Novel Mechanisms in Primary Aldosteronism

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Hypertension is a major cardiovascular risk factor that affects between 10% and 40% of the general population in an age-dependent manner. Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. With the application of wider screening for PA, more than 70% of cases of aldosterone excess have been defined as caused by idiopathic hyperaldosteronism, with aldosterone producing adenoma making up the remainder. The application of next-generation sequencing methods over the last 3 years has resulted in the identification of genetic contributors for the endocrine autonomy of aldosterone producing adenomas in roughly 50% of cases. These developments present a major breakthrough in the field and highlight the power of current state-of-the art genetic and molecular tools. In sharp contrast, the pathophysiology of IHA remains obscure.The overarching hypothesis of this proposal is that as yet unidentified factors can drive excessive aldosterone release. We hypothesize that these aldosterone secretagogues may contribute to, putatively cause and sustain aldosterone excess in patients with primary aldosteronism. This hypothesis is founded on results from in vitro and in vivo models as well as from clinical evidence. We will define their contribution, prevalence and longitudinal persistence in selected population based cohorts and in the cohort of the German Conn registry. We will also use blood specimens collected during adrenal vein sampling which will provide a window into the paracrine environment of the adrenals of PA patients. The proposal has the following specific aims: 1. To establish the existence of agonistic AT1R autoantibodies in primary aldosteronism, 2. To establish the existence of novel autocrine/paracrine mechanisms in primary aldosteronism and 3. To establish if elevated prolactin levels arising from systemic hyperprolactinemia comprise a novel mechanism in primary aldosteronism. To achieve these aims we will develop and apply state of the art functional assays and molecular techniques that have the potential to improve understanding of the most prevalent form of secondary hypertension with the future prospect of improved diagnosis and treatment.