1

Introduction

Catheter-based renal sympathetic denervation (RDN) has been developed as an interventional treatment option for patients with uncontrolled hypertension . The interpretation of current randomized, controlled, trials in RDN is contentious. The DENERHTN study confirmed the superiority of RDN compared with medical therapy alone. The Prague-15 trial demonstrated equivalent blood pressure reductions in the catheter-based RDN group when compared with the intensified pharmacological treatment group, but documented more serious adverse events in the latter cohort. The Leipzig RSD study confirmed the importance of accurate procedural performance as the trial failed to show a significant reduction in the primary endpoint of 24-h systolic blood pressure at 6 months between groups in the intention to treat analysis. However, in the per-protocol population of patients who received the treatment as planned, RDN was followed by a significant reduction in systolic blood pressure compared with a sham procedure . The results of the Symplicity HTN-3 trial showed no statistically significant difference between the RDN group and the sham-treated patients. An ineffective method has been postulated as a possible cause for non-response to treatment . The published, controlled and uncontrolled trials only enrolled patients with favorable renal anatomy, which was defined as i) absence of accessory renal arteries (ARA) or renal atherosclerotic disease including previous angioplasty or stenting, ii) diameter of ≥4 mm and iii) length of ≥20 mm of the main renal artery. Current knowledge on the relevance of anatomical and procedural parameters on future BP changes is limited, although it is important for ongoing and subsequent clinical studies. The lack of reliable markers of procedural success to establish immediately whether denervation has been completely achieved in a specific patient remains the major challenge . The present study therefore aims to investigate the association between anatomical and procedural parameters and later BP change in patients with resistant hypertension undergoing RDN in established centers in Europe and Australia.

2

Methods

Local ethics committees approved the study. All patients gave written informed consent and were treated between March 2009 and June 2013 with subsequent follow-up to 6 months. Eligible patients were ≥18 years old and had an office systolic blood pressure (SBP) ≥140 mmHg, despite treatment with ≥3 antihypertensive drugs (including one diuretic). A total of 564 patients from 9 centers in Europe and in Australia were enrolled prospectively following protocols of ongoing RDN trials. For the present investigation, office-based SBP and diastolic blood pressure (DBP), and pulse pressure (PP) were measured at study entry, and 6 months following treatment. Office BP readings were taken in a seated position with an automatic oscillometric monitor in a seated position after 5 min of rest according to the Standard Joint National Committee VII Guidelines . Averages of the triplicate measures were calculated and used for analysis.

2

Methods

Local ethics committees approved the study. All patients gave written informed consent and were treated between March 2009 and June 2013 with subsequent follow-up to 6 months. Eligible patients were ≥18 years old and had an office systolic blood pressure (SBP) ≥140 mmHg, despite treatment with ≥3 antihypertensive drugs (including one diuretic). A total of 564 patients from 9 centers in Europe and in Australia were enrolled prospectively following protocols of ongoing RDN trials. For the present investigation, office-based SBP and diastolic blood pressure (DBP), and pulse pressure (PP) were measured at study entry, and 6 months following treatment. Office BP readings were taken in a seated position with an automatic oscillometric monitor in a seated position after 5 min of rest according to the Standard Joint National Committee VII Guidelines . Averages of the triplicate measures were calculated and used for analysis.

3

Renal denervation procedure

Eligible patients underwent bilateral RDN using the single-electrode radiofrequency (RF) Symplicity Flex catheter (Medtronic, Mountain View, California) as previously described . Interventionists with an operative experience of at least 10 RDN procedures performed all procedures. The number of ablations as well as treatment of ASA was left to the discretion of the interventionist. In patients with renal artery disease (RAD), RF ablations were performed with a distance of at least 5 mm to the diseased area or the stent struts. Patients with hemodynamically significant renal artery stenosis or patients with unilateral RDN were excluded from the current analyses. Peri-procedural parameters and complications as well as the number of ablations on each side were recorded by the operator. Duration of the RDN procedure was defined as the time from arterial access to the removal of the arterial sheath.

4

Anatomic parameters and prevalence of variations of renal arterial vascularization

The CAAS II Research System (Pie Medical, the Netherlands) was used for quantitative renal artery analysis in all 564 RDN cases. Two experienced investigators, who were blinded to patient’s characteristics and BP results, performed all analyses. The end of the main renal artery was defined at the bifurcation/trifurcation in vessels >3 mm. An early branch did not define the end of the main renal artery if the branch vessel was <3 mm in diameter. Accessory renal arteries included multiple arteries, defined as more than one artery of similar size supplying the kidney, as well as small arteries supplying a minor part of the kidney. RAD included patients with non-significant renal artery stenosis (<50%) or prior renal angioplasty or stenting. Fig. 1 depicts the nomenclature.

Nomenclature of the renal artery (figure → left renal artery).

5

Results

The 564 enrolled patients ( Table 1 ) had a mean age of 63.6 ± 10.6 years; 56% were male, with a mean body mass index of 30.4 ± 6.0 kg/m ² . Despite an ingestion of 4.8 ± 1.6 antihypertensive agents, the mean BP at baseline was 173 ± 25/92 ± 18 mmHg. Office-based BP after 6 months was significantly reduced in the overall cohort: SBP by 19 ± 26 mmHg, DBP by 8 ± 14 mmHg, and PP by 11 ± 20 mmHg ( p for all <0.0001). At baseline 384 (68%) patients had a baseline SBP of ≥160 mmHg and 225 (40%) patients had an SBP ≥180 mmHg. These patients experienced a reduction of 26 ± 26 mmHg and 32 ± 28 mmHg in SBP at 6 months, respectively. A total of 369 patients (65%) had an SBP reduction of ≥10 mmHg and were subsequently defined as responders. Compared to non-responders, responders had a higher baseline BP (SBP 180 ± 24 vs. 160 ± 21; p < 0.0001; DBP 95 ± 18 vs. 87 ± 17; p < 0.0001), and were more frequently treated with central sympatholytics (56% vs. 47%; p = 0.046).

Table 2 summarizes the anatomical parameters. Accessory renal arteries were present in 171 patients (30%) and RAD was documented in 71 patients (13%). Patients with a diameter ≤4.0 mm had a higher reduction of SBP compared to patients with a diameter >4 mm ( Fig. 2 A and B ). In a linear regression analysis, the association between main renal artery diameter and SBP change at 6-month follow-up remained stable after adjusting for SBP at baseline, age, and GFR at the left side ( p = 0.036) with a trend at the right side ( p = 0.084), respectively. Patients with a bilateral diameter ≤4.0 mm had the strongest reduction of BP ( Fig. 3 ). The diameter of the left and right main renal artery correlated with age (right: r = −0.213; p < 0.0001; left: r = −0.201; p < 0.0001) and glomerular filtration rate (right r = 0.165; p < 0.0001; left: r = 0.212; p < 0.0001), respectively. However, only the left-sided but not the right-sided main renal artery diameter correlated with SBP at baseline (right: r = −0.077; p = 0.069; left: r = −0.108; p = 0.01). The diameter was not influenced by the presence of RAD.

Table 2

Procedural and anatomical details

	All		Responder		Non-responder
	Value	N	Value	N	Value	N	p
Procedure duration, min	73 ± 45	545	71 ± 45	356	76 ± 45	189	0.240
Contrast dye, ml	103 ± 59	518	104 ± 62	338	100 ± 53	180	0.52
Fluoroscopy time, min	11.0 ± 5.4	420	11.0 ± 5.7	275	11.0 ± 4.7	145	0.934
Fluoroscopy doses, cGy * cm 2	4376 ± 290	462	4289 ± 301	305	4583 ± 298	157	0.582
Total number of ablations	11.0 ± 2.7	564	10.8 ± 2.5	369	11.4 ± 2.7	195	0.03
Right renal artery
Presence of renal artery disease	37 (7%)	564	23 (6%)	369	14 (7%)	195	0.378
Length of main artery, mm (R1M)	43.7 ± 15.4	564	43.4 ± 15	369	44.5 ± 16.2	195	0.713
Length < 20 mm	30 (5%)	564	17 (5%)	369	13 (7%)	195	0.321
Mean diameter of main artery, mm (R1M)	5.4 ± 1.2	564	5.3 ± 1.2	369	5.5 ± 1.3	195	0.341
Diameter < 4 mm	34 (6%)	564	24 (7%)	369	10 (5%)	195	0.101
Ostial diameter, mm (R1M0)	5.9 ± 1.8	564	5.9 ± 1.8	369	6.1 ± 2	195	0.150
Diameter proximal segment, mm (R1M1)	5.6 ± 1.3	564	5.5 ± 1.2	369	5.8 ± 1.5	195	0.103
Diameter middle segment, mm (R1M2)	5.2 ± 1.2	564	5.2 ± 1.2	369	5.3 ± 1.3	195	0.484
Diameter distal segment, mm (R1M3)	5.2 ± 1.3	564	5.2 ± 1.2	369	5.3 ± 1.3	195	0.232
Number of ablations	5.6 ± 1.5	564	5.5 ± 1.4	369	5.8 ± 1.7	195	0.101
Length—ablation quotient, mm a	8.6 ± 5.6	564	8.5 ± 4.6	369	8.7 ± 7.1	195	0.447
Diameter—ablation quotient, mm b	1.1 ± 0.6	564	1.1 ± 0.5	369	1.1 ± 0.8	195	0.764
Left renal artery
Renal artery disease	34 (6%)	564	21 (6%)	369	13 (7%)	195	0.995
Length of main artery, mm (L1 M)	36.5 ± 12.5	564	36.7 ± 12.4	369	36.2 ± 12.8	195	0.48
Length < 20 mm	37 (7%)	564	25 (7%)	369	12 (6%)	195	0.321
Mean diameter of main artery, mm (L1 M)	5.5 ± 1.2	564	5.5 ± 1.3	369	5.6 ± 1.1	195	0.206
Diameter < 4 mm	21 (4%)	564	14 (4%)	369	7 (4%)	195	0.556
Ostial diameter, mm (L1 M0)	6.5 ± 1.9	564	6.4 ± 1.9	369	6.6 ± 1.9	195	0.187
Diameter proximal segment, mm (L1 M1)	5.8 ± 1.4	564	5.8 ± 1.4	369	5.8 ± 1.2	195	0.567
Diameter middle segment, mm (L1 M2)	5.4 ± 1.2	564	5.4 ± 1.3	369	5.5 ± 1.1	195	0.251
Diameter distal segment, mm (L1 M3)	5.4 ± 1.2	564	5.3 ± 1.3	369	5.5 ± 1.1	195	0.112
Number of ablations—left	5.5 ± 1.5	564	5.4 ± 1.4	369	5.6 ± 1.6	195	0.239
Length—ablation quotient, mm a	7.5 ± 5.3	564	7.6 ± 5.4	369	7.2 ± 5.1	195	0.207
Diameter—ablation quotient, mm b	1.1 ± 0.6	564	1.1 ± 0.6	369	1.1 ± 0.6	195	0.894

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