 69, hypotension 325, hypoglycaemia 472, amputations 1578 and fractures 9569., Conclusions and Relevance: The cardiovascular and renal protective benefits of SGLT2 inhibitors far outweigh the risks. This paper puts into perspective the benefits and risks of treatment with SGLT2 inhibitors for clinicians and patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking., Methods: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first., Results: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group., Conclusions: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.)., (Copyright © 2021 Massachusetts Medical Society.)

Aims: This study aimed to explore the rapid effects of dapagliflozin in heart failure with reduced ejection fraction (HFrEF)., Methods and Results: We studied the functional, echocardiographic, electrophysiological, lung ultrasound, ambulatory blood pressure (BP), microvascular and macrovascular function, and biochemical effects of 2 week treatment with dapagliflozin in 19 type 2 diabetic HFrEF patients in a double-blind, crossover, placebo-controlled trial. Dapagliflozin had no significant effect on clinical, functional, or quality of life parameters. Dapagliflozin reduced systolic BP [114 (105, 131) vs. 106 (98, 113) mmHg, P < 0.01] and diastolic BP [71 (61, 78) vs. 62 (55, 70) mmHg, P < 0.01]. There was no effect on cardiac chamber size, ventricular systolic function, lung ultrasound, or arterial wave reflection. Dapagliflozin increased creatinine [117 (92, 129) vs. 122 (107, 135) μmol/L, P < 0.05] and haemoglobin [135 (118, 138) vs. 136 (123, 144) g/L, P < 0.05]. There was a reduction in ventricular ectopy [1.4 (0.1, 2.9) vs. 0.2 (0.1, 1.4) %, P < 0.05] and an increase in standard deviation of normal heart beat intervals [70 (58, 90) vs. 74 (62, 103), P < 0.05]. Unexpectedly, dapagliflozin increased high-sensitivity troponin T [25 (19, 37) vs. 28 (20, 42) ng/L, P < 0.01] and reduced reactive hyperaemia index [1.29 (1.21, 1.56) vs. 1.40 (1.23, 1.84), P < 0.05]., Conclusions: After 2 weeks, while multiple parameters supported BP reduction and haemoconcentration with dapagliflozin, reduction in cardiac filling pressure, lung water, and functional improvement was not shown. Reduced ventricular ectopic burden suggests an early antiarrhythmic benefit. The small increase in troponin T and the reduction in the reactive hyperaemia index warrant further mechanistic exploration in this treatment of proven mortality benefit in HFrEF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited., Methods: The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance., Conclusions: The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Background: In pulmonary arterial hypertension (PAH), progressive right ventricular (RV) dysfunction is believed to be largely secondary to RV ischaemia. A recent pilot study has demonstrated the feasibility of Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) to detect in-vivo RV myocardial oxygenation. The aims of the present study therefore, were to assess the prevalence of RV myocardial ischaemia and relationship with RV myocardial interstitial changes in PAH patients with non-obstructive coronaries, and corelate with functional and haemodynamic parameters., Methods: We prospectively recruited 42 patients with right heart catheter (RHC) proven PAH and 11 healthy age matched controls. The CMR examination involved standard functional imaging, OS-CMR imaging and native T1 mapping. An ΔOS-CMR signal intensity (SI) index (stress/rest signal intensity) was acquired at RV anterior, RV free-wall and RV inferior segments. T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at the inferior RV segment., Results: The inferior RV ΔOS-CMR SI index was significantly lower in PAH patients compared with healthy controls (9.5 (- 7.4-42.8) vs 12.5 (9-24.6)%, p = 0.02). The inferior RV ΔOS-CMR SI had a significant correlation to RV inferior wall thickness (r = - 0.7, p < 0.001) and RHC mean pulmonary artery pressure (mPAP) (r = - 0.4, p = 0.02). Compared to healthy controls, patients with PAH had higher native T1 in the inferior RV wall: 1303 (1107-1612) vs 1232 (1159-1288)ms, p = 0.049. In addition, there was a significant difference in the inferior RV T1 values between the idiopathic PAH and systemic sclerosis associated PAH patients: 1242 (1107-1612) vs 1386 (1219-1552)ms, p = 0.007., Conclusion: Blunted OS-CMR SI suggests the presence of in-vivo microvascular RV dysfunction in PAH patients. The native T1 in the inferior RV segments is significantly increased in the PAH patients, particularly among the systemic sclerosis associated PAH group.

Background: Hydrostatic lung injury followed by pulmonary remodelling variably complicates cardiogenic acute pulmonary oedema (APO). Pulmonary remodelling may be regulated by the balance between distinct phenotypes of pulmonary macrophages; activated/inflammatory (M1), and reparative/anti-inflammatory (M2), derived from circulating monocyte populations. The aim of this study was to identify biomarkers in peripheral blood that are consistent with hydrostatic lung injury and pulmonary remodelling in APO and which follow the variable clinical course., Methods: To examine peripheral markers of lung inflammation, resolution and remodelling, 18 patients, admitted to the intensive care unit (ICU) with a clinical diagnosis of APO, were enrolled. Admission, 12- and 24-hour post-admission bloods were assayed for cytokines by ELISA (R&D Systems, Minneapolis, MN, USA) and leukocyte surface markers by flow cytometry., Results: Admission PaO 2 to FiO 2 ratio was positively correlated with Mon 2 (intermediate) monocyte prevalence, through increasing ratio of CD16 + monocytes to CD11b + and CD40 + monocytes, and negatively correlated with Mon 1 (classical) monocyte prevalence, through decreasing ratio of CD16 + monocytes to CD62L + . Secondary cohort analysis compared 10 APO patients with established chronic heart failure (CHF) to eight without CHF. An increase in monocyte chemotactic peptide (MCP)-1, monocyte prevalence, and CD16 - CD62L + monocytes with CHF, all characteristic of monocyte activation to a Mon 1 phenotype, were found in the CHF APO patients., Conclusions: Increased systemic monocyte prevalence and expression of cell surface markers suggest a Mon 1 profile in CHF patients during episodes of APO. Future studies should define the role of systemic monocyte prevalence and activation in decompensated CHF., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Background: Aortic stenosis (AS) is a common valvular disorder with a large symptomatic burden resulting from increased myocardial workload due to valvular obstruction. The contribution of increased afterload from arterial stiffness on symptoms is uncertain. The purpose of this analysis was to determine the symptomatic impact of arterial stiffness as determined by Applanation Tonometry., Methods: Eighty-eight patients with severe AS undergoing intervention with transcatheter aortic valve replacement (TAVR) (n = 65) or surgical aortic valve replacement (SAVR) (n = 23) were prospectively enrolled. Symptoms were recorded using the NYHA Class, Kansas City Cardiomyopathy Questionnaire (KCCQ) and a 6 min walk test (6MWT) at baseline, and 1- and 6-months post intervention. Pulse Wave Analysis (PWA) using Applanation Tonometry was performed at all reviews, including the augmentation index (AIx)., Results: Patients undergoing TAVR were older, with worse renal function and lower aortic valve areas, but were otherwise similar. There was no significant difference between the augmentation index of our AS population compared with an age matched reference population (p = 0.89).Symptoms significantly improved after intervention according to NYHA Class, KCCQ and 6MWT. Additionally, with adjustment, the initial augmentation index correlated with the final KCCQ (Coeff. = -0.383, p = 0.02) and NYHA Class (Coeff. = 0.012, p = 0.03) and a baseline AIx value in the top quartile resulted in a significantly worse final KCCQ (95.1 v 85.2, p = 0.048) relative to the bottom 3 quartiles., Conclusions: According to our analysis, an elevated baseline AIx is associated with a poorer symptomatic recovery after aortic valve intervention and so is worthy of consideration when assessing potential symptomatic benefit., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Background: Prognosis in pulmonary arterial hypertension (PAH) is largely dependent on right ventricular (RV) function. However, recent studies have suggested the presence of left ventricular (LV) dysfunction in PAH patients. The potential role of LV ischemia, as a contributor to progressive LV dysfunction, has not been systematically studied in PAH. We aim to assess the presence and extent of LV myocardial ischemia in patients with known PH and without obstructive coronary artery disease (CAD), using oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) and stress/rest CMR T1 mapping., Methods: We prospectively recruited 28 patients with right heart catheter-proven PH and no significant CAD, 8 patients with known CAD and 11 normal age-matched controls (NC). OS-CMR images were acquired using a T2* sequence and T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at rest and adenosine-induced stress vasodilatation; ΔOS-CMR signal intensity (SI) index (stress/rest SI) and ΔT1 reactivity (stress-rest/rest T1 mapping) were calculated., Results: Global LV ΔOS SI index was significantly lower in PH patients compared with controls (11.1%±6.7% vs. 20.5%±10.5%, P=0.016), as was ΔT1 reactivity (5.2%±4.5% vs. 8.0%±2.9%, P=0.047). The ischemic segments of CAD patients had comparable ΔOS SI (10.3%±6.4% vs. 11.1%±6.7%, P=0.773) to PH patients, but lower ΔT1 reactivity (1.1%±4.2% vs. 5.2%±4.5%, P=0.036)., Conclusions: Decreased OS-CMR SI and T1 reactivity signify the presence of impaired myocardial oxygenation and vasodilatory response in PH patients. Given their unobstructed epicardial coronary arteries, this is likely secondary to coronary microvascular dysfunction (CMD)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-698). Prof. JBS reports that he serves as a current Editorial Board Member. Dr. SP and Dr. JGW receive grants from Actelion, outside from submitted work. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: Acute decompensated heart failure (ADHF) carries a high event rate following discharge. The complex interplay between age, frailty and decongestion may lend itself to a functional test., Methods: In the doorbell test the patient simulates answering the doorbell. They are timed rising from a recumbent position, bending over twice and walking 10 metres, this time is added to the change in respiratory rate. We aimed to determine if the doorbell test was associated with post ADHF events (death or readmission). The test was performed at hospital discharge, with follow up at 30-days and 1-year., Results: In 74 patients at 30-days there was a 14% event rate. At 1-year there were 40 (54%) events (9 deaths and 31 readmissions, 28 were cardiovascular of which 14 were [heart failure] HF). Amongst those who had an event at 30-days only doorbell test scores were different (58 [36,72] vs 32 [26,53] p < 0.05). One-year (1-year) events were associated with doorbell test scores (47 [29,62] vs 30 [26,42] p < 0.05), body weight (78 kg [68,94] vs 95 [76,105] (p < 0.05), creatinine (134 mmol/L [114, 173] vs 99 [82, 133] p < 0.01) and age (76 years [61,86] vs 67 [53, 73] p < 0.01). Heart failure readmissions were associated with doorbell test scores (56 [46,68] vs 30 [26,47] p < 0.001). Death was associated with body weight (74 kg [69,81] vs 88 [72,101] p < 0.05) and age (83 years [78,86] vs 69 [55,77] p < 0.01). After age stratification, the hazard ratio for heart failure readmission associated with a high doorbell test score was 11.08 (95%C.I. 2.01-61.17 p = 0.006), while the hazard ratio for 1-year cardiovascular readmission was 4.62 (95%C.I. 1.71-12.51 p = 0.003). There was no association with 1-year mortality., Conclusion: The doorbell test represents a novel test of multiple domains of the ADHF pre-discharge state and demonstrates an association with 30-day and 1-year rehospitalisation., (Copyright © 2019. Published by Elsevier B.V.)

Background: Nutraceuticals are pharmacologically active substances extracted from vegetable or animal food and administered to produce health benefits. We recently reviewed the current evidence for nutraceuticals in patients diagnosed with heart failure as part of the writing of the Australian Guidelines for the prevention, diagnosis, and management of heart failure., Methods: A systematic search for studies that compared nutraceuticals to standard care in adult patients with heart failure was performed. Studies were included if >50 patients were enrolled, with ≥6 months follow-up. If no studies met criteria then studies <50 patients and <6 months follow-up were included. The primary outcomes included mortality/survival, hospitalization, quality of life, and/or exercise tolerance. Iron was not included in this review as its role in heart failure is already well established., Results: Forty studies met the inclusion criteria. The strongest evidence came from studies of polyunsaturated fatty acids, which modestly decreased mortality and cardiovascular hospitalizations in patients with mostly New York Heart Association class II and III heart failure across a range of left ventricular ejection fraction. Coenzyme Q10 may decrease mortality and hospitalization, but definite conclusions cannot be drawn. Studies that examined nitrate-rich beetroot juice, micronutrient supplementation, hawthorn extract, magnesium, thiamine, vitamin E, vitamin D, L-arginine, L-carnosine, and L-carnitine were too small or underpowered to properly appraise clinical outcomes., Conclusion: Only one nutraceutical, omega-3 polyunsaturated fatty acid, received a positive recommendation in the Australian heart failure guidelines. Although occasionally showing some promise, all other nutraceuticals are inadequately studied to allow any conclusion on efficacy. Clinicians should favor other treatments that have been clearly shown to decrease mortality., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Progressive right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH) which is contributed by RV ischemia leads to adverse clinical outcomes. Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) has been used to determine the in vivo myocardial oxygenation of the left ventricle (LV). The aims of the present study were therefore to determine the feasibility of RV targeted rest/stress OS-CMR imaging in PAH patients and healthy volunteers., Methods: We prospectively recruited 20 patients with right heart catheter proven PAH and 9 healthy age matched controls (NC). The CMR examination involved standard functional imaging and OS-CMR imaging. An OS-CMR signal intensity (SI) index (stress/rest SI) was acquired at RV anterior, RV free-wall and RV inferior segments. In the LV, the OS-CMR SI index was acquired globally., Results: Reliable OS SI changes were only obtained from the RV inferior segment. As RV dysfunction in PAH is a global process, hence this segment was used in both patients and NC for further comparison. RV OS-CMR SI change between rest and stress in the NC was 17%±5% (mean ± SD). Nine of 20 (45%) of the PAH patients had a mean OS SI change of less than 9% (or ≥2 SD different from the mean values in NC). Overall, RV OS SI index between the PAH patients and NC was 11%±9% vs. 17%±5% (P=0.045) in the RV inferior segment. In the LV, the global OS-CMR SI index between the PAH patients and NC was 11%±7% vs. 21%±9% (P=0.019). There was a strong correlation between RV Inf OS-CMR SI and LV OS-CMR SI (r=0.86, P<0.001)., Conclusions: In this small pilot study, pharmacological induced OS-CMR is a feasible and safe technique to identify and study myocardial oxygenation in the RV of PAH patients., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: Extreme levels of both strength and aerobic training result in increased left ventricular (LV) and right ventricular (RV) volumes and LV mass, a key component of athletes' heart. The aim of this study was to document temporal changes in the hearts of elite professional athletes (Australian Football League players) over a 2- to 6-year period., Methods: Thirty-six Australian Football League players with 3.5 ± 2.7 years of professional training at enrollment prospectively underwent echocardiography in the preseasons of 2009, 2013, and 2015. At each time point, LV dimension and contractility and RV dimension, area, and contractility were measured using two-dimensional echocardiography. LV volumes, ejection fraction, and mass were measured using three-dimensional echocardiography., Results: The mean age at baseline was 21.8 ± 2.6 years (range, 18-29 years). Most players (n = 20) had increases in fitness between studies (mean maximal oxygen uptake, 62.3 ± 3.6 vs 64.3 ± 2.1 mL/kg/min). In these players, there were increases in both LV and RV size and in LV mass. Players who were >25 years of age at their baseline scans demonstrated a trend toward increases in RV size and a decline in RV global longitudinal strain. Fitness level and playing position also affected the degree of physiological athletic cardiac remodeling., Conclusions: Australian football is a sport that involves both strength and aerobic training. This study, unique in its length and detail, demonstrates that remodeling in the athlete's heart is a continuous spectrum of change. This remodeling occurs over time in response to high levels of exercise, with proportional increase in LV mass and LV dimensions., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background Cognitive impairment is a prevalent, independent marker of readmission in heart failure (HF), but the screening is time-consuming. This study sought (1) to identify HF patients at low risk of cognitive impairment (obviating screening) and (2) to simplify a predictive model of HF outcomes by only using cognitive domains that are most predictive. Methods and Results The Montreal Cognitive Assessment was performed in 1152 Australian patients with HF who were followed for 12 months. One-third (376/1152) of the patients were enrolled into an HF disease management plan to reduce early readmission. Postdischarge outcomes in HF included 30- and 90-day readmission or death and days alive and out of hospital within 12 months of discharge. Cognitive impairment-present in 54% of patients-independently predicted HF outcomes. Normal cognition could be predicted with common clinical and sociodemographic factors with good discrimination (C statistic=0.74 [0.69-0.78]). The visuospatial/executive and orientation domains were most predictive of HF postdischarge outcomes. Using either Montreal Cognitive Assessment score or these 2 domains provided similar incremental values ( P=0.0004 and P=0.0008, respectively) in predicting HF outcomes (both C statistic=0.76) and could similarly identify a group of high-risk patients who benefited most from an HF disease management plan. Conclusions Cognitive function independently predicts HF outcomes and may also contribute to how a patient responds to intervention. The time and resources spent on cognitive assessment for risk-stratification in HF may be minimized by (1) identifying patients with low risk of cognitive impairment and (2) simplifying the screening instrument to include only the domains that are most predictive of postdischarge outcomes in HF.

Background: Presence of myocardial fibrosis in well-established non-ischaemic dilated cardiomyopathy (NIDCM) is associated with adverse clinical outcomes. However, the impact of myocardial fibrosis at first presentation in NIDCM, and its long-term association with left ventricular (LV) dysfunction, heart failure (HF) and ventricular arrhythmia (VA) remains unclear. We investigated whether the presence of myocardial fibrosis quantified by late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) at presentation, is independently associated with long-term major adverse cardiovascular events (MACE) in patients with first presentation NIDCM., Methods: Consecutive patients with a first diagnosis of NIDCM were recruited. Patients underwent LGE-CMR at baseline. Replacement myocardial fibrosis by LGE-CMR was quantified by experienced observers blinded to patient outcome. MACE was defined as a composite end-point including cardiac death, HF rehospitalisation and the occurrence of sustained VA., Results: Fifty-one patients with first presentation NIDCM were included, of which 49 (96%) had follow up and outcome data. Median follow up was 8.2 years. Both the LGE positive and LGE negative groups had similar clinical characteristics at follow up. In univariate Cox regression analysis, positive LGE was associated with MACE (HR:3.44; 95% CI:1.89 to 6.24, p-value < 0.001) and HF rehospitalisation (HR:2.89; 95% CI:1.42 to 5.85, p-value = 0.003). In multivariate Cox regression, positive LGE-CMR was independently associated with MACE (HR:3.53; 95% CI:1.51 to 8.27, p-value = 0.004) and HF rehospitalisation (HR:3.07; 95% CI:1.24 to 7.59, p-value = 0.015)., Conclusions: The presence of myocardial fibrosis in first presentation NIDCM is independently associated with an increased risk of HF rehospitalisation, at long term follow-up., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Heart failure (HF) is a clinical syndrome that is secondary to an abnormality of cardiac structure or function. These clinical practice guidelines focus on the diagnosis and management of HF with recommendations that have been graded on the strength of evidence and the likely absolute benefit versus harm. Additional considerations are presented as practice points. Main recommendations: Blood pressure and lipid lowering decrease the risk of developing HF. Sodium-glucose cotransporter 2 inhibitors decrease the risk of HF hospitalisation in patients with type 2 diabetes and cardiovascular disease. An echocardiogram is recommended if HF is suspected or newly diagnosed. If an echocardiogram cannot be arranged in a timely fashion, measurement of plasma B-type natriuretic peptides improves diagnostic accuracy. Angiotensin-converting enzyme inhibitors, β-blockers and mineralocorticoid receptor antagonists improve outcomes in patients with HF associated with a reduced left ventricular ejection fraction. Additional treatment options in selected patients with persistent HF associated with reduced left ventricular ejection fraction include switching the angiotensin-converting enzyme inhibitor to an angiotensin receptor neprilysin inhibitor; ivabradine; implantable cardioverter defibrillators; cardiac resynchronisation therapy; and atrial fibrillation ablation. Multidisciplinary HF disease management facilitates the implementation of evidence-based HF therapies. Clinicians should also consider models of care that optimise medication titration (eg, nurse-led titration). Changes in management as a result of the guideline: These guidelines have been designed to facilitate the systematic integration of recommendations into HF care. This should include ongoing audit and feedback systems integrated into work practices in order to improve the quality of care and outcomes of patients with HF.

Existing prediction algorithms for the identification of patients with heart failure (HF) at high risk of readmission or death after hospital discharge are only modestly effective. We sought to validate a recently developed predictive model of 30-day readmission or death in HF using an Australia-wide sample of patients. This study used data from 1,046 patients with HF at teaching hospitals in 5 Australian capital cities to validate a predictive model of 30-day readmission or death in HF. Besides standard clinical and administrative data, we collected data on individual sociodemographic and socioeconomic status, mental health (Patient Health Questionnaire [PHQ]-9 and Generalized Anxiety Disorder [GAD]-7 scale score), cognitive function (Montreal Cognitive Assessment [MoCA] score), and 2-dimensional echocardiograms. The original sample used to develop the predictive model and the validation sample had similar proportions of patients with an adverse event within 30 days (30% vs 29%, p = 0.35) and 90 days (52% vs 49%, p = 0.36). Applying the predicted risk score to the validation sample provided very good discriminatory power (C-statistic = 0.77) in the prediction of 30-day readmission or death. This discrimination was greater for predicting 30-day death (C-statistic = 0.85) than for predicting 30-day readmission (C-statistic = 0.73). There was a small difference in the performance of the predictive model among patients with either a left ventricular ejection fraction of <40% or a left ventricular ejection fraction of ≥40%, but an attenuation in discrimination when used to predict longer-term adverse outcomes. In conclusion, our findings confirm the generalizability of the predictive model that may be a powerful tool for targeting high-risk patients with HF for intensive management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Chronic elevation of pulmonary microvascular pressure (Pmv) consistently leads to alveolocapillary barrier thickening and reduction in the filtration coefficient. In animal models of chronic heart failure (CHF) the lung remains dry despite hydrostatic forces. As fluid flux is bi-directional, it has been postulated that an increase in alveolar fluid clearance may facilitate the dry lung when Pmv is chronically elevated. In this study we aimed to examine alveolar fluid clearance in ambulatory patients with CHF secondary to left ventricular (LV) systolic dysfunction compared against non-CHF controls. Lung clearance following aerosol delivery of 99m technetium (Tc)-diethyl triaminepentaacetic acid (DTPA) was measured non-invasively by scintigraphy and half time of 99m Tc-DTPA clearance (T (1/2)) was calculated by mono-exponential curve fit. Alveolar fluid clearance measured as half time DTPA clearance was significantly faster in CHF patients than controls (P=0.001). This was further defined by NYHA classification. No correlation was found between DTPA clearance and plasma epinephrine, norepinephrine or aldosterone hormone (P>0.05). Our results support an association between increasing alveolar fluid clearance and disease severity in CHF, and the concept of controlled bi-directional fluid flux in CHF associated with increasing Pmv, and represents another defence mechanism of the lung against pulmonary oedema., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Background: Cognitive impairment is highly prevalent in heart failure (HF), and may be associated with short-term readmission. This study investigated the role of cognition, incremental to other clinical and non-clinical factors, independent of depression and anxiety, in predicting 30-day readmission or death in HF., Methods: This study followed 565 patients from an Australia-wide HF longitudinal study. Cognitive function (MoCA score) together with standard clinical and non-clinical factors, mental health and 2D echocardiograms were collected before hospital discharge. The study outcomes were death and readmission within 30days of discharge. Logistic regression, Harrell's C-statistic, integrated discrimination improvement (IDI) and net reclassification index were used for analysis., Results: Among 565 patients, 255 (45%) had at least mild cognitive impairment (MoCA≤22). Death (n=43, 8%) and readmission (n=122, 21%) within 30days of discharge were more likely to occur among patients with mild cognitive impairment (OR=2.00, p=0.001). MoCA score was also negatively associated with 30-day readmission or death (OR=0.91, p<0.001) independent of other risk factors. Adding MoCA score to an existing prediction model of 30-day readmission significantly improved discrimination (C-statistic=0.715 vs. 0.617, IDI estimate 0.077, p<0.001). From prediction models developed from our study, adding MoCA score (C-statistic=0.83) provided incremental value to that of standard clinical and non-clinical factors (C-statistic=0.76) and echocardiogram parameters (C-statistic=0.81) in predicting 30-day readmission or death. Reclassification analysis suggests that addition of MoCA score improved classification for a net of 12% of patients with 30-day readmission or death and of 6% of patients without (p=0.002)., Conclusions: Mild cognitive impairment predicts short-term outcomes in HF, independent of clinical and non-clinical factors., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Inpatient management of cardiac patients by cardiologists results in reduced mortality and hospitalisation. With increasing subspecialisation of the field because of growing management complexity and use of technological innovations, the impact of sub-specialisation on patient outcomes is unclear., Aim: To investigate whether management by subspecialty cardiologists impacts the outcomes of patients with subspecialty-specific diseases., Methods: All patients admitted to a tertiary centre over nine years with a diagnosis of heart failure, acute coronary syndrome (ACS) or primary arrhythmia were reviewed. The outcomes of these patients managed by cardiologists subspecialised in their admission diagnosis (heart failure specialists, interventionalists and electrophysiologists) were compared with those treated by general cardiologists., Results: Heart failure was diagnosed in 1704 patients, ACS in 7763 and arrhythmia in 4398. There was no difference in length of stay (LOS) (P = 0.26), mortality (P = 0.57) or cardiovascular readmissions (P = 0.50) in heart failure patients treated by general cardiologists compared with subspecialists. In ACS patients, subspecialty management was associated with reduced LOS, cardiovascular readmissions and mortality (all P < 0.05). This reduction in mortality was seen mainly in lower risk patients (P < 0.05). There was a reduction in LOS and cardiovascular readmissions in arrhythmia patients receiving subspecialty management (both P < 0.05) but no difference in mortality (P = 0.14). ACS patients managed by interventionalists were more likely to undergo coronary intervention (P < 0.05). Electrophysiologists more frequently referred patients for catheter ablation and pacemaker implantation than general cardiologists (P < 0.05)., Conclusions: The benefits of subspecialty care seem attributable to the appropriate selection of patients who would benefit from technological innovations in care. These results suggest that the development of healthcare systems which align cardiovascular disease with the subspecialist may be more effective., (© 2016 Royal Australasian College of Physicians.)

Rapid intravenous (iv) infusion of 0.9% saline alters respiratory mechanics in healthy subjects. However, the relative cardiovascular and respiratory effects of bolus iv crystalloid vs. colloid are unknown. Six healthy male volunteers were given 30 ml/kg iv 0.9% saline, 4% albumin, and 5% glucose at a rate of 100 ml/min on 3 separate days in a double-blinded, randomized crossover study. Impulse oscillometry, spirometry, lung volumes, diffusing capacity (DLCO), and blood samples were measured before and after fluid administration. Lung ultrasound B-line score (indicating interstitial pulmonary edema) and Doppler echocardiography indices of cardiac preload were measured before, midway, immediately after, and 1 h after fluid administration. Infusion of 0.9% saline increased small airway resistance at 5 Hz (P = 0.04) and lung ultrasound B-line score (P = 0.01) without changes in Doppler echocardiography measures of preload. In contrast, 4% albumin increased DLCO, decreased lung volumes, and increased the Doppler echocardiography mitral E velocity (P = 0.001) and E-to-lateral/septal e' ratio, estimated blood volume, and N-terminal pro B-type natriuretic peptide (P = 0.01) but not lung ultrasound B-line score, consistent with increased pulmonary blood volume without interstitial pulmonary edema. There were no significant changes with 5% glucose. Plasma angiopoietin-2 concentration increased only after 0.9% saline (P = 0.001), suggesting an inflammatory mechanism associated with edema formation. In healthy subjects, 0.9% saline and 4% albumin have differential pulmonary effects not attributable to passive fluid filtration. This may reflect either different effects of these fluids on active signaling in the pulmonary circulation or a protective effect of albumin., (Copyright © 2015 the American Physiological Society.)

Background: Coronary artery disease and left ventricular hypertrophy are prevalent in the chronic kidney disease (CKD) and renal transplant (RT) population. Advances in cardiovascular magnetic resonance (CMR) with blood oxygen level-dependent (BOLD) technique provides capability to assess myocardial oxygenation as a measure of ischemia. We hypothesized that the myocardial oxygenation response to stress would be impaired in CKD and RT patients., Methods and Results: Fifty-three subjects (23 subjects with CKD, 10 RT recipients, 10 hypertensive (HT) controls, and 10 normal controls without known coronary artery disease) underwent CMR scanning. All groups had cine and BOLD CMR at 3 T. The RT and HT groups also had late gadolinium CMR to assess infarction/replacement fibrosis. The CKD group underwent 2-dimensional echocardiography strain to assess fibrosis. Myocardial oxygenation was measured at rest and under stress with adenosine (140 μg/kg per minute) using BOLD signal intensity. A total of 2898 myocardial segments (1200 segments in CKD patients, 552 segments in RT, 480 segments in HT, and 666 segments in normal controls) were compared using linear mixed modeling. Diabetes mellitus (P=0.47) and hypertension (P=0.57) were similar between CKD, RT, and HT groups. The mean BOLD signal intensity change was significantly lower in the CKD and RT groups compared to HT controls and normal controls (-0.89±10.63% in CKD versus 5.66±7.87% in RT versus 15.54±9.58% in HT controls versus 16.19±11.11% in normal controls, P<0.0001). BOLD signal intensity change was associated with estimated glomerular filtration rate (β=0.16, 95% CI=0.10 to 0.22, P<0.0001). Left ventricular mass index and left ventricular septal wall diameter were similar between the CKD predialysis, RT, and HT groups. None of the CKD patients had impaired global longitudinal strain and none of the RT group had late gadolinium hyperenhancement., Conclusions: Myocardial oxygenation response to stress is impaired in CKD patients and RT recipients without known coronary artery disease, and unlikely to be solely accounted for by the presence of diabetes mellitus, left ventricular hypertrophy, or myocardial scarring. The impaired myocardial oxygenation in CKD patients may be associated with declining renal function. Noncontrast BOLD CMR is a promising tool for detecting myocardial ischemia in the CKD population., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Myocardial ischemia is a major cause of death in chronic kidney disease (CKD) patients, which can be caused by either epicardial or microvascular coronary artery disease (CAD). Although renal transplantation improves survival, cardiovascular disease remains a major cause of mortality in post renal transplant recipients, including those with no significant epicardial CAD pre-transplant. We aim to utilize stress cardiovascular magnetic resonance (CMR) and MR coronary angiography (MRCA) to assess silent myocardial ischemia and epicardial CAD in renal transplant recipients., Methods: Forty-five subjects: twenty renal transplant (RT) with no known CAD, fifteen liver transplant (LT) controls without prior CKD and no known CAD, and ten hypertensive (HT) controls underwent stress perfusion CMR and MRCA., Results: A total of 1308 myocardial segments (576 of RT, 468 of LT, and 264 of HT) were compared using mixed linear modeling. Left ventricular mass index, septal diameter and presence of diabetes mellitus were similar between the groups. The mean transmural MPRI was significantly lower in the RT and LT groups compared to HT controls (1.19 ± 0.50 in RT versus 1.23 ± 0.36 in LT versus 2.04 ± 0.32 in HT controls, p < 0.0001), in the subepicardium (1.33 ± 0.57 in RT versus 1.30 ± 0.33 in LT versus 2.01 ± 0.30 in HT controls, p < 0.001), and in the subendocardium (1.19 ± 0.54 in RT versus 1.11 ± 0.31 in LT versus 1.85 ± 0.34 in HT controls, p < 0.0001). Seven (35%) RT and five (33%) LT had significant epicardial CAD compared to none in HT controls, p = 0.12. One RT and one LT had LGE suggesting sub-endocardial infarction., Conclusions: RT recipients have impaired myocardial perfusion independent of LVH or diabetes mellitus. The impaired myocardial perfusion in RT is similar to LT without prior renal disease, thus unlikely related to previous CKD. It is not fully explained by the presence of significant epicardial CAD, and therefore most likely represents microvascular CAD.

Background: Paravalvular aortic regurgitation (PAR) following transcatheter aortic valve implantation (TAVI) is well acknowledged. Despite improvements, echocardiographic measurement of PAR largely remains qualitative. Cardiovascular magnetic resonance (CMR) directly quantifies AR with accuracy and reproducibility. We compared CMR and transthoracic echocardiography (TTE) analysis of pre-operative and post-operative aortic regurgitation in patients undergoing both TAVI and surgical aortic valve replacement (AVR)., Methods: Eighty-seven patients with severe aortic stenosis undergoing TAVI (56 patients) or AVR were recruited. CMR (1.5 T) and transthoracic echocardiography (TTE) were carried out pre-operatively and a median of 6 days post-operatively. The CMR protocol included regurgitant aortic flows using through-plane phase-contrast velocity. None/trivial, mild, moderate and severe AR by CMR was defined as ≤8%, 9-20%, 21-39%, >40% regurgitant fractions respectively., Results: Pre- and post-operative left ventricular ejection fraction (LVEF) was similar. Post-procedure aortic regurgitant fraction using CMR was higher in the TAVI group (TAVI 16 ± 13% vs. AVR 4 ± 4%, p < 0.01). Comparing CMR to TTE, 27 of 56 (48%) TAVI patients had PAR which was at least one grade more severe on CMR than TTE (Z = -4.56, p <0.001). Sensitivity analysis confirmed the difference in PAR grade between TTE and CMR in the TAVI group (Z = -4.49, p < 0.001)., Conclusion: When compared to CMR based quantitative analysis, TTE underestimated the degree of paravalvular aortic regurgitation. This underestimation may in part explain the findings of increased mortality associated with mild or greater AR by TTE in the PARTNER trial. Paravalvular aortic regurgitation post TAVI assessed as mild by TTE may in fact be more severe.

Objectives: There remains a paucity of mechanistic data on the effect of transcatheter aortic valve implantation (TAVI) on early left and right ventricular function and quantitative aortic valve regurgitation. We sought to assess and compare the early effects on myocardial function and aortic valve hemodynamics of TAVI and aortic valve replacement (AVR) using serial cardiovascular magnetic resonance (CMR) imaging and echocardiography., Methods: A prospective comparison study of 47 patients with severe aortic stenosis undergoing either TAVI (n = 26) or high-risk AVR (n = 21). CMR (for left ventricle/right ventricle function, left ventricular mass, left atrial volume, and aortic regurgitation) was carried out before the procedure and early postprocedure (<14 days)., Results: Groups were similar with respect to Society of Thoracic Surgeons score (TAVI, 7.7 vs AVR, 5.9; P = .11). Preoperative left ventricular (TAVI, 69% ± 13% vs AVR, 73% ± 10%; P = .10) and right ventricular (TAVI, 61% ± 11% vs AVR, 59% ± 8%; P = .5) ejection fractions were similar. Postoperative left ventricular ejection fraction was preserved in both groups. In contrast, decline in right ventricular ejection fraction was more significant in the TAVI group (61%-54% vs 59%-58%; P = .01). Postprocedure aortic regurgitant fraction was significantly greater in the TAVI group (16% vs 4%; P = .001), as was left atrial size (110 vs 84 mL; P = .02). Further analysis revealed a significant relationship between the increased aortic regurgitant fraction and greater left atrial size (P = .006), and a trend toward association between the decline in right ventricle dysfunction and increased postprocedure aortic regurgitation (P = .08)., Conclusions: There was no significant difference in early left ventricular systolic function between techniques. Whereas right ventricle systolic function was preserved in the AVR group, it was significantly impaired early after TAVI, possibly reflecting a clinically important pathophysiologic consequence of paravalvular aortic regurgitation., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Chronic heart failure (CHF) following coronary artery ligation and myocardial infarction in the rat leads to a homeostatic reduction in surface tension with associated alveolar type II cell hyperplasia and increased surfactant content, which functionally compensates for pulmonary collagen deposition and increased tissue stiffness. To differentiate the effects on lung remodelling of the sudden rise in pulmonary microvascular pressure (Pmv) with myocardial infarction from its consequent chronic elevation, we examined a hypertensive model of CHF., Methods: Cardiopulmonary outcomes due to chronic pulmonary capillary hypertension were assessed at six and 15 weeks following abdominal aortic banding (AAB) in the rat., Results: At six weeks post-surgery, despite significantly elevated left ventricular end-diastolic pressure, myocardial hypertrophy and increased left ventricular internal circumference in AAB rats compared with sham operated controls (p≤0.003), lung weights and tissue composition remained unchanged, and lung compliance was normal. At 15 weeks post-surgery increased lung oedema was evident in AAB rats (p=0.002) without decreased lung compliance or evidence of tissue remodelling., Conclusion: Despite chronically elevated Pmv, comparable to that resulting from past myocardial infarction (LVEDP>19mmHg), there is no evidence of pulmonary remodelling in the AAB model of CHF., (Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Coronary artery disease is the leading cause of mortality and morbidity in the chronic kidney disease (CKD) population and often presents with atypical symptoms. Current diagnostic investigations of myocardial ischemia in CKD lack sensitivity and specificity or may have adverse effects. We present a case vignette and explore the challenges of diagnostic myocardial stress investigation in patients with CKD.

Group 3 pulmonary hypertension (PH) is a common complication of chronic lung disease (CLD), including chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered breathing. Development of PH is associated with poor prognosis and may progress to right heart failure, however, in the majority of the patients with CLD, PH is mild to moderate and only a small number of patients develop severe PH. The pathophysiology of PH in CLD is multifactorial and includes hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, small vessel destruction, and fibrosis. The effects of PH on the right ventricle (RV) range between early RV remodeling, hypertrophy, dilatation, and eventual failure with associated increased mortality. The golden standard for diagnosis of PH is right heart catheterization, however, evidence of PH can be appreciated on clinical examination, serology, radiological imaging, and Doppler echocardiography. Treatment of PH in CLD focuses on management of the underlying lung disorder and hypoxia. There is, however, limited evidence to suggest that PH-specific vasodilators such as phosphodiesterase-type 5 inhibitors, endothelin receptor antagonists, and prostanoids may have a role in the treatment of patients with CLD and moderate-to-severe PH.