Renal denervation improves glucose metabolism, sleep apnea

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.

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.

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.