Skip to main content
Search
Search
Quick Search anywhere
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Quick Search in Journals
Skip main navigation
JACC Journals › JACC: BTS › Archives › Vol. 7 No. 3_Part_1
Previous
Next

Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director WorkshopOpen Access

Translational Perspective

J Am Coll Cardiol Basic Trans Science. 2022 Mar, 7 (3_Part_1) 265–293
Topic(s):
Sections

Central Illustration

Highlights

•

The ANS is a key regulator of cardiopulmonary health and disease and sleep/circadian pathophysiology.

•

Understanding cardiopulmonary sympathetic and parasympathetic nerve structure/function over disease time-course and cell type interactions is essential.

•

In vitro autonomic nervous system and experimental and computational integrative studies are necessary.

•

Clarifying sex-and race-specific cardiopulmonary and sleep/circadian influence on autonomic nerve function in response to neurotherapeutic interventions is critical to inform personalized strategies.

Summary

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund’s SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

References

  • 1. Hadaya J., Ardell J.L. "Autonomic modulation for cardiovascular disease". Front Physiol 2020;11:617459.

    CrossrefMedlineGoogle Scholar

  • 2. Carandina A., Rodrigues G.D., Di Francesco P., et al. "Effects of transcutaneous auricular vagus nerve stimulation on cardiovascular autonomic control in health and disease". Auton Neurosci 2021;236:102893.

    CrossrefMedlineGoogle Scholar

  • 3. Joyner M.J. "Preclinical and clinical evaluation of autonomic function in humans". J Physiol 2016;594:4009-4013.

    CrossrefMedlineGoogle Scholar

  • 4. Herring N., Kalla M., Paterson D.J. "The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies". Nat Rev Cardiol 2019;16:707-726.

    CrossrefMedlineGoogle Scholar

  • 5. Shivkumar K., Ajijola O.A., Anand I., et al. "Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics". J Physiol 2016;594:3911-3954.

    CrossrefMedlineGoogle Scholar

  • 6. Habecker B.A., Anderson M.E., Birren S.J., et al. "Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease". J Physiol 2016;594:3853-3875.

    CrossrefMedlineGoogle Scholar

  • 7. Kupari J., Häring M., Agirre E., Castelo-Branco G., Ernfors P. "An atlas of vagal sensory neurons and their molecular specialization". Cell Rep 2019;27:2508-2523.e4.

    CrossrefMedlineGoogle Scholar

  • 8. Kim S.H., Hadley S.H., Maddison M., et al. "Mapping of sensory nerve subsets within the vagal ganglia and the brainstem using reporter mice for Pirt, TRPV1, 5-HT3, and Tac1 expression". eNeuro 2020;7:2: ENEURO.0494-19.2020.

    CrossrefGoogle Scholar

  • 9. Farrell M.J., Bautista T.G., Liang E., Azzollini D., Egan G.F., Mazzone S.B. "Evidence for multiple bulbar and higher brain circuits processing sensory inputs from the respiratory system in humans". J Physiol 2020;598:5771-5787.

    CrossrefMedlineGoogle Scholar

  • 10. Rajendran P.S., Challis R.C., Fowlkes C.C., et al. "Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies". Nat Commun 2019;10:1944.

    CrossrefMedlineGoogle Scholar

  • 11. Saucerman J.J., Brunton L.L., Michailova A.P., McCulloch A.D. "Modeling beta-adrenergic control of cardiac myocyte contractility in silico". J Biol Chem 2003;278:47997-48003.

    CrossrefMedlineGoogle Scholar

  • 12. Foreman R.D., Garrett K.M., Blair R.W. "Mechanisms of cardiac pain". Compr Physiol 2015;5:929-960.

    CrossrefMedlineGoogle Scholar

  • 13. Liu X., Zhang Q., Han M., Du J. "Intrapericardial capsaicin and bradykinin induce different cardiac-somatic and cardiovascular reflexes in rats". Auton Neurosci 2016;198:28-32.

    CrossrefMedlineGoogle Scholar

  • 14. Yoshie K., Rajendran P.S., Massoud L., et al. "Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarction". JCI Insight 2020;5:124477.

    CrossrefMedlineGoogle Scholar

  • 15. Wang H.J., Wang W., Cornish K.G., Rozanski G.J., Zucker I.H. "Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure". Hypertension 2014;64:745-755.

    CrossrefMedlineGoogle Scholar

  • 16. Hanna P., Dacey M.J., Brennan J., et al. "Innervation and neuronal control of the mammalian sinoatrial node a comprehensive atlas". Circ Res 2021;128:9: 1279-1296.

    CrossrefMedlineGoogle Scholar

  • 17. Hooper J.S., Hadley S.H., Morris K.F., Breslin J.W., Dean J.B., Taylor-Clark T.E. "Characterization of cardiovascular reflexes evoked by airway stimulation with allylisothiocyanate, capsaicin, and ATP in Sprague-Dawley rats". J Appl Physiol 2016;120:580-591.

    CrossrefMedlineGoogle Scholar

  • 18. Hooper J.S., Stanford K.R., Alencar P.A., et al. "Nociceptive pulmonary-cardiac reflexes are altered in the spontaneously hypertensive rat". J Physiol 2019;597:3255-3279.

    CrossrefMedlineGoogle Scholar

  • 19. James T.N., Zipes D.P., Finegan R.E., Eisele J.W., Carter J.E. "Cardiac ganglionitis associated with sudden unexpected death". Ann Intern Med 1979;91:727-730.

    CrossrefMedlineGoogle Scholar

  • 20. Ajijola O.A., Hoover D.B., Simerly T.M., et al. "Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm". JCI Insight 2017;2:18: e94715.

    CrossrefMedlineGoogle Scholar

  • 21. Deng J., Zhou X., Wang M., et al. "The effects of interleukin 17A on left stellate ganglion remodeling are mediated by neuroimmune communication in normal structural hearts". Int J Cardiol 2019;279:64-71.

    CrossrefMedlineGoogle Scholar

  • 22. Kabata H., Artis D. "Neuro-immune crosstalk and allergic inflammation". J Clin Invest 2019;129:1475-1482.

    CrossrefMedlineGoogle Scholar

  • 23. Røsand Ø., Høydal M.A. "Cardiac exosomes in ischemic heart disease--a narrative review". Diagnostics (Basel) 2021;11:2: 269.

    CrossrefMedlineGoogle Scholar

  • 24. Quiroz-Baez R., Hernández-Ortega K., Martínez-Martínez E. "Insights into the proteomic profiling of extracellular vesicles for the identification of early biomarkers of neurodegeneration". Front Neurol 2020;11:580030.

    CrossrefMedlineGoogle Scholar

  • 25. Sahoo S., Kariya T., Ishikawa K. "Targeted delivery of therapeutic agents to the heart". Nat Rev Cardiol 2021;18:6: 389-399.

    CrossrefMedlineGoogle Scholar

  • 26. Himura Y., Felten S.Y., Kashiki M., Lewandowski T.J., Delehanty J.M., Liang C.S. "Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure". Circulation 1993;88:1299-1309.

    CrossrefMedlineGoogle Scholar

  • 27. Cao J.M., Fishbein M.C., Han J.B., et al. "Relationship between regional cardiac hyperinnervation and ventricular arrhythmia". Circulation 2000;101:1960-1969.

    CrossrefMedlineGoogle Scholar

  • 28. Cao J.M., Chen L.S., KenKnight B.H., et al. "Nerve sprouting and sudden cardiac death". Circ Res 2000;86:816-821.

    CrossrefMedlineGoogle Scholar

  • 29. Eisenhofer G., Friberg P., Rundqvist B., et al. "Cardiac sympathetic nerve function in congestive heart failure". Circulation 1996;93:1667-1676.

    CrossrefMedlineGoogle Scholar

  • 30. Kanazawa H., Ieda M., Kimura K., et al. "Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents". J Clin Invest 2010;120:408-421.

    CrossrefMedlineGoogle Scholar

  • 31. Ajijola O.A., Chatterjee N.A., Gonzales M.J., et al. "Coronary sinus neuropeptide Y levels and adverse outcomes in patients with stable chronic heart failure". JAMA Cardiol 2020;5:318-325.

    CrossrefMedlineGoogle Scholar

  • 32. Han S., Kobayashi K., Joung B., et al. "Electroanatomic remodeling of the left stellate ganglion after myocardial infarction". J Am Coll Cardiol 2012;59:954-961.

    View ArticleGoogle Scholar

  • 33. Wang H.J., Rozanski G.J., Zucker I.H. "Cardiac sympathetic afferent reflex control of cardiac function in normal and chronic heart failure states". J Physiol 2017;595:2519-2534.

    CrossrefMedlineGoogle Scholar

  • 34. Vaseghi M., Barwad P., Malavassi Corrales F.J., et al. "Cardiac sympathetic denervation for refractory ventricular arrhythmias". J Am Coll Cardiol 2017;69:3070-3080.

    View ArticleGoogle Scholar

  • 35. Bristow M.R., Ginsburg R., Umans V., et al. "Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure". Circ Res 1986;59:297-309.

    CrossrefMedlineGoogle Scholar

  • 36. Chatzidou S., Kontogiannis C., Tsilimigras D.I., et al. "Propranolol versus metoprolol for treatment of electrical storm in patients with implantable cardioverter-defibrillator". J Am Coll Cardiol 2018;71:1897-1906.

    View ArticleGoogle Scholar

  • 37. Bardsley E.N., Davis H., Buckler K.J., Paterson D.J. "Neurotransmitter switching coupled to beta-adrenergic signaling in sympathetic neurons in prehypertensive states". Hypertension 2018;71:1226-1238.

    CrossrefMedlineGoogle Scholar

  • 38. Dunlap M.E., Kinugawa T., Sica D.A., Thames M.D. "Cardiopulmonary baroreflex control of renal sympathetic nerve activity is impaired in dogs with left ventricular dysfunction". J Card Fail 2019;25:819-827.

    CrossrefMedlineGoogle Scholar

  • 39. Grassi G., Quarti-Trevano F., Esler M.D. "Sympathetic activation in congestive heart failure: an updated overview". Heart Fail Rev 2021;26:173-182.

    CrossrefMedlineGoogle Scholar

  • 40. Becker B.K., Tian C., Zucker I.H., Wang H.J. "Influence of brain-derived neurotrophic factor-tyrosine receptor kinase B signalling in the nucleus tractus solitarius on baroreflex sensitivity in rats with chronic heart failure". J Physiol 2016;594:5711-5725.

    CrossrefMedlineGoogle Scholar

  • 41. Li Y.L., Zhang D., Tu H., Muelleman R.L. "Altered ENaC is associated with aortic baroreceptor dysfunction in chronic heart failure". Am J Hypertens 2016;29:582-589.

    CrossrefMedlineGoogle Scholar

  • 42. Tu H., Zhang D., Li Y.L. "Cellular and molecular mechanisms underlying arterial baroreceptor remodeling in cardiovascular diseases and diabetes". Neurosci Bull 2019;35:98-112.

    CrossrefMedlineGoogle Scholar

  • 43. Mifflin S.W. "Inhibition of chemoreceptor inputs to nucleus of tractus solitarius neurons during baroreceptor stimulation". Am J Physiol 1993;265:R14-R20.

    MedlineGoogle Scholar

  • 44. Gao L., Schultz H.D., Patel K.P., Zucker I.H., Wang W. "Augmented input from cardiac sympathetic afferents inhibits baroreflex in rats with heart failure". Hypertension 2005;45:1173-1181.

    CrossrefMedlineGoogle Scholar

  • 45. Tubek S., Niewinski P., Paleczny B., Langner A., Banasiak W., Ponikowski P. "Human carotid bodies as a therapeutic target: new insights from a clinician's perspective". Kardiol Pol 2018;76:10: 1426-1433.

    CrossrefMedlineGoogle Scholar

  • 46. Kaur J., Krishnan A.C., Senador D., Alvarez A., Hanna H.W., O'Leary D.S. "Altered arterial baroreflex-muscle metaboreflex interaction in heart failure". Am J Physiol Heart Circ Physiol 2018;315:H1383-H1392.

    CrossrefMedlineGoogle Scholar

  • 47. Seravalle G., Quarti-Trevano F., Dell'Oro R., et al. "Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction". J Hypertens 2019;37:443-448.

    CrossrefMedlineGoogle Scholar

  • 48. Schiattarella G.G., Altamirano F., Tong D., et al. "Nitrosative stress drives heart failure with preserved ejection fraction". Nature 2019;568:351-356.

    CrossrefMedlineGoogle Scholar

  • 49. Tong D., Schiattarella G.G., Jiang N., et al. "Female sex is protective in a preclinical model of heart failure with preserved ejection fraction". Circulation 2019;140:1769-1771.

    CrossrefMedlineGoogle Scholar

  • 50. Abdellatif M., Trummer-Herbst V., Koser F., et al. "Nicotinamide for the treatment of heart failure with preserved ejection fraction". Sci Transl Med 2021;13:580: eabd7064.

    CrossrefMedlineGoogle Scholar

  • 51. Funakoshi K., Hosokawa K., Kishi T., Ide T., Sunagawa K. "Striking volume intolerance is induced by mimicking arterial baroreflex failure in normal left ventricular function". J Card Fail 2014;20:53-59.

    CrossrefMedlineGoogle Scholar

  • 52. Mostarda C., Moraes-Silva I.C., Moreira E.D., et al. "Baroreflex sensitivity impairment is associated with cardiac diastolic dysfunction in rats". J Card Fail 2011;17:519-525.

    CrossrefMedlineGoogle Scholar

  • 53. Fudim M., Boortz-Marx R.L., Ganesh A., et al. "Splanchnic nerve block for chronic heart failure". J Am Coll Cardiol HF 2020;8:742-752.

    Google Scholar

  • 54. Lu Y., Ma X., Sabharwal R., et al. "The ion channel ASIC2 is required for baroreceptor and autonomic control of the circulation". Neuron 2009;64:885-897.

    CrossrefMedlineGoogle Scholar

  • 55. Zeng W.Z., Marshall K.L., Min S., et al. "PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex". Science 2018;362:464-467.

    CrossrefMedlineGoogle Scholar

  • 56. Min S., Chang R.B., Prescott S.L., et al. "Arterial baroreceptors sense blood pressure through decorated aortic claws". Cell Rep 2019;29:2192-2201.e3.

    CrossrefMedlineGoogle Scholar

  • 57. Lu H.J., Nguyen T.L., Hong G.S., et al. "Tentonin 3/TMEM150C senses blood pressure changes in the aortic arch". J Clin Invest 2020;130:3671-3683.

    CrossrefMedlineGoogle Scholar

  • 58. Marina N., Christie I.N., Korsak A., et al. "Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow". Nat Commun 2020;11:131.

    CrossrefMedlineGoogle Scholar

  • 59. Mastitskaya S., Turovsky E., Marina N., et al. "Astrocytes modulate baroreflex sensitivity at the level of the nucleus of the solitary tract". J Neurosci 2020;40:3052-3062.

    CrossrefMedlineGoogle Scholar

  • 60. Pacak K., Palkovits M., Yadid G., Kvetnansky R., Kopin I.J., Goldstein D.S. "Heterogeneous neurochemical responses to different stressors: a test of Selye's doctrine of nonspecificity". Am J Physiol 1998;275:R1247-R1255.

    MedlineGoogle Scholar

  • 61. Goldstein D.S. "Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine". Johns Hopkins University Press, 2006.

    Google Scholar

  • 62. Goldstein D.S. "How does homeostasis happen? Integrative physiological, systems biological, and evolutionary perspectives". Am J Physiol Regul Integr Comp Physiol 2019;316:R301-R317.

    CrossrefMedlineGoogle Scholar

  • 63. Wittstein I.S., Thiemann D.R., Lima J.A., et al. "Neurohumoral features of myocardial stunning due to sudden emotional stress". N Engl J Med 2005;352:539-548.

    CrossrefMedlineGoogle Scholar

  • 64. Li 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;109:120-124.

    CrossrefMedlineGoogle Scholar

  • 65. De 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;32:847-855.

    CrossrefMedlineGoogle Scholar

  • 66. Lopshire J.C., Zhou X., Dusa C., et al. "Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model". Circulation 2009;120:286-294.

    CrossrefMedlineGoogle Scholar

  • 67. Torre-Amione G., Alo K., Estep J.D., et al. "Spinal cord stimulation is safe and feasible in patients with advanced heart failure: early clinical experience". Eur J Heart Fail 2014;16:788-795.

    CrossrefMedlineGoogle Scholar

  • 68. Tse H.-F., Turner S., Sanders P., et al. "Thoracic Spinal Cord Stimulation for HEArt Failure as a Restorative Treatment (SCS HEART study): first-in-man experience". Heart Rhythm 2015;12:3: 588-595.

    CrossrefMedlineGoogle Scholar

  • 69. Zucker I.H., Hackley J.F., Cornish K.G., et al. "Chronic baroreceptor activation enhances survival in dogs with pacing-induced heart failure". Hypertension 2007;50:904-910.

    CrossrefMedlineGoogle Scholar

  • 70. Abraham W.T., Zile M.R., Weaver F.A., et al. "Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction". J Am Coll Cardiol HF 2015;3:487-496.

    Google Scholar

  • 71. Zile M.R., Lindenfeld J., Weaver F.A., et al. "Baroreflex activation therapy in patients with heart failure with reduced ejection fraction". J Am Coll Cardiol 2020;76:1-13.

    View ArticleGoogle Scholar

  • 72. Zipes D.P., Neuzil P., Theres H., et al. "Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure: the DEFEAT-HF study". J Am Coll Cardiol HF 2016;4:129-136.

    Google Scholar

  • 73. Gold M.R., Van Veldhuisen D.J., Hauptman P.J., et al. "Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial". J Am Coll Cardiol 2016;68:149-158.

    View ArticleGoogle Scholar

  • 74. Ackerman M.J., Priori S.G., Dubin A.M., et al. "Beta-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: are all beta-blockers equivalent?"Heart Rhythm 2017;14:e41-e44.

    CrossrefMedlineGoogle Scholar

  • 75. Benjamin E.J., Wolf P.A., D'Agostino R.B., Silbershatz H., Kannel W.B., Levy D. "Impact of atrial fibrillation on the risk of death: the Framingham Heart Study". Circulation 1998;98:946-952.

    CrossrefMedlineGoogle Scholar

  • 76. Go A.S., Hylek E.M., Phillips K.A., et al. "Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study". JAMA 2001;285:2370-2375.

    CrossrefMedlineGoogle Scholar

  • 77. January C.T., Wann L.S., Alpert J.S., et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society". J Am Coll Cardiol 2014;64:21: 2246-2280.

    View ArticleGoogle Scholar

  • 78. Chen P.S., Chen L.S., Fishbein M.C., Lin S.F., Nattel S. "Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy". Circ Res 2014;114:1500-1515.

    CrossrefMedlineGoogle Scholar

  • 79. Stavrakis S., Nakagawa H., Po S.S., Scherlag B.J., Lazzara R., Jackman W.M. "The role of the autonomic ganglia in atrial fibrillation". J Am Coll Cardiol EP 2015;1:1-13.

    Google Scholar

  • 80. Stavrakis S., Humphrey M.B., Scherlag B.J., et al. "Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation". J Am Coll Cardiol 2015;65:867-875.

    View ArticleGoogle Scholar

  • 81. Stavrakis S., Stoner J.A., Humphrey M.B., et al. "TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): a randomized clinical trial". J Am Coll Cardiol EP 2020;6:282-291.

    Google Scholar

  • 82. Waldron N.H., Fudim M., Mathew J.P., Piccini J.P. "Neuromodulation for the treatment of heart rhythm disorders". J Am Coll Cardiol Basic Trans Science 2019;4:546-562.

    View ArticleGoogle Scholar

  • 83. Manolis A.A., Manolis T.A., Apostolopoulos E.J., Apostolaki N.E., Melita H., Manolis A.S. "The role of the autonomic nervous system in cardiac arrhythmias: the neuro-cardiac axis, more foe than friend?"Trends Cardiovasc Med 2021;31:290-302.

    CrossrefMedlineGoogle Scholar

  • 84. Driessen A.H.G., Berger W.R., Krul S.P.J., et al. "Ganglion plexus ablation in advanced atrial fibrillation: the AFACT study". J Am Coll Cardiol 2016;68:1155-1165.

    View ArticleGoogle Scholar

  • 85. Wang H., Zhang Y., Xin F., et al. "Calcium-induced autonomic denervation in patients with post-operative atrial fibrillation". J Am Coll Cardiol 2021;77:57-67.

    View ArticleGoogle Scholar

  • 86. Scanavacca M., Pisani C.F., Hachul D., et al. "Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation". Circulation 2006;114:876-885.

    CrossrefMedlineGoogle Scholar

  • 87. Giannopoulos G., Kossyvakis C., Efremidis M., et al. "Central sympathetic inhibition to reduce postablation atrial fibrillation recurrences in hypertensive patients: a randomized, controlled study". Circulation 2014;130:1346-1352.

    CrossrefMedlineGoogle Scholar

  • 88. Stavrakis S., Humphrey M.B., Scherlag B., et al. "Low-level vagus nerve stimulation suppresses post-operative atrial fibrillation and inflammation: a randomized study". J Am Coll Cardiol EP 2017;3:929-938.

    Google Scholar

  • 89. Frangos E., Ellrich J., Komisaruk B.R. "Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans". Brain Stimul 2015;8:624-636.

    CrossrefMedlineGoogle Scholar

  • 90. Koopman F.A., Chavan S.S., Miljko S., et al. "Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis". Proc Natl Acad Sci U S A 2016;113:8284-8289.

    CrossrefMedlineGoogle Scholar

  • 91. Gami A.S., Hodge D.O., Herges R.M., et al. "Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation". J Am Coll Cardiol 2007;49:565-571.

    View ArticleGoogle Scholar

  • 92. Gami A.S., Pressman G., Caples S.M., et al. "Association of atrial fibrillation and obstructive sleep apnea". Circulation 2004;110:364-367.

    CrossrefMedlineGoogle Scholar

  • 93. Kanagala R., Murali N.S., Friedman P.A., et al. "Obstructive sleep apnea and the recurrence of atrial fibrillation". Circulation 2003;107:2589-2594.

    CrossrefMedlineGoogle Scholar

  • 94. Konecny T., Somers V.K. "Things we have always wanted to know about sleep apnea and atrial fibrillation (but were afraid to ask)". J Am Coll Cardiol EP 2019;5:702-704.

    Google Scholar

  • 95. Linz D., Hendriks J. "Central sleep apnea in atrial fibrillation: risk factor or marker of untreated underlying disease?"Int J Cardiol Heart Vasc 2020;30:100650.

    MedlineGoogle Scholar

  • 96. Mehra R., Benjamin E.J., Shahar E., et al. "Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study". Am J Respir Crit Care Med 2006;173:910-916.

    CrossrefMedlineGoogle Scholar

  • 97. Mehra R., Stone K.L., Varosy P.D., et al. "Nocturnal arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study". Arch Intern Med 2009;169:1147-1155.

    CrossrefMedlineGoogle Scholar

  • 98. Monahan K., Storfer-Isser A., Mehra R., et al. "Triggering of nocturnal arrhythmias by sleep-disordered breathing events". J Am Coll Cardiol 2009;54:1797-1804.

    View ArticleGoogle Scholar

  • 99. Ghias M., Scherlag B.J., Lu Z., et al. "The role of ganglionated plexi in apnea-related atrial fibrillation". J Am Coll Cardiol 2009;54:2075-2083.

    View ArticleGoogle Scholar

  • 100. Linz D., Hohl M., Nickel A., et al. "Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea". Hypertension 2013;62:767-774.

    CrossrefMedlineGoogle Scholar

  • 101. Linz D., Hohl M., Khoshkish S., et al. "Low-level but not high-level baroreceptor stimulation inhibits atrial fibrillation in a pig model of sleep apnea". J Cardiovasc Electrophysiol 2016;27:1086-1092.

    CrossrefMedlineGoogle Scholar

  • 102. Yu L., Li X., Huang B., et al. "Atrial fibrillation in acute obstructive sleep apnea: autonomic nervous mechanism and modulation". J Am Heart Assoc 2017;6:9: e006264.

    CrossrefGoogle Scholar

  • 103. Congrete S., Bintvihok M., Thongprayoon C., et al. "Effect of obstructive sleep apnea and its treatment of atrial fibrillation recurrence after radiofrequency catheter ablation: a meta-analysis". J Evid Based Med 2018;11:145-151.

    CrossrefMedlineGoogle Scholar

  • 104. Deneke T., Chaar H., de Groot J.R., et al. "Shift in the pattern of autonomic atrial innervation in subjects with persistent atrial fibrillation". Heart Rhythm 2011;8:1357-1363.

    CrossrefMedlineGoogle Scholar

  • 105. Aistrup G.L., Cokic I., Ng J., et al. "Targeted nonviral gene-based inhibition of Galpha(i/o)-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation". Heart Rhythm 2011;8:1722-1729.

    CrossrefMedlineGoogle Scholar

  • 106. Aistrup G.L., Villuendas R., Ng J., et al. "Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic attenuation". Cardiovasc Res 2009;83:481-492.

    CrossrefMedlineGoogle Scholar

  • 107. Scherschel K., Hedenus K., Jungen C., et al. "Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation". Sci Transl Med 2019;11:493: eaav7770.

    CrossrefMedlineGoogle Scholar

  • 108. Zhang H., Yuan X., Jin P.F., et al. "Alteration of parasympathetic/sympathetic ratio in the infarcted myocardium after Schwann cell transplantation modified electrophysiological function of heart: a novel antiarrhythmic therapy". Circulation 2010;122:S193-S200.

    CrossrefMedlineGoogle Scholar

  • 109. Meyer C., Rana O.R., Saygili E., et al. "Augmentation of left ventricular contractility by cardiac sympathetic neural stimulation". Circulation 2010;121:1286-1294.

    CrossrefMedlineGoogle Scholar

  • 110. Ito M., Zipes D.P. "Efferent sympathetic and vagal innervation of the canine right ventricle". Circulation 1994;90:1459-1468.

    CrossrefMedlineGoogle Scholar

  • 111. Jungen C., Scherschel K., Eickholt C., et al. "Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias". Nat Commun 2017;8:14155.

    CrossrefMedlineGoogle Scholar

  • 112. Gardner R.T., Wang L., Lang B.T., et al. "Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias". Nat Commun 2015;6:6235.

    CrossrefMedlineGoogle Scholar

  • 113. Kalla M., Hao G., Tapoulal N., et al. "The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade". Eur Heart J 2020;41:2168-2179.

    CrossrefMedlineGoogle Scholar

  • 114. Wang L., Olivas A., Francis Stuart S.D., et al. "Cardiac sympathetic nerve transdifferentiation reduces action potential heterogeneity after myocardial infarction". Am J Physiol Heart Circ Physiol 2020;318:H558-H565.

    CrossrefMedlineGoogle Scholar

  • 115. Ardell J.L., Shivkumar K. "Sympathetic neural recording--it is all in the details". Heart Rhythm 2017;14:972-973.

    CrossrefMedlineGoogle Scholar

  • 116. Doytchinova A., Hassel J.L., Yuan Y., et al. "Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram". Heart Rhythm 2017;14:25-33.

    CrossrefMedlineGoogle Scholar

  • 117. Kusayama T., Wong J., Liu X., et al. "Simultaneous noninvasive recording of electrocardiogram and skin sympathetic nerve activity (neuECG)". Nat Protoc 2020;15:1853-1877.

    CrossrefMedlineGoogle Scholar

  • 118. Gillis A.M. "Atrial fibrillation and ventricular arrhythmias: sex differences in electrophysiology, epidemiology, clinical presentation, and clinical outcomes". Circulation 2017;135:593-608.

    CrossrefMedlineGoogle Scholar

  • 119. Alonso A., Agarwal S.K., Soliman E.Z., et al. "Incidence of atrial fibrillation in whites and African-Americans: the Atherosclerosis Risk in Communities (ARIC) study". Am Heart J 2009;158:111-117.

    CrossrefMedlineGoogle Scholar

  • 120. Liao D., Barnes R.W., Chambless L.E., Simpson R.J., Sorlie P., Heiss G. "Age, race, and sex differences in autonomic cardiac function measured by spectral analysis of heart rate variability--the ARIC study. Atherosclerosis Risk in Communities". Am J Cardiol 1995;76:906-912.

    CrossrefMedlineGoogle Scholar

  • 121. Antzelevitch C., Yan G.X., Ackerman M.J., et al. "J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge". Heart Rhythm 2016;13:e295-e324.

    CrossrefMedlineGoogle Scholar

  • 122. Willich S.N., Levy D., Rocco M.B., Tofler G.H., Stone P.H., Muller J.E. "Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population". Am J Cardiol 1987;60:801-806.

    CrossrefMedlineGoogle Scholar

  • 123. Levine R.L., Pepe P.E., Fromm R.E., Curka P.A., Clark P.A. "Prospective evidence of a circadian rhythm for out-of-hospital cardiac arrests". JAMA 1992;267:2935-2937.

    CrossrefMedlineGoogle Scholar

  • 124. Bagai A., McNally B.F., Al-Khatib S.M., et al. "Temporal differences in out-of-hospital cardiac arrest incidence and survival". Circulation 2013;128:2595-2602.

    CrossrefMedlineGoogle Scholar

  • 125. Kutyifa V., Moss A.J., Schuger C., et al. "Reduction in inappropriate ICD therapy in MADIT-RIT patients without history of atrial tachyarrhythmia". J Cardiovasc Electrophysiol 2015;26:879-884.

    CrossrefMedlineGoogle Scholar

  • 126. Maron B.J., Kogan J., Proschan M.A., Hecht G.M., Roberts W.C. "Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy". J Am Coll Cardiol 1994;23:1405-1409.

    View ArticleGoogle Scholar

  • 127. Matsuo K., Kurita T., Inagaki M., et al. "The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome". Eur Heart J 1999;20:465-470.

    CrossrefMedlineGoogle Scholar

  • 128. Miyake C.Y., Asaki S.Y., Webster G., et al. "Circadian variation of ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia". J Am Coll Cardiol EP 2017;3:1308-1317.

    Google Scholar

  • 129. Adler A., Novelli V., Amin A.S., et al. "An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome". Circulation 2020;141:418-428.

    CrossrefMedlineGoogle Scholar

  • 130. Takigawa M., Kawamura M., Noda T., et al. "Seasonal and circadian distributions of cardiac events in genotyped patients with congenital long QT syndrome". Circ J 2012;76:2112-2118.

    CrossrefMedlineGoogle Scholar

  • 131. Schwartz P.J., Priori S.G., Spazzolini C., et al. "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias". Circulation 2001;103:89-95.

    CrossrefMedlineGoogle Scholar

  • 132. Thosar S.S., Butler M.P., Shea S.A. "Role of the circadian system in cardiovascular disease". J Clin Invest 2018;128:2157-2167.

    CrossrefMedlineGoogle Scholar

  • 133. Muller J.E., Tofler G.H., Stone P.H. "Circadian variation and triggers of onset of acute cardiovascular disease". Circulation 1989;79:733-743.

    CrossrefMedlineGoogle Scholar

  • 134. Shen M.J., Zipes D.P. "Role of the autonomic nervous system in modulating cardiac arrhythmias". Circ Res 2014;114:1004-1021.

    CrossrefMedlineGoogle Scholar

  • 135. Meyer C., Scherschel K. "Ventricular tachycardia in ischemic heart disease: the sympathetic heart and its scars". Am J Physiol Heart Circ Physiol 2017;312:H549-H551.

    CrossrefMedlineGoogle Scholar

  • 136. Vaseghi M., Gima J., Kanaan C., et al. "Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: intermediate and long-term follow-up". Heart Rhythm 2014;11:360-366.

    CrossrefMedlineGoogle Scholar

  • 137. Won S.M., Cai L., Gutruf P., Rogers J.A. "Wireless and battery-free technologies for neuroengineering". Nat Biomed Eng Published online March8, 2021. https://doi.org/10.1038/s41551-021-00683-3.

    Google Scholar

  • 138. Black N., D'Souza A., Wang Y., et al. "Circadian rhythm of cardiac electrophysiology, arrhythmogenesis, and the underlying mechanisms". Heart Rhythm 2019;16:298-307.

    CrossrefMedlineGoogle Scholar

  • 139. Kong T.Q., Goldberger J.J., Parker M., Wang T., Kadish A.H. "Circadian variation in human ventricular refractoriness". Circulation 1995;92:1507-1516.

    CrossrefMedlineGoogle Scholar

  • 140. Malpas S.C., Purdie G.L. "Circadian variation of heart rate variability". Cardiovasc Res 1990;24:210-213.

    CrossrefMedlineGoogle Scholar

  • 141. Man A.W.C., Li H., Xia N. "Circadian rhythm: potential therapeutic target for atherosclerosis and thrombosis". Int J Mol Sci 2021;22:2: 676.

    CrossrefGoogle Scholar

  • 142. Portaluppi F., Tiseo R., Smolensky M.H., Hermida R.C., Ayala D.E., Fabbian F. "Circadian rhythms and cardiovascular health". Sleep Med Rev 2012;16:151-166.

    CrossrefMedlineGoogle Scholar

  • 143. Rubenstein J.C., Freher M., Kadish A., Goldberger J.J. "Diurnal heart rate patterns in inappropriate sinus tachycardia". Pacing Clin Electrophysiol 2010;33:911-919.

    MedlineGoogle Scholar

  • 144. Cuspidi C., Tadic M., Sala C., Gherbesi E., Grassi G., Mancia G. "Blood pressure non-dipping and obstructive sleep apnea syndrome: a meta-analysis". J Clin Med 2019;8:9: 1367.

    CrossrefGoogle Scholar

  • 145. Bernardi J., Aromolaran K.A., Zhu H., Aromolaran A.S. "Circadian mechanisms: cardiac ion channel remodeling and arrhythmias". Front Physiol 2020;11:611860.

    CrossrefMedlineGoogle Scholar

  • 146. Baschieri F., Cortelli P. "Circadian rhythms of cardiovascular autonomic function: Physiology and clinical implications in neurodegenerative diseases". Auton Neurosci 2019;217:91-101.

    CrossrefMedlineGoogle Scholar

  • 147. Foster R.G. "Sleep, circadian rhythms and health". Interface Focus 2020;10:20190098.

    CrossrefMedlineGoogle Scholar

  • 148. Malpas S.C., Maling T.J. "Heart-rate variability and cardiac autonomic function in diabetes". Diabetes 1990;39:1177-1181.

    CrossrefMedlineGoogle Scholar

  • 149. Mayuga K.A., Thattassery E., Taneja T., et al. "Circadian and gender effects on repolarization in healthy adults: a study using harmonic regression analysis". Ann Noninvasive Electrocardiol 2010;15:3-10.

    CrossrefMedlineGoogle Scholar

  • 150. Montag S.E., Knutson K.L., Zee P.C., et al. "Association of sleep characteristics with cardiovascular and metabolic risk factors in a population sample: the Chicago Area Sleep study". Sleep Health 2017;3:107-112.

    CrossrefMedlineGoogle Scholar

  • 151. Bray M.S., Shaw C.A., Moore M.W.S., et al. "Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression". Am J Physiol Heart Circ Physiol 2008;294:H1036-H1047.

    CrossrefMedlineGoogle Scholar

  • 152. D'Souza A., Wang Y., Anderson C., et al. "A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate". Heart Rhythm 2021 May;18:5: 801-810.

    CrossrefMedlineGoogle Scholar

  • 153. Schroder E.A., Burgess D.E., Zhang X., et al. "The cardiomyocyte molecular clock regulates the circadian expression of Kcnh2 and contributes to ventricular repolarization". Heart Rhythm 2015;12:1306-1314.

    CrossrefMedlineGoogle Scholar

  • 154. Angelousi A., Kassi E., Nasiri-Ansari N., Weickert M.O., Randeva H., Kaltsas G. "Clock genes alterations and endocrine disorders". Eur J Clin Invest 2018;48: e12927.

    CrossrefGoogle Scholar

  • 155. Shimba S., Ogawa T., Hitosugi S., et al. "Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation". PLoS One 2011;6: e25231.

    CrossrefMedlineGoogle Scholar

  • 156. Vukolic A., Antic V., Van Vliet B.N., Yang Z., Albrecht U., Montani J.-P. "Role of mutation of the circadian clock gene Per2 in cardiovascular circadian rhythms". Am J Physiol Regul Integr Comp Physiol 2010;298:R627-R634.

    CrossrefMedlineGoogle Scholar

  • 157. Harper R.M., Verrier R.L. "Cardiovascular physiology and coupling with respiration: central and autonomic regulation". In: Kryger M.H., Roth T., Dement W.C. , eds. Principles and Practice of Sleep Medicine 6th ed.WB Saunders, 2016. 132-141.

    Google Scholar

  • 158. Verrier R.L., Josephson M.E. "Impact of sleep on arrhythmogenesis". Circ Arrhythm Electrophysiol 2009;2:450-459.

    CrossrefMedlineGoogle Scholar

  • 159. Somers V.K., Dyken M.E., Mark A.L., Abboud F.M. "Sympathetic-nerve activity during sleep in normal subjects". N Engl J Med 1993;328:303-307.

    CrossrefMedlineGoogle Scholar

  • 160. Verrier R.L., Muller J.E., Hobson J.A. "Sleep, dreams, and sudden death: the case for sleep as an autonomic stress test for the heart". Cardiovasc Res 1996;31:181-211.

    CrossrefMedlineGoogle Scholar

  • 161. Javaheri S., Barbe F., Campos-Rodriguez F., et al. "Sleep apnea: types, mechanisms, and clinical cardiovascular consequences". J Am Coll Cardiol 2017;69:841-858.

    View ArticleGoogle Scholar

  • 162. Guyenet P.G. "Regulation of breathing and autonomic outflows by chemoreceptors". Compr Physiol 2014;4:1511-1562.

    CrossrefMedlineGoogle Scholar

  • 163. van Duijvenboden S., Hanson B., Child N., et al. "Effect of autonomic blocking agents on the respiratory-related oscillations of ventricular action potential duration in humans". Am J Physiol Heart Circ Physiol 2015;309:H2108-H2117.

    CrossrefMedlineGoogle Scholar

  • 164. Waypa G.B., Smith K.A., Schumacker P.T. "O2 sensing, mitochondria and ROS signaling: the fog is lifting". Mol Aspects Med 2016;47-48:76-89.

    CrossrefMedlineGoogle Scholar

  • 165. Yeo E.J. "Hypoxia and aging". Exp Mol Med 2019;51:1-15.

    Google Scholar

  • 166. Henderson L.A., Macefield V.G. "Obstructive sleep apnoea and hypertension: the role of the central nervous system". Curr Hypertens Rep 2016;18:59.

    CrossrefMedlineGoogle Scholar

  • 167. Mashaqi S., Gozal D. "Obstructive sleep apnea and systemic hypertension: gut dysbiosis as the mediator?"J Clin Sleep Med 2019;15:1517-1527.

    CrossrefMedlineGoogle Scholar

  • 168. Dedhia R.C., Shah A.J., Bliwise D.L., et al. "Hypoglossal nerve stimulation and heart rate variability: analysis of STAR trial responders". Otolaryngol Head Neck Surg 2019;160:165-171.

    CrossrefMedlineGoogle Scholar

  • 169. Won C.H.J., Reid M., Sofer T., et al. "Sex differences in obstructive sleep apnea phenotypes, the Multi-Ethnic Study of Atherosclerosis". Sleep 2020;43:5: zsz274.

    CrossrefMedlineGoogle Scholar

  • 170. Edwards B.A., Redline S., Sands S.A., Owens R.L. "More than the sum of the respiratory events: personalized medicine approaches for obstructive sleep apnea". Am J Respir Crit Care Med 2019;200:691-703.

    CrossrefMedlineGoogle Scholar

  • 171. Azarbarzin A., Sands S.A., Younes M., et al. "The sleep apnea-specific pulse rate response predicts cardiovascular morbidity and mortality". Am J Respir Crit Care Med 2021;203:12: 1546-1555.

    CrossrefMedlineGoogle Scholar

  • 172. May A.M., May R.D., Bena J., et al. "Osteoporotic Fractures in Men (MrOS) Study Group. Individual periodic limb movements with arousal are temporally associated with nonsustained ventricular tachycardia: a case-crossover analysis". Sleep 2019;42:11: zsz165.

    CrossrefMedlineGoogle Scholar

  • 173. Winkelman J.W., Blackwell T., Stone K., Ancoli-Israel S., Redline S. "Associations of incident cardiovascular events with restless legs syndrome and periodic leg movements of sleep in older men, for the outcomes of sleep disorders in older men study (mros sleep study)". Sleep 2017;40:4: zsx023.

    CrossrefGoogle Scholar

  • 174. Javaheri S., Redline S. "Insomnia and risk of cardiovascular disease". Chest 2017;152:435-444.

    CrossrefMedlineGoogle Scholar

  • 175. de Man F.S., Handoko M.L., Guignabert C., Bogaard H.J., Vonk-Noordegraaf A. "Neurohormonal axis in patients with pulmonary arterial hypertension: friend or foe?"Am J Respir Crit Care Med 2013;187:14-19.

    CrossrefMedlineGoogle Scholar

  • 176. Rain S., Handoko M.L., Trip P., et al. "Right ventricular diastolic impairment in patients with pulmonary arterial hypertension". Circulation 2013;128:18: 2016-2025.

    CrossrefMedlineGoogle Scholar

  • 177. van Campen J.S., de Boer K., van de Veerdonk M.C., et al. "Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study". Eur Respir J 2016;48:787-796.

    CrossrefMedlineGoogle Scholar

  • 178. Hemnes A.R., Rathinasabapathy A., Austin E.A., et al. "A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension". Eur Respir J 2018;51:6: 1702638.

    CrossrefMedlineGoogle Scholar

  • 179. da Silva Gonçalves Bós D., Van Der Bruggen C.E.E., Kurakula K., et al. "Contribution of impaired parasympathetic activity to right ventricular dysfunction and pulmonary vascular remodeling in pulmonary arterial hypertension". Circulation 2018;137:910-924.

    CrossrefMedlineGoogle Scholar

  • 180. van Grunsven P.M., van Schayck C.P., Molema J., Akkermans R.P., van Weel C. "Effect of inhaled corticosteroids on bronchial responsiveness in patients with “corticosteroid naive” mild asthma: a meta-analysis". Thorax 1999;54:316-322.

    CrossrefMedlineGoogle Scholar

  • 181. Hanxiang N., Jiong Y., Yanwei C., et al. "Persistent airway inflammation and bronchial hyperresponsiveness in patients with totally controlled asthma". Int J Clin Pract 2008;62:599-605.

    CrossrefMedlineGoogle Scholar

  • 182. Peters S.P., Kunselman S.J., Icitovic N., et al. "Tiotropium bromide step-up therapy for adults with uncontrolled asthma". N Engl J Med 2010;363:1715-1726.

    CrossrefMedlineGoogle Scholar

  • 183. Nie Z., Maung J.N., Jacoby D.B., Fryer A.D. "Lung eosinophils increase vagus nerve-mediated airway reflex bronchoconstriction in mice". Am J Physiol Lung Cell Mol Physiol 2020;318:2: L242-L251.

    CrossrefMedlineGoogle Scholar

  • 184. Canning B.J. "Reflex regulation of airway smooth muscle tone". J Appl Physiol 2006;101:971-985.

    CrossrefMedlineGoogle Scholar

  • 185. Undem B.J., Potenzieri C. "Autonomic neural control of intrathoracic airways". Compr Physiol 2012;2:1241-1267.

    CrossrefMedlineGoogle Scholar

  • 186. McAlexander M.A., Gavett S.H., Kollarik M., Undem B.J. "Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse". Respir Physiol Neurobiol 2015;212-214:20-24.

    CrossrefMedlineGoogle Scholar

  • 187. Trankner D., Hahne N., Sugino K., Hoon M.A., Zuker C. "Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways". Proc Natl Acad Sci U S A 2014;111:11515-11520.

    CrossrefMedlineGoogle Scholar

  • 188. Awad M., Czer L.S.C., Hou M., et al. "Early denervation and later reinnervation of the heart following cardiac transplantation: a review". J Am Heart Assoc 2016;5:11: e004070.

    CrossrefMedlineGoogle Scholar

  • 189. Buendía Fuentes F., Martínez-Dolz L., Almenar Bonet L., et al. "Normalization of the heart rate response to exercise 6 months after cardiac transplantation". Transplant Proc 2010;42:3186-3188.

    CrossrefMedlineGoogle Scholar

  • 190. Grupper A., Gewirtz H., Kushwaha S. "Reinnervation post-heart transplantation". Eur Heart J 2018;39:1799-1806.

    MedlineGoogle Scholar

  • 191. Bleecker E.R. "Cholinergic and neurogenic mechanisms in obstructive airways disease". Am J Med 1986;81:93-102.

    CrossrefMedlineGoogle Scholar

  • 192. Niewoehner D.E., Rice K., Cote C., et al. "Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial". Ann Intern Med 2005;143:317-326.

    CrossrefMedlineGoogle Scholar

  • 193. Vogelmeier C., Hederer B., Glaab T., et al. "Tiotropium versus salmeterol for the prevention of exacerbations of COPD". N Engl J Med 2011;364:1093-1103.

    CrossrefMedlineGoogle Scholar

  • 194. Slebos D.J., Shah P.L., Herth F.J.F., et al. "Safety and Adverse Events after Targeted Lung Denervation for Symptomatic Moderate to Severe Chronic Obstructive Pulmonary Disease (AIRFLOW). A multicenter randomized controlled clinical trial". Am J Respir Crit Care Med 2019;200:1477-1486.

    CrossrefMedlineGoogle Scholar

  • 195. Valipour A., Shah P.L., Herth F.J., et al. "Two-year outcomes for the double-blind, randomized, sham-controlled study of targeted lung denervation in patients with moderate to severe COPD: AIRFLOW-2". Int J Chron Obstruct Pulmon Dis 2020;15:2807-2816.

    CrossrefMedlineGoogle Scholar

  • 196. Slebos D.J., Degano B., Valipour A., Shah P.L., Deslée G., Sciurba F.C. "Design for a multicenter, randomized, sham-controlled study to evaluate safety and efficacy after treatment with the Nuvaira® lung denervation system in subjects with chronic obstructive pulmonary disease (AIRFLOW-3)". BMC Pulm Med 2020;20:41.

    CrossrefMedlineGoogle Scholar

  • 197. Hummel J.P., Mayse M.L., Dimmer S., Johnson P.J. "Physiologic and histopathologic effects of targeted lung denervation in an animal model". J Appl Physiol (1985) 2019;126:67-76.

    CrossrefMedlineGoogle Scholar

  • 198. Valipour A., Mayse M.L., Peterson A.D., et al. "Respiratory sinus arrhythmia attenuation via targeted lung denervation in sheep and humans". Respiration 2019;98:434-439.

    CrossrefMedlineGoogle Scholar

  • 199. Mazzone S.B., Undem B.J. "Vagal afferent innervation of the airways in health and disease". Physiol Rev 2016;96:975-1024.

    CrossrefMedlineGoogle Scholar

  • 200. Taylor-Clark T.E. "Molecular identity, anatomy, gene expression and function of neural crest vs. placode-derived nociceptors in the lower airways". Neurosci Lett 2021;742:135505.

    CrossrefMedlineGoogle Scholar

  • 201. Goldstein D.S. "Concepts of scientific integrative medicine applied to the physiology and pathophysiology of catecholamine systems". Compr Physiol 2013;3:1569-1610.

    CrossrefMedlineGoogle Scholar

  • 202. Goldberger J.J., Arora R., Buckley U., Shivkumar K. "Autonomic nervous system dysfunction: JACC focus seminar". J Am Coll Cardiol 2019;73:1189-1206.

    View ArticleGoogle Scholar