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.