Non-invasive Programmed Stimulation in Hypertensive Patients with Heart Failure and ICD after Renal Sympathetic Denervation

The relationship between structural heart disease and the occurrence of sudden cardiac death (SCD) is well established in the literature. In more than 70% of cases, the underlying heart disease is myocardial ischemia. The pathophysiology results from the interaction between the generator event and electrical instability inducing ventricular tachycardia, which degenerates into ventricular fibrillation. The high mortality resulting from these recurring ventricular tachyarrhythmias stimulated the development of various therapies with the purpose of prevent SCD, among which the surgical approach or radiofrequency ablation or resection aiming the elimination of arrhythmogenic focus and electrical treatment for cardiac stimulation artificial implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) [1]. The ICD was introduced in clinical practice in patients surviving a cardiac arrest due to ventricular fibrillation or sustained ventricular tachycardia hemodynamically unstable and associated with structural heart disease, so for secondary prevention of sudden cardiac death[2-6]. Given the early results, clinical trials focused on primary prevention have been proposed, including patients with coronary artery disease and patients with the following eligibility criteria: reduced left ventricular ejection fraction (LVEF), non-sustained ventricular tachycardia spontaneous, sustained ventricular tachycardia induced by electrophysiology study. Recently, Armaganijan et al. [7] reported in patients with ICDs and refractory ventricular arrhythmias that renal sympathetic denervation (RSD) was associated with reduced arrhythmic burden with no procedure-related complications.

The relationship between structural heart disease and the occurrence of sudden cardiac death (SCD) is well established in the literature.In more than 70% of cases, the underlying heart disease is myocardial ischemia.The pathophysiology results from the interaction between the generator event and electrical instability inducing ventricular tachycardia, which degenerates into ventricular fibrillation.The high mortality resulting from these recurring ventricular tachyarrhythmias stimulated the development of various therapies with the purpose of prevent SCD, among which the surgical approach or radiofrequency ablation or resection aiming the elimination of arrhythmogenic focus and electrical treatment for cardiac stimulation artificial implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) [1].The ICD was introduced in clinical practice in patients surviving a cardiac arrest due to ventricular fibrillation or sustained ventricular tachycardia hemodynamically unstable and associated with structural heart disease, so for secondary prevention of sudden cardiac death [2][3][4][5][6].Given the early results, clinical trials focused on primary prevention have been proposed, including patients with coronary artery disease and patients with the following eligibility criteria: reduced left ventricular ejection fraction (LVEF), non-sustained ventricular tachycardia spontaneous, sustained ventricular tachycardia induced by electrophysiology study.
Recently, Armaganijan et al. [7] reported in patients with ICDs and refractory ventricular arrhythmias that renal sympathetic denervation (RSD) was associated with reduced arrhythmic burden with no procedure-related complications.
In this study, we evaluated 20 controlled hypertensive patients with heart failure using amiodarone 200 mg once a day and β-blocker (carvedilol 25 mg/day or bisoprolol 5 mg/day).The study was conducted in accordance with the Helsinki Declaration and approved by the Ethics Committee.All patients gave written informed consent before inclusion.All patients underwent ICD implantation for primary prevention to SCD, and at the end of the procedure, the patients were submitted to a non-invasive programmed stimulation (NIPS) with three extra-stimuli coupled to a programmed cycle length of 400 ms (150 ppm).The results were expressed as the mean and standard deviation (mean±SD) of the mean in the case of normal distribution and as the median with inter-quartile range otherwise.Statistical tests were all two sided.Comparisons between two-paired values were performed by the paired t-test in case of Gaussian distribution or, alternatively, by the Wilcoxon test.All statistical analysis was performed using the program Graphpad Prism v 7.0 (Graphpad software, La Jolla, CA, USA).
The patients were divided into two groups, the group 1 would have an increase in β-blocker dosage, and the group 2 would have an increase in β-blocker dosage and also would undergo RSD one month after receiving the ICD.Baseline features are presented in table 1. Immediately after ICD implantation the mean extra-stimuli sequence to induce ventricular tachycardia was a programmed cycle length of 400 ms (S1S1) composed by 8 extra-stimuli (S1 count), followed by S1S2=326±13,5 ms, S2S3=296±13,5 ms and S3S4=284±11.7 ms (P<0.0001 for all the comparisons between extra-stimuli) in the group 1, and the mean extra-stimuli sequence to induce ventricular tachycardia was a programmed cycle length of 400 ms (S1S1) composed by 8 extra-stimuli (S1 count), followed by S1S2=329±14,5 ms, S2S3=299±14,5 ms and S3S4=285±11.8ms (P<0.0001 for all the comparisons between extra-stimuli) in the group 2. The comparison between groups did not show a significant difference at baseline.One month after ICD implantation the group 1 remained using amiodarone 200 mg once a day and had β-blocker dosage increased to the maximum tolerated dose (carvedilol 50 mg/day or bisoprolol 10 mg/day).The group 2 remained using amiodarone 200 mg once a day, had β-blocker dosage increased to the maximum tolerated dose (carvedilol 50 mg/day or bisoprolol 10 mg/day) and underwent RSD.
Based on the angiographies we performed rotational RSD.The procedures were performed in the catheterization laboratory with direct visualization using fluoroscopy and radiopaque contrast.Patients were pretreated with diazepam or midazolam by an anesthesiologist.Catheterization of the femoral artery by the standard Seldinger technique was performed after s.c.injection of local anaesthetic in the inguinal region.An 8-Fr valved sheath was introduced into this artery, and unfractionated heparin was administered as i.v.bolus, targeting an activated coagulation time (ACT) >250 s in the first 10min.During the procedure, the ACT targeted range was 250-350 s.Subsequently, using an RDC catheter (St.Jude Medical, St. Paul, Minnesota, USA) by the standard "over the wire" technique, an angiogram of the aorta and renal arteries was performed.Subsequently, the EnligHTNTM ablation catheter (St.Jude Medical, St. Paul, Minnesota, USA) was inserted, alternately, inside the left and right renal arteries, respectively, allowing the delivery of radiofrequency energy to the renal artery innervation.Because the application of radiofrequency is usually very painful, fentanyl was intravenously administered before the procedure.

Figure 1. (A) mean extra-stimuli sequence to induce ventricular tachycardia was a programmed cycle length of 400 ms (S1S1)
composed by 8 extra-stimuli (S1 count), followed by S1S2, S2S3 and S3S4 in the group 1 and 2. The comparison between groups showed a significant difference at the 3rd month after ICD implantation.(B) Percentage of patients in both groups presenting ventricular tachycardia or ventricular fibrillation during NIPS at baseline and at the 3rd month after ICD implantation.Group 1: using amiodarone 200 mg once a day and had β-blocker dosage increased to the maximum tolerated dose (carvedilol 50 mg/day or bisoprolol 10 mg/day) for the 1st month after ICD implantation.The group 2: using amiodarone 200 mg once a day, had β-blocker dosage increased to the maximum tolerated dose and underwent RSD at the 1st month after ICD implantation.aMean±SD; Group 1: using amiodarone 200 mg once a day and had β-blocker dosage increased to the maximum tolerated dose (carvedilol 50 mg/day or bisoprolol 10 mg/day) at the 1st month after ICD implantation.The group 2: using amiodarone 200 mg once a day, had β-blocker dosage increased to the maximum tolerated dose and underwent RSD at the 1st month after ICD implantation.ABPM, ambulatory blood pressure measurements; ACE, angiotensinconverting enzyme; ARB, angiotensin receptor blocker; DHP, dihydropyridine; LVEF, left ventricular ejection fraction; N, number of patients; RSD, renal sympathetic denervation.
Three months after the ICD implantation (2 months after the β-blocker increase or/and RSD) both groups underwent a new NIPS with three extra-stimuli coupled to a programmed cycle length of 400 ms (150 ppm).The mean extra-stimuli sequence to induce ventricular tachycardia was a programmed cycle length of 400 ms (S1S1) composed by 8 extra-stimuli (S1 count), followed by S1S2=274±19.0ms, S2S3=244±18.9ms and S3S4=236±16.5 ms (P<0.0001 for all the comparisons between extra-stimuli) in the group 1, and the mean extra-stimuli sequence to induce ventricular tachycardia was a programmed cycle length of 400 ms (S1S1) composed by 8 extra-stimuli (S1 count), followed by S1S2=249±14,4 ms, S2S3=216±15,1 ms and S3S4=208±9.2 ms (P<0.0001 for all the comparisons between extra-stimuli) in the group 2. The comparison between groups showed a significant difference at the 3rd month after ICD implant (S1S2, P=0.0039; S2S3, P=0.0018; S3S4, P=0.0002), as shown in Figure 1A.At baseline, 100% of patients in both groups presented ventricular tachycardia (VT) or ventricular fibrillation (VF) during NIPS.However, the 3rd month post ICD implant, 100% of patients in the group 1 presented VT/VF and 60% of patients in the group 2 showed VT/VF during NIPS (P=0.0368 vs. baseline , and P=0.0248 vs. group 1 at the 3rd month post ICD), as shown in Figure 1B.
As showed in table 2, the mean of 24-hour ambulatory blood pressure measurements did not change from baseline to the 3rd month after ICD implantation in both groups.
Our results show that after RSD it becomes more difficult to induce VT/VF using the NIPS protocol in comparison to patients who received only an increased dosage of β-blocker, and also that the number of subjects who developed VT/VF was 40% lower in the group submitted to RSD, in the third month after ICD implantation.Values are expressed as mean±SD; Group 1: using amiodarone 200 mg once a day and had β-blocker dosage increased to the maximum tolerated dose (carvedilol 50 mg/day or bisoprolol 10 mg/ day) at the 1st month after ICD implantation.The group 2: using amiodarone 200 mg once a day, had β-blocker dosage increased to the maximum tolerated dose and underwent RSD at the 1st month after ICD implantation; ABPM, ambulatory blood pressure measurements.There was no difference between comparisons into the same group at baseline and 3rd month after ICD implantation or between groups at the same time point.

Table 1 .
General features of patients at baseline