Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol, flecainide, and sympathectomy

Abstract

Conventional treatment strategies for catecholaminergic polymorphic ventricular tachycardia (CPVT) include avoidance of strenuous exercise and competitive sports, drugs such as ß-blockers and flecainide and, cervical sympathectomy. An implantable cardioverter-defibrillator (ICD) has been utilized if the response to these strategies is inadequate; however, ICD use in CPVT patients, in addition to usual complications, is associated with an increased risk of life-threatening electrical storm. Ivabradine is a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 generated funny current (I f ), which has been shown to be efficacious in suppression of inappropriate sinus tachycardia, junctional tachycardia, atrial tachycardia, and ventricular ectopy in humans. We report an 18-year-old male with a severe CPVT phenotype refractory to flecainide, nadolol, and sympathectomy who exhibited suppression of ventricular arrhythmias after initiation of ivabradine. These findings are of importance as ivabradine could be an important add-on therapy in CPVT patients who are drug refractory or are unable to continue conventional therapies at the recommended doses. K E Y W O R D Scatecholaminergic polymorphic ventricular tachycardia, drug and sympathectomy refractory, ivabradine, malignant syncope, RYR2 exon 3 deletion

The Bradycardic Agent Ivabradine Acts as an Atypical Inhibitor of Voltage-Gated Sodium Channels

“…A weak frequency dependence may also serve as an explanation that changes in QRS duration by ivabradine were not rate-dependent ( Amstetter et al, 2021 ). In any case, ivabradine was recently shown to control catecholaminergic polymorphic ventricular tachycardia ( Vaksmann and Klug, 2018 ; Kohli et al, 2020 ) and junctional ectopic tachycardia ( Al-Ghamdi et al, 2013 ; Dieks et al, 2016 ; Kumar et al, 2017 ; Ergul et al, 2018 ; Ergul and Ozturk, 2018 ; Mert et al, 2018 ; Janson et al, 2019 ; Kumar et al, 2019 ). While some of these arrhythmias may be of automatic origin, potentially tied to the function of HCN channels, the antiarrhythmic activity of ivabradine could also stem from the inhibition of VGSCs, in particular under ischemic conditions and in the failing heart, when resting membrane potentials are substantially depolarized ( Bean et al, 1983 ) and channel block would be favored ( Figure 4 ).…”

“…Recent meta-analyses suggested an increased risk of atrial fibrillation associated with ivabradine treatment ( Martin et al, 2014 ; Tanboğa et al, 2016 ; Mengesha et al, 2017 ). On the other hand, ivabradine was able to control ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia ( Vaksmann and Klug, 2018 ; Kohli et al, 2020 ) and junctional ectopic tachycardia ( Al-Ghamdi et al, 2013 ; Dieks et al, 2016 ; Kumar et al, 2017 ; Ergul et al, 2018 ; Ergul and Ozturk, 2018 ; Mert et al, 2018 ; Janson et al, 2019 ; Krishna et al, 2019 ; Kumar et al, 2019 ). Recently, ivabradine has also been considered as a rate control therapy for atrial fibrillation ( Moubarak et al, 2014 ; Kosiuk et al, 2015 ; Turley et al, 2016 ; Wongcharoen et al, 2016 ; Fossati et al, 2017 ), with a current clinical trial to test for this potential new indication ( Fontenla et al, 2019 ), and for other forms of atrial and ventricular tachyarrhythmias [e.g., ( Cohen et al, 2020 ; Kohli et al, 2020 )].…”

“…On the other hand, ivabradine was able to control ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia ( Vaksmann and Klug, 2018 ; Kohli et al, 2020 ) and junctional ectopic tachycardia ( Al-Ghamdi et al, 2013 ; Dieks et al, 2016 ; Kumar et al, 2017 ; Ergul et al, 2018 ; Ergul and Ozturk, 2018 ; Mert et al, 2018 ; Janson et al, 2019 ; Krishna et al, 2019 ; Kumar et al, 2019 ). Recently, ivabradine has also been considered as a rate control therapy for atrial fibrillation ( Moubarak et al, 2014 ; Kosiuk et al, 2015 ; Turley et al, 2016 ; Wongcharoen et al, 2016 ; Fossati et al, 2017 ), with a current clinical trial to test for this potential new indication ( Fontenla et al, 2019 ), and for other forms of atrial and ventricular tachyarrhythmias [e.g., ( Cohen et al, 2020 ; Kohli et al, 2020 )]. Moreover, ivabradine is currently being investigated for its autochthone and cardioprotective actions ( Heusch, 2008 ; Kleinbongard et al, 2015 ; Heusch and Kleinbongard, 2016 ), for post-infarction ( Suffredini et al, 2012 ) and post-heart transplantation treatment ( Rivinius et al, 2020 ), and for its anti-epileptic potential ( Cavalcante et al, 2019 ; Iacone et al, 2021 ).…”

Pharmacologic Management for Ventricular Arrhythmias: Overview of Anti-Arrhythmic Drugs

“…Ivabradine is approved as an adjunctive medication to GDMT in patients with HFrEF and NYHA class II-III symptoms following the results of the SHIFT trial, which demonstrated a reduction in heart failure hospitalizations and subsequently cardiovascular death [ 148 ]. Given its unique electrophysiologic effects to reduce heart rate, a small randomized crossover trial of 21 patients found improvement in symptoms if patients with inappropriate sinus tachycardia [ 149 ]. Recent case reports document ivabradine as an effective adjunctive agent in CPVT refractory to nadolol, flecainide, and cervical sympathectomy [ 150 , 151 ].…”

The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia

“…Kohli et al . suggested that ivabradine could be an important add-on therapy for CPVT patients, who are drug-refractory or unable to continue conventional therapies [ 75 ]. Using CASQ2 D307H/D307H mice and iPSC-CM, Bueno-Levy et al .…”