<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04500938</url>
  </required_header>
  <id_info>
    <org_study_id>0404-92-02062020</org_study_id>
    <nct_id>NCT04500938</nct_id>
  </id_info>
  <brief_title>Cardiac Mitochondrial Function in Explanted Human Hearts</brief_title>
  <official_title>Cardiac Mitochondrial Function in Explanted Human Hearts</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Aarhus</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Treatment of heart failure has improved considerably in the past decades. Despite this&#xD;
      improvement, the disease may progress into an end-stage ultimately leaving the physicians&#xD;
      with no other treatment option than heart transplantation (HTx). There are multiple&#xD;
      etiologies underlying heart failure. Cardiomyopathy is the leading cause for HTx in any&#xD;
      age-group with coronary artery disease being the second most common cause in adult patients.&#xD;
&#xD;
      Alterations in the mitochondrial function have been recognized as key factors in heart&#xD;
      failure.&#xD;
&#xD;
      During the transplant procedure the diseased heart is removed, providing a unique opportunity&#xD;
      to collect samples eligible for thorough mitochondrial examination.&#xD;
&#xD;
      Hopefully, the knowledge gained from this investigation will contribute with important&#xD;
      insights in the diseased myocardial energy metabolism. Such knowledge may pave the way for&#xD;
      development of treatments targeting both energy substrate supply for adenosine-triphosphate&#xD;
      generation produced by the mitochondria as well as mitochondrial function in the failing&#xD;
      heart.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      The pathological myocardial function seen in heart failure is related to dysfunctional&#xD;
      cardiac mitochondria&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To examine if cardiac mitochondrial function in end-stage heart failure of multiple&#xD;
      etiologies is inferior to mitochondrial function in transplanted hearts with no signs of&#xD;
      rejection or vasculopathy.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Myocardial mitochondrial function analyzed from 24 explanted hearts will be compared to&#xD;
      endomyocardial biopsies from 20 HTx patients at scheduled biopsies (1 or 2 years after&#xD;
      implantation).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Treatment of heart failure has improved considerably in the past decades. Despite this&#xD;
      improvement, the disease may progress into an end-stage ultimately leaving the physicians&#xD;
      with no other treatment option than heart transplantation (HTx). There are multiple&#xD;
      etiologies underlying heart failure. Cardiomyopathy is the leading cause for HTx in any&#xD;
      age-group with coronary artery disease being the second most common cause in adult patients.&#xD;
&#xD;
      Alterations in the mitochondrial function have been recognized as key factors in heart&#xD;
      failure. The understanding of the complex interaction of the mitochondria in regulation of&#xD;
      the metabolism and cellular apoptosis has brought new perspectives to research in heart&#xD;
      failure. It is now known that the myocardial mitochondrial density changes and their function&#xD;
      and integrity is impaired during heart failure.&#xD;
&#xD;
      During the transplant procedure the diseased heart is removed, providing a unique opportunity&#xD;
      to collect samples eligible for thorough mitochondrial examination.&#xD;
&#xD;
      The collected myocardial tissue samples will be evaluated with High Resolution Respirometry,&#xD;
      examining the glucose coupled respiratory capacity of permeabilized myocardial fibers. The&#xD;
      respiratory capacity in the diseased fibers will be compared to the respiratory capacity in&#xD;
      fibers from coronary healthy HTx patients transplanted 1 to 2 years prior to acquisition of&#xD;
      the fibers.&#xD;
&#xD;
      Hopefully, the knowledge gained from this investigation will contribute with important&#xD;
      insights in the diseased myocardial energy metabolism. Such knowledge may pave the way for&#xD;
      development of treatments targeting energy substrate supply for adenosine-triphosphate&#xD;
      generation produced by the mitochondria as well as mitochondrial function in the failing&#xD;
      heart.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      The pathological myocardial function seen in heart failure is related to dysfunctional&#xD;
      cardiac mitochondria.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To examine if cardiac mitochondrial function in end-stage heart failure of multiple&#xD;
      etiologies is inferior to mitochondrial function in transplanted hearts with no signs of&#xD;
      rejection or vasculopathy.&#xD;
&#xD;
      Design and Endpoint:&#xD;
&#xD;
      Myocardial mitochondrial function analyzed from 24 explanted hearts will be compared to&#xD;
      endomyocardial biopsies from 20 HTx patients at scheduled biopsies (1 or 2 years after&#xD;
      implantation).&#xD;
&#xD;
      Endpoints: 1) Mitochondrial respiratory capacity. 2) Mitochondrial complex function, outer&#xD;
      membrane integrity and mitochondrial content.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      High-resolution respirometry:&#xD;
&#xD;
      High-resolution respirometry is used to measure mitochondrial respiratory capacity in&#xD;
      endomyocardial biopsies. After appropriate preparation, two biopsies are transferred to an&#xD;
      oxygraph (Oxygraph-2k; Oroboros, Innsbruck, Austria) for high resolution respirometry.&#xD;
      Mitochondrial respiratory capacity will be analyzed in a step-by-step manner using titrations&#xD;
      of substrates and inhibitors to evaluate glucose coupled respiration in the fibers.&#xD;
      High-resolution respirometry analysis is performed within 8 hours after the biopsy has been&#xD;
      taken.&#xD;
&#xD;
      After analysis the tissue will be snap-frozen in liquid nitrogen and stored in a research&#xD;
      biobank at -80 degrees celsius until examination of citrate synthase activity is carried out.&#xD;
      Hereafter, any remaining tissue will be destroyed.&#xD;
&#xD;
      Electron microscopy:&#xD;
&#xD;
      A sample from each biopsy used for high-resolution respirometry will be used for electron&#xD;
      microscopy (EM) to evaluate mitochondrial volume density (MitoVD) and integrity. Muscle&#xD;
      samples are fixated for 24 hours in glutaraldehyde and washed 4x15 minutes with Na-cacodylate&#xD;
      buffer before being casted in Epon. The Epon casted tissue will be stored in a research&#xD;
      biobank until EM analysis. Ultra-thin sections of the Epon-blocks (60 nm) are cut in three&#xD;
      depths and dyed with uranyl acetate and lead citrate. Imaging is performed with an EM 208&#xD;
      transmission electron microscope and a Megaview III camera. All fibers are photographed at&#xD;
      10.000 × magnification in a randomized order. MitoVD is estimated from mitochondrial&#xD;
      fractional area and only distinct fibers will be used in the final analysis.&#xD;
&#xD;
      Statistics:&#xD;
&#xD;
      Normally distributed data will be presented as mean ± standard deviation; non-normally&#xD;
      distributed data will be presented as median and interquartile range. Categorical data are&#xD;
      presented as absolute values or percentages. Histograms and Q-Q plots will be used to check&#xD;
      continuous values for normality. Between-group differences will be assessed by t-test for&#xD;
      normally distributed data and Mann-Whitney U test for non-normally distributed data.&#xD;
      Statistical significance at a p-value of &lt;0.05.&#xD;
&#xD;
      Sample size calculation:&#xD;
&#xD;
      At present there are no test-retest evaluation of mitochondrial respiratory analysis in&#xD;
      endomyocardial biopsies from explanted human hearts. However, a recent study performed at our&#xD;
      department on myocardial biopsies demonstrated that a total sample size of 40 human subjects&#xD;
      in a 1:1 parallel group design was able to identify differences between the two groups&#xD;
      (unpublished data).&#xD;
&#xD;
      Data collection and processing:&#xD;
&#xD;
      Source data will be recorded in the patient's electronic patient record or on specific&#xD;
      worksheets.&#xD;
&#xD;
      A centralized electronic Case Report Form (CRF) will be constructed for data capture. Data&#xD;
      will be stored until completion of the project, after which, it will be transmitted to the&#xD;
      Danish Data Archives.&#xD;
&#xD;
      Perspectives:&#xD;
&#xD;
      HTx is the golden standard treatment for patients suffering from end-stage heart failure, but&#xD;
      its limitations cannot be ignored. Firstly, the procedure is accompanied by a substantial&#xD;
      risk and a significant percentage of patients suffer from acute graft failure. Furthermore,&#xD;
      HTx patients have a higher risk of severe infections and cancer, and up to 50% of HTx&#xD;
      patients suffer from cardiac allograft vasculopathy 10 years after transplantation, all of&#xD;
      which are highly related to mortality. Hence, postponing HTx is desirable, if health and&#xD;
      life-quality can be kept at an acceptable level. In this context, mitochondrial function&#xD;
      seems to be pivotal, as approaches to assess mitochondrial function in the failing heart may&#xD;
      prove to pave the way for new follow-up algorithms and even treatment targets.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">August 30, 2020</start_date>
  <completion_date type="Anticipated">February 28, 2024</completion_date>
  <primary_completion_date type="Anticipated">February 28, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>State 2 respiration (GM)</measure>
    <time_frame>Within 5 minutes.</time_frame>
    <description>Complex I-linked respiration, induced by Malate and Glutamate.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>State 3 respiration (GM3)</measure>
    <time_frame>Within 10 minutes.</time_frame>
    <description>Complex I-linked respiration with adenosine diphosphate (ADP), induced by Malate, Glutamate and ADP.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>State 3 respiration (GMS3)</measure>
    <time_frame>Within 15 minutes.</time_frame>
    <description>Complex I+II-linked respiration, induced by Malate, Glutamate, ADP and Succinate.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>State 4 respiration (4o)</measure>
    <time_frame>Within 30 minutes.</time_frame>
    <description>Complex I+II-linked respiration not linked to adenosine triphosphate production, induced by inhibition of complex V by Oligomycin.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Residual Oxygen Consumption (ROX)</measure>
    <time_frame>Within 45 minutes.</time_frame>
    <description>Respiration not linked to the electron transport chain, induced by inhibition of complex I by Rotenone, complex III by Antimycin A and complex V by Oligomycin.</description>
  </primary_outcome>
  <enrollment type="Anticipated">24</enrollment>
  <condition>End-stage Heart Failure</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Endomyocardial biopsies taken from the explanted heart after removal during heart&#xD;
      transplantation.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        All heart transplanted patients, transplanted at Aarhus University Hospital, Denmark.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Informed consent from the recipient&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Myocardial biopsy from the explanted heart not feasible&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hans Eiskjær, MD, DMSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Aarhus</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Roni Nielsen, MD, PhD</last_name>
    <phone>51219363</phone>
    <email>bent.niels@midt.rm.dk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Katrine Berg, PhD student</last_name>
    <phone>28897429</phone>
    <email>katrbe@rm.dk</email>
  </overall_contact_backup>
  <reference>
    <citation>Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, Levvey BJ, Meiser B, Rossano JW, Yusen RD, Stehlik J. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report--2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant. 2015 Oct;34(10):1244-54. doi: 10.1016/j.healun.2015.08.003. Epub 2015 Aug 28. No abstract available.</citation>
    <PMID>26454738</PMID>
  </reference>
  <reference>
    <citation>Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GW 2nd, Kitsis RN, Otsu K, Ping P, Rizzuto R, Sack MN, Wallace D, Youle RJ; American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology. Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association. Circ Res. 2016 Jun 10;118(12):1960-91. doi: 10.1161/RES.0000000000000104. Epub 2016 Apr 28.</citation>
    <PMID>27126807</PMID>
  </reference>
  <reference>
    <citation>Jespersen NR, Yokota T, Stottrup NB, Bergdahl A, Paelestik KB, Povlsen JA, Dela F, Botker HE. Pre-ischaemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion. J Physiol. 2017 Jun 15;595(12):3765-3780. doi: 10.1113/JP273408. Epub 2017 Feb 27.</citation>
    <PMID>28093764</PMID>
  </reference>
  <reference>
    <citation>Gormsen LC, Svart M, Thomsen HH, Sondergaard E, Vendelbo MH, Christensen N, Tolbod LP, Harms HJ, Nielsen R, Wiggers H, Jessen N, Hansen J, Botker HE, Moller N. Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study. J Am Heart Assoc. 2017 Feb 27;6(3):e005066. doi: 10.1161/JAHA.116.005066.</citation>
    <PMID>28242634</PMID>
  </reference>
  <reference>
    <citation>Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JG, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ, Gheorghiade M. Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017 Apr;14(4):238-250. doi: 10.1038/nrcardio.2016.203. Epub 2016 Dec 22.</citation>
    <PMID>28004807</PMID>
  </reference>
  <reference>
    <citation>Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, Dobbels F, Kirk R, Rahmel AO, Yusen RD, Stehlik J; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Official Adult Heart Transplant Report--2013; focus theme: age. J Heart Lung Transplant. 2013 Oct;32(10):951-64. doi: 10.1016/j.healun.2013.08.006. No abstract available.</citation>
    <PMID>24054804</PMID>
  </reference>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>August 3, 2020</last_update_submitted>
  <last_update_submitted_qc>August 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Aarhus</investigator_affiliation>
    <investigator_full_name>Roni Nielsen</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Mitochondrial function</keyword>
  <keyword>High Resolution Respirometry</keyword>
  <keyword>Heart Transplantation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04500938
org study id: 0404-92-02062020
nct id: NCT04500938
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Background:

      Treatment of heart failure has improved considerably in the past decades. Despite this
      improvement, the disease may progress into an end-stage ultimately leaving the physicians
      with no other treatment option than heart transplantation (HTx). There are multiple
      etiologies underlying heart failure. Cardiomyopathy is the leading cause for HTx in any
      age-group with coronary artery disease being the second most common cause in adult patients.

      Alterations in the mitochondrial function have been recognized as key factors in heart
      failure.

      During the transplant procedure the diseased heart is removed, providing a unique opportunity
      to collect samples eligible for thorough mitochondrial examination.

      Hopefully, the knowledge gained from this investigation will contribute with important
      insights in the diseased myocardial energy metabolism. Such knowledge may pave the way for
      development of treatments targeting both energy substrate supply for adenosine-triphosphate
      generation produced by the mitochondria as well as mitochondrial function in the failing
      heart.

      Hypothesis:

      The pathological myocardial function seen in heart failure is related to dysfunctional
      cardiac mitochondria

      Objective:

      To examine if cardiac mitochondrial function in end-stage heart failure of multiple
      etiologies is inferior to mitochondrial function in transplanted hearts with no signs of
      rejection or vasculopathy.

      Design:

      Myocardial mitochondrial function analyzed from 24 explanted hearts will be compared to
      endomyocardial biopsies from 20 HTx patients at scheduled biopsies (1 or 2 years after
      implantation).
Background:

      Treatment of heart failure has improved considerably in the past decades. Despite this
      improvement, the disease may progress into an end-stage ultimately leaving the physicians
      with no other treatment option than heart transplantation (HTx). There are multiple
      etiologies underlying heart failure. Cardiomyopathy is the leading cause for HTx in any
      age-group with coronary artery disease being the second most common cause in adult patients.

      Alterations in the mitochondrial function have been recognized as key factors in heart
      failure. The understanding of the complex interaction of the mitochondria in regulation of
      the metabolism and cellular apoptosis has brought new perspectives to research in heart
      failure. It is now known that the myocardial mitochondrial density changes and their function
      and integrity is impaired during heart failure.

      During the transplant procedure the diseased heart is removed, providing a unique opportunity
      to collect samples eligible for thorough mitochondrial examination.

      The collected myocardial tissue samples will be evaluated with High Resolution Respirometry,
      examining the glucose coupled respiratory capacity of permeabilized myocardial fibers. The
      respiratory capacity in the diseased fibers will be compared to the respiratory capacity in
      fibers from coronary healthy HTx patients transplanted 1 to 2 years prior to acquisition of
      the fibers.

      Hopefully, the knowledge gained from this investigation will contribute with important
      insights in the diseased myocardial energy metabolism. Such knowledge may pave the way for
      development of treatments targeting energy substrate supply for adenosine-triphosphate
      generation produced by the mitochondria as well as mitochondrial function in the failing
      heart.

      Hypothesis:

      The pathological myocardial function seen in heart failure is related to dysfunctional
      cardiac mitochondria.

      Objective:

      To examine if cardiac mitochondrial function in end-stage heart failure of multiple
      etiologies is inferior to mitochondrial function in transplanted hearts with no signs of
      rejection or vasculopathy.

      Design and Endpoint:

      Myocardial mitochondrial function analyzed from 24 explanted hearts will be compared to
      endomyocardial biopsies from 20 HTx patients at scheduled biopsies (1 or 2 years after
      implantation).

      Endpoints: 1) Mitochondrial respiratory capacity. 2) Mitochondrial complex function, outer
      membrane integrity and mitochondrial content.

      Methods:

      High-resolution respirometry:

      High-resolution respirometry is used to measure mitochondrial respiratory capacity in
      endomyocardial biopsies. After appropriate preparation, two biopsies are transferred to an
      oxygraph (Oxygraph-2k; Oroboros, Innsbruck, Austria) for high resolution respirometry.
      Mitochondrial respiratory capacity will be analyzed in a step-by-step manner using titrations
      of substrates and inhibitors to evaluate glucose coupled respiration in the fibers.
      High-resolution respirometry analysis is performed within 8 hours after the biopsy has been
      taken.

      After analysis the tissue will be snap-frozen in liquid nitrogen and stored in a research
      biobank at -80 degrees celsius until examination of citrate synthase activity is carried out.
      Hereafter, any remaining tissue will be destroyed.

      Electron microscopy:

      A sample from each biopsy used for high-resolution respirometry will be used for electron
      microscopy (EM) to evaluate mitochondrial volume density (MitoVD) and integrity. Muscle
      samples are fixated for 24 hours in glutaraldehyde and washed 4x15 minutes with Na-cacodylate
      buffer before being casted in Epon. The Epon casted tissue will be stored in a research
      biobank until EM analysis. Ultra-thin sections of the Epon-blocks (60 nm) are cut in three
      depths and dyed with uranyl acetate and lead citrate. Imaging is performed with an EM 208
      transmission electron microscope and a Megaview III camera. All fibers are photographed at
      10.000 × magnification in a randomized order. MitoVD is estimated from mitochondrial
      fractional area and only distinct fibers will be used in the final analysis.

      Statistics:

      Normally distributed data will be presented as mean ± standard deviation; non-normally
      distributed data will be presented as median and interquartile range. Categorical data are
      presented as absolute values or percentages. Histograms and Q-Q plots will be used to check
      continuous values for normality. Between-group differences will be assessed by t-test for
      normally distributed data and Mann-Whitney U test for non-normally distributed data.
      Statistical significance at a p-value of <0.05.

      Sample size calculation:

      At present there are no test-retest evaluation of mitochondrial respiratory analysis in
      endomyocardial biopsies from explanted human hearts. However, a recent study performed at our
      department on myocardial biopsies demonstrated that a total sample size of 40 human subjects
      in a 1:1 parallel group design was able to identify differences between the two groups
      (unpublished data).

      Data collection and processing:

      Source data will be recorded in the patient's electronic patient record or on specific
      worksheets.

      A centralized electronic Case Report Form (CRF) will be constructed for data capture. Data
      will be stored until completion of the project, after which, it will be transmitted to the
      Danish Data Archives.

      Perspectives:

      HTx is the golden standard treatment for patients suffering from end-stage heart failure, but
      its limitations cannot be ignored. Firstly, the procedure is accompanied by a substantial
      risk and a significant percentage of patients suffer from acute graft failure. Furthermore,
      HTx patients have a higher risk of severe infections and cancer, and up to 50% of HTx
      patients suffer from cardiac allograft vasculopathy 10 years after transplantation, all of
      which are highly related to mortality. Hence, postponing HTx is desirable, if health and
      life-quality can be kept at an acceptable level. In this context, mitochondrial function
      seems to be pivotal, as approaches to assess mitochondrial function in the failing heart may
      prove to pave the way for new follow-up algorithms and even treatment targets.
observational model: Cohort
time perspective: Prospective
measure: State 2 respiration (GM)
time frame: Within 5 minutes.
description: Complex I-linked respiration, induced by Malate and Glutamate.
measure: State 3 respiration (GM3)
time frame: Within 10 minutes.
description: Complex I-linked respiration with adenosine diphosphate (ADP), induced by Malate, Glutamate and ADP.
measure: State 3 respiration (GMS3)
time frame: Within 15 minutes.
description: Complex I+II-linked respiration, induced by Malate, Glutamate, ADP and Succinate.
measure: State 4 respiration (4o)
time frame: Within 30 minutes.
description: Complex I+II-linked respiration not linked to adenosine triphosphate production, induced by inhibition of complex V by Oligomycin.
measure: Residual Oxygen Consumption (ROX)
time frame: Within 45 minutes.
description: Respiration not linked to the electron transport chain, induced by inhibition of complex I by Rotenone, complex III by Antimycin A and complex V by Oligomycin.
Endomyocardial biopsies taken from the explanted heart after removal during heart
      transplantation.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Hans Eiskjær, MD, DMSc
role: Principal Investigator
affiliation: University of Aarhus
last name: Roni Nielsen, MD, PhD
phone: 51219363
email: bent.niels@midt.rm.dk
last name: Katrine Berg, PhD student
phone: 28897429
email: katrbe@rm.dk
citation: Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, Levvey BJ, Meiser B, Rossano JW, Yusen RD, Stehlik J. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report--2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant. 2015 Oct;34(10):1244-54. doi: 10.1016/j.healun.2015.08.003. Epub 2015 Aug 28. No abstract available.
PMID: 26454738
citation: Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GW 2nd, Kitsis RN, Otsu K, Ping P, Rizzuto R, Sack MN, Wallace D, Youle RJ; American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology. Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association. Circ Res. 2016 Jun 10;118(12):1960-91. doi: 10.1161/RES.0000000000000104. Epub 2016 Apr 28.
PMID: 27126807
citation: Jespersen NR, Yokota T, Stottrup NB, Bergdahl A, Paelestik KB, Povlsen JA, Dela F, Botker HE. Pre-ischaemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion. J Physiol. 2017 Jun 15;595(12):3765-3780. doi: 10.1113/JP273408. Epub 2017 Feb 27.
PMID: 28093764
citation: Gormsen LC, Svart M, Thomsen HH, Sondergaard E, Vendelbo MH, Christensen N, Tolbod LP, Harms HJ, Nielsen R, Wiggers H, Jessen N, Hansen J, Botker HE, Moller N. Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study. J Am Heart Assoc. 2017 Feb 27;6(3):e005066. doi: 10.1161/JAHA.116.005066.
PMID: 28242634
citation: Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JG, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ, Gheorghiade M. Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017 Apr;14(4):238-250. doi: 10.1038/nrcardio.2016.203. Epub 2016 Dec 22.
PMID: 28004807
citation: Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, Dobbels F, Kirk R, Rahmel AO, Yusen RD, Stehlik J; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: Thirtieth Official Adult Heart Transplant Report--2013; focus theme: age. J Heart Lung Transplant. 2013 Oct;32(10):951-64. doi: 10.1016/j.healun.2013.08.006. No abstract available.
PMID: 24054804
responsible party type: Principal Investigator
investigator affiliation: University of Aarhus
investigator full name: Roni Nielsen
investigator title: Principal Investigator
mesh term: Heart Failure
sharing ipd: No