Microstructural and microvascular phenotype of sarcomere mutation carriers and overt hypertrophic cardiomyopathy

Joy, G. et al. (2023) Microstructural and microvascular phenotype of sarcomere mutation carriers and overt hypertrophic cardiomyopathy. Circulation, 148(10), pp. 808-818. (doi: 10.1161/circulationaha.123.063835) (PMID:37463608) (PMCID:PMC10473031)

Abstract

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups—overt, either genotype-positive (G+LVH+) or genotype-negative (G−LVH+), and subclinical (G+LVH−) HCM—exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G−LVH+), 77 patients with G+LVH−, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G−LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle ( P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G− patients (100% [51/51] versus 82% [41/50]; P =0.001). Patients with G+LVH− compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [ P =0.015] with perfusion defects in 28% versus 0 healthy volunteers [ P =0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P =0.01; stress myocardial blood flow: odds ratio, 2.8, P =0.015; subclinical: fractional anisotropy odds ratio, 4.0, P =0.001; myocardial perfusion reserve odds ratio, 2.2, P =0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G− patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

• Item Type: Articles
• Additional Information: Dr Joy is funded by a British Heart Foundation clinical research training fellowship (FS/CRTF/21/2469) and has received funding from a Barts Charity project grant (MRC0281). Dr Das has received funding from Heart Research UK (RG2668/18/20). Dr Lorenzini has received consultancy fees from Pfizer, UK. Dr Manisty receives funding directly and indirectly from the National Institute for Health and Care Research Biomedical Research Centres at University College London Hospitals and Barts Health NHS trusts. Dr Lambiase is funded from University College London/University College London Hospitals National Institutes of Health and Care Research Biomedical Research Centre and Barts Biomedical Research Centre and by educational grants from Abbott and Boston Scientific. Dr Teh acknowledges funding from the British Heart Foundation (PG/19/1/34076). Dr Schneider acknowledges grant funding from aWellcome Trust investigator award (219536/Z/19/Z). Dr Dall’Armellina has received funding from a British Heart Foundation intermediate clinical research fellowship (FS/13/71/30378). Dr Moon receives funding directly and indirectly from the National Institutes of Health and Care Research Biomedical Research Centres at University College London Hospitals and Barts Health NHS trusts, is the chief executive officer of MyCardium AI Ltd, and has served on advisory boards for Sanofi and Genzyme. Dr Lopes is supported by a Medical Research Council UK Research and Innovation Clinical Academic Research Partnership award (MR/T005181/1),
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Macfarlane, Professor Peter
• Authors: Joy, G., Kelly, C. I., Webber, M., Pierce, I., Teh, I., McGrath, L., Velazquez, P., Hughes, R. K., Kotwal, H., Das, A., Chan, F., Bakalakos, A., Lorenzini, M., Savvatis, K., Mohiddin, S. A., Macfarlane, P. W., Orini, M., Manisty, C., Kellman, P., Davies, R. H., Lambiase, P. D., Nguyen, C., Schneider, J. E., Tomé, M., Captur, G., Dall’Armellina, E., Moon, J. C., and Lopes, L. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > General Practice and Primary Care
• Journal Name: Circulation
• Publisher: American Heart Association
• ISSN: 0009-7322
• ISSN (Online): 1524-4539
• Published Online: 18 July 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Circulation 148: 808-818
• Publisher Policy: Reproduced under a Creative Commons licence