J. of Cardiovasc. Trans. Res. DOI 10.1007/s12265-014-9549-5
Renal Denervation: A Novel Non-pharmacological Approach in Heart Failure Michael Böhm & Sebastian Ewen & Dominik Linz & Jan-C Reil & Stephan Schirmer & Christian Ukena & Felix Mahfoud
Received: 12 December 2013 / Accepted: 11 February 2014 # Springer Science+Business Media New York 2014
Abstract Heart failure is associated with activation of the sympathetic nervous system which presumably results in a progression of the syndrome and thereby in poor outcome. Renal denervation has shown to be effective in conditions with enhanced sympathetic activity like resistant hypertension and metabolic syndrome associated with sleep apnea. The first pilot trials assessing the effect of renal denervation on signs and symptoms of heart failure in patients with both preserved and reduced left ventricular ejection fraction are presently ongoing. The results of these studies will determine whether to proceed with larger prospective outcome trials. Altogether, renal denervation is a promising novel technique that may improve the outcome of patients with sympathetic hyperactivity and cardiovascular diseases. Keywords Renal denervation . Heart failure . Sympathetic nervous system . Cardiorenal syndrome . Resistant hypertension
Activation of the Sympathetic Nervous System in Heart Failure In chronic heart failure, neuroendocrine activation leads to the activation of the sympathetic nervous system [1], to an increase in the activity of the renin-angiotensin system [2], and to a pro-inflammatory state [3]; these, in turn induce remodeling processes with replacement fibrosis and changes in
Associate Editor Craig Stolen oversaw the review of this article M. Böhm (*) : S. Ewen : D. Linz : J.100 mmHg systolic), Symplicity HF (NCT 01392196) that investigates safety as well as myocardial function and exercise tolerance, the OLMEC study (NCT 01870310) that focuses on NT-BNP, and the PRESERVE (NCT 01954160) and REACH (NCT 01639378) studies that focus on urine sodium excretion and symptom improvement, respectively. Two studies (DIASTOLE, NCT 01583681; RDT-PEP, NCT 01840059) investigate myocardial function and biomarkers in a population with heart failure with preserved ejection fraction. Most of the trials will
J. of Cardiovasc. Trans. Res.
Exercise Toleranceafter RDN
preserved or impaired left ventricular fraction. Indeed, heart failure is associated with a high prevalence and incidence of atrial fibrillation that causes a symptomatic burden and increases the risk of stroke [18]. Furthermore, heart failure is associated with sleep apnea, which in turn is associated with atrial fibrillation. In an experimental study, intermittent negative tracheal pressure was associated with an enhanced inducibility of atrial fibrillation, which was accompanied by a shortening of the atrial effective refractory period [44]. Renal denervation abolished the electrophysiological changes and reduced atrial fibrillation by 70 % [45]. The atrial fibrillation cycle length was not affected, but there was a better rate control reflected by an increase of the cycle length of the ventricle during atrial fibrillation. Trials are ongoing to study the effect of renal denervation on atrial remodeling and on the recurrence rate after pulmonary vein isolation [46].
Fig. 5 Exercise tolerance after renal denervation (RDN) in patients with chronic heart failure. Approximately 1 week after renal denervation, there was an improvement of the 6-min walk test peaking at about 1 to 2 months. Modified according to Davis et. al from Ref [42]
Ventricular Arrhythmias In a model of acute myocardial ischemia and reperfusion in pigs, renal denervation reduced ventricular ectopies and ventricular fibrillation [47]. This effect was not accompanied by action potential changes and was not occurring during reperfusion showing that the prevention of ventricular fibrillation during ischemia might be due to a direct effect of renal denervation. The effect on ventricular ectopies in heart failure is largely unknown. There is a preliminary report on two patients with cardiomyopathy suffering an electrical storm in whom renal denervation, on the background of full antiarrhythmic therapy and optimized heart failure treatment, abolished discharges from an implanted ICD [48], Fig. 7. More data and larger case series are necessary to substantiate these effects.
start shortly and will investigate exercise tolerance and cardiac markers in order to pave the way for an outcome study in chronic heart failure.
Accompanying Diseases in Heart Failure Atrial Fibrillation and Sleep Apnea Atrial fibrillation is strongly favored by functional changes in the atria, which follow the progressive remodeling of the ventricles in case of hypertrophy or of heart failure with Fig. 6 Mechanisms of sympathetic activation in aggravating congestion. These provide the rationale to reduce sympathetic activation in order to relieve congestion. Modified from Ref [43]
Fast and Slow Mechanisms of Circulatory Congestion Precipitant (minor)
Sympathetic Activation
Renal and Dietary Mechanisms
Mobilization of Venous Reservoir
Sodium and Water Retention
fast
↑ Effective Circulatory Volume Congestion
slow
J. of Cardiovasc. Trans. Res.
RDN for Treatment of Electrical Storm 20
Number of VF Episodes
150
17
140
16
130
14
11
12
12
120 110
10
100
8
90
6
80
4 2
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0
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Systolic blood pressure (mm Hg)
18
0
week -1
day 0
day 1
week 1
prae
week 4
week 12
week 24
post ablationem
Fig. 7 Effect of renal denervation in a patient with dilated cardiomyopathy presenting with an electrical storm. Depicted are the numbers of ventricular fibrillation episodes (left) and the systolic blood pressure values (right). It becomes clear that after 1 week of renal denervation,
no further discharges of the ICD were observed. The blood pressure was particularly low in this patient but remained stable over time. Modified according to Ukena et al. 2012 from Ref [48]
Renal Dysfunction
fasting C-peptide concentrations. Accordingly, there was a reduction of the HOMA-index indicating that insulin sensitivity was improved in patients with glucose intolerance and resistant hypertension [52]. Whether further advanced stages of the diabetic syndrome in heart failure, in the absence of hypertension, can be influenced by renal denervation is presently unknown. However, it appears likely that renal denervation could provide an upstream therapy for the development of metabolic diseases in conditions in which sympathetic activity is enhanced.
In patients with resistant hypertension enrolled in the Symplicity-HTN trials, renal denervation did not reduce renal function. However, these trials enrolled only patients with a GFR>45 ml/min. Preliminary studies have shown similar blood pressure reductions in patients with impaired renal function [36] or terminal renal failure [49] with no signal of deterioration of renal function, provided renal denervation was performed by experienced investigators and contrast medium was used carefully [36, 49]. Renal denervation was shown to reduce microalbuminuria, most likely by an improvement of intrarenal hemodynamics [50]. In sleep apnea induced in pigs, renal denervation was able to abolish the drop in renal perfusion and to attenuate the rise in renin activation after obstructive episodes [51]. Data on the long-term renal effects in conditions other than hypertension are presently lacking and will be captured in the ongoing heart failure pilot trials. Diabetes Patients with symptomatic heart failure suffer from insulin resistance and diabetes in 50 % of the cases. Insulin resistance is caused by sympathetic activation and is most likely due to a shift of blood flow away from insulin sensitive organs [11–14]. In patients with resistant hypertension, renal denervation has been shown to improve an impaired fasting glucose level. Furthermore, there was a reduction of fasting insulin and
Summary Heart failure is associated with activation of the sympathetic nervous system which presumably results in a progression of the syndrome and thereby in poor outcome. Renal denervation has proven to be effective in conditions with enhanced sympathetic activity like resistant hypertension and potentially in metabolic syndrome and sleep apnea. More information on hypertensive patients is needed, because a 15 mmHg reduction of blood pressure was not achieved in a placebo controlled trial (Symplicity HTN3). The first pilot trials assessing the effect of renal denervation on signs and symptoms of heart failure in patients with both preserved and reduced left ventricular ejection fraction are presently ongoing The results of these studies will determine whether to proceed with larger prospective outcome trials.
J. of Cardiovasc. Trans. Res.
Altogether, renal denervation is a promising novel technique that may improve the outcome of patients with sympathetic hyperactivity and various cardiovascular diseases including heart failure.
Conflict of Interests The authors received scientific support and speakers honoraria from Medtronic, St. Jude, and Covidien. MB is supported by the Deutsche Forschungsgemeinschaft and DL, and FM by the Hochdruckliga and the German Cardiac Society.
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15. Dunlap, M. E., & Sobotka, P. A. (2013). Fluid re-distribution rather than accumulation causes most cases of decompensated heart failure. Journal of the American College of Cardiology, 62, 165–166. 16. Peppard, P. E., Young, T., Palta, M., & Skatrud, J. (2000). Prospective study of the association between sleep-disordered breathing and hypertension. New England Journal of Medicine, 342, 1378–1384. 17. Logan, A. G., Perlikowski, S. M., Mente, A., Tisler, A., Tkacova, R., Niroumand, M., Leung, R. S., & Bradley, T. D. (2001). High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. Journal of Hypertension, 19, 2271–2277. 18. McMurray, J. J., Adamopoulos, S., Anker, S. D., Auricchio, A., Böhm, M., Dickstein, K., Falk, V., Filippatos, G., Fonseca, C., Gomez-Sanchez, M. A., Jaarsma, T., Køber, L., Lip, G. Y., Maggioni, A. P., Parkhomenko, A., Pieske, B. M., Popescu, B. A., Rønnevik, P. K., Rutten, F. H., Schwitter, J., Seferovic, P., Stepinska, J., Trindade, P. T., Voors, A. A., Zannad, F., & Zeiher, A. (2012). ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. European Heart Journal, 33, 1787–1847. 19. Ljungqvist, A., & Wågermark, J. (1970). The adrenergic innervation of intrarenal glomerular and extra-glomerular circulatory routes. Nephron, 7, 218–229. 20. Stella, A., & Zanchetti, A. (1991). Functional role of renal afferents. Physiological Reviews, 71, 659–682. 21. Katholi, R. E., Whitlow, P. L., Hageman, G. R., & Woods, W. T. (1984). Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. Journal of Hypertension, 2, 349–359. 22. Esler, M., Lambert, G., & Jennings, G. (1989). Regional norepinephrine turnover in human hypertension. Clinical and Experimental Hypertension. Part A, Suppl 1, 75–89. 23. Hausberg, M., Kosch, M., Harmelink, P., Barenbrock, M., Hohage, H., Kisters, K., Dietl, K. H., & Rahn, K. H. (2002). Sympathetic nerve activity in end-stage renal disease. Circulation, 106, 1974–1979. 24. Swedberg, K., Viquerat, C., Rouleau, J. L., Roizen, M., Atherton, B., Parmley, W. W., & Chatterjee, K. (1984). Comparison of myocardial catecholamine balance in chronic congestive heart failure and in angina pectoris without failure. American Journal of Cardiology, 54, 783–786. 25. Böhm, M., Beuckelmann, D., Brown, L., Feiler, G., Lorenz, B., Näbauer, M., Kemkes, B., & Erdmann, E. (1988). Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium. European Heart Journal, 9, 844–852. 26. Böhm, M., Gierschik, P., Jakobs, K. H., Pieske, B., Schnabel, P., Ungerer, M., & Erdmann, E. (1990). Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation, 82, 1249–1265. 27. Goldstein, D. S., Brush, J. E., Jr., Eisenhofer, G., Stull, R., & Esler, M. (1988). In vivo measurement of neuronal uptake of norepinephrine in the human heart. Circulation, 78, 41–48. 28. Böhm, M., La Rosée, K., Schwinger, R. H., & Erdmann, E. (1995). Evidence for reduction of norepinephrine uptake sites in the failing human heart. Journal of the American College of Cardiology, 25, 146–153. 29. Hasking, G. J., Esler, M. D., Jennings, G. L., Burton, D., Johns, J. A., & Korner, P. I. (1986). Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation, 73, 615–621. 30. Petersson, M., Friberg, P., Eisenhofer, G., Lambert, G., & Rundqvist, B. (2005). Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure. European Heart Journal, 26, 906–913.
J. of Cardiovasc. Trans. Res. 31. Page, I. H. (1934). The effect on renal efficiency of lowering arterial blood pressure in cases of essential hypertension and nephritis. Journal of Clinical Investigation, 13, 909–915. 32. Page, I. H., & Heuer, G. J. (1935). The effect of renal denervation on the level of arterial blood pressure and renal function in essential hypertension. Journal of Clinical Investigation, 14, 27–30. 33. Smithwick, R. H., & Thompson, J. E. (1953). Splanchnicectomy for essential hypertension; results in 1,266 cases. Journal of the American Medical Association, 152, 1501–1504. 34. Krum, H., Schlaich, M., Whitbourn, R., Sobotka, P. A., Sadowski, J., Bartus, K., Kapelak, B., Walton, A., Sievert, H., Thambar, S., Abraham, W. T., & Esler, M. (2009). Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet, 373, 1275–1281. 35. Symplicity HTN-1 Investigators. (2011). Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension, 57, 911–917. 36. Hering, D., Mahfoud, F., Walton, A. S., Krum, H., Lambert, G. W., Lambert, E. A., Sobotka, P. A., Böhm, M., Cremers, B., Esler, M. D., & Schlaich, M. P. (2012). Renal denervation in moderate to severe CKD. Journal of the American Society of Nephrology, 23, 1250–1257. 37. Symplicity HTN-2 Investigators, Esler, M. D., Krum, H., Sobotka, P. A., Schlaich, M. P., Schmieder, R. E., & Böhm, M. (2010). Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet, 376, 1903–1909. 38. Esler, M. D., Krum, H., Schlaich, M., Schmieder, R. E., Böhm, M., Sobotka, P. A., & Symplicity HTN-2 Investigators. (2012). Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation, 126, 2976–2982. 39. Ukena, C., Mahfoud, F., Kindermann, I., Barth, C., Lenski, M., Kindermann, M., Brandt, M. C., Hoppe, U. C., Krum, H., Esler, M., Sobotka, P. A., & Böhm, M. (2011). Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. Journal of the American College of Cardiology, 58, 1176–1182. 40. Brandt, M. C., Reda, S., Mahfoud, F., Lenski, M., Böhm, M., & Hoppe, U. C. (2012). Effects of renal sympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension. Journal of the American College of Cardiology, 60, 1956–1965. 41. Brandt, M. C., Mahfoud, F., Reda, S., Schirmer, S. H., Erdmann, E., Böhm, M., & Hoppe, U. C. (2012). Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. Journal of the American College of Cardiology, 59, 901–909. 42. Davies, J. E., Manisty, C. H., Petraco, R., Barron, A. J., Unsworth, B., Mayet, J., Hamady, M., Hughes, A. D., Sever, P. S., Sobotka, P. A., & Francis, D. P. (2013). First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from
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REACH-Pilot study. International Journal of Cardiology, 162, 189–192. Fallick, C., Sobotka, P. A., & Dunlap, M. E. (2011). Sympathetically mediated changes in capacitance: redistribution of the venous reservoir as a cause of decompensation. Circulation. Heart Failure, 4, 669–675. Linz, D., Schotten, U., Neuberger, H. R., Böhm, M., & Wirth, K. (2011). Negative tracheal pressure during obstructive respiratory events promotes atrial fibrillation by vagal activation. Heart Rhythm, 8, 1436–1443. Linz, D., Mahfoud, F., Schotten, U., Ukena, C., Neuberger, H. R., Wirth, K., & Böhm, M. (2012). Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea. Hypertension, 60, 172–178. Ahmed, H., Miller, M. A., Dukkipati, S. R., Cammack, S., Koruth, J. S., Gangireddy, S., Ellsworth, B. A., D’Avila, A., Domanski, M., Gelijns, A. C., Moskowitz, A., & Reddy, V. Y. J. (2013). Adjunctive renal sympathetic denervation to modify hypertension as upstream therapy in the treatment of atrial fibrillation (H-FIB) study: clinical background and study design. Journal of Cardiovascular Electrophysiology, 24, 503–509. Linz, D., Wirth, K., Ukena, C., Mahfoud, F., Pöss, J., Linz, B., Böhm, M., & Neuberger, H. R. (2013). Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs. Heart Rhythm. doi:10.1016/j.hrthm.2013.07.015. Ukena, C., Bauer, A., Mahfoud, F., Schreieck, J., Neuberger, H. R., Eick, C., Sobotka, P. A., Gawaz, M., & Böhm, M. (2012). Renal sympathetic denervation for treatment of electrical storm: first-inman experience. Clinical Research in Cardiology, 101, 63–67. Schlaich, M. P., Bart, B., Hering, D., Walton, A., Marusic, P., Mahfoud, F., Böhm, M., Lambert, E. A., Krum, H., Sobotka, P. A., Schmieder, R. E., Ika-Sari, C., Eikelis, N., Straznicky, N., Lambert, G. W., & Esler, M. D. (2013). Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. International Journal of Cardiology, 168, 2214–2220. Mahfoud, F., Cremers, B., Janker, J., Link, B., Vonend, O., Ukena, C., Linz, D., Schmieder, R., Rump, L. C., Kindermann, I., Sobotka, P. A., Krum, H., Scheller, B., Schlaich, M., Laufs, U., & Böhm, M. (2012). Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. Hypertension, 60, 419–424. Linz, D., Hohl, M., Nickel, A., Mahfoud, F., Wagner, M., Ewen, S., Schotten, U., Maack, C., Wirth, K., & Böhm, M. (2013). Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea. Hypertension, 62, 767–774. Mahfoud, F., Schlaich, M., Kindermann, I., Ukena, C., Cremers, B., Brandt, M. C., Hoppe, U. C., Vonend, O., Rump, L. C., Sobotka, P. A., Krum, H., Esler, M., & Böhm, M. (2011). Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation, 123, 1940–1946.
Renal Denervation: A Novel Non-pharmacological Approach in Heart Failure Michael Böhm & Sebastian Ewen & Dominik Linz & Jan-C Reil & Stephan Schirmer & Christian Ukena & Felix Mahfoud
Received: 12 December 2013 / Accepted: 11 February 2014 # Springer Science+Business Media New York 2014
Abstract Heart failure is associated with activation of the sympathetic nervous system which presumably results in a progression of the syndrome and thereby in poor outcome. Renal denervation has shown to be effective in conditions with enhanced sympathetic activity like resistant hypertension and metabolic syndrome associated with sleep apnea. The first pilot trials assessing the effect of renal denervation on signs and symptoms of heart failure in patients with both preserved and reduced left ventricular ejection fraction are presently ongoing. The results of these studies will determine whether to proceed with larger prospective outcome trials. Altogether, renal denervation is a promising novel technique that may improve the outcome of patients with sympathetic hyperactivity and cardiovascular diseases. Keywords Renal denervation . Heart failure . Sympathetic nervous system . Cardiorenal syndrome . Resistant hypertension
Activation of the Sympathetic Nervous System in Heart Failure In chronic heart failure, neuroendocrine activation leads to the activation of the sympathetic nervous system [1], to an increase in the activity of the renin-angiotensin system [2], and to a pro-inflammatory state [3]; these, in turn induce remodeling processes with replacement fibrosis and changes in
Associate Editor Craig Stolen oversaw the review of this article M. Böhm (*) : S. Ewen : D. Linz : J.100 mmHg systolic), Symplicity HF (NCT 01392196) that investigates safety as well as myocardial function and exercise tolerance, the OLMEC study (NCT 01870310) that focuses on NT-BNP, and the PRESERVE (NCT 01954160) and REACH (NCT 01639378) studies that focus on urine sodium excretion and symptom improvement, respectively. Two studies (DIASTOLE, NCT 01583681; RDT-PEP, NCT 01840059) investigate myocardial function and biomarkers in a population with heart failure with preserved ejection fraction. Most of the trials will
J. of Cardiovasc. Trans. Res.
Exercise Toleranceafter RDN
preserved or impaired left ventricular fraction. Indeed, heart failure is associated with a high prevalence and incidence of atrial fibrillation that causes a symptomatic burden and increases the risk of stroke [18]. Furthermore, heart failure is associated with sleep apnea, which in turn is associated with atrial fibrillation. In an experimental study, intermittent negative tracheal pressure was associated with an enhanced inducibility of atrial fibrillation, which was accompanied by a shortening of the atrial effective refractory period [44]. Renal denervation abolished the electrophysiological changes and reduced atrial fibrillation by 70 % [45]. The atrial fibrillation cycle length was not affected, but there was a better rate control reflected by an increase of the cycle length of the ventricle during atrial fibrillation. Trials are ongoing to study the effect of renal denervation on atrial remodeling and on the recurrence rate after pulmonary vein isolation [46].
Fig. 5 Exercise tolerance after renal denervation (RDN) in patients with chronic heart failure. Approximately 1 week after renal denervation, there was an improvement of the 6-min walk test peaking at about 1 to 2 months. Modified according to Davis et. al from Ref [42]
Ventricular Arrhythmias In a model of acute myocardial ischemia and reperfusion in pigs, renal denervation reduced ventricular ectopies and ventricular fibrillation [47]. This effect was not accompanied by action potential changes and was not occurring during reperfusion showing that the prevention of ventricular fibrillation during ischemia might be due to a direct effect of renal denervation. The effect on ventricular ectopies in heart failure is largely unknown. There is a preliminary report on two patients with cardiomyopathy suffering an electrical storm in whom renal denervation, on the background of full antiarrhythmic therapy and optimized heart failure treatment, abolished discharges from an implanted ICD [48], Fig. 7. More data and larger case series are necessary to substantiate these effects.
start shortly and will investigate exercise tolerance and cardiac markers in order to pave the way for an outcome study in chronic heart failure.
Accompanying Diseases in Heart Failure Atrial Fibrillation and Sleep Apnea Atrial fibrillation is strongly favored by functional changes in the atria, which follow the progressive remodeling of the ventricles in case of hypertrophy or of heart failure with Fig. 6 Mechanisms of sympathetic activation in aggravating congestion. These provide the rationale to reduce sympathetic activation in order to relieve congestion. Modified from Ref [43]
Fast and Slow Mechanisms of Circulatory Congestion Precipitant (minor)
Sympathetic Activation
Renal and Dietary Mechanisms
Mobilization of Venous Reservoir
Sodium and Water Retention
fast
↑ Effective Circulatory Volume Congestion
slow
J. of Cardiovasc. Trans. Res.
RDN for Treatment of Electrical Storm 20
Number of VF Episodes
150
17
140
16
130
14
11
12
12
120 110
10
100
8
90
6
80
4 2
0
0
0
0
0
70
Systolic blood pressure (mm Hg)
18
0
week -1
day 0
day 1
week 1
prae
week 4
week 12
week 24
post ablationem
Fig. 7 Effect of renal denervation in a patient with dilated cardiomyopathy presenting with an electrical storm. Depicted are the numbers of ventricular fibrillation episodes (left) and the systolic blood pressure values (right). It becomes clear that after 1 week of renal denervation,
no further discharges of the ICD were observed. The blood pressure was particularly low in this patient but remained stable over time. Modified according to Ukena et al. 2012 from Ref [48]
Renal Dysfunction
fasting C-peptide concentrations. Accordingly, there was a reduction of the HOMA-index indicating that insulin sensitivity was improved in patients with glucose intolerance and resistant hypertension [52]. Whether further advanced stages of the diabetic syndrome in heart failure, in the absence of hypertension, can be influenced by renal denervation is presently unknown. However, it appears likely that renal denervation could provide an upstream therapy for the development of metabolic diseases in conditions in which sympathetic activity is enhanced.
In patients with resistant hypertension enrolled in the Symplicity-HTN trials, renal denervation did not reduce renal function. However, these trials enrolled only patients with a GFR>45 ml/min. Preliminary studies have shown similar blood pressure reductions in patients with impaired renal function [36] or terminal renal failure [49] with no signal of deterioration of renal function, provided renal denervation was performed by experienced investigators and contrast medium was used carefully [36, 49]. Renal denervation was shown to reduce microalbuminuria, most likely by an improvement of intrarenal hemodynamics [50]. In sleep apnea induced in pigs, renal denervation was able to abolish the drop in renal perfusion and to attenuate the rise in renin activation after obstructive episodes [51]. Data on the long-term renal effects in conditions other than hypertension are presently lacking and will be captured in the ongoing heart failure pilot trials. Diabetes Patients with symptomatic heart failure suffer from insulin resistance and diabetes in 50 % of the cases. Insulin resistance is caused by sympathetic activation and is most likely due to a shift of blood flow away from insulin sensitive organs [11–14]. In patients with resistant hypertension, renal denervation has been shown to improve an impaired fasting glucose level. Furthermore, there was a reduction of fasting insulin and
Summary Heart failure is associated with activation of the sympathetic nervous system which presumably results in a progression of the syndrome and thereby in poor outcome. Renal denervation has proven to be effective in conditions with enhanced sympathetic activity like resistant hypertension and potentially in metabolic syndrome and sleep apnea. More information on hypertensive patients is needed, because a 15 mmHg reduction of blood pressure was not achieved in a placebo controlled trial (Symplicity HTN3). The first pilot trials assessing the effect of renal denervation on signs and symptoms of heart failure in patients with both preserved and reduced left ventricular ejection fraction are presently ongoing The results of these studies will determine whether to proceed with larger prospective outcome trials.
J. of Cardiovasc. Trans. Res.
Altogether, renal denervation is a promising novel technique that may improve the outcome of patients with sympathetic hyperactivity and various cardiovascular diseases including heart failure.
Conflict of Interests The authors received scientific support and speakers honoraria from Medtronic, St. Jude, and Covidien. MB is supported by the Deutsche Forschungsgemeinschaft and DL, and FM by the Hochdruckliga and the German Cardiac Society.
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