Abstract 098: Aldosterone-Producing Cell Clusters in Essential Hypertension

Introduction: Primary aldosteronism (PA) is one of the major causes of secondary hypertension and has two major subtypes. One is unilateral aldosterone-producing adenoma (APA), which is positive for aldosterone synthase (CYP11B2) by immunohistochemistry (IHC), and the other is bilateral idiopathic hyperaldosteronism (IHA), which has image-undetectable CYP11B2-positive cell clusters (termed aldosterone-producing cell clusters, APCC) beneath the adrenal capsule. We and others have previously shown that APCC present in normotensive adrenals and the number is significantly less than IHA adrenals, supporting the disease-causing role of APCC in hyperaldosteronism of IHA. Furthermore, we have also shown that most of APCCs in the IHA and normotensive adrenals harbor somatic mutations in a L-type calcium channel, CACNA1D, whereas most of APA has been previously shown to harbor those in a potassium channel, KCNJ5. These mutations are reported to increase intracellular calcium levels, resulting in aldosterone overproduction. Here, we seek for the first time to identify the potential role of APCC in non-PA hypertensive patients and to clarify whether these adrenals could be precursor of APA or IHA by performing next-generation sequencing (NGS) on observed APCC.

Method and Results: We selected fifteen adrenal glands with the evidence of hypertension and/or antihypertensive agents from a cohort of serial Japanese autopsy cases. None of the cases harbored adrenal tumors, but instead nine cases harbored 23 APCCs. We then isolated DNA from each APCC and performed NGS targeting genes mutated in APA. Of observed APCCs, 9 (39%) APCCs harbored somatic mutations in CACNA1D.

Interpretations: These results show that autonomous aldosterone production in a part of patients with essential hypertension is caused by APCCs with aldosterone-driving somatic mutations. In addition, the mutation spectrum observed in this cohort suggests that essential hypertension could potentially develop into IHA through aldosterone overproduction by APCC.