Normal Cardiac Excitation: Generation, Propagation and Coupling to Contraction



Project Summary
Cardiac arrhythmia is a major cause of morbidity and mortality in Europe and of growing socioeconomic concern. Recent data suggest that novel mechanisms such as HCN channels, mechanical effects on Ca handling and ion flux balances, and cellular heterogeneity may trigger and/or permit the sustenance of arrhythmias. The novelty of our approach is to focus on these potentially crucial, but illinvestigated, mechanisms by uniting 8 leading labs from 5 EU countries who focus on individual arrhythmogenic aspects, in a bid to combine their expertise and shed light on how physiological or compensatory mechanisms may turn arrhythmogenic, and how this may be controlled or corrected.

Prime targets are structured along three levels of functional integration:

  • Membrane level:
    • Role of HCN channels in the generation of normal and abnormal rhythm.
  • Cellular level:
    • Role of electro-mechanical interaction in modulating contractile activity and electrophysiology.
  • Multicellular level:
    • Role of heterogeneity in normal and remodelled tissue on electrical excitation and conduction.

Scientific and technological objectives:

  • To develop suitable experimental tools, including HCN transgenic mice, novel bradycardic and antiarrhythmic agents, control of mechano-electrical interactions, and the symbiosis of the above.
  • To acquire new knowledge on molecular mechanisms and pathways controlling generation and spread of excitation in normal and diseased cardiac tissue.
  • To combine advanced engineering techniques for 'top-down' development of novel experimental tools with mathematical 'bottom-up' integration of data from the molecular level to fundamental and clinical relevance.

Based on the combination of skills and techniques not currently available in any single lab worldwide, we will provide novel insight into novel arrhythmogenic mechanisms, quantify their interrelation, target preventive and therapeutic interventions to reduce the societal and economical impact of cardiac arrhythmia.