Reduced lymphatic reserve in heart failure with preserved ejection fraction

Rossitto, G. et al. (2020) Reduced lymphatic reserve in heart failure with preserved ejection fraction. Journal of the American College of Cardiology, 76(24), pp. 2817-2829. (doi: 10.1016/j.jacc.2020.10.022)

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Abstract

Background: Microvascular dysfunction plays an important role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, no mechanistic link between systemic microvasculature and congestion, a central feature of the syndrome, has yet been investigated. Objectives: This study aimed to investigate capillary–interstitium fluid exchange in HFpEF, including lymphatic drainage and the potential osmotic forces exerted by any hypertonic tissue Na+ excess. Methods: Patients with HFpEF and healthy control subjects of similar age and sex distributions (n = 16 per group) underwent: 1) a skin biopsy for vascular immunohistochemistry, gene expression, and chemical (water, Na+, and K+) analyses; and 2) venous occlusion plethysmography to assess peripheral microvascular filtration coefficient (measuring capillary fluid extravasation) and isovolumetric pressure (above which lymphatic drainage cannot compensate for fluid extravasation). Results: Skin biopsies in patients with HFpEF showed rarefaction of small blood and lymphatic vessels (p = 0.003 and p = 0.012, respectively); residual skin lymphatics showed a larger diameter (p = 0.007) and lower expression of lymphatic differentiation and function markers (LYVE-1 [lymphatic vessel endothelial hyaluronan receptor 1]: p < 0.05; PROX-1 [prospero homeobox protein 1]: p < 0.001) compared with control subjects. In patients with HFpEF, microvascular filtration coefficient was lower (calf: 3.30 [interquartile range (IQR): 2.33 to 3.88] l × 100 ml of tissue–1 × min–1 × mm Hg–1 vs. 4.66 [IQR: 3.70 to 6.15] μl × 100 ml of tissue–1 × min–1 × mm Hg–1; p < 0.01; forearm: 5.16 [IQR: 3.86 to 5.43] l × 100 ml of tissue–1 × min–1 × mm Hg–1 vs. 5.66 [IQR: 4.69 to 8.38] μl × 100 ml of tissue–1 × min–1 × mm Hg–1; p > 0.05), in keeping with blood vascular rarefaction and the lack of any observed hypertonic skin Na+ excess, but the lymphatic drainage was impaired (isovolumetric pressure in patients with HFpEF vs. control subjects: calf 16 ± 4 mm Hg vs. 22 ± 4 mm Hg; p < 0.005; forearm 17 ± 4 mm Hg vs. 25 ± 5 mm Hg; p < 0.001). Conclusions: Peripheral lymphatic vessels in patients with HFpEF exhibit structural and molecular alterations and cannot effectively compensate for fluid extravasation and interstitial accumulation by commensurate drainage. Reduced lymphatic reserve may represent a novel therapeutic target.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rossitto, Dr Giacomo and Samji, Dr Sheon and Rocchiccioli, Dr John and Delles, Professor Christian and Haddow, Mrs Laura and Petrie, Professor Mark and Lang, Dr Ninian and Murphy, Dr Clare and Neves, Dr Karla and Touyz, Professor Rhian
Authors: Rossitto, G., Mary, S., McAllister, C., Neves, K. B., Haddow, L., Rocchiccioli, J. P., Lang, N. N., Murphy, C. L., Touyz, R. M., Petrie, M. C., and Delles, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Journal of the American College of Cardiology
Publisher:Elsevier
ISSN:0735-1097
ISSN (Online):1558-3597
Published Online:07 December 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Journal of the American College of Cardiology 76(24): 2817-2829
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences
303944BHF Centre of ExcellenceRhian TouyzBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science
300689Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)CH/12/4/29762CAMS - Cardiovascular Science