Physiology of the heartbeat and other cardiac rhythms in health and disease

Cardiovascular diseases (CVDs) are the number one cause of death worldwide. In fact, more people annually die from CVDs than from any other reason. Current calculations predict that by 2030, 23.6 million people will die from CVDs. It is therefore essential to understand the underlying mechanisms of these diseases and to develop novel cardioprotective and therapeutic strategies to halt this dramatic development. The performance of the cardiac muscle is controlled by the spontaneous activity of pacemaker cells in the sinoatrial node (SAN), which generate the heartbeat. Heart rate (HR) is an important prognostic factor for cardiac morbidity and mortality. Our group investigates the role of HCN channels and other ion channels in the generation of a regular and well-coordinated HR. In general, pacemaking requires functional interactions between individual pacemaker cells within the SAN itself (a process called „phasic“ entrainment), between SAN cells and regulating neurons of the autonomic nervous system (neuronal entrainment), and finally between SAN cells and the hormone system (humoral entrainment). We hypothesize that in particular cAMP-dependent regulation of HCN4 channels contributes to the neuronal and humoral entrainment (Fenske et al. Nature Communications 2020), and that HCN1 and other ion channels are responsible for the “phasic“-entrainment, the actual synchronization process within the sinoatrial node itself (Fenske et al. Circulation 2013).

Using a series of genetic knock-out and knock-in models, reporter as well as sensor lines, my group aims at investigating the role of these HCN channels as well as additional cation channels and their regulation for the three entrainment processes. We also investigate how the intracardiac nervous system (ICNS) regulates the spontaneous heartbeat and contractility. The ICNS, like other extracranial neuronal networks located in distinct organs, operates independently of the autonomic and the central nervous system. For our projects, we use state-of-the-art methods such as patch clamp, confocal FRET microscopy (Direnberger et al. Nature Communications 2012), confocal Ca2+ and voltage imaging, optogenetics, ECG telemetry (Fenske et al. Nature Protocols 2016), cardiac catheterization-based in vivo electrophysiological (Hennis et al. Nature Protocols 2022) and pressure-volume analysis, as well as optical mapping using voltage-sensitive dyes to visualize the spread of electrical excitation throughout the heart with ultra-high time resolution (10-30.000 Frames/s). This work is funded by the DFG.