The ‘black swan’ for percutaneous renal denervation (RDN) was firstly ‘spotted’ on the ‘horizon’ of hypertension when the first randomized sham-controlled study failed to provide greater reduction in blood pressure (BP) levels with RDN as compared to sham procedure in patients with drug-resistant hypertension.1–3 These results led to severe scepticism regarding this interventional method but it was soon replaced by constructive thinking that identified study limitations and methodological drawbacks of the SYMPLICITY HTN-3.1,2 It was one of the cases in modern medical science that the community understood and further explored the mainstay role of adherence to medication as a driver of BP response and the importance of ambulatory BP as a target for hypertension therapy interventions. Apart from that there was an additional ‘deep-dive’ into the anatomy and function of the sympathetic nervous system as a whole and more specifically in the renal nerve district.4–6 The brainstorming on the optimal design of RDN trials led to significant improvements and also to clinical important results. In the completed sham-controlled randomized controlled trials, radiofrequency ablation by the use of Spyral catheter as well as ultrasound-based RDN via the Paradise system were effective in BP lowering with a remarkable safety profile.7–10 However, there was up to now no available study directly showing the effects of RDN on BP endpoint in the setting of resistant hypertension after the ‘neutral’ SYMPLICITY HTN-3.1 Only indirect evidence can be extrapolated from the SPYRAL HTN-ON trial in which patients on 1–3 antihypertensive drugs and uncontrolled hypertension participated, including a group of patients with resistant hypertension.8 In this particular trial, the overall results showed that the change in BP was more pronounced in the RDN group than the sham control group.8 The recently published RADIANCE-HTN TRIO offers the missing robust evidence that RDN reduces BP at 2 months in patients with hypertension resistant to a standardized triple combination pill.11 As the authors of the article suggest if the BP-lowering effect is maintained long term this could signify that RDN can be proposed as the fourth add-on therapy in the high-risk setting of resistant hypertensive patients.11
The results of the RADIANCE-HTN TRIO are pathophysiological sound given the contribution of the sympathetic overdrive in hypertension that is uncontrolled and resistant to drug therapy.2,5,6 Renal efferent sympathetic nerves decreases renal perfusion, increases tubular sodium reabsorption causing sodium retention, and stimulation the renin–angiotensin aldosterone system.2,5,6 On the other hand, augmented sensory signalling from the hypertensive kidneys stimulate central sympathetic outflows leading to high peripheral vascular resistance, increased BP, rarefaction and dysfunction of the microcirculation, left ventricular hypertrophy, dysmetabolic processes, as well as progression of atherosclerosis with accompanying cardiovascular and renal damage.1,4 In this unfavourable vascular and humoral ‘milieu’, RDN interrupts the crosstalk between the kidney and the central nervous system.2,4–6 This is evident by reduction of norepinephrine spill-over in the kidney and the attenuation of plasma renin activity in the renal vein.2,4–6 The latter was recently shown to be a predictive parameter for the BP fall in the SPYRAL HTN-OFF MED study.12 Moreover, RDN also decreases muscle sympathetic nerve activity in hypertensive patients with resistant hypertension as well as in the setting of hypertension-metabolic syndrome clinical duet.1,5,6 According to the RADIANCE-HTN TRIO results, the decrease in sympathetic nervous system activity that is the main mechanism for the observed BP drop could lead to important reduction of the long-term cardiovascular risk, which can be translated with less events of heart failure, acuter coronary syndromes, strokes, and renal failure. Future studies focusing on prognosis of these hypertensive population could further elucidate the potential role of RDN in favourable altering overall risk.
Detailed anatomical studies for further in-depth knowledge of the variations of nerve distribution in human constitute a future basic research target, along with quantification of the amount of sympathetic innervation needed to be ablated to cause significant BP reduction in hypertensives.4–6,12 In addition, scientific works on the exact pathophysiological pathways of RDN-induced alterations in renal, arterial, and cardiac function and structure will ‘fuel’ the rationale behind the intervention.2,5,6 Lastly, estimation of the acute changes of renal blood flow after RDN, determination of reliable biomarkers for RDN effectiveness during ablation and the concept of nerve ‘mapping’ should be thoroughly addressed via well designed from ‘bench to bedside’ studies towards optimization of RDN methodology.
The findings of the RADIANCE-HTN TRIO trial regarding the ambulatory BP modulation are of major clinical importance. Irrespective of the adherence profile of the subjects to drugs, RDN compared to the sham procedure was accompanied by greater reduction of −4.5 mmHg for daytime ambulatory systolic BP, by −4.2 mmHg for 24 h ambulatory systolic BP and by −3.9 mmHg for nighttime systolic BP.11 These effects are maintained throughout the day and night mimicking the results of the radiofrequency ablation sham-controlled studies, underlying the mainstay role of sympathetic modulation for better BP control even in resistant hypertension.7,8,10 However, although office systolic BP is decreased more in the RDN arm compared to the sham group by −7 mmHg, ultrasound ablation is neutral in the diastolic BP reduction when compared with sham.11 This is a point that could only be justified by the phenotype of the patients and the design of the study given that in the RADIANCE SOLO, both ambulatory systolic and diastolic BP parameters were more decreased in the RDN arm compared to sham procedure.9 Apart from that, the impressive reduction of nighttime systolic BP in the TRIO trial further enhances the positive clinical implication of RDN in hypertension since reduction of heightened BP during the night (that usually characterizes difficult to control and resistant hypertension) can be translated to less cardiovascular events and is difficulty induced by pharmacological therapy alone.2,3
If RDN enters everyday clinical practice durability of the BP effects is an important issue. In the RADIANCE SOLO the favourable effect of the interventional ultrasound therapy is maintained up to 12 months,13,14 while from the radiofrequency ablation strategies we have data for efficacy up to 3 years.2,7–11 Another point is safety when a methodology is proposed for more wide use. The available evidence from registries and randomized trials clearly shows that RDN is a safe procedure with minor short- and long-term adverse effects.2,7–11,13,14 One should note that impaired glomerular filtration rate of <40–45 mL/min/1.73 m2 is an exclusion criterion for all major studies2,7–11,13,14 and there is an urgent need for more research in patients with renal dysfunction since they represent a clinical measurable portion of high-risk hypertensive population.
Nowadays, shared decision-making is an emerging and clinical meaningful trend for modern cardiovascular practice, thus a structured approach for RDN therapy proposal should be implemented to patients fulfilling the characteristics of the published positive trials. This means that hypertensive patients without antihypertensive therapy or on drugs and even those with resistant hypertension (as shown in the RADIANCE-HTN TRIO) could be potential candidates for RDN. Additionally, the average RDN-induced reduction in systolic office BP is ∼8–10 mmHg in diverse settings which is estimated to reduce major cardiovascular events by 20% and particularly stroke by almost 30%.15 Future hypertension management will have to take into account the favourable results of all randomized sham-controlled trials including RADIANCE-HTN TRIO. It seems that the continuing saga of RDN finally comes to an important time point. The point in which RDN can revisit hypertension therapy for many patients in the near future.
Conflict of interest: K.P.T. has received research grants or honoraria for advisory boards and lectures from Medtronic, Servier, Bayer, Menarini, Novartis, Astra Zeneca, Boehringer In, Pfizer, Chiesi, Pharmanel, Sanofi, Amgen, ELPEN, Recor. He was Member of Task Force of 2018 ESC/ESH HTN GDLs. K.D. has received research grants or honoraria for advisory boards and lectures from Medtronic, Pfizer, Astra Zeneca, ELPEN.
References
Authors
Biography: Dr Konstantinos P. Tsioufis, Professor of Cardiology in the National and Kapodistrian University of Athens, is Chief of the First Cardiology Clinic, Hippokration Hospital, Athens, Greece. Clinical Training: In Interventional Cardiology and Hypertension at the University of Athens, Greece and later at the Veterans Affairs Medical Center, Georgetown University, Washington, DC, USA. He has published widely on hypertensive disease, cardiorenal disease, atherosclerotic cardiovascular disease, and interventional cardiology and he is involved in major clinical trials regarding novel interventional therapies of hypertension and particularly renal denervation. He has more than 470 publications in peer-reviewed journals (H-index > 62). He is co-editor of the book ‘Interventional Therapies of Secondary and Essential Hypertension’ and he has contributed with more than 25 chapters in books. He is Member of the Editorial Board and Reviewer in major Cardiology, Hypertension, and Critical Care journals. Prof Tsioufis is immediate past-President of ESH (European Society of Hypertension) and immediate past-President of the Hellenic Society of Cardiology.
Biography: Dr Kyriakos Dimitriadis is a consultant interventional cardiologist working at the Cardiology Clinic in Hippokration Hospital (Athens, Greece). He is a Fellow of the European Society of Cardiology (FESC) and European Society of Hypertension (ESH) specialist. He was trained in clinical research on the sympathetic nervous system activation in patients with cardiovascular disease in the University of Milan and he was Fellow in Interventional Cardiology in Clinique Pasteur (Toulouse, France). His current main research interests are sympathetic nervous system regulation in cardiovascular diseases, chronic coronary syndromes, and interventional therapy of hypertension. He is President Elect of the Working Group ‘Hypertension and the Heart’ of the Hellenic Society of Cardiology and Secretary of the Working Group ‘Interventional Therapies in Hypertension’ of the ESH. He has published 120 scientific papers and participates in the editorial board and as a reviewer in diverse journals in the hypertension and cardiovascular field.
