(BQ) Part 2 book Heart failure management the neural pathways presents the following contents: The autonomic cardiorenal crosstalk - pathophysiology and implications for heart failure management, barorefl ex activation therapy in heart failure, renal refl exes and denervation in heart failure, back to the future,...
Part III Modulation of Autonomic Function in Heart Failure The Autonomic Cardiorenal Crosstalk: Pathophysiology and Implications for Heart Failure Management 10 Maria Rosa Costanzo and Edoardo Gronda 10.1 Introduction The autonomic nervous system (ANS), which comprises the sympathetic and parasympathetic branches, has numerous essential physiologic functions, including modulation of blood pressure, heart rate, and body fluid volume [1] It is now recognized that the ANS is organized to elicit organ-specific responses to maintain homeostasis in the face of external challenges [2] An example of the differential organ effects of the ANS is the coordinated response to increase sodium concentration aimed at restoring normal plasma sodium concentration and volume This process is especially relevant to the normal interactions between heart and kidney and to the understanding of their dysregulation in the settings of hypertension, heart failure (HF), and the cardiorenal syndrome (CRS) (Fig. 10.1) Experiments in conscious sheep have shown that increases in brain sodium concentration simultaneously augment cardiac sympathetic nerve activity (SNA) and arterial pressure and reduce renal SNA, promoting reduced renin secretion, renal vasodilatation, and renal sodium excretion [1] Thus, inhibition of renal SNA is the logical homeostatic response to a sodium load, aimed at restoring normal plasma volume and sodium concentration These organ-specific effects are mediated via a neural pathway that includes an angiotensinergic synapse, the lamina terminalis, and the paraventricular nucleus of the hypothalamus [3, 4] In contrast to normal conditions, in experimental animal models of HF induced by rapid pacing, the M.R Costanzo, MD, FACC, FAHA (*) Medical Director, Midwest Heart Specialists-Advocate Medical Group Heart Failure and Pulmonary Arterial Hypertension Programs, Medical Director, Edward Hospital Center for Advanced Heart Failure Edward Heart Hospital, Naperville, Illinois 60566, USA e-mail: Mariarosa.costanzo@advocatehealth.com E Gronda, MD Cardiology and Heart Failure Research Unit, IRCCS MultiMedica - Sesto San Giovanni, Milan, Italy e-mail: edoardo.gronda@multimedica.it © Springer International Publishing Switzerland 2016 E Gronda et al (eds.), Heart Failure Management: The Neural Pathways, DOI 10.1007/978-3-319-24993-3_10 131 132 M.R Costanzo and E Gronda Fig 10.1 Organization of the autonomic nervous system demonstrating the key interactions involving the brain, heart, and kidney SA sino-atrial node (Reproduced with permission from Singh et al [159]) cardiac and renal SNA activities increased to similar, almost maximal levels and the response of cardiac SNA to changes in blood volume was significantly attenuated [1, 5] These data confirm many previous observations that in HF, a decreased arterial pressure reduces baroreflex inhibition of SNA, which, together with the lack of an inhibitory response to the increased volume and cardiac pressures, contributes to the heightened sympathetic activity typical of HF [1] Excessive sympathetic drive is undoubtedly a major contributing factor to the pathogenesis of hypertension and to the progression of HF. Importantly, much of the excessive SNA in these conditions targets the kidney, where it leads to inappropriate sodium retention and renin stimulation and diminished renal function In addition, the kidney itself is a source of increased SNA by way of the renal somatic afferent nerves Therefore, in both hypertension and HF, the kidney is both the target and contributor to increased SNA [6] 10.2 Measurements of Autonomic Nervous System Activity One important challenge to the understanding of the bidirectional autonomic interactions between the heart and the kidney is the ability to quantify individual regional SNA activity For this purpose, sympathetic nerve recording techniques and radiotracer-derived measurements of norepinephrine (NE) spillover into the plasma from individual organs have been used The limitations of each technique have led 10 The Autonomic Cardiorenal Crosstalk 133 to the recommendation that they be used together [7] Microneurography provides instantaneous multiunit or single-fiber recordings of electrical transmission in sympathetic nerves, but assessment may be skewed by interpreter’s bias [8, 9] The NE spillover method provides objective information on the release of this neurotransmitter from internal organs where microneurography is not feasible [10–12] During infusion of titrated NE at a constant rate, output of endogenous NE from a given organ (NE “spillover”) can be measured by isotope dilution according to the formula: Regional norepinephrine spillover = ( CV − CA ) + CA E PF where CV and CA are the plasma concentrations of NE in the organ’s venous and arterial plasma, E is the fractional extraction of titrated NE while the blood is flowing through the organ, and PF is the organ plasma flow [7] Computer analysis of heart rate variability (HRV) predominantly reflects selective autonomic control of the heart Vagal and sympathetic cardiac influences operate on the heart rate in different frequency bands While vagal regulation has a relatively high cutoff frequency, modulating heart rate both at low and high frequencies (up to 1.0 Hz), sympathetic cardiac control operates only at 71 b.p.m., by b.p.m., in patients with hypertension This mechanism might also be effective in heart failure because selective heart rate reduction provides a better arterioventricular coupling and unloading of the failing heart and is associated with an improved collateral growth and an improved vascular stiffness in a model of diastolic heart failure Since the majority of the patients might be on treatment with beta-blockers as recommended by the guidelines, not all patients will be above the critical heart rate threshold Thus, heart rate reduction might apply only for a part of the heart failure population [33] 13.6 Perspectives Chronic systolic heart failure is characterised by overactivity of sympathetic pathways, which contributes to a detrimental triad of arterial vasoconstriction, increased chronotropic and inotropic stimulus and enhanced salt and water reabsorption [34] Renal sympathetic denervation has the potential to positively influence the course and outcome in chronic heart failure The first proof-of-concept trials in HFREF and HFPEF have been initiated to verify improvement of exercise tolerance and safety and also to provide data on the biological plausibility with marker studies Furthermore, several subanalyses from these trials will address the question of whether co-morbidities such as renal dysfunction, arrhythmias or metabolic disease can be favourably influenced It is fundamental to continue with further appropriately designed renal denervation trials to identify markers for the confirmation that the renal sympathetic denervation clearly occurred and was effective exists The renal denervation procedure may be technically easy; however, it is becoming more obvious that the importance of the complex underlying anatomy and physiology as well as the biophysics of radiofrequency lesion formation has been widely underestimated Investigators and device manufactures should be stimulated to perform rigorous preclinical and clinical studies to resolve essential unanswered questions If long-term follow-up shows that renal denervation might determine measurable benefits in terms of harder end points of morbidity and mortality, this new approach could have the potential to become a strong candidate for representing a new devicebased standard of care in heart failure 212 F Pieruzzi References Kaplan NM Resistant hypertension J Hypertens 2005;23:1441–4 Patel HC, Rosen SD, Lindsay A, Hayward C, Lyon AR, di Mario C Targeting the autonomic nervous system: measuring autonomic function and novel devices for heart failure management Int J Cardiol 2013;170(2):107–17 doi:10.1016/j.ijcard.2013.10.058 Epub 2013 Oct 25 Shen MJ, Zipes DP Interventional and device-based autonomic modulation in heart failure Heart Fail Clin 2015;11(2):337–48 doi:10.1016/j.hfc.2014.12.010 Epub 2015 Feb 17 Floras JS Sympathetic nervous system activation in human heart failure: clinical implications of an updated model J Am Coll Cardiol 2009;54:375–85 Eppel GA, Luff SE, Denton KM, Evans RG Type neuropeptide Y receptors and alpha1adrenoceptors in the neural control of regional renal perfusion Am J Physiol 2006;290:R331–40 DiBona GF, Kopp UC Neural control of renal function Physiol Rev 1997;77:75–197 Genovesi S, Pieruzzi F, Camisasca P, Golin R, Zanchetti A, Stella A Renal afferents responsive to chemical and mechanical pelvic stimuli in the rabbit Clin Sci (Lond) 1997;92(5):505–10 Stella A, Zanchetti A Functional role of renal afferents Physiol Rev 1991;71(3):659–82 Kopp UC Role of renal sensory nerves in physiological and pathophysiological conditions Am J Physiol Regul Integr Comp Physiol 2015;308(2):R79–95 doi:10.1152/ajpregu.00351.2014 Epub 2014 Nov 19 10 Kline RL, Mercer PF Functional reinnervation and development of supersensitivity to NE after renal denervation in rats Am J Physiol 1980;238:R353–8 11 Ramchandra R, Hood SG, Denton DA, Woods RL, McKinley MJ, McAllen RM, May CN Basis for the preferential activation of cardiac sympathetic nerve activity in heart failure Proc Natl Acad Sci U S A 2009;106:924–8 12 Villarreal D, Freeman RH, Johnson RA, Simmons JC Effects of renal denervation on postprandial sodium excretion in experimental heart failure Am J Physiol 1994;266:R1599–604 13 Schrier RW Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (1) N Engl J Med 1988;319:1065–72 14 Galiwango PJ, McReynolds A, Ivano J, Chan CT, Floras JS Activity with ambulation attenuates diuretic responsiveness in chronic heart failure J Card Fail 2011;17:797–803 15 Francis GS, Benedict C, Johnstone DE, et al Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure A substudy of the Studies of Left Ventricular Dysfunction (SOLVD) Circulation 1990;82:1724–9 16 Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, Dietl KH, Rahn KH Sympathetic nerve activity in end-stage renal disease Circulation 2002;106:1974–9 17 Smithwick RH, Thompson JE Splanchnicectomy for essential hypertension: results in 1,266 cases JAMA 1953;152:1501–4 18 Morrissey DM, Brookes VS, Cooke WT Sympathectomy in the treatment of hypertension; review of 122 cases Lancet 1953;1:403–8 19 Krum H, Schlaich M, Sobotka P, Scheffers I, Kroon AA, de Leeuw PW Novel procedure and device-based strategies in the management of systemic hypertension Eur Heart J 2011;32(5):537–44 doi:10.1093/eurheartj/ehq457 Epub 2011 Jan 18 20 Sobotka PA, Krum H, Böhm M, Francis DP, Schlaich MP The role of renal denervation in the treatment of heart failure Curr Cardiol Rep 2012;14(3):285–92 doi:10.1007/ s11886-012-0258-x 21 Schlaich MP, Sobotka PA, Krum H, Lambert EA, Esler MD Renal sympathetic nerve ablation for the treatment of uncontrolled hypertension N Engl J Med 2009;361:932–4 22 Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study Lancet 2009;373:1275–81 13 Renal Reflexes and Denervation in Heart Failure 213 23 Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial Lancet 2010;376:1903–9 24 Symplicity HTN-1 Investigators Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months Hypertension 2011;57:911–7 25 Schirmer SH, Sayed M, Reil JC, Ukena C, Linz D, Kindermann M, Laufs U, Mahfoud F, Böhm M Improvements of left-ventricular hypertrophy and diastolic function following renal denervation—effects beyond blood pressure and heart rate reduction J Am Coll Cardiol 2014 doi:10.1016/j.jacc.2013.10.073 26 Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity Circulation 1986;73:615–21 27 Ahmed H, Miller MA, Dukkipati SR, Cammack S, Koruth JS, Gangireddy S, Ellsworth BA, D’Avila A, Domanski M, Gelijns AC, Moskowitz A, Reddy VY Adjunctive renal sympathetic denervation to modify hypertension as upstream therapy in the treatment of atrial fibrillation (H-FIB) study: clinical background and study design J Cardiovasc Electrophysiol 2013;24(5):503–9 doi:10.1111/jce.12095 Epub 2013 Feb 19 28 Nozawa T, Igawa A, Fujii N, Kato B, Yoshida N, Asanoi H, Inoue H Effects of long-term renal sympathetic denervation on heart failure after myocardial infarction in rats Heart Vessels 2002;16:51–6 29 Souza DR, Mill JG, Cabral AM Chronic experimental myocardial infarction produces antinatriuresis by a renal nerve-dependent mechanism Braz J Med Biol Res 2004;37:285–93 30 Davies JE, Manisty CH, Petraco R, Barron AJ, Unsworth B, Mayet J, Hamady M, Hughes AD, Sever PS, Sobotka PA, Francis DP 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 31 Böhm M, Ewen S, Kindermann I, Linz D, Ukena C, Mahfoud F Renal denervation and heart failure Eur J Heart Fail 2014;16:608–13 doi:10.1002/ejhf.83 32 Napoli C, Casamassimi A, Crudele V, Infante T, Abbondanza C Kidney and heart interactions during cardiorenal syndrome: a molecular and clinical pathogenic framework Future Cardiol 2011;7:485–97 33 Ukena C, Mahfoud F, Spies A, Kindermann I, Linz D, Cremers B, Laufs U, Neuberger HR, Böhm M Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension Int J Cardiol 2013;167:2846–51 34 Fong MW, Shavelle D, Weaver FA, Nadim MK Renal denervation in heart failure Curr Hypertens Rep 2015;17(3):17 doi:10.1007/s11906-014-0528-7 Back to the Future 14 Emilio Vanoli and Edoardo Gronda To Donatella (1958–2010) If you have made it here by skipping the entire book, to read just the end of it, well, our suggestion is to give it a try from the beginning and you may find good reasons to justify yourself for the time spent on these pages If you have gotten here after reading through it, we hope you enjoyed this book How many times did we hear: back to the future? Many times, probably, and the fortune of that great movie will never fade away Here, once more, the same common recall of a great hit? Well, try to think about reading great science of the 1950s through the 1970s telling us how much damage would an uncontrolled sympathetic activation to a wounded heart Back to the future now, we wonder how much benefit can be given to the heart controlling such outrage Back to the future because after so many years of misunderstanding that hampered the development of dedicated research to integrated physiology, we are now using a more comprehensive approach, yet far from being satisfactory, to the autonomic nervous system This book speaks of symphony orchestra, harmony, and serenades, but when harmony is broken and it is replaced by restless hyperactivity, swelling, and pain, then failure is about to come The key word is indeed ANS activation, which is not the consequence but, mostly, the cause of left ventricle dysfunction evolving towards heart failure This is because an unrestrained acceleration is the killer of any engine, even the most sophisticated ones, like the human heart and the cardiovascular system The burden E Vanoli Department of Molecular Medicine, University of Pavia, Pavia, Italy IRCCS MultiMedica, Sestso S Giovanni, Italy E Gronda (*) Cardiology and Heart Failure Research Unit, IRCCS MultiMedica - Sesto San Giovanni, Milan, Italy e-mail: edoardo.gronda@multimedica.it © Springer International Publishing Switzerland 2016 E Gronda et al (eds.), Heart Failure Management: The Neural Pathways, DOI 10.1007/978-3-319-24993-3_14 215 216 E Vanoli and E Gronda of the failing and dying heart triggers a genetic remodeling, which prompts cardiac cells to express new proteins with diuretic and vasodilating actions or to remodel contractile proteins However, if we lose the capability to control the drive, then the horse race can only have a fatal end There are now new molecules able to modulate the effects of endogenous diuretics/vasodilators, namely, brain natriuretic peptides, and new devices are now able to modulate the neural traffic to the two major players of the game: the heart and the kidneys This while the central nervous system is standing by, expecting to see its needs of oxygen fulfilled This is a book we all (editors and authors) are proud of, and we sincerely hope that it will bring a small but strong contribution to a novel thinking of heart failure and the autonomic nervous system ... MP. The role of renal denervation in the treatment of heart failure Curr Cardiol Rep 20 12; 14 :28 5– 92 Parati G, Esler M. The human sympathetic nervous system: its relevance in hypertension and heart. .. systolic heart failure population Eur J Heart Fail 20 10; 12: 861–5 80 Cruz DN, Bagshaw SM. Heart- kidney interaction: epidemiology of cardiorenal syndromes Int J Nephrol 20 10 ;20 11:35 129 1 doi:10.4061 /20 11/35 129 1... (eds.), Heart Failure Management: The Neural Pathways, DOI 10.1007/978-3-319 -24 993-3_10 131 1 32 M.R Costanzo and E Gronda Fig 10.1 Organization of the autonomic nervous system demonstrating the