Neuromatous Regeneration as a Nerve Response After Catheter-Based Renal Denervation Therapy in a Large Animal Model

Abstract

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...

Sub-acute Safety and Efficacy Evaluation of Single versus Double Treatment Cycles of a Monopolar Radiofrequency Catheter-Based Renal Nerve Ablation and its Chronic Evolution in a Large Animal Model

“…This negative correlation offers some surrogate histological endpoints as assurance that an effective physiologic disconnection is established. Concordant with existing studies, 14 the immunohistochemistry results in our study showed that ablated nerves display decreased staining for tyrosine hydroxylase (TH) and S100 at 7 and 30 days, with some partial recovery of TH staining at 90 days. The regenerative activity was evidenced by the presence of GAP43 at all time points.…”

“…[21][22][23] This study strongly suggests that renal sympathetic nerves attempt to regenerate but without apparent functional reconnection based on persistent NE level suppression. 14,[24][25][26] The high degree of distal nerve atrophy observed at 7 and 30 days in this study reported at chronic time points in other large animal experiments where RF ablation of renal nerves was performed. 14,20 It is necessary to further establish if the apparent morphological "recovery" of distal nerves could be responsible for the late increase in NE levels and whether this partial recovery may or may not produce a physiologic increase in blood pressure.…”

“…14,[24][25][26] The high degree of distal nerve atrophy observed at 7 and 30 days in this study reported at chronic time points in other large animal experiments where RF ablation of renal nerves was performed. 14,20 It is necessary to further establish if the apparent morphological "recovery" of distal nerves could be responsible for the late increase in NE levels and whether this partial recovery may or may not produce a physiologic increase in blood pressure. The available clinical data though suggest sustained blood pressure lowering effects up to 36 months following the procedure.…”

“…These features are consistent with the current literature describing the histopathologic observations following RF ablation with other devices. 14,17,18 Effective RF nerve ablation has been previously shown to decrease NE levels in large animal models. 19,20 In this study, the norepinephrine levels measured in the single ablation animals demonstrated a significant NE decrease at all time points compared to naïve kidneys.…”

Renal Sympathetic Denervation in Patients with Resistant Hypertension: A Feasibility Study

“…A catheter provided radial access to minimize vascular complications as well as femoral access. The safety and efficacy of the system were validated by the preclinical animal studies [11][12][13]. This system obtained CE approval in March 2013.…”