Discussion
The LV summit is a triangular region located at the most superior aspect of LV ostium. The apex of the triangle is bounded by the bifurcation of left anterior descending (LAD) and left circumflex (LCX) arteries and its base is formed by the arch between the first septal perforator of the LAD and LCX. The region is transected laterally by the great cardiac vein (GCV) at its junction with anterior interventicular vein (AIV) giving rise to two separate regions; a medial and more superior area which is inaccessible to catheter ablation and a lateral and more inferior area which is more easily accessible with ablation catheters. Arrhythmias that are originated from the LVS constitute approximately 14.5% of LV VA’s10. Success rates of catheter ablation directing LVS VA’s are lower compared to other outflow VA’s due to inability to advance catheters to the site of interest, proximity to coronary arteries and high probability of epicardial site of origin9.
Frequent PVC’s are a well known risk factor for the development of cardiomyopathy in the absence of structural heart disease11. Although the time interval between the first diagnosis of PVC’s and the occurrence of LV dysfunction has a wide range, several variables were proposed as the predictor of PVC induced cardiomyopathy including high PVC burden, male gender, epicardial origin, wide QRS and short coupling interval12. LV dysfunction was not present in our patient but high PVC burden with LV epicardial origin and wide QRS increased the risk of developing PVC cardiomyopathy. Thus, suppressing PVC’s not only provided symptom relief but also mitigated the risk of subsequent LV dysfunction. 72 hour Holter monitoring that was performed a week after the ivabradine treatment revealed 12000 PVC’s. We did not increase the dose of ivabradine to 10 mg BID because the patient was asymptomatic. Serial clinical visits were planned for the further evaluation of PVC burden and LV functions. Frequent PVC’s can be observed during the course of several cardiac conditions including sarcoidosis, arrhythmogenic right ventricular dysplasia (ARVD) and myocarditis. Absence of structural abnormalities in TTE, normal cardiac troponins and QRS configuration that was atypical for ARVD in our patient made these diagnoses less likely. We do not have cardiac magnetic resonance imaging (cMRI) in our hospital, which could be performed for the differential diagnosis.
Ivabradine binds to cytoplasmic side of the HCN channel and inhibits If current in cardiac pacemaker cells. Ivabradine blocks these channels only when they are in open state causing use dependent action explaining its greater effectiveness in higher heart rates13. HCN channels are of 4 isomers (HCN 1-4) and among them HCN 4 and HCN 3 are predominant through the sinoatrial and atrioventricular (AV) node respectively14. HCN 2 isoform is abundant in infant ventricular myocardium but its expression is much weaker in adult and healthy myocardium15. Their expression in ventricular myocardium can increase in certain conditions such as ventricular hypertrophy and dilated cardiomyopathy16. In addition, different isoforms are found in atrial appendages and pulmonary veins17.
Previous reports demonstrated that ivabradine reduced the heart rate without negative inotropic effects in patients who are in sinus rhythm and atrial fibrillation by decreasing If current in the sinus node and AV node respectively18. In several cases and observational studies ivabradine was used successfully for treating patients with junctional and atrial tachycardias6,7. In their prospective single center study Banavalikar et al evaluated ivabradine treatment in patients with incessant focal atrial tachycardia and without structural heart disease19. Conversion to sinus rhythm was achieved in 17 out of 28 patients approximately 4 hours after ivabradine administration. All patients underwent subsequent electrophysiological (EP) study independent of their response to the treatment, which demonstrated that atrial tachycardias originating from the left and right atria appendage were more likely to convert to sinus rhythm. In a more recent report ivabradine was shown to successfully suppressed ventricular arrhythmias in a patient with catecholaminergic polymorphic ventricular tachycardia who was resistant to other AAD’s or could not continue using them due to serious side effects20. In a patient with non-ischemic dilated cardiomyopathy ivabradine effectively suppressed PVC’s that were resistant to beta blockers and optimized the response to cardiac resynchronization therapy by increasing the rate biventricular pacing21.
Ivabradine has good safety profile with neutral effect on hemodynamics unlike other AAD’s, which makes it an attractive option particularly in the context of tachycardia induced cardiomyopathy where most of AAD’s are contraindicated. Although ivabradine can lead to QT interval prolongation by causing bradycardia and hERG inhibition, it is much less frequently observed compared to other AAD’s22.
Precise mechanisms underlying the efficacy of ivabradine in the treatment of tachycardias originating from areas other than sinus node and caused by increased automaticity is yet to be elucidated. One possible mechanism is that increased expression of HCN channels in ventricular myocytes may predispose to enhanced automaticity. Elevated β-adrenergic stimulus may increase the susceptibility of myocytes to early after-depolarization and spontaneous action potential through increased cAMP production, which can be prevented by ivabradine. However, it is not certain that which conditions trigger re-expression of genes that are responsible for coding HCN channels. Another potential explanation is that ivabradine may prevent triggered activity mediated arrhythmias by prolonging ventricular repolarization through its inhibitory effects on hERG/IKr channels. In their in vivo rat model, Mackiewicz et al. studied the effect of ivabradine on VA within 24 h after non-reperfused myocardial infarction23. They found that VA incidence and arrhythmic mortality were lower in rats that were administered ivabradine. This finding was further supported by that ivabradine partially prevented the increase in calcium sensitivity of ryanodine receptors and If current in the LV, HCN 4 up-regulation and heterogeneity in action potential duration between the remote LV wall and infarct border zone, which all were observed within 24 h after myocardial infarction and were considered as major pro-arrhythmic mechanisms caused by ischemia.
In conclusion, with its acceptable safety profile ivabradine may be used in case other AAD’s and catheter ablation fails to suppress idiopathic VA’s. However, there are several issues to be addressed before recommending ivabradine in this context: i) What drives the increased expression of HCN in myocytes other pacemaker cells and how is it regulated? ii) What are the reasons for heterogeneity in clinical response to ivabradine among patients with cardiac arrhythmias? iii) Which isoforms of HCN channels in particular are contributory in the pathogenesis of specific arrhythmias and finally, iv) Randomized clinical trials are needed to better identify specific patient population that would benefit most from ivabradine and to determine optimal dosing strategies.