Shahrzad Sepehrkhouy1, Johannes M I H Gho2, René van Es2, Magdalena Harakalova3, Nicolaas de Jonge2, Dennis Dooijes4, Jasper J van der Smagt4, Marc P Buijsrogge5, Richard N W Hauer6, Roel Goldschmeding1, Roel A de Weger1, Folkert W Asselbergs7, Aryan Vink8. 1. Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. 2. Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands. 3. Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands. 4. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands. 5. Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht, the Netherlands. 6. Netherlands Heart Institute, Utrecht, the Netherlands. 7. Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom. 8. Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: a.vink@umcutrecht.nl.
Abstract
BACKGROUND: Desmosomal and phospholamban (PLN) mutations are associated with arrhythmogenic cardiomyopathy. Ultimately, most cardiomyopathic hearts develop significant cardiac fibrosis. OBJECTIVE: To compare the fibrosis patterns of desmosomal and p. Arg14del PLN-associated cardiomyopathies with the pattern in hearts with other hereditary cardiomyopathies. METHODS: A midventricular transversal slice was obtained from hearts of 30 patients with a cardiomyopathy with a known underlying mutation and from 8 controls. Fibrosis and fatty changes were quantitatively analyzed using digital microscopy. RESULTS: Hearts from patients with desmosomal mutations (n = 6) showed fibrosis and fibrofatty replacement in the left ventricular (LV) outer myocardium, mainly in the posterolateral wall, and in the right ventricle. A similar phenotype, but with significantly more severe fibrotic changes in the LV, was found in the PLN mutation group (n = 8). Cardiomyopathies associated with lamin A/C (n = 5), sarcomeric (n = 8), and desmin (n = 3) mutations all showed a different pattern from that of the desmosomal and PLN mutation carriers. The posterolateral LV wall appeared to be the most discriminative area with fibrosis and fatty changes predominantly at the outer compact myocardium in 13 of 14 hearts with desmosomal and PLN mutations (93%), in 0 of 13 hearts with lamin A/C and sarcomeric mutations (0%), and in 1 of 3 desminopathic hearts (33%) (P < .001). CONCLUSION: Desmosomal- and PLN-associated cardiomyopathies have a fibrosis pattern distinct from the patterns in other hereditary cardiomyopathies. The posterolateral LV wall appeared to be the most discriminative region between mutation groups. These results may provide a roadmap for cardiac imaging interpretation and may help in further unraveling disease mechanisms.
BACKGROUND: Desmosomal and phospholamban (PLN) mutations are associated with arrhythmogenic cardiomyopathy. Ultimately, most cardiomyopathic hearts develop significant cardiac fibrosis. OBJECTIVE: To compare the fibrosis patterns of desmosomal and p. Arg14del PLN-associated cardiomyopathies with the pattern in hearts with other hereditary cardiomyopathies. METHODS: A midventricular transversal slice was obtained from hearts of 30 patients with a cardiomyopathy with a known underlying mutation and from 8 controls. Fibrosis and fatty changes were quantitatively analyzed using digital microscopy. RESULTS: Hearts from patients with desmosomal mutations (n = 6) showed fibrosis and fibrofatty replacement in the left ventricular (LV) outer myocardium, mainly in the posterolateral wall, and in the right ventricle. A similar phenotype, but with significantly more severe fibrotic changes in the LV, was found in the PLN mutation group (n = 8). Cardiomyopathies associated with lamin A/C (n = 5), sarcomeric (n = 8), and desmin (n = 3) mutations all showed a different pattern from that of the desmosomal and PLN mutation carriers. The posterolateral LV wall appeared to be the most discriminative area with fibrosis and fatty changes predominantly at the outer compact myocardium in 13 of 14 hearts with desmosomal and PLN mutations (93%), in 0 of 13 hearts with lamin A/C and sarcomeric mutations (0%), and in 1 of 3 desminopathic hearts (33%) (P < .001). CONCLUSION: Desmosomal- and PLN-associated cardiomyopathies have a fibrosis pattern distinct from the patterns in other hereditary cardiomyopathies. The posterolateral LV wall appeared to be the most discriminative region between mutation groups. These results may provide a roadmap for cardiac imaging interpretation and may help in further unraveling disease mechanisms.
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