2018 ACC/AHA/HRS guideline on the evaluation and

management of patients with bradycardia and

cardiac conduction delay
A Report of the American College of Cardiology/American Heart Association Task Force on
Clinical Practice Guidelines and the Heart Rhythm Society
Writing Committee Members*
Fred M. Kusumoto, MD, FACC, FAHA, FHRS (Chair),
Mark H. Schoenfeld, MD, FACC, FAHA, FHRS (Vice Chair), Coletta Barrett, RN, FAHA,†
James R. Edgerton, MD, FACC, FHRS,‡ Kenneth A. Ellenbogen, MD, FACC, FAHA, FHRS,*†
Michael R. Gold, MD, PhD, FACC,*x Nora F. Goldschlager, MD, FACC, FAHA, FHRS,†
Robert M. Hamilton, MD,k José A. Joglar, MD, FACC, FAHA, FHRS,{ Robert J. Kim, MD,†
Richard Lee, MD, MBA,# Joseph E. Marine, MD, MBA, FACC, FHRS,x
Christopher J. McLeod, MB, ChB, PhD, FACC, FAHA, FHRS,† Keith R. Oken, MD, FACC,†
Kristen K. Patton, MD, FACC, FAHA, FHRS,† Cara N. Pellegrini, MD, FHRS,*x**
Kimberly A. Selzman, MD, MPH, FACC, FHRS,† Annemarie Thompson, MD,†
Paul D. Varosy, MD, FACC, FAHA, FHRS††
ACC/AHA Task Force Members
Glenn N. Levine, MD, FACC, FAHA, Chair Joshua A. Beckman, MD, MS, FAHA
Patrick T. O’Gara, MD, MACC, FAHA, Chair-Elect Kim K. Birtcher, PharmD, MS, AACC
Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair‡‡ Biykem Bozkurt, MD, PhD, FACC, FAHA‡‡
Sana M. Al-Khatib, MD, MHS, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC‡‡

*Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see
Appendix 1 for detailed information.†ACC/AHA Representative.‡STS Representative.xHRS Representative.kPACES Representative.{ACC/AHA Task Force on
Clinical Practice Guidelines Liaison.#AATS Representative.**Dr. Pellegrini contributed to this article in her personal capacity. The views expressed are her
own and do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government.††ACC/AHA Performance Measures Repre-
sentative.

KEYWORDS ACC/AHA Clinical Practice Guidelines; Ablation; Ambu- and the American Heart Association Executive Committee in October 2018,
latory electrocardiography; Aminophylline; Atrioventricular block; and the Heart Rhythm Society in August 2018. The Heart Rhythm Society
Atropine; AV block; Beta-adrenergic agonist; Bradyarrhythmia; requests that this document be cited as follows: Kusumoto FM, Schoenfeld
Bradycardia; Bundle branch block; Cardiac pacing; Cardiac resynch- MH, Barrett CN, Edgerton JR, Ellenbogen KA, Gold MR, Goldschlager NF,
ronization therapy; Cardiac sinus pause; Cardiac surgery; Congenital Hamilton RM, Joglar JA, Kim RJ, Lee R, Marine JE, McLeod CJ, Oken KR,
Patton KK, Pellegrini CN, Selzman KA, Thompson A, Varosy PD. 2018
heart disease; Digoxin antibodies Fab fragments; Electrocardio-
ACC/AHA/HRS guideline on the evaluation and management of patients with
gram; Glucagon; Heart block; Holter monitoring; Intraoperative; bradycardia and cardiac conduction delay: a report of the American College of
Isoproterenol; Lamin A-C; Left bundle branch block; Muscular dys- Cardiology/American Heart Association Task Force on Clinical Practice
trophies; Myocardial infarction; Myotonic dystrophy; Pacemaker; Guidelines and the Heart Rhythm Society. Heart Rhythm 2019;16:e128–e226.
Pacing; Preoperative; Quality of life; Right bundle branch block; This article has been copublished in the Journal of the American College of
Sarcoidosis; Shared decision-making; Sick sinus syndrome; Sinus ar- Cardiology and Circulation. Copies: This document is available on the web-
rest; Sinus bradycardia syndrome; Sinus node dysfunction; Spinal sites of the American College of Cardiology (www.acc.org), the American
cord injuries; Syncope; Theophylline; Transcatheter aortic valve Heart Association (https://professional.heart.org/), and the Heart Rhythm
replacement (Heart Rhythm 2019;16:e128–e226) Society (www.hrsonline.org). For copies of this document, please contact the
Elsevier Inc. Reprint Department via fax (212-633-3820) or e-mail (reprints@
Developed in Collaboration With the American Association for Thoracic elsevier.com). Permissions: Multiple copies, modification, alteration,
Surgery, the Pediatric & Congenital Electrophysiology Society, and the enhancement, and/or distribution of this document are not permitted without
Society of Thoracic Surgeons. Endorsed by the American Association for the express permission of the Heart Rhythm Society. Requests may be
Thoracic Surgery, the Pediatric & Congenital Electrophysiology Society, completed online via the Elsevier site (https://www.elsevier.com/about/our-
and the Society of Thoracic Surgeons. This document was approved by the business/policies/copyright/permissions).
American College of Cardiology Clinical Policy Approval Committee, the
American Heart Association Science Advisory and Coordinating Committee,

1547-5271/$-see front matter © 2019 American College of Cardiology Foundation, the American Heart https://doi.org/10.1016/j.hrthm.2018.10.037
Association, Inc., and the Heart Rhythm Society.
   

Abstract

Isoproterenol excretion and metabolism in the

isolated perfused rat kidney.
S J Szefler and M Acara
Journal of Pharmacology and Experimental Therapeutics August 1979, 210 (2) 295-300;

Article Info & Metrics eLetters  PDF

Abstract

[3H]isoproterenol excretion and metabolism were studied in the isolated perfused rat kidney using a
one-pass, non-recirculating perfusion system with constant infusion rates of [3H]isoproterenol. The
[3H]isoproterenol (U/P) to inulin (U/P) ratio was approximately 15 indicating extensive tubular secretion.
A major renal metabolite, 3-O-methylisoproterenol, appeared in the urine and renal vein perfusate and
also accumulated in the renal tissue. The fractional excretion of isoproterenol decreased with time
while fractional excretion of p-aminohippurate remained stable. The observed decreasing urinary
clearance and percent extraction of isoproterenol with time may be due to the progressive intrarenal
accumulation of 3-O-methylisoproterenol.

JPET articles become freely available 12 months after publication, and remain freely
available for 5 years.

https://jpet.aspetjournals.org/content/210/2/295 23/11/24, 10:27 a.m.

Página 1 de 5
Korean J Physiol Pharmacol 2019;23(3):203-217
https://doi.org/10.4196/kjpp.2019.23.3.203

Original Article

Effects of heme oxygenase-1 upregulation on isoproterenol-

induced myocardial infarction
Somaia A.G. Eltobshy1, Abdelaziz M. Hussein1,*, Asaad A. Elmileegy1, Mona H. Askar1, Yomna Khater2,
Emile F. Metias1, and Ghada M. Helal3
1
Department of Physiology, 2Medical Experimental Research Center, and 3Department of Medical Biochemistry, Faculty of Medicine, Mansoura University,
Mansoura 35516, Egypt

ARTICLE INFO
ABSTRACT The present study was designed to examine the effect of heme oxygen-
Received November 17, 2018
Revised December 23, 2018
ase-1 (HO-1) induction by cobalt protoporphyrin (CoPP) on the cardiac functions and
Accepted December 31, 2018 morphology, electrocardiogram (ECG) changes, myocardial antioxidants (superoxide
dismutase [SOD] and glutathione [GSH]), and expression of heat shock protein (Hsp)
*Correspondence 70 and connexin 43 (Cx-43) in myocardial muscles in isoproterenol (ISO) induced
Abdelaziz M. Hussein myocardial infarction (MI). Thirty two adult male Sprague Dawely rats were divided
E-mail: menhag@mans.edu.eg into 4 groups (each 8 rats): normal control (NC) group, ISO group: received ISO at
dose of 150 mg/kg body weight intraperitoneally (i.p.) for 2 successive days; ISO +
Key Words Trizma group: received (ISO) and Trizma (solvent of CoPP) at dose of 5 mg/kg i.p.
Connexin 43 injection 2 days before injection of ISO, with ISO at day 0 and at day 2 after ISO injec-
Heme oxygenase-1
tions; and ISO + CoPP group: received ISO and CoPP at a dose of 5 mg/kg dissolved in
HSP70 heat-shock proteins
Isoproterenol-myocardial infarction Trizma i.p. injection as Trizma. We found that, administration of ISO caused significant
increase in heart rate, corrected QT interval, ST segment, cardiac enzymes (lactate
dehydrogenase, creatine kinase-muscle/brain), cardiac HO-1, Hsp70 with significant
attenuation in myocardial GSH, SOD, and Cx-43. On the other hand, administration of
CoPP caused significant improvement in ECG parameters, cardiac enzymes, cardiac
morphology; antioxidants induced by ISO with significant increase in HO-1, Cx-43,
and Hsp70 expression in myocardium. In conclusions, we concluded that induction
of HO-1 by CoPP ameliorates ISO-induced myocardial injury, which might be due to
up-regulation of Hsp70 and gap junction protein (Cx-43).

INTRODUCTION ISO-induced MI such as relative myocardial hypoxia due to ex-

cessive cardiac work and myocardial O2 demands which is inten-
Despite the significant advances that have been achieved in sified by hypotension or hypoxia due to direct O2-wasting effect
the management of coronary heart disease (CHD), it remains the of catecholamines or their autoxidation products [4].
leading cause of mortality and morbidity worldwide [1]. The main Heme oxygenase (HO), a key-regulating enzyme in heme
cause of death from CHD is myocardial infarction (MI), which is degradation, catalyzes the oxidation of heme to produce several
an ischemic necrosis of cardiac myocytes results from prolonged active molecules such as ferrous iron (Fe+2), biliverdin and carbon
interruption of blood supply to certain area of heart [2]. Isopro- monoxide (CO) [5]. Heme oxygenase-1 (HO-1) is normally ex-
terenol (ISO)-induced MI is a well-established animal model of pressed at low levels in most of organs; however, it is highly induc-
pharmacologically induced MI [3]. Several hypotheses have been ible in response to a variety of stimuli to protect cells against oxi-
postulated to explain pathophysiology of the myocardial injury in dative and inflammatory injury [6]. It has several cytoprotective

This is an Open Access article distributed under the terms Author contributions: S.A.G.E. performed the animal model, experi-
of the Creative Commons Attribution Non-Commercial mental procedures and data collection and biochemical assay. A.M.H. per-
License, which permits unrestricted non-commercial use, distribution, and formed the statistics, graphs and paper writing. Y.K. and M.H.A. performed
reproduction in any medium, provided the original work is properly cited. the animal model, experimental procedures. A.A.E. and E.F.M. supervised
Copyright © Korean J Physiol Pharmacol, pISSN 1226-4512, eISSN 2093-3827 and coordinated the study. G.M.H. performed Real time PCR.

www.kjpp.net 203 Korean J Physiol Pharmacol 2019;23(3):203-217

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 Clinical Reviews in Allergy and Immunology
© Copyright 2006 by Humana Press Inc.
Historical Background 107
All rights of any nature whatsoever reserved.
1080–0549/06/107–118/$30.00
ISSN (Online) 1559–0267

Current Issues With β2-Adrenoceptor Agonists

Historical Background

Anne E. Tattersfield
Division of Respiratory Medicine, University of Nottingham, Clinical Sciences Building, Nottingham
University Hospital, City Hospital Campus, Nottingham, England.
E-mail: anne.tattersfield@nottingham.ac.uk.

The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900
following a vogue for studying organotherapy at the end of the 19th century. The adrenal
hormone adrenaline was found to have sympathomimetic properties and was isolated and
synthesized in 1901. The first nonselective β-agonist, isoproterenol, was isolated in 1940, fol-
Abstract

lowed by the development of selective β2-agonists in the 1960s and the introduction of the
long-acting β2-agonists in the 1990s. The introduction of β2-selectivity reduced adverse effects,
as did developments in inhaler technology that allowed subjects to inhale much smaller doses
of drug selectively to the airways. The β2-agonists are some of the more important drugs to
have been developed in the 20th century. Excessive doses can cause problems, and attempts to
maximize the benefit from β2-agonists and to reduce adverse effects has led to considerable
epidemiological, clinical, and mechanistic research over the last 50 yr.

Index Entries
Adrenaline; epinephrine; isoprotenerol; β2-selectivity; history of β2-agonists.

Sympathomimetics: A Serendipitous tually produced the β2-selective adreneceptor

Start agonists—some of the most valuable drugs
The story of β2-agonists spans the 20th cen- introduced in the 20th century.
tury, following a serendipitous observation in Interest in the clinical effects of extract of
1900 by Solomon Solis-Cohen (1). The interpre- the adrenal gland was first documented at the
tation of this observation was probably wrong, end of the 19th century, when the study of orga-
but it led to a pathway of discovery that even- notherapy was fashionable (2). In 1893, George

Clinical Reviews in Allergy & Immunology 107 Volume 31, 2006

SHOCK, Vol. 26, No. 4, pp. 353 Y 357, 2006

A REAPPRAISAL OF ISOPROTERENOL IN GOAL-DIRECTED

THERAPY OF SEPTIC SHOCK

Marc Leone, Ioanna Boyadjiev, Emile Boulos, Fran$cois Antonini,

Pierre Visintini, Jacques Albanèse, and Claude Martin
Département d’Anesthésie et de Réanimation, UPRES Equipe d’Accueil 3784, Centre Hospitalier
Universitaire Nord, 13915 Marseille cedex 20, France

Received 23 Dec 2005; first review completed 13 Jan 2006; accepted in formal form 10 Apr 2006

ABSTRACT—The goal of the study was to evaluate the effect of isoproterenol prescribed in goal-directed therapy for septic
shock. Out of a cohort of 89 patients with septic shock, 14 patients treated with fluid and norepinephrine had inappropriate
mixed venous oxygen saturation (SvO2 G 70%) not responding to correction of hypoxemia and anemia (98 gIdLj1).
Isoproterenol administration was started at a dose of 0.04 2gIkgj1Iminutej1 with 0.025 2gIkgj1Iminutej1 increments
every 30 minutes until SvO2 was greater than 70%. Mean arterial pressure was maintained Q65 mmIHg by adjusting the
norepinephrine infusion. Hemodynamic, oxygen, and renal variables were collected during a 12-h period. Patients with a
known prior history of coronary disease were not eligible. Isoproterenol administration increased significantly SvO2 (62% T
10% to 71% T 9%), cardiac index (3.1 T 0.6 to 4.4 T 1.4 LIminj1Imj2), stroke index (27 T 3.4 to 38 T 6.1 mLImj2), and left
ventricular stroke work index (24 T 3.4 to 40 T 5.0 gImj1Imj2). Heart rate rise did not reach a significant level. Arterial
lactate concentration decreased significantly during the study period (5.7 T 2.8 to 3.4 T 1.6 mmolILj1). No cardiac adverse
events occurred with any electrocardiographic aspects of myocardial ischemia. This study suggests that isoproterenol is
efficient to improve hemodynamics and oxygen variables in septic shock patients. There is a need for future investigations
in larger groups of patients to determine whether isoproterenol can be an alternative to dobutamine.
KEYWORDS—Beta-receptor, cardiac depression, hemodynamics, cardiac index, catecholamine, oxygen

Isoproterenol is a synthetic catecholamine, which has only "- obstruction, isoproterenol is possibly an alternative to dobut-
adrenergic stimulating effects. Isoproterenol has been used in amine for the treatment of sepsis-induced myocardial depres-
the treatment of cardiogenic shock, but it has been associated sion in septic shock patients. The use of an early goal-directed
with a significant increase in myocardial infarct size in therapy has been demonstrated to improve patient survival
experiments using animals with coronary artery occlusion (1). during severe sepsis (2). After fluid challenge and use of
Significant myocardial depression requiring treatment with vasopressors, use of dobutamine is advocated if ScvO2 is less
a positive inotropic agent occurs in 10% to 20% of septic shock than 70% (after control of arterial oxygen saturation and
patients (2). However, a number of studies have demonstrated hemoglobin). Given the higher potency of isoproterenol on "-
preserved or increased coronary blood flow, net myocardial adrenergic receptors, we speculated that this drug can be an
lactate extraction, and increased availability of oxygen to the alternative to dobutamine to restore a ScvO2 9 70% in septic
myocardium in humans with septic shock (3). Although shock patients.
troponin I is increased in septic shock patients, coronary
angiography, autopsy, and stress echocardiography ruled out MATERIALS AND METHODS
significant coronary artery disease in most patients (4).
This prospective study was approved by our local ethic committee, and written
Actually, late cardiac depression in septic patients seems to consent was obtained from the closest next of kin before study enrollment.
involve an inducible nitric oxide synthase-dependent defect of
"-1-adrenergic signal transduction. In clinical practice, the Patients
stroke work of septic shock patients decreases in response to Septic shock was defined according to the criteria of the International Sepsis
Definitions Conference (8). Eighty-nine patients were treated in the unit for septic
fluid resuscitation (5). A decline in central venous oxygen shock over a 2-year period. During this period, 14 patients (15.7%) fulfilled the
saturation (ScvO2) below 70% is considered as a surrogate inclusion criteria (Table 1) and needed a positive inotrope agent in addition to
marker of an inadequate cardiac index (2). norepinephrine. They were 59 T 16 years, with a Simplified Acute Physiologic
Score II of 44 T 17 on admission and a Sequential Organ Failure Assessment of
To counteract the defect of "-adrenergic signal transduction, 13 T 3 on inclusion day (Table 1). All patients received fluid expansion (crystalloids
inotropic agents have been added to vasopressor in septic or 6% hydroxyethyl starch, 2345 T 1634 mL), and then required norepinephrine to
shock patients developing cardiac depression. Among ino- raise mean arterial pressure to 65 mmIHg or more (9). All patients received broad-
spectrum antibiotic coverage, usually a beta-lactam and a quinolone. Vancomcyin
tropic agents, dobutamine is recommended as the agent of was added when oxacillin-resistant staphylococci were suspected. Because of acute
choice to increase cardiac output (6, 7). However, because respiratory failure, all patients needed mechanical ventilation and sedatives.
mechanisms for cardiac depression in septic shock patients are Corticosteroids (50 mg ! 4 per day of hydrocortisone) were given to nonresponder
patients after an adrenocorticotropic hormone test, generally 6 hours after the onset
unrelated to myocardial hypoperfusion, or coronary vessels of septic shock, as described in a prior study (10). Three patients received activated
protein C and most of them were treated with prophylactic doses of low-molecular
Address reprint requests to Marc Leone, MD, Département d’Anesthésie et de weight heparin.
Réanimation, CHU Nord, 13915 Marseille cedex 20, France. E-mail:
marc.leone@ap-hm.fr. Measurements
DOI: 10.1097/01.shk.0000226345.55657.66 Heart rate was continuously monitored (Merlin, Hewlett-Packard, Palo Alto,
Copyright ! 2006 by the Shock Society Calif). Recorded data were stored in the databank of our unit, and then analyzed for

353

Copyright @ 2006 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Received: 10 July 2019 Revised: 1 September 2019 Accepted: 7 September 2019
DOI: 10.1111/bph.14883

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Hongping Chen1 | Bohai Kuang1 | Guangqin Fan1,2 | Qingxian Zhu1 |
Lijian Shao1,2

1
Department of Occupational Health and
Toxicology, Medical College of Nanchang Background and Purpose: Damage to intestinal epithelial cells and mucosa limits the
University, Nanchang, China
effectiveness of several anti-cancer chemotherapeutic agents but the underlying
2
Jiangxi Provincial Key Laboratory of
Preventive Medicine, Nanchang University, mechanism (s) remain unknown. Little is known of how enteric nervous system regu-
Nanchang, China lates proliferation, differentiation, impairment, and regeneration of intestinal stem
3
Department of Pathology, The Second
cells. Here we have investigated the effects of isoprenaline on the damaged intestinal
Affiliated Hospital of Nanchang University,
Nanchang, China stem cells induced by chemotherapeutic treatments in mice.
Experimental Approach: The effects of inhibiting sympathetic and parasympathetic
Correspondence
Lijian Shao, Medical College of Nanchang nerves on intestinal stem cells were examined in male C57BL/6J mice. Protection by
University, No. 461 Bayi Road, Nanchang,
isoprenaline of intestinal stem cells was assessed in the presence or absence of
Jiangxi 330006, China.
Email: lshao@ncu.edu.cn 5-fluorouracil (5FU) or cisplatin. Cellular apoptosis, cell cycle, PI3K/Akt signalling, and
NF-κB signalling in intestinal stem cells were mechanistically evaluated.
Funding information
National Natural Science Foundation of China, Key Results: The sympathetic nerve inhibitor 6-OHDA decreased the number and
Grant/Award Numbers: 81460110, 30900574
function of intestinal stem cells. 5FU or cisplatin treatment damaged both intestinal
and 81160050; Graduate Innovation Special
Fund of Jiangxi Province, Grant/Award stem cells and sympathetic nerves. Notably, isoprenaline accelerated the recovery of
Numbers: YC2018-S086 and YC2016-B028
intestinal stem cells after 5FU or cisplatin treatment. This protective effect of iso-
prenaline on damaged intestinal stem cells was mediated by β2-adrenoceptors. The
benefits of isoprenaline were mainly mediated by inhibiting cellular apoptosis
induced by 5FU treatment, which might contribute to fine-tuning regulating NF-κB
signalling pathway by isoprenaline administration.
Conclusions and Implications: Treatment with isoprenaline is a new approach to
ameliorate the damage to intestinal stem cells following exposure to cancer chemo-
therapeutic agents.

Abbreviations: 5FU, 5-fluorouracil; 6-OHDA, 6-hydroxydopamine; CBC, crypt base columnar cell; ENS, enteric nervous system; Lgr5, leucine-rich repeat containing GPCR 5; Lrig1, leucine-rich
repeats and immunoglobulin-like domains; mTOR, mammalian target of rapamycin; NET, noradrenaline transporter; Olfm4, olfactomedin-4; PNS, parasympathetic nervous system; SNS,
sympathetic nervous system.

Huihong Zeng and Huan Li contributed equally to this article.

Br J Pharmacol. 2020;177:687–700. wileyonlinelibrary.com/journal/bph © 2019 The British Pharmacological Society 687

Cellular and Molecular Life Sciences (2024) 81:18
https://doi.org/10.1007/s00018-023-05037-7 Cellular and Molecular Life Sciences

ORIGINAL ARTICLE

JOSD2 mediates isoprenaline-induced heart failure

by deubiquitinating CaMKIIδ in cardiomyocytes
Jiachen Xu1 · Shiqi Liang1 · Qinyan Wang2 · Qingsong Zheng2 · Mengyang Wang2,4 · Jinfu Qian1 · Tianxiang Yu2 ·
Shuaijie Lou2 · Wu Luo1 · Hao Zhou1 · Guang Liang1,2,3

Received: 5 July 2023 / Revised: 1 October 2023 / Accepted: 3 October 2023 / Published online: 10 January 2024
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024

Abstract
Prolonged stimulation of β-adrenergic receptor (β-AR) can lead to sympathetic overactivity that causes pathologic cardiac
hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation
may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of
a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction
(MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression
aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2
interacts with Calcium–calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked
polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling,
hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2
overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2
in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential
as a therapeutic target for combating the disease.

Extended author information available on the last page of the article

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