Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.

Background-Infarct border zone (IBZ) geometry likely affects inducibility and characteristics of postinfarction reentrant ventricular tachycardia, but the connection has not been established.

Electromechanical Wave Imaging is a novel technique for the noninvasive mapping of conduction waves in the left ventricle through the combination of ECG gating, high frame rate ultrasound imaging and radio-frequency (RF)-based displacement estimation techniques. In this paper, we describe this new technique and characterize the origin and velocity of the wave under distinct pacing schemes. First, in vivo imaging (30 MHz) was performed on anesthetized wildtype mice (n=12) at high frame rates in order to take advantage of the transient electromechanical coupling occurring in the myocardium. The RF signal acquisition in a long-axis echocardiographic view was triggered on the R-wave peak of the mouse electrocardiogram (ECG) and yielded an ultra-high RF frame rate of 8000 fps. The ultrasound RF signals in each frame were digitized at 160 MHz. Axial, frame-to-frame displacements were estimated using 1D cross-correlation (window size of 240 microns, overlap of 90%). Three pacing protocols were sequentially applied in each mouse: 1) sinus rhythm (SR), 2) right-atrial (RA) pacing and 3) right-ventricular (RV) pacing. Pacing was performed using an eight-electrode catheter placed into the right side of the heart with the capability of pacing from any adjacent bipole. During a cardiac cycle, several waves were depicted on the electromechanical wave images that propagated transmurally and/or from base to apex, or apex to base, depending on the type of pacing and the cardiac phase. Through comparison between the ciné-loops and their corresponding ECG obtained at different pacing protocols, we were able to identify and separate the electrically induced, or contraction, waves from the hemodynamic (or, blood-wall coupling) waves. In all cases, the contraction wave was best observed along the posterior wall starting at the S-wave of the ECG, which occurs after Purkinje fiber, and during myocardial, activation. The contraction wave was identified based on the fact that it changed direction only when the pacing origin changed, i.e., it propagated from the apex to the base at SR and RA pacing and from base to apex at RV pacing. This reversal in the wave propagation direction was found to be consistent in all mice scanned and the wave velocity values fell within the previously reported conduction wave range with statistically significant differences between SR/RA pacing (0.85 +/− 0.22 m/s and 0.84 +/− 0.20 m/s, respectively) and RV pacing (−0.52 +/− 0.31 m/s; p<.0001). This study thus shows that imaging the electromechanical function of the heart noininvasively is feasible. It may therefore constitute a unique noninvasive method for conduction wave mapping of the entire left ventricle. Such a technology can be extended to 3D mapping and/or used for early detection of dyssynchrony, arrhythmias, left bundle branch block, or other conduction abnormalities as well as diagnosis and treatment thereof.

Heart rate variability (HRV) is a measure of variation in time interval between heartbeats and reflects the influence of autonomic nervous system and circulating/locally released factors on sinoatrial node discharge. Here, we tested whether electrocardiograms (ECGs) obtained in conscious, restrained mice, a condition that affects sympathovagal balance, reveal alterations of heart rhythm dynamics with aging. Moreover, based on emergence of sodium channels as modulators of pacemaker activity, we addressed consequences of altered sodium channels on heart rhythm. C57Bl/6 mice and mice with enhanced late sodium current due to Nav1.5 mutation at Ser571 (S571E), at ~4 to ~24 months of age were studied. HRV was assessed using time- and frequency-domain and nonlinear parameters. For C57Bl/6 and S571E mice, standard deviation of RR intervals (SDRR), total power of RR interval variation, and nonlinear standard deviation 2 (SD2) were maximal at ~4 months and decreased at ~18 and ~24 months, together with attenuation of indices of sympathovagal balance. Modulation of sympathetic and/or parasympathetic divisions revealed attenuation of autonomic tone at ~24 months. At ~4 months, S571E mice presented lower heart rate and higher SDRR, total power, and SD2 with respect to C57Bl/6, properties reversed by late sodium current inhibition. At ~24 months, heart rate decreased in C57Bl/6 but increased in S571E, a condition preserved after autonomic blockade. Collectively, our data indicate that aging is associated with reduced HRV. Moreover, sodium channel function conditions heart rate and its age-related adaptations, but does not interfere with HRV decline occurring with age.

Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (I Ks ) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that β-adrenergic receptor (β-AR)-mediated regulation of the I Ks channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic I Ks channel mouse model, we studied the role of the channel and its regulation by β-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes I Ks channel transgenic mice but not wild-type (WT) littermates that lack I Ks to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of I Ks in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that β-AR stimulation-dependent accumulation of open I Ks channels accounts for the pro-arrhythmic substrate. Our results provide evidence that β-AR-regulated I Ks channels can play a role in AF and imply that specific I Ks deregulation, perhaps through disruption of the I Ks macromolecular complex necessary for β-AR-mediated I Ks channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.