- Email: [email protected]
Pathophysiologic Mechanisms in Heart Failure: Role of the Sympathetic Nervous System
Author's Accepted Manuscript
Pathophysiologic Mechanisms in Heart Failure. Role of the Sympathetic Nervous System Steve Antoine MD, Gaurang Vaidya MD, Haider Imam MD, Daniel Villarreal MD
www.amjmedsci.com
PII: DOI: Reference:
S0002-9629(16)30373-1 http://dx.doi.org/10.1016/j.amjms.2016.06.016 AMJMS233
To appear in:
Am J Med Sci
Received date: 22 June 2016 Accepted date: 24 June 2016 Cite this article as: Steve Antoine MD, Gaurang Vaidya MD, Haider Imam MD, Daniel Villarreal MD, Pathophysiologic Mechanisms in Heart Failure. Role of the Sympathetic Nervous System, Am J Med Sci, http://dx.doi.org/10.1016/j. amjms.2016.06.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pathophysiologic Mechanisms in Heart Failure. Role of the Sympathetic Nervous System Steve Antoine, MD₁ Gaurang Vaidya, MD₁ Haider Imam, MD₁ Daniel Villarreal, MD₁,₂
Department of Internal Medicine and Division of Cardiology, SUNY Upstate Medical University₁ And Veterans Affairs Medical Center, Syracuse, NY₂
Running Title: Renal Nerves and Sodium Excretion in Heart Failure
Correspondence: Daniel Villarreal, MD, FACC, FAHA, FACP Division of Cardiology SUNY Upstate Medical University 750 East Adams Street, Syracuse, NY, 13210, USA Telephone Number: (315)-464-4535 Fax Number: (315) 464-9571 E-mail: [email protected]
1
ABSTRACT The syndrome of heart failure involves complex pathophysiologic mechanisms and is associated with an extremely high morbidity, mortality, and economic costs. This growing global epidemic has diverse etiologies and is fundamentally characterized by dyshomeostasis between heart and kidneys, leading to development and progression of the cardio-renal syndrome. Excessive and sustained sympatho-excitation has emerged as one prominent factor involved in the structural and functional dysfunction of multiple organ systems during this disease. Studies in experimental models of heart failure indicate that ablation of the renal nerves may help restore renal sodium and water equilibrium as well as the attenuation of adverse cardiac remodeling. With the recent development of minimally invasive endovascular renal denervation in humans, it is anticipated that this technology would become a novel and important paradigm shift in the management of heart failure.
Indexing Terms Renal Denervation, Natriuresis, Diuresis, Cardiac Peptides
2
INTRODUCTION
Over the last several decades and into the 21st century, heart failure has become a global epidemic of serious magnitude. In the United States the incidence of cardiac dysfunction accounts for over 800,000 new cases per year, and approximately 6 million Americans suffer from the disease (1). Its morbidity includes 1 million hospitalizations and 3 million office visits annually, and it has become one of the most frequent categories for disease related group admissions in patients older than 65 years of age (1). It causes or contributes to over 300,000 deaths per year and up to 70% of these patients die suddenly (1). From the economic point of view, the cost of this epidemic is over 30 billion dollars and it is anticipated that these expenditures will continue to increase over the next several decades (1). The high morbidity and mortality of this disease is fundamentally related to abnormal activation and synergism of diverse and potent complex pathophysiological mechanisms, including excessive sympatho-excitation, which adversely impact the cardiovascular and renal systems. Herein, this mini-review focuses on the role of the sympathetic nervous system (SNS) in the natural history of heart failure.
The SNS in Heart Failure
In addition to the renin–angiotensin–aldosterone system (RAAS) and other various noxious hormones and cytokines including vasopressin and endothelin, elevated sympathetic drive is increasingly being recognized to play a primary role in the complex pathophysilogy of heart failure and the cardio-renal syndrome (2,3,4,5,6). 3
Excessive and sustained sympatho-excitation can impact cardiovascular function at several organ system levels. In the heart it promotes adverse remodeling leading to hypertrophy, mechanical dysfunction, arrhythmias and ischemia (2,7). In the systemic vasculature it fosters smooth muscle cell migration, vasoconstriction, and atherosclerosis therefore altering systemic and regional hemodynamics (7). At the level of the kidneys progressive cardiac deterioration and sympathetic tone excess leads to increased renal venous congestion as well renal arterial vasoconstriction with a reduction in renal perfusion pressure and renal blood flow, promoting a decrement in glomerular filtration rate and the filtered load of sodium (4,5,8,9,10). Concomitantly, other various SNS mediated salt avid renal mechanisms are activated, including the RAAS, angiotensin II type 1 renal receptor upregulation, and the enhancement of tubular Na⁺ K⁺ 2Cl⁻ co-transporter, all of which, in turn, produce marked sodium and water retention with profound progressive multi- organ congestion and adverse cardio-renal remodeling (4,5,8,11). Important in this pathophysiologic conundrum is the development or renal resistance to the beneficial diuretic and natriuretic actions of the endogenous compensatory cardiac natriuretic peptides, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). In addition to the RAAS and excessive renal sympatho-excitation , other counterregulatory mechanisms contributing to the renal resistance to ANP and BNP are down regulation of natriuretic peptide receptors, increased activity of the neutral endopeptidase EC 24.11 that actively catabolizes the natriuretic peptides, and reduction in renal hemodynamic function (4,5,8) .
4
Effects of Renal Denervation in Experimental Heart Failure To determine the importance of the renal SNS in the natural history of heart failure, Villarreal et al (4) examined the effects of the bilateral renal denervation, or sham denervation, on post-prandial renal sodium excretion in conscious dogs with chronic compensated high-output heart failure produced by a large infra-renal aortocaval fistula (Fig 1,2). After control observations in the post-absorptive state, ingestion of a high salt meal produced a robust two-fold higher level of sodium excretion and the fractional excretion sodium in the renal denervated dogs compared to the sham denervated controls (Fig 1). The plasma levels of ANP, and plasma renin activity (Fig 2), as well as systemic venous and arterial hemodynamics (data not shown), were similar in the two groups of animals, indicating that the enhanced natriuretic effect was primarily related to the ablation of the renal nerves (4). Additional investigations in the same animal model of heart failure demonstrated that chronic renal denervation also was associated with a striking natriuresis and diuresis to the acute infusion of ANP (5), a response that is markedly attenuated in the A-V fistula model of heart failure with intact renal nerves (5). Subsequent studies by Souza et al with renal denervation in the myocardial rat model of heart failure have obtained similar results (6). In their investigation, bilateral renal denervation was associated with a significant higher natriuresis during an intravenous load of sodium compared to the sham denervated rats. Similar to the studies by Villarreal et al, systemic hemodynamics were not different between the two experimental groups (6). These and other information (3,4,5,6) indicate that the renal nerves significantly modulate sodium and water balance in heart failure, and ablation of the efferent and afferent renal nerves facilitates sodium excretion and the actions of both 5
endogenous and exogenous natriuetic and diuretic agents, including the family of cardiac peptides (4,5,8). The effects of renal denervation on cardiac structure and function have not been extensively investigated. However earlier studies in anesthetized pigs with ventricular ischemia have suggested that renal denervation attenuates malignant ventricular arrhythmias (12). Similarly, in rats with heart failure induced by myocardial infarction, chronic renal denervation improved ventricular end-diastolic diameter and fractional shortening (13). These findings indicate a role of the afferent renal nerves in the pathophysologic modulation of excessive systemic sympathetic excitation and therefore suggests that the beneficial effects of renal denervation could be extended beyond the kidneys into the heart as well. In this context, a recent clinical study has reported that bilateral renal denervation in patients with hypertension improved systolic and diastolic function and reduced cardiac mass at 6 months post-denervation (14). These salutary effects occurred whether or not arterial blood pressure was reduced by the renal denervation procedure (14).
Renal Denervation in Clinical Heart Failure Recently, a minimally invasive technique for human renal denervation has been developed (15). Following cannulation of the renal arteries, radiofrequency energy is applied via a specialized catheter throughout the length of vessel allowing thermal heat to penetrate the adventitia and ablate both afferent and efferent renal nerves. The technique is well tolerated without major side effects, but it continues to be refined to maximize its completness and duration. Indeed, this technology was utilized in the SYMPLICITY HTN-3 6
Trial, and it has been suggested that the procedure was unevenly performed across the participating centers due to difference in operator experience which in turn led to inconsistent results on the anticipated reduction of systemic vascular resistance in human hypertension (16). In clinical heart failure however, the small Reach-Pilot non-randomized study has investigated the effects of non-invasive radio-frequency bilateral renal denervation in seven patients with compensated NYHA class III – IV heart failure, with an average left ventricular ejection fraction of 43% and on optimal medical regimen (17). After 6 months of longitudinal observations the procedure was well tolerated and both systolic and diastolic arterial blood pressure, as well as, renal function remained stable and unchanged from pre-denervation levels (17). Moreover, all patients exhibited progressive improvement in exercise tolerance (17). Although sodium and water balance studies were not performed, loop diuretics were reduced or stopped in four out of seven patients (17), suggesting that the procedure may have contributed to the achievement of euvolemia.
Summary and Future Perspectives A major hallmark in the pathophysiology of heart failure is marked sympathoexcitation which contributes to progressive cardio-renal dyshomeostatsis associated with high morbidity and mortality (8). Studies in animal models of heart failure indicate that efferent renal nerve ablation is associated with a significant improvement in renal excretory function as well as an increased response to endogenous and exogenous natriuretic agents (3,4,5,6). Additional research is needed to better characterize the precise pathophysiologic role and impact of renal afferent sympathetic fibers, as well as any 7
possible role of the sparse renal parasympathetic nervous system in the control of renal hemodynamic and excretory function in heart failure. In addition, although initial information suggests that minimally invasive renal denervation is safe and well tolerated in patients with heart failure, it has to be pointed out that the completeness as well as the short and long term efficacy of this procedure in humans is not well established. However, it is anticipated that improvement in the technology of radio frequency ablation, as well as, other experimental modalities such as chemical denervation with micro doses of ethanol injected in the renal adventitia via an intra-renal catheter (18), in the near future may prove compelling modalities in the management of the cardio-renal syndrome during cardiac dysfunction.
8
ACKNOWLEDGEMENT The authors wish to acknowledge the expert technical assistance of Stephanie Harper.
This work was presented, in part, at the SSCI scientific sessions, New Orleans, LA 2016.
Funding This work was supported in part by the Veteran Affairs and Research Program (Merit Review), the American Heart Association, the Joseph C. George Research Award , and the Hendricks Research Award. The authors confirm that the funding agencies had no influence over the study design, content of the article, or selection of this journal.
REFERENCES 1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guidelines for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:e240-e327. 2. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res. 2014;114:1815–26. 3. Dibona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77:75–197. 4. Villarreal D, Freeman RH, Johnson RA, Simmons JC. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol. 1994;26:R1599– 604. 5. Villarreal D, Freeman RH, Johnson RA. Neurohumoral modulators and sodium balance in experimental heart failure. Am J Physiol. 1993;264:H1187–93. 6. Souza DRB, Mill JG, Cabral AM. Chronic experimental myocardial infarction produces antinatriuresis by a renal nerve dependent mechanism. Braz J Biol Res. 2004;73:285–93. 7. Schlaich MP, Sobotka PA, Krum H, et al. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension. 2009 Dec;54(6):1195201.
9
8. Kshatriya S, Kozman H, Siddiqui D, et al. The kidney in heart failure: friend or foe? Am J Med Sci. 2012;344(3):228–32. 9. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol. 2009;53:582–8. 10. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53(7):589–96. 11. Schiller AM, Pellegrino PR, Zucker IH. The renal nerves in chronic heart failure: efferent and afferent mechanisms. Front Physiol. 2015 Aug 7;6:224. 12. Linz D, Wirth K, Ukena C, et al. Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs. Heart Rhythm. 2013 Oct;10(10):1525-30. 13. Nozawa T, Igawa A, Fujii N, et al. Effects of long-term renal sympathetic denervation on heart failure after myocardial infarction in rats. Heart Vessels. 2002 Jan;16(2):51-6. 14. Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012;59:901–9. 15. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81. 16. Bhatt DL, Kandzari DE, O’Neill WW, et al; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–401. 17. Davies JE, Manisty CH, Petraco R, et al. First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol. 2013;162:189–92. 18. Fischell DE, Fischell TA, Ghazarossian V. Peregrime system infusion catheter for perivascular renal denervation. J Med Dev: 2015; (9): 209051-2.
10
FIGURE LEGENDS
Figure 1 Effects of high-sodium meal in dogs with arteriovenous fistula and chronic compensated high-output heart failure. Values are means ± SE n=5 dogs with bilateral; renal denervation (closed bars) and 4 dogs with intact renal nerves (open bars). UNaV, urinary sodium excretion; FENA, fractional excretion of sodium. *P <0.05 between groups. Reproduced with permission from Villarreal D, Freeman RH, Johnson RA, et al. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol. 1994;26:R1599-R1604.
FIGURE LEGENDS Figure 2 Effects of high-sodium meal in dogs with arteriovenous fistula and chronic compensated high-output heart failure. Values are means ± SE n=5 dogs with bilateral; renal denervation (closed bars) and 4 dogs with intact renal nerves (open bars). P[IANF] plasma concentration of atrial natriuretic factor; PRA, plasma rennin activity. *P <0.05 between groups. Reproduced with permission from Villarreal D, Freeman RH, Johnson RA, et al. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol. 1994;26:R1599-R1604.
11
Figure 1
12
Figure 2
13
Pathophysiologic Mechanisms in Heart Failure. Role of the Sympathetic Nervous System Steve Antoine MD, Gaurang Vaidya MD, Haider Imam MD, Daniel Villarreal MD
www.amjmedsci.com
PII: DOI: Reference:
S0002-9629(16)30373-1 http://dx.doi.org/10.1016/j.amjms.2016.06.016 AMJMS233
To appear in:
Am J Med Sci
Received date: 22 June 2016 Accepted date: 24 June 2016 Cite this article as: Steve Antoine MD, Gaurang Vaidya MD, Haider Imam MD, Daniel Villarreal MD, Pathophysiologic Mechanisms in Heart Failure. Role of the Sympathetic Nervous System, Am J Med Sci, http://dx.doi.org/10.1016/j. amjms.2016.06.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pathophysiologic Mechanisms in Heart Failure. Role of the Sympathetic Nervous System Steve Antoine, MD₁ Gaurang Vaidya, MD₁ Haider Imam, MD₁ Daniel Villarreal, MD₁,₂
Department of Internal Medicine and Division of Cardiology, SUNY Upstate Medical University₁ And Veterans Affairs Medical Center, Syracuse, NY₂
Running Title: Renal Nerves and Sodium Excretion in Heart Failure
Correspondence: Daniel Villarreal, MD, FACC, FAHA, FACP Division of Cardiology SUNY Upstate Medical University 750 East Adams Street, Syracuse, NY, 13210, USA Telephone Number: (315)-464-4535 Fax Number: (315) 464-9571 E-mail: [email protected]
1
ABSTRACT The syndrome of heart failure involves complex pathophysiologic mechanisms and is associated with an extremely high morbidity, mortality, and economic costs. This growing global epidemic has diverse etiologies and is fundamentally characterized by dyshomeostasis between heart and kidneys, leading to development and progression of the cardio-renal syndrome. Excessive and sustained sympatho-excitation has emerged as one prominent factor involved in the structural and functional dysfunction of multiple organ systems during this disease. Studies in experimental models of heart failure indicate that ablation of the renal nerves may help restore renal sodium and water equilibrium as well as the attenuation of adverse cardiac remodeling. With the recent development of minimally invasive endovascular renal denervation in humans, it is anticipated that this technology would become a novel and important paradigm shift in the management of heart failure.
Indexing Terms Renal Denervation, Natriuresis, Diuresis, Cardiac Peptides
2
INTRODUCTION
Over the last several decades and into the 21st century, heart failure has become a global epidemic of serious magnitude. In the United States the incidence of cardiac dysfunction accounts for over 800,000 new cases per year, and approximately 6 million Americans suffer from the disease (1). Its morbidity includes 1 million hospitalizations and 3 million office visits annually, and it has become one of the most frequent categories for disease related group admissions in patients older than 65 years of age (1). It causes or contributes to over 300,000 deaths per year and up to 70% of these patients die suddenly (1). From the economic point of view, the cost of this epidemic is over 30 billion dollars and it is anticipated that these expenditures will continue to increase over the next several decades (1). The high morbidity and mortality of this disease is fundamentally related to abnormal activation and synergism of diverse and potent complex pathophysiological mechanisms, including excessive sympatho-excitation, which adversely impact the cardiovascular and renal systems. Herein, this mini-review focuses on the role of the sympathetic nervous system (SNS) in the natural history of heart failure.
The SNS in Heart Failure
In addition to the renin–angiotensin–aldosterone system (RAAS) and other various noxious hormones and cytokines including vasopressin and endothelin, elevated sympathetic drive is increasingly being recognized to play a primary role in the complex pathophysilogy of heart failure and the cardio-renal syndrome (2,3,4,5,6). 3
Excessive and sustained sympatho-excitation can impact cardiovascular function at several organ system levels. In the heart it promotes adverse remodeling leading to hypertrophy, mechanical dysfunction, arrhythmias and ischemia (2,7). In the systemic vasculature it fosters smooth muscle cell migration, vasoconstriction, and atherosclerosis therefore altering systemic and regional hemodynamics (7). At the level of the kidneys progressive cardiac deterioration and sympathetic tone excess leads to increased renal venous congestion as well renal arterial vasoconstriction with a reduction in renal perfusion pressure and renal blood flow, promoting a decrement in glomerular filtration rate and the filtered load of sodium (4,5,8,9,10). Concomitantly, other various SNS mediated salt avid renal mechanisms are activated, including the RAAS, angiotensin II type 1 renal receptor upregulation, and the enhancement of tubular Na⁺ K⁺ 2Cl⁻ co-transporter, all of which, in turn, produce marked sodium and water retention with profound progressive multi- organ congestion and adverse cardio-renal remodeling (4,5,8,11). Important in this pathophysiologic conundrum is the development or renal resistance to the beneficial diuretic and natriuretic actions of the endogenous compensatory cardiac natriuretic peptides, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). In addition to the RAAS and excessive renal sympatho-excitation , other counterregulatory mechanisms contributing to the renal resistance to ANP and BNP are down regulation of natriuretic peptide receptors, increased activity of the neutral endopeptidase EC 24.11 that actively catabolizes the natriuretic peptides, and reduction in renal hemodynamic function (4,5,8) .
4
Effects of Renal Denervation in Experimental Heart Failure To determine the importance of the renal SNS in the natural history of heart failure, Villarreal et al (4) examined the effects of the bilateral renal denervation, or sham denervation, on post-prandial renal sodium excretion in conscious dogs with chronic compensated high-output heart failure produced by a large infra-renal aortocaval fistula (Fig 1,2). After control observations in the post-absorptive state, ingestion of a high salt meal produced a robust two-fold higher level of sodium excretion and the fractional excretion sodium in the renal denervated dogs compared to the sham denervated controls (Fig 1). The plasma levels of ANP, and plasma renin activity (Fig 2), as well as systemic venous and arterial hemodynamics (data not shown), were similar in the two groups of animals, indicating that the enhanced natriuretic effect was primarily related to the ablation of the renal nerves (4). Additional investigations in the same animal model of heart failure demonstrated that chronic renal denervation also was associated with a striking natriuresis and diuresis to the acute infusion of ANP (5), a response that is markedly attenuated in the A-V fistula model of heart failure with intact renal nerves (5). Subsequent studies by Souza et al with renal denervation in the myocardial rat model of heart failure have obtained similar results (6). In their investigation, bilateral renal denervation was associated with a significant higher natriuresis during an intravenous load of sodium compared to the sham denervated rats. Similar to the studies by Villarreal et al, systemic hemodynamics were not different between the two experimental groups (6). These and other information (3,4,5,6) indicate that the renal nerves significantly modulate sodium and water balance in heart failure, and ablation of the efferent and afferent renal nerves facilitates sodium excretion and the actions of both 5
endogenous and exogenous natriuetic and diuretic agents, including the family of cardiac peptides (4,5,8). The effects of renal denervation on cardiac structure and function have not been extensively investigated. However earlier studies in anesthetized pigs with ventricular ischemia have suggested that renal denervation attenuates malignant ventricular arrhythmias (12). Similarly, in rats with heart failure induced by myocardial infarction, chronic renal denervation improved ventricular end-diastolic diameter and fractional shortening (13). These findings indicate a role of the afferent renal nerves in the pathophysologic modulation of excessive systemic sympathetic excitation and therefore suggests that the beneficial effects of renal denervation could be extended beyond the kidneys into the heart as well. In this context, a recent clinical study has reported that bilateral renal denervation in patients with hypertension improved systolic and diastolic function and reduced cardiac mass at 6 months post-denervation (14). These salutary effects occurred whether or not arterial blood pressure was reduced by the renal denervation procedure (14).
Renal Denervation in Clinical Heart Failure Recently, a minimally invasive technique for human renal denervation has been developed (15). Following cannulation of the renal arteries, radiofrequency energy is applied via a specialized catheter throughout the length of vessel allowing thermal heat to penetrate the adventitia and ablate both afferent and efferent renal nerves. The technique is well tolerated without major side effects, but it continues to be refined to maximize its completness and duration. Indeed, this technology was utilized in the SYMPLICITY HTN-3 6
Trial, and it has been suggested that the procedure was unevenly performed across the participating centers due to difference in operator experience which in turn led to inconsistent results on the anticipated reduction of systemic vascular resistance in human hypertension (16). In clinical heart failure however, the small Reach-Pilot non-randomized study has investigated the effects of non-invasive radio-frequency bilateral renal denervation in seven patients with compensated NYHA class III – IV heart failure, with an average left ventricular ejection fraction of 43% and on optimal medical regimen (17). After 6 months of longitudinal observations the procedure was well tolerated and both systolic and diastolic arterial blood pressure, as well as, renal function remained stable and unchanged from pre-denervation levels (17). Moreover, all patients exhibited progressive improvement in exercise tolerance (17). Although sodium and water balance studies were not performed, loop diuretics were reduced or stopped in four out of seven patients (17), suggesting that the procedure may have contributed to the achievement of euvolemia.
Summary and Future Perspectives A major hallmark in the pathophysiology of heart failure is marked sympathoexcitation which contributes to progressive cardio-renal dyshomeostatsis associated with high morbidity and mortality (8). Studies in animal models of heart failure indicate that efferent renal nerve ablation is associated with a significant improvement in renal excretory function as well as an increased response to endogenous and exogenous natriuretic agents (3,4,5,6). Additional research is needed to better characterize the precise pathophysiologic role and impact of renal afferent sympathetic fibers, as well as any 7
possible role of the sparse renal parasympathetic nervous system in the control of renal hemodynamic and excretory function in heart failure. In addition, although initial information suggests that minimally invasive renal denervation is safe and well tolerated in patients with heart failure, it has to be pointed out that the completeness as well as the short and long term efficacy of this procedure in humans is not well established. However, it is anticipated that improvement in the technology of radio frequency ablation, as well as, other experimental modalities such as chemical denervation with micro doses of ethanol injected in the renal adventitia via an intra-renal catheter (18), in the near future may prove compelling modalities in the management of the cardio-renal syndrome during cardiac dysfunction.
8
ACKNOWLEDGEMENT The authors wish to acknowledge the expert technical assistance of Stephanie Harper.
This work was presented, in part, at the SSCI scientific sessions, New Orleans, LA 2016.
Funding This work was supported in part by the Veteran Affairs and Research Program (Merit Review), the American Heart Association, the Joseph C. George Research Award , and the Hendricks Research Award. The authors confirm that the funding agencies had no influence over the study design, content of the article, or selection of this journal.
REFERENCES 1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guidelines for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:e240-e327. 2. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res. 2014;114:1815–26. 3. Dibona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77:75–197. 4. Villarreal D, Freeman RH, Johnson RA, Simmons JC. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol. 1994;26:R1599– 604. 5. Villarreal D, Freeman RH, Johnson RA. Neurohumoral modulators and sodium balance in experimental heart failure. Am J Physiol. 1993;264:H1187–93. 6. Souza DRB, Mill JG, Cabral AM. Chronic experimental myocardial infarction produces antinatriuresis by a renal nerve dependent mechanism. Braz J Biol Res. 2004;73:285–93. 7. Schlaich MP, Sobotka PA, Krum H, et al. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension. 2009 Dec;54(6):1195201.
9
8. Kshatriya S, Kozman H, Siddiqui D, et al. The kidney in heart failure: friend or foe? Am J Med Sci. 2012;344(3):228–32. 9. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol. 2009;53:582–8. 10. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53(7):589–96. 11. Schiller AM, Pellegrino PR, Zucker IH. The renal nerves in chronic heart failure: efferent and afferent mechanisms. Front Physiol. 2015 Aug 7;6:224. 12. Linz D, Wirth K, Ukena C, et al. Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs. Heart Rhythm. 2013 Oct;10(10):1525-30. 13. Nozawa T, Igawa A, Fujii N, et al. Effects of long-term renal sympathetic denervation on heart failure after myocardial infarction in rats. Heart Vessels. 2002 Jan;16(2):51-6. 14. Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012;59:901–9. 15. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81. 16. Bhatt DL, Kandzari DE, O’Neill WW, et al; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–401. 17. Davies JE, Manisty CH, Petraco R, et al. First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol. 2013;162:189–92. 18. Fischell DE, Fischell TA, Ghazarossian V. Peregrime system infusion catheter for perivascular renal denervation. J Med Dev: 2015; (9): 209051-2.
10
FIGURE LEGENDS
Figure 1 Effects of high-sodium meal in dogs with arteriovenous fistula and chronic compensated high-output heart failure. Values are means ± SE n=5 dogs with bilateral; renal denervation (closed bars) and 4 dogs with intact renal nerves (open bars). UNaV, urinary sodium excretion; FENA, fractional excretion of sodium. *P <0.05 between groups. Reproduced with permission from Villarreal D, Freeman RH, Johnson RA, et al. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol. 1994;26:R1599-R1604.
FIGURE LEGENDS Figure 2 Effects of high-sodium meal in dogs with arteriovenous fistula and chronic compensated high-output heart failure. Values are means ± SE n=5 dogs with bilateral; renal denervation (closed bars) and 4 dogs with intact renal nerves (open bars). P[IANF] plasma concentration of atrial natriuretic factor; PRA, plasma rennin activity. *P <0.05 between groups. Reproduced with permission from Villarreal D, Freeman RH, Johnson RA, et al. Effects of renal denervation on postprandial sodium excretion in experimental heart failure. Am J Physiol. 1994;26:R1599-R1604.
11
Figure 1
12
Figure 2
13