During the ERC project PAPA we gained insights in the classification of PA treatment as we were the lead researchers in an international study to develop consensus criteria for outcomes after unilateral adrenalectomy for unilateral PA and for the histological classification of aldosterone-producing adrenal lesion, the HISTALDO consensus. This is endorsed by the 2022 WHO classification of adrenal cortical tumors. We established a scoring system which allows preoperatively to identify patients with a high probability of clinical remission after surgery. We showed, that agonistic AT1R antibodies in PA plays a role in patients with bilateral adrenal hyperplasia more than in unilateral PA. Studies related to glucocorticoid co-secretion in PA identified significant glucocorticoid co-secretion as a major phenotype of PA, associated with metabolic co-morbidities, cardiac remodeling and impaired glucose metabolism. We were the first to report adrenal insufficiency postoperatively in a significant fraction of patients. We also identified major problems with currently used immunoassays in routine diagnostics for PA. We identified new molecular mechanism for pathophysiology of APAs, multiple aldosterone-producing micronodules (APMs), identified TSPAN12 as a negative regulator of aldosterone production in PA, and BEX1 as promoter of cell survival in adrenal cells by mediating the inhibition of ferroptosis. To gain further insight into genotype-related tumorigenesis, we investigated the transcriptomic and metabolomic divergence of APA from adjacent adrenal tissue using special transcriptomics in combination with MALDI metabolomics. Using Maldi imaging, we demonstrated specific subgroups of multiple APMs with strikingly divergent distribution patterns of metabolites. In collaborative research projects we identified first-in-field zinc transporter ZnT1 mutations using next-generation sequencing. We discovered mutations in the neuronal cell-adhesion gene CADM1. We identified also risk loci for PA in genome-wide association studies on chromosomes 1 and 13. In an international multicentre proof-of-principle study we showed, that adrenal sparing bilateral resections can bring PA into remission, challenging the current dogma of the routine medical management of bilateral aldosterone excess. We found evidence for major dysfunction of salt perception, consumption and handling and found strong evidence for a beneficial effect of moderate dietary salt restriction on blood pressure control and mental well-being in patients with PA in the Salt CONNtrol trial. Finally, we developed a pig model providing mechanistic insights into the physiologic adaptations to salt excess and salt withdrawal in a species closely related to humans. In summary, within the six years of the ERC action we have made significant advances in basic and translational research to elucidate the humoral and molecular mechanisms underlying aldosterone. Dissemination of our main findings have been achieved by 60 publications in international journals, congress presentations, international symposia and press releases.
