暂无摘要。

To understand the ionic mechanism behind the genesis of Torsade de Pointes (TdP) occurring with long QT syndrome 2 (LQTS2) in a remodelled transmural tissue.
The TP06 model is used to simulate the electrical activity of cells in a 2D transmural ventricular model. LQTS2 is realised by reducing the potassium current (IKr) to 0.5 in each cell. Each cell of the tissue is remodelled by increasing the conductance of calcium current (GCaL). The above two factors make the cells prone to early after depolarizations (EADs) development. The rise in GCaL that can develop a sustained TdP at normal pacing rate is determined from this study. A look at the calcium dynamics, sodium-calcium exchanger current (INaCa) and slow delayed rectifier potassium current (IKs) distribution maps of the tissue helps us in analysing the mechanism of TdP generation.
A TdP type pattern at normal pacing rate is generated when GCaL is more than 3.5 times the control parameter. From the M-cell island, an adequate number of cells spontaneously release calcium from their sarcoplasmic reticulum leading to increased intracellular calcium and inward sodium current through the sodium calcium exchanger current (INaCa). These contribute to the development of EADs which create a depolarising wavefront that triggers TdP in the tissue. When GCaL is less than 3.5 times the control value, premature ventricular complexes (PVC) occur interspersed between normal beats.
Normal pacing rates can induce a multi focal TdP when sufficient number of M-cells simultaneously undergo spontaneous calcium release (SCR) events.

β-Blockers are a standard treatment for heart failure and cardiac arrhythmias. There are ∼30 commonly used β-blockers, representing a diverse class of drugs with different receptor affinities and pleiotropic properties. We reported that among 14 β-blockers tested previously, only carvedilol effectively suppressed cardiac ryanodine receptor (RyR2)-mediated spontaneous Ca2+ waves during store Ca2+ overload, also known as store overload-induced Ca2+ release (SOICR). Given the critical role of SOICR in arrhythmogenesis, it is of importance to determine whether there are other β-blockers that suppress SOICR. Here, we assessed the effect of other commonly used β-blockers on RyR2-mediated SOICR in HEK293 cells, using single-cell Ca2+ imaging. Of the 13 β-blockers tested, only nebivolol, a β-1-selective β-blocker with nitric oxide synthase (NOS)-stimulating action, effectively suppressed SOICR. The NOS inhibitor (N-nitro-l-arginine methyl ester) had no effect on nebivolol\'s SOICR inhibition, and the NOS activator (histamine or prostaglandin E2) alone did not inhibit SOICR. Hence, nebivolol\'s SOICR inhibition was independent of NOS stimulation. Like carvedilol, nebivolol reduced the opening of single RyR2 channels and suppressed spontaneous Ca2+ waves in intact hearts and catecholaminergic polymorphic ventricular tachycardia (CPVT) in the mice harboring a RyR2 mutation (R4496C). Interestingly, a non-β-blocking nebivolol enantiomer, (l)-nebivolol, also suppressed SOICR and CPVT without lowering heart rate. These data indicate that nebivolol, like carvedilol, possesses a RyR2-targeted action that suppresses SOICR and SOICR-evoked VTs. Thus, nebivolol represents a promising agent for Ca2+-triggered arrhythmias.