The Burden of Hypertension
Hypertension (HT) is a leading cause of cardiovascular disease and death worldwide. A recent analysis attributed 7.6 million deaths and 92 million disability-adjusted life years, as well as around 50% of strokes and coronary artery disease cases to high blood pressure (BP) . Such statistics support the importance of improving BP control, and it has been shown that even small decreases in BP are sufficient to improve cardiovascular risk . A recent analysis from the National Health and Nutrition examination Survey (NHANES) in the United States reported an increase in HT control from less than 30% to 50% since the early nineties . Increased patient awareness, diverse drug options, data from large clinical trials and implementation of widely accepted guidelines may all have offered to such improvements. Indeed, the basis of HT treatment is the combination of lifestyle modification that included a low-salt healthy diet and adequate physical activity with antihypertensive drugs. However, uncontrolled HT still represents an important health burden. Accordingly, of great interest from both a pathophysiologic as well as a population perspective is HT that is not easily controlled even with multiple drugs, namely resistant HT . The latter is defined as uncontrolled BP despite the use of at least three drugs, including a diuretic, at optimal doses or BP control achieved with at least four drugs. Prevalence of this condition reportedly ranges from 5 to 30% of hypertensives that reflects a large number of patients in absolute numbers.
Pathophysiology of hypertension, sympathetic nervous system and the kidney
With the exception of a small frequency of cases that have secondary hypertension, i.e. attributed to a specific, usually reversible condition, such as renal artery stenosis or intake of drugs that raise BP, most patients suffer from so-called essential hypertension, the pathophysiology of which is not fully clarified but unequivocally multifactorial. Genetic predisposition, a decreased nephron number, overactivation of the renin-angiotensin-aldosterone axis, abnormal sodium handling, as well as endothelial dysfunction, vasoactive substances and structural vascular changes, are proposed mechanisms that variably combined eventually lead to an increase in BP . It is now also established, that the overactivity of the sympathetic nervous system plays a crucial role in BP control and HT development and constitutes an active field of research for antihypertensive therapies . Enhanced sympathetic nervous system activity has been reported in systolic-diastolic, isolated systolic HT, white-coat HT and its mirror-image masked HT, as well as abnormal nighttime BP patterns. Accordingly, by the midst of the previous century, surgical sympathectomy was examined as a radical, yet highly efficient treatment which had provided astonishing results with respect to BP decreases and improvement in cardiovascular mortality, in patients with malignant HT . However, severe side effects and the dawn of antihypertensive drugs brought interest to such procedures into a halt. Widespread minimally interventional medicine along with new insights in the bidirectional association of the sympathetic nervous system with the kidney has recently led to the development of a procedure that targets ablation of the renal sympathetic nerves (renal nerve ablation-RNA).
The concept for RNA relies on the fact that interactions of the sympathetic nervous system with the kidney, through the renal nerves that lie within the renal artery wall, multiply mediate BP control and participate in HT development. Innervation of the kidneys starts with the preganglionic neuron axons exiting from the thoracic and lumbar sympathetic trunk, and reaching the pre- and paravertebral sympathetic ganglia and from there off post ganglionic nerves transverse the renal arteries, enter the hilus of the kidney and divide into multiple branches that penetrate the cortical and juxtamedullary areas. Efferent renal activity induces renal vasoconstriction, reduces renal blood flow and increases renin release, sodium reabsorption and volume retention. Afferent renal nerves, that is nerves that send signals from the kidneys to the brain, serve as triggers for sympathetic neural discharge to important elements of cardiovascular control such as the heart and the vasculature. It has been proposed that characteristics associated with resistant HT such as an older age, obesity and sleep apnea, insulin resistance and aldosterone excess exert their effect on BP via an overactivated SNS .
Procedural Principles of Renal Nerve Ablation: Who and how
The aim of the procedure is to disrupt the renal innervation and thus restrain interaction of the SNS with the kidney . Eligible patients for RNA are currently those with resistant HT and very high office BP levels, that is systolic BP over 160mmHg (over 150mmHg in type 2 diabetics). All steps for the evaluation of the resistant hypertensive patient should take place at first according to guidelines [3,8]: assurance of optimal antihypertensive treatment, exclusion of secondary HT, identification of conditions that affect BP control such as salt-rich diets, and assessment of pseudoresistance such as non-adherence to treatment and isolated office resistant HT. Subsequently, imaging of the renal arteries with computed tomography or magnetic resonance will reveal anatomical eligibility and provide in total useful information for the renal artery anatomy. Subjects with a history of previous renal artery interventions, evidence of >50% renal artery stenosis, multiple main renal arteries, renal artery diameter less than 4mm, or less than 20mm in length, and significantly impaired renal function are not eligible for the procedure.
RNA is a minimally invasive therapy, with short procedural and recovery times and with side effects comparable to traditional angiography. A specially designed radiofrequency ablation catheter is percutaneously inserted into the femoral artery, and then inside the ostium of the renal artery, where the tip is positioned proximal to the bifurcation. The site of the initial ablation is chosen, the impedance as well as the temperature and resistance are measured, and radiofrequency is delivered according to the pre-specified computer-controlled algorithm. Then, according to the design of the catheter used, successive ablations (4-8 in total) are applied at both a longitudinal and rotational manner, in order to achieve maximum nerve ablation with minimum risk for renal artery stenosis. As pain may be experienced during ablation, intravenous analgesics may be needed. The procedure is performed in both renal arteries, the catheter is removed and patient remains hospitalized for about 24 hours. Duration of the procedure is approximately 40 to 60 minutes.
Clinical study data so far
The study that provided proof of principle for RNA was Symplicity HTN-1, that reported results on 45 patients who underwent the procedure and were followed for up to 12-months . The primary eligibility criterion was resistant HT with office BP of at least 160mmHg, and RNA was performed with the single-electrode Symplicity catheter (Ardian Inc). Regarding safety of the study, non-serious periprocedural complications were reported in only 2 subjects. With respect to efficacy, systolic/diastolic BP was reduced by -14/10mmHg at one month and by 27/17mmHg at one year. These results were later corroborated by an extended follow-up study of a sample of 153 patients in total, which included the initial cohort, with data of up to two years . BP reduction was sustained in the long-term with a decrease in BP by -20/-10, -24/-11, -25/-11, -23/-11, -26/-14, -32/-14 mm Hg at 1, 3, 6, 12, 18 and 24 months, respectively.
Another major clinical study was Symplicity HTN-2, a multicentre prospective, this time randomized clinical trial . Ultimately, after eligibility screening, 106 patients with uncontrolled resistant hypertension (office BP≥160mm Hg or 150mm Hg in case of diabetes mellitus type 2) were randomly separated into two groups; the first undergoing RNA on top of previous treatment, and the second continuing previous treatment alone. The primary end-point assessment was set to the first 6-month period after the ablation. Office-based blood pressure measurements in the ablation group were reduced by 32/12 mm Hg, baseline levels being 178/96 mm Hg. In the control group, no considerable differentiation was detected (only by 1/0mmHg), indicating a between group difference at 6 months of 33/11mmHg. Similar changes were documented in home BP monitoring, while ambulatory monitoring where available showed a significant -11/-7mmHg decrease in the ablation group compared to non-significant changes in the control group. As expected the active group had more common reductions of 10mmHg or greater, and more often decreases in number of medications. No serious procedure related complications were reported while renal function remained unchanged during the follow-up period.
It is of special interest the fact that RNA may exert various beneficial effects apart from the decreases in BP levels. Preliminary reports have documented that RNA may decrease severity of OSA , improve glucose metabolism , reduce left ventricular mass and improve diastolic function , reduce arterial stiffness , present with antiarrhytmic effects  and be beneficial and safe for patients with moderate to severe kidney disease . Such findings shall need further evaluation in future studies.
Conclusions and future expectations
RNA presents as a safe procedure that leads to significant and sustained reductions in BP, something that seems of utmost importance in patients with severe resistant HT. A prospective, randomized, and most importantly masked-procedure, single blind trial (Symplicity HTN-3) , is on the way, that has been designed to further evaluate the safety and effectiveness of RNA. Apart from the original commercially available catheter, new systems are under evaluation, such as a multi-electrode catheter with a basket design (Saint Jude Medical). Questions remain to be answered such as the exact effect of the procedure on out of office BP, on cardiovascular morbidity and mortality, as well as on cases with milder forms of HT. In total, it represents the hi-tech rebirth of an old idea, and all in all, an interventional approach to a traditionally drug-based therapy of a potentially devastating disease such as HT.
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Costas Tsioufis, Periandros Hatzigiannis, Alexandros Kasiakogias, Christodoulos Stefanadis 1st University Cardiology Clinic, Hippocration Hospital, Athens, Greece.