Recent international milestones for renal denervation treatment of hypertension: achievements in China

Effective treatment of hypertension began toward the middle of the 20th century. At the time it was commonly thought that the sympathetic nervous system was central in the pathogenesis of essential hypertension. This influential idea was derived primarily from earlier designation of the sympathetic nerves as the "pressor nerves" by the distinguished physiologist Claude Bernard. This designation was based on their ability to elevate blood pressure upon electrical stimulation[1]. There was no proof, in fact, that hypertension was neurogenic, but this prevailing idea had a large impact on attempts to develop antihypertensive treatment. Initially, treatment focused on anti-adrenergic therapies, such as surgical resection of sympathetic ganglia and disconnection of the thoraco-lumbar sympathetic chain. These surgical treatments lowered blood pressure and prolonged life in patients with severe hypertension[2], but the procedures were problematic in terms of operative risk and adverse effects, and were soon replaced by drugs antagonizing the sympathetic nervous system, including ganglionic blockers, β-adrenergic blockers, centrally acting sympathetic suppressants, and α-adrenergic blockers. Anti-adrenergic antihypertensive drugs were of central importance in hypertension care for 30 years. Diuretic drugs were prescribed in parallel. With the introduction of anti-renin drugs (angiotensin-converting enzyme inhibitors [ACEI] and angiotensin receptor blockers [ARB]) and dihydropyridine calcium channel blockers, use of anti-adrenergic antihypertensive drugs fell sharply, ranking low in Hypertension Guidelines by the start of the 21st century. This paradoxically was at a time when proof actually emerged that essential hypertension was commonly neurogenic, with the blood pressure elevation being initiated and maintained by activation of the sympathetic nervous system. Nerve recording methodology demonstrated increased sympathetic nerve firing in the sympathetic outflow to the skeletal muscle vasculature[3]. Additionally, isotope dilution methodology utilizing radiolabelled noradrenaline documented high rates of noradrenaline spillover from the sympathetic nerves of the heart and kidneys[4–5], indicative of increased cardiac and notably renal sympathetic activity. It was in this context that an innovative anti-adrenergic device treatment of hypertension was devised by Levin and Gelfand[6], involving percutaneous catheter-based ablation of the renal sympathetic nerves. This approach became feasible due to the proximity of the renal nerves to the renal arteries as they passed to the kidneys. US patents were secured for this technique between 2002 and 2004[6]. Earlier experiments had already highlighted the significance of renal sympathetic nerves in experimental hypertension[4]. Subsequent research revealed high-level renal sympathetic activation in essential hypertension[7]. The first two positive clinical trials of renal denervation were conducted in Melbourne by the author and the late Professor Henry Krum[8–9]. In 2014, however, the subsequent sham-controlled trial, Symplicity HTN-3 Trial (Renal Denervation in Patients With Uncontrolled Hypertension Trial), posted results demonstrating a lack of efficacy for renal denervation in hypertension[10]. Procedural deficiencies in the performance of the catheter-based denervation were documented[11–12], but it turned out that in this trial, as well as in several subsequent sham-controlled renal denervation trials[13], an unusual form of patient sham group drug non-compliance played a significant role in lowering blood pressure in the sham arms of the trials. With knowledge of their blood pressure reading during the trial, often provided by home blood pressure measurement, and no doubt with concerns and anxiety about their persistently elevated pressures, sham-group patients took unauthorized additional medication[13]. This contrasts with drug non-compliance in clinical practice, which usually involves under-dosing. Despite the setbacks incurred from the Symplicity HTN-3 Trial, the field of renal denervation underwent rehabilitation. Closer attention was paid to renal nerve anatomy, highlighting the convergence of efferent sympathetic nerves on the distal main renal artery and its branches. Single-electrode radiofrequency devices were re-engineered into more efficient multi-electrode units. Testing was applied to detect sham-group drug non-compliance. Subsequent multiple sham-controlled trials, using both radiofrequency and ultrasonic energy, demonstrated both safety and efficacy of renal denervation. Long-term renal denervation registries were established, affirming sustained blood pressure reduction[14]. In 2023, a watershed moment was reached for renal denervation treatment of hypertension when the Treatment of Hypertension Guidelines of the European Society of Hypertension concluded that renal denervation was now a proven treatment option for uncontrolled hypertension[15]. In November 2023, the US Food and Drug Administration (FDA) recommended both radiofrequency and ultrasound renal denervation for uncontrolled hypertension. Observed lack of blood pressure control is very commonly due to patient drug non-compliance. Elsewhere in medicine, this issue of non-compliance is often countered by long-acting, or depot, medication forms. Drugs of this type are currently not available for the treatment of hypertension, although I think of renal denervation as in some ways analogous, and particularly well suited to treat hypertension when patient non-compliance is present. The accompanying Chinese Expert Scientific Statement on Percutaneous Renal Denervation in the Management of Hypertension provides a comprehensive and thorough overview of the history of renal denervation in hypertension[16]. The expert scientific statement also documents substantial contribution to the field made by Chinese investigators. Renal denervation research milestones were achieved by experimental and clinical researchers in China soon after the publication of the Symplicity I and II Trials[8–9]. Research efforts were spearheaded by key figures such as Drs. Yong Huo, Junbo Ge, Weimin Wang, and Lang Li, who showcased three renal denervation cases during the Chine Cardiovascular Intervention Forum in 2012. Early clinical studies and their long-term follow-up reports were published[17–19]. Pivotal advancements in renal denervation technology were marked by the securing of the first renal mapping/selective denervation patent in 2012 by Jie Wang. This patent laid the foundation for the establishment of a patent portfolio, serving as the cornerstone for emerging renal denervation entities in China[20]. Influential experimental renal denervation studies with denervation guidance were conducted in Kunming hypertensive dogs by Liu et al.[21]. Four ongoing or just completed trials are referenced in the Chinese Expert Scientific Statement. These are innovative in design and in catheter technology. The devices are the SyMap Renal Nerve Mapping/Selective Renal Denervation System from Suzhou SyMap Medical Co. Ltd[22], the Netrod multi-electrode mesh basket-like renal sympathetic nerve RFA System from Shanghai Golden Leaf MedTech Co Ltd.[23], the Iberis (Bioheart) multi-electrode system from Shanghai Bioheart Biotechnology Co. Ltd, and the Cryofocus cryogenic system from Cryofocus Biology Co. Ltd. The SyMap system is unique on the world stage in selecting ablation sites from "mapping" of the renal afferent nerves, based on evoked blood pressure changes with electrical stimulation of the renal artery, and in using the reduction in needed antihypertensive drugs for blood pressure control as the primary trial endpoint[22]. The Netrod device is unique in its basket electrode configuration. The Cryofocus system provides an alternative to the usual radiofrequency or ultrasonic energy methodologies. A particular concern regarding renal denervation treatment of hypertension has been the potential for regrowth of ablated nerves, leading to the nullification of initial blood pressure reduction. Surgical renal denervation in rodents does tend to follow this course. Catheter-based renal denervation in hypertensive sheep, however, was durable, out to nearly 3 years of observation[24]. In human hypertension, markers of renal denervation such as lowered renal noradrenaline spillover[9] have not been followed long-term, but blood pressure reductions observed in renal denervation registries do not diminish with time[14]. In the past year, long-term follow-up data have become available for patient cohorts, out to 10 years post-denervation. The early falls in pressure are sustained long-term, even in the face of reduction in antihypertensive drug dosages[18,25]. This demonstrated durability of the antihypertensive effect of renal denervation has given me further confidence that this will be an antihypertensive treatment in the future. The Chinese Expert Scientific Statement similarly conveys this optimism. I propose that in the future there will be the Three Pillars of Hypertension Treatment: (1) Lifestyle and dietary modification; (2) Antihypertensive drug prescribing; (3) Device treatment, exemplified by renal denervation. CONFLICT OF INTEREST STATEMENT The author has served on Renal Denervation Medical Advisory Boards of SyMap (China) and Medtronic (US) and received payment for this, and also travel support. DATA SHARING STATEMENT All data generated or analyzed during this study are included in this published article.