Cardiac Autonomic Nerve Stimulation in the Treatment of Heart Failure
2013; Elsevier BV; Volume: 96; Issue: 1 Linguagem: Inglês
10.1016/j.athoracsur.2012.12.060
ISSN1552-6259
AutoresMariko Kobayashi, Alex Massiello, Jamshid H. Karimov, David R. Van Wagoner, Kiyotaka Fukamachi,
Tópico(s)Heart rate and cardiovascular health
ResumoResearch on the therapeutic modulation of cardiac autonomic tone by electrical stimulation has yielded encouraging early clinical results. Vagus nerve stimulation has reduced the rates of morbidity and sudden death from heart failure, but therapeutic vagus nerve stimulation is limited by side effects of hypotension and bradycardia. Sympathetic nerve stimulation that has been implemented in the experiment may exacerbate the sympathetic-dominated autonomic imbalance. In contrast, concurrent stimulation of both sympathetic and parasympathetic cardiac nerves increases myocardial contractility without increasing heart rate. This review assesses the current state of electrical stimulation of the cardiac autonomic nervous system to treat heart failure. Research on the therapeutic modulation of cardiac autonomic tone by electrical stimulation has yielded encouraging early clinical results. Vagus nerve stimulation has reduced the rates of morbidity and sudden death from heart failure, but therapeutic vagus nerve stimulation is limited by side effects of hypotension and bradycardia. Sympathetic nerve stimulation that has been implemented in the experiment may exacerbate the sympathetic-dominated autonomic imbalance. In contrast, concurrent stimulation of both sympathetic and parasympathetic cardiac nerves increases myocardial contractility without increasing heart rate. This review assesses the current state of electrical stimulation of the cardiac autonomic nervous system to treat heart failure. Heart disease is the leading cause of death worldwide [1Gaziano T.A. Gaziano J.M. Global burden of cardiovascular disease.in: Bonow R.O. Mann D.L. Zipes D.P. Libby P. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Saunders/Elsevier Inc, Philadelphia, Pennsylvania2012http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-1-4377-0398-6..00001-9&isbn=978-1-4377-0398-6&uniqId=364060231-4#4-u1.0-B978-1-4377-0398-6..00001-9Google Scholar]. Progress in developing pharmacologic therapies, interventional and surgical cardiovascular procedures, heart transplants, and mechanical circulatory support devices to treat heart failure (HF) has slowed the increase in HF-associated mortality. In spite of this improvement, aging of the population has led to a steadily increasing incidence of HF in the United States [2Hunt S.A. Abraham W.T. Chin M.H. et al.2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation.J Am Coll Cardiol. 2009; 53: e1-e90Abstract Full Text Full Text PDF PubMed Scopus (1344) Google Scholar]. Currently available HF therapies have limited efficacy. Thus, innovative therapies are needed to reduce the incidence of the costly morbidity and devastating mortality associated with HF. HF pathophysiology is associated with neurohormonal activation of the sympathetic nervous and renin-angiotensin systems, resulting in increased plasma levels of norepinephrine (NE), angiotensin II, and endothelin-1. In addition, plasma levels of inflammatory biomarkers and cytokines increase (eg., tumor necrosis factor-α and C-reactive protein), as do markers of systemic and cardiac oxidant stress [3Van Wagoner D.R. Chronic vagal nerve stimulation for the treatment of human heart failure: progress in translating a vision into reality.Eur Heart J. 2011; 32: 788-790Crossref PubMed Scopus (9) Google Scholar]. The sympathetic and parasympathetic autonomic nervous systems exert opposing influences on cardiac function; thus, addressing the imbalance is crucial in finding effective new modes of intervention. To address these factors, a number of efforts in translational research are being made to evaluate the therapeutic potential of modulating cardiac function by stimulating cardiac autonomic nerves [4Schwartz P.J. De Ferrari G.M. Sanzo A. et al.Long term vagal stimulation in patients with advanced heart failure: first experience in man.Eur J Heart Fail. 2008; 10: 884-891Crossref PubMed Scopus (237) Google Scholar, 5Zhang Y. Popovic Z.B. Bibevski S. et al.Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model.Circ Heart Fail. 2009; 2: 692-699Crossref PubMed Scopus (271) Google Scholar, 6Meyer C. Rana O.R. Saygili E. et al.Augmentation of left ventricular contractility by cardiac sympathetic neural stimulation.Circulation. 2010; 121: 1286-1294Crossref PubMed Scopus (47) Google Scholar, 7Zarse M. Plisiene J. Mischke K. et al.Selective increase of cardiac neuronal sympathetic tone: a catheter-based access to modulate left ventricular contractility.J Am Coll Cardiol. 2005; 46: 1354-1359Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. Use of vagus nerve stimulation (VNS) as a medical therapy to counter sympathetic nervous system activation in HF has yielded encouraging results [8Levy M.N. Sympathetic-parasympathetic interactions in the heart.Circ Res. 1971; 29: 437-445Crossref PubMed Scopus (578) Google Scholar, 9Hauptman P.J. Mann D.L. The vagus nerve and autonomic imbalance in heart failure: past, present, and future.Heart Fail Rev. 2011; 16: 97-99Crossref PubMed Scopus (11) Google Scholar, 10Upton A.R. White A.M. Autonomic stimulation.Pacing Clin Electrophysiol. 1991; 14: 50-69Crossref PubMed Scopus (17) Google Scholar, 11Lopshire J.C. Zipes D.P. Device therapy to modulate the autonomic nervous system to treat heart failure.Curr Cardiol Rep. 2012; 14: 593-600Crossref PubMed Scopus (19) Google Scholar, 12Kishi T. Heart failure as an autonomic nervous system dysfunction.J Cardiol. 2012; 59: 117-122Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar]. In both animal and early clinical studies, it is clear that optimal cardiac neurostimulation therapy varies, based on the type and severity of HF and on the individual balance of sympathetic and parasympathetic autonomic activity. This article reviews cardiac innervation and sympathovagal cardiac autonomic imbalance in chronic HF and highlights the state of the art with regard to the use of electrical stimulation of the cardiac autonomic nervous system as a treatment for both chronic and acute HF. Efforts to use vagal and sympathetic cardiac nerve stimulation, as well as new results from concomitant stimulation of both sympathetic and parasympathetic cardiac nerves at the cardiac plexus, are summarized. We focus on the impact of these therapies on cardiac function and cardiovascular physiology and compare and contrast these with conventional HF treatment algorithms. Cardiac autonomic innervation originates from the central nervous system as parasympathetic preganglionic nerve fibers from the vagus nerve (10th cranial nerve) and from sympathetic preganglionic nerves originating from the spinal cord. Vagal preganglionic fibers travel directly to an array of ganglia located on the epicardium. Sympathetic preganglionic nerves communicate with sympathetic paravertebral and prevertebral ganglia located close to the spinal cord. Sympathetic postganglionic peripheral nerves then travel to the heart (Fig 1). Cardiac autonomic nerves are concentrated in the cardiac plexus, a network of autonomic nerves formed by postganglionic sympathetic nerve fibers from the cervical and thoracic ganglion and preganglionic parasympathetic branches from the vagus nerves, parasympathetic ganglion, and parasympathetic postganglionic fibers. The cardiac plexus is embedded in the adventitia of the great vessels, in the concavity of the aortic arch, in front of the right pulmonary artery and of the bifurcation of the trachea, above the point of division of the pulmonary artery, and behind the aortic arch. Sympathetic postganglionic nerves that are extensions of the cardiac plexus run along the coronary arteries (coronary plexus). Intrinsic cardiac neurons are present throughout the atria (especially in the sinoatrial node) and ventricles, including the conduction system of the heart. A second important pathway modulating cardiac activity by sympathetic innervation is the sympatho-adrenal response, by which the secretion of catecholamines (adrenaline and NE) into the bloodstream is the result of activation of preganglionic sympathetic fibers innervating the adrenal medulla. This response results in a strong positive inotropic effect on the heart (β1 adrenergic agonist) accompanied by peripheral vasodilation in the skeletal muscle vasculature at low blood levels (β2-adrenergic dominant), with generalized peripheral vasoconstriction at higher levels (α-adrenergic dominant). Cardiac neurons interact through a number of synaptic mechanisms to influence heart rate (HR), ventricular function, and secretion of natriuretic peptides [13Zamotrinsky A.V. Kondratiev B. de Jong J.W. Vagal neurostimulation in patients with coronary artery disease.Auton Neurosci. 2001; 88: 109-116Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. The primary sympathetic neurotransmitter (NE) produces an increase in HR, myocardial conduction velocity, and contractility. Conversely, the parasympathetic neurotransmitter acetylcholine (ACh) reduces HR. From the perspective of cardiac function, sympathetic stimulation increases cardiac output, myocardial work, and myocardial oxygen consumption (MVo2), whereas parasympathetic stimulation increases cardiac efficiency by slowing HR to take advantage of preload effects, decreases MVo2, and increases coronary diastolic perfusion times with a much less significant effect on cardiac output. In canine studies using concurrent sympathetic and parasympathetic cardiac nerve stimulation, Levy [8Levy M.N. Sympathetic-parasympathetic interactions in the heart.Circ Res. 1971; 29: 437-445Crossref PubMed Scopus (578) Google Scholar] and Levy and Zieske [14Levy M.N. Zieske H. Autonomic control of cardiac pacemaker activity and atrioventricular transmission.J Appl Physiol. 1969; 27: 465-470PubMed Google Scholar] concluded that vagal effects on HR predominate over sympathetic effects, showing that the positive chronotropic effects produced by strong sympathetic stimulation can be inhibited by relatively weak vagal stimulation. This observation was later supported in studies by Brack and colleagues [15Brack K.E. Coote J.H. Ng G.A. Interaction between direct sympathetic and vagus nerve stimulation on heart rate in the isolated rabbit heart.Exp Physiol. 2004; 89: 128-139Crossref PubMed Scopus (44) Google Scholar]. Cardiac autonomic control requires a dynamic balance of sympathetic and parasympathetic tone. Baseline cardiac sympathetic tone is adjusted in response to inputs from cardiopulmonary receptors, arterial baroreceptors, and afferent central nervous system chemoreceptors. Adjustments are immediate in response to changes in blood pressure. However, they occur over minutes in response to changes in blood volume as cardiac sympathetic nerve activity increases with increased blood volume and occur chronically in response to stress, alterations in hormonal levels, or chronic stimuli (eg, obesity, hypertension, and persistent HF) [16Malpas S.C. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease.Physiol Rev. 2010; 90: 513-557Crossref PubMed Scopus (463) Google Scholar]. These chronic factors are additive with respect to their effects on plasma NE and sympathetic nerve activity [17Grassi G. Seravalle G. Quarti-Trevano F. Dell'Oro R. Bolla G. Mancia G. Effects of hypertension and obesity on the sympathetic activation of heart failure patients.Hypertension. 2003; 42: 873-877Crossref PubMed Scopus (83) Google Scholar]. Parasympathetic (vagal) tone may protect cardiac function by decreasing HR and mitigating sympathetic arousal [18Porges S.W. Vagal tone: a physiologic marker of stress vulnerability.Pediatrics. 1992; 90: 498-504PubMed Google Scholar]. As stated above, the sympathetic and parasympathetic autonomic systems affect cardiac function differently, but they also have direct inhibitory effects on each other at the neurotransmitter level. The NE release from sympathetic nerve terminals inhibits ACh release from neighboring vagal fibers, whereas ACh can prevent the release of NE [8Levy M.N. Sympathetic-parasympathetic interactions in the heart.Circ Res. 1971; 29: 437-445Crossref PubMed Scopus (578) Google Scholar, 19Grodner A.S. Lahrtz H.S. Pool P.E. Braunwald E. Neurotransmitter control of sinoatrial pacemaker frequency in isolated rat atria and in intact rabbits.Circ Res. 1970; 27: 867-873Crossref PubMed Scopus (44) Google Scholar]. With concurrent sympathetic and parasympathetic cardiac stimulation, the initial response is expected to be primarily parasympathetic because of the slower rate of release of NE and slower rate of adrenergic signal transduction [20Mokrane A. Nadeau R. Dynamics of heart rate response to sympathetic nerve stimulation.Am J Physiol. 1998; 275: H995-H1001PubMed Google Scholar]. Also, ACh acts almost immediately on release and can markedly suppress the release of NE from the sympathetic nerves very soon after the onset of stimulation. The baroreflex is one of the body's homeostatic mechanisms for maintaining blood pressure and its primary physiologic role is in afterload control. Baroreceptors located in the aortic arch, carotid sinus, systemic vein, pulmonary vessel, atria, and ventricles sense blood pressure and increase or decrease vascular resistance and cardiac output through the autonomic nervous system. Baroreflex electrical stimulation inducing parasympathetic activation and sympathetic inhibition has been reported to decrease hypertension and has been recently applied to HF as summarized by Lopshire and Zipes [11Lopshire J.C. Zipes D.P. Device therapy to modulate the autonomic nervous system to treat heart failure.Curr Cardiol Rep. 2012; 14: 593-600Crossref PubMed Scopus (19) Google Scholar]. Imbalance of the cardiac autonomic nervous system is characterized by marked sympathetic activation and abnormally low levels of parasympathetic activity under conditions of obesity, stress, hypertension, and cardiovascular diseases, including coronary artery disease [13Zamotrinsky A.V. Kondratiev B. de Jong J.W. Vagal neurostimulation in patients with coronary artery disease.Auton Neurosci. 2001; 88: 109-116Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 16Malpas S.C. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease.Physiol Rev. 2010; 90: 513-557Crossref PubMed Scopus (463) Google Scholar, 17Grassi G. Seravalle G. Quarti-Trevano F. Dell'Oro R. Bolla G. Mancia G. Effects of hypertension and obesity on the sympathetic activation of heart failure patients.Hypertension. 2003; 42: 873-877Crossref PubMed Scopus (83) Google Scholar, 21Zipes D.P. Rubart M. Neural modulation of cardiac arrhythmias and sudden cardiac death.Heart Rhythm. 2006; 3: 108-113Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 22Cao J.M. Fishbein M.C. Han J.B. et al.Relationship between regional cardiac hyperinnervation and ventricular arrhythmia.Circulation. 2000; 101: 1960-1969Crossref PubMed Scopus (385) Google Scholar]. In the early stages of HF, activation of cardiac sympathetic nerves provides a compensatory physiologic response that improves cardiac function by its positive inotropic and chronotropic effects during transient periods of increased physiologic demand. However, in later stages of HF, excessive upregulation of sympathetic neural tone has pathologic effects [13Zamotrinsky A.V. Kondratiev B. de Jong J.W. Vagal neurostimulation in patients with coronary artery disease.Auton Neurosci. 2001; 88: 109-116Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 21Zipes D.P. Rubart M. Neural modulation of cardiac arrhythmias and sudden cardiac death.Heart Rhythm. 2006; 3: 108-113Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 22Cao J.M. Fishbein M.C. Han J.B. et al.Relationship between regional cardiac hyperinnervation and ventricular arrhythmia.Circulation. 2000; 101: 1960-1969Crossref PubMed Scopus (385) Google Scholar, 23Cohn J.N. Levine T.B. Olivari M.T. et al.Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.N Engl J Med. 1984; 311: 819-823Crossref PubMed Scopus (2767) Google Scholar]. Persistent sympathetic activation and parasympathetic withdrawal in HF patients is believed to contribute to the progression and pathogenesis of HF [24Olshansky B. Sabbah H.N. Hauptman P.J. Colucci W.S. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy.Circulation. 2008; 118: 863-871Crossref PubMed Scopus (289) Google Scholar]. The level of sympathetic activity is closely linked to the severity of symptoms and hemodynamic derangement in HF. Elevated plasma NE levels, due in part to release from the adrenal medulla, are highly predictive of short-term mortality [23Cohn J.N. Levine T.B. Olivari M.T. et al.Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.N Engl J Med. 1984; 311: 819-823Crossref PubMed Scopus (2767) Google Scholar]. Sympathetic excitation can lead to peripheral vasoconstriction and acutely shorten the refractory period of ventricles, reducing the threshold of ventricular fibrillation [13Zamotrinsky A.V. Kondratiev B. de Jong J.W. Vagal neurostimulation in patients with coronary artery disease.Auton Neurosci. 2001; 88: 109-116Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Sympathetic-dominant autonomic imbalance increases the incidence of life-threatening arrhythmia and sudden cardiac death in chronic HF [21Zipes D.P. Rubart M. Neural modulation of cardiac arrhythmias and sudden cardiac death.Heart Rhythm. 2006; 3: 108-113Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 22Cao J.M. Fishbein M.C. Han J.B. et al.Relationship between regional cardiac hyperinnervation and ventricular arrhythmia.Circulation. 2000; 101: 1960-1969Crossref PubMed Scopus (385) Google Scholar]. In chronic HF exacerbated by increased sympathetic tone, rebalancing cardiac autonomic control attenuates systemic inflammation and slows HF progression [5Zhang Y. Popovic Z.B. Bibevski S. et al.Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model.Circ Heart Fail. 2009; 2: 692-699Crossref PubMed Scopus (271) Google Scholar, 13Zamotrinsky A.V. Kondratiev B. de Jong J.W. Vagal neurostimulation in patients with coronary artery disease.Auton Neurosci. 2001; 88: 109-116Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. The pathophysiology of HF is also associated with activation of the renin-angiotensin system and elevation of plasma biomarkers of inflammatory activation, cytokines, and systemic and cardiac oxidant stress [3Van Wagoner D.R. Chronic vagal nerve stimulation for the treatment of human heart failure: progress in translating a vision into reality.Eur Heart J. 2011; 32: 788-790Crossref PubMed Scopus (9) Google Scholar]. The pathophysiologic effects of a decrease in parasympathetic tone may reflect the vagus nerve's role as the efferent arm of the “cholinergic anti-inflammatory pathway” [25Tracey K.J. Reflex control of immunity.Nat Rev Immunol. 2009; 9: 418-428Crossref PubMed Scopus (783) Google Scholar]. Studies have shown that the parasympathetic nervous system acts as a physiologic regulator of the inflammatory response to immune system activation. The parasympathetic nervous system senses and attenuates inflammation by efferent neural outflow to the reticuloendothelial system. It has been postulated that parasympathetic stimulation reduces production of systemically active cytokines by spleen cells and activates ACh receptors on the surface of macrophages within the spleen, resulting in reduced expression of inflammatory mediators and adhesion molecules [26Zitnik R.J. Treatment of chronic inflammatory diseases with implantable medical devices.Ann Rheum Dis. 2011; 70: i67-i70Crossref PubMed Scopus (9) Google Scholar]. Parasympathetic nervous system inhibition of the renin-angiotensin system has been demonstrated in animal studies: one showed that vagal efferent nerves inhibit release of renin by the kidneys [27Mancia G. Romero J.C. Shepherd J.T. Continuous inhibition of renin release in dogs by vagally innervated receptors in the cardiopulmonary region.Circ Res. 1975; 36: 529-535Crossref PubMed Scopus (68) Google Scholar] and another that vagal blockade significantly increased plasma renin activity [28Elsner D. Kromer E.P. Riegger G.A. Effects of vagal blockade on neurohumoral systems in conscious dogs with heart failure.J Cardiovasc Pharmacol. 1990; 15: 586-591Crossref PubMed Scopus (15) Google Scholar]. Our studies showed that VNS treatment significantly reduced elevated levels of plasma NE, angiotensin II, and C-reactive protein in HF dogs [5Zhang Y. Popovic Z.B. Bibevski S. et al.Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model.Circ Heart Fail. 2009; 2: 692-699Crossref PubMed Scopus (271) Google Scholar]. Current HF pharmacologic treatment utilizes angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone antagonists [29Pitt B. Zannad F. Remme W.J. et al.The effect of spironolactone on morbidity and mortality in patients with severe heart failure. 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Although direct VNS primarily has a negative chronotropic effect, some animal and human studies have shown a decrease in left ventricular (LV) work and efficiency with VNS [33Lewis M.E. Al-Khalidi A.H. Bonser R.S. et al.Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.J Physiol. 2001; 534: 547-552Crossref PubMed Scopus (96) Google Scholar, 34Dickerson L.W. Rodak D.J. Fleming T.J. et al.Parasympathetic neurons in the cranial medial ventricular fat pad on the dog heart selectively decrease ventricular contractility.J Auton Nerv Syst. 1998; 70: 129-141Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 35Matsuura W. Sugimachi M. Kawada T. et al.Vagal stimulation decreases left ventricular contractility mainly through negative chronotropic effect.Am J Physiol. 1997; 273: H534-H539PubMed Google Scholar]. There is general agreement, however, on its potential benefit in reestablishing cardiac autonomic balance in response to the increased sympathetic tone in HF animal models and in HF patients [5Zhang Y. Popovic Z.B. Bibevski S. et al.Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model.Circ Heart Fail. 2009; 2: 692-699Crossref PubMed Scopus (271) Google Scholar, 13Zamotrinsky A.V. Kondratiev B. de Jong J.W. Vagal neurostimulation in patients with coronary artery disease.Auton Neurosci. 2001; 88: 109-116Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 36Li M. Zheng C. Sato T. Kawada T. Sugimachi M. Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats.Circulation. 2004; 109: 120-124Crossref PubMed Scopus (440) Google Scholar, 37Klein H.U. Ferrari G.M. Vagus nerve stimulation: a new approach to reduce heart failure.Cardiol J. 2010; 17: 638-644PubMed Google Scholar, 38De Ferrari G.M. Crijns H.J. Borggrefe M. et al.Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure.Eur Heart J. 2011; 32: 847-855Crossref PubMed Scopus (377) Google Scholar]. Along with its hemodynamic effects, VNS attenuates the systemic inflammatory response and activation of the renin-angiotensin system in animal HF models, which has been shown to be beneficial in HF treatment [8Levy M.N. Sympathetic-parasympathetic interactions in the heart.Circ Res. 1971; 29: 437-445Crossref PubMed Scopus (578) Google Scholar, 28Elsner D. Kromer E.P. Riegger G.A. Effects of vagal blockade on neurohumoral systems in conscious dogs with heart failure.J Cardiovasc Pharmacol. 1990; 15: 586-591Crossref PubMed Scopus (15) Google Scholar]. The most therapeutic effect of VNS in treating chronic HF is its reduction of elevated HR created by increased sympathetic tone, which improves diastolic filling and coronary perfusion and reduces MVo2. These VNS effects combine to slow or reverse the progression of chronic HF. In patients with severe coronary artery disease, VNS reduced sympathetic tone by inhibiting the release of NE, resulting in improved microcirculation and LV contractility. Vagal activation has also been shown to have a powerful antifibrillatory effect [39Schwartz P.J. De Ferrari G.M. Vagal stimulation for heart failure: background and first in-man study.Heart Rhythm. 2009; 6: S76-S81Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. In recent pilot VNS clinical studies, patients diagnosed with New York Heart Association (NYHA) class II/III HF were treated with an implantable VNS system (CardioFit, BioControl Medical USA, New Hope, MN) that delivered pulses to the right cervical vagus nerve through a multiple contact bipolar nerve cuff electrode [4Schwartz P.J. De Ferrari G.M. Sanzo A. et al.Long term vagal stimulation in patients with advanced heart failure: first experience in man.Eur J Heart Fail. 2008; 10: 884-891Crossref PubMed Scopus (237) Google Scholar, 38De Ferrari G.M. Crijns H.J. Borggrefe M. et al.Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure.Eur Heart J. 2011; 32: 847-855Crossref PubMed Scopus (377) Google Scholar]. At 1-year follow-up, VNS was associated with a reduction in HR (p = 0.003), increase in LV ejection fraction (p < 0.0001), and improvements in NYHA class (p < 0.001) and 6-minute walk (p = 0.012). The negative chronotropic effects of VNS mimic the actions of anti-adrenergic beta-blockers, which have been proved effective in reducing mortality and improving cardiac function in chronic HF patients [40Swedberg K. Kjekshus J. Snapinn S. Long-term survival in severe heart failure in patients treated with enalapril Ten year follow-up of CONSENSUS I.Eur Heart J. 1999; 20: 136-139Crossref PubMed Scopus (190) Google Scholar]. However, systemic side effects, such as arterial hypotension and bradycardia, limit the use of beta-blockers in the acute HF setting. The recent systolic HF treatment with the If inhibitor ivabradine trial (SHIFT) evaluated the effects of ivabradine, a selective inhibitor of the If current in the sinoatrial node, without inotropic effects [41Swedberg K. Komajda M. Bohm M. et al.Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.Lancet. 2010; 376: 875-885Abstract Full Text Full Text PDF PubMed Scopus (1922) Google Scholar]. This randomized, double-blind study in NYHA class II-III HF patients demonstrated that HR in patients on ivabradine fell by 15.4 ± 10.7 beats per minute at 28 days and that hospital admission rates for worsening HF were significantly lower in patients taking ivabradine than placebo (21% placebo versus 16% ivabradine; p < 0.0001) with significantly fewer deaths attributable to HF (5% vs 3%; p = 0.014). Although the effects of VNS on HR are similar to those of ivabradine or beta-blockers, VNS also attenuates the systemic inflammatory activation and the effects of renin-angiotensin system activation that are associated with the progression of heart disease. It is notable that, relative to adjusting medication levels, the effects of VNS can be much more quickly titrated by changing stimulation parameters. As noted above, VNS significantly improved NYHA functional class and LV ejection fraction in initial clinical trials in NYHA class II-III HF patients [37Klein H.U. Ferrari G.M. Vagus nerve stimulation: a new approach to reduce heart failure.Cardiol J. 2010; 17: 638-644PubMed Google Scholar]. As a result, VNS is being proposed as an adjuvant to defibrillator and resynchronization therapies for this population [42Jessup M. Brozena S. Heart failure.N Engl J Med. 2003; 348: 2007-2018Crossref PubMed Scopus (1610) Google Scholar]. Both VNS and pharmacologic HF therapies target stable chronic HF patients to achieve long-term therapeutic effects and are not recommended for endstage or acute-phase severe HF patients in need of increased cardiac output. Cardiac sympathetic nerve stimulation (SNS) alone produces a cardioselective positive inotropic effect without significant effects on systemic vascular tone. In ex vivo studies using isolated rabbit and canine hearts, cardiac SNS increased LV pressure by increased contractility [43Brack K.E. Coote J.H. Ng G.A. The effect of direct autonomic nerve stimulation on left ventricular force in the isolated innervated Langendorff perfused rabbit heart.Auton Neurosci. 2006; 124: 69-80Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 44Miyano H. Nakayama Y. Shishido T. et al.Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart.Am J Physiol. 1998; 275: H400-H408PubMed Google Scholar]. The SNS at the subclavian artery also increased the adrenergic neural tone of the heart [7Zarse M. Plisiene J. Mischke K. et al.Selective increase of cardiac neuronal sympathetic tone: a catheter-based access to modulate left ventricular contractility.J Am Coll Cardiol. 2005; 46: 1354-1359Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. Unfortunately, SNS also significantly increases HR, leading to a significant increase in MVo2, the same adverse effect associated with the use of inotropic drugs such as dobutamine to override beta-receptor downregulation and acutely augment LV contractility in patients with acute and endstage HF [45Steen P.A. Tinker J.H. Pluth J.R. Barnhorst D.A. Tarhan S. Efficacy of dopamine, dobutamine, and epinephrine during emergence from cardiopulmonary bypass in man.Circulation. 1978; 57: 378-384Crossref PubMed Scopus (76) Google Scholar, 46Stephens J. Ead H. Spurrell R. Haemodynamic effects of dobutamine with special reference to myocardial blood flow A comparison with dopamine and isoprenaline.Br Heart J. 1979; 42: 43-50Crossref PubMed Scopus (31) Google Scholar]. The mortality rate for inotrope-dependent patients at 6 months is more than 50%, with few survivors at 1 year [44Miyano H. Nakayama Y. Shishido T. et al.Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart.Am J Physiol. 1998; 275: H400-H408PubMed Google Scholar, 47Stevenson L.W. Clinical use of inotropic therapy for heart failure: looking backward or forward? Part II: chronic inotropic therapy.Circulation. 2003; 108: 492-497Crossref PubMed Scopus (100) Google Scholar]. Positive inotropic agents are no longer recommended for long-term treatment of HF, even in its advanced stages, and are in some cases reserved for the palliative care of endstage HF patients, in whom the increased mortality risks are traded for an improved quality of life [48Jessup M. Abraham W.T. Casey D.E. et al.2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.Circulation. 2009; 119: 1977-2016Crossref PubMed Scopus (1347) Google Scholar, 49Hunt S.A. Abraham W.T. Chin M.H. et al.ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society.Circulation. 2005; 112: e154-e235Crossref PubMed Google Scholar]. As a result, there has been no significant clinical application of direct cardiac SNS as HF therapy. It has long been known that the positive inotropic effects of SNS are stronger with stimulation of the left-sided cervical sympathetic nerves, whereas the chronotropic effects are stronger with right-sided SNS [44Miyano H. Nakayama Y. Shishido T. et al.Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart.Am J Physiol. 1998; 275: H400-H408PubMed Google Scholar]. Future research into the identification of separate cardiac sympathetic neural elements that selectively affect LV contractility over HR may allow sympathetic neuromodulation in HF therapy. More recent animal studies have investigated the impact of selective SNS by stimulation directly at the heart in isolated heart experiments (ex vivo) and by in vivo deployment of stimulating catheters into the coronary sinus [6Meyer C. Rana O.R. Saygili E. et al.Augmentation of left ventricular contractility by cardiac sympathetic neural stimulation.Circulation. 2010; 121: 1286-1294Crossref PubMed Scopus (47) Google Scholar, 7Zarse M. Plisiene J. Mischke K. et al.Selective increase of cardiac neuronal sympathetic tone: a catheter-based access to modulate left ventricular contractility.J Am Coll Cardiol. 2005; 46: 1354-1359Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. Efforts to therapeutically manipulate the balance of parasympathetic and sympathetic nerve activity are complicated by the range of organ systems and noncardiac functions that these nerves regulate (systemic arterial pressure, body temperature, gastrointestinal motility, glandular secretion, respiration, renal and urinary bladder function, etc). Pharmacologic manipulation has been performed using NE, Ach, and their analogs to mimic the effects of autonomic nerve stimulation, yet it remains difficult to determine the extent to which such manipulation models the effects of activating neural pathways. Previous end-organ studies using concurrent sympathetic and parasympathetic stimulation have focused on direct stimulation of the vagus nerve and its branches while also stimulating either cervical sympathetic nerves or sympathetic paravertebral and prevertebral ganglia [4Schwartz P.J. De Ferrari G.M. Sanzo A. et al.Long term vagal stimulation in patients with advanced heart failure: first experience in man.Eur J Heart Fail. 2008; 10: 884-891Crossref PubMed Scopus (237) Google Scholar, 5Zhang Y. Popovic Z.B. Bibevski S. et al.Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model.Circ Heart Fail. 2009; 2: 692-699Crossref PubMed Scopus (271) Google Scholar, 6Meyer C. Rana O.R. Saygili E. et al.Augmentation of left ventricular contractility by cardiac sympathetic neural stimulation.Circulation. 2010; 121: 1286-1294Crossref PubMed Scopus (47) Google Scholar, 7Zarse M. Plisiene J. 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Borggrefe M. et al.Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure.Eur Heart J. 2011; 32: 847-855Crossref PubMed Scopus (377) Google Scholar, 43Brack K.E. Coote J.H. Ng G.A. The effect of direct autonomic nerve stimulation on left ventricular force in the isolated innervated Langendorff perfused rabbit heart.Auton Neurosci. 2006; 124: 69-80Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 44Miyano H. Nakayama Y. Shishido T. et al.Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart.Am J Physiol. 1998; 275: H400-H408PubMed Google Scholar]. An ex vivo study focusing on the chronotropic effects of SNS and VNS was performed on isolated rabbit hearts [15Brack K.E. Coote J.H. Ng G.A. Interaction between direct sympathetic and vagus nerve stimulation on heart rate in the isolated rabbit heart.Exp Physiol. 2004; 89: 128-139Crossref PubMed Scopus (44) Google Scholar]. Background VNS reduced the overall positive chronotropic effect of SNS with the level of inhibition increasing with increasing background VNS frequency. Background SNS, however, acted to enhance the negative chronotropic effects of VNS. These observations reinforce previously discussed studies showing that VNS activity has a dominant role in regulating chronotropic effects on the heart and that the cardiac parasympathetic system has an important protective role in limiting sympathetically driven physiologic effects. In reviewing the literature, we could find no in vivo animal studies that focused on concurrent stimulation of parasympathetic and sympathetic cardiac nerves to affect cardiac and hemodynamic function. In recent studies, we have examined the cardiac effects of stimulation at the cardiac plexus, which contains both sympathetic and parasympathetic nerves traversing the adventitia of the great vessels at the base of the heart. Stimulation at this site produces localized cardiac effects that minimize or eliminate the other end-organ side effects that are associated with stimulation of autonomic nerves above the level of the heart. We stimulated the cardiac plexus of healthy dogs using a single bipolar electrode at the epivascular surface of the right branch of the pulmonary artery. We reported increased LV contractility secondary to sympathetic stimulation with no increase in HR in all (12 of 12) dogs. This study demonstrated that, during use of concurrent sympathetic and parasympathetic cardiac nerve stimulation, parasympathetic stimulation has a dominant-negative chronotropic effect over that of sympathetic cardiac stimulation [50Kobayashi M. Sakurai S. Takaseya T. et al.Effect of epivascular cardiac autonomic nerve stimulation on cardiac function.Ann Thorac Surg. 2012; 94: 1150-1156Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. Although this reproducible response to cardiac plexus stimulation (CPS) was demonstrated in healthy dogs, it also has potentially therapeutic applications in the treatment of advanced HF. Clinical evaluation of simultaneous stimulation of parasympathetic and sympathetic cardiac nerves has not been reported, and its potential therapeutic effects are still unclear for HF patients. Jessup and Brozena [42Jessup M. Brozena S. Heart failure.N Engl J Med. 2003; 348: 2007-2018Crossref PubMed Scopus (1610) Google Scholar] stratified patient treatment options relative to their American College of Cardiology/American Heart Association stage of systolic HF. Stage A is a high-risk group with no symptoms. Stage B covers structural heart disease with no symptoms; angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are recommended for all patients, and beta-blockers in selected patients. Treatment for stage C patients with structural disease with previous or current symptoms includes angiotensin-converting enzyme inhibitors, beta-blockers, cardiac resynchronization therapy for bundle branch block, revascularization and mitral valve surgery, aldosterone antagonists and nesiritide. Stage D patients have symptoms refractory to the listed treatments that require inotropes or special interventions such as the implantation of a ventricular assist device or even heart transplantation. Although VNS is being proposed as an adjuvant therapy to defibrillator and resynchronization therapies for stage C patients (or chronic NYHA class II/III patients), we propose that concurrent parasympathetic stimulation and SNS may also be useful as an alternative treatment even for stage D/NYHA class IV patients. Results from recent cardiac neurostimulation studies in both HF animal models and early clinical studies are encouraging. Efforts to optimize stimulation sites and stimulation parameters may lead to increased use of cardiac neurostimulation that can be tailored to the type and severity of HF, based on the balance of sympathetic and parasympathetic autonomic control, the individual patient's hemodynamics and myocardial reserve capacity, and the degree of myocardial ischemia and dysfunction. Sympathovagal imbalance is associated with both hemodynamic and systemic effects, resulting in the activation of inflammatory and hypertensive mediators. To date, VNS is the only form of cardiac neuromodulation that has reached clinical application and thus far, only for the treatment of chronic early stage HF. VNS seems likely to decrease rates of long-term morbidity and mortality by alleviating the hemodynamic and systemic chronic pathology related to sympathetic-dominant cardiac autonomic imbalance.
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