Abnormal mitochondrial function and morphology in heart transplanted patients with cardiac allograft vasculopathy

Emil Dariush Lichscheidt; Nichlas Riise Jespersen; Bent Roni Ranghøj Nielsen; Katrine Berg; Jacob Seefeldt; Jens Randel Nyengaard; Hans Erik Bøtker; Hans Eiskjær

doi:10.1016/j.healun.2022.01.1376

Abnormal mitochondrial function and morphology in heart transplanted patients with cardiac allograft vasculopathy

J Heart Lung Transplant. 2022 Jun;41(6):732-741. doi: 10.1016/j.healun.2022.01.1376. Epub 2022 Feb 3.

Authors

Emil Dariush Lichscheidt¹, Nichlas Riise Jespersen², Bent Roni Ranghøj Nielsen², Katrine Berg³, Jacob Seefeldt³, Jens Randel Nyengaard⁴, Hans Erik Bøtker², Hans Eiskjær²

Affiliations

¹ Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: emilic@clin.au.dk.
² Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
³ Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
⁴ Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark; Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University Hospital, Aarhus, Denmark.

PMID: 35249802
DOI: 10.1016/j.healun.2022.01.1376

Abstract

Background: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival of HTx patients. Mitochondrial dysfunction has been reported in both arteriosclerotic coronary disease and heart failure. However, myocardial mitochondrial function has not been examined in HTx patients with CAV.

Methods: 43 HTx patients (21 patients with CAV and 22 patients without CAV) ≥12 months after HTx were enrolled. Endomyocardial biopsies were analyzed using high-resolution respirometry for glucose-coupled mitochondrial respiration. Number and area of mitochondria profiles as well as cristae morphology were assessed by transmission electron microscopy. Echocardiography and coronary angiography were used to measure global longitudinal strain (GLS) and grade CAV.

Results: Complex I+II-linked respiration was reduced in patients with CAV compared with patients without CAV (82.7 ± 31.9 pmol O2/(s•mg) vs 116 ± 35.9 pmol O2/(s•mg), p = 0.003). Mitochondrial respiratory function measured as oxidative phosphorylation coupling efficiency was positively associated with left ventricular GLS (r = 0.49, p = 0.002) and negatively associated with elevated biomarkers (Troponin T: r=-0.33, p = 0.04 and NT-proBNP: r = -0.41, p = 0.009). Mitochondrial profile number and area did not differ. However, patients with CAV had a larger proportion of mitochondria with abnormal cristae morphology (p < 0.001).

Conclusions: Myocardial mitochondrial respiration is impaired in patients with CAV and is associated with an abnormal cristae morphology. The mitochondrial dysfunction appears to be associated with reduced myocardial contractile function and elevated biomarkers. These results highlight that mitochondrial targeted treatment in patients with CAV should be assessed in future clinical studies.

Keywords: basic; cardiac allograft vasculopathy; heart failure; metabolism; mitochondria; translational and Clinical Research; vascular disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Biomarkers
Coronary Angiography / methods
Coronary Artery Disease* / diagnosis
Coronary Artery Disease* / etiology
Heart Transplantation* / adverse effects
Heart Transplantation* / methods
Humans
Mitochondria

Substances

Biomarkers