RF energy is a form of alternating electrical current that produces an ablation area by two mechanisms: (1) direct resistive heating of the tissue in contact with the catheter tip, and (2) thermal conduction or passive heat transfer to deeper tissue layers [31]. While direct resistive heating in regions close to the RF current is rapid, passive heat transfer to deeper tissue layers is a slower process [32]. Since the heat transfer continues even after discontinuation of RF current delivery, ablation area may expand following RF current cessation. Both bipolar mode and unipolar mode are used for the generation of RF electrical current. RF current is delivered to the target regions through transarterial electrode catheters with a catheter tip ranging in length from 4 to 10 mm.

Steigerwald et al. reported the acute (45 min) and sub-acute (10 days) histopathologic changes and optical coherence tomographic (OCT) findings following RF ablation in the swine model [33]. Seven pigs underwent RF ablations of the renal arteries utilizing the Symplicity Catheter System (Medtronic Ardian, Mountain View, CA). In the acute phase, angiography showed vessel notches at the site of ablation where the catheter tip had been positioned. OCT at acute phase showed thrombotic material and a loss in signal intensity of the media wall as a result of acute cell depletion and cellular edema, whereas thrombotic material was absent at 10-day follow-up (Fig. 3.2). Histologic findings revealed the presence of thrombus formation and depletion of endothelial cells, which were confirmed by absence of von Willebrand factor (vWF) staining (Fig. 3.3) [33]. The arterial media showed edematous cell swelling with a reduction in cellularity [33] (Fig. 3.4). Also, the adjacent adventitial layer showed coagulation necrosis of the connective tissue and cell depletion. The number of nerve fascicles around the treated arteries were significantly affected as compared to the untreated arteries. Immunostaining against neurofilament protein did not show abnormal staining pattern in the acute injured nerves (Fig. 3.5). In the sub-acute phase, re-endothelialization was evident by the presence of vWF staining (91 %) and thrombus was absent (Fig. 3.3) [33]. The recovered media showed fibrotic scar tissue comprising 11 % of the media area, however substantial variability in the degree of medial fibrosis was evident (Fig. 3.4) [33]. Nerve fascicles showed degenerative morphologic changes consisting of vacuolization and thickening of the perineurium [33]. Also, Immunostaining against neurofilament protein showed weak or loss of staining (Fig. 3.5) [33]. This study suggests the importance of difference between acute and subacute in the nerve injury and staining characteristics of pre-clinical porcine model following RF sympathetic denervation.

Rippy et al. reported on the chronic histopathologic changes of RF ablation in swine [22]. Seven swine were treated with the Symplicity Catheter System, with angiography and histopathology performed at 6-months. By angiography, there was no restenosis or other vascular complication at 6-month follow-up [22]. Histopathology of the renal arteries at 6-months showed media injury consisting of fibrotic replacement of the smooth muscle cells of the media with disruption of the IEL (10–25 %) [22]. Minimal intimal thickening was observed in treated renal arteries with complete endothelializatio [22] (Fig. 3.6). The renal nerve injury at 6 months was characterized by fibrosis of the nerve fibers and perineural thickening (Fig. 3.6) [22]. These findings show the long-term safety of RF ablation.

Cryoablation has evolved as an alternative therapy to conventional RF ablation of the conduction system since the late 1990s [34]. The catheter tip is cooled to −70 °C to −80 °C by instilling liquid NO₂ in the catheter [35]. As compared to the thermal injury caused by RF ablation, the targeted tissue is frozen, and tissue structure remains almost unchanged when used for the treatment of arrhythmia [36]. On the other hand, the limitations include a higher recurrence rate of arrhythmia following cryoablation [35].

Prochnau et al. reported the histopathologic changes of cryoablation of perirenal nerves in a sheep model [37]. A standard seven French cryocatheter, with a 6 mm tip (Freezor Xtra; Medtronic Inc., Minneapolis, MN) was used for renal denervation and the temperature was lowered to minus 81 °C for 4 min. Changes were determined at 48 h, at 1 month, and at 3 months. Histopathology of renal arteries showed focal coagulation necrosis of the intima and media at 48-h [37]. At 1 month, regeneration of endothelium, which was confirmed by immunostaining (CD31), was observed [37]. At 3 months, there was a loss of axons which was confirmed by immunohistochemistry against neurofilament protein [37].

Ultrasound energy has also been applied to achieve renal sympathetic denervation. Overall, both intravascular and extracorporeal ultrasound ablation have been used for renal denervation [14]. Mabin et al. reported the first experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension [38]. They enrolled 11 consecutive patients with resistant hypertension for the treatment by transcatheter renal denervation using the CE-marked PARADISE^TM technology (ReCor Medical, Ronkonkoma, NY). Clinically, 3-months results were comparable to RF renal denervation with an average reduction in office and home blood pressure of −36/−17 mmHg and −22/−12 mmHg, respectively.