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- Roberts, Jason D., et al.
(författare)
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Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
- 2019
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 129:8, s. 3171-3184
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Tidskriftsartikel (refereegranskat)abstract
- Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease.
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| 2. |
- Carlsson, Marcus, et al.
(författare)
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Coronary microembolization causes long-term detrimental effects on regional left ventricular function.
- 2011
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Ingår i: Scandinavian cardiovascular journal : SCJ. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 45, s. 205-214
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objectives. To investigate whether coronary microemboli have long-term effects on left ventricular (LV) function in an experimental model. Furthermore, to determine if first-pass perfusion and late gadolinium enhancement (LGE) patterns differs between small- and large-sized microemboli. Design. Six pigs underwent left anterior descending (LAD)-coronary microembolization with small-sized (40-120 μm, n∼250 000) microemboli using a combined x-ray and MRI-system. MR-images before, one hour after and 7-8 weeks after microembolization were obtained. Results were compared to MRI obtained by large-sized (100-300 μm, n∼7200) microemboli. Results. Cine MRI showed an acute drop in ejection fraction (from 49.5 ± 2.6% to 32.5 ± 2.8) that substantially recovered at 7-8 weeks (47.5 ± 3.2%). Regional LV-function assessed as circumferential, longitudinal and radial strain declined in both microinfarcts and remote regions followed by partial recovery at 7-8 weeks. The decline in LV function and the severe perfusion deficit from the small microemboli was similar to the large microemboli at one hour. There was a significant recovery in perfusion at 7-8 weeks in the microinfarcts. LGE demonstrated the microinfarcts at 7-8 weeks but not at one hour and the microinfarcts were confirmed by histopathology. Conclusion. Microembolization causes long-term, regional LV dysfunction and this study confirmed the need of a comprehensive MRI-protocol for the detection of microinfarcts. These findings suggest that even small microemboli (40-120 μm in diameter), which may escape the distal protective devices influence cardiac function.
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