TY - JOUR
T1 - Arrhythmogenic cardiomyopathy
T2 - Pathology, genetics, and concepts in pathogenesis
AU - Hoorntje, Edgar T.
AU - Te Rijdt, Wouter P.
AU - James, Cynthia A.
AU - Pilichou, Kalliopi
AU - Basso, Cristina
AU - Judge, Daniel P.
AU - Bezzina, Connie R.
AU - Van Tintelen, J. Peter
PY - 2017/10/1
Y1 - 2017/10/1
N2 - Arrhythmogenic cardiomyopathy (ACM) is a rare, heritable heart disease characterized by fibro-fatty replacement of the myocardium and a high degree of electric instability. It was first thought to be a congenital disorder, but is now regarded as a dystrophic heart muscle disease that develops over time. There is no curative treatment and current treatment strategies focus on attenuating the symptoms, slowing disease progression, and preventing life-threatening arrhythmias and sudden cardiac death. Identification of mutations in genes encoding desmosomal proteins and in other genes has led to insights into the disease pathogenesis and greatly facilitated identification of family members at risk. The disease phenotype is, however, highly variable and characterized by incomplete penetrance. Although the reasons are still poorly understood, sex, endurance exercise and a gene-dosage effect seem to play a role in these phenomena. The discovery of the genes and mutations implicated in ACM has allowed animal and cellular models to be generated, enabling researchers to start unravelling it's underlying molecular mechanisms. Observations in humans and in animal models suggest that reduced cell-cell adhesion affects gap junction and ion channel remodelling at the intercalated disc, and along with impaired desmosomal function, these can lead to perturbations in signalling cascades like the Wnt/β-catenin and Hippo/YAP pathways. Perturbations of these pathways are also thought to lead to fibro-fatty replacement. A better understanding of the molecular processes may lead to new therapies that target specific pathways involved in ACM.
AB - Arrhythmogenic cardiomyopathy (ACM) is a rare, heritable heart disease characterized by fibro-fatty replacement of the myocardium and a high degree of electric instability. It was first thought to be a congenital disorder, but is now regarded as a dystrophic heart muscle disease that develops over time. There is no curative treatment and current treatment strategies focus on attenuating the symptoms, slowing disease progression, and preventing life-threatening arrhythmias and sudden cardiac death. Identification of mutations in genes encoding desmosomal proteins and in other genes has led to insights into the disease pathogenesis and greatly facilitated identification of family members at risk. The disease phenotype is, however, highly variable and characterized by incomplete penetrance. Although the reasons are still poorly understood, sex, endurance exercise and a gene-dosage effect seem to play a role in these phenomena. The discovery of the genes and mutations implicated in ACM has allowed animal and cellular models to be generated, enabling researchers to start unravelling it's underlying molecular mechanisms. Observations in humans and in animal models suggest that reduced cell-cell adhesion affects gap junction and ion channel remodelling at the intercalated disc, and along with impaired desmosomal function, these can lead to perturbations in signalling cascades like the Wnt/β-catenin and Hippo/YAP pathways. Perturbations of these pathways are also thought to lead to fibro-fatty replacement. A better understanding of the molecular processes may lead to new therapies that target specific pathways involved in ACM.
KW - Arrhythmogenic cardiomyopathy
KW - Arrhythmogenic right ventricular cardiomyopathy
KW - Genetics
KW - Pathogenesis
KW - Pathology
UR - http://www.scopus.com/inward/record.url?scp=85030782451&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/cvr/cvx150
DO - https://doi.org/10.1093/cvr/cvx150
M3 - Review article
C2 - 28957532
SN - 0008-6363
VL - 113
SP - 1521
EP - 1531
JO - Cardiovascular research
JF - Cardiovascular research
IS - 12
ER -