Circulating metabolites in atrial biology and disease

The proposed project aims to help us understand the connection between the transport form of an unsaturated fatty acid, C18:1 acyl-carnitine (AC), in the serum of patients and atrial fibrillation (AF). AF is the most common sustained arrhythmia and poses a considerable public health burden, as it affects up to 2% of the population. The asynchronous fast movement of the heart’s atria leads to reduced cardiac output and an increased risk of secondary damage, such as stroke and heart failure, increasing the mortality of patients suffering from AF. New means of early diagnosis would help to reduce the risk and contribute to a better understanding of the disease mechanisms to create new and effective therapeutic approaches.Our groups have recently worked on both of these aspects, early diagnosis and mechanistic insight. With regard to early diagnosis, biomarkers play an important role. In this regard, we have recently conducted a large screen, capitalising on a novel idea: The use of circulating metabolites as biomarkers. In this screen in two large cohorts of AF patients and healthy control individuals, we identified the mono-unsaturated fatty acid C18:1 in its acyl-carnitine transport form (C18:1 AC) as significantly associated with the risk of developing AF.In parallel, we have developed new in vitro models to study AF, based on engineered heart tissue (EHT). To consider AF, we have established EHT from rat atria and improved EHT from human induced pluripotent stem-cell derived atrial-like cardiomyocytes. These new tools, together with other novel methods recently developed in our department, such as optical pacing in EHT, can serve as test systems for in vitro characterisation of AF mechanisms and risk factors, such as AF promoting substances.In this project we aim to combine these findings and use all available expertise in order to obtain a comprehensive view of the link between C18:1 AC and AF. In the frame of 5 concise work packages, we will i) evaluate the sub-cellular localization of C18:1 AC within treated EHT, ii) analyse the effect of C18:1 AC on the electrophysiology of atrial and ventricular EHT, iii) evaluate the influence of C18:1 AC on Ca2+ handling, iv) probe the effect of C18:1 AC on cardiac mitochondrial metabolism and v) further develop the abovementioned in vitro system and establish an EHT based in vitro model of AF to assess the effect of C18:1 AC on susceptibility to fibrillation induction. Thus, by the end of the project, we aim to know if C18:1 AC can act as a suitable biomarker for AF risk prediction and to have gained insight into its mechanism of action that will contribute to the general understanding of AF development and aid in the development of future therapies.