Norepinephrine Transporter Blockade as a Pathophysiological Biomarker in Neurogenic Orthostatic Hypotension

The clinical picture of autonomic failure is dominated by disabling orthostatic hypotension. Recent developments in the understanding of the underlying pathophysiology of the discrete clinical forms of autonomic failure have revealed that participants with multiple system atrophy (MSA) are characterized by impairment of central autonomic pathways crucial for autonomic cardiovascular control, but have intact peripheral postganglionic noradrenergic fibers. Participants with MSA have peripheral residual sympathetic tone that is no longer modulated by central autonomic centers and is not under baroreflex control and, therefore, cannot be harnessed to improve their orthostatic hypotension. On the other hand, participants with pure autonomic failure (PAF) and with Parkinson' s disease (PD) are characterized by neurodegeneration and loss of peripheral noradrenergic fibers, as evidenced by low levels of plasma norepinephrine and absent cardiac uptake of labeled catechols. Pharmacological inhibition of the norepinephrine transporter (NET) is an example of an approach that can take advantage of the participants' own residual sympathetic tone. NET inhibition will increase synaptic norepinephrine that is tonically released in MSA participants by preventing its reuptake. This should result in an increase in blood pressure.

This is a longitudinal study of 50 participants, age 18-80 years with neurogenic orthostatic hypotension associated with impaired reflexes. The purpose of this study is to determine if the magnitude of the pressor response to atomoxetine at study entry, will be useful as a biomarker to differentiate those participants that will ultimately be shown to have pre-ganglionic (central) lesions (MSA) with those shown to have post ganglionic (peripheral) lesions (PAF and PD).

• Study Weblinks:
  • Autonomic Disorders Consortium
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Longitudinal
  • Observational
• Total number of consented subjects: 50
• Subject Sample Telemetry Report (SSTR)

Inclusion Criteria

• Age 18-80 years
• Neurogenic orthostatic hypotension, ≥ 30 mmHg drop in SBP within 5 minutes of standing
• Associated with impaired autonomic reflexes, as determined by absence of blood pressure overshoot during phase IV of the Valsalva maneuver
• Absence of other identifiable causes of autonomic neuropathy, and
• Able and willing to provide informed consent

Exclusion Criteria

• Pregnancy
• Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies.
• Known intolerance to atomoxetine
• Pre-existing sustained severe hypertension (BP ≥ 180/110 mmHg in the sitting position)
• Clinically unstable coronary artery disease, or major cardiovascular or neurological event in the past 6 months
• Any other significant systemic, hepatic, cardiac or renal illness
• Use of MAO-I within 14 days
• Known closed-angle glaucoma
• Life-threatening arrhythmias

• Study Activated February 01, 2011
• First Accrual March 7, 2011
• Last Accrual May 10, 2013

• Primary Phenotype: Hypotension, Orthostatic
• Pure Autonomic Failure
• Multiple System Atrophy
• Parkinson Disease

• BioProject
• PubMed
• MeSH
• PMC

• Study Chairs
  • Italo Biaggioni, MD. Vanderbilt University Medical Center, Nashville, TN, USA.
• Participating Site Principal Investigators
  • Phillip Low, MD. Mayo Clinic, Rochester, MN, USA.
  • Roy Freeman, MD. Beth Israel Deaconess Medical Center, Boston, MA, USA.
  • Horacio Kaufmann, MD. NYU Medical Center, New York, NY, USA.
  • David Goldstein, MD, PhD. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Jeffrey Krischer, PhD. Data Management and Coordinating Center, University of South Florida, Tampa, FL, USA.
• Funding Source
  • 5U54 NS065736-02. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.