Inter- and Intraindividual Variations in Shortening of Ventricular Effective Refractory Period After an Abrupt Decrease in Pacing Cycle Length

After an abrupt decrease in pacing cycle length (PCL), the ventricular effective refractory period (VERP) shortens. The pacing protocol needed to determine accurate and reproducible values for the VERP during this process is elaborate and time consuming. In this study, steady-state values of VERP at 800 and 350 msec PCL and dynamic values of VERP due to an abrupt change in PCL from 800 to 350 msec were determined. This was done for 11 different dogs to test the interindividual variation and repetitively in the same dog to test the intraindividual variation. The results for steady-state and dynamic values of the VERP show a wide range for both groups. This means that accurate prediction of steady-state and dynamic values of VERP based on previous measurements is not possible.     

Is the Ventricular Effective Refractory Period Different When Determined by Incremental Versus Decremental Scanning?: The Effect of Pacing Cycle Length,d-Sotalol,and Levcromakalim

In tbe clinical setting, the ventricular effective refractory period (VERP) is determined by an 8-beat drive train (S1S1), followed by a premature stimulus (S2), which is decremented in subsequent drive trains until capture is lost. Variation in intertrain pauses and capturing extra stimuli disturb steady-state conditions and reduce reproducibility of values found for the VERP. To increase reproducibility, a protocol without intertrain pause and incremental scanning (IS) of S2 was developed. In anesthetized dogs with chronic AV block, determination of the VERP using IS and decremental scanning (DS) without intertrain pause was compared at 800 and 350 msec pacing cycle length (PCL). The measurements were repeated after the administration of d-sotalol to lengthen the VERP and levcromakalim to shorten the VERP. The results showed no difference between IS and DS at both PCLs with or without medication. Recurrent and abrupt rate changes were avoided daring IS, making this the protocol of choice when induction of arrhythmias is to be avoided.     

The Effect of Flunarizine and Ryanodine on Acquired Torsades de Pointes Arrhythmias in the Intact Canine Heart

Flunarizine and Ryanodine in Acquired TdP. Introduction: Ryanodine, a specific blocker of the Ca²⁺ release channel of the sarcoplasmic reticulum, and flunarizine, a[Ca²⁺], overload blocker, possess antiarrhythmic effects against delayed after depolarizations (DADs) and DAD-dependent arrhythmias. In vitro controversy exists about their effect on early after depolarizations (EADs): no effect was reported on cesium-induced EADs, while ryanodine did prevent EADs induced by isoproterenol. To study the possible role of intracellular Ca²⁺ overload in acquired EAD-dependent torsades de pointes (TdP) arrhythmias, we tested the effects of flunarizine and ryanodine in our animal model of TdP. Methods and Results: Anaesthetized dogs with chronic AV block received d-sotalol or almokalant followed by pacing. A subset of dogs with reproducible TdP (≥ 3 times) were selected to receive flunarizine (2 mg/kg per 2 min) or ryanodine (10 μg/kg per 10 min). After dsotalol, TdP was induced at a mean cycle length of the idioventricular rhythm (CL-IVR) of 2070 ± 635 msec and a QT(U) interval of 535 ± 65 msec. Induction of TdP was prevented by flunarizine in all experiments (8/8): electrophysiologically this was associated with a decrease in CL-IVR, QT(U), and QT_c interval (390 ± 100 to 320 ± 45, P < 0.05). Ryanodine prevented TdP induction in 4 of 5 experiments and decreased the CL-IVR, QT(U), and the QT_c interval from 385 ± 75 to 320 ± 20 msec (P < 0.05). Both drugs also suppressed the almokalant-induced EADs and related ectopic activity. This antiarrhythmic action corresponded with the inability to reinduce TdP by pacing. Conclusions: Blockade of the Ca²⁺ release channel of the sarcoplasmic reticulum by ryanodine or the reduction of [Ca²⁺] overload by flunarizine prevents induction of EAD-dependent acquired TdP arrhythmias, suggesting a role for [Ca²⁺]_i overload in acquired TdP.     

Steady-State and Dynamic Behavior of Ventricular Repolarization and Refractoriness in the Dog: The Effect of Multiple Cycle Length Changes and d-Sotalol Administration

In anesthetized dogs with chronic, complete AV block we studied the characteristics of ventricular repolar-ization and refractoriness. Therefore, we determined: (1) steady-state values of ventricular effective refractory period (VERP), action potential duration (APD), and stimulus T interval (STI) before and after d-sotalol treatment at various pacing cycle lengths (PCLs); and (2) the dynamics of VERP, APD, and STI before and after d-sotalol treatment after the abrupt PCL decreases. VEHP, APD, and STI showed a normal frequency dependency. All three parameters increased significantly after d-sotalol administration. During steady-state and dynamic measurements, STI was always longer than APD and APD was always longer than VERP in an individual animal, irrespective of PCL and conditions. Standard deviations of steady-state and dynamic values indicated a considerable interindividual variation. However, the dynamics of VERP, APD, and STI after an abrupt decrease in PCL were highly correlated (linear regression analysis: r²± 0.93). The best mathematical model to describe these dynamics was a bi-exponential model (r²± 0.98) with a very short first and a much longer second time constant. We found that there was a very consistent relation between VERP, APD, and STI, not only during steady-state but also in the dynamic situation after various abrupt PCL decreases. This relation does not change after the administration ofd-so-talol. Therefore, STI could be used to predict steady-state and dynamic values of VERP and APD. Since STI can be made available online in implantable pacing systems this could lead to the development of new features in these devices.