Autonomous Epinephrine Release by KCNJ5 Mutation Drives Familial Thoracic Aortic Aneurysm and Dissection.

Background: The pathophysiology of familial thoracic aortic aneurysm and dissection (TAAD) is linked to genetic variants that affect aortic components. Although hypertension is a risk factor for TAAD, the precise genetic link remains unclear.

Methods: A family with autosomal dominant TAAD complicated by hypertension was studied to identify candidate mutations. The effect of the identified mutation on TAAD development was investigated using a CRISPR-Cas9-generated knock-in mouse model to elucidate the mechanism underlying hypertension-induced TAAD.

Results: The KCNJ5 p.R242Q mutation was identified in the family and met the criteria for cosegregation, rarity, and conservation. Utilizing our mouse model, we observed that a significant proportion of heterozygous mice with the mutation displayed dilated thoracic aortas. The mutation's allele dose was positively correlated with TAAD incidence following β-aminopropionitrile monofumarate treatment. Pathological changes in the thoracic aorta, including collagen deposition and dilation, elevated transforming growth factor-β activity, and extracellular matrix remodeling, were associated with hypertension. Furthermore, the mutation was found to induce lifelong isolated systolic hypertension, attributable to autonomous epinephrine secretion from the adrenal medulla. Unlike wild-type, mutated KCNJ5 was highly expressed in the adrenal medulla instead of the adrenal cortex. Treatment with the adrenergic β-receptor blocker propranolol reduced systolic hypertension and mitigated TAAD in the heterozygous mice.

Conclusions: Familial TAAD may stem from KCNJ5 dysfunction in the G-protein-coupling domain, causing isolated systolic hypertension via increased epinephrine secretion and disruption of thoracic aortic homeostasis. These findings establish a genetic link between systolic hypertension and TAAD.