New interventional strategies in the treatment of resistant hypertension




Michael BÖHM,MD
Felix MAHFOUD,MD
Christian UKENA,MD
Universitätsklinikum des Saarlandes, Klinik für Innere
Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin
Homburg/Saar, GERMANY

New interventional strategies in the treatment of resistant hypertension

by M. Böhm, F. Mahfoud, and C. Ukena, Germany

Resistant hypertension, defined as the failure to reach blood pressure targets despite treatment with ≥3 antihypertensive drugs (one being a diuretic), is a major challenge. Blood pressure in the general population is frequently uncontrolled. Therefore, new interventional techniques are necessary to improve blood pressure control. A novel catheter-based procedure, which leads to the ablation of the sympathetic nerves in the adventitia of the renal arteries, has been developed. The first-in-man studies and one controlled trial (Symplicity [not an acronym] HTN-2 [hypertension]) showed that reducing sympathetic afferent and efferent activity achieved marked reductions in blood pressure, by up to 35 mm Hg, as well as much better control rates than conservative drug treatment. Furthermore, there is evidence that such a procedure can improve metabolic parameters, which is a common comorbidity of resistant hypertension. Further studies will be needed to address the value of this procedure in reducing hypertension and its associated morbidity and mortality.

Medicographia. 2012;34:100-104 (see French abstract on page 104)

Arterial hypertension is the most common cardiovascular disease and a major risk factor for cardiovascular events, in particular stroke and myocardial infarction. In the developing world there is a continuous increase in its incidence and prevalence, and projections suggest that, by 2025, up to 50% of the adult population of Western countries will meet the criteria for the diagnosis of hypertension.1 Since blood pressure in the elderly tends to increase with time, there is a growing need for blood pressure control in the aging population.2 Furthermore, mechanisms that counterregulate the blood pressure–reducing effects of drugs necessitate a progression in the intensity of blood pressure–lowering treatments. Therefore, a majority of patients in the general population, as well as those involved in clinical trials, require more than one medication for blood pressure control.3

Although safe and effective blood pressure–lowering drugs are available, hypertension is undertreated in Western countries, with only a minority of individuals achieving the blood pressure targets recommended by guidelines.4 In addition to undertreatment, there may be a large number of individuals in whom blood pressure elevations are not detected and hypertension is not diagnosed.4 Several efforts have been made to increase awareness of hypertension, a condition that is often present, but may remain undetected in the absence of significant symptoms.3 Despite polypharmacy, many patients do not meet the target values for blood pres-sure control.4 If, following treatment with ≥3 hypertensive drug classes (one being a diuretic), blood pressure values do not meet the targets set by hypertension management guidelines, patients fulfill the criteria for resistant hypertension.5 Using this definition, it is estimated that about 10% of diagnosed hypertensive individuals are resistant to drug treatment. Resistant hypertension frequently occurs in the presence of 6 or 7 or more antihypertensive agents.6 Thus, there is a clear need for novel nonpharmaceutical approaches such as devices or interventional treatments.

Figure 1
Figure 1. Schematic representation of the effect of sympathetic nerve activity on blood pressure
regulation by neurohormone mechanisms in the kidneys, heart, and vessels.

Abbreviations: Aldo, aldosterone; Ang II, angiotensin II; BP, blood pressure; NE, norepinephrine; GFR, glomerular
filtration rate; RBF, renal blood flow. © 2011, Medtronic Inc.

Pathophysiology

The pathophysiology of essential hypertension often involves the activation of the sympathetic nervous system.7 Moreover, sympathetic activation may be one mechanism that counteracts the blood pressure–reducing effects of several antihypertensive agents.8 The renal sympathetic nerves, which arise from the sympathetic ganglia of the thoracolumbar segments (Th10-L1), are a crucial component of sympathetic regulation.9 They lie, netlike, in the adventitia of the renal arteries and innervate the kidneys. Sympathetic outflow from the central nervous system to the kidneys by efferent sympathetic fibers activates the renin-angiotensin-aldosterone system in the juxtaglomerular apparatus of the kidneys via β1-adrenergic receptors.10 Besides the β1-adrenergic-mediated increase in renin release, there is also a direct stimulation of tubular sodium reabsorption via α2-adrenoceptors, followed by renal vasoconstriction with a consecutive reduction in renal blood flow.11-13 Afferent fibers increase the efferent sympathetic efflux from the central nervous system: (i) to the vasculature, in- ducing vasoconstriction; (ii) to the liver, inducing gluconeogenesis; and (iii) to the heart, producing positive inotropic, chronotropic, and dromotropic effects as well as facilitating proarrhythmic events.14,15 In addition, myocardial hypertrophy occurs as a direct consequence of α- and β-adrenergic stimulation and cardiac remodeling processes like myocardial concentric hypertrophy, as a result of pressure overload. Efferent sympathetic activation is involved in the development of insulin resistance,16 as shown by the fact that 50% of all patients with therapy-resistant hypertension exhibit hyperinsulinemia17 and signs of metabolic syndrome due to excessive sympathetic activation (Figure 1).

Historical data on surgical renal denervation in the early 1930s and 1950s have shown that supradiaphragmatic splanchnicectomy was used as an ultima ratio for malignant hypertension.18,19 Significant reductions in blood pressure by up to 70 mm Hg were observed.18 However, there were severe postoperative complications such as orthostatic hypotension, syncope, incontinence, erectile dysfunction, and neurological disturbances.20 Several animal experiments have also shown that renal denervation reduces the activity of the sympathetic nervous system, which is followed by a reduction in blood pressure and end organ damage.11,21

Interventional renal denervation

In order to overcome the shortcomings of surgical renal denervation, an interventional technique requiring femoral artery catheterization was developed.22 By placing the tip of the catheter (Figure 2, page 102) into the distal renal artery and applying high radiofrequency energy to the vascular wall, heating occurs at the adventitia of the lumen of the renal artery. Thanks to the cooling action generated by the relatively high blood flow in the renal artery, the effects of the applied radiofrequency primarily occur in the adventitia, thereby denervating the sympathetic nerve fibers. After the initial radiofrequency application, the catheter is pulled back by about 5 mm, and then rotated circumferentially before energy is applied again. This procedure is repeated 4 to 6 times in each renal artery. The goal of the procedure is to hit the whole circumference of the renal arteries, thereby eliciting the most complete renal denervation possible (Figure 3, page 102). Since the renal sympathetic fibers are accompanied by C fibers, patients often require intravenous morphine and sedative agents during the ablation.23

Figure 2
Figure 2. SymplicityTM ablation catheter for interventional renal
denervation.

Radiofrequency energy is emitted by the tip of the catheter.
After reference 23: Mahfoud and Böhm. Dtsch Med Wochenschr. 2010;135:
2422-2425. © 2010, Georg Thieme Verlag KG.

Figure 3
Figure 3. Schematic representation of circumferential energy delivery for renal denervation.

The tip of the ablation catheter is placed in the distal renal artery, rotated, and pulled back for 4 to 6 energy applications in order to denervate sympathetic nerves over the whole circumference of the renal artery. © 2011, Medtronic Inc.

Proof-of-concept study

The first-in-man study evaluated the safety and efficacy of the blood pressure reduction obtained following a reduction in sympathetic activation.24 Patients with a blood pressure >160 mm Hg, uncontrolled at study entry despite the use of ≥3 antihypertensive agents, were recruited after confirmation of their adherence to treatment and exclusion of secondary hypertension. Imaging of the renal arteries was used to exclude patients with significant arterial stenotic disease and renal abnormalities including more than one artery. Renal denervation in 45 patients significantly reduced blood pressure beginning at 1 month, and the reduction persisted until the final visit at 12 months.24 The data of an extended cohort with a 24-month follow-up are available. There was a significant reduction (by about 35 mm Hg) in systolic blood pressure, which remained stable over a 24-month period.25

Recently, a randomized parallel-group design study (Symplicity [not an acronym] HTN-2 [hypertension]) was performed and published. The Symplicity HTN-2 trial assessed 106 patients with treatment-resistant hypertension and office systolic blood pressure >160 mm Hg (>150 mm Hg for patients with diabetes mellitus) despite the use of ≥3 antihypertensive drugs.26 The patients were randomly assigned to a treatment group (52 patients) or to a parallel controlled group (54 patients), which were both followed up for 6 months. Renal denervation resulted in a significant reduction in office blood pres- sure by 32 mm Hg (systolic) and 12 mm Hg (diastolic) after 6 months. In the control group, the blood pressure remained completely unchanged (Figure 4). The procedure was performed safely without any significant adverse events. According to the available data, renal vasospasm responsive to nitroglycerin occurred temporarily in some patients. The complications were similar to those consecutive to routine cardiac catheterizations, with the development of some pseudoaneurysms. There was no apparent change in renal function. Therefore, in patients with therapy-resistant hypertension, this interventional procedure is effective and apparently safe. Blood pressure control was achieved by this novel interventional technique in the majority of treated patients, while there were no changes in the control group.

Figure 4
Figure 4. Time course of office blood pressure changes in Symplicity
HTN-2.

There was a time-dependent decrease in systolic and diastolic blood pressure,
while there was no significant change in the control group.
Abbreviation: RDN, renal denervation.
After reference 26: Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
© 2010, Elsevier Ltd.

Open questions

Some questions remain, some of which will be answered during the long-term follow-up of the patients undergoing this novel procedure, and some of which will require further investigation.27 Reinnervation occurs in mammals, particularly in rodents,27,28 and this may be a concern in treated patients.29 Therefore, long-term follow-up in these patients will determine whether the decline in blood pressure is sustained. During exercise, the adaptation of cardiac output, blood pressure, and heart rate during stress conditions crucially depends on an intact sympathetic nervous system. Therefore, data will have to be generated to determine whether treated patients exhibit impaired adaptation to exercise, and in particular whether a phenomenon related to chronotropic incompetence may be limiting their exercise capacity. Furthermore, following a reduction in sympathetic activation, other clinically important effects, like a reduction in its metabolic effects, may be important.16

First evidence shows that there may be some positive effects such as an improvement in metabolic syndrome or type 2 diabetes mellitus.30 In addition, the reversal or prevention of the adverse consequences of hypertensive end organ damage, such as impaired renal function, development of microalbuminuria, arterial stiffness, and left ventricular hypertrophy, have to be addressed by long-term follow-up.22 Finally, it will be most exciting to see whether or not this procedure could achieve a reduction in cardiovascular outcomes, like morbidity and mortality, that will exceed the effects of blood pressure adjustment achieved by pharmacological interventions.

Summary

The novel technique of sympathetic renal denervation provides fascinating perspectives for the treatment of patients with resistant hypertension who are at high risk due to significant comorbidities like diabetes mellitus. More investigations will be needed to clarify the underlying pathophysiology and safety issues and provide insight into indications for a broader use. These new indications may include: patients with mild hypertension and metabolic syndrome, patients with type 2 diabetes mellitus and even, when safety issues are resolved, the treatment of patients with heart failure. _

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Keywords: catheterization; denervation; renal artery; resistant hypertension; sympathetic activation