Cardiac Mitochondrial Function After Heart Transplantation

NCT04105803 | Unknown

• 1 other identifier: 1-10-72-367-18
• Study Type: observational
• Target: 64
• Locations: 1 country
• Sites: 1

Brief Summary

Studies have shown that cardiac function is affected immediately after heart transplantation (HTx), but seems to recover to some extent over the first year. This immediate effect is associated with lack of oxygen in the tissue and reperfusion injury causing cellular energy depletion, mitochondrial failure and cellular damage. This condition may progress into full blown primary graft failure (PGF), characterized as deterioration of the transplanted heart, which is seen in 3-30 % of HTx patients. In addition to PGF, chronic rejection owing to cardiac allograft vasculopathy (CAV) may develop. PGF and CAV remain the major heart related mortality causes, and additional assessment and treatments are therefore needed. Acute cellular rejection (ACR) is diagnosed based on endomyocardial biopsies (EMB), which are routinely performed to ensure prober immunosuppression in HTx patients. ACR occur in approximately 25% of HTx patients, and is associated with PGF and CAV. However, mitochondrial function and integrity may prove to be a more sensitive marker of allograft rejection than endomyocardial biopsies. Therefore, assessment of mitochondrial function may allow for earlier detection of allograft rejection and dysfunction. This may be of particular importance as emerging treatments are targeting both energy substrate supply for adenosine-triphosphate generation produced by the mitochondria and mitochondrial function in the failing heart. Despite the association between graft rejection and mitochondrial function, it remains unsettled whether mitochondrial function associate with PGF, ACR and CAV. Such findings may be of prognostic importance and even elucidate new treatment targets. Hence, we evaluate the mitochondrial status in HTx patients through four studies designed to assess different aspects of the interplay between cardiac function and mitochondrial integrity and function. Hypotheses: Study 1: Primary graft pump function is correlated to mitochondrial function in the first myocardial biopsy taken from the donor heart during the operation. Study 2: Cardiac mitochondrial function improves over the first 3 months after a heart transplantation. Study 3: Heart transplant patients with moderate to severe coronary graft vasculopathy has impaired mitochondrial function. Study 4: Myocardial external energy efficiency by positron-emission tomography can be used as a marker of mitochondrial function and chronic rejection in HTx patients.

Conditions

Cardiac Allograft Vasculopathy; Acute Cellular Graft Rejection; Primary Graft Failure; Mitochondrial Function

Outcome Measures

Primary Outcomes (3)

• Study 1+3: Differences in Mitochondrial oxidative capacity

  Mitochondrial respiratory capacity evaluated with high resolution respirometry,

  unpaired comparison differences between groups through study completion, an average of 2 years)

• Study 2: Changes in mitochondrial oxidative capacity

  Changes in mitochondrial respiratory capacity evaluated with high resolution respirometry,

  unpaired comparison differences between groups (through study completion, an average of 2 years)

• Study 4: Changes in myocardial external energy efficiency

  Changes Myocardial external energy efficiency evaluated by PET-scans with 11C-acetate tracer. Calculated by the ratio of myocardial external work (EW) and oxidative metabolism (MVO2).

  Changes from baseline (following HTX) to 6-month post-HTX (paired data)

Secondary Outcomes (5)

• Biochemistry

  Through study completion, an average of 2 years.

• Cardiac function

  Through study completion, an average of 2 years.

• Invasive hemodynamics

  Through study completion, an average of 2 years.

• Cellular function

  Through study completion, an average of 2 years.

• Mitochondrial structure

  Through study completion, an average of 2 years.

Study Arms (3)

De novo HTx

Procedure: Two perprocedural biopsies under transplantation is performed from the left ventricular septum. Procedure: Endomyocardial biopsies from the right ventricular septum, taken at scheduled standard HTx follow-up visits at our department (protocol is to take 4-5 biopsies, two additional biopsies will be taken at this visit). Procedure: is part of the scheduled standard HTx follow-up visits. This recording will be used for CAV evaluation. In addition to the protocol procedure, we will evaluate the hemodynamic status in the patients. Diagnostic test: Echocardiography and coronary angiography is part of the scheduled standard HTx follow-up visits.

Longterm HTx

Procedure: Endomyocardial biopsies from the right ventricular septum, taken at scheduled standard HTx follow-up visits at our department (protocol is to take 4-5 biopsies, two additional biopsies will be taken at this visit). Procedure: Coronary Angiography is part of the scheduled standard HTx follow-up visits. This recording will be used for CAV evaluation. In addition to the protocol procedure, we will evaluate the hemodynamic status in the patients. Diagnostic test: Echocardiography is part of the scheduled standard HTx follow-up visits. No additional examinations will be performed. We will use the standard recordings to calculate the desired parameters.

PET-scan de novo HTx

Radiation: Two PET-scans with 11C-acetate tracer will be performed. Procedure: Two perprocedural biopsies under transplantation is performed from the left ventricular septum. Procedure: Endomyocardial biopsies from the right ventricular septum, taken at scheduled standard HTx follow-up visits at our department (protocol is to take 4-5 biopsies, two additional biopsies will be taken at this visit). Procedure: Coronary Angiography is part of the scheduled standard HTx follow-up visits. This recording will be used for CAV evaluation. In addition to the protocol procedure, we will evaluate the hemodynamic status in the patients. Diagnostic test: Echocardiography is part of the scheduled standard HTx follow-up visits. No additional examinations will be performed. We will use the standard recordings to calculate the desired parameters.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

HTx patients Patients older than 18 years old can be included in this study provided that they give written consent. Pregnant women will not be included in study 4 because of a risk of genetic modifications based on the radiation from the PET-scans.

You may qualify if:

• Informed consent from participants

You may not qualify if:

• Under 18 years of age
• Endomyocardial biopsy not feasible assessed by surgeon
• Pregnancy (Study 4 only)
• Myocardial infarction, or hospitalization within 1 month due to any cardiac cause (Study 4 only)

Sponsors & Collaborators

• University of Aarhus: lead
• Novo Nordisk A/S: collaborator

Study Sites (1)

Aarhus University Hospital Department of Cardiology

Aarhus, 8200 Aarhus, Denmark

Location

Related Publications (14)

• Clemmensen TS, Logstrup BB, Eiskjaer H, Poulsen SH. Serial changes in longitudinal graft function and implications of acute cellular graft rejections during the first year after heart transplantation. Eur Heart J Cardiovasc Imaging. 2016 Feb;17(2):184-93. doi: 10.1093/ehjci/jev133. Epub 2015 Jun 1.

  PMID: 26034093 BACKGROUND

• Di Lisa F, Bernardi P. Mitochondria and ischemia-reperfusion injury of the heart: fixing a hole. Cardiovasc Res. 2006 May 1;70(2):191-9. doi: 10.1016/j.cardiores.2006.01.016. Epub 2006 Feb 23.

  PMID: 16497286 BACKGROUND

• DePasquale EC, Ardehali A. Primary graft dysfunction in heart transplantation. Curr Opin Organ Transplant. 2018 Jun;23(3):286-294. doi: 10.1097/MOT.0000000000000523.

  PMID: 29553954 BACKGROUND

• Sipahi I, Starling RC. Cardiac allograft vasculopathy: an update. Heart Fail Clin. 2007 Jan;3(1):87-95. doi: 10.1016/j.hfc.2007.02.007.

  PMID: 17545012 BACKGROUND

• 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 BACKGROUND

• Kobayashi Y, Kobayashi Y, Yang HM, Bouajila S, Luikart H, Nishi T, Choi DH, Schnittger I, Valantine HA, Khush KK, Yeung ACY, Haddad F, Fearon WF. Long-term prognostic value of invasive and non-invasive measures early after heart transplantation. Int J Cardiol. 2018 Jun 1;260:31-35. doi: 10.1016/j.ijcard.2018.01.070.

  PMID: 29622448 BACKGROUND

• Schneeberger S, Amberger A, Mandl J, Hautz T, Renz O, Obrist P, Meusburger H, Brandacher G, Mark W, Strobl D, Troppmair J, Pratschke J, Margreiter R, Kuznetsov AV. Cold ischemia contributes to the development of chronic rejection and mitochondrial injury after cardiac transplantation. Transpl Int. 2010 Dec;23(12):1282-92. doi: 10.1111/j.1432-2277.2010.01126.x.

  PMID: 20561305 BACKGROUND

• Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol. 2004 Feb 15;555(Pt 1):1-13. doi: 10.1113/jphysiol.2003.055095. Epub 2003 Dec 5.

  PMID: 14660709 BACKGROUND

• Gvozdjakova A, Kucharska J, Mizera S, Braunova Z, Schreinerova Z, Schramekova E, Pechan I, Fabian J. Coenzyme Q10 depletion and mitochondrial energy disturbances in rejection development in patients after heart transplantation. Biofactors. 1999;9(2-4):301-6. doi: 10.1002/biof.5520090227.

  PMID: 10416044 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Hansson NH, Harms HJ, Kim WY, Nielsen R, Tolbod LP, Frokiaer J, Bouchelouche K, Poulsen SH, Wiggers H, Parner ET, Sorensen J. Test-retest repeatability of myocardial oxidative metabolism and efficiency using standalone dynamic 11C-acetate PET and multimodality approaches in healthy controls. J Nucl Cardiol. 2018 Dec;25(6):1929-1936. doi: 10.1007/s12350-018-1302-z. Epub 2018 May 31.

  PMID: 29855984 BACKGROUND

• Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, Madsen J, Parameshwar J, Starling RC, Uber PA. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant. 2010 Jul;29(7):717-27. doi: 10.1016/j.healun.2010.05.017.

  PMID: 20620917 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples and endomyocardial biopsies.

Study Officials

• Hans Eiskjær, Prof.

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2019
• First Posted: September 26, 2019
• Study Start: April 25, 2019
• Primary Completion: March 1, 2024
• Study Completion: March 1, 2024
• Last Updated: August 11, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)