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

问题是：心力衰竭（HF）是影响超过1500万欧洲人的最相关疾病之一，平均5年死亡率为50%，给我们的社会带来越来越大的经济负担。动脉高血压和糖尿病是心脏肥大和HF的重要原因，尤其是舒张期HF（DHF）占所有HF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的相关机制尚不清楚，尤其是从舒张功能障碍进展为DHF的机制。与SHF相反，没有具体的循证和病理生理学基础的治疗存在DHF导致在一个巨大的临床未满足的需求，除了巨大的社会经济relevance.Current知识：我们以前表明，CaMKIIdeltaC在小鼠中的过度表达导致终末期HF由于钙稳态紊乱。除了收缩功能障碍，这些动物还发展舒张功能障碍。我们在这些小鼠中发现了一种新的CaMKII依赖性Na通道调节，其持续（或晚期）Na电流（晚期INa）增加，导致细胞内Na超载。迟发性INa伴随随后通过Na/Ca-交换剂（NCX）的Ca内流也可导致细胞内Ca超载。虽然有迹象表明这会损害舒张功能，但迄今为止尚未在DHF中研究这些病理机制。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，表明靶向舒张期Ca超载（即通过晚期INa抑制）可为DHF患者提供急需治疗的途径。不幸的是，目前尚不清楚哪些代偿性心脏肥大和舒张功能障碍的患者进展为终末期DHF。然而，我们的目标必须是了解参与DHF的机制，并及早确定患者谁将受益于一个特定的抑制晚INa和/或CaMKII.Proposal：我们建议，改变钠处理连续导致钙超载由于CaMKII激活参与DHF的发展。拟议项目的结果将导致创新的差异化治疗方法舒张功能障碍和DHF超越目前的最先进水平。我们将测试什么样的作用晚INa和CaMKII激活DHF和在什么阶段的疾病。我们相信，这项工作将为DHF的新机制提供重要的见解，超越最先进的水平，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.