Cerebrovascular Outcomes in Ischemic Heart Disease
Condition: Cardiovascular Disease
MeSH terms: Cardiovascular Diseases; Heart Diseases; Myocardial Ischemia; Coronary Artery Disease
Study type: Interventional

Summary: 
      This project will examine the association between (cardio)vascular disease, blood supply to
      the brain, and cerebrovascular endothelial activation. Also, we will investigate the impact
      of exercise rehabilitation on brain vascularization, cerebrovascular endothelial function and
      blood flow control.
    

Detailed description: 
      This is a randomized control trial, with randomization nested within rationally-formed
      groups. Three major groups will be assessed: 1) Coronary artery disease (CAD) patients, 2)
      Metabolic Syndrome (MetS), and 3) healthy Control (CTL) participants. Allocation into the
      Healthy CTL versus MeTS groups will be confirmed at the pre-study screening visit based on
      medical questionnaires, blood sample outcomes, and ultrasound imaging (see below). All CTL
      and MeTS participants will be allocated by random assignment to a six-month exercise training
      group, or a 6-month "wait-list" training group followed by a 6-month exercise training
      period. The exercise training will be in accordance with American College of Sports Medicine
      and Canadian Society for Exercise Physiology guidelines supporting 3 days/week in the
      laboratory with target heart rate-based aerobic activity (~30 minutes/day) and two days of
      at-home activity. Based on target heart rate, levels of exercise intensity and/or duration
      will be adjusted every two weeks to sustain the training stimulus. CAD patients are defined
      here as those with a diagnosis of coronary artery disease having been hospitalized for a
      cardiac event. Within the recruited CAD participants, Group 1 (CADcr) will volunteer to
      receive a structured cardiac rehabilitation (CR) program. Group 2 (CADuc) will receive the
      recommendation for cardiac rehabilitation and choose not to participate (due to various
      reasons including distance to cardiac rehabilitation site), yet volunteer to the testing
      procedures at baseline and following a six month period. While random assignment is
      preferred, it is not feasible in CAD patients because, in our experience, geographical
      constraints or other personal barriers restrict access to CR and because CR is often
      considered the normal standard of care (they won't volunteer to avoid CR if they want CR).
      Instead, a naturalistic control approach will be used whereby patients who do not participate
      in CR may still participate by undergoing the testing before and following a six month period
      of time. Use of recall surveys will establish activity patterns in the non-exercise training
      groups or wait periods. Both groups will receive the same in-hospital education, referral to
      a CR program, personal prescription (referral), encouragement and follow-up. All subjects
      will complete a series of tests before and following the six-month interval of exercise or
      time control. Exercise training and the majority of testing will occur in the Laboratory for
      Brain and Heart Health (Labatt Health Sciences Building, Rm 402). Protocols:
      Cardio-respiratory Fitness: Fitness will be determined using a self-paced six-minute walk
      test (6MWT) that will be administered as per American Thoracic Society (ATS) guidelines
      whereby a physician's presence is not required. Blood Sample: After resting quietly for up to
      30 min, a fasting (>3 hours) venous blood sample will be taken from the antecubital vein for
      analysis of blood glucose, lipids, and insulin (LifeLabs), markers of astrocyte and vascular
      damage (D. Fraser), endothelial function (e.g. endothelin, P-selectin) and inflammation (e.g.
      hsCRP, TNFa, IL-1, IL-6, IL-10), neural function markers (e.g. epinephrine, norepinephrine),
      and proliferative factors (e.g. NFK-B, brain-derived neurotrophic factor (BDNF), VEGF) (K.
      Summers). Additional samples of 10 mL whole blood will be taken to Robarts Research Institute
      for analysis of genetic markers of vascular risk (e.g. Apolipoprotein E (APOE) or BDNF
      polymorphisms (R. Hegele)) and for monocyte inflammatory profiles using flow-cytometry (G.
      Dekaban). Up to 5 samples of plasma (~1 mL) will be sent to Victoria Hospital for cell
      culture fluid-flow analysis of polymorphonuclear cell binding (G. Cepinskas). The total
      volume of blood sample will not exceed 60 mL. Vascular Ultrasound: Ultrasound will be used to
      measure artery diameters and blood flow in the Carotid Artery, Carotid Sinus, Brachial Artery
      and Femoral Artery. Dilation of the brachial artery will also be measured following five
      minutes of forearm ischemia (flow-mediated dilation) and for four minutes following a
      sublingual single dose (0.4 mg) of sodium nitroglycerine (standard over-the-counter
      self-treatment for angina). Sympathetic Nerve Activity: Peripheral sympathetic nerve activity
      will be obtained from the peroneal nerve using microneurography. A 200 µm-diameter, 35 mm
      long tungsten microelectrode tapered to an uninsulated 1- to 5-µm tip is inserted
      transcutaneously into the peroneal nerve just posterior to the fibular head. A reference
      electrode is positioned subcutaneously 1-3 cm from the recording site. A sympathetic nerve
      site is confirmed by the characteristic pulse-synchronous burst pattern that does not produce
      skin paraesthesias and that increases in frequency during a voluntary apnea and/or a Valsalva
      manoeuvre but not during arousal to a loud noise. Transcranial Ultrasound: A small probe held
      against each of the temporal windows (just behind the eyes) with a headband will measure flow
      velocity within the middle and/or posterior cerebral arteries. Cerebrovascular Reactivity
      (Hypercapnia): Subjects will breathe a hypercapnic gas mixture of 5% CO2/21% O2/Balance N2
      through a 2-way non-rebreathing valve. This gas will be inspired for up to 5 minutes in each
      of two repeated trials separated by at least 5 minutes of recovery. Sit-to-stand test: To
      test dynamic rate of recovery in cerebral blood flow during transient changes in blood
      pressure, brain blood flow by transcranial Doppler ultrasound, blood pressure, heart rate,
      and end tidal CO2 (with a mask) will be measured during ~3 min of seated rest, two minutes of
      standing, and then a period of seated rest. This protocol may be repeated up to three times.
      A gas analyzer and face mask mechanism will enable measurement of expired oxygen and carbon
      dioxide in each of the hypercapnia and sit-to-stand tests. Electrocardiogram: A standard
      electrocardiogram will be collected via small surface electrodes on the chest to determine
      heart rate. Ventilation Patterns: A respitrace strain gauge will be placed around the chest
      to record breathing patterns. Blood pressure will be measured using a small cuff place on a
      finger (Finometer), and confirmed with upper arm sphygmomanometry. Hemoglobin saturation will
      be measured by a pulse oximeter on one of the digits. 1. 6-min walk test: Using a self-paced
      format, participants will walk back and forth along a long hallway for six minutes while the
      distance covered will be recorded. Participants may rest as needed throughout the test. 2.
      Leg and arm muscle strength (isometric). Participants will push a single arm or leg against a
      resistance machine while the force is measured. Three maximal-effort 3-sec repetitions will
      be repeated separated by a minute or two of rest. Neuropsychology Tests: These tests will
      study the key functional outcomes in vascular cognitive impairment and include measures
      related to mood, memory and cognition. The tests are pen-and-paper, will be administered by
      trained personnel, and, based on published standards (Hachinski et al., 2006) will include
      the following: Overall Cognitive Function: Montreal Cognitive Assessment (MOCA), Trail making
      test, and The Stroop Word-Colour Test. The latter task takes advantage of our ability to read
      words more quickly and automatically than we can name colors. Executive Function (Animal
      Naming, Controlled Oral Word), Association (Trail Making Test); Language (Boston Naming Test
      2nd Edition, short form); Visuospatial (Rey-Osterrieth Complex, Figure Copy, Complex Figure
      Memory); Digit Span and Digit Symbol coding from the Wechsler Adult Intelligence Scale IV
      (WAIS-III; with Canadian norms) Memory (Rey Auditory Verbal Learning Test;
      http://www.wpspublish.com/store/Search?Q=Rey%20Auditory%20Verbal%20Learning%20Test%E2%84%A2%2
      0(RAVLT%E2%84%A2); NOTE: In an attempt to address the practice effect problem related to
      repeated trials of the same test, alternate forms of some scales may be administered in a
      counter-balanced manner when appropriate. (Reference: V. Hachinski et al. National Institute
      of Neurological Disorders and Stroke - Canadian Stroke Network Vascular Cognitive Impairment
      Harmonization Standards, Stroke, 2006, 37:2220-2241) Magnetic Resonance Imaging (MRI): Two
      separate MRI protocols will be performed by each participant. These will be completed on
      either the 3 Tesla or 7 Tesla imaging systems at Robarts. The series of images acquired will
      include: 1) T1 MPRAGE anatomical, 2) FLAIR for white matter hyperintensities, 3) MR
      angiography for vascular architecture, 4) black-blood angiography of middle cerebral artery
      at baseline and again after up to five minutes of hypercapnia. Sample Schedule of Testing:
      These will be performed at each of the pre and post training periods. Visit 1 - Laboratory
      Testing 1 (3 hours) Consent: 15 min Supine rest: 30 min Blood samples: 10 min (used partly
      for group allocation in the pre test) Snack: 10 min Instrumentation (including transcranial
      Doppler and carotid artery vascular ultrasound imaging): 60 min Cerebrovascular Reactivity to
      hypercapnia and sit-to-stand tasks: 45 min Visit 2 - Laboratory Testing 2 (2h) Cognitive
      tests: 45 min Vascular imaging: 30 min Six-min walk: 10 min Leg Muscle Strength: 10 min Visit
      3 - MRI Testing (<1.5 hours total time) Baseline blood pressure: 10 min MRI Preparation: 10
      min Anatomical: 10 min White Matter Hyperintensities: 10 min Angiography: 20 min MR
      angiography of middle cerebral artery with hypercapnia: 20 min The Interventions:
      Rehabilitative Exercise: The cardiac rehabilitation (CR) programs will provide the initial
      exercise intervention for referred CAD patients (Dr. Suskin). The CR program uses
      standardized, prescriptive and progressive exercise (primarily aerobic exercise) practices to
      improve the functional capacity of patients following a clinical cardiac intervention. The CR
      program in London lasts for 6 months. In general, aerobic exercise training is at an
      intensity of 40%-70% heart rate reserve or, a rate of perceived exercise score of 11-14 (on
      the 6-20 Borg scale), 3-7 d/wk, at 20-60 min/session (or multiple 10-min sessions).
    

Intervention name(s): exercise
Intervention type(s): Other
Intervention description(s): six-month interval of exercise
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: blood flow; brain health; exercise; endothelial activation