Atrial myopathy: A primary substrate for atrial fibrillation

The pathophysiology underlying atrial fibrillation (AF), the most common sustained cardiac arrhythmia, traditionally has been viewed as secondary to external atrial stressors rather than reflecting a primary atrial disorder. 1 Benjamin E.J. Levy D. Vaziri S.M. D'Agostino R.B. Belanger A.J. Wolf P.A. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA. 1994; 271: 840-844 Crossref PubMed Scopus (2542) Google Scholar Prominent risk factors such as hypertension, obstructive sleep apnea, and ventricular cardiomyopathy have generally been assumed to exert hemodynamic strains leading to atrial dilation and arrhythmia vulnerability. 2 Staerk L. Sherer J.A. Ko D. Benjamin E.J. Helm R.H. Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes. Circ Res. 2017; 120: 1501-1517 Crossref PubMed Scopus (431) Google Scholar Although increased atrial filling pressures and associated stretch may be contributors, our evolving understanding of AF pathogenesis has begun to suggest more nuanced underlying pathways that may be mediated by primary genetic disease. 2 Staerk L. Sherer J.A. Ko D. Benjamin E.J. Helm R.H. Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes. Circ Res. 2017; 120: 1501-1517 Crossref PubMed Scopus (431) Google Scholar ,3 Roberts J.D. Gollob M.H. Impact of genetic discoveries on the classification of lone atrial fibrillation. J Am Coll Cardiol. 2010; 55: 705-712 Crossref PubMed Scopus (79) Google Scholar Rapidly growing insight into the genetic architecture of AF has suggested that a primary atrial myopathy, as opposed to primary channelopathies or increased intracardiac filling pressures secondary to ventricular dysfunction, may be a critical substrate for AF development. 4 Li Q. Huang H. Liu G. et al. Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing. Biochem Biophys Res Commun. 2009; 380: 132-137 Crossref PubMed Scopus (86) Google Scholar , 5 Nielsen J.B. Thorolfsdottir R.B. Fritsche L.G. et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet. 2018; 50: 1234-1239 Crossref PubMed Scopus (262) Google Scholar , 6 Roselli C. Chaffin M.D. Weng L.-C. et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet. 2018; 50: 1225-1233 Crossref PubMed Scopus (291) Google Scholar , 7 Choi S.H. Weng L.-C. Roselli C. et al. Association between titin loss-of-function variants and early-onset atrial fibrillation. JAMA. 2018; 320: 2354-2364 Crossref PubMed Scopus (91) Google Scholar , 8 Lazarte J. Laksman Z.W. Wang J. et al. Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in "lone" atrial fibrillation. Europace. 2021; 23: 844-850 Crossref PubMed Scopus (5) Google Scholar Familial atrial myopathy in a large multigenerational heart-hand syndrome pedigree carrying an LMNA missense variant in rod 2B domain (p.R335W)Heart RhythmVol. 19Issue 3PreviewThe literature on laminopathy with ventricular phenotype is extensive. However, the pathogenicity of LMNA variations in atrial lesions still lacks research. Full-Text PDF