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Aims This study uniquely explored the relationship between coronary microvascular function and exercise haemodynamics using concurrent invasive testing. Methods and results Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive coronary artery disease and normal left ventricular ejection fraction (>50%) underwent haemodynamic exercise assessment and concurrent coronary reactivity testing. Heart failure with preserved ejection fraction (HFpEF) was defined as a pulmonary arterial wedge pressure (PAWP) >= 15 mmHg at rest and/or >= 25 mmHg at peak exercise. Endothelium-independent coronary microvascular dysfunction (CMD) was defined as a coronary flow reserve (CFR)

Heart failure is characterized by pathologic hemodynamic derangements, including elevated cardiac filling pressures ("backward" failure), which may or may not coexist with reduced cardiac output ("forward" failure). Even when normal during unstressed conditions such as rest, hemodynamics classically become abnormal during stressors such as exercise in patients with heart failure. This has important upstream and downstream effects on multiple organ systems, particularly with respect to the lungs and kidneys. Hemodynamic abnormalities in heart failure are affected by processes that extend well beyond the cardiac myocyte, including important roles for pericardial constraint, ventricular interaction, and altered venous capacity. Hemodynamic perturbations have widespread effects across multiple heart failure phenotypes, ranging from reduced to preserved ejection fraction, acute to chronic disease, and cardiogenic shock to preserved perfusion states. In the lung, hemodynamic derangements lead to the development of abnormalities in ventilatory control and efficiency, pulmonary congestion, capillary stress failure, and eventually pulmonary vascular disease. In the kidney, hemodynamic perturbations lead to sodium and water retention and worsening renal function. Improved understanding of the mechanisms by which altered hemodynamics in heart failure affect the lungs and kidneys is needed in order to design novel strategies to improve clinical outcomes. Dr Verbrugge is supported by a Fellowship of the Belgian American Educational Foundation and by the Special Research Fund of Hasselt University (grant no. BOF19PD04). Dr Borlaug is supported by grants R01 HL128526 and U01 HL125205, both from the US National Heart, Lung, and Blood Institute. Borlaug, BA (corresponding author), Mayo Clin & Mayo Fdn, 200 First St SW, Rochester, MN 55905 USA. borlaug.barry@mayo.edu

This article refers to 'Diuretic and renal effects of spirono-lactone and heart failure hospitalizations: a TOPCAT Americas analysis' by A.P. Kalogeropoulos et al., published in this issue on pages 1600-1610. With monthly costs of approximately US$12 in the USA and €5 in Europe, spironolactone is by a landslide the most cost-effective drug in the management of heart failure (HF) with reduced ejection fraction (HFrEF). In the Randomized Aldactone Evaluation Study (RALES), the treatment of 10 patients with HFrEF in New York Heart Association functional class III or IV saved one life after 2 years, 1 a number that still looks favourable in comparison with any other HF drug. The story is more nuanced in HF with preserved ejection fraction (HFpEF), but given the high number of treatment strategies that have failed over the past 15 years, the results of spironolactone in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial remain among the best we have to offer our patients. In the TOPCAT trial, spironolactone use was associated with a non-significant 10% lower relative risk for all-cause mortality after 3.3 years, and a borderline significant 17% relative risk reduction for HF readmission was observed. 2 However, the primary endpoint of the trial, which combined both individual endpoints together with aborted cardiac arrest, was not statistically significant. Post hoc analyses of the TOPCAT trial identified significant regional differences in patient profiles, event rates and compliance with the study medication, demonstrating that the trial would have been positive if it had been limited to the subpopulation recruited in America or with objective evidence for HFpEF under the form of elevated natriuretic peptide levels. These somewhat ambiguous results make it even more important to understand how spironolactone exerts its beneficial effects in HF. Spironolactone is a prodrug that is rapidly metabolized in its major active metabolites with a long half-life (t 1/2): 7α-thiomethylspironolactone (t 1/2 = 13.8 h) and canrenone The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. F.H.V. is supported by a Fellowship of the Belgian American Educational Foundation (B.A.E.F.) and by the Special Research Fund (BOF) of Hasselt University (BOF19PD04). Conflict of interest: none declared. Verbrugge, FH (corresponding author), Hasselt Univ, Fac Med & Life Sci, Biomed Res Inst, Campus Diepenbeek,Agoralaan Gebouw D, B-3590 Diepenbeek, Belgium. frederik.verbrugge@zol.be

Novel pharmacologic treatment options reduce mortality and morbidity in a cost-effective manner in patients with heart failure (HF). Undisputedly, the effective implementation of these agents is an essential element of good clinical practice, which is endorsed by the European Society of Cardiology (ESC) guidelines on acute and chronic HF. Yet, physicians struggle to implement these therapies as they have to balance the true and/or perceived risks versus their substantial benefits in clinical practice. Any worsening of biomarkers of renal function is often perceived as being disadvantageous and is in clinical practice one of the most common reasons for ineffective drug implementation. However, even in this context, they clearly reduce mortality and morbidity in HF with reduced ejection fraction (HFrEF) patients, even in patients with poor renal function. Furthermore these agents are also beneficial in HF with mildly reduced ejection fraction (HFmrEF) and sodium-glucose cotransporter 2 (SGLT2) inhibitors more recently demonstrated a beneficial effect in HF with preserved ejection fraction (HFpEF). The emerge of several new classes (angiotensin receptor-neprilysin inhibitor [ARNI], SGLT2 inhibitors, vericiguat, omecamtiv mecarbil) and the recommendation by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF of early initiation and titration of quadruple disease-modifying therapies (ARNI/angiotensin-converting enzyme inhibitor + beta-blocker + mineralocorticoid receptor antagonist and SGLT2 inhibitor) in HFrEF increases the likelihood of treatment-induced changes in renal function. This may be (incorrectly) perceived as deleterious, resulting in inertia of starting and uptitrating these lifesaving therapies. Therefore, the objective of this consensus document is to provide advice of the effect HF drugs on renal function.

Background: Left atrial (LA) myopathy is common in patients with heart failure and preserved ejection fraction and leads to the development of atrial fibrillation (AF). We investigated whether the likelihood of LA remodeling, LA dysfunction, altered hemodynamics, and risk for incident AF could be identified from a single 12-lead ECG using a novel artificial intelligence (AI)-enabled ECG analysis. Methods: Patients with heart failure and preserved ejection fraction (n=613) underwent AI-enabled ECG analysis, echocardiography, and cardiac catheterization. Individuals were grouped by AI-enabled ECG probability of contemporaneous AF, taken as an indicator of underlying LA myopathy. Results: Structural heart disease was more severe in patients with higher AI-probability of AF, with more left ventricular hypertrophy, larger LA volumes, and lower LA reservoir and booster strain. Cardiac filling pressures and pulmonary artery pressures were higher in patients with higher AI-probability, while cardiac output reserve was more impaired during exercise. Among patients with sinus rhythm and no prior AF, each 10% increase in AI-probability was associated with a 31% greater risk of developing new-onset AF (hazard ratio, 1.31 [95% CI, 1.20–1.42]; P P Conclusions: A novel AI-enabled score derived from a single 12-lead ECG identifies the presence of underlying LA myopathy in patients with heart failure and preserved ejection fraction as evidenced by structural, functional, and hemodynamic abnormalities, as well as long-term risk for incident AF. Further research is required to determine the role of the AI-enabled ECG in the evaluation and care of patients with heart failure and preserved ejection fraction.

Background: The evolution and prognostic impact of loop diuretic efficiency according to chronic kidney disease (CKD) severity is unclear. Methods: This retrospective cohort study includes 783 CKD patients on oral loop diuretic therapy with a 24-h urine collection available. Acute kidney injury and history of renal replacement therapy were exclusion criteria. Patients were stratified according to Kidney Disease Improving Global Outcomes (KDIGO) glomerular filtration rate class. Loop diuretic efficiency was calculated as urine output, natriuresis, and chloruresis, each adjusted for loop diuretic dose, and compared among strata. Risk for onset of dialysis and all-cause mortality was evaluated. Results: Loop diuretic efficiency metrics decreased from KDIGO class IIIB to IV in furosemide users and from KDIGO class IV to V with all loop diuretics (p value ρ 0.298–0.436; p value Conclusion: Low loop diuretic efficiency is independently associated with a shorter time to dialysis initiation and a higher risk for all-cause mortality in CKD.

Aims To investigate the prognostic value of diagnostic scores for heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results Consecutive patients with HFpEF admitted for unequivocal decompensated HF treated with intravenous loop diuretics were evaluated (n = 443; mean age 78 +/- 12 years; 60% women). The HFA-PEFF and H2FPEF scores were calculated for all patients with echocardiography data available within 1 year and the population was stratified according to HFA-PEFF scores 2-4 (n = 79), 5 (n = 93), or 6 (n = 271) and H2FPEF score probabilities

The use of mechanical circulatory support for patients presenting with cardiogenic shock is rapidly increasing. Currently, there is only limited and conflicting evidence available regarding the role of the Impella (a microaxial, continuous-flow, short-term, left or right ventricular assist device) in cardiogenic shock; further randomized trials are needed. Patient selection, timing of implantation, and post-implantation management in the cardiac intensive care unit are crucial elements for success. Particular challenges at the bedside include the practical management of anticoagulation, evaluation of correct device position, and the approach to use in a patient with signs of insufficient hemodynamic support. Profound knowledge of these issues is required to enable the maximal potential of the device. This review provides a comprehensive overview of the short-term assist device and describes a practical approach to optimize care for patients supported with the device. (c) 2021 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved. Drs. Balthazar, Vandenbriele, Engstrom, Meyns, Van Mieghem, and Price have reported receiving research and/or travel funding, as well as speaker fees, from Abiomed. Dr. Balthazar was supported by a grant from the Van De Werf fund for clinical research. Dr. Vandenbriele has reported being supported by a grant from University Hospitals Leuven (Klinische onderzoeks-en opleidingsraad). Dr. Verbrugge has reported being supported by a Fellowship of the Belgian American Educational Foundation and by the Special Research Fund of Hasselt University (BOF19PD04). Dr. Adriaenssens has received speaker fees from Abiomed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Balthazar, T (corresponding author), Univ Hosp Leuven, Dept Cardiovasc Dis, Herestr 49, B-3000 Leuven, Belgium. tim.balthazar@uzleuven.be

Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy. Dr. Fudim is supported by an American Heart Association Grant, 17MCPRP33460225; he consults for Coridea, AxonTherapies, Galvani, and Daxor. Dr. Greene has received research support from a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis, Amgen, Bristol-Myers Squibb and Novartis; and serves on an advisory board for Amgen. Dr. Sharma has received research support from the Fonds de la recherche en sante du Quebec (FRSQ)-Junior 1, Jean Roy award in Cardiology (McGill University), Akcea, Pharma, Solutions, Alberta Innovates Health Solutions, Bayer-Canadian Cardiovascular Society, Boehringer-Ingelheim, Roche Diagnostics, and Takeda. Dr. Verbrugge was supported by a Fellowship of the Belgian American Educational Foundation. Dr. Martens has received consultancy fees from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Novartis, and Vifor Pharma and an unrestricted research grant from Vifor Pharma. Dr. Grodin receives research support from the Texas Health Resources Clinical Scholars fund and has received consultancy fees from Pfizer, Inc. Dr. Hernandez receives Grant/Research Support; Company Relationship; AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold Pharmaceuticals, Merck, Novartis. Honoraria; Company Relationship; Bayer, Boston Scientific, Novartis. Dr. Felker has received research funding from Otsuka, Novartis, Roche Diagnostics, Amgen, Merck, American Heart Association, and the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis, Roche Diagnostics, Amgen, Trevena, Cytokinetics, Madeliene, Myokardia, Bristol-Myers Squibb, Stealth Biotherapeutics, and GlaxoSmithKline. Dr. Mentz receives research support from the National Institutes of Health (U01HL125511-01A1, U10HL110312, and R01AG045551-01A1), Akros, Amgen, AstraZeneca, Bayer, GlaxoSmithKline, Gilead, Luitpold, Medtronic, Merck, Novartis, Otsuka, and ResMed; honoraria from Abbott, AstraZeneca, Bayer, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, and ResMed; and has served on an advisory board for Amgen, Luitpold, Merck, and Boehringer Ingelheim. The remaining authors have no disclosures to report. Fudim, M (corresponding author), 2301 Erwin Rd, Durham, NC 27713 USA. marat.fudim@gmail.com

Background Pulmonary hypertension (PH) results in increased right ventricular (RV) afterload and ventricular remodeling. Sacubitril/valsartan (sac/val) is a dual acting drug, composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, that has shown promising outcomes in reducing the risk of death and hospitalization for chronic systolic left ventricular heart failure. In this study, we aimed to examine if angiotensin receptor‐neprilysin inhibition using sac/val attenuates RV remodeling in PH. Methods and Results RV pressure overload was induced in Sprague–Dawley rats via banding the main pulmonary artery. Three different cohorts of controls, placebo‐treated PH, and sac/val‐treated PH were studied in a 21‐day treatment window. Terminal invasive hemodynamic measurements, quantitative histological analysis, biaxial mechanical testing, and constitutive modeling were employed to conduct a multiscale analysis on the effects of sac/val on RV remodeling in PH. Sac/val treatment decreased RV maximum pressures (29% improvement, P=0.002), improved RV contractile (30%, P=0.012) and relaxation (29%, P=0.043) functions, reduced RV afterload (35% improvement, P=0.016), and prevented RV‐pulmonary artery uncoupling. Furthermore, sac/val attenuated RV hypertrophy (16% improvement, P=0.006) and prevented transmural reorientation of RV collagen and myofibers (P=0.011). The combined natriuresis and vasodilation resulting from sac/val led to improved RV biomechanical properties and prevented increased myofiber stiffness in PH (61% improvement, P=0.032). Conclusions Sac/val may prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen, and myofiber reorientation as well as tissue stiffening both at the tissue and myofiber level.