Cardiac Mitochondrial Function After Heart Transplantation

Cardiac Allograft Vasculopathy Clinical Trial

— ENERGY-HTX  

Official title:

Cardiac Mitochondrial Function After Heart Transplantation

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04105803
• Other study ID #: 1-10-72-367-18
• Status: Enrolling by invitation
• Start date: April 25, 2019
• Est. completion date: March 1, 2024

Study information

• Verified date: July 2020
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

Background

The prognosis after heart transplantation (HTx) has improved considerably since the first HTx was performed in 1967. Studies from our group have shown both left and right ventricular function is affected immediately after heart transplantation, but this seems to recover to some extent over the first year. This immediate effect on the graft organ following HTx is associated with tissue ischemia and reperfusion injury causing cellular energy depletion, mitochondrial failure and subsequent apoptosis. The condition may progress into full blown primary graft failure (PGF) with a need for mechanical cardiovascular support or inotropes which is seen in 3-30 % of HTx patients. The cardiac injury will consequently increase the risk of morbidity as well as mortality. In addition to acute PGF, a chronic rejection owing to coronary arterial vasculopathy (CAV) may develop. Hence, despite advances in peritransplantation treatment and immunosuppression, PGF and CAV remain the major heart related mortality causes following HTx and additional assessment and treatments are therefore needed.

Graft rejection is diagnosed, and the severity graded based on endomyocardial biopsies (EMB) taken percutaneously through the jugular or femoral veins. These biopsies are routinely performed at our institution to ensure prober immunosuppression following HTx.1 Acute cellular rejection (ACR) may occur in approximately 25% of the patients which is associated with PGF, CAV and later chronic rejection. However, mitochondrial function and integrity may prove to be a more sensitive marker of allograft rejection. In heart failure, mitochondria density changes while function and integrity is impaired linking the failing heart to energy deprivation. Animal studies demonstrate that deterioration in total mitochondrial function precedes histopathological changes during cardiac graft rejection following HTx. Therefore, assessment of mitochondrial function following HTx may allow for earlier detection of rejection and allograft dysfunction. This may be of particular importance as emerging treatments are targeting both energy substrate supply for adenosine-triphosphate (ATP) generation produced by the mitochondria as well as mitochondrial function in the failing heart. At our institution, we have established methods to evaluate mitochondrial function in myocardial tissue, and pilot studies have demonstrated feasibility with the use of EMB. In addition, by use of non-invasive 11C-acetate positron-emission tomography (PET), we can assess myocardial external energy efficiency (MEE) calculated by the ratio of myocardial external work (EW) and oxidative metabolism (MVO2). Thus, enabling quantification of coupling between mitochondrial energy production and mechanical work.

Despite the overt association between graft dysfunction/rejection and mitochondrial function, it remains unsettled whether mitochondrial content and function associate with PGF, ACR and CAV. Such findings may be of prognostic importance and even elucidate a new treatment target.

Hypotheses

1. Primary graft pump function is correlated to mitochondrial function in the first myocardial biopsy taken from the donor heart during the operation

2. Cardiac mitochondrial function improves over the first 3 months after a heart transplantation

3. Heart transplant patients with moderate to severe coronary graft vasculopathy has impaired mitochondrial function

4. MEE can be used as a marker of mitochondrial function and chronic rejection in HTx patients

Objectives

Study 1: To examine whether primary myocardial function is related to cardiac mitochondrial function in de novo HTx patients

Study 2: To investigate whether cardiac mitochondrial function improves over time after HTx along with improvement of cardiac function

Study 3: To examine whether heart transplanted patients with chronic rejection and graft vasculopathy have impaired mitochondrial function

Study 4: To evaluate whether MEE can be used as marker of mitochondrial function and chronic rejection

Design and endpoints

Study 1: The association between cardiac and mitochondrial function following HTx

Design: Myocardial mitochondrial function analyzed from 15 HTx patients taken from the donor heart during the transplantation will be compared to EMB from 15 HTx patients at scheduled biopsies (1 or 2 years after implantation)

Study 2: Development in cardiac and mitochondrial function following HTx Design:

Mitochondrial function measured at scheduled EBM follow-up (1,2,3,4,8,12 weeks and 6 months after HTx) from 24 HTx patients. These results are compared to 15 patients with biopsies performed at 1 and 2 years after HTx.

Study 3: The impact of coronary arterial vasculopathy on mitochondrial function Design:

Mitochondrial function assessed at scheduled EMB follow-up visits of patients with CAV as determined by coronary angiography (scheduled procedure) 15 HTx patients CAV are compared to 15 HTx patients with without CAV.

Study 4: MEE as a non-invasive marker of mitochondrial function and allograft rejection Design: 24 HTX patients scheduled for EMB will be examined twice with 11C-acetate-PET. It is intended that we consecutively recruit patients enrolled in study 2. The first examination is performed within 3 weeks following HTx and the second examination after 6 months. Up to 4 weeks between EMB and the second 11C-acetate PET examination is accepted.

(The HTx patient cohort which is subjected to biopsies 1 and 2 years after HTx in study 3 (n=15) is reused in study 1 and 2 as a comparable cohort. Hence, a total of 69 patients are enrolled. However, it is anticipated that several patients from study 1 and are enrolled in study 2 which will decrease the total number of participants.)

Methods

Mitochondrial function will be assessed in myocardial biopsies by High-resolution respirometry and Electron microscopy

Cardiac functions is assessed by transthoracic echocardiography

Coronary Angiography is performed to assess the degree of CAV

Blood samples will be taken

In study 4, MEE will be assessed by positron emission tomography using validated kinetic methods.

Ethical considerations

The project will be carried out in accordance with the principles of the Helsinki Declaration II. The protocol, including the written participant information and consent forms must be finally approved by the Research Ethics Committee of the Central Denmark Region and .

Publication and study plan All results, whether positive, negative or inconclusive will be published in an international peer-reviewed scientific journal.

Perspectives Cellular rejection (ACR) shortly after HTx is strongly associated with the long-term development of CAV and subsequent myocardial dysfunction. As graft failure and CAV are the major long-term heart-related late mortality causes following HTx, it seems paramount to modify long-term hazards such as ACR, CAV, and graft failure to significantly improve post-transplant outcome.5 In this context mitochondrial function seems to be pivotal, hence, approaches to assess mitochondrial function in HTx patient may prove to pave the way for new follow-up algorithms and even treatment targets.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 64
• Est. completion date: March 1, 2024
• Est. primary completion date: March 1, 2024
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Informed consent from participants

Exclusion Criteria:

• 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)

Related Conditions & MeSH terms

• Acute Cellular Graft Rejection
• Cardiac Allograft Vasculopathy
• Mitochondrial Function
• Primary Graft Failure
• Vascular Diseases

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital Department of Cardiology	Aarhus

Sponsors (2)

Lead Sponsor	Collaborator
University of Aarhus	Novo Nordisk A/S

Country where clinical trial is conducted

Denmark, 

References & Publications (14)

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. Review. — View Citation

Clemmensen TS, Løgstrup BB, Eiskjær 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. — View Citation

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. Review. — View Citation

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. Epub 2006 Feb 23. Review. — View Citation

Gormsen LC, Svart M, Thomsen HH, Søndergaard E, Vendelbo MH, Christensen N, Tolbod LP, Harms HJ, Nielsen R, Wiggers H, Jessen N, Hansen J, Bøtker HE, Møller 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). pii: e005066. doi: 10.1161/JAHA.116.005066. — View Citation

Gvozdjáková A, Kucharská J, Mizera S, Braunová Z, Schreinerová Z, Schrameková E, Pechán I, Fabián J. Coenzyme Q10 depletion and mitochondrial energy disturbances in rejection development in patients after heart transplantation. Biofactors. 1999;9(2-4):301-6. — View Citation

Hansson NH, Harms HJ, Kim WY, Nielsen R, Tolbod LP, Frøkiær J, Bouchelouche K, Poulsen SH, Wiggers H, Parner ET, Sörensen J. Test-retest repeatability of myocardial oxidative metabolism and efficiency using standalone dynamic (11)C-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. — View Citation

Jespersen NR, Yokota T, Støttrup NB, Bergdahl A, Paelestik KB, Povlsen JA, Dela F, Bøtker 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. — View Citation

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. — View 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. — View Citation

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. Erratum in: J Heart Lung Transplant. 2011 Mar;30(3):360. — View Citation

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. — View Citation

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* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	Biochemistry	TNT, proBNP, IL-1, IL-6, TNFalpha, sST2	Through study completion, an average of 2 years.
Secondary	Cardiac function	Left ventricular function (GLS) assessed by echocardiography	Through study completion, an average of 2 years.
Secondary	Invasive hemodynamics	Pulmonary (mPAP) and wedge pressures (mPCWP) assessed by right heart catheterization	Through study completion, an average of 2 years.
Secondary	Cellular function	Rejection state in cardiac tissue (assessed on the international scale for tissue rejection by pathologist): Grade 0R - No rejection. Grade 1R, mild - Interstitial and/or perivascular infiltrate with up to 1 focus of myocyte damage.; Grade 2R, moderate - Two or more foci of infiltrate with associated myocyte damage.; Grade 3R, severe Diffuse infiltrate with multifocal myocyte damage ± edema, ± hemorrhage ± vasculitis.	Through study completion, an average of 2 years.
Secondary	Mitochondrial structure	Assessed by electron microscopy (mitochondrial density and matrix folding)	Through study completion, an average of 2 years.