title: Sympathetic nervous system alterations with HER2+ antagonism: an early marker of cardiac dysfunction with breast cancer treatment?
abstract: BACKGROUND
  HER2 antagonists (anti-HER2; e.g., trastuzumab and lapatinib) are effective in treating an aggressive form of breast cancer (BC), but can cause cardiotoxicity due to the disruption in neuregulin (NRG)/HER2+ ligand receptor signalling. The recent data show that NRG-HER2 receptors located in the medulla oblongata are important regulators of vasomotor tone. Disrupting the NRG-HER2 signalling in mouse medulla results in increased sympathetic nerve output and blood pressure. We hypothesized that anti-HER2 agents would cause increased sympathetic tone with changes in plasma catecholamines and NRG.
  
  
  METHODS
  In 15 newly diagnosed HER2+ BC patients receiving anti-HER2 agents, vital signs were measured along with supine plasma epinephrine (EPI), norepinephrine (NE), and NRG at baseline and three months. Serial echocardiography was performed.
  
  
  RESULTS
  With three months of anti-HER2 treatment, NE increased (2.334 ± 1.294 nmol/L vs. 3.262 ± 2.103 nmol/L; p = 0.004) and NRG decreased (12.7±15.7 ng/ml vs. 10.9 ± 13.3 ng/ml; p = 0.036) with a corresponding increase in systolic blood pressure (110 ± 10 mmHg vs. 120 ± 16 mmHg, p = 0.049) and diastolic blood pressure (67 ± 14 vs. 77 ± 10, p = 0.009). There was no change, however, in EPI (0.183 ± 0.151 nmol/L vs. 0.159 ± 0.174 nmol/L; p = 0.519) or heart rate (73 ± 12 bpm vs. 77 ± 10 bpm, p = 0.146). Left ventricular ejection function declined over the follow-up period (baseline 63 ± 6% vs. follow-up 56 ± 5%).
  
  
  CONCLUSIONS
  Anti-HER2 treatment results in increased NE, blood pressure, and decreased NRG; this suggests that the inhibition of NRGHER2 signalling leads to increased sympathoneural tone. Larger studies are needed to determine if these observations have prognostic value and may be offset with medical interventions, such as beta-blockers.
  
  
  BACKGROUND
  The study was registered with www.clinicaltrials.gov (NCT00875238).
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA ; Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Carrie G
authors.initials: CG
authors.lastname: Lenneman
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Wissam M
authors.initials: WM
authors.lastname: Abdallah
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Smith
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Abramson
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Cheri
authors.initials: C
authors.lastname: Silverstein
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA ; Department of Medicine, University of California Los Angeles School of Medicine, CA 90404, USA.
authors.forename: Cheri
authors.initials: C
authors.lastname: Silverstein
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Means-Powell
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Sachin Y
authors.initials: SY
authors.lastname: Paranjape
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lenihan
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA ; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville TN 37232, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, TN, USA ; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville TN 37232, USA.
authors.forename: Satish R
authors.initials: SR
authors.lastname: Raj
keywords: cardio-oncology; catecholamine; heart failure; sympathetic nervous system
references.citation: Circulation. 1997 Jul 15;96(2):575-80
references.pmid: 9244228
references.citation: J Clin Oncol. 2001 May 15;19(10):2587-95
references.pmid: 11352950
references.citation: J Card Fail. 2013 Jan;19(1):10-5
references.pmid: 23273589
references.citation: Circulation. 2004 Jun 8;109(22):2749-54
references.pmid: 15148277
references.citation: J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62
references.pmid: 17161256
references.citation: J Clin Oncol. 2005 Nov 1;23(31):7820-6
references.pmid: 16258084
references.citation: BMC Cancer. 2011 Jul 27;11:318
references.pmid: 21794114
references.citation: J Mol Cell Cardiol. 2006 Aug;41(2):228-35
references.pmid: 16769082
references.citation: Exp Cell Res. 2005 Nov 15;311(1):135-46
references.pmid: 16185687
references.citation: Circulation. 2009 Sep 1;120(9):725-34
references.pmid: 19687359
references.citation: J Am Coll Cardiol. 2009 Jun 16;53(24):2231-47
references.pmid: 19520246
references.citation: N Engl J Med. 2011 Oct 6;365(14):1273-83
references.pmid: 21991949
references.citation: Am J Physiol Cell Physiol. 2004 Feb;286(2):C222-9
references.pmid: 14522821
references.citation: J Am Coll Cardiol. 2013 Jun 11;61(23):2355-62
references.pmid: 23583763
references.citation: J Natl Cancer Inst. 2012 Sep 5;104(17):1293-305
references.pmid: 22949432
references.citation: Coron Artery Dis. 2011 Dec;22(8):577-82
references.pmid: 22027878
references.citation: N Engl J Med. 2005 Oct 20;353(16):1659-72
references.pmid: 16236737
references.citation: N Engl J Med. 2001 Mar 15;344(11):783-92
references.pmid: 11248153
references.citation: J Clin Oncol. 2010 Sep 1;28(25):3910-6
references.pmid: 20679614
references.citation: J Am Coll Cardiol. 2012 Dec 18;60(24):2504-12
references.pmid: 23158536
references.citation: J Hypertens. 2011 Sep;29(9):1735-42
references.pmid: 21738056