Abstract
Peripheral and central chemoreflexes are the dominant autonomic mechanisms regulating ventilatory patterns in response to changes in partial pressures of oxygen and carbon dioxide in arterial blood and exert powerful effects on neural circulatory control. Both reflex pathways are capable of eliciting increases in sympathetic nerve traffic and consequent increases in blood pressure. Chronic heart failure is accompanied by a sustained elevation in sympathetic nerve traffic, which is thought to be an important component in the pathophysiology and progression of the disease. The role of chemoreflex mechanisms in the control of sympathetic function during heart failure is an important topic for which there are many questions and few answers. This review summarizes available evidence documenting peripheral and central chemoreflex function in heart failure, possible mechanisms for their alteration, and their possible contribution to ventilatory, and circulatory abnormalities that occur in heart failure.
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Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol 1993;22(suppl. A):72A–84A.
Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73:913–919.
Mark AL. Sympathetic dysregulation in heart failure: mechanisms and therapy. Clin Cardiol 1995;18(suppl. I):I-3–I-8.
Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. New Engl J Med 1971;285(16):877–883.
Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S, for the SOLVD Investigators. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of left ventricular dysfunction (SOLVD). Circulation 1990;82:1724–1729.
Zucker IH, Wang W, Brandle M, Schultz HD. Baroreflex and cardiac reflex control of the circulation in pacing-induced heart failure. In Pathophysiology of Tachycardia-Induced Heart Failure, ed. FG Spinale, Futura Pub. Co., 1996; Chapter 11, pp. 193-226.
Zucker IH, Wang W, Brändle M, Schultz HD, Patel KP. Neural regulation of sympathetic nerve activity in heart failure. Prog Cardiovasc Dis 1995;37:397–414.
Thames MD, Kinugawa T, Smith ML, Dibner-Dunlap ME. Abnormalities of baroreflex control in heart failure. J Am Coll Cardiol 1993;22(suppl. A):56A–60A.
Brandle M, Patel KP, Wang W, Zucker IH. Hemodynamic and norepinephrine responses to pacinginduced heart failure in conscious sino-aortic denervated dogs. J Appl Physiol 1996;81:1855–1866.
Levett JM, Marinelli CC, Lund DD, Pardini BJ, Nader S, Scott BD, Augelli NV, Kerber RE, Schmid PG. Effects of beta-blockade on neurohumoral responses and neurochemical markers in pacing-induced heart failure. Am J Physiol 1994;266:H468–475.
Wang W, Schultz HD, Ma R. Cardiac sympathetic afferent activity is enhanced in heart failure. Am J Physiol 1999;277:H812–H817.
Sinoway LI. Neural responses to exercise in humans: implications for congestive heart failure. Clin Exp Pharmacol Physiol 1996;23:693–699.
Chugh SS, Chua TP, Coats AJS. Peripheral chemoreflex in chronic heart failure: Friend and foe. Am Heart J 1996;132:900–904.
Narkiewicz K, Pesek CA, Philippe JH, van deBorne JH, Kato M, Somers VK. Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Circulation 1999;100:262–267.
Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol 1999;86:1264–1272.
van de Borne P, Oren R, Anderson EA, Mark AL, Somers VK. Tonic chemoreflex activation does not contribute to elevated muscle sympathetic nerve activity in heart failure. Circulation 1996;94:1325–1328.
Haque WA, Boehmer J, Clemson BS, Leuenberger UA, Silber DH, Sinoway LI. Hemodynamic effects of supplemental oxygen administration in congestive heart failure. J Am Coll Cardiol 1996;27:353–357.
Chua TP, Ponikowski PP, Harrington D, Chambers J, Coats AJS. Contribution of peripheral chemoreceptors to ventilation and the effects of their suppression on exercise tolerance in chronic heart failure. Heart 1996;76:483–489.
Chua T, Clark AL, Amadi AA, Coats AJS. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1996;27:650–657.
Chua TP, Ponikowski P, Webb-Peploe K, Harrington D, Anker S, Piepoli M, Coats AJS. Clinical characteristics of patients with an augmented peripheral chemoreflex in chronic heart failure. Eur Heart J 1997;18:480–487.
Ponikowski PP, Chua TP, Piepoli M, Ondusova D, Harrington D, Anker SD, Volterrani M, Columbo R, Mazzuero G, Giordano A, Coats AJS. Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation 1997;96:2586–2594.
Chua TP, Harrington D, Ponikowski PP, Webb-Peploe K, Poole-Wilson PA, Coats AJS. Effects of dihydrocodeine on chemosensitivity and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 1997;29:147–152.
Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev 1994;74:543–594.
Somers VK, Mark AL, Zavala DC, Abboud FM. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol 1989;67:2095–2100.
Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest 1991;87(6):1953–1957.
Seals DR, Johnson DG, Fregosi RF. Hyperoxia lowers sympathetic nerve activity at rest but not during exercise in humans. Am J Physiol 1991;260:R873–R878.
Przybylski J, Trzebski A, Czyewski T, Jodkowski J. Responses to hyperoxia, hypoxia, hypercapnia, and almitine in spontaneously hypertensive rat. Bull Eur Physiopathol Respir 1982;18:145–154.
Narkiewicz K, Philippe JH, van deBorne JH, Pesek CA, Dyken ME, Montano N, Somers VK. Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 1999;99:1183–1189.
Liu JL, Zucker IH. Regulation of sympathetic nerve activity in heart failure: a role for nitric oxide and angiotensin II. Circ Res 1999;84:417–423.
Murakami H, Liu JL, Zucker IH. Angiotensin II blockade enhances baroreflex control of sympathetic outflow in heart failure. Hypertension 1997;29:564–569. [published erratum appears in Hypertension 1997;29:1211].
Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. J Appl Physiol 1999;86:1273–1282.
Prabhakar NR. Neurotransmitters in the carotid body. In Arterial Chemoreceptors Cell to System, ed. R. O'Regan et al., Plenum Press, New York, 1994; pp. 57–69.
Grimes P, Lahiri S, Stone R, Mokashi A, Chug D. Nitric oxide synthase occurs in neurons and nerve fibers of the carotid body. In R. O'Regan, et al. eds. Arterial Chemoreceptors: Cell to System. New York, Plenum Press, 1994, 221–224.
Wang ZZ, Bredt DS, Fidone SJ, Stensaas LJ. Neurons synthesizing nitric oxide innervate the mammalian carotid body. J Comp Neurol 1993;336:419–432.
Prabhakar NR, Kumar GK, Chang CH, Agani FH, Haxhiu MA. Nitric oxide in the sensory function of the carotid body. Brain Res 1993;625:16–22.
Wang ZZ, Stensaas LJ, Bredt DS, Dinger B, Fidone SJ. Localization and actions of nitric oxide in the cat carotid body. Neuroscience 1994;60:275–286.
Wang ZZ, Stensaas LJ, Dinger BG, Fidone SJ. Nitric oxide mediates chemoreceptor inhibition in the cat carotid body. Neuroscience 1995;65:217–229.
Trzebski A, Sato Y, Suzuki A, Sato A. Inhibition of nitric oxide synthesis potentiates the responsiveness of carotid chemoreceptors to systemic hypoxia in the rat. Neurosci Letters 1995;190:29–32.
Mohri M, Egashira K, Tagawa T, Kuga T, Tagawa H, Harasawa Y, Shimokawa H, Takeshita A. Basal release of nitric oxide is decreased in the coronary circulation in patients with heart failure. Hypertension 1997;30:50–56.
Smith CJ, Sun D, Hoegler C, Roth BS, Zhang X, Zhao G, Xu XB, Kobary Y, Pritchard K, Sessa WC, Hintze TH. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res 1996;78:58–65.
Zhao G, Shen W, Zhang X, Smith CJ, Hintze TH. Loss of nitric oxide production in the coronary circulation after the development of dilated cardiomyopathy: a specific defect in the neural regulation of coronary blood flow. Clin Exp Pharmacol Physiol 1996;23:715–721.
Billiar TR. Nitric oxide: novel biology with clinical relevance. Ann Surgery 1995;221:339–349.
Beesley JE. Histochemical methods for detecting nitric oxide synthase. Histochem J 1995;27:757–769.
Gozal D, Gozal E, Gozal YM, Torres JE. Nitric oxide synthase isoforms and peripheral chemoreceptor stimulation in conscious rats. NeuroReport 1996;7:1145–1148.
Wang WJ, He L, Chen J, Dinger B, Fidone S. Mechanisms underlying chemoreceptor inhibition induced by atrial natriuretic peptide in rabbit carotid body. J Physiol 1993;460:427–441.
Summers BA, Overholt JL, Prabhakar NR. Modulation of Ca.. currents by nitric oxide in glomus cells of the carotid body: evidence for a cGMP-independent mechanism. The FASEB J 1998;12:A167.
Wennergren G, Little R, Oberg B. Studies on the central integration of excitatory chemoreceptor influences and inhibitory baroreceptor and cardiac receptor influences. Acta Physiol Scand 1976;96(1): 1–18.
Trzebski A, Lipski J, Majcherczyk S, Szulczyk P, Chruscielewski L. Central organization and interaction of the carotid body baroreceptor and chemoreceptor sympathetic reflex. Brain Res 1975;87:227–237.
Marshall JM. Interaction between the responses to stimulation of peripheral chemoreceptors and baroreceptors: the importantce of chemoreceptor activation of the defence area. J Auto Nerv Syst 1981;3:389–400.
Langhorst P, Schulz B, Schulz G, Lambertz M. Reticular formation of the lower brainstem. A common system for cardiorespiratory and somatomotor functions: discharge patterns of neighboring neurons influenced by cardiovascular and respiratory afferents. J Auto Nerv Syst 1983;9:411–432.
Caverson M, Cirello J, Calaresu F. Chemoreceptor and baroreceptor inputs to ventrolateral medullar neurons. Am J Physiol 1984;247:R872–R879.
Francis GS. The relationship of the sympathetic nervous system and the renin angiotensin system in congestive heart failure. Am Heart J 1989;118:642–648.
Reid IA. Interactions between ANGII, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol 1992;262:E763–E778.
Ohtake PJ, Jennings DB. Angiotensin II stimulates respiration in awake dogs and antagonizes baroreceptor inhibition. Respir Physiol 1993;91:335–351.
DiBona GF, Jones SY, Brooks VL. ANG II receptor blockade and arterial baroreflex regulation of renal Chemoreflexes in heart failure 55 nerve activity in cardiac failure. Am J Physiol 1995;269:R1189-R1196.
Liu JL, Murakami H, Sanderford M, Bishop VS, Zucker IH. ANG II and baroreflex function in rabbits with CHF and lesions of the area postrema. Am J Physiol 1999;277:H324–H350.
Sun SY, Wang W, Zucker IH, Schultz HD. Alteration of peripheral chemoreflex and arterial baroreflex in heart failure: Role of central angiotensin II. The FASEB J 1999;13:A444.
Wilcox I, Grunstein RR, Collins FL, Berthon-Jones M, Kelly DT, Sullivan CE. The role of central chemosensitivity in central apnea of heart failure. Sleep 1993;16:S37–38.
Tankersley C, Kleeberger S, Russ B, Schwartz A, Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol 1996;81:716–723.
Levya F, Anker SD, Egerer K, Stevenson JC, Kox WJ, Coats AJS. Hyperleptinaemia in chronic heart failure: relationships with insulin. Eur Heart J 1998;19:1547–1551.
Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A. Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87:V140–V148.
Gordon A, Tyni-Lenne R, Jansson E, Kaijser L, Theodorsson-Norheim E, Sylven C. Improved ventilation and decreased sympathetic stress in chronic heart failure patients following local endurance training with leg muscles. J Card Fail 1997;3:3–12.
European Heart Failure Training Group. Experience from controlled trials of physical training in chronic heart failure. Protocol and patient factors in effectiveness in the improvement in exercise tolerance. Eur Heart J 1998;19:466–75.
Coats AJ, Adamopoulos S, Radaelli A, McCance A, Meyer TE, Bernardi L, Solda PL, Davey P, Ormerod O, Forfar C, et al. Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function. Circulation 1992;85:2119–31.
Kiilavuori K, Toivonen L, Naveri H, Leinone H. Reversal of autonomic derangements by physical training in chronic heart failure assessed by heart rate variability. Eur Heart J 1995;16:490–5.
Toepfer M, Meyer K, Maier P, Dambacher M, Theisen K, Roskamm H, Frey AW. Influence of exercise training and restriction of activity on autonomic balance in patients with severe congestive heart failure. Clin Sci (Colch) 1996;91(Suppl):116.
Zhao G, Zhang X, Xu X, Ochoa M, Hintze TH. Shortterm exercise training enhances reflex cholinergic nitric oxide-dependent coronary vasodilation in conscious dogs. Circ Res 1997;80:868-76.
Woodman CR, Muller JM, Laughlin MH, Price EM. Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs. Am J Physiol 1997;273:H2575–9.
Katz SD, Yuen J, Bijou R, LeJemtel TH. Training improves endothelium-dependent vasodilation in resistance vessels of patients with heart failure. J Appl Physiol 1997;82:1488–1492.
Wang J, Yi GH, Knecht M, Cai BL, Poposkis S, Packer M, Burkhoff D. Physical training alters the pathogenesis of pacing-induced heart failure through endothelium-mediated mechanisms in awake dogs. Circulation 1997;96:2683–92.
Sun SY, Wang L, Wang W, Zucker IH, Schultz HD. Exercise training normalizes enhanced peripheral chemoreflex function in rabbits with heart failure. The FASEB J 1999;13:A444.
Buller SA, Poole-Wilson PA. Mechanisms of increased ventilatory responses to exercise in patients with chronic heart failure. Br Heart J 1990;63:281–283.
Yokoyama H, Sato H, Hori M et al. A characteristic change in ventilation mode during exertional dyspnea in patients with heart failure. Chest 1994;104:1007–1013.
Clark AL, Coats AJS. The mechanisms underlying the increased ventilatory response to exercise in chronic stable heart failure. Eur Heart J 1992;13:1698–1708.
Chua TP, Clark AL, Amadi AA, Coats AJS. Increased chemoreceptor sensitivity: a contributory cause of dyspnea in chronic heart failure. J Am Coll Cardiol 1995;February(special issue):265A.
Andreas S, Weidel K, Hagernah G, Heindl S. Treatment of Cheyne-Stokes respiration with nasal oxygen and carbon dioxide. Eur Resp J 1998;12:414–419.
Andreas S, von Breska B, Kopp E. et al. Periodic respiration in patients with heart failure. Clin Invest 1993;71:281–285.
Hanly MJ, Zuberi N, Gray R. Pathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure: Relationship with CO2. Chest 1993;104:1079–1084.
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Schultz, H.D., Sun, SY. Chemoreflex Function in Heart Failure. Heart Fail Rev 5, 45–56 (2000). https://doi.org/10.1023/A:1009846123893
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DOI: https://doi.org/10.1023/A:1009846123893