A drug-induced hypotensive challenge to verify catheter-based radiofrequency renal denervation in an obese hypertensive swine model

Abstract

Objective: Sham-controlled trials provided proof-of-principle for the blood pressure-lowering effect of catheter-based renal denervation (RDN). However, indicators for the immediate assessment of treatment success are lacking. This study sought to investigate the impact of RDN on renal renin arteriovenous difference (renal renin AV-Δ) following a hypotensive challenge (HC).

Methods: Twelve hypertensive Ossabaw swine underwent either combined surgical and chemical (n = 3) or catheter-based RDN (n = 9). A telemetry monitor was implanted to acquire hemodynamic data continuously. Before and after RDN, a sodium nitroprusside-induced HC was performed. Renal renin AV-Δ was calculated as the difference of plasma renin concentrations drawn from the renal artery and vein.

Results: In total, complete renal renin AV data were obtained in eight animals at baseline and six animals at baseline and 3 months of follow-up. Baseline renal renin AV-Δ correlated inversely with change in 24-h minimum systolic (- 0.764, p = 0.02), diastolic (r = - 0.679, p = 0.04), and mean (r = - 0.663, p = 0.05) blood pressure. In the animals with complete renin secretion data at baseline and follow-up, the HC increased renal renin AV-Δ at baseline, while this effect was attenuated following RDN (0.55 ± 0.34 pg/ml versus - 0.10 ± 0.16 pg/ml, p = 0.003). Renin urinary excretion remained unchanged throughout the study (baseline 0.286 ± 0.187 pg/ml versus termination 0.305 ± 0.072 pg/ml, p = 0.789).

Conclusion: Renin secretion induced by HC was attenuated following RDN and may serve as an indicator for patient selection and guide successful RDN procedures.

Keywords: Arterial hypertension; Hypotensive challenge; Renal arterial microanatomy; Renal denervation.

Fig. 1

Study design. A total of 12 Ossabaw swine underwent renal denervation. Nine animals underwent minimally invasive catheter-based renal denervation (RDN) using a multielectrode radiofrequency (RF) catheter (EnligHTN Renal Artery ablation Catheter, Abbott, MN, USA) with four (RF-4), eight (RF-8) or 12 (RF-12) ablation lesions. Three Ossabaw swine had a combined surgical and chemical RDN. Five months (– 5 M) before RDN, a telemetry device was implanted. The hypotensive challenge was performed 5 months before (− 5 M) and 3 months after (+ 3 M) RDN. 10 domestic swine served as controls for comparisons of renal tissue norepinephrine concentrations between treated and untreated animals. M months, RDN renal denervation, RF radiofrequency

Fig. 2

Hypertensive model development. The figure shows the change in bodyweight for all animals with complete follow-up. The hypertensive model development has been described previously in detail [9]. At the start of the study, all swine were on a standard diet. After the telemetry implant procedure and 21-day recovery period, a high-fat diet was initiated, causing a significant increase in bodyweight, cholesterol, and blood glucose levels. At the time of renal denervation (RDN) therapy, all animals had developed arterial hypertension. RDN renal denervation

Fig. 3

Example of blood pressure recordings during a hypotensive challenge. The figure shows an example of blood pressure recordings during a hypotensive challenge of five representative animals at baseline (prior to RDN). The hypotensive challenge was induced by a 5-minute intravenous infusion of 2 μg sodium nitroprusside per kg of bodyweight per minute. The red and blue lines depict the systolic and diastolic blood pressure values, respectively. DBP diastolic blood pressure, SBP systolic blood pressure

Fig. 4

Association of baseline renal renin AV-Δ and weight-normalized blood pressure at 45 days and 90 days post-RDN

Fig. 5

Renal renin arteriovenous difference following a hypotensive challenge before and after RDN. At baseline (prior to RDN) and before termination (after RDN), the treatment group animals underwent a hypotensive challenge. Blood samples from the renal artery and vein were drawn before and after the hypotensive challenge. Renin concentrations were measured using a porcine renin ELISA kit (NeoBiolab, Cambridge, MA, USA) and renal renin arteriovenous difference (AV-Δ) was calculated by subtracting the arterial from venous renin concentration. Complete renin secretion data was available in 6 animals at baseline and termination

Fig. 6

Renal tissue norepinephrine concentrations at 90 days post-RDN. At the end of the 8-month study period, a necropsy was performed in all animals that completed 90 days of post-RDN follow-up (n = 9) and ten domestic swine which served as controls for comparisons of treated and untreated animals. Renal tissue norepinephrine concentrations were assessed for both the left and right kidney in every animal using high-performance liquid chromatography (HPLC). RF radiofrequency