Thom Stams

ENGLISH SUMMARY

Role of electrical activation of the heart

The heart is normally paced by the sinus node, in humans at a rate of about 60-100 beats per minute. The sinus node is located in the right atrium. Conduction of this electrical ‘signal’ over the tissue is required for contraction, a process called excitation-contraction coupling. The atria and ventricles are electrically isolated, except for a small area, which is slowly conducting: the AV-node. Therefore, a delay occurs before the ventricles are activated via the specialized His-Purkinje system. This well-timed delay allows an atrial contraction that improves ventricular filling before the contraction (preload). The ventricles are most important, because they pump the blood to the body (left ventricle) or lungs (right ventricle). A good pump function requires a well-coordinated ventricular contraction and because of the excitation-contraction coupling, also well-coordinated electrical activation. Both asystole (absence of electrical activations) and fast ventricular arrhythmias can acutely interrupt the pump function and thereby cause loss of consciousness in seconds and sudden cardiac death in minutes.

If the conduction through the left bundle branch of the ventricular conduction system is blocked (disease) or if the heart is paced from the right ventricle (the most commonly applied method of ventricular pacemaker therapy), the contraction of the left ventricle becomes dyssynchronous, resulting in less efficient pump function. On the longer term this is associated with development of heart failure, in a minority of patients. Symptomatic, chronic heart failure is a severe disease with a mortality of about 50% within 5 years after onset. Not only terminal pump failure itself is an important cause of death, but also sudden death due to ventricular arrhythmias, which can also occur when pump function is not severely decreased yet.

Torsade de Pointes

Torsade de Pointes (TdP) is an example of a fast ventricular arrhythmia that can result in sudden death. TdP most commonly ends within seconds but typically several episodes occur and episodes can have a long duration or degenerate into ventricular fibrillation. Ventricular fibrillation will result in sudden cardiac death if defibrillation is not applied immediately. To diagnose TdP, an electrocardiogram (ECG) recording is required to record the electrical activity of the heart; TdP has a typical sinusoid pattern.

The ECG is also very important for risk prediction of TdP. An ECG shows the atrial and ventricular electrical excitation (P wave and QRS complex, respectively) and also the ventricular repolarization (T wave). The total duration of ventricular electrical activity (from QRS onset to end of T wave: QT interval), is used as a measure of ventricular repolarization, because the repolarization is a much slower process than the excitation. Typically TdP occurs in the setting of a prolonged QT interval, due to a delayed repolarization process. QT prolongation can be caused by congenital factors, most importantly the congenital long QT syndrome, caused by a genetic mutation of one of the involved ion channels, but also caused by acquired factors, e.g. chronic heart failure and drugs. Drugs that block one or more of the ion currents that underlie normal ventricular repolarization are often involved in the induction of the arrhythmia. The block of repolarizing currents can be an intended effect, in anti-arrhythmic drugs like dofetilide and sotalol, but is commonly an adverse effect of the drug (secondary pharmacology). Usually only in a very low fraction of patients TdP will be induced by the drug, because a significant risk of life-threatening arrhythmias is usually not acceptable.

Repolarization prolongation is not only used for risk prediction of TdP in patients, but is also important in safety pharmacology to evaluate the proarrhythmic risk of drugs. Because TdP itself is usually a rare adverse event, the arrhythmia is often not detected in healthy animals or humans and therefore a central question in the safety evaluation is: does the drug prolong repolarization? Unfortunately, repolarization prolongation is not closely associated with TdP risk and some drugs that prolong QT are even safe (for example the antibiotic moxifloxacin).

One way to improve safety evaluation, especially if concerns about safety exist due to QT prolongation, is to investigate the proarrhythmic effect in animal models that are more sensitive to TdP arrhythmias. Important model is the chronic, complete AV-block dog model. In these dogs, under general anesthesia, complete AV-block is artificially created. The result is that electrical excitations from the atria are no longer conducted to the ventricles. Instantaneous death due to asystole is prevented due to spontaneously emerging escape rhythm in the ventricles: a physiological backup pacemaker. This spontaneous rhythm (idioventricular rhythm) is much slower (bradycardia) and as a consequence, the amount of blood that is pumped out by the heart per minute (the cardiac output) is reduced. To compensate, the heart adapts by contracting more powerful (increased contractility) and by becoming larger and increasing the amount of muscle fibers in the tissue (hypertrophy). This ‘remodeling’ of the heart results in almost complete restoration of the cardiac output, but is associated with electrical remodeling. This is visible as QT prolongation on the ECG and is associated with an increased susceptibility to TdP. The model is used in research to evaluate the safety of novel drugs and to study the underlying mechanisms of TdP. Drugs that were free of TdP even if prolonging QT, did not result in TdP in the model, while drugs that cause TdP in (a minority of) humans, resulted in TdP in up to 75% of these dogs.

The drug dofetilide is used as a reference compound (positive control) in the model, because this drug results in the highest inducibility of 75%, within 15 minutes after start of infusion under general anesthesia. Dofetilide specifically blocks one potassium ion current that is important for ventricular repolarization. This drug is used in the USA to treat patients with atrial fibrillation, an atrial arrhythmia that is very common, especially at older age. Due to the significant risk of TdP in patients treated with dofetilide, strict monitoring of the patients is required during initiation of the therapy. Also other drugs, like sotalol which is also used in the Netherlands, are associated with TdP as side effect. The risk of TdP is one of the reasons that novel drugs are being developed for the treatment of atrial fibrillation. One of those drugs is K2ON. This drug’s primary mode of action is prevention of leakage of calcium from the intracellular Ca 2+ storage compartment (the sarcoplasmic reticulum) during diastole. This calcium is important for contraction (systole) but especially the leakage during diastole may cause arrhythmias. However, K2ON also blocks other ion channels, including the potassium ion current that is also blocked by dofetilide. In Chapter 2, we investigated whether K2ON would be anti-arrhythmic against TdP due to its effect on the sarcoplasmic reticulum; however no anti-arrhythmic effects against TdP were observed, while at the higher dose even some proarrhythmia was observed: one out of seven dogs showed spontaneous TdP episodes after K2ON treatment.

Because QT interval is not a reliable parameter to predict risk of TdP, we also did an additional measurement using a monophasic action potential catheter that was inserted via the aorta in the left ventricle and positioned on the wall of the left ventricle. Increased beat-to-beat variability of left ventricular repolarization (‘instability of repolarization’) was observed after the higher dose of K2ON. This provided additional evidence that the higher dose was not safe.

In the chronic AV-block dog model, calcium channel blockers are a highly effective treatment against TdP, but drawback is the negative inotropic effect: they usually impair the pump function of the heart, because calcium is required for contraction. This is especially a drawback if this treatment would be applied in patients with heart failure. On the other hand, these patients have an increased risk of life-threatening arrhythmias like TdP. This is discussed in Chapter 3, which is a commentary to a study of Milberg et al. who studied the calcium channel blocker verapamil to suppress TdP arrhythmias in rabbits with heart failure.

In Chapter 4, the relation between the duration of mechanical contraction and QT interval was studied, because this had been shown to be a better predictor of TdP than QT interval per se. However, we observed that in the chronic AV-block model in dogs no additional was present over QT interval measurements.

Dyssynchronous ventricular activation

Most important aim of this thesis was to study the role of pathologically altered ventricular activation in the arrhythmogenesis of TdP. It is known that dyssynchronous ventricular activation (DVA) due to right ventricular pacing or left bundle branch block can decrease pump function and result in ventricular remodeling, but it is unknown whether DVA increases susceptibility to TdP arrhythmias. In Chapter 5, the effect of DVA in combination with bradycardia on arrhythmogenesis of TdP was studied in eight AV-block dogs. After the remodeling period, TdP could be induced in 75% of the dogs during a standard dofetilide test. However, the parameters that we used to quantify electrical remodeling did not show evidence of significant electrical remodeling. For example the duration and beat-to-beat variability of the left ventricular monophasic action potential duration were not increased (compared to acutely after initiation of DVA and bradycardia). Next, we studied whether regional differences within the left ventricle were present. During DVA (in this study by right ventricular apical pacing) the heart is electrically activated from the right ventricle to the left ventricle. This results in an earliest left ventricular activation at the area between left and right ventricle (the septum), whereas the free wall at the base of the heart generally activated latest. Interestingly we found that the remodeling was associated with development of a clear relation between the monophasic action potential duration and the activation time in these two dogs. We also studied the effect of dofetilide administration in one dog and these results suggested that the regional differences in repolarization within the left ventricle were important for arrhythmogenesis of TdP.

In Chapter 6 the effects of DVA in combination with bradycardia were compared with other groups of dogs from previously conducted experiments: unremodeled dogs (acute AV-block), normal AV-block dogs with chronic idioventricular rhythm and dogs with remodeling due to chronic bradycardia in combination with a more physiological activation pattern (high-septal paced dogs).

In studies in chronic AV-block dogs, usually arrhythmias are quantified as TdP inducibility. This parameter is dichotomous (the outcome is either ‘yes’ or ‘no’). In this study also arrhythmia score was introduced, with the aim to obtain more detailed information of arrhythmogenesis. This score can range from 1 to 100 and provided more detailed quantification. In the same study, also the initial prolongation of left ventricular repolarization (monophasic action potential duration) during dofetilide infusion was introduced, to determine whether this was predictive for TdP. This was quantified as time required to obtain a 25ms-increase (T2S). The parameter was a good predictor of TdP.

In Chapter 8, we studied whether chronic DVA in absence of chronic bradycardia would be proarrhythmic and whether a subsequent period of cardiac resynchronization therapy (CRT) could reverse this. We found that DVA was proarrhythmic, but the outcome was less severe than we had observed during DVA in combination with chronic bradycardia. Analysis of the parameters used for TdP prediction revealed that the proarrhythmic effect of DVA was only linked to a reduction of T2S. We also found that CRT was anti-arrhythmic against the DVA-induced proarrhythmia.

In Chapter 7, we studied the underlying mechanism of beat-to-beat variability of repolarization. We found that the mechanical variation due to preload variation caused small differences in the repolarization from beat to beat (mechano-electrical feedback), but only after proarrhythmic remodeling due to chronic complete AV-block. This was enhanced after administration of dofetilide. Further we showed that this may be caused via stretch-activated channels in the heart, because streptomycin (a drug that blocks stretch-activated channels) interrupted the mechano-electrical feedback.

The final chapter (Chapter 9) is a general discussion of the thesis.