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Regurgitation Hemodynamics Alone Cause Mitral Valve Remodeling Characteristic of Clinical Disease States In Vitro

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Abstract

Mitral valve regurgitation is a challenging clinical condition that is frequent, highly varied, and poorly understood. While the causes of mitral regurgitation are multifactorial, how the hemodynamics of regurgitation impact valve tissue remodeling is an understudied phenomenon. We employed a pseudo-physiological flow loop capable of long-term organ culture to investigate the early progression of remodeling in living mitral valves placed in conditions resembling mitral valve prolapse (MVP) and functional mitral regurgitation (FMR). Valve geometry was altered to mimic the hemodynamics of controls (no changes from native geometry), MVP (5 mm displacement of papillary muscles towards the annulus), and FMR (5 mm apical, 5 mm lateral papillary muscle displacement, 65% larger annular area). Flow measurements ensured moderate regurgitant fraction for regurgitation groups. After 1-week culture, valve tissues underwent mechanical and compositional analysis. MVP conditioned tissues were less stiff, weaker, and had elevated collagen III and glycosaminoglycans. FMR conditioned tissues were stiffer, more brittle, less extensible, and had more collagen synthesis, remodeling, and crosslinking related enzymes and proteoglycans, including decorin, matrix metalloproteinase-1, and lysyl oxidase. These models replicate clinical findings of MVP (myxomatous remodeling) and FMR (fibrotic remodeling), indicating that valve cells remodel extracellular matrix in response to altered mechanical homeostasis resulting from disease hemodynamics.

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Abbreviations

FMR:

Functional mitral regurgitation

GAG:

Glycosaminoglycan

LOX:

Lysyl oxidase

MMP-1:

Matrix metalloproteinase-1

MVP:

Mitral valve prolapse

RUFLS:

Rice University flow loop system

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Acknowledgments

The authors would like to acknowledge Dr. Larry Fisher, NIH, for his gift of decorin antibody used in the course of this research. This work was supported by the National Institutes of Health [T32HL007676]; and the American Heart Association [13PRE14110003 to P.C.].

Conflict of interest

Dr. Stephen H. Little has received research funds from St. Jude Medical, Medtronic Inc, Abbott Vascular Structural Heart. Dr. Jane Grande-Allen has served as a consultant for Edwards Lifesciences. Other authors have no disclosures.

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Authors and Affiliations

  1. Department of Bioengineering, Rice University, MS142, 6100 Main St., Houston, TX, USA

    Patrick S. Connell, Anam F. Azimuddin, Seulgi E. Kim, Fernando Ramirez & K. Jane Grande-Allen

  2. Department of Cardiology, Houston Methodist Hospital, Houston, TX, USA

    Matthew S. Jackson & Stephen H. Little

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  1. Patrick S. Connell
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  2. Anam F. Azimuddin
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Correspondence to K. Jane Grande-Allen.

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Associate Editor Ender Finol oversaw the review of this article.

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Supplemental Video 1

Control Valve in Imaging Flow Loop (MP4 2186 kb)

Supplemental Video 2

MVP Valve in Imaging Flow Loop (MP4 592 kb)

FMR Valve in Imaging Flow Loop (MOV 19665 kb)

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Connell, P.S., Azimuddin, A.F., Kim, S.E. et al. Regurgitation Hemodynamics Alone Cause Mitral Valve Remodeling Characteristic of Clinical Disease States In Vitro . Ann Biomed Eng 44, 954–967 (2016). https://doi.org/10.1007/s10439-015-1398-0

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