Today, LCSD is increasingly recognised as a viable treatment for therapy-resistant LQTS and CPVT patients [
13‐
15]. Here we report the experience in the only tertiary referral centre in the Netherlands for this treatment in 17 patients with inherited arrhythmia syndromes. Most patients (94 %) were referred because of therapy-refractory cardiac events. In 87 % of the symptomatic patients, the annual cardiac event rate decreased. However, after 2 years the probability of cardiac event-free survival was 59 % in LQTS and 60 % in CPVT patients. There were four patients (24 %) with minor reversible complications who did not require any intervention, which is a similar number compared with other centres [
14,
15,
21], and one patient (5.9 %) with a non-reversible post-procedural Harlequin face. Also, one LQT8 patient (5.9 %) died after the LCSD procedure due to complications secondary to bradycardias followed by an arrhythmic storm in combination with electrolytic disturbances and hypoglycaemia during the procedure. An identical case was reported by Schwartz et al. [
12] in 1991, where a 3-year-old female patient died early postoperatively with suspected post-anaesthesia hypoxic distress (hypoglycaemia, respiratory failure, complete heart block and asystole). This patient was later identified as a LQT8 patient, and extreme caution should be taken in this type of patients.
Success of LCSD
Our results are in agreement with previously published experience. Indeed, multiple studies have reported a significant decrease of cardiac events in 90 % of the symptomatic patients with inherited arrhythmia syndromes after LCSD, although approximately 40 % remained symptomatic [
13‐
15,
19,
21‐
23]. The antiarrhythmic and antifibrillatory effects of LCSD are attributed to the reduced release of norepinephrine at the level of the ventricles [
11]. This sympathetic blockade prolongs ventricular refractoriness and increases the ventricular fibrillation threshold, resulting in the prevention or suppression of triggered activity [
11]. The denervation has a highly specific antiarrhythmic effect, without reducing the heart rate (which might be especially important for LQT3 patients) and without impairing myocardial contractility [
11]. Additionally, because the denervation does not completely eliminate catecholamine input to the heart, surgery does not lead to hypersensitivity [
11]. And lastly, re-innervation is not expected because the denervation is pre-ganglionic, which makes it likely that the effects are durable [
18]. However, especially in highly symptomatic patients with inherited arrhythmia syndromes, LCSD has so far been advocated merely as an adjuvant therapy besides β-blockers (in LQTS and CPVT) or flecainide (in CPVT), as also demonstrated by the breakthrough cardiac event of patient #16 after lowering the β-blocker dosage. Indeed, ICDs should still be considered in patients at high risk for SCD.
Recently, percutaneous renal sympathetic denervation has emerged as a therapeutic option for patients with hyperactivity of the sympathetic system such as therapy-resistant hypertension [
24]. Additionally, in animal models renal denervation suppressed ventricular arrhythmias [
25]. These findings support the hypothesis that renal denervation might also be useful in reducing sympathetic activity in highly symptomatic patients with inherited arrhythmia syndromes and thereby reducing cardiac event rate, although this needs to be studied in the future.
Response to LCSD among the different genotypes
Although there was a significant decrease in cardiac events in most patients, half of the patients remained symptomatic. Post-LCSD cardiac events recurred in 3/6 of the LQT2 patients, 2/2 of the LQT3 patients, and 2/5 of the CPVT patients, while none of the LQT1 patients had events. The number of patients is too small to draw any meaningful conclusions, but the various results among the different genotypes are in agreement with the underlying pathophysiological mechanism. During gradual progressive sympathetic activation (such as exercise), the reduced, catecholamine-sensitive, slow delayed rectifier potassium current (I
Ks) in LQT1 patients prevents the necessary QT adaptation, causing a risk for triggered activity and ventricular arrhythmias [
26,
27]. Therefore, removing the sympathetic activation of the heart with LCSD appeared to be very successful in LQT1 patients [
15].
On the other hand, cardiac events in LQT2 patients are often triggered by a sudden heart rate acceleration, such as during a loud noise or surprising emotion [
28]. In LQT2 patients with a reduced rapid delayed rectifier potassium current (I
Kr), possible extrasystoles triggered by these triggers result in a markedly pause-dependent prolongation of the action potential duration of the following heart beat and attendant risk of early afterdepolarisations [
27,
29]. Sudden heart rate increment is caused by vagal withdrawal rather than sympathetic activation [
30] and this might explain that removal of the sympathetic activation by LCSD is not so successful in all LQT2 patients. Also the occurrence of extrasystoles might not be prevented.
In both LQT3 patients, the number of cardiac events decreased, but the effect of LCSD was not complete. Also, failure of complete LCSD success in CPVT may be attributed to the fact that only the local, cardiac, release of catecholamines is blocked. Systemic release of catecholamines is still pertinent and may be sufficient to elicit triggered arrhythmias during physical exercise, despite β-blockade and flecainide therapy. Furthermore, one CPVT patient (#2) with recurrent events carries an unclassified variant in the RyR2 gene, which might indicate that the diagnosis CPVT might not be correct.
Although the success of LCSD was not complete among the different genotypes, the number of events decreased in almost all patients (87 %), thus significantly improving the quality of life of the patients and their families. Therefore, LCSD continues to be worthwhile in highly symptomatic patients with primary arrhythmias.
Limitations
This is retrospective study with a small number of patients, secondary to the rare prevalence of therapy-resistant LQTS and CPVT patients. Due to the retrospective nature, a quantitative marker of arrhythmia burden has been difficult to express in statistically comparable data due to the large variability in presenting symptoms, resulting in a wide definition of cardiac events. Also, in patients without an ICD, the lack of continuous heart rate monitoring could have resulted in an underestimation of cardiac events, especially NSVT. However, cardiac event monitoring before and after LCSD was identical in all patients except for one LQT patient who received an ICD 1 month after LCSD.