How does the renal sympathetic system help to regulate blood pressure? The sympathetic system fuels the release of certain hormones that are an augmenter to blood pressure. These hormones are typically used in the “fight or flight” type mechanisms in our body. If we need a surge of adrenaline, it’s these hormones that come to serve us if we have to run or fight. In hypertension, however, the continued release of low-dose amounts of these hormones can actually increase blood pressure by a variety of mechanisms at the level of the blood vessel and at the level of the kidney. So the “release” or the disconnection of this sympathetic nervous system with regards to hypertension is the proof of concept that has been established with the very new and novel technique of catheter-based renal denervation. How does catheter-based renal denervation work? It has been established for years that if you go in surgically to cut renal nerves, an improvement in blood pressure will occur. Initially, there was a fair amount of mortality and morbidity associated with these radical surgical procedures, moreover, they did not isolate the renal sympathetic nerves, and the procedures resulted in global sympathetic denervation below the nipples. Being able to de-nervate, or silence, only the renal nerves through a catheter-based system is a crucial development. A small catheter is placed in the femoral artery and we gain access to the nerves through the renal artery. The nerves are embedded in the casings or layers around the renal arteries. We are able to impair or ablate the nerves by passing an energy source into the renal artery and transmitting a low-dose energy, radiofrequency ablation, through the catheter tip that is placed in the kidneys. The energy is transmitted through the vessel wall to damage the renal nerves. At the end of the procedure, the catheter is removed, the patient is literally walking around within hours of the procedure, and in the future, may go home potentially the same day. As part of the current protocol, the patient goes home the following day. How much of the nerve is ablated? We are not damaging a single nerve throughout its length, but are treating it at one point. The operator delivers anywhere from 4 to 5 treatments along the renal artery, distally to proximally. By placing these treatments at the 12 o’clock, 3 o’clock, 6 o’clock and 9 o’clock positions, circumferentially around the renal arteries, it deactivates a significant number of the inbound and exiting renal sympathetic nerves. How long does the procedure take? The actual treatment time for both sides is probably around an hour. Just like any procedure, however, as the interventionalist becomes more adept and the technology improves, the actual time will be reduced. What patient population will benefit most from this procedure? Patients who have what we call resistant or recalcitrant hypertension. These patients have been subjected to medical therapy and despite all attempts, using large doses and multiple medications, medical therapy still will not control their blood pressure. This cohort of patients with recalcitrant or resistant hypertension is potentially huge worldwide. There is some very good data suggesting that many patients, despite the best efforts of their physicians, remain uncontrolled. That population, therefore, is subjected to the risks and ravages of hypertension, meaning progression to stroke, myocardial infarction, heart failure and renal failure. The public health implications for this therapy are enormous. Are there established guidelines for determining whether a patient is hypertension resistant? Yes. There is a consensus document called JNC 7, a Joint Commission National Consensus document. Experts in hypertension, on a regular basis, sit down and write treatment guidelines. They establish the definitions of patients who would be termed clinically resistant, with resistant hypertension. Does resistant hypertension cross ethnic groups, age, gender, etc.? That’s a good question. There clearly are different profiles with regards to blood pressure. The African-American population tends to have a certain hormonal blueprint as opposed to the Caucasian population, for example. And it is possible that the therapy may have even greater value for African-Americans with hypertension. The simple fact is that this therapy will address a very large cohort and specifically deal with one mechanism that is driving hypertension. We do not yet know if there is a particular patient population in whom the therapy will effectively remove the need for any medications. At the moment, we are considering the intervention as a powerful new tool to treat hypertension. Do patients continue taking medication after the procedure? Yes. Follow up will need to continue. We have one-year follow up on a small number of patients that were part of the first-in-man trial, and that experience is compelling. It may come to pass that patients’ blood pressure will come under control with the same number of medications or a reduced number of medications. We don’t know yet what patient medication requirements will be as far out as 3 to 5 years. Regardless, by any combination of anti-hypertensives, we need to get the blood pressure under control and this procedure will help. What did the first-in-man trial data (see sidebar) released at the American College of Cardiology tell us? This is a very important first addition to the medical literature. Researchers in Australia enrolled 50 patients to receive this therapy. As it turned out, 5 of those 50 patients were excluded from receiving the therapy because they had dual renal arteries. The anatomy in regards to the renal artery has to be compatible with delivering the appropriate amount of treatment. The other 45 were treated and this group of patients had an average blood pressure of over 175 mm Hg, which is substantial. Clearly, they fell within the definition of resistant hypertension. It is important to note that despite still having poorly controlled blood pressure of over 175 mm Hg, the average patient was taking almost five medications. Not only were these patients taking several medications, but those medications that they were taking were not successful. The procedure was successful 90% of the time, defined as greater than a 10 mm Hg drop of blood pressure. There was one patient that had a dissection in the lining of the renal artery and needed a stent during the procedure, but in the treated 45 patients, safety was not a major issue. Patients were followed up with regular office visits and the drop in blood pressure recorded at regular intervals. The mean blood pressure dropped significantly over the year period. Initially the drop was 10-14 mm Hg, then it went down to 20 mm Hg, then at the end of 12 months (and again, not all 45 patients had one-year follow up, but a significant number did) that number had gone to 27 mm Hg. We defined an appropriate population that is not well treated. We are able to do a procedure that is safe and appears to be effective. Now, the next question is whether researchers can show that the amount of hormone supplied by the renal sympathetic system, noradrenaline, went down. Indeed, the amount of renal noradrenaline spillover actually declined. It’s nice story in a small cohort of patients, and that’s the entry into doing a large, randomized, multi-center trial in Europe, which I understand is soon to be initiated. From what I understand, the company is also moving quickly to get a trial started in the United States. Can you tell us about your own experience with the procedure? Our site has done a total of 13 renal denervation procedures. My experience reflects that of the Australian trial researchers — each patient has experienced improvements in blood pressure. It’s been safe and there have been no complications. In the future, there may be a defined group of “non-responders,” but the patient numbers are so small right now that whole issue remains open. What are potential complications of the procedure? Just like any generational change, with advancements in technology, catheters will become smaller and more flexible. I suspect that what happened with the dissection in the first-in-man trial is that the first-generation catheter may have been inadvertently pushed forward, causing something similar to a divot to form in the renal artery. The researchers, I think appropriately, put in a stent and the patient had no other untoward effects. That, potentially, is one side effect. Could a perforation occur? Yes. Could plaque that occurs in these arteries break off and go into the kidney? Yes. Could the contrast media cause a problem? Yes. I think these are all anticipatable complications and in a large cohort of appropriately defined patients with skilled physicians, the complication rate will be very, very low. What about harm to the arterial wall from the radiofrequency ablation? In the Lancet report, 18 patients underwent repeat angiography, demonstrating no abnormalities, and 34 have now undergone magnetic resonance angiography at 6 months; again, none have vascular abnormalities. In the upcoming trial, there will be follow-up computed tomography imaging of the renal artery to make sure that the application transmission of radiofrequency energy causes no long-term injury to the lining of the renal artery. It’s been emphasized that this treatment should only be utilized on those who are truly hypertension resistant. But if a patient with high blood pressure is getting a PCI, why not add on this procedure? As we start looking at other cohorts of patients, that type of question, from my point of view, has to be better defined. With time and understanding of the potential public health issues, it may come to pass that potentially, earlier treatment of patients may be offered. After making a presentation on this procedure, I received a call from a gentleman who asked if he could be part of the study. I went through the exclusion criteria, and he said, “Well, you know, doc, I really just don’t like taking these two medications every day. It would be great if you could just fix it.” It’s the culture of our society. I call it “the drive-thru at McDonald’s.” We want it now, we want it fast and we don’t want to think about it. But I do think this is a medically relevant question, because there will be cohort of patients where this is proven to be effective and appropriate, and earlier treatment may be offered. Imagine that you are 35 and you have high blood pressure, and your life expectancy is 80. What is the cost to medical insurance and Medicare for treating your blood pressure for 40 years or providing this therapy, which could potentially reduce the number of medications? Hopefully, the procedure would clearly reduce or control your blood pressure, which would then translate into a reduced risk of heart attack and stroke, among other problems. Clearly, there are many public health and cost issues that this type of trial will raise. The potential global impact is substantial. Dr. Rocha-Singh has no conflicts of interest, financial or otherwise, with Ardian. He can be contacted at email@example.com *The Symplicity® Catheter System (Ardian, Palo Alto, CA) is not yet commercially available.