The effects of systemic hypertension on public health and the beneficial effects of antihypertensive drug therapy are unquestionable. Antihypertensive drug therapy, however, is not without limitations. A significant minority of patients continues to have poor blood pressure control (resistant hypertension) despite multiple drugs (three or more medications). Other patients cannot tolerate multidrug therapy due to the drugs' adverse effects.
Recently, catheter-based interventional strategies that interrupt the renal sympathetic nervous system have shown promising results in providing better blood pressure control in patients with resistant hypertension.
The role of systemic sympathetic activity in causing hypertension is well-known. Historically, surgical sympathectomy has been used to improve blood pressure control. This procedure, however, was abandoned because of its high operative morbidity and mortality.
Building on this knowledge base, subsequent experimental and clinical studies demonstrated that the renal sympathetic nervous system also plays a major role in the pathogenesis of systemic hypertension. In spontaneously hypertensive rats, bilateral renal sympathetic denervation delayed and reduced the severity of hypertension. In patients with end-stage renal disease and those with kidney transplants, bilateral nephrectomy of native kidneys improved or normalized blood pressure.
The renal sympathetic nervous system has two components:
Both efferent and afferent nerve fibers are located in the adventitia of the renal arteries, making them a potentially modifiable target.
Percutaneous renal artery sympathetic denervation has already been used in patients with resistant hypertension, initially in clinical trials and subsequently in clinical practice in Europe. The procedure remains investigational in the United States.
The therapeutic catheter has a steerable tip and is connected to a console that delivers radiofrequency energy. The level of energy delivered is monitored with a sensor at the tip of the catheter so that excessive tissue injury is avoided.
The technique involves introducing a 6F femoral artery sheath and a 6F guide catheter to engage the renal arteries and subsequently deliver the radiofrequency catheter into the renal arteries to perform circumferential radiofrequency ablation. This procedure requires administration of anticoagulation and analgesics for control of abdominal pain during the ablation.
Two clinical trials evaluating this therapeutic modality have been conducted and the results published:
Symplicity HTN-1 (Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension: A Multicenter Safety and Proof-of-Principle Cohort Study)
In the Symplicity HTN-1 study (a single-arm proof of concept study), 45 patients with drug-resistant hypertension underwent bilateral application of radiofrequency to the renal arteries. Significant blood pressure reduction was observed at one month, followed by a sustained response at 12 months.
Symplicity HTN-2 (Renal Sympathetic Denervation in Patients with Treatment-Resistant Hypertension)
In the Symplicity HTN-2 trial (a randomized controlled trial), 106 patients with resistant hypertension were randomly assigned in a 1-to-1 ratio to receive catheter-based therapy in addition to conventional antihypertensive medications or to receive antihypertensive medications only. The primary endpoint was systolic blood pressure at six-month follow-up. There was a significant difference in blood pressure changes from baseline between patients treated with catheter-based renal sympathectomy and those treated medically.
Although this procedure can be associated with complications, the experience thus far suggests a low rate of occurrence. In Symplicity HTN-1, two patients had complications — one renal artery dissection, which was treated with stenting, and one femoral artery pseudoaneurysm. In Symplicity HTN-2, only one patient had a complication — a pseudoaneurysm at the femoral access site.
Although the results of these trials are encouraging, they lack the power to provide unequivocal proof to support a change in clinical practice. Mayo Clinic has begun screening and enrollment in the pivotal Symplicity HTN-3 trial. In this study, 545 patients will be randomly assigned in a 2-to-1 ratio to receive catheter-based therapy in addition to conventional antihypertensive medications or to receive antihypertensive medications only. The primary endpoint is systolic blood pressure at six-month follow-up. The results of this trial may lay the groundwork for a change in how patients with drug-resistant hypertension are treated.