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.