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Development and prevention of ischemic contracture (“stone heart”) in the pig heart

Li, Mei LU ; Qin, Zhi ; Steen, Erik ; Terry, Ann LU ; Wang, Bowen ; Wohlfart, Björn LU ; Steen, Stig LU and Arner, Anders LU (2023) In Frontiers in Cardiovascular Medicine 10.
Abstract

Stone heart (ischemic contracture) is a rare and serious condition observed in the heart after periods of warm ischemia. The underlying mechanisms are largely unknown and treatment options are lacking. In view of the possibilities for cardiac donation after circulatory death (DCD), introducing risks for ischemic damage, we have investigated stone heart in pigs. Following cessation of ventilation, circulatory death (systolic pressure <8 mmHg) occurred within 13.1 ± 1.2 min; and a stone heart, manifested with asystole, increased left ventricular wall thickness and stiffness, established after a further 17 ± 6 min. Adenosine triphosphate and phosphocreatine levels decreased by about 50% in the stone heart. Electron microscopy showed... (More)

Stone heart (ischemic contracture) is a rare and serious condition observed in the heart after periods of warm ischemia. The underlying mechanisms are largely unknown and treatment options are lacking. In view of the possibilities for cardiac donation after circulatory death (DCD), introducing risks for ischemic damage, we have investigated stone heart in pigs. Following cessation of ventilation, circulatory death (systolic pressure <8 mmHg) occurred within 13.1 ± 1.2 min; and a stone heart, manifested with asystole, increased left ventricular wall thickness and stiffness, established after a further 17 ± 6 min. Adenosine triphosphate and phosphocreatine levels decreased by about 50% in the stone heart. Electron microscopy showed deteriorated structure with contraction bands, Z-line streaming and swollen mitochondria. Synchrotron based small angle X-ray scattering of trabecular samples from stone hearts revealed attachment of myosin to actin, without volume changes in the sarcomeres. Ca2+ sensitivity, determined in permeabilized muscle, was increased in stone heart samples. An in vitro model for stone heart, using isolated trabecular muscle exposed to hypoxia/zero glucose, exhibited the main characteristics of stone heart in whole animals, with a fall in high-energy phosphates and development of muscle contracture. The stone heart condition in vitro was significantly attenuated by the myosin inhibitor MYK-461 (Mavacamten). In conclusion, the stone heart is a hypercontracted state associated with myosin binding to actin and increased Ca2+ sensitivity. The hypercontractile state, once developed, is poorly reversible. The myosin inhibitor MYK-461, which is clinically approved for other indications, could be a promising venue for prevention.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Ca2+-sensitivity, donation after circulatory death (DCD), ischemic contracture, Mavacamten, stone heart, transplantation
in
Frontiers in Cardiovascular Medicine
volume
10
article number
1105257
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85149695797
  • pmid:36891241
ISSN
2297-055X
DOI
10.3389/fcvm.2023.1105257
language
English
LU publication?
yes
id
1a47e740-05a2-457b-bb3f-3dd5a66e42b6
date added to LUP
2023-04-03 11:18:53
date last changed
2024-06-13 13:55:12
@article{1a47e740-05a2-457b-bb3f-3dd5a66e42b6,
  abstract     = {{<p>Stone heart (ischemic contracture) is a rare and serious condition observed in the heart after periods of warm ischemia. The underlying mechanisms are largely unknown and treatment options are lacking. In view of the possibilities for cardiac donation after circulatory death (DCD), introducing risks for ischemic damage, we have investigated stone heart in pigs. Following cessation of ventilation, circulatory death (systolic pressure &lt;8 mmHg) occurred within 13.1 ± 1.2 min; and a stone heart, manifested with asystole, increased left ventricular wall thickness and stiffness, established after a further 17 ± 6 min. Adenosine triphosphate and phosphocreatine levels decreased by about 50% in the stone heart. Electron microscopy showed deteriorated structure with contraction bands, Z-line streaming and swollen mitochondria. Synchrotron based small angle X-ray scattering of trabecular samples from stone hearts revealed attachment of myosin to actin, without volume changes in the sarcomeres. Ca<sup>2+</sup> sensitivity, determined in permeabilized muscle, was increased in stone heart samples. An in vitro model for stone heart, using isolated trabecular muscle exposed to hypoxia/zero glucose, exhibited the main characteristics of stone heart in whole animals, with a fall in high-energy phosphates and development of muscle contracture. The stone heart condition in vitro was significantly attenuated by the myosin inhibitor MYK-461 (Mavacamten). In conclusion, the stone heart is a hypercontracted state associated with myosin binding to actin and increased Ca<sup>2+</sup> sensitivity. The hypercontractile state, once developed, is poorly reversible. The myosin inhibitor MYK-461, which is clinically approved for other indications, could be a promising venue for prevention.</p>}},
  author       = {{Li, Mei and Qin, Zhi and Steen, Erik and Terry, Ann and Wang, Bowen and Wohlfart, Björn and Steen, Stig and Arner, Anders}},
  issn         = {{2297-055X}},
  keywords     = {{Ca2+-sensitivity; donation after circulatory death (DCD); ischemic contracture; Mavacamten; stone heart; transplantation}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Cardiovascular Medicine}},
  title        = {{Development and prevention of ischemic contracture (“stone heart”) in the pig heart}},
  url          = {{http://dx.doi.org/10.3389/fcvm.2023.1105257}},
  doi          = {{10.3389/fcvm.2023.1105257}},
  volume       = {{10}},
  year         = {{2023}},
}