The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.

2009;54;1747-1762 J. Am. Coll. Cardiol. George Louridas, and Javed Butler Filippos Triposkiadis, George Karayannis, Grigorios Giamouzis, John Skoularigis, Pathophysiology, and Clinical Implications The Sympathetic Nervous System in Heart Failure: Physiology, This information is current as of November 7, 2009 http://content.onlinejacc.org/cgi/content/full/54/19/1747 located on the World Wide Web at: The online version of this article, along with updated information and services, is

[1]  G. Tomlinson,et al.  Continuous positive airway pressure for central sleep apnea and heart failure. , 2005, The New England journal of medicine.

[2]  T. Douglas Bradley,et al.  Sleep Apnea and Heart Failure: Part I: Obstructive Sleep Apnea , 2003, Circulation.

[3]  H. Sabbah,et al.  744 Long-term therapy with neuroselective electric Vagus nerve stimulation improves LV function and attenuates global LV remodelling in dogs with chronic heart failure , 2005 .

[4]  W. Frishman,et al.  Left Ventricular Assist Device and Drug Therapy for the Reversal of Heart Failure , 2007 .

[5]  A. Sandilands,et al.  Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 β1‐adrenoceptors versus Gly389 β1‐adrenoceptors in isolated human atrial myocardium , 2003, British journal of pharmacology.

[6]  F. Triposkiadis,et al.  Left atrial remodelling contributes to the progression of asymptomatic left ventricular systolic dysfunction to chronic symptomatic heart failure , 2008, Heart Failure Reviews.

[7]  D. Ferguson,et al.  Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Direct evidence from sympathetic neural recordings. , 1989, Circulation.

[8]  W. Zang,et al.  Effects of carvedilol on M2 receptors and cholinesterase-positive nerves in adriamycin-induced rat failing heart , 2006, Autonomic Neuroscience.

[9]  Lie Gao,et al.  Exercise Training Normalizes Sympathetic Outflow by Central Antioxidant Mechanisms in Rabbits With Pacing-Induced Chronic Heart Failure , 2007, Circulation.

[10]  Barry R. Davis,et al.  Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. , 2000, JAMA.

[11]  H. Middlekauff,et al.  Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol , 2007, European journal of heart failure.

[12]  M. Ingelman-Sundberg,et al.  Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. , 2007, Pharmacology & therapeutics.

[13]  G. Dorn,et al.  β1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure , 2003, Nature Medicine.

[14]  B. Massie,et al.  Can Further Benefit Be Achieved by Adding Flosequinan to Patients With Congestive Heart Failure Who Remain Symptomatic on Diuretic, Digoxin, and an Angiotensin Converting Enzyme Inhibitor? Results of the Flosequinan‐ACE Inhibitor Trial (FACET) , 1993, Circulation.

[15]  M. Dunlap,et al.  Prevention of diminished parasympathetic control of the heart in experimental heart failure. , 2004, American journal of physiology. Heart and circulatory physiology.

[16]  S. Hsu,et al.  Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF alpha-caspase signaling pathway. , 2004, Cardiovascular research.

[17]  K. Griendling,et al.  NADPH oxidases and angiotensin II receptor signaling , 2009, Molecular and Cellular Endocrinology.

[18]  S. Green,et al.  A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. , 1993, The Journal of biological chemistry.

[19]  David M. Harris,et al.  Targeted Inhibition of Cardiomyocyte Gi Signaling Enhances Susceptibility to Apoptotic Cell Death in Response to Ischemic Stress , 2008, Circulation.

[20]  I. Meredith,et al.  Region-specific neuropeptide Y overflows at rest and during sympathetic activation in humans. , 1997, Hypertension.

[21]  L. Langeberg,et al.  The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways , 2005, Nature.

[22]  D. Reis,et al.  An endogenous substance with clonidine-like properties: selective binding to imidazole sites in the ventrolateral medulla , 1988, Brain Research.

[23]  P. Angelini.  Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning , 2008, Nature Clinical Practice Cardiovascular Medicine.

[24]  L. Lazzeroni,et al.  A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Bristow.  Antiadrenergic therapy of chronic heart failure: surprises and new opportunities. , 2003, Circulation.

[26]  Brian Olshansky,et al.  Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. , 2008, Circulation.

[27]  K. Adams,et al.  In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). , 2005, Journal of the American College of Cardiology.

[28]  F. Triposkiadis,et al.  Hemodynamic effects of dobutamine in patients with an exacerbation of chronic systolic heart failure treated with low doses of carvedilol. , 2008, International journal of clinical pharmacology and therapeutics.

[29]  D. Pimentel,et al.  Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. , 1998, Circulation.

[30]  Australia..  Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease , 1997, The Lancet.

[31]  J. McMurray,et al.  Neurohumoral pathways in heart failure with preserved systolic function. , 2005, Progress in cardiovascular diseases.

[32]  K. Santos,et al.  Impact of beta1-adrenergic receptor polymorphisms on susceptibility to heart failure, arrhythmogenesis, prognosis, and response to beta-blocker therapy. , 2008, The American journal of cardiology.

[33]  N. Hollenberg,et al.  Relation of the Renin‐Angiotensin-Aldosterone System to Clinical State in Congestive Heart Failure , 1981, Circulation.

[34]  M. Pfeffer,et al.  Adverse mortality effect of central sympathetic inhibition with sustained‐release moxonidine in patients with heart failure (MOXCON) , 2003, European journal of heart failure.

[35]  G. Norton,et al.  Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic beta-adrenoreceptor activation. , 2007, American journal of physiology. Heart and circulatory physiology.

[36]  Y. Pinto,et al.  Beta-adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy. , 1998, Cardiovascular research.

[37]  G. S. Pepper,et al.  Sympathetic activation in heart failure and its treatment with beta-blockade. , 1999, Archives of internal medicine.

[38]  J. Bigger,et al.  Long-term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure. , 1997, The American journal of cardiology.

[39]  M. Neri,et al.  Correlation between cardiac oxidative stress and myocardial pathology due to acute and chronic norepinephrine administration in rats , 2007, Journal of cellular and molecular medicine.

[40]  D. DeMets,et al.  Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure: Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study , 2002, Circulation.

[41]  Fach,et al.  Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF) , 1999, The Lancet.

[42]  J. Violin,et al.  Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. , 2007, The Journal of clinical investigation.

[43]  E. Braunwald,et al.  Increased plasma norepinephrine levels during prazosin therapy for severe congestive heart failure. , 1980, Annals of internal medicine.

[44]  M. Raizada,et al.  Angiotensin II stimulates norepinephrine uptake in hypothalamus-brain stem neuronal cultures. , 1986, The American journal of physiology.

[45]  H. Rockman,et al.  Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. , 2005, Journal of the American College of Cardiology.

[46]  S. Kardia,et al.  Synergistic Polymorphisms of β1- and α2C-Adrenergic Receptors and the Risk of Congestive Heart Failure , 2002 .

[47]  S. Gerber,et al.  The neuronal norepinephrine transporter in experimental heart failure: evidence for a posttranscriptional downregulation. , 2001, Journal of molecular and cellular cardiology.

[48]  J. Floras,et al.  Sustained effect of continuous positive airway pressure on baroreflex sensitivity in congestive heart failure patients with obstructive sleep apnea , 2008, Journal of hypertension.

[49]  J. Spertus,et al.  A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure , 2008, Nature Network Boston.

[50]  G. Dorn,et al.  Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. , 2000, Circulation.

[51]  W. Little,et al.  Endogenous beta3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure. , 2004, American journal of physiology. Heart and circulatory physiology.

[52]  T Douglas Bradley,et al.  Sleep Apnea and Heart Failure: Part II: Central Sleep Apnea , 2003, Circulation.

[53]  K. Starke,et al.  Modulation of neurotransmitter release by presynaptic autoreceptors. , 1989, Physiological reviews.

[54]  A. Cohen-Solal,et al.  Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). , 2005, European heart journal.

[55]  T. Eschenhagen.  β-adrenergic signaling in heart failure—adapt or die , 2008, Nature Medicine.

[56]  W. Abraham,et al.  Cardiac effects of continuous and bilevel positive airway pressure for patients with heart failure and obstructive sleep apnea: a pilot study. , 2008, Chest.

[57]  M. Yamani,et al.  Is digoxin a drug of the past? , 2006, Cleveland Clinic journal of medicine.

[58]  Julie A. Johnson,et al.  Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. , 2005, Pharmacogenetics and genomics.

[59]  G G Turrigiano,et al.  Nerve Growth Factor Modulates Synaptic Transmission between Sympathetic Neurons and Cardiac Myocytes , 1997, The Journal of Neuroscience.

[60]  M. Weber,et al.  Catecholamine-mediated constrictor effects of aldosterone on vascular smooth muscle. , 1982, Life sciences.

[61]  M. Yacoub,et al.  Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure , 2008, Cardiovascular research.

[62]  T. R. I. Nvestigators.  A TRIAL OF THE BETA-BLOCKER BUCINDOLOL IN PATIENTS WITH ADVANCED CHRONIC HEART FAILURE , 2001 .

[63]  C A Beltrami,et al.  Apoptosis in the failing human heart. , 1997, The New England journal of medicine.

[64]  C. May,et al.  MECHANISMS OF SYMPATHETIC ACTIVATION IN HEART FAILURE , 2006, Clinical and experimental pharmacology & physiology.

[65]  J. Balligand,et al.  Upregulation of &bgr;3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium , 2001, Circulation.

[66]  M. Böhm,et al.  Analysis of beta-adrenergic receptor mRNA levels in human ventricular biopsy specimens by quantitative polymerase chain reactions: progressive reduction of beta 1-adrenergic receptor mRNA in heart failure. , 1996, Journal of the American College of Cardiology.

[67]  S. Ball,et al.  An evaluation of the beta‐1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT‐HF sub‐study , 2003, European journal of heart failure.

[68]  H. Dargie,et al.  Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial , 2001, The Lancet.

[69]  L. Sinoway,et al.  Muscle Reflex Control of Sympathetic Nerve Activity in Heart Failure: The Role of Exercise Conditioning , 2000, Heart Failure Reviews.

[70]  F. Abboud,et al.  Sensitization of vagal cardiopulmonary baroreflex by chronic digoxin. , 1982, The American journal of physiology.

[71]  C. Petrilli,et al.  Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure. , 2008, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[72]  R. Lenkinski,et al.  Contribution of Skeletal Muscle Atrophy to Exercise Intolerance and Altered Muscle Metabolism in Heart Failure , 1992, Circulation.

[73]  W. Mayhan,et al.  Angiotensin-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[74]  K. Chien,et al.  The alpha 1A-adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. , 1993, The Journal of biological chemistry.

[75]  R. Graham,et al.  Transgenic alpha1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival. , 2006, Cardiovascular research.

[76]  T. LeJemtel,et al.  Systemic and coronary effects of intravenous milrinone and dobutamine in congestive heart failure. , 1986, Journal of the American College of Cardiology.

[77]  A. Skene,et al.  Effect on Survival and Hospitalization of Initiating Treatment for Chronic Heart Failure With Bisoprolol Followed by Enalapril, as Compared With the Opposite Sequence: Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III , 2005, Circulation.

[78]  D. DeMets,et al.  Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. , 1991, The New England journal of medicine.

[79]  C. Lang,et al.  Effect of sympathoinhibition on exercise performance in patients with heart failure. , 1997, Circulation.

[80]  T. Giles,et al.  Acute and Short-Term Effects of Clonidine in Heart Failure , 1987, Angiology.

[81]  B. Pitt,et al.  The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure , 2000 .

[82]  P. Molenaar,et al.  The low-affinity site of the beta1-adrenoceptor and its relevance to cardiovascular pharmacology. , 2008, Pharmacology & therapeutics.

[83]  Katherine C. Wu,et al.  Neurohumoral features of myocardial stunning due to sudden emotional stress. , 2005, The New England journal of medicine.

[84]  B. Pitt,et al.  Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction , 2003 .

[85]  G. Schuler,et al.  Impact of physical exercise on alterations in the skeletal muscle in patients with chronic heart failure. , 2008, Frontiers in bioscience : a journal and virtual library.

[86]  R. Nechwatal,et al.  [Physical training as interval or continuous training in chronic heart failure for improving functional capacity, hemodynamics and quality of life--a controlled study]. , 2002, Zeitschrift fur Kardiologie.

[87]  P. Adamson,et al.  Reducing the risk of sudden death in heart failure with beta-blockers. , 2006, Journal of cardiac failure.

[88]  G. Tomlinson,et al.  Suppression of Central Sleep Apnea by Continuous Positive Airway Pressure and Transplant-Free Survival in Heart Failure: A Post Hoc Analysis of the Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure Trial (CANPAP) , 2007, Circulation.

[89]  Jukka Corander,et al.  CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure , 2007, Pharmacogenetics and genomics.

[90]  D. Ganten,et al.  Prevention of Sympathetic and Cardiac Dysfunction After Myocardial Infarction in Transgenic Rats Deficient in Brain Angiotensinogen , 2004, Circulation research.

[91]  J. Parker,et al.  Parasympathetic control of cardiac sympathetic activity: normal ventricular function versus congestive heart failure. , 1999, Circulation.

[92]  R. Mobini,et al.  Ser49Gly of β1‐adrenergic receptor is associated with effective β‐blocker dose in dilated cardiomyopathy , 2005 .

[93]  Y. Horikiri,et al.  Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. , 1998, Journal of pharmaceutical sciences.

[94]  F. Leenen.  Brain mechanisms contributing to sympathetic hyperactivity and heart failure. , 2007, Circulation research.

[95]  E. Fleck,et al.  Myocardial catecholamine concentrations in dilated cardiomyopathy and heart failure of different origins. , 1991, European heart journal.

[96]  C. D. Wright,et al.  An α1A-Adrenergic–Extracellular Signal-Regulated Kinase Survival Signaling Pathway in Cardiac Myocytes , 2007, Circulation.

[97]  H. Middlekauff,et al.  Adaptations in autonomic function during exercise training in heart failure , 2008, Heart Failure Reviews.

[98]  J. Bigger,et al.  Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. , 1995, Journal of the American College of Cardiology.

[99]  D. Reis,et al.  Clonidine binds to imidazole binding sites as well as alpha 2-adrenoceptors in the ventrolateral medulla. , 1987, European journal of pharmacology.

[100]  G. Felker,et al.  Inotropes in the management of acute heart failure , 2008, Critical care medicine.

[101]  M. Hamon,et al.  Blockade of beta 1- and desensitization of beta 2-adrenoceptors reduce isoprenaline-induced cardiac fibrosis. , 2004, European journal of pharmacology.

[102]  L. Rohde,et al.  Role of Genetic Polymorphisms To Predict Appropriate Therapies in Patients with Implantable Cardioverter Defibrillators , 2008 .

[103]  M. Fujimaki.  Oxidation of R(+)- and S(-)-carvedilol by rat liver microsomes. Evidence for stereoselective oxidation and characterization of the cytochrome P450 isozymes involved. , 1994, Drug metabolism and disposition: the biological fate of chemicals.

[104]  J. Atherton,et al.  Arg389Gly-&bgr;1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol , 2007, Pharmacogenetics and genomics.

[105]  F. Triposkiadis,et al.  Acute hemodynamic effects of moderate doses of nebivolol versus metoprolol in patients with systolic heart failure. , 2007, International journal of clinical pharmacology and therapeutics.

[106]  Donald M Bers,et al.  Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes , 2003, Circulation research.

[107]  B. Parsons,et al.  Adrenergic Effects on the Biology of the Adult Mammalian Cardiocyte , 1992, Circulation.

[108]  H. Mori,et al.  Increased responsiveness of left ventricular apical myocardium to adrenergic stimuli. , 1993, Cardiovascular research.

[109]  M. Börjesson,et al.  A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure. , 2000, European heart journal.

[110]  M. Packer,et al.  Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure. , 1984, Circulation.

[111]  D C Harrison,et al.  Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. , 1982, The New England journal of medicine.

[112]  W. Kraus,et al.  Lack of association between adrenergic receptor genotypes and survival in heart failure patients treated with carvedilol or metoprolol. , 2008, Journal of the American College of Cardiology.

[113]  F. Leenen,et al.  Critical role of CNS effects of aldosterone in cardiac remodeling post-myocardial infarction in rats. , 2004, Cardiovascular research.

[114]  K. Swedberg,et al.  Expert consensus document on beta-adrenergic receptor blockers. , 2004, European heart journal.

[115]  Michael Böhm,et al.  Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol‐associated adverse effects , 2002, Clinical pharmacology and therapeutics.

[116]  W. Kraus,et al.  Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. , 2009, JAMA.

[117]  P. Picton,et al.  Vagal heart rate responses to chronic beta‐blockade in human heart failure relate to cardiac norepinephrine spillover , 2005, European journal of heart failure.

[118]  P. Amouyel,et al.  Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure , 2005, Pharmacogenetics and genomics.

[119]  G. Mancia,et al.  Sympathetic and Baroreflex Cardiovascular Control in Hypertension-Related Left Ventricular Dysfunction , 2009, Hypertension.

[120]  CIBIS-II Investigators and Committees.  The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial , 1999, The Lancet.

[121]  R. Califf,et al.  Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. , 2002, JAMA.

[122]  B. Kobilka,et al.  Two functionally distinct α2-adrenergic receptors regulate sympathetic neurotransmission , 1999, Nature.