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      • Record: found
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      Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension

      research-article
      Author(s): , MD a , , MD, PhD b , ∗ , , MD a , , MD, PhD a , , MD a , c , , MD a , , MD a , , MD, PhD b , , MD, PhD d , , MD, PhD a
      Publication date (Electronic):
      Journal: JACC: Basic to Translational Science
      Publisher: Elsevier
      Keywords: autonomic imbalance, pulmonary arterial hypertension, pulmonary vascular remodeling, vagal nerve stimulation, BNP, brain natriuretic peptide, eNOS, endothelial nitric oxide synthase, HF, high-frequency, HRV, heart rate variability, IL, interleukin, MCP, monocyte chemotactic protein, mRNA, messenger ribonucleic acid, NE, norepinephrine, NO, nitric oxide, PA, pulmonary artery, PAH, pulmonary arterial hypertension, PAP, pulmonary arterial pressure, PVR, pulmonary vascular resistance, RV, right ventricular, RVEDP, right ventricular end-diastolic pressure, SS, sham-stimulated, VNS, vagal nerve stimulation

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          Highlights

          • •

            Autonomic imbalance has been documented in patients with PAH.

          • •

            Electrical VNS is known to restore autonomic balance and improve heart failure.

          • •

            This study aimed to elucidate the therapeutic effects of VNS on severe PAH in a rat model.

          • •

            VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In addition, VNS markedly improved the survival of rats with PAH.

          • •

            Our findings may contribute greatly to the development of device therapy for PAH and widen the clinical applicability of VNS.

          Summary

          This study aimed to elucidate the therapeutic effects of electrical vagal nerve stimulation (VNS) on severe pulmonary arterial hypertension in a rat model. In a pathophysiological study, VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In a survival study, VNS significantly improved the survival rate in both the prevention (VNS from 0 to 5 weeks after a SU5416 injection) and treatment (VNS from 5 to 10 weeks) protocols. Thus, VNS may serve as a novel therapeutic strategy for pulmonary arterial hypertension.

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          Most cited references26

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          Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.

          Marlene Rabinovitch, Christophe Guignabert, Marc Humbert … (2014)
          This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.
          Article 0 comments Cited 367 times – based on 0 reviews     Review now
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            Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.

            Mariëlle van de Veerdonk, Taco Kind, J. Marcus … (2011)
            The purpose of this study was to examine the relationship between changes in pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) and survival in patients with pulmonary arterial hypertension (PAH) under PAH-targeted therapies. Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function. A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy. Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis. After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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              Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats.

              Meihua Li, Can Zheng, Takayuki Sato … (2004)
              Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1+/-5.9 versus 23.5+/-4.2 mm Hg, P<0.05) and higher maximum dp/dt of left ventricular pressure (4152+/-237 versus 2987+/-192 mm Hg/s, P<0.05) than the untreated rats. Improvement of cardiac pumping function was accompanied by a decrease in normalized biventricular weight (2.75+/-0.25 versus 3.14+/-0.22 g/kg, P<0.01). Although the 140-day survival of the untreated group was only half, vagal stimulation markedly improved the survival rate (86% versus 50%, P=0.008). Vagal stimulation therapy achieved a 73% reduction in a relative risk ratio of death. Vagal nerve stimulation markedly improved the long-term survival of CHF rats through the prevention of pumping failure and cardiac remodeling.
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                Author and article information

                Contributors
                Keita Saku
                Journal
                Journal ID (nlm-ta): JACC Basic Transl Sci
                Journal ID (iso-abbrev): JACC Basic Transl Sci
                Title: JACC: Basic to Translational Science
                Publisher: Elsevier
                ISSN (Electronic): 2452-302X
                Publication date PMC-release: 12 November 2018
                Publication date Collection: October 2018
                Publication date (Electronic): 12 November 2018
                Volume: 3
                Issue: 5
                Pages: 657-671
                Affiliations
                [a ]Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
                [b ]Department of Advanced Risk Stratification for Cardiovascular Diseases, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka, Japan
                [c ]Department of Anesthesiology and Critical Care Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
                [d ]Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka, Japan
                Author notes
                [∗ ] Address for correspondence: Dr. Keita Saku, Department of Advanced Risk Stratification for Cardiovascular Diseases, Center for Disruptive Cardiovascular Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. saku@ 123456cardiol.med.kyushu-u.ac.jp
                Article
                Publisher ID: S2452-302X(18)30217-1
                DOI: 10.1016/j.jacbts.2018.07.007
                PMC ID: 6234524
                PubMed ID: 30456337
                SO-VID: 12d482bf-a4f4-4a45-a901-c6ecc2379688
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 14 May 2018
                Date revision received : 25 July 2018
                Date accepted : 30 July 2018
                Categories
                Subject: PRECLINICAL RESEARCH

                Keywords: autonomic imbalance,pulmonary arterial hypertension,pulmonary vascular remodeling,vagal nerve stimulation,bnp, brain natriuretic peptide,enos, endothelial nitric oxide synthase,hf, high-frequency,hrv, heart rate variability,il, interleukin,mcp, monocyte chemotactic protein,mrna, messenger ribonucleic acid,ne, norepinephrine,no, nitric oxide,pa, pulmonary artery,pah, pulmonary arterial hypertension,pap, pulmonary arterial pressure,pvr, pulmonary vascular resistance,rv, right ventricular,rvedp, right ventricular end-diastolic pressure,ss, sham-stimulated,vns, vagal nerve stimulation
                Data availability:
                Keywords: autonomic imbalance, pulmonary arterial hypertension, pulmonary vascular remodeling, vagal nerve stimulation, bnp, brain natriuretic peptide, enos, endothelial nitric oxide synthase, hf, high-frequency, hrv, heart rate variability, il, interleukin, mcp, monocyte chemotactic protein, mrna, messenger ribonucleic acid, ne, norepinephrine, no, nitric oxide, pa, pulmonary artery, pah, pulmonary arterial hypertension, pap, pulmonary arterial pressure, pvr, pulmonary vascular resistance, rv, right ventricular, rvedp, right ventricular end-diastolic pressure, ss, sham-stimulated, vns, vagal nerve stimulation

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