Lee, Matthew M.Y.

Lewis, Gregory D.

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\       Lee, Matthew M.Y. and Lewis, Gregory D. (2025) Peak oxygen uptake vs ventilatory efficiency - in reply. JAMA Cardiology, 10(5), 517. (doi: 10.1001/jamacardio.2025.0219)   The material cannot be used for any other purpose without further permission of the publisher and is for private use only.  There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it.    https://eprints.gla.ac.uk/357168/           Deposited on 20 June 2025      Enlighten – Research publications by members of the University of                  Glasgow http://eprints.gla.ac.uk   JAMA Cardiology 1 Peak Oxygen Uptake vs. Ventilatory Efficiency: A Challenge in Z-Score Interpretation–2 Reply 3  4 Authors:  Matthew M. Y., Lee PhD, MBChBa , Gregory D. Lewis, MDb 5 Author Affiliations:  6 aSchool of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland 7 bCardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical 8 School, Boston, MA 9  10 Word count: 366/500 11 Corresponding Author: 12 Gregory D. Lewis, MD Heart Failure Section, Massachusetts General Hospital Bigelow 800, 55 Fruit Street Boston, MA 02114 E-mail: glewis@mgb.org Phone: 617-724-9254  13 Conflict of Interest Disclosures: 14 Dr. Lewis has received research contracts and consultation fees via his institution for 15 oversight of the CPET core laboratory activities from Cytokinetics. 16   17 In Reply–We thank Du and Hou for their interest in our SEQUOIA-HCM cardiopulmonary 18 exercise testing (CPET) substudy, which introduced a novel 2-component Z-score integrating 19 peak oxygen uptake (pVO2) and ventilatory efficiency throughout exercise (minute 20 ventilation [VE]/carbon dioxide output [VCO2] slope) with equal weighting.1 Impaired pVO2 21 and ventilatory efficiency independently carry prognostic significance in HCM,2 and 22 predispose patients to exertional symptoms and exercise intolerance. 23  24 We acknowledge that equal weighting of component Z-score variables may not always reflect 25 the complexity of exercise physiology in HCM. However, the composite Z-score was 26 designed as a general approach to provide a broader measure of exercise performance than 27 either metric alone. Further, individual components were presented alongside the composite 28 measure to allow for independent interpretation. To our knowledge, there is no way to 29 accurately assign differential weights to the components of the z-score based on “clinical 30 relevance” or “patient-centered outcomes,” which is also inherently subjective, and which 31 may not be generalizable across a heterogenous cohort with HCM. 32  33 There is the possibility of developing distinct approaches to composite variables within a 34 contingent Z-score that could adapt to varying test characteristics. For example, if a post-35 treatment CPET shows diminution in peak respiratory exchange ratio achieved, greater 36 weight could be assigned to variables that do not depend on volitional effort, such as oxygen 37 uptake at the ventilatory anaerobic threshold and VE/VCO2 slope within a composite score. 38 However, while such an approach may offer potential benefits, we opted to advance a 39 uniform simple composite of pVO2 and VE/VCO2 that reflects the complementary temporal 40 aspects of these two CPET measures that were only modestly correlated in SEQUIOA-HCM.  41 Our choice of composite Z-score variables was further corroborated by improvements in each 42 component variable being significantly correlated with improvements in symptom burden and 43 haemodynamics.  44  45 We agree that the mechanisms of benefit of cardiac myosin inhibitors extend beyond left 46 ventricular outflow tract gradient reduction, encompassing improvements in diastolic 47 function, cardiac remodeling and biomarkers, and a broad range of clinically relevant efficacy 48 measures.3–5 Varying correlations between changes in CPET variables and other parameters 49 observed in studies of mavacamten and aficamten may indeed reflect pharmacodynamic 50 differences between these two cardiac myosin inhibitors, although the clinical significance of 51 these differences remains uncertain and head-to-head comparison studies have not been 52 performed. 53  54 (366 words) 55   56 References 57 1. Lee MMY, Masri A, Nassif ME, et al. Aficamten and Cardiopulmonary Exercise Test 58 Performance. JAMA Cardiol. 2024;9(11):990-1000. 59 doi:10.1001/jamacardio.2024.2781 60 2. Coats CJ, Rantell K, Bartnik A, et al. Cardiopulmonary Exercise Testing and Prognosis 61 in Hypertrophic Cardiomyopathy. Circ Heart Fail. 2015;8(6):1022-1031. 62 doi:10.1161/CIRCHEARTFAILURE.114.002248 63 3. Hegde SM, Claggett BL, Wang X, et al. Impact of Aficamten on Echocardiographic 64 Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic 65 Cardiomyopathy. J Am Coll Cardiol. 2024;84(19):1789-1802. 66 doi:10.1016/j.jacc.2024.08.002 67 4. Masri A, Cardoso RN, Abraham TP, et al. Effect of Aficamten on Cardiac Structure 68 and Function in Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 69 2024;84(19):1806-1817. doi:10.1016/j.jacc.2024.08.015 70 5. Maron MS, Masri A, Nassif ME, et al. Impact of Aficamten on Disease and Symptom 71 Burden in Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 72 2024;84(19):1821-1831. doi:10.1016/j.jacc.2024.09.003 73   74 

Peak oxygen uptake vs ventilatory efficiency - in reply

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Peak oxygen uptake vs ventilatory efficiency - in reply

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