Microvascular dysfunction in heart transplantation is associated with altered cardiomyocyte mitochondrial structure and unimpaired excitation-contraction coupling

Felix Hohendanner (Berlin)1, M. Bögner (Berlin)2, H. Judith (Berlin)1, S. Dreysse (Berlin)1, C. Knosalla (Berlin)3, V. Falk (Berlin)4, F. Schönrath (Berlin)3, I. A. Just-Lauer (Berlin)2, P. Stawowy (Berlin)1

1Deutsches Herzzentrum der Charite (DHZC) Klinik für Kardiologie, Angiologie und Intensivmedizin | CBF Berlin, Deutschland; 2Charité - Universitätsmedizin Berlin CC11: Med. Klinik m.S. Kardiologie Berlin, Deutschland; 3Deutsches Herzzentrum der Charite (DHZC) Klinik für Herz-, Thorax- und Gefäßchirurgie Berlin, Deutschland; 4Charité - Universitätsmedizin Berlin Klinik für kardiovaskuläre Chirurgie Berlin, Deutschland


Introduction: Microvascular dysfunction (MVD) is a hallmark feature of chronic graft dysfunction in patients that underwent orthotopic heart transplantation (OHT) and is the main contributor to impaired long-term graft survival. The aim of this study was to determine the effect of MVD on functional and structural properties of cardiomyocytes isolated from ventricular biopsies of OHT patients.

Methods: We included 14 patients post-OHT, who had been transplanted for 8.1 years [5.0; 15.7 years]. Mean age was 49.6 ± 14.3 years; 64% were male. Coronary microvasculature was assessed using guidewire-based coronary flow reserve(CFR)/index of microvascular resistance (IMR) measurements. Ventricular myocardial biopsies were obtained and cardiomyocytes were isolated using enzymatic digestion. Cells were electrically stimulated and subcellular Ca2+ signalling as well as mitochondrial density were measured using confocal imaging.

Results: MVD measured by IMR was present in 6 of 14 patients with a mean IMR of 53±10 vs. 12±2 in MVD vs. controls (CTRL), respectively. CFR did not differ between MVD and CTRL. Ca2+ transients during excitation-contraction coupling in isolated ventricular cardiomyocytes from a subset of patients showed unaltered amplitudes. In addition, Ca2+ release and Ca2+ removal were not significantly different between MVD and CTRL. However, mitochondrial density was significantly increased in MVD vs. CTRL (34±1 vs. 29±2%), indicating subcellular changes associated with MVD.

Conclusion: In-vivo ventricular microvascular dysfunction post OHT is associated with preserved excitation-contraction coupling in-vitro, potentially owing to compensatory changes on the mitochondrial level or due to the potentially reversible cause of the disease.

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