Computer simulation models were developed to characterize and optimize the thermal profile of the system. Simulations provide information regarding the heating pattern and depth of thermal energy delivered from the transducer. The model demonstrates the heating pattern emanating from the length of the transducer and the depth of heating with peak temperatures reached at several millimeters of depth with cooling on the surface.

In vitro studies confirmed the thermal profile observed in computer simulations. A gel model was utilized which mimics characteristics of tissue. The Paradise Catheter was inserted into the gel and thermocouples were placed at specific depths surrounding the balloon/transducer to measure the energy (heat) delivered. A temperature curve was generated based on the thermocouple readings. Based on this model and animal data, treatment parameters have been optimized for clinical use. At near depths (0–0.5 mm) temperatures remained below 60 °C and then reached ablation temperatures in the 0.5–6 mm range. Beyond 6 mm, the temperatures dropped off again below ablation levels. Figure 9.3 shows the average temperature at specific depths (thermal profile) in the gel model.

The animal studies have demonstrated that the target thermal profile has been achieved in vivo with preservation through cooling of the arterial wall, and ablation of nerves at the target ablation zone of 1–6 ± 2 mm. The actual tissue ablation zone varies depending on the biological structures present. The renal vein, arterioles, and lymph nodes serve as heat sinks, preventing adjacent tissues from reaching ablation temperatures. Effective ablation of the nerves, characterized by irreversible necrosis, has been demonstrated histologically. A decrease in nerve function has further been demonstrated by immunohistochemical staining for specific nerve proteins; and by measurement of norepinephrine levels in the kidney, the end organ target of the renal sympathetic nerves.

Figure 9.4 is a representative histologic image of a porcine renal artery treated with the Paradise System at 7 days. As indicated, the renal artery (first millimeter of tissue) is spared whereas the ablation zone extends out to 6 mm, to target the majority of sympathetic nerves surrounding the renal artery. Quantification of affected nerves determined that on average 75 % of the nerves along the length of the artery were ablated with the Paradise System in animal models. In contrast, radiofrequency ablation ablates in a non-circumferential manner and heats at depths of 0–3 mm thereby potentially missing a large percentage of nerves.

Further confirmation of the effectiveness of the Paradise System was demonstrated through specific immunostaining of the renal nerves for structural nerve and functional nerve proteins. Positive staining was observed for two structural proteins [neurofilament protein, NFP, and S-100, nervous system specific protein] whereas reduced staining was observed for tyrosine hydroxylase (TH), a functional nerve protein. These data illustrate that in nerves (clearly identified through the structural proteins), function was greatly diminished consistent with thermal ablation.

Further evidence for a decrease in nerve function is demonstrated by kidney norepinephrine levels (Table 9.1). Eight animals were selected to get either one (n = 3), two (n = 3), or three (n = 2) 30 s treatments in the proximal, mid, and/or distal regions of both renal arteries. A significant decrease in norepinephrine levels was evident at 7 days for 1, 2 or 3 treatment emissions per artery when compared to control animals (n = 2), which correlated with the percentage of ablated nerves. Two or three emissions resulted in far greater reduction than one emission, consistent with the current clinical protocol.

In addition, in vivo animal studies confirmed that the Paradise System does not cause clinically significant renal artery damage or functional impairment. As illustrated in the histology image in Fig. 9.4, the renal arterial wall (endothelium and medial layer) is preserved with minimal to no injury, which is important in minimizing any risk of renal stenosis. Preservation of the arterial wall is primarily due to the cooling feature of the system. Further, there is no evidence of ultrasound related damage to the renal vein, ureter, or kidney detected.