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Cardioprotective treatment strategies

vanderPals, Jesper LU (2011) In Lund University Faculty of Medicine Doctoral Dissertation Series 2011:15.
Abstract
In myocardial ischemia-reperfusion (I/R) injury, complement activation, tissue plasminogen activator (t-PA) and extracellular adenosine triphosphate (ATP) release contribute to myocardial injury. ATP is degraded into adenosine by the enzyme apyrase, and adenosine possesses cardioprotective properties. ADC-1004 is an antagonist of the receptor to the activated complement factor C5a. Hypothermia has been shown to suppress the development of I/R injury.



In this thesis, the cardioprotective effects of ADC-1004 (paper I), apyrase (paper II) and hy- pothermia (paper III) were investigated. The effects of hypothermia on coronary t-PA release (paper IV), and on systemic t-PA release in cardiogenic shock (paper V) were also... (More)
In myocardial ischemia-reperfusion (I/R) injury, complement activation, tissue plasminogen activator (t-PA) and extracellular adenosine triphosphate (ATP) release contribute to myocardial injury. ATP is degraded into adenosine by the enzyme apyrase, and adenosine possesses cardioprotective properties. ADC-1004 is an antagonist of the receptor to the activated complement factor C5a. Hypothermia has been shown to suppress the development of I/R injury.



In this thesis, the cardioprotective effects of ADC-1004 (paper I), apyrase (paper II) and hy- pothermia (paper III) were investigated. The effects of hypothermia on coronary t-PA release (paper IV), and on systemic t-PA release in cardiogenic shock (paper V) were also studied. An experimental porcine ischemia/reperfusion model was used. Infarct size (IS), microvascular obstruction and area at risk (AAR) were measured with ex-vivo MRI and SPECT.



ADC-1004 treatment (paper I) was found to reduce infarct size (ADC-1004: 58.3±3.4 vs control: 74.1±2.9 %AAR, p=0.007) but not microvascular obstruction (ADC-1004: 2.2±1.2 vs control: 5.3±2.5 %AAR, p=NS). Treatment with apyrase (paper II) did not reduce infarct size (apyrase: 75.7±4.2 vs saline: 69.4±5.0 %AAR, p=NS) nor microvascular obstruction (apyrase: 10.7±4.8 vs saline: 11.4±4.8 %IS, p=NS). Hypothermia (paper III) reduced both infarct size (hypothermia: 60.8±4.9 vs normothermia: 73.8±4.0 %AAR, p<0.05) and microvascular obstruction (hypothermia: 0.5±0.5 vs normothermia: 21.5±5.2 %IS, p<0.001). Hypothermia also inhibited an increase in coronary net t-PA release during reperfusion (paper IV; hypothermia: 0.79±0.45 ng/ml vs normothermia: 9.44±4.34 ng/ml, p<0.05); and an increase in systemic net t-PA release in cardiogenic shock (paper V; hypothermia: 0.60 ± 0.12 ng/ml vs normothermia: 2.16 ± 1.09 ng/ml, p<0.05).



In conclusion, complement inhibition by ADC-1004 and therapeutic hypothermia reduces myocardial ischemia-reperfusion injury, and represents clinically applicable treatment strategies. Mechanistically, therapeutic hypothermia acts to reduce t-PA release in myocardial ischemia and cardiogenic shock. Treatment with apyrase does not protect the heart from ischemia/reperfusion injury. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Atar, Dan, Dept of Cardiology, Oslo University Hospital, Norway
organization
publishing date
type
Thesis
publication status
published
subject
keywords
ADC-1004, apyrase, Cardioprotection, ischemia/reperfusion, hypothermia, t-PA
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2011:15
pages
78 pages
publisher
Department of Cardiology, Clinical sciences, Lund University
defense location
Segerfalksalen, BMC, Lund
defense date
2011-03-04 09:00:00
ISSN
1652-8220
ISBN
978-91-86671-64-8
language
English
LU publication?
yes
id
95e86895-bd85-4558-9b39-811c8ea29242 (old id 1785599)
date added to LUP
2016-04-01 13:33:39
date last changed
2019-05-21 23:35:06
@phdthesis{95e86895-bd85-4558-9b39-811c8ea29242,
  abstract     = {{In myocardial ischemia-reperfusion (I/R) injury, complement activation, tissue plasminogen activator (t-PA) and extracellular adenosine triphosphate (ATP) release contribute to myocardial injury. ATP is degraded into adenosine by the enzyme apyrase, and adenosine possesses cardioprotective properties. ADC-1004 is an antagonist of the receptor to the activated complement factor C5a. Hypothermia has been shown to suppress the development of I/R injury. <br/><br>
<br/><br>
In this thesis, the cardioprotective effects of ADC-1004 (paper I), apyrase (paper II) and hy- pothermia (paper III) were investigated. The effects of hypothermia on coronary t-PA release (paper IV), and on systemic t-PA release in cardiogenic shock (paper V) were also studied. An experimental porcine ischemia/reperfusion model was used. Infarct size (IS), microvascular obstruction and area at risk (AAR) were measured with ex-vivo MRI and SPECT.<br/><br>
<br/><br>
ADC-1004 treatment (paper I) was found to reduce infarct size (ADC-1004: 58.3±3.4 vs control: 74.1±2.9 %AAR, p=0.007) but not microvascular obstruction (ADC-1004: 2.2±1.2 vs control: 5.3±2.5 %AAR, p=NS). Treatment with apyrase (paper II) did not reduce infarct size (apyrase: 75.7±4.2 vs saline: 69.4±5.0 %AAR, p=NS) nor microvascular obstruction (apyrase: 10.7±4.8 vs saline: 11.4±4.8 %IS, p=NS). Hypothermia (paper III) reduced both infarct size (hypothermia: 60.8±4.9 vs normothermia: 73.8±4.0 %AAR, p&lt;0.05) and microvascular obstruction (hypothermia: 0.5±0.5 vs normothermia: 21.5±5.2 %IS, p&lt;0.001). Hypothermia also inhibited an increase in coronary net t-PA release during reperfusion (paper IV; hypothermia: 0.79±0.45 ng/ml vs normothermia: 9.44±4.34 ng/ml, p&lt;0.05); and an increase in systemic net t-PA release in cardiogenic shock (paper V; hypothermia: 0.60 ± 0.12 ng/ml vs normothermia: 2.16 ± 1.09 ng/ml, p&lt;0.05).<br/><br>
<br/><br>
In conclusion, complement inhibition by ADC-1004 and therapeutic hypothermia reduces myocardial ischemia-reperfusion injury, and represents clinically applicable treatment strategies. Mechanistically, therapeutic hypothermia acts to reduce t-PA release in myocardial ischemia and cardiogenic shock. Treatment with apyrase does not protect the heart from ischemia/reperfusion injury.}},
  author       = {{vanderPals, Jesper}},
  isbn         = {{978-91-86671-64-8}},
  issn         = {{1652-8220}},
  keywords     = {{ADC-1004; apyrase; Cardioprotection; ischemia/reperfusion; hypothermia; t-PA}},
  language     = {{eng}},
  publisher    = {{Department of Cardiology, Clinical sciences, Lund University}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Cardioprotective treatment strategies}},
  url          = {{https://lup.lub.lu.se/search/files/3449330/1785600.pdf}},
  volume       = {{2011:15}},
  year         = {{2011}},
}