LQT, HCN, and epilepsy model

…I learn that the unusual slowness of pulse has continued, with occasional attacks of epilepsy 1 Recently, I was surprised by the above-mentioned observation made 188 years ago. I therefore read with great interest the commentary in Epilepsy Currents by Smith and Delisle2 on the study in Epilepsia by Powell et al.3 addressing the hyperpolarization-activated cyclic nucleotide (HCN or Ih) gated nonselective cation channels. Both the commentary and article along another recent paper4 shed light on two of the most important and interrelated organs: the brain and heart. Of interest, as it is evidenced, even their pathologies are related. It is a simple fact that HCN channels are present throughout the brain5 and heart,3 but prevailingly only the medial septum in the former and sinoatrial/atrioventricular (SA/AV) nodes in the latter exhibit a pacemaker electrical activity. This calls into question the established global pacemaker role for HCN–pacemaker channels. Despite the advances in understanding all four α (HCN1–4) and auxiliary subunits, a very first and plain question still cannot be answered: Why does the functional expression of HCN channels in a few regions of the heart/brain result in recurrent high frequency action potentials, but not in the other compartments of these organs? Indeed a specified and crucial function should logically not be a global phenomenon, but rather originate in a minority of cells for many reasons. However, why? Powell et al. has evidenced the transient recurrent arrhythmias (attributed to HCN2 down-regulation) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). These irregularities occur every ~2 s in Figure 1C (legends are mismatched), and are the consequences of interictal activities in the brain. There is an increase in one or two R–R intervals followed by the compensatory pause/decrease before the subsequent beats. The heart rates (HRs) in two sets of nonepileptic controls (NECs, 420 vs. 314 beats/min) and in the temporal lobe epilepsy (TLE) model compared to GAERS (400 vs. 337) are different in vivo. The same is true for the HR variability as reflected by the standard deviation of R–R (SDRR) intervals in NEC (2 vs. 0.2 msec). These differences could not be attributed solely to saline injections. Because the QTc interval (corrected for HR, first used by Fridericia in 1920) increased (i.e., long QT [LQT]) from 128 to 169 msec in the TLE model, the involvement of K+ channels are warranted.6 The most important observation3 in TLE perhaps is the fact that behaviorally observed seizures matched timely the changes in electrocardiography (ECG), whereas those of electroencephalography (EEG) were delayed by ~15 s. In contrast, the heart response and spike wave discharges (SWDs) in the spontaneous absence epilepsy (AE) model overlap.4 Mamalyga documented that there is a correlation between the SWDs in WAG/Rij rats and the acceleration of the HR occurring with some latency. There is to some degree also mild arrhythmia in the AE model. Collectively, none of pathologies could be defined either by a single channel/receptor type or target the one and only one organ/region. I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. I have no conflict of interests.