1197The development and validation of a novel transcatheter microwave renal denervation system

Background Clinical studies of transcatheter radiofrequency renal denervation for treating hypertension have been hampered by the lack of consistent denervation efficacy. Microwave energy is well suited to renal denervation due to its capacity to spare vascular structures due to cooling from adjacent blood flow while enabling deep perivascular heating. Purpose We aimed to: 1) develop a transcatheter microwave system capable of safely delivering deep and circumferential perivascular renal nerve ablation, and 2) demonstrate the feasibility, short-term efficacy and safety of transcatheter microwave renal denervation. Method A novel 7F transcatheter microwave denervation system was designed, built, and iteratively prototyped in vitro and in 15 sheep. A histological grading system for microwave induced renal arterial and renal nerve injury was devised. The microwave denervation system was validated in an additional 9 sheep, which underwent unilateral renal denervation. Up to 2 microwave ablations were delivered to each artery with maximum power at 100–110W for 480s. Sheep were euthanised at 2–3 weeks post procedure. Gross microscopic histological examination as well as renal tissue norepinephrine content was analysed. Results Catheter deployment and ablation was successful in all 19 targeted vessel segments and ablation produced substantial circumferential perivascular injury; median ablation lesion area >395 (IQR 251–437) mm2, depth 17.1 (IQR 15.8–18.4) mm, length 16 (IQR 12–20) mm, without collateral visceral injury. Limiting power to 100W minimised arterial injury, while maintaining a deep circumferential perivascular ablation. At microwave ablation sites, a total of 292 nerve fascicles were identified, median distance from the renal artery of 4.2mm (IQR 2.1–8.8mm), of which 249 (85%) had sustained thermal injury with 128/249 (51%) showing grade 3–4 (moderate to severe) injury. Microwave denervation reduced median functional sympathetic nerve surface area at the renal hilum on anti-tyrosine hydroxylase staining by 100% (IQR 87%-100%), p=0.0039, and median renal cortical norepinephrine content by 83% (IQR 76%–92%), p=0.0078, compared to the paired control kidney. Conclusion Transcatheter microwave ablation can produce deep circumferential perivascular ablations over a long segment of the renal artery without significant arterial or collateral visceral injury to provide effective renal denervation. Clinical translation may enable more consistent and complete transcatheter renal denervation and antihypertensive efficacy. Acknowledgement/Funding University of Sydney; Western Sydney Local health District; National Health and Medical Research Council of Australia; National Heart Foundation (Au)

Melatonin treatment affects changes in adrenal gene expression of catecholamine biosynthesizing enzymes and norepinephrine transporter in the rat model of chronic-stress-induced depression

This study investigated the effects of melatonin treatment on adrenal catecholamine content, synthesis, uptake, and vesicular transport induced by the chronic unpredictable mild stress (CUMS) model of depression in rats. This entailed quantifying the norepinephrine, epinephrine, mRNA, and protein levels of tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), norepinephrine transporter (NET), and vesicular monoamine transporter 2 (VMAT2) in the adrenal medulla. CUMS caused a significant depletion of norepinephrine stores and protein levels of TH, DBH, and NET, whereas the gene expression of PNMT was increased. It was observed that melatonin treatment in the CUMS rats prevented the stress-induced decrease in norepinephrine content and the protein expression of TH, DBH, and NET in the adrenal medulla of chronically stressed rats. The present study demonstrates the stimulatory effect of melatonin on adrenomedullary synthesis, the uptake and content of catecholamine in the rat model of chronic stress-induced depression.

Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function

Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart.