Progress DHF - Mechanisms for the Progression from Diastolic Dysfunction to Diastolic Heart Failure

问题：心力衰竭（HF）是影响150万欧洲人的最相关疾病之一，平均5年死亡率为50%，并成为我们社会日益增加的经济负担。动脉高血压和糖尿病是心脏肥厚和心衰的重要原因，尤其是舒张性心衰（DHF）占所有心衰患者的50%。虽然Ca和Na稳态紊乱被证明是收缩期HF （SHF）的主要原因，但DHF的机制尚不清楚，特别是从舒张功能障碍到DHF的进展。与SHF相反，对于DHF，除了巨大的社会经济相关性之外，还没有特定的基于证据和病理生理学的治疗方法，这导致了巨大的临床未满足需求。目前的知识：我们之前的研究表明，CaMKIIdeltaC在小鼠中的过表达会导致终末期HF，原因是Ca稳态受到干扰。除了收缩功能障碍外，这些动物还会出现舒张功能障碍。我们在这些小鼠中发现了一种新的camkii依赖的Na通道调节，其持续（或晚期）Na电流（晚期INa）的增加导致细胞内Na过载。晚期的钙通过Na/Ca交换器（NCX）内流也会导致细胞内钙超载。虽然有迹象表明这损害了舒张功能，但迄今为止尚未对DHF的这些病理机制进行研究。然而，我们的小型安慰剂对照概念验证研究（RALI-DHF）显示，抑制晚期INa可改善DHF患者的舒张功能，这表明靶向舒张期Ca过载（即通过晚期INa抑制）可以为DHF患者提供急需的治疗途径。不幸的是，目前尚不清楚哪些伴有代偿性心脏肥厚和舒张功能不全的患者进展为终末期DHF。然而，我们的目标必须是了解DHF的机制，并尽早识别出能够从特异性抑制晚期INa和/或CaMKII中获益的患者。建议：我们认为，由于CaMKII激活，连续改变的Na处理导致Ca过载参与了DHF的发展。拟议项目的结果将导致舒张功能障碍和DHF的创新差异治疗方法，超越目前的艺术状态。我们将测试晚期INa和CaMKII激活在DHF中的作用以及在疾病的哪个阶段。我们相信，这项工作将为DHF的新机制提供重要的见解，这是目前没有得到充分治疗的患者所需要的，但希望在不久的将来。

The problem: Heart failure (HF) is one of the most relevant diseases affecting >15 Mio Europeans with an average 5-year mortality of 50% and an increasing economic burden for our society. Arterial hypertension and diabetes are important causes for cardiac hypertrophy and HF, especially for diastolic HF (DHF) making up 50% of all HF patients. While disturbed Ca and Na homeostasis was shown to be a main cause for systolic HF (SHF), the mechanisms involved in DHF are unclear, especially in the progression from diastolic dysfunction to DHF. In contrast to SHF, no specific evidence-based and pathophysiologically founded therapy exists for DHF resulting in a tremendous clinical unmet need in addition to the huge socioeconomic relevance.Current knowledge: We previously showed that CaMKIIdeltaC overexpression in mice causes end-stage HF due to disturbed Ca homeostasis. In addition to systolic dysfunction, these animals also develop diastolic dysfunction. We discovered in these mice a novel CaMKII-dependent Na channel regulation with an increased persistent (or late) Na current (late INa) leading to intracellular Na overload. Late INa with subsequent Ca influx via Na/Ca-exchanger (NCX) can also lead to intracellular Ca overload. While there are hints that this compromises diastolic function, these pathomechanisms have not been investigated in DHF so far. However, our small placebo-controlled proof-of-concept study (RALI-DHF) showed that inhibition of late INa improves diastolic function in DHF patients suggesting that targeting diastolic Ca overload (i.e. by late INa inhibition) could provide a path to urgently needed therapies in DHF. Unfortunately, it is unclear which patients with compensated cardiac hypertrophy and diastolic dysfunction progress to end-stage DHF. Yet, the goal must be to understand the mechanisms involved in DHF and to identify patients early enough who would benefit from a specific inhibition of late INa and/or CaMKII.Proposal: We propose that altered Na handling consecutively leading to Ca overload due to CaMKII activation is involved in the development of DHF. The results of the proposed project will lead to innovative differential therapeutic approaches for diastolic dysfunction and DHF going beyond the current state of the art. We will test what role late INa and CaMKII activation play in DHF and in what stage of the disease. We believe that the work will provide important insights into novel mechanisms for DHF beyond the state of the art, which is needed for patients that are currently not adequately treated but hopefully in the near future.