Periodic Reporting for period 2 - MOLEC ANTI-ARRHYT (Resilience and Trigger Factors in Cardiac Arrhythmia: Risk Stratification and Drug Design)
Reporting period: 2021-09-01 to 2023-02-28
Cardiac arrhythmias comprise a group of syndromes with various clinical outcomes, the most severe of which are life-threatening arrhythmias and sudden cardiac death. Although numerous mutations in the genes encoding for cardiac ion channels have been identified as an underlying cause of cardiac arrhythmias, the anticipated revolution in terms of personalized risk stratification and clinical management has not been achieved. A major hurdle remains in the poor correlation between the genetic profile and clinical manifestations, the cause of which remains largely unknown. As a consequence, with our present mechanistic understanding of inherited arrhythmias and the treatment thereof, affected individuals are at risk of receiving inappropriate clinical management and remain at risk of suffering sudden cardiac death. This project utilizes diverse approaches such as electrophysiology, molecular dynamics simulations, and synthetic chemistry to explore innovative approaches to personalized risk stratification and novel concepts for drug design. One important aspect of this proposal is the systematic mapping of major endogenous ligands with therapeutic or pathological effects on cardiac ion channels, which we refer to as resilience and trigger factors, and how these factors are tied to major classes of inherited mutations. Another important aspect of this proposal is the fundamentally novel concept of Resilience-Mimetic Drug development, which utilizes and tweaks the effect of resilience factors on cardiac ion channels. Hence, the overall objective is to provide a molecular framework for how major arrhythmia factors determine arrhythmia severity in a predictable and mutation-specific manner, and to utilize these mechanistic insights to develop a fundamentally novel concept of anti-arrhythmic treatment. Ultimately, future personalized risk stratification and clinical management will improve the clinical outcome for individuals who suffer from inherited arrhythmias.
We have assessed the effect of endogenous compounds on the cardiac ion channel Kv7.1/KCNE1 and identified modulators belonging to the major classes of endocannabinoids, free fatty acids, steroid hormones, sterols, and reactive oxygen species. We find support of specific endogenous modulators within these classes as putative resilience factors (through channel activation), whereas others are putative trigger factor (through channel inhibition). For endocannabinoids, free fatty acids, and steroid hormones, we have provided mechanistic insights into where on the ion channel protein these modulators act, how they induce their effects, and what structural elements of the modulators a required to induce effects. We have identified mutation-specific responses of each class of modulator, with some mutations being clearly responsive whereas other mutations are left without modulator effects. Moreover, we find that the effects are translational between different experimental models addressing different aspects of cardiac function. Altogether, our work so far supports the concept of endogenous compounds implicated in cardiac arrhythmia acting as ion channel modulators and that their effect depends on the genetic background.
Our work until now progresses beyond the state of the art by demonstrating mutation-specific responses to endogenous modulators implicated in cardiac arrhythmia, with the subsequent quantification of the combined load thereof. Until the end of the project, we expect to further develop this concept, by expanding with additional modulators and mutations and providing a mechanistic explanation for observed effects. Moreover, with additional mechanistic insights, we expect to utilize this knowledge to successfully re-design endogenous modulators into synthetic modulators with defined pharmacological effects. In addition, as a side finding, we have together with collaborators developed a new delivery method for ion channel modulators, with precise temporal and spatial resolution. Until the end of the project, we expect to further develop this concept by optimizing the design of the delivery device and by demonstrating modulation of additional ion channels.