Novel Mechanisms in Primary Aldosteronism

高血压是一个主要的心血管危险因素，以年龄相关的方式影响10%至40%的一般人口。原发性醛固酮增多症(PA)是继发性高血压最常见的原因。随着PA筛查的广泛应用，超过70%的醛固酮过剩病例被定义为由特发性醛固酮增多症引起，其余的病例是由产生醛固酮的腺瘤引起的。在过去的三年中，下一代测序方法的应用已经导致在大约50%的病例中发现了产生醛固酮的腺瘤内分泌自主性的基因贡献者。这些发展代表了该领域的重大突破，并突出了当前最先进的遗传和分子工具的力量。与此形成鲜明对比的是，IHA的病理生理学机制仍然不清楚。这一提议的主要假设是，目前尚不确定的因素可能导致过度的醛固酮释放。我们推测，这些醛固酮促分泌剂可能导致和维持了原发性醛固酮增多症患者的醛固酮过剩。这一假说建立在体外和体内模型以及临床证据的结果基础上。我们将在选定的基于人群的队列和德国康涅狄格州登记的队列中定义它们的贡献、流行率和纵向持久性。我们还将使用在肾上腺静脉采样时采集的血液样本，这将为了解PA患者肾上腺旁分泌环境提供一个窗口。该提案有以下具体目的：1.证实原发性醛固酮增多症患者中存在激活性AT1R自身抗体，2.证实原发性醛固酮增多症患者存在新的自分泌/旁分泌机制，3.确定全身性高催乳素血症引起的催乳素水平升高是否构成原发性醛固酮增多症的一种新机制。为了实现这些目标，我们将开发和应用最先进的功能分析和分子技术，这些技术有可能提高对继发性高血压最普遍形式的了解，并在未来改进诊断和治疗。

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.