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Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions., Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach., Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023., Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death., Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk., Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Aims: Red cell distribution width (RDW) is a strong prognostic marker in patients with heart failure (HF) and reduced ejection fraction and other conditions. However, very little is known about its prognostic significance in HF with preserved ejection fraction. We examined the relationship between RDW and outcomes and the effect of sacubitril/valsartan, compared with valsartan, on RDW and clinical outcomes in PARAGON-HF., Methods and Results: PARAGON-HF enrolled patients with a left ventricular ejection fraction of ≥45%, structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary endpoint was a composite of total HF hospitalizations and cardiovascular deaths. Median RDW at randomization was 14.1% (interquartile range 13.5-15.0%). Patients with higher RDW levels were more often men and had more comorbidity, a higher heart rate and NT-proBNP concentration, more advanced New York Heart Association class, and worse Kansas City Cardiomyopathy Questionnaire scores. There was a graded relationship between quartiles of RDW at randomization and the primary endpoint, with a significantly higher risk associated with increasing RDW, even after adjustment for NT-proBNP and other prognostic variables {Quartile 1, reference; Quartile 2, rate ratio 1.03 [95% confidence interval (CI) 0.83 to 1.28]; Quartile 3, 1.25 [1.01 to 1.54]; Quartile 4, 1.70 [1.39 to 2.08]}. This association was seen for each of the secondary outcomes, including cardiovascular and all-cause death. Compared with valsartan, sacubitril/valsartan reduced RDW at 48 weeks [mean change -0.09 (95% CI -0.15 to -0.02)]. The effect of sacubitril/valsartan vs. valsartan was not significantly modified by RDW levels at randomization., Conclusions: RDW, a routinely available and inexpensive biomarker, provides incremental prognostic information when added to established predictors. Compared with valsartan, sacubitril/valsartan led to a small reduction in RDW., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Neuropeptide Y (NPY) is the most abundant neuropeptide found in the heart and is released alongside norepinephrine following prolonged sympathetic activation, a process that is implicated in the pathophysiology of heart failure (HF). In patients with severely impaired left ventricular ejection fraction (LVEF) undergoing cardiac resynchronization therapy, higher levels of NPY measured in coronary sinus blood, are associated with poorer outcome. The aim was to examine the association of peripheral venous NPY levels and outcomes in a HF population with a range of LVEF, using a highly sensitive and specific assay., Methods and Results: The association between NPY and the composite outcome of cardiovascular death or HF hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 833 patients using a threshold of elevated NPY identified through binary recursive partitioning adjusted for prognostic variables including estimated glomerular filtration rate (eGFR), ejection fraction and B-type natriuretic peptide (BNP). The mean value of NPY was 25.8 ± 18.2 pg/ml. Patients with high NPY levels (≥29 pg/ml) compared with low values were older (73 ± 10 vs. 71 ± 11 years), more often male (58.5% vs. 55.6%), had higher BNP levels (583 [261-1096] vs. 440 [227-829] pg/ml), lower eGFR (46.4 ± 13.9 vs. 52.4 ± 11.7 ml/min/1.73 m 2 ), and were more often treated with diuretics. There was no associated risk of HF hospitalization with NPY levels ≥29 vs. <29 pg/ml. Higher NPY levels were associated with a greater risk of cardiovascular and all-cause death (adjusted hazard ratio 1.56 [95% confidence interval 1.21-2.10], p = 0.003 and 1.30 [1.04-1.62], p = 0.02, respectively). There was no associated risk of HF hospitalization with higher NPY levels., Conclusions: Peripherally measured NPY is an independent predictor of all-cause and cardiovascular death even after adjustment for other prognostic variables, including BNP., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: It is uncertain how much candidate biomarkers improve risk prediction when added to comprehensive models including routinely collected clinical and laboratory variables in heart failure., Methods and Results: Aldosterone, cystatin C, high-sensitivity troponin T (hs-TnT), galectin-3, growth differentiation factor-15 (GDF-15), kidney injury molecule-1, matrix metalloproteinase-2 and -9, soluble suppression of tumourigenicity-2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and urinary albumin to creatinine ratio were measured in 1559 of PARADIGM-HF participants. We tested whether these biomarkers, individually or collectively, improved the performance of the PREDICT-HF prognostic model, which includes clinical, routine laboratory, and natriuretic peptide data, for the primary endpoint and cardiovascular and all-cause mortality. The mean age of participants was 67.3 ± 9.9 years, 1254 (80.4%) were men and 1103 (71%) were in New York Heart Association class II. During a mean follow-up of 30.7 months, 300 patients experienced the primary outcome and 197 died. Added individually, only four biomarkers were independently associated with all outcomes: hs-TnT, GDF-15, cystatin C and TIMP-1. When all biomarkers were added simultaneously to the PREDICT-HF models, only hs-TnT remained an independent predictor of all three endpoints. GDF-15 also remained predictive of the primary endpoint; TIMP-1 was the only other predictor of both cardiovascular and all-cause mortality. Individually or in combination, these biomarkers did not lead to significant improvements in discrimination or reclassification., Conclusions: None of the biomarkers studied individually or collectively led to a meaningful improvement in the prediction of outcomes over what is provided by clinical, routine laboratory, and natriuretic peptide variables., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Elevated circulating carbohydrate antigen 125 (CA125) is a marker of congestion and a predictor of outcomes in acute heart failure (HF). Less is known about CA125 in chronic ambulatory HF with reduced ejection fraction., Objectives: This study examined the association between baseline CA125 (and changes in CA125) and outcomes in patients with HF with reduced ejection fraction in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; NCT03036124) trial and its relationship with the effect of dapagliflozin., Methods: The primary outcome was a composite of a first episode of worsening HF or cardiovascular death. CA125 was measured at baseline and 12 months following randomization., Results: Median baseline CA125 was 13.04 U/mL (IQR: 8.78-21.13 U/mL) in 3,123 of 4,774 patients with available data. Compared with CA125 ≤35 U/mL (upper limit of normal), patients with CA125 >35 U/mL were at a higher risk of the primary outcome (adjusted HR: 1.59; 95% CI: 1.29-1.96). The adjusted risks of the primary outcome relative to quartile 1 (Q1) (≤8.78 U/mL) were as follow: Q2, 8.79-13.04 U/mL (HR: 0.94; 95% CI: 0.71-1.24); Q3, 13.05-21.13 U/mL (HR: 1.22; 95% CI: 0.94-1.59); Q4, ≥21.14 U/mL (HR: 1.63; 95% CI: 1.28-2.09). The beneficial effect of dapagliflozin compared with placebo on the primary outcome was consistent whether CA125 was analyzed in quartiles (interaction P = 0.13) or as a continuous variable (interaction P = 0.75). The placebo-corrected relative change in CA125 at 12 months was -5.2% (95% CI: -10.6% to 0.5%; P = 0.07)., Conclusions: In DAPA-HF, elevated CA125 levels were an independent predictor of the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of worsening HF or cardiovascular death regardless of baseline CA125., Competing Interests: Funding Support and Author Disclosures The DAPA-HF trial was funded by AstraZeneca. Roche Diagnostics supported this study through provision of CA125 tests, free of charge. Dr Docherty’s employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on the DAPA-HF and DELIVER trials; has received speaker fees from AstraZeneca and Radcliffe Cardiology; has served on Advisory Boards for Us2.ai and Bayer AG; has served on a Clinical Endpoint Committee for Bayer AG; and has received grant support from AstraZeneca, Roche, and Boehringer Ingelheim, outside the submitted work. Dr Welsh has received grant income from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and has received speaker fees from Novo Nordisk, outside the submitted work. Dr Annad has served as a consultant for Novartis, Amgen, Cyberonics, and Zensun. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Køber has received speaker fees from Novo Nordisk, Novartis, Bayer, Boehringer Ingelheim, and AstraZeneca. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on Advisory Boards for Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Martinez has received consultation fees and research grants from AstraZeneca, Baliarda, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Gador, Milestone, Novartis, Pfizer, and St Lukes University. Dr O’Meara has received research funds (paid to her institution) for clinical trials from American Regent, Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Pfizer; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, and Janssen; and has received speaker fees from AstraZeneca, Bayer, and Boehringer Ingelheim. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Dr Schou has received lecture fees from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim. Dr Berg has received support from Harvard Catalyst KL2/CMeRIT (National Institutes of Health/National Center for Advancing Translational Sciences grant UL 1TR002541); has received research grant support to his institution from AstraZeneca and Pfizer; has received consulting fees from AstraZeneca; and has served on a Clinical Endpoint Committee for a study sponsored by Kowa Pharmaceuticals. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; has been a consultant for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, ARCA Biopharma Inc, Janssen Research and Development LLC, Siemens Healthcare Diagnostics Inc, Softcell Medical Limited, Regeneron, Roche, and Zora Biosciences. Dr Morrow has received grants paid to the Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, AstraZeneca, Eisai, The Medicines Company, Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; has received consultant fees from InCardia, Inflammatix, Merck and Co, Novartis, and Roche Diagnostics; and is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Dr Jarolim has received research support from Abbott Laboratories, Amgen Inc, AstraZeneca LP, Daiichi-Sankyo Inc, GlaxoSmithKline, Merck and Co Inc, Regeneron, Roche Diagnostics Corporation, and Siemens Healthineers. Drs Hammarstedt, Sjöstrand, and Langkilde are employees of AstraZeneca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. Dr Sattar has received support from a British Heart Foundation Centre of Research Excellence grant RE/18/6/34217; has received consulting or speaker fees from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp and Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and has received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics, outside the submitted work. Dr Jhund has received support from a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; his employer has been remunerated for his work on the DELIVER and DAPA-HF trials by AstraZeneca; has received consulting and speaker fees from Novartis, AstraZeneca, and Boehringer Ingelheim; has received research funding from Boehringer Ingelheim; and has received remuneration for clinical trial work from Novo Nordisk and Bayer. Dr McMurray has received support from a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consulting fees from Alnylam Pharma, Bayer, Bristol Myers Squibb, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors have revolutionized treatment for patients with BRAF-mutated melanoma. Although left ventricular systolic dysfunction associated with these therapies has been reported in clinical trials, the real-world incidence is poorly defined, as are risk factors for its development., Objectives: This study sought to characterize the incidence, time course, and risk factors for cancer therapy-related cardiac dysfunction (CTRCD) in patients with melanoma receiving BRAF and MEK inhibitors., Methods: Patients with melanoma treated with BRAF and MEK inhibitors at a cancer hospital network between June 1, 2017, and June 30, 2020, were included retrospectively. CTRCD was defined as mild, moderate, or severe according to International Cardio-Oncology Society (ICOS) definitions. Baseline cardiotoxicity risk stratification was performed using the Heart Failure Association/ICOS tool., Results: Of the 63 patients included, 27% developed CTRCD (17% mild and 10% moderate). No patients developed severe CTRCD or symptomatic heart failure. CTRCD occurred most frequently in patients considered to be at "low" and "medium" baseline risk of cardiotoxicity (82%). The baseline left ventricular ejection fraction and global longitudinal strain were not different in patients who developed moderate CTRCD vs those who did not. Left ventricular internal diameters in diastole and systole were larger in patients who developed moderate CTRCD compared with those who did not (left ventricular internal diameter in diastole: 4.9 ± 0.6 cm vs 4.3 ± 0.6 cm; P = 0.023; left ventricular internal diameter in systole: 3.3 ± 0.4 cm vs 2.8 ± 0.5 cm; P = 0.039)., Conclusions: BRAF and MEK inhibitor-associated CTRCD is common. The utility of the Heart Failure Association/ICOS risk stratification tool appears limited in this group, and better risk prediction tools are needed. The long-term consequences of CTRCD, particularly mild CTRCD, warrant evaluation in larger prospective studies., Competing Interests: Drs Glen and Lang are supported by an unrestricted grant from Roche Diagnostics. Drs Petrie and Lang are supported by a British Heart Foundation Centre of Research Excellence grant (RE/18/6/34217). Dr Petrie has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, Pharmacosmos, and 3R LifeSciences; and is a consultant and on clinical trials committees for Boehringer Ingelheim, Novartis, Roche, Corvia, AstraZeneca, Novo Nordisk, Medtronic, Abbvie, Bayer, Takeda, Cardiorentis, Pharmacosmos, and Siemens. Dr Lang has received speaker fees from Roche, Pfizer, and Novartis., (© 2023 The Authors.)

Aims: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium-glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial., Methods and Results: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dl) versus tertile 1 (<5.4 mg/dl) were younger (66.3 ± 10.8 vs. 68 ± 10.2 years), more often male (83.1% vs. 71.5%), had lower estimated glomerular filtration rate (58.2 ± 17.4 vs. 70.6 ± 18.7 ml/min/1.73 m 2 ), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06-1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI -0.93 to -0.74) over 12 months (p < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration., Conclusion: Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose of Review: The aim of the review was to identify and describe recent advances (over the last 3 years) in cardiac magnetic resonance (CMR) imaging in patients with chronic kidney disease (CKD). We conducted a literature review in line with current guidelines., Recent Findings: The authors identified 22 studies. Patients with CKD had left ventricular global and regional dysfunction and adverse remodeling. Stress testing with CMR revealed a reduced stress-response in CKD patients. Native T1 relaxation times (as a surrogate markers of fibrosis) are elevated in CKD patients, proportional to disease duration. Patients with CKD have reduced strain magnitudes and reduced aortic distensibility., Summary: CMR has diagnostic utility to identify and characterize cardiac involvement in this patient group. A number of papers have described novel findings over the last 3 years, suggesting that CMR has potential to become more widely used in studies in this patient group., Competing Interests: Compliance with Ethical StandardsThe University of Glasgow has a research agreement with Siemens Healthcare UK. No author has any conflict of interest to declare. Patrick Mark reports personal fees from Astrazeneca, personal fees from Vifor, personal fees from Eli Lilly, grants from Boehringer Ingelheim, personal fees from Astellas, other from Pharmacosmos, personal fees from Novartis, outside the submitted work. All other authors declare that they have no conflict of interest.All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Competing Interests: Competing interests: None declared.