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

Progress DHF - 从舒张功能障碍进展为舒张性心力衰竭的机制

• 批准号: 316914177
• 负责人: Professor Lars Maier
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/316914177?language=en
• 关键词: Progress; DHF; Mechanisms; Progression; Diastolic

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.

问题：心力衰竭(HF)是影响1500万欧洲人的最相关疾病之一，5年平均死亡率为50%，给我们的社会带来了越来越大的经济负担。动脉高血压和糖尿病是导致心肌肥厚和心力衰竭的重要原因，尤其是舒张性心力衰竭(DHF)，占心力衰竭患者总数的50%。尽管钙、钠平衡失调被认为是收缩期心衰的主要原因，但其发生机制尚不清楚，尤其是在舒张期功能障碍向舒张期心力衰竭的发展过程中。与SHF相比，DHF没有特定的循证和病理生理学基础的治疗方法，除了巨大的社会经济学相关性外，还存在巨大的临床未得到满足的需求。目前的知识：我们先前表明，CaMKIIdeltaC在小鼠中的过度表达由于钙稳态的破坏而导致终末期HF。除了收缩功能障碍外，这些动物还会出现舒张性功能障碍。我们在这些小鼠中发现了一种新的依赖于CaMKII的钠通道调节，其持续(或晚期)钠电流增加(晚期INA)导致细胞内钠超载。晚期INA后通过钠/钙交换器(NCX)的钙内流也可导致细胞内钙超载。虽然有迹象表明这会损害舒张期功能，但到目前为止，这些发病机制在DHF中还没有被研究过。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可以改善DHF患者的舒张期功能，这表明靶向舒张期钙超载(即通过抑制晚期INA)可能为DHF急需的治疗提供一条途径。不幸的是，目前尚不清楚哪些有代偿性心肌肥厚和舒张期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DHF的相关机制，并及早识别哪些患者将受益于对晚期INA和/或CaMKII的特异性抑制。建议：我们认为，由于CaMKII激活导致的钠处理的改变连续导致钙超载，参与了DHF的发生。拟议项目的结果将导致针对舒张期功能障碍和DHF的创新的差异化治疗方法，超出目前的技术水平。我们将测试晚期INA和CaMKII激活在DHF中起什么作用，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，超越最先进的水平，这是目前没有得到充分治疗但有望在不久的将来得到充分治疗的患者所需的。

项目成果

C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation

• DOI: 10.1074/jbc.m117.787788
• 发表时间: 2017-10-20
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Burel, Sophie;Coyan, Fabien C.;Marionneau, Celine
• 通讯作者: Marionneau, Celine

Enhanced CaMKII-Dependent Late INa Induces Atrial Proarrhythmic Activity in Patients With Sleep-Disordered Breathing

• DOI: 10.1161/circresaha.119.315755
• 发表时间: 2020-02-28
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Lebek, Simon;Pichler, Konstantin;Wagner, Stefan
• 通讯作者: Wagner, Stefan

Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites.

• DOI: 10.1085/jgp.202012646
• 发表时间: 2021-02-01
• 期刊: The Journal of general physiology
• 作者: Lorenzini M;Burel S;Lesage A;Wagner E;Charrière C;Chevillard PM;Evrard B;Maloney D;Ruff KM;Pappu RV;Wagner S;Nerbonne JM;Silva JR;Townsend RR;Maier LS;Marionneau C
• 通讯作者: Marionneau C

Empagliflozin directly improves diastolic function in human heart failure

• DOI: 10.1002/ejhf.1328
• 发表时间: 2018-12-01
• 期刊: EUROPEAN JOURNAL OF HEART FAILURE
• 影响因子: 18.2
• 作者: Pabel, Steffen;Wagner, Stefan;Sossalla, Samuel
• 通讯作者: Sossalla, Samuel