Altered Autonomic Nervous System Function in Sickle Cell Disease

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PAH worldwide. In the human form of chronic pulmonary schis- tosomiasis, Schistosoma mansoni eggs derived from the mesen- teric venules of the intestine ...
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PAH worldwide. In the human form of chronic pulmonary schistosomiasis, Schistosoma mansoni eggs derived from the mesenteric venules of the intestine bypass the liver and become lodged in the lung, producing a massive inflammatory response. The pulmonary vascular remodeling in human patients includes the most extreme forms of intimal remodeling discussed above, including complex fibrin thrombus organization, obliteration of the lumen through endothelial cell hyperplasia, and plexiform lesions in arteries and arterioles (17). Crosby and coworkers have previously reported development of a mouse model of chronic pulmonary schistosomiasis that reproduces most of the features of the human disease, including the formation of plexiform-like lesions (18). This study was particularly interesting because it demonstrated that only the most extreme remodeling was capable of increasing PVR enough to drive increased RVSP. In the present study, Crosby and colleagues show that praziquantel, a standard treatment for schistosomiasis that kills the adult worms, results in clearance of the eggs from the lung and a dramatic reversal of the worst of the remodeling, including reversal of the obliterative lesions, which have often been thought to be irreversible. The results of this study are important for those suffering from chronic pulmonary schistosomiasis, but also have important implications for those suffering from any form of PAH. We have previously said that reversibility of PAH will require not only the elimination of the underlying cause of the vascular injury, but also regression of the existing vascular lesions. The study by Crosby and coworkers implies that if one eliminates the underlying cause, even the worst of the existing vascular lesions may regress on their own. This exciting research still leaves many questions unanswered. What is the longer-term course of regression in this model? How well does regression in the mouse lung reflect regression in human patients? Are the apparent differences in regression between human patients the result of differences in severity of pathology, or differences in underlying genetic factors? Is regression an active or a passive process, at a molecular level? The work of Crosby and colleagues is a first step in addressing these important questions, and gives us the first solid model system in which to address them. Author Disclosure: J.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

James West, Ph.D. Department of Medicine Vanderbilt University Medical Center Nashville, Tennessee References 1. Dammann JF Jr,Mc EJ, Thompson WM Jr, Smith R, Muller WH Jr. The regression of pulmonary vascular disease after the creation of pulmonary stenosis. J Thorac Cardiovasc Surg 1961;42:722–734. 2. Wagenvoort CA. Morphological substrate for the reversibility and irreversibility of pulmonary hypertension. Eur Heart J 1988;9:7–12.

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3. Ferguson DJ, Berkas EM, Varco RL. Process of healing in experimental pulmonary arteriosclerosis. Proc Soc Exp Biol Med 1955;89:492–494. 4. Heath D, Helmholz HF Jr, Burchell HB, Dushane JW, Kirklin JW, Edwards JE. Relation between structural change in the small pulmonary arteries and the immediate reversibility of pulmonary hypertension following closure of ventricular and atrial septal defects. Circulation 1958;18:1167–1174. 5. Blank RH, Muller WH Jr, Dammann JF Jr. Changes in pulmonary vascular lesions after restoring normal pulmonary artery pressure. Surg Forum 1958;9:356–359. 6. Geer JC, Glass BA, Albert HM. The morphogenesis and reversibility of experimental hyperkinetic pulmonary vascular lesions in the dog. Exp Mol Pathol 1965;26:399–415. 7. Huang JB, Liu YL, Yu CT, Lv XD, Du M, Wang Q, Kong B. Lung biopsy findings in previously inoperable patients with severe pulmonary hypertension associated with congenital heart disease. Int J Cardiol (In press) 8. Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis 2011;6:199–208. 9. Naeije R, Barbera JA. Pulmonary hypertension associated with COPD. Crit Care 2001;5:286–289. 10. Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 2009;10:6. 11. Voelkel NF, Tuder RM, Wade K, Hoper M, Lepley RA, Goulet JL, Koller BH, Fitzpatrick F. Inhibition of 5-lipoxygenase-activating protein (flap) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats. J Clin Invest 1996;97:2491– 2498. 12. Morecroft I, Doyle B, Nilsen M, Kolch W, Mair K, Maclean M. Mice lacking the raf-1 kinase inhibitor protein exhibit exaggerated hypoxia-induced pulmonary hypertension. Br J Pharmacol 2011;163: 948–963. 13. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009;104:236–244. 14. Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, Jiang YP, Chen JJ, Waschek JA, Kort S. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation 2007;115:1260–1268. 15. Nagayoshi M, Tada Y, West J, Ochiai E, Watanabe A, Toyotome T, Tanabe N, Takiguchi Y, Shigeta A, Yasuda T, et al. Inhalation of stachybotrys chartarum evokes pulmonary arterial remodeling in mice, attenuated by rho-kinase inhibitor. Mycopathologia (In press) 16. Crosby A, Jones FM, Kolosionek E, Southwood M, Purvis I, Soon E, Butrous G, Dunne DW, Morrell NW. Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis. Am J Respir Crit Care Med 2011;184:467–473. 17. Bethlem EP, Schettino Gde P, Carvalho CR. Pulmonary schistosomiasis. Curr Opin Pulm Med 1997;3:361–365. 18. Crosby A, Jones FM, Southwood M, Stewart S, Schermuly R, Butrous G, Dunne DW, Morrell NW. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med 2010;181:279–288.

DOI: 10.1164/rccm.201106-1095ED

Altered Autonomic Nervous System Function in Sickle Cell Disease The few studies have investigated autonomic nervous system (ANS) function in patients with sickle cell disease (SCD) have reported alterations such as decreased parasympathetic activity and sympathetic activity predominance in steady-state conditions (1–3). Imbalances in ANS activity have been demonstrated as powerful and independent predictors of cardiovascular and

cerebrovascular adverse events, as well as of death (of any cause), in the general population and in patients with already established heart disease or metabolic syndrome (4, 5). However, the mechanisms by which ANS dysfunction could modulate or reflect the clinical severity of SCD are still poorly understood.

Editorials

In this issue of the Journal, Sangkatumvong and coworkers (pp. 474) investigated (1) the effect of a short transient hypoxic stress on the ANS response and peripheral microvascular perfusion; and (2) the relationships between respiration, ANS activity, and peripheral microvascular perfusion in patients with SCD and control subjects (6). Their current findings confirm their previous results (7) showing that transient hypoxic stress elicits parasympathetic withdrawal in patients with SCD, but not in control subjects. The reason of this ANS hypersensitivity to hypoxia in SCD is unknown. Setty and colleagues (8) previously reported that a significant percentage of SCD children presents prolonged nocturnal hypoxemic episodes with a mean sleeping oxygen saturation lower than 93%. Repeated nocturnal hypoxemia in patients with obstructive sleep apnea syndrome leads to higher sympathetic and lower parasympathetic tones (9), a finding that has been extensively investigated and confirmed in rodent models (10–12). Chronic intermittent hypoxia in rats results in a significant cell loss in the nucleus ambiguus (12), a structure from which several vagal efferent axons innervate ganglionated plexuses in the dorsal surface of cardiac atria, which in turn may have different functional roles in cardiac regulation (13). In addition, chronic intermittent hypoxia alters the structure of cardiac ganglia and results in reorganized vagal efferent projections to cardiac ganglia (11). One could infer that chronic and repeated hypoxic episodes in SCD could be at the origin of the ANS hypersensitivity to hypoxia and the alterations in parasympathetic responses observed by Sangkatumvong and coworkers (6). Further studies are needed to test the relationships between nocturnal oxygen desaturation and ANS function in SCD to clarify the underlying mechanisms of ANS dysfunction in this population. Surprisingly, this ANS hypersensitivity to hypoxia was not followed by a decrease in microvascular perfusion. Although not discussed by the authors, altered ANS function/reactivity could play a role in the pathophysiology of SCD independently of its effects on the vasomotor tone. Recently, it has been reported that parasympathetic activity may regulate inflammation (5). Indeed, decreased parasympathetic activity has been shown to affect the acetylcholine-driven inhibition of cytokines production/release by leukocytes (5). The hypersensitivity of ANS to hypoxia (6), and the altered baseline ANS activity in SCD (1–3), could therefore modulate the proinflammatory state observed in this disease, similar to what has been reported for obstructive sleep apnea syndrome (14), and thus play a role in SCD clinical severity. Altogether, these findings should stimulate further studies in SCD to test whether clinical severity, ANS dysfunction, and inflammatory state are related. Interestingly, under normoxia, Sangkatumvong and colleagues (6) observed that although patients with SCD exhibited the same sigh frequency as a control group, the probability of a sigh inducing a peripheral microvascular perfusion drop was greater in the SCD group (78%) than in control subjects (17%). In addition, their data suggest a sigh-induced sympathetic nervous system dominance in patients with SCD but not in control subjects. Since transient hypoxic stress induced ANS dysfunction without affecting peripheral vasoconstriction, the authors concluded that respiratory neural-mediated signals, rather than global hypoxia, could be the primary triggering event of vaso-occlusion. However, the mechanism underlying the vasoconstrictor response following a spontaneous sigh is not fully understood. During normal breathing, oscillations in blood flow coincident with respiration occur (15). These oscillations are probably mainly generated by the vagally mediated lung inflation feedback from active rhythms initiated during the inspiratory phase (involving lung and thorax afferents) causing discharge of sympathetic neurons (16). During a sigh, lung inflation is deeper and probably the

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activation of lung and thorax afferents is more pronounced, leading to greater vasoconstriction. Galland and coworkers (17) observed in infants that the deeper the inflation of the sigh relative to the previous breaths, the greater the vasoconstrictor response. It is unknown whether patients with SCD from the study of Sangkatumvong and colleagues (6) exhibited greater sigh inflations than control subjects, but the results from Galland and coworkers (17) suggest that breathing pattern may widely influence the vasoconstrictive response. Respiratory diseases including asthma and chronic sickle cell lung disease, characterized by restrictive lung function, decreased lung compliance, and ventilation/perfusion inequality, are common in SCD (18). Since basal lung function is expected to influence breathing (and sigh) patterns, the results obtained by Sangkatumvong and colleagues (6) will undoubtedly stimulate further researches investigating the relationships between ANS activity, peripheral blood flow, and lung function in SCD. This could be particularly relevant in the context of SCD, since several groups reported strong relationships between ANS dysfunction and respiratory diseases in subjects without SCD (19, 20). Of note, a more pronounced vasoconstriction to a sigh maneuver has been reported in patients with obstructive sleep apnea, in whom intermittent hypoxia is an important constituent of the disease (21). An important limitation of the study of Sangkatumvong and coworkers (6) relates to the lack of differentiation of patients with SCD according to their b-globin genotype. It appears that their results obtained in the whole SCD group (n ¼ 11) were the same with or without the three patients with sickle-hemoglobin C disease (SC). The limited number of patients with SC does not allow the authors to scrutinize potential differences between patients with sickle cell anemia (SCA) and SC disease. However, the frequency of vaso-occlusive crises, the clinical severity, and the hematological profile are very different between these two SCD entities. One should expect to find differences in ANS function as well. Larger cohort studies on SCD could improve our knowledge of the pathophysiological mechanisms of SCA and SC disease. In summary, the study by Sangkatumvong and colleagues (6) clearly demonstrates the presence of ANS dysfunction in patients with SCD. Although the involvement of the ANS in determining the phenotype of this disease is not yet fully understood, the findings support the concept of a role of ANS dysfunction in SCD-associated pathophysiological mechanisms. The reduced nitric oxide bioavailability in SCD (22) and the marked ANS dysfunction reported here could definitively increase the risks for vasoconstriction and vaso-occlusion in SCD. Author Disclosure: P.C. is employed by the University of the French West Indies.

Philippe Connes, Ph.D. Inserm U763 Universite´ des Antilles et de la Guyane Guadeloupe and Laboratory ACTES University of the French West Indies Guadeloupe References 1. Inamo J, Connes P, Barthelemy JC, Dan V, Coates T, Loko G. Pulmonary hypertension does not affect the autonomic nervous system dysfunction of sickle cell disease. Am J Hematol 2009;84:311–312. 2. Pearson SR, Alkon A, Treadwell M, Wolff B, Quirolo K, Boyce WT. Autonomic reactivity and clinical severity in children with sickle cell disease. Clin Auton Res 2005;15:400–407. 3. Romero Mestre JC, Hernandez A, Agramonte O, Hernandez P. Cardiovascular autonomic dysfunction in sickle cell anemia: a possible risk factor for sudden death? Clin Auton Res 1997;7:121–125.

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4. Kleiger RE, Stein PK, Bigger JT Jr. Heart rate variability: measurement and clinical utility. Ann Noninvasive Electrocardiol 2005;10:88–101. 5. Tracey KJ. The inflammatory reflex. Nature 2002;420:853–859. 6. Sangkatumvong S, Khoo MCK, Kato R, Detterich JA, Bush A, Keens TG, Meiselman HJ, Wood JC, Coates TD. Peripheral vasoconstriction and abnormal parasympathetic response to sighs and transient hypoxia in sickle cell disease. Am J Resp Crit Care Med 2011;184:474–481. 7. Sangkatumvong S, Coates TD, Khoo MC. Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia. Physiol Meas 2008;29:655–668. 8. Setty BN, Stuart MJ, Dampier C, Brodecki D, Allen JL. Hypoxaemia in sickle cell disease: biomarker modulation and relevance to pathophysiology. Lancet 2003;362:1450–1455. 9. Pepin JL, Levy P. [Pathophysiology of cardiovascular risk in sleep apnea syndrome (sas).] Rev Neurol (Paris) 2002;158:785–797. 10. Gu H, Lin M, Liu J, Gozal D, Scrogin KE, Wurster R, Chapleau MW, Ma X, Cheng ZJ. Selective impairment of central mediation of baroreflex in anesthetized young adult fischer 344 rats after chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol 2007;293:H2809–H2818. 11. Lin M, Ai J, Li L, Huang C, Chapleau MW, Liu R, Gozal D, Wead WB, Wurster RD, Cheng ZJ. Structural remodeling of nucleus ambiguus projections to cardiac ganglia following chronic intermittent hypoxia in c57bl/6j mice. J Comp Neurol 2008;509:103–117. 12. Yan B, Soukhova-O’Hare GK, Li L, Lin Y, Gozal D, Wead WB, Wurster RD, Cheng ZJ. Attenuation of heart rate control and neural degeneration in nucleus ambiguus following chronic intermittent hypoxia in young adult fischer 344 rats. Neuroscience 2008;153:709–720. 13. Ai J, Epstein PN, Gozal D, Yang B, Wurster R, Cheng ZJ. Morphology and topography of nucleus ambiguus projections to cardiac ganglia in rats and mice. Neuroscience 2007;149:845–860.

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14. Kim J, Hakim F, Kheirandish-Gozal L, Gozal D. Inflammatory pathways in children with insufficient or disordered sleep. Respir Physiol Neurobiol (In press) 15. Baron R, Habler HJ, Heckmann K, Porschke H. Respiratory modulation of blood flow in normal and sympathectomized skin in humans. J Auton Nerv Syst 1996;60:147–153. 16. Seals DR, Suwarno NO, Joyner MJ, Iber C, Copeland JG, Dempsey JA. Respiratory modulation of muscle sympathetic nerve activity in intact and lung denervated humans. Circ Res 1993;72:440–454. 17. Galland BC, Taylor BJ, Bolton DP, Sayers RM. Vasoconstriction following spontaneous sighs and head-up tilts in infants sleeping prone and supine. Early Hum Dev 2000;58:119–132. 18. Young RC Jr, Rachal RE, Reindorf CA, Armstrong EM, Polk OD Jr, Hackney RL Jr, Scott RB. Lung function in sickle cell hemoglobinopathy patients compared with healthy subjects. J Natl Med Assoc 1988;80:509–514. 19. Pichon A, de Bisschop C, Diaz V, Denjean A. Parasympathetic airway response and heart rate variability before and at the end of methacholine challenge. Chest 2005;127:23–29. 20. Velez-Roa S, Ciarka A, Najem B, Vachiery JL, Naeije R, van de Borne P. Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 2004;110:1308–1312. 21. O’Brien LM, Gozal D. Autonomic dysfunction in children with sleepdisordered breathing. Sleep 2005;28:747–752. 22. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007;21:37–47.

DOI: 10.1164/rccm.201105-0941ED