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 CaMKIIdC 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.