Primary Aldosteronism: CXCR4- and FAP-Targeted PET/MR for Adrenal-Cardiac Axis

BACKGROUND: Primary aldosteronism (PA) carries excess cardiovascular risk not fully explained by hemodynamic load. While aldosterone promotes fibroblast activation experimentally, in vivo evidence linking adrenocortical activity with myocardial remodeling remains limited. This study integrated CXCR4 (C-X-C chemokine receptor type 4)-targeted 68 Ga-Pentixafor positron emission tomography (PET)/magnetic resonance and FAP (fibroblast activation protein)-targeted 68 Ga-FAPI (fibroblast activation protein inhibitor)-04 PET/cardiac magnetic resonance to evaluate the adrenal-cardiac axis in PA. METHODS: Eighty-two participants (40 with PA [21 aldosterone-producing adenoma (APA), 19 idiopathic hyperaldosteronism], 21 with essential hypertension, and 21 normotensive controls) underwent 68 Ga-FAPI-04 PET/cardiac magnetic resonance; 48 concurrently underwent 68 Ga-Pentixafor PET/magnetic resonance. Adrenal CXCR4 and myocardial FAPI uptake, as well as integrated volumetric-uptake burdens, were quantified and correlated with clinical and cardiac magnetic resonance indices. Eight patients with APA underwent follow-up imaging postadrenalectomy. RESULTS: Adrenal volume-adjusted CXCR4 signal served as a reliable marker of in vivo aldosterone burden and was significantly associated with adverse left ventricular remodeling, independent of blood pressure levels or hypertension duration. Myocardial 68 Ga-FAPI-04 uptake was detected in 55% of patients with PA (APA 71.4%, idiopathic hyperaldosteronism 36.8%), compared with 19% of patients with essential hypertension and 0% of controls ( P <0.001), localizing predominantly to the basal septum. Importantly, total adrenal volume-adjusted CXCR4 signal correlated with myocardial FAPI activity ( r =0.38–0.64; all P <0.05) and cardiac magnetic resonance markers of remodeling, both of which were positively associated with aldosterone levels. At 5.2±1.2 months post-adrenalectomy, myocardial FAPI uptake in 8 patients with APA declined significantly ( P <0.01), whereas late gadolinium enhancement and global cardiac function showed no significant change. CONCLUSIONS: Dual-tracer PET/magnetic resonance provided in vivo molecular evidence of a CXCR4-FAP–mediated adrenal-cardiac axis in PA, revealing cross-talk between adrenocortical function, aldosterone secretion, and myocardial fibroblast activation beyond blood pressure effects. FAPI PET demonstrated more severe myocardial activation in APA, with partial postadrenalectomy reversibility, underscoring the value of early diagnosis and timely surgical intervention. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06756737.