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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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| 4. |
- Kalantarian, Shadi, et al.
(författare)
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Long-Term Electrocardiographic and Echocardiographic Progression of Arrhythmogenic Right Ventricular Cardiomyopathy and Their Correlation With Ventricular Tachyarrhythmias.
- 2021
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Ingår i: Circulation Heart Failure. - : LIPPINCOTT WILLIAMS & WILKINS. - 1941-3289 .- 1941-3297. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prior studies of structural and electrocardiographic changes in arrhythmogenic right ventricular (RV) cardiomyopathy and their role in predicting ventricular arrhythmias (ventricular tachycardia) have shown conflicting results.METHODS: We reviewed 405 ECGs, 315 transthoracic echocardiographies, and 441 implantable cardioverter defibrillator interrogations in 64 arrhythmogenic RV cardiomyopathy patients (56% men, mean age [SD], 44.2 [14.6] years) over a mean follow-up of 10 (range, 2.3-19) years. Generalized estimating equations were used to identify the association between ECG abnormalities, clinical variables, and transthoracic echocardiographic measurements (>mild degree of tricuspid regurgitation, RV outflow tract diameter in parasternal long axis and short axis, RV end-diastolic area, fractional area change).RESULTS: There was a 4.65 (95% CI, 0.51%-8.8%) increase in RV end-diastolic area, a 3.75 (95% CI, 1.17%-6.34%) decrease in fractional area change, and 1.9 (95% CI, 1.3-2.8) higher odds (odds ratio) of RV wall motion abnormality with every 5-year increase in age after patients' first transthoracic echocardiography. >Mild tricuspid regurgitation was an independent predictor of RV enlargement and dysfunction (hazard ratio of >10% drop in fractional area change from baseline [95% CI], 3.51 [1.77-6.95] and hazard ratio of >10% increase in RV end-diastolic area from baseline [95% CI], 4.90 [2.52-9.52]). Patients with implantable cardioverter defibrillator were more likely to develop >mild tricuspid regurgitation and larger structural and functional disease progression. More pronounced increase in RV end-diastolic area was translated into higher rates of any ventricular tachycardia. Inferior T-wave inversions and sum of R waves (mm) in V1 to V3 were predictors of RV enlargement and dysfunction with the former also predicting risk of any ventricular tachycardia.CONCLUSIONS: Arrhythmogenic RV cardiomyopathy is a progressive disease. Tricuspid regurgitation is an independent predictor of structural disease progression, which may be exacerbated by use of a transvenous implantable cardioverter defibrillator lead.
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