肾脏去神经可改善糖代谢与睡眠呼吸暂停

迈阿密海滩——麻省总医院血管中心医学总监Michael R. Jaff博士在2013国际血管内治疗研讨会(ISET)上报告的初步研究结果显示，肾动脉去神经可改善糖代谢和耐药性高血压的控制情况。

Michael R. Jaff博士

在被纳入这项初步研究的50例耐药性高血压患者中，有37例接受了双侧肾脏去神经，其余13例作为对照。接受治疗的患者不仅3个月时血压水平明显改善(收缩压下降32 mmHg，对照组仅下降5 mmHg；舒张压下降12 mmHg，对照组仅下降3 mmHg)，而且空腹血糖水平明显降低。3个月时，治疗组的空腹血糖水平降低了9.4 mg/dl，而对照组升高了0.9 mg/dl(Circulation 2011;123:1940-6)。

“然而，我认为最令人兴奋的莫过于肾脏去神经对血浆胰岛素水平的影响。治疗组患者的1个月和3个月血浆胰岛素水平均有显著降低。”1个月时，治疗组患者的血浆胰岛素水平降低了8.7 mcU/ml，而对照组升高了6.4 mcU/ml；3个月时，前者降低了11.6 mcU/ml，而后者升高了0.5 mcU/ml。

3个月时，治疗组中仍符合糖尿病和糖耐量受损诊断标准的患者数量有所减少，而对照组中符合糖尿病诊断标准的患者比例由23%增至38%，糖耐量正常率由31%降至24%。

“假如上述发现得到证实，那么肾脏去神经将具有令人难以置信的应用前景。我们真的能使耐药性高血压患者避免罹患糖尿病吗？我们能治愈那些已患糖尿病的患者吗？所有这些都可能是以血压控制为基础的。我们都知道，随着危险因素的增加，动脉粥样硬化风险呈指数性增加。因此，用一种简单的手术控制两项主要的粥样硬化危险因素，其意义是难以估量的。”

对于肾脏去神经改善糖代谢的潜在机制，他的解释是：交感神经过度兴奋直接调节血管阻力，血管阻力增加可使血液由横纹肌流向内脏组织，而内脏组织的胰岛素敏感性弱于横纹肌。

一项针对交感神经兴奋的长期研究纳入了原发性高血压患者和血压正常对照者，结果显示2型糖尿病患者的交感神经兴奋水平高于对照者，合并高血压与糖尿病的患者的交感神经兴奋度最高。这项随访时间长达18年的研究表明，交感神经兴奋与糖耐量受损直接相关(Metabolism Clin. Exper. 2008;57:1422-7)。“以6个月时肾脏去甲肾上腺素溢出作为评价指标，经导管去神经已被证明可降低交感神经兴奋。”

圣约翰医院Prairie血管研究所主任Krishna T. Rocha-Singh博士指出，这一病理生理学机制——尤其是中枢神经系统外流及其对肺充血临床症状的影响——还能解释肾脏去神经多种“附带益处”，例如改善阻塞性睡眠呼吸暂停。

据他介绍，一项纳入肾脏去神经患者的小型研究显示，70%的患者不仅血压得到改善，而且3个月和6个月时的睡眠呼吸暂停严重程度也下降。此外，在一项纳入27例肺静脉分离或房颤消融患者的小型试验中，还接受了肾脏去神经的患者有69%在12个月内未出现房颤复发，而这一比例在未接受肾脏去神经的患者中仅为29%(J. Am. Coll. Cardiol. 2012;60:1163-70)。

Rocha-Singh博士表示，他和Jaff博士都认为，在获得更大样本和更长期数据之前不宜太过兴奋，但“肾脏去神经的多重效应确实是我职业生涯中前所未见的”。

Jaff博士是多家企业的顾问，包括Symplicity肾脏去神经装置的生产商美敦力。他还持有多家医疗器械公司的普通股，包括掌握着一种肾脏去神经新机制的Northwind医疗公司。他还担任非赢利性VIVA医生组织的董事。Rocha-Singh博士是美敦力和CardioSonic的顾问。

爱思唯尔版权所有  未经授权请勿转载

By: SHARON WORCESTER, Cardiology News Digital Network

MIAMI BEACH – Denervation of the renal arteries improved glucose metabolism and control of drug-resistant hypertension, according to findings from a 2011 pilot study.

"If you thought the impact of renal denervation on hypertension was big, certainly the consideration of renal sympathetic denervation on glucose metabolism raises some real eye-opening opportunities," Dr. Michael R. Jaff said at the International Symposium on Endovascular Therapy 2013.
 
In 50 patients with drug-resistant hypertension who were enrolled in the pilot study, 37 underwent bilateral renal denervation, and 13 served as controls. Not only did the treated patients experience improvements in blood pressure compared with controls at 3 months (decreases in systolic BP of 32 mm Hg vs. 5 mm Hg, and decreases in diastolic BP of 12 mm Hg vs. 3 mm Hg in treated patients vs. controls, respectively), they also experienced improvements in fasting blood glucose levels.

At 3 months, the treatment group had a 9.4-mg/dL decrease in fasting blood glucose, compared with a 0.9-mg/dL increase in the controls (Circulation 2011;123:1940-6).

"However, I think the most exciting thing is the impact on plasma insulin levels, where there was a real reduction in plasma insulin levels at 1 month and 3 months in patients treated with renal denervation," said Dr. Jaff, who is medical director of the vascular center, the vascular diagnostic laboratory, and the vascular ultrasound core laboratory at Massachusetts General Hospital, Boston.

At 1 month, plasma insulin had decreased by 8.7 mcU/mL in the treated patients, and increased by 6.4 mcU/mL increase in the controls; at 3 months, plasma insulin had decreased by 11.6 mcU/mL in the treated patients, and increased by 0.5 mcU/mL in the controls.

A reduction in the number of patients diagnosed with diabetes and with impaired glucose tolerance was seen at 3 months in the treatment group, while the diabetic cases increased from 23% to 38% and normal glucose tolerance dropped from 31% to 24% in the control group, Dr. Jaff said.

"Admittedly this is a small sample size, but nonetheless, given the basic pathophysiology of this and these early findings, this is a tantalizing impact," he said, adding that if the findings are confirmed, the potential reach of renal denervation is mind-boggling.

"I think the potential is amazing. Could we actually say we could prevent diabetes mellitus in those with resistant hypertension? Could we cure those who already have diabetes? All of this would potentially be on a background of blood pressure control. We’ve all seen these charts that show that the more risk factors you have, it’s almost logarithmic, the impact on atherosclerosis. So being able to manage two major atherosclerotic risk factors with one simple procedure is almost hard to comprehend," he said.

But the "basic pathophysiology" he mentioned offers a plausible path to comprehension of the potential impact of renal sympathetic denervation.

Specifically, sympathetic hyperactivity directly mediates vascular resistance, and increases in vascular resistance shift blood flow from striated muscle to visceral tissues, he said, explaining that visceral tissue is less insulin sensitive than striated muscle.

In one long-term study looking at sympathetic drive in patients with essential hypertension and in normotensive controls, patients with type 2 diabetes had higher sympathetic drive than did controls, and those with hypertension and diabetes had the highest sympathetic drive. The study, which followed patients for 18 years, indicated that sympathetic drive and impaired glucose tolerance were directly related, he said (Metabolism Clin. Exper. 2008;57:1422-7).

"The background on this is that catheter-based denervation has been shown to reduce sympathetic drive as measured by renal norepinephrine spillover at 6 months, with a near 50% reduction in spillover," he said.

The pathophysiology – particularly outflow from the central nervous system and its effect on the clinical symptom of lung congestion – also provides a rationale for multiple other observed and potential "collateral benefits" of renal denervation, such as improvements in obstructive sleep apnea, said Dr. Krishna T. Rocha-Singh, who is director of the Prairie Vascular Institute at St. John’s Hospital, Springfield, Ill.

"Renal sympathetic outflow results in volume reduction and renal blood flow, retention of sodium and volume retention, and can relate to congestion. We can also have an internal reset, if you will, of the chemoreceptors on the brain that can lead to dyspnea and central sleep apnea. And, as [Dr. Jaff] suggested, there can be a reduction in peripheral vascular resistance due to vascular remodeling that improves insulin resistance.

"But more importantly, we have the effect of increased hypertrophy that may induce arrhythmias, oxygen consumption, and promote dyspnea. There’s also a direct connection between that and the brain, again relating to congestion," he said.

Dr. Rocha-Singh said this synergy between two pathophysiological systems – the activation of the sympathetic nervous system and the retention of sodium – relates to vascular resistance and excess volume, and to congestion and the perception of dyspnea.

When a person is in a reclining position, fluid shifts from the legs to the soft tissues. This effect is greater in patients with drug-resistant hypertension than in those with controlled blood pressure, and it occurs irrespective of body mass index and neck circumference, he said.

In a small study of patients who underwent renal denervation, 70% experienced not only blood pressure improvements but also decreases in the severity of sleep apnea as measured using the apnea-hypopnea index at 3 and 6 months’ follow-up, he said.

Additionally, in a small trial involving 27 patients who underwent pulmonary vein isolation or ablation of atrial fibrillation, 69% of those who also underwent renal denervation were free of recurrence of atrial fibrillation at 12 months, compared with only 29% of those who did not undergo renal denervation (J. Am. Coll. Cardiol. 2012;60:1163-70).

These encouraging findings contribute to what Dr. Rocha-Singh called a "tsunami of excitement" surrounding renal denervation. He noted that a quick Internet search identified more than 145 papers that have been published on the topic, and showed that more than 1,700 related provisional patents have been filed.

While, he – like Dr. Jaff – agreed that the enthusiasm must be tempered pending additional procedural and long-term data, he noted that the diversity of the primary and observed collateral benefits of renal denervation is something of a "vuja de" – the opposite of déjà vu.

"We have never experienced anything like this in our professional lives," he said.

Dr. Jaff is a consultant for numerous companies, including Medtronic, the maker of the Symplicity renal denervation device, but he is not compensated by Medtronic. He also has equity in numerous medical device companies, including one – Northwind Medical – that has a renal denervation strategy utilizing a novel mechanism. He is a board member for the nonprofit VIVA Physicians organization. Dr. Rocha-Singh is also a consultant or advisory board member for Medtronic, as well as for CardioSonic.