Autonomic Nervous System in Pulmonary Arterial Hypertension
2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 9 Linguagem: Inglês
10.1161/circulationaha.117.032355
ISSN1524-4539
AutoresAnna R. Hemnes, Evan L. Brittain,
Tópico(s)Heart rate and cardiovascular health
ResumoHomeCirculationVol. 137, No. 9Autonomic Nervous System in Pulmonary Arterial Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAutonomic Nervous System in Pulmonary Arterial HypertensionTime to Rest and Digest Anna R. Hemnes, MD and Evan L. Brittain, MD, MSCI Anna R. HemnesAnna R. Hemnes Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H.) and Evan L. BrittainEvan L. Brittain Division of Cardiovascular Medicine (E.L.B.), Vanderbilt University Medical Center, Nashville, TN. Originally published27 Feb 2018https://doi.org/10.1161/CIRCULATIONAHA.117.032355Circulation. 2018;137:925–927Article, see p 910The care of patients with pulmonary arterial hypertension (PAH) has made great advances in the past 20 years with tangible improvements in survival. At present, 12 drugs have been approved by the US Food and Drug Administration to treat PAH, and all 12 target 1 of 3 pathways primarily involved in vasoconstriction. Although some may have beneficial off-target effects on the right ventricle (RV),1,2 no currently approved PAH therapies directly target right heart failure, which is the major cause of death among patients with PAH. This deficit is particularly unfortunate because RV failure often develops independently of pulmonary hemodynamics in preclinical and human PAH, arguing in favor of developing RV-specific therapies.3,4 By contrast, 7 classes of medications are currently US Food and Drug Administration approved to reduce clinical outcomes in patients with chronic left ventricular (LV) systolic dysfunction.5 Why have interventions targeting the RV lagged behind?The answer to this question is complex. First, we now recognize that RV stress responses differ from the LV on physiological and molecular levels.6 Thus, treatments that are successful for LV dysfunction cannot simply be extrapolated to the RV. Pathological divergence between the LV and RV may relate to their different embryological origins,7 which may have implications for therapeutic strategies. Second, animal models of right heart failure have major limitations, with some such as monocrotaline imprecisely replicating human disease and thus yielding less translational knowledge.8 Third, human RV tissue from patients with PAH is limited. Patients with PAH do not routinely undergo RV biopsy, and autopsy specimens only reflect end stage disease, limiting understanding of the early molecular determinants of RV failure. Lack of human tissue further confounds knowledge of how well animal models recapitulate human pathology.Recent work is beginning to shed light on the mechanisms of RV failure in human PAH. Mitochondrial metabolism, sex hormones, and PAH subphenotypes9 are all emerging as key regulators of the ability of the RV to adapt or fail in the PAH context. The autonomic nervous system has also been an important area of discovery. In this issue of Circulation, da Silva Gonçalves Bos and colleagues10 provide evidence that impaired parasympathetic nervous system activity may contribute to RV failure in PAH.Targeting the autonomic nervous system has been a controversial area in PAH. Sympathetic nervous system activity is increased in patients with PAH11 and is associated with adverse outcomes in patients with PAH.12 However, translating these findings to humans has been met with caution. PAH patients are dependent on heart rate to preserve cardiac output because stroke volume is often relatively fixed, especially with end-stage disease. Initial reports suggested that beta blocker use to address sympathetic system upregulation reduced exercise capacity in PAH associated with cirrhosis.13 In contrast, studies in preclinical models have demonstrated beneficial effects of suppressing sympathetic tone on exercise capacity and RV function.14,15 Given the promising results of studies in the RV and the large body of efficacy literature in left heart failure, there have been two recent small randomized, placebo controlled trials of beta blockers in PAH. Bisorprolol for 6 months in 18 subjects with idiopathic PAH was associated with a decline in cardiac output and a trend toward reduced 6-minute walk distance.16 Carvedilol, which also exhibits alpha receptor antagonism, was well tolerated and associated with maintenance of cardiac output and no improvement in 6-minute walk distance.17 Although some patients may respond favorably to β-blockade, these studies do not suggest widespread efficacy in the PAH population.17 This further confirms the general approach that the RV requires separate investigation from the LV.A complementary approach to targeting the altered autonomic nervous system in PAH patients is through the parasympathetic nervous system. da Silva Goncalves Bos and colleagues explored the role that this feed-and-breed side to the nervous system may play in human and experimental PAH. First, they demonstrated that patients with PAH with reduced RV function also had reduced heart rate recovery, a surrogate for impaired parasympathetic activity. When examining RV tissue from patients with PAH undergoing heart-lung transplantation, the authors found increased presynaptic nicotinic receptor expression and reduced acetylcholinesterase activity, both of which would promote increased parasympathetic activity.The authors hypothesize that these compensatory mechanisms are adaptive but insufficient, which provides rationale for interventions that further increase parasympathetic stimulation. To test this hypothesis, they used pyridostigmine (PYR), an oral inhibitor of acetylcholinesterase activity, to increase parasympathetic activity. In the sugen-hypoxia model of pulmonary hypertension, PYR delayed progression to RV failure and improved load-independent indices of RV function in a reversal experimental protocol. Finally, the authors present evidence of decreased RV inflammation through reduced leukocyte infiltration and reduced indices of pulmonary vascular remodeling.The work is significant for several reasons. First, autonomic dysfunction appears to be an important feature of the PAH RV, with dysregulation of both the sympathetic and parasympathetic nervous systems. However, reducing sympathetic activity may not improve RV function as it has in the LV. Therefore, exploration of the parasympathetic system is of value as demonstrated by this work. Pyridostigmine is generally well tolerated in human patients with myasthenia gravis and has a long track record of safety. Thus, it holds promise as a new treatment for RV failure.However, enthusiasm for PYR as a therapy for RV failure in PAH based on this work should be tempered. In the human data, a likely explanation for the increased baseline heart rate and reduced heart rate reserve in the low-RV ejection fraction group is the need to maintain a higher heart rate to maintain cardiac output in the setting of reduced stroke volume. On the basis of the authors' conclusions, the optimal population for a human trial of PYR would be patients with low heart rate reserve and low RV ejection fraction, but this group may be the most vulnerable to heart rate suppression. The studies presented here would benefit from a control group with PYR exposure. It is unknown what pyridostigmine would do to the well-compensated or even normal RV based on the data presented here. In addition, because the human tissues were generated from patients with end-stage PAH undergoing heart-lung transplantation, it cannot be gleaned from these data whether the changes in parasympathetic signaling are pathological or compensatory. The underlying mechanisms for the observed reductions in inflammation and vascular remodeling are as yet unknown. As the authors acknowledge, the data presented do not support a nicotinic receptor-dependent mechanism, which suggests that PYR may have pleiotropic effects through alternate mechanisms. Finally, it is not known whether these findings are unique to the PAH RV or a universal feature of pre- or postcapillary pulmonary hypertension. For instance, if the chronic thromboembolic pulmonary hypertension RV has similar findings, it would greatly broaden the impact and suggest unique and universal features of RV failure from isolated pulmonary vascular disease without hypoxia or increased venous congestion.RV failure is often fatal and has no present therapies. As physicians, watching patients develop this condition without specific therapies is disheartening. The use of β-blockers may not be the answer we seek to address RV failure in PAH, and pyridostigmine appears to hold promise. Given the dependence of patients with PAH on this critical survival mechanism and the preliminary yet exciting data presented here, early stage clinical trials seem reasonable but should proceed with extreme caution and careful assessment of exercise capacity and RV function. In our haste to develop new treatments for this deadly syndrome, we need to remember our pledge as physicians: primum non nocere (first do no harm).DisclosuresDr Hemnes received grant funding from the National Institutes of Health and Cardiovascular Medical Research and Education Fund and served as a consultant to Actelion, Bayer, GSK, United Therapeutics, and Acceleron. The other author declares no conflicts of interest.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circ.ahajournals.orgAnna R. 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Mercurio V, Pellegrino T, Bosso G, Campi G, Parrella P, Piscopo V, Tocchetti C, Hassoun P, Petretta M, Cuocolo A and Bonaduce D (2019) Cardiac sympathetic dysfunction in pulmonary arterial hypertension: lesson from left‐sided heart failure, Pulmonary Circulation, 10.1177/2045894019868620, 9:3, (1-10), Online publication date: 1-Jul-2019. Halliday S and Brittain E (2018) Basic Science and Clinical Trials: Accelerating the Future, Advances in Pulmonary Hypertension, 10.21693/1933-088X-17.4.148, 17:4, (148-152), Online publication date: 1-Jan-2018. February 27, 2018Vol 137, Issue 9 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.032355PMID: 29483171 Originally publishedFebruary 27, 2018 Keywordspulmonary hypertensionEditorialsPDF download Advertisement
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