T hirteen percent of global mortality has been associated with arterial hypertension. Approximately 34% of the total adult population worldwide is hypertensive, and 13% of this segment of the population is further categorized as having resistant hypertension (RHTN).1 Criteria for the diagnosis of RHTN are the following: any patient requiring ≥3 antihypertensive drugs, including a diuretic, and still maintaining a blood pressure (BP) >140/90 mm Hg.2 RHTN has been previously described as a multifactorial phenomenon involving multiple biological mechanisms; however, the hyperactivity of the sympathetic nervous system plays a paramount role in the onset, maintenance, and progression of RHTN. 3 The renal sympathetic nervous system, composed of afferent and efferent nerves, courses immediately adjacent to the wall of the renal artery. 4 The afferent renal sensory nerves, with neuronal cell bodies located in the ipsilateral dorsal root ganglia, modulate the central sympathetic outflow by providing sensory information from mechanoreceptors and chemoreceptors in the renal tissue. Renal injuries (ie, hypoxia) increase afferent sensory signals, resulting in an increase in efferent sympathetic nerve activity, peripheral arterial vasoconstriction, and subsequent increase in arterial BP. The efferent renal sympathetic nerves transmit signals from the central sympathetic nervous system to the kidneys (ie, renal vasculature, tubules, and juxtaglomerular apparatus). Efferent renal sympathetic activity is moderated by an inhibitory renorenal reflex and central sympathetic nervous system outflow. Elevated efferent renal sympathetic activity increases sodium reabsorption and renin release and causes renal arterial vasoconstriction, leading to hypertension. Catheter-based ablation of afferent and efferent sympathetic nerves surrounding the renal arteries has been proposed Background-Renal denervation (RDN) emerged as a therapeutic option for resistant hypertension. Nerve regrowth after RDN has been questioned. We aimed to characterize the nerve response after RDN. Methods and Results-Swine underwent bilateral RDN and were followed up for 7, 30, and 90 days and evaluated with S100 (Schwann cell), tyrosine hydroxylase (TH; efferent nerves), and growth-associated protein 43 (neurite regeneration) markers. At 7 days, nerve changes consisted of necrosis associated with perineurial fibrosis and distal atrophy with inflammation. At 30 days changes were substituted by healing changes (ie, fibrosis). This response progressed through 90 days resulting in prominent neuroma formation. Immunohistochemistry at 7 days: TH staining was strongly decreased in treated nerves. Early regenerative attempts were observed with strongly TH and growth-associated protein 43 positive and weak S100 disorganized nerve sprouts within the thickened perineurium. Distal atrophic nerves show weak staining for all 3 markers. At 30 days, affected nerves show a weak TH and S100 staining. Evident growth-associated protein 43+ disorganized neuromatous tangles in the thick...
Background—Ablation lesion depth caused by radiofrequency-based renal denervation (RDN) was limited to <4 mm in previous animal studies, suggesting that radiofrequency-RDN cannot ablate a substantial percentage of renal sympathetic nerves. We aimed to define the true lesion depth achieved with radiofrequency-RDN using a fine sectioning method and to investigate biophysical parameters that could predict lesion depth.Methods and Results—Radiofrequency was delivered to 87 sites in 14 renal arteries from 9 farm pigs at various ablation settings: 2, 4, 6, and 9 W for 60 seconds and 6 W for 120 seconds. Electric impedance and electrode temperature were recorded during ablation. At 7 days, 2470 histological sections were obtained from the treated arteries. Maximum lesion depth increased at 2 to 6 W, peaking at 6.53 (95% confidence interval, 4.27–8.78) mm under the 6 W/60 s condition. It was not augmented by greater power (9 W) or longer duration (120 seconds). There were statistically significant tendencies at 6 and 9 W, with higher injury scores in the media, nerves, arterioles, and fat. Maximum lesion depth was positively correlated with impedance reduction and peak electrode temperature (Pearson correlation coefficients were 0.59 and 0.53, respectively).Conclusions—Lesion depth was 6.5 mm for radiofrequency-RDN at 6 W/60 s. The impedance reduction and peak electrode temperature during ablation were closely associated with lesion depth. Hence, these biophysical parameters could provide prompt feedback during radiofrequency-RDN procedures in the clinical setting.
Swine are the most common animal model in preclinical studies of cardiovascular devices. Because of the recent trend for development of new devices for percutaneous catheterization, especially for the renal arteries (RAs), we examined the quantitative anatomical dimensions of the RAs and adjacent aorta in swine. Angiographic images were analyzed in 66 female Yorkshire/Landrace crossbred swine. The diameter of both the right and left main RA was 5.4 ± 0.6 mm. The length of the right main RA was significantly longer than that of the left (29.8 ± 7.5 mm vs. 20.6 ± 5.4 mm, respectively; P<0.001). The diameter of both the right and left branch RA with diameters ≥3 mm (the target vessel diameter of recently developed devices) was 3.8 ± 0.5 mm. The right branch RA was significantly longer than that of the left (18.9 ± 7.8 mm vs. 16.4 ± 7.4 mm, respectively; P<0.05). The branching angle of the right RA from the aorta was significantly smaller than that of the left (91 ± 12° vs. 103 ± 15°, respectively; P<0.001). The diameters of the suprarenal and infrarenal aorta were 10.6 ± 1.1 mm and 9.7 ± 0.9 mm, respectively. In conclusion, because of their similar dimensions to human, swine are an appropriate animal model for assessing the safety of, and determining optimal design of, catheter devices for RAs in simulated clinical use. However, there were species differences in the branching angle and adjacent aorta diameter, suggesting that swine models alone are inadequate to assess the delivery performance of catheter devices for RAs.
<p><strong>Aims:</strong>We aimed to evaluate the transcatheter renal denervation(RDN) effects delivered by a mono-electrode catheter in a large animal model including safety implications of delivery of one cycle versus two cycles of ablations.</p><p><strong>Methods and Results:</strong>18 animals underwent bilateral RDN; 4 untreated naïve swine were enrolled as controls for norepinephrine levels(NE) only. Animals recieved 120-second (follow up-7,30 and 90 days) or 240-second cycles ablations (follow up-7 days). Norepinephrine evaluation, histology and immunohistochemistry evaluation was performed. No luminal obstruction was observed at follow up. A 70% decrease in NE levels (76.68±57.87ng/g) was observed at 7 days, 81% at 30 days(49.05±45.81ng/g), and 51% at 90 days(12.7±73.2 ng/g) compared to naïve controls(254.1±54.1ng/g;p<0.05). Histologically, the thermal effect extended to a complete circumferential involvement with a depth ~8mm. The primary histological feature at 7 days was nerve necrosis and distal atrophy; at 30 days, necrosis was replaced by healing changes of fibrosis. Neuromatous regeneration was apparent at 30 days at RF treated levels. At 90 days these features progressed to become more conspicuous. There were no appreciable differences in depth and circumferential extent of RF injury between one and two cycle treatment groups.<strong></strong></p><p><strong>Conclusion:</strong>RDN performed with a mono-electrode catheter (Iberis) appears to be safe following single or double-cycle RF ablation.NE decrease following RDN was demonstrated at 7, 30, and 90 days compared to naïve controls, suggesting efficient nerve ablation with the device as intended for human use.</p>
Introduction:Several renal denervation (RDN) systems are currently under investigation for treatment of hypertension by ablation of renal sympathetic nerves. The procedural efficacy of devices, however, is variable and incompletely understood. This study aimed at investigating procedural and anatomical predictors of RDN efficacy by comparing two radiofrequency catheter systems in a porcine model.Methods:Domestic swine were assigned into two treatment groups (n = 10) and one sham group (n = 3). Bilateral RDN in main and in branch segments of renal arteries was performed using two different multielectrode catheter systems [Symplicity Spyral (SPY) and IberisBloom (IBB)]. After 7 days, measurement of norepinephrine (NEPI) tissue concentrations and histological analyses have been performed.Results:Renal NEPI tissue concentration following RDN was significantly reduced when compared with Sham (SPY: −95 ± 3% vs. Sham, P < 0.001; IBB: −88 ± 11% vs. Sham, P < 0.001). Histological evaluation showed comparable lesion depth and lesion area (lesion depth: SPY-main 6.26 ± 1.62 mm vs. SPY-branch 3.49 ± 1.11 mm; IBB-main 5.93 ± 1.88 mm vs. IBB-branch: 3.26 ± 1.26 mm, P < 0.001; lesion area: SPY-main 43.5 ± 29.5 mm2 vs. SYP-branch 45.0 ± 38.0 mm2; IBB-main 52.3 ± 34.8 mm2 vs. IBB-branch 44.0 ± 42.6 mm2, P = 0.77; intergroup SPY vs. IBB, P = 0.73). Histological investigations documented a significant correlation between number of ablations per millimeter length of renal artery and reduction in NEPI tissue concentration.Conclusion:The two devices under investigation demonstrated similar histopathological lesion characteristics and similar reduction of renal NEPI levels. An increase in number of ablations per millmeter length of renal artery resulted in improved efficacy and reduced variability in treatment effects.
The level of endothelial coverage in BioPol-BES was comparable to BMS at four weeks, with no significant increase of inflammatory reaction up to 15 months.
Nitinol stents are widely used for the treatment of peripheral arterial diseases in lower extremity arteries and have shown different clinical outcomes depending on implanted arterial segments. We aimed to compare histopathological responses to nitinol stents in femoral artery (FA) with those in femoropopliteal artery (FPA), which is markedly bended during knee flexion. A single nitinol stent was implanted in FA and FPA of 21 domestic swine. The stented vessels were angiographically assessed and then harvested for histopathology at 1 and 3 months after implantation. Angiographic late lumen loss was significantly greater in FPA than in FA at 3 months. Neointimal area decreased in FA and increased in FPA from 1 to 3 months. Compared with FA, peri-strut area of FPA showed more pronounced hemorrhage and fibrin deposition at 1 month and angiogenesis and inflammation at 1 and 3 months. Injury to internal elastic lamina or media was minimal in both FA and FPA at both time points. In conclusion, vascular responses to nitinol stents were different between FA and FPA with respect to time course of neointimal formation and progress of healing, suggesting that repetitive interaction between stent and vessel wall during dynamic vessel motion affected vascular responses.
Objectives: We first aimed to identify the histopathological changes occurring immediately after renal denervation (RDN) with radiofrequency energy, and then to assess the feasibility of determining procedural success using currently available clinical intravascular imaging techniques.Background: Catheter-based RDN has been used as an alternative therapy for hypertension.
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