- Email: [email protected]
Cerebral Hemodynamics During Exercise and Recovery in Heart Transplant Recipients
Accepted Manuscript Cerebral hemodynamics during exercise and recovery in heart transplant recipients Mathieu Gayda, Ph.D, Audrey Desjardins, B.Sc, Gabriel Lapierre, B.Sc, Olivier Dupuy, Ph.D, Sarah Fraser, Ph.D, Louis Bherer, Ph.D, Martin Juneau, M.D, Michel White, M.D, Vincent Gremeaux, Ph.D, M.D, Véronique Labelle, Ph.D, Anil Nigam, M.D PII:
S0828-282X(15)00539-5
DOI:
10.1016/j.cjca.2015.07.011
Reference:
CJCA 1753
To appear in:
Canadian Journal of Cardiology
Received Date: 5 May 2015 Revised Date:
17 July 2015
Accepted Date: 17 July 2015
Please cite this article as: Gayda M, Desjardins A, Lapierre G, Dupuy O, Fraser S, Bherer L, Juneau M, White M, Gremeaux V, Labelle V, Nigam A, Cerebral hemodynamics during exercise and recovery in heart transplant recipients, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.07.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Cerebral hemodynamics during exercise and recovery in heart transplant recipients 1-3
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Mathieu Gayda (Ph.D)
, Audrey Desjardins (B.Sc)
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Dupuy (Ph.D) 7, Sarah Fraser (Ph.D)
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Michel White (M.D)
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Nigam (M.D) 1-3.
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University of Montreal, Montreal, Quebec, Canada.
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Canada.
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1-3
, Gabriel Lapierre (B.Sc) 1,2, Olivier
, Louis Bherer (Ph.D)
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1-3
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, Vincent Gremeaux (Ph.D, M.D) 6, Véronique Labelle (Ph.D) 5, Anil
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, Martin Juneau (M.D)
Cardiovascular Prevention and Rehabilitation Centre (ÉPIC), Montreal Heart Institute and
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Research Center, Montreal Heart Institute and University of Montreal, Montreal, Quebec,
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Canada.
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Perform Centre, Department of Psychology. Concordia University, Montreal, Quebec, Canada
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Research Centre, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada
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Dijon F-21078, France.
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Laboratory, MOVE (EA6314), Faculty of Sport Sciences, Université de Poitiers, France
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The School of Social Work, McGill University, Montreal, Canada.
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Article type: Original article
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Short title: Brain and exercise in heart transplant
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Word count: 4500
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Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec,
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CIC INSERM 1432, Plateforme d'Investigation Technologique, Dijon University Hospital,
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Corresponding author: Dr Mathieu Gayda (Ph.D)
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Cardiovascular Prevention and Rehabilitation Centre (Centre ÉPIC), Montreal Heart Institute and
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Université de Montréal", 5055 St-Zotique Street East, Montreal, Quebec H1T 1N6, Canada.
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Telephone: (514) 374-1480, ext 268; Fax: (514) 374-2445
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E-mail: [email protected]
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Brief summary
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Cerebral oxygenation-perfusion (COP) and central hemodynamics were compared in 26 heart
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transplant recipients (HTR) vs. 27 aged-matched healthy controls (AMHC) during maximal
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exercise and its recovery. In HTR, COP was lower during exercise and recovery vs. AMHC
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(P<0.05) and was positively correlated with maximal cardiac index (P<0.01). In HTR, COP is
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impaired during exercise and its recovery vs. AMHC, potentially due to a combination of blunted
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cerebral vasodilatation by CO2, reduced cardiac output and medication.
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Abstract
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Background: The aims of this work were: 1) To compare cerebral oxygenation-perfusion (COP),
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& peak in heart transplant recipients (HTR) vs. aged-matched central hemodynamics and VO 2
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healthy controls (AMHC) during exercise and recovery. 2) To study the relationships between
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& peak in HTR and AMHC. cerebral oxygenation-perfusion, central hemodynamic and VO 2
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Methods: Twenty-six HTR (3 women) and 27 AMHC (5 women) were recruited. Maximal
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cardiopulmonary function (gas exchange analysis), cardiac hemodynamics (impedance
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cardiography) and left frontal cerebral oxygenation-perfusion (near-infrared spectroscopy) were
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measured continuously during and after a maximal ergocycle test. Results: Compared to AMHC,
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& peak, maximal cardiac index (CI max), and maximal ventilatory variables HTR had a lower VO 2
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(P<0.05). Cerebral oxygenation/perfusion was lower during exercise (∆O2 Hb: 50 and 75% of
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& peak, ∆tHb: 100% of VO & peak; P<0.05) and recovery in HTR (∆O2 Hb: min 2 to 5; ∆tHb: VO 2 2
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min 1 to 5; P<0.05) as compared to AMHC. End tidal pressure of CO2 was lower during exercise
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vs. AMHC (P<0.0001). In HTR, CI max was positively correlated with exercise cerebral
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hemodynamics (R=0.54 to 0.60, P<0.01). Conclusions: In HTR, COP was reduced during
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exercise and recovery vs. AMHC, potentially due to a combination of blunted cerebral
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vasodilatation by CO2, cerebrovascular dysfunction, reduced cardiac function and medication.
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& peak observed in HTR was mainly due to reduced maximal ventilation and CI. In Impaired VO 2
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HTR, COP is impaired and is correlated to cardiac function, potentially impacting their cognitive
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function. Therefore, we need to study which interventions (e.g., exercise training) are most
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effective for improving and/or normalizing COP during and after exercise in HTR.
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Key words: cardiopulmonary exercise test, cerebral oxygenation-perfusion, cardiac output,
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recovery, heart transplant recipients.
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Introduction
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Heart transplantation is an accepted therapeutic intervention for select patients with advanced
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heart failure. This intervention improves their survival 1, quality of life and ability to return to
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& peak) remains 40 to 60 % lower in heart transplant work 2. However, peak oxygen uptake ( VO 2
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recipients (HTR) compared to healthy aged-matched subjects
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limitation during exercise includes chronotropic incompetence due to cardiac denervation, a
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diastolic dysfunction
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& peak in HTR peripheral vascular factors are also limiting VO 2
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effects of immunosuppressive agents and/or corticosteroids 7. Previous studies in patients with
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valvular disease demonstrated lower cerebral oxygenation (assessed by near-infra red
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spectroscopy: NIRS) during a maximal incremental exercise compared to healthy controls,
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& peak and ventilatory threshold 8. Similarly, patients cerebral oxygenation being related to VO 2
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with chronic heart failure showed lower cerebral oxygenation/perfusion (NIRS) during exercise 9,
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10
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peak
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disease, decreased cerebral oxygenation was shown to be an independent predictor of future
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cardiovascular deaths 11 and to be related in part to cerebral arteriosclerosis 12. In addition, studies
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with small sample sizes have demonstrated a restored cerebral blood flow (at rest: measured by
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echography) after transplantation
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but may not be fully restored in the long term as compared to AMHC
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their daily activities and their quality of life. At present, it is unknown if HTR have an impaired
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cerebral oxygenation-perfusion (COP) during and after exercise (vs. AMHC) and if exercise
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(including their daily activities) would chronically expose them to a reduced cerebral
80
& peak) and preserved central oxygenation. Additionally, it is unclear if a higher fitness level ( VO 2
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. In HTR, central factors for this
, and a 30 to 40 % reduction of maximal cardiac output 7. In addition,
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, with negative vascular
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& and recovery 10 compared to healthy controls, with cerebral oxygenation being related to VO 2 and resting cardiac function (LVEF %)
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. Finally, in patients with coronary heart
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. Cognitive function is also improved after transplantation, 16
, potentially affecting
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hemodynamic function are protective factors that are associated with better COP during and after
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exercise.
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Therefore, the aims of this work were: 1) To compare cerebral oxygenation-perfusion (COP),
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& peak in heart transplant recipients (HTR) vs. aged-matched central hemodynamics and VO 2
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healthy controls (AMHC) during exercise and recovery. 2) To study the relationships between
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& peak in HTR and AMHC. cerebral oxygenation-perfusion, central hemodynamic and VO 2
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Methods
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Subjects
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A total of 53 adults were recruited from the Cardiovascular Prevention and Rehabilitation Centre
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of the Montreal Heart Institute, including 26 HTR (age: 27 to 76 years) and 27 AMHC (age: 26 to
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85 years). For AMHC, inclusion criteria were: age >18 years, no evidence of coronary heart
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disease (CHD), ability to perform a maximal incremental exercise test and at most one following
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cardiovascular risk factor (dyslipidemias, hypertension or overweight) and/or its medication 17-19.
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The exclusion criteria for AMHC were: recent acute coronary syndrome (<3 months), significant
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resting ECG abnormality, history of ventricular arrhythmias or congestive heart failure, stroke,
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uncontrolled hypertension, recent coronary bypass surgery (<3 months), recent percutaneous
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transluminal coronary angioplasty (<6 months), left ventricular ejection fraction <45%,
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pacemaker or implantable cardioverter defibrillator, recent modification of medication (<2
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weeks), and musculoskeletal conditions making exercise on ergocycle difficult or contraindicated.
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In AMHC, 1 subject was treated for dyslipidemia (statin) and one for hypertension (calcium
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channel blocker) (table S1). In HTR, inclusion criteria were: age >18 years, to have undergone a
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heart transplantation, to be in a stable clinical condition including optimal medication and with no
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cardiac allograft rejection and to be able to perform a maximal incremental exercise test 17-19. All
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subjects provided written informed consent and the protocol was approved by the local Ethics
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Committee. All subjects underwent a baseline evaluation that included a medical history, physical
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examination with measurement of height and weight, body composition (bioimpedance, Tanita,
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model BC418, Japan) and fasting blood sample (glucose and lipid profile)
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performed a maximal cardiopulmonary exercise test (CPET) with gas exchange analysis on
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ergocycle
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central hemodynamics (impedance cardiography) were measured continuously
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Maximal cardiopulmonary exercise testing
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This test was performed on an ergocycle (Ergoline 800S, Bitz, Germany), with an individualized
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protocol that included a 3 min warm up at 20 Watts, followed by a power increase of 10 to 20
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Watts/min until exhaustion at a pedaling speed > 60 rpm
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continuously at rest, during exercise, and after exercise cessation using a metabolic system
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(Oxycon Pro, Jaegger, Germany) as previously published
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details).
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Cerebral oxygenation/perfusion
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Cerebral oxygenation/perfusion was measured using a near-infrared spectroscopy (NIRS) system
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(Oxymon Mk III, Artinis Medical, Netherlands) during maximal exercise and recovery
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Two optodes were placed on the left prefrontal cortical area between Fp1 and Fp3, according to
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the modified international EEG 10-20 system 20, 23-25 (see supplemental text for details).
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Central hemodynamics
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Central hemodynamics were measured continuously at rest, during exercise and recovery using
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an impedance cardiography device (PhysioFlow®, Enduro model, Manatec, France)
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noninvasive technique has proven to be valid, accurate, and reproducible at rest and during
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exercise in healthy subjects and cardiac patients
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. All subjects
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. During CPET, cerebral oxygenation-perfusion (near-infra red spectroscopy) and 17, 20
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(see supplemental text for
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. This
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. Data were averaged every 15 consecutive
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heartbeats for cardiac index (CI: in L/min/m2, stroke volume index (SVi: in mL/m2), heart rate (in
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beats/min), end diastolic and systolic volume index (EDVi and ESVi: in mL/m2), and systemic
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vascular resistance index (SVRi: in dynes/s/cm5/m2) 17. C(a-v)O2 was calculated according to the
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& /cardiac output. Fick principle: C(a-v)O2 = VO 2
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Statistical analysis
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Results are presented as mean ± standard deviation except where otherwise indicated. Statistical
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analysis was performed using Statview software 5.0 (SAS, Cary, USA). Normal Gaussian
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distribution of the data was verified by the Shapiro–Wilk test. A Student's unpaired t-test
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was used to compare cardiopulmonary and cardiac hemodynamic function variables
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between HTR and AMHC. A two-way ANOVA with repeated measure for time (group ×
139
time) was performed to compare NIRS variables (∆O2Hb, ∆HHb and ∆tHb) during
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exercise and recovery between HTR and AMHC. All post-hoc tests were Bonferroni
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corrected. Statistical significance was set at P<0.05 level for all analyses. Relationships
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& peak, CI max and NIRS maximal variables (∆O2Hb, ∆HHb, ∆tHb) during between VO 2
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exercise were assessed with a Pearson coefficient of correlation (R).
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Results
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Clinical characteristics
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Clinical characteristics of AMHC and HTR subjects are described in supplemental text and in
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Table S1. As expected, medication usage was higher in HTR vs. AMHC with a large
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proportion of patients taking immunosuppressive agents (100%), statins (95%), 7
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antiplatelet agents (80%), calcium channels blockers (70%) and angiotensin II receptor
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antagonist (50%). As well, compared to AMHC, HTR had a larger BMI, and a greater
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total and trunk fat mass (P<0.05). Compared to AMHC, HTR had a higher fasting
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glycemia, total and LDL-cholesterol (P<0.0001).
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154 Cardiopulmonary exercise testing variables
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The cardiopulmonary exercise testing variables in AMHC and HTR subjects are described
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in supplemental text and in Table S2. Compared to AMHC, HTR had a higher resting HR
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& and SBP (P<0.05). Compared to AMHC, HTR had a lower VO 2 and power at ventilatory
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threshold (VT) and peak exercise (P<0.0001). Compared to AMHC, HTR had a lower V
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E peak, % V E peak predicted, tidal volume and breathing frequency at peak effort
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(P<0.05). At peak effort, HTR had a lower peak HR, heart rate reserve, arteriovenous
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difference, CImax, SVi and SVRi (P<0.05). Compared to AMHC, HTR had a higher
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& peak was related to V Emax, CImax and C(a-v)O2 ESVi (P<0.05). In AMHC, VO 2
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whereas, in HTR, it was related to
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materials).
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Left prefrontal NIRS variables during exercise and recovery
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Figures 1 and 2 describe left prefrontal NIRS variables during exercise and recovery in AMHC
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& and HTR subjects. During exercise, HTR had lower values for ∆O2Hb (at 50% and 75% of VO 2
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& peak, P<0.05) and ∆Hb diff. (at 50% to 75% of VO & peak, P<0.05), ∆tHb (at 100% of VO 2 2
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.
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V Emax and CImax (Table S3, supplementary
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peak, P<0.05) vs. AMHC. During recovery, HTR had lower values for ∆O2Hb, ∆Hb diff. (from 2
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to 5 min, P<0.05) and ∆tHb (from 1 to 5 min, P<0.05) vs. AMHC.
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End tidal pressure of CO2 , blood pressure and cardiac index during exercise and
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recovery
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Figures 3 and 4 describe end tidal pressure of CO2 (PETCO2), SBP, DBP and CI during exercise
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and recovery in AMHC and HTR subjects. During exercise, HTR had lower values for
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PETCO2 at each intensities (Fig 3 a) as compared to AMHC. During exercise, SBP and
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DBP were not different between both groups (Fig 3 b and c). Finally, HTR had lower
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& peak (Fig 3 d) as compared to values for cardiac index from 25% to 100% of VO 2
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AMHC. During recovery, HTR had lower values for PETCO2 at 4 min (Fig 4 a) as
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compared to AMHC. During recovery, HTR had lower values for SBP at 0 and 1 min
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(Fig 4 b) as compared to AMHC. During recovery, DBP was not different between
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groups (Fig 4 c). Finally, during recovery, HTR had lower values for cardiac index at 0, 1
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and 2 min (Fig 4 d) as compared to AMHC.
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& peak, CI max, and left prefrontal NIRS variables Relationships between VO 2
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& peak, CI max and left prefrontal NIRS Table S4 presents the relationships between VO 2
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variables (NIRS maximal values during exercise: ∆O2Hb, ∆HHb, ∆tHb) in all subjects, AMHC
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& peak was positively correlated with ∆O2 Hb and ∆tHb. In HTR, only and HTR. In AMHC, VO 2
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CI max positively correlated with ∆O2Hb, ∆HHb and ∆tHb.
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Discussion
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The main findings of this study were that: 1) Compared to AMHC, HTR had a reduced cerebral
192
& peak) and perfusion (∆tHb: 100 % of VO & peak) oxygenation (∆O2Hb: 50 and 75% of VO 2 2
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during exercise. 2) However, cerebral oxygenation/perfusion was impaired during exercise
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recovery (∆O2Hb: 2nd to 5th min; ∆tHb: 1st to 5th min) in HTR as compared to AMHC. 3) In HTR,
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PETCO2 during exercise and central hemodynamics (CI) during exercise and recovery were both
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reduced vs. AMHC. 4) Cerebral hemodynamics (∆O2Hb, ∆tHb) was positively correlated with
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& peak in AMHC and with maximal cardiac output (CI max) in HTR. In addition, the findings VO 2
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& peak in HTR as compared to AMHC might originates from support that the impairment of VO 2
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altered ventilation and central hemodynamics. To the best of our knowledge, this study is the first
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to integrate simultaneous measures of cerebral oxygenation/perfusion, cardiac hemodynamics and
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& peak during exercise in HTR and the first to examine cerebral oxygenation/perfusion during VO 2
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recovery from maximal exercise in HTR.
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& peak values of HTR obtained in our study is in agreement with previous The reduced VO 2
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studies
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chronotropic incompetence (cardiac denervation), reduced cardiac output, reduced cardiac
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compliance and diastolic dysfunction 3, 6, 7, 32, 33. Our central hemodynamics results confirm some
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of those mechanisms: chronotropic incompetence (reduced % HR reserve), reduced cardiac
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output (CImax), reduced ejection fraction and higher end systolic volume. We also showed that
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& peak was related to maximal cardiac index in HTR. In addition, we the reduced VO 2
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demonstrated a reduced arterio-venous difference [(C(a-v)O2)] during exercise in HTR vs.
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& peak. These AMHC, underlying also a peripheral limitation origin for the reduced VO 2
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peripheral limitations in HTR have been previously described and they include skeletal muscle
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myopathy, impaired muscle metabolism, blood flow and vascular dilatation
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demonstrated an impaired maximal ventilation and its components (tidal volume and respiratory
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frequency at peak effort) in HTR, in agreement with one previous study
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explained by ventilatory muscle deconditioning, abnormal and/or intrapulmonary pressure. In
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& peak in HTR, underlying its important addition, maximal ventilation was related to VO 2
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contribution to reduced maximal aerobic capacity in HTR. An increased systemic vascular
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resistance was found in HTR that could explain in part a higher end systolic volume as compared
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to AMHC. Previous studies have documented negative vascular effects of immunosuppressive
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agents that include hypertension, endothelial and microvascular dysfunction 7, 35.
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Our results demonstrated that HTR had a lower cerebral oxygenation (∆O2 Hb) (at 50 and 75 %
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& peak) and perfusion (∆tHb: 100% of VO & peak) during exercise vs. AMHC. As well, of VO 2 2
224
HTR did present a reduced cerebral oxygenation (∆O2 Hb: from 2 to 5 min) and perfusion (∆tHb:
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from 1 to 5 min) during recovery as compared to AMHC. In addition, we showed that PETCO2
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and cardiac output were reduced during exercise in HTR as compared to AMHC. During
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exercise, those two important factors (PETCO2 and CI) might have greatly contributed to
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difference in cerebral oxygenation/perfusion between groups. During exercise, PETCO2 generally
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& peak in AHMC, and CO2 is known to be a powerful cerebral increases up to 50% of VO 2
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& peak vasodilator, as shown by our data and those of others group 36. From 75 to 100% of VO 2
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(both groups), PETCO2 decreases and was shown to be accompanied by a cerebral
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vasoconstriction and thus as reduction of cerebral oxygenation/perfusion
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& peak, and could reflect a more blunted cerebral does not increase from 0 to 50% of VO 2
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vasodilatation by CO2. The mechanisms of this blunted cerebral vasodilatation by CO2 in HTR
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vs. AMHC are not clear, but might result from a reduced lung and chest wall compliance,
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respiratory muscle fatigue and differences in chemosensitivity 39. Our results agree with previous
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studies in patients with valvular disease and heart failure (NHYA class III) that demonstrated a
34
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. In HTR, PETCO2
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reduced cerebral oxygenation/perfusion (∆O2 ∆HHb, ∆tHb: left prefrontal NIRS) during exercise
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compared to aged matched healthy controls
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immunosuppressive agents and/or corticosteroids could have deleterious effects on cerebral
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endothelial and microvascular functions in HTR, and could also have also influenced our cerebral
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oxygenation/perfusion results 7. However, differences in cerebral oxygenation/perfusion during
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exercise may differ according to the patients studied. In a study by Fu and colleagues, with a
244
similar design, they showed similar values of cerebral oxygenation/perfusion (∆O2, ∆tHb: left
245
prefrontal NIRS) between heart failure patients (NHYA class II) and AMHC 9. We showed that
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brain perfusion (∆tHb) only differed at peak effort in HTR, and that this function was not
247
different for other exercise intensities. For NIRS variables, an important inter-individual
248
variability (high standard deviation) during exercise was observed, potentially explained that
249
∆tHb only differed at maximal intensity. As well, at peak effort, an important contribution of the
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sympathetic tone on heart rate may have contributed to this difference. Similarly, one study
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demonstrated that cerebral blood flow (measured by transcranial Doppler) was similar between
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HTR and AMHC during incremental exercise 39. In that study, sample size was low (n=7, in each
253
& peak vs. HTR, and transcranial Doppler was used to assess group), AMHC had similar VO 2
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cerebral blood flow, potentially explaining differences with our results
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etiology of heart disease, patient’s aerobic capacity and cardiac function are important factors
256
accounting for the different findings seen across studies. Major differences in cerebral
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oxygenation/perfusion and cardiac output in HTR were observed during recovery (lower values).
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This agrees with a previous study in heart failure patients
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oxygenation (∆O2Hb),perfusion (∆tHb) and cardiac function were reduced vs. AMHC. As
260
suggested, cardiac output is a major contributor to cerebral oxygenation/perfusion post-exercise
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independently of PaCO2, and is reduced in HTR during recovery
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overshoot phenomenon has been previously suggested as a factor implicated in higher ∆O2Hb
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. We believe that the
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where post-exercise cerebral
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. An hemodynamic
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observed during recovery in AMHC as compared to heart failure patients
. Because cardiac
264
function during recovery is also regulated by the autonomic nervous system and metabolic
265
mediators (i.e: NO, adenosine), those factors could also be implicated in the differences observed
266
between the HTR and AMHC
267
to cerebral oxygenation/perfusion (∆O2Hb, ∆tHb) in AMHC and that maximal cardiac output was
268
correlated to cerebral hemodynamics (∆O2Hb, ∆HHb, ∆tHb) in HTR during exercise. These
269
& peak and maximal cardiac output were findings align with Fu et al. who demonstrated that VO 2
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related to cerebral perfusion (∆tHb) in healthy controls and patients with chronic heart failure 9.
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Clinical implications of our findings are that HTR with an impaired cardiac function could suffer
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from cerebral hemodynamic dysfunction during and more particularly after an exercise period
273
10
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their lifespan to preserve their aerobic fitness, cardiac and cerebrovascular function.
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Our study has limitations, including the enrolment of fit healthy subjects and stable HTR
276
recruited in a single centre, hence inducing a potential recruitment bias. It is important to note that
277
& peak predicted), which could have amplified our AMHC were high fit subjects (141 % of VO 2
278
differences in most exercise variables as compared to an age-matched sedentary sample. Heart
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transplant recipients were also primarily male, undergoing optimal or near-optimal medical
280
therapy and our results may differ in women HTR and/or in other HTR in the real-world setting.
281
As well, cerebral oxygenation and perfusion were assessed non-invasively using NIRS at the left
282
prefrontal area level implicating a very limited spatial resolution and a relatively superficial brain
283
tissue measurement (light penetration ≈ 2.25 cm). Therefore, our results may differ from other
284
more invasive and global measurement of brain oxygenation and perfusion (ex: catheters,
285
transcranial Doppler) or from other brain regions. Finally, as recently suggested 43, cerebral NIRS
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O2Hb and tHb signals can be contaminated by extracranial tissues (particularly scalp blood flow)
& peak was correlated . In addition, we demonstrated that VO 2
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during exercise. The AMHC exercised longer and to a greater absolute work rate so they might
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have had a greater skin temperature response. Therefore, to minimize factors influencing skin
289
blood flow, we have attempted to standardize the thermo neutral environment (room temperature
290
: 20°C) and we have used a more important interoptode distance (4.5 cm) to allow deeper light
291
penetration into intracranial tissues 37, 44, 45.
292
Conclusions
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We demonstrate that HTR may be exposed to cerebral hemodynamic dysfunction during and/or
294
after an exercise period as compared to AMHC. In HTR, this cerebral hemodynamic dysfunction
295
was mainly due to a blunted cerebral vasodilatation by CO2 and to a reduced cardiac function. As
296
well, HTR with poor cardiac function seem to be more susceptible to this dysfunction. In
297
perspective, future studies in HTR exploring the potential relation between cerebral
298
oxygenation/perfusion during exercise and cognitive function would be of important clinical
299
interest. As well, future studies particularly in HTR are required to document the optimal aerobic
300
& exercise training program (intensity, duration, frequency) that would optimally improve VO 2
301
peak, cardiac output, and cerebral oxygenation-perfusion.
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Funding sources: ÉPIC Foundation, Montreal Heart Institute Foundation.
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Disclosures: none
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Figures Legend:
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Figure 1 a-d: Brain near-infrared spectroscopy (NIRS) variables during exercise in aged
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matched healthy controls (AMHC) and heart transplant recipients (HTR). ANOVA p
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value: A (intensity), B (group), C (interaction). Post hoc group effect: *= P<0.05, O2Hb :
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oxyhemoglobin, HHb : desoxyhemoglobin, tHb : total hemoglobin, Hb Diff. : differential
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hemoglobin.
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Figure 2 a-d: Brain near-infrared spectroscopy (NIRS) variables during recovery in aged
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matched healthy controls (AMHC) and heart transplant recipients (HTR). ANOVA p
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value: A (time), B (group), C (interaction). Post hoc group effect: *= P<0.05, † = P<0.01,
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‡= P<0.001, O2Hb : oxyhemoglobin, HHb : desoxyhemoglobin, tHb : total hemoglobin,
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Hb Diff. : differential hemoglobin.
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Figures 3 a-d: End tidal pressure of CO2 (PETCO2), systolic blood pressure (SBP), diastolic
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blood pressure (DBP) and cardiac index during exercise in aged matched healthy controls
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(AMHC) and heart transplant recipients (HTR). ANOVA p value: A (intensity), B
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(group), C (interaction). Post hoc group effect: *= P<0.05, † = P<0.01, §= P<0.0001.
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Figures 4 a-d: End tidal pressure of CO2 (PETCO2), systolic blood pressure (SBP), diastolic
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blood pressure (DBP) and cardiac index during recovery in aged matched healthy controls 18
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(AMHC) and heart transplant recipients (HTR). ANOVA p value: A (time), B (group), C
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(interaction). Post hoc group effect: *= P<0.05, † = P<0.01.
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Supplementary Materials Maximal cardiopulmonary exercise testing
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The calibrations of the flow module and gas concentration were performed according to manufacturer recommendations. Data were measured every four respiratory cycles during testing and then averaged every 15 sec for minute ventilation (VE, in L/min BTPS),
L/mim, STPD)
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& , in L/min, STPD), and carbon dioxide production (VCO2, in oxygen uptake ( VO 2 . The exercise test lasted until the attainment of one of two primary
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maximal criteria: (1) a plateau of despite an increase in work rate 21, (2) R.E.R > 1.1, or one of the two secondary maximal criteria: (3) measured maximal heart rate attaining 95% of age-predicted maximal heart rate, (4) inability to maintain the cycling cadence, (5) subject exhaustion with cessation caused by fatigue and/or other clinical symptoms
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(dyspnea, abnormal BP responses) or ECG abnormalities that required exercise cessation . The ventilatory threshold was determined using a combination of the V-slope,
ventilatory equivalents, and end-tidal oxygen pressure methods
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The highest
value
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reached during the exercise phase of each test was considered as the peak and peak power
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output (PPO) was defined as the power output reached at the last fully completed stage 17,
Cerebral oxygenation/perfusion During exercise test, optodes were secured with a tensor bandage wrapped around the forehead, a neoprene pad (with two holes for optodes) was place between the skin and the optodes plastic holder and ambient room light (dimmer) was reduced 20, 24. To correct for scattering of photons in the tissue, a differential path-length factor of 5.93 was used for
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the calculation of absolute concentration changes with an interoptode distance of 45 mm 25
. Two wavelengths (780 and 855 nm) were used during NIRS measurement. Data were
sampled at 10 Hz during the rest period (3 min), the exercise phase and the 5-min
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recovery period. Data were displayed in real time and stored on disk for off-line analysis. Raw NIRS signals were filtered via the oxysoft/DAQ software (Artinis Medical, Netherlands) using a running average function with a filter width of 1. Thereafter, NIRS
statistical treatment
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signals were exported into excel files with the oxysoft/DAQ software at 0.2 Hz for . Relative concentration changes (∆µM) were measured from
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resting baseline of oxyhaemoglobin (∆O2Hb), deoxyhaemoglobin (∆HHb), total haemoglobin (∆tHb = O2Hb + HHb), and differential haemoglobin (∆Hb diff. = ∆O2Hb ∆HHb). The baseline period was set at the end of the 3-min resting period, defined as 0 µM 20, 23, 24. Cerebral oxygenation was represented by the oxyhaemoglobin (∆O2Hb) and
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cerebral perfusion by the total haemoglobin (∆tHb) measured in the left prefrontal cortex.
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Table S1: Clinical characteristics of aged-matched healthy controls (AMHC) and heart transplant recipients (HTR).
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Blood analysis Fasting glucose (mmol/l) Total cholesterol (mmol/l) HDL-cholesterol (mmol/l) LDL- cholesterol (mmol/l)
P value
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0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (4%) 1 (4%) 0 (0%) 0 (0%)
26 (100%) 5 (25%) 1 (5%) 16 (80%) 10 (50%) 19 (95%) 14 (70%) 1 (5%) 2 (10%)
4.95 ± 0.34 5.01 ± 0.82 1.60 ± 0.48 3.04 ± 0.70
6.16 ± 1.23 3.95 ± 0.73 1.63 ± 0.94 1.85 ± 0.51
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Medication Immunosuppressive agents Beta–blockers ACE inhibitors Antiplatelet agents Angiotensin receptor blockers Statins Calcium channel blockers Anticoagulants Spironolactone
HTR (n = 26) 58 ± 11 169 ± 7 3 (12%) 76 ± 14 27 ± 5 84 ± 12 58 ± 9 19 ± 8 11 ± 5 51 ± 11 8±5
0.6991 0.1498
0.0746 0.0027 0.1647 0.7793 0.0072 0.0042
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Age (years) Height (cm) Female (n and %) Body mass (kg) BMI (kg/m2) WC (cm) LBM (kg) TFM(kg) Trunk FM (kg) Age at trans. (years) Years post trans. (years)
AMHC (n = 27) 57 ± 15 172 ± 8 5 (19%) 70 ± 8 24 ± 2 88 ± 7 57 ± 9 14 ± 4 8±3 -
<0.0001 <0.0001 0.9225 <0.0001
BMI: body mass index, WC: waist circumference, LBM: lean body mass, TFM: total fat mass, FM: fat mass, trans.: transplantation, ACE: angiotensin–converting enzyme.
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Table S2: Cardiopulmonary exercise testing data in aged-matched healthy controls
At peak effort
& peak (ml/min/LBM) VO 2 & VO peak (ml/min/kg) 2
& plateau (%) VO 2 & peak predicted (%) % VO 2 Power (Watts) .
.
V E max (l/min) .
ANOVA P value
65 ± 11 117 ± 9 71 ± 7
87 ± 13 125 ± 16 74 ± 9
<0.0001 0.0324 0.2150
31 ± 8
15 ± 5
<0.0001
61 ± 22
<0.0001
168 ± 55
50 ± 10
28 ± 7
<0.0001
41 ± 10
21 ± 7
<0.0001
88
76
0.2461
141 ± 20
77 ± 24
<0.0001
226 ± 72 3329 ± 930
90 ± 43 1810 ± 499
<0.0001 <0.0001
1.17 ± 0,07 107 ± 34
1.13 ± 0.08 66 ± 16
0.1310 <0.0001
152 ± 31
95 ± 25
<0.0001
2.63 ± 0,57 40 ± 10 163 ± 16 105 ± 15 182 ± 19 78 ± 10 -22 ± 9 18 ± 4 55 ± 4 9±1 61 ± 10 92 ± 14 37 ± 14 1028 ± 172
1.89 ± 0.50 35 ± 5 127 ± 21 55 ± 29 172 ± 24 78 ± 10 -7 ± 10 13 ± 4 52 ± 7 7±2 53 ± 16 106 ± 35 54 ± 36 1402 ± 406
<0.0001 0.0243 <0.0001 <0.0001 0.1227 0.8929 <0.0001 0.0003 0.0364 <0.0001 0.0540 0.0833 0.0348 <0.0001
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V CO2 (ml/min) R.E.R
HTR (n = 26)
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% V E max predicted (%) VT max (l) Bf (breaths/min) HRmax (bpm) HR reserve (%) SBP max (mm Hg) DBP max (mm Hg) HRR at 1 min (bpm) C(a-v)O2 (ml O2 /100 ml blood) SVi (ml/m2) CI (l/min/m2) EF (%) EDVi (ml/m2) ESVi (ml/m2) SVRi (dynes.s/cm5/m2)
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At ventilatory threshold & (ml/min/kg) VO 2 Power (Watts)
AMHC (n = 27)
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Cardiopulmonary and hemodynamic variables Rest HR (bpm) SBP (mm Hg) DBP (mm Hg)
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(AMHC) and heart transplant recipients (HTR).
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HR: heart rate, SBP: systolic blood pressure, DBP: diastolic blood pressure, LBM: lean body mass, R.E.R: respiratory exchange ratio, VT: volume tidal, Bf: breathing frequency, HR: heart rate, HRR: heart rate recovery, C(a-v)O2 : arteriovenous difference, SVi: stroke
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volume index, CI: cardiac index, EF: ejection fraction, EDVi: end diastolic volume index,
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ESVi: end systolic volume index, SVRi: systemic vascular resistance index.
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& peak, V Emax, CImax and C(a-v)O2 in agedTable S3: Correlation between VO 2 matched healthy controls (AMHC) and heart transplant recipients (HTR).
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& peak (ml/min/LBM) VO 2 AMHC
R=0.68, p<0.0001
.
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V Emax
R=0.51, p=0.0051
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CImax C(a-v)O2
R=0.85, p<0.0001
HTR
R=0.69, p=0.0004
.
CImax
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C(a-v)O2
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V Emax
R=0.66, p=0.0014 R=0.11, p=0.6469
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& peak (ml/min/kg), maximal cardiac index (CI max) Table S4. Relationship between VO 2 and brain NIRS parameters in all subjects, in aged-matched healthy controls (AMHC)
All subjects (n = 53)
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and heart transplant recipients (HTR).
∆ HHb
& peak (ml/min/kg) VO 2
R = 0.33, P = 0.0133
R = 0.19, P = 0.1450
R = 0.35, P = 0.0077
CI max
R = 0.36, P = 0.0057
R = 0.37, P = 0.0047
R = 0.44, P = 0.0006
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∆ O2Hb
∆ tHb
AMHC (n = 32) ∆ O2Hb
R = 0.35, P = 0.0458
CI max
R = 0.27, P = 0.1301
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& peak (ml/min/kg) VO 2
∆ HHb
∆ tHb
R = 0.29, P = 0.1038
R = 0.47, P = 0.0058
R = 0.28, P = 0.1154
R = 0.34, P = 0.0522
HTR (n = 21) ∆ HHb
∆ tHb
& peak (ml/min/kg) VO 2
R = 0.17, P = 0.4214
R = -0.03, P = 0.8635
R = 0.09, P = 0.6780
CI max
R = 0.54, P = 0.0099
R = 0.55, P = 0.0078
R = 0.60, P = 0.0028
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∆ O2Hb
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CI max: maximal cardiac index, O2Hb : oxyhemoglobin, HHb : desoxyhemoglobin, tHb :
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total hemoglobin.
S0828-282X(15)00539-5
DOI:
10.1016/j.cjca.2015.07.011
Reference:
CJCA 1753
To appear in:
Canadian Journal of Cardiology
Received Date: 5 May 2015 Revised Date:
17 July 2015
Accepted Date: 17 July 2015
Please cite this article as: Gayda M, Desjardins A, Lapierre G, Dupuy O, Fraser S, Bherer L, Juneau M, White M, Gremeaux V, Labelle V, Nigam A, Cerebral hemodynamics during exercise and recovery in heart transplant recipients, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.07.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Cerebral hemodynamics during exercise and recovery in heart transplant recipients 1-3
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Mathieu Gayda (Ph.D)
, Audrey Desjardins (B.Sc)
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Dupuy (Ph.D) 7, Sarah Fraser (Ph.D)
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Michel White (M.D)
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Nigam (M.D) 1-3.
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University of Montreal, Montreal, Quebec, Canada.
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Canada.
1,8
1-3
, Gabriel Lapierre (B.Sc) 1,2, Olivier
, Louis Bherer (Ph.D)
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1-3
,
, Vincent Gremeaux (Ph.D, M.D) 6, Véronique Labelle (Ph.D) 5, Anil
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, Martin Juneau (M.D)
Cardiovascular Prevention and Rehabilitation Centre (ÉPIC), Montreal Heart Institute and
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Research Center, Montreal Heart Institute and University of Montreal, Montreal, Quebec,
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Canada.
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Perform Centre, Department of Psychology. Concordia University, Montreal, Quebec, Canada
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Research Centre, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada
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Dijon F-21078, France.
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Laboratory, MOVE (EA6314), Faculty of Sport Sciences, Université de Poitiers, France
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The School of Social Work, McGill University, Montreal, Canada.
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Article type: Original article
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Short title: Brain and exercise in heart transplant
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Word count: 4500
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Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec,
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CIC INSERM 1432, Plateforme d'Investigation Technologique, Dijon University Hospital,
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Corresponding author: Dr Mathieu Gayda (Ph.D)
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Cardiovascular Prevention and Rehabilitation Centre (Centre ÉPIC), Montreal Heart Institute and
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Université de Montréal", 5055 St-Zotique Street East, Montreal, Quebec H1T 1N6, Canada.
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Telephone: (514) 374-1480, ext 268; Fax: (514) 374-2445
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E-mail: [email protected]
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Brief summary
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Cerebral oxygenation-perfusion (COP) and central hemodynamics were compared in 26 heart
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transplant recipients (HTR) vs. 27 aged-matched healthy controls (AMHC) during maximal
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exercise and its recovery. In HTR, COP was lower during exercise and recovery vs. AMHC
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(P<0.05) and was positively correlated with maximal cardiac index (P<0.01). In HTR, COP is
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impaired during exercise and its recovery vs. AMHC, potentially due to a combination of blunted
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cerebral vasodilatation by CO2, reduced cardiac output and medication.
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Abstract
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Background: The aims of this work were: 1) To compare cerebral oxygenation-perfusion (COP),
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& peak in heart transplant recipients (HTR) vs. aged-matched central hemodynamics and VO 2
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healthy controls (AMHC) during exercise and recovery. 2) To study the relationships between
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& peak in HTR and AMHC. cerebral oxygenation-perfusion, central hemodynamic and VO 2
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Methods: Twenty-six HTR (3 women) and 27 AMHC (5 women) were recruited. Maximal
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cardiopulmonary function (gas exchange analysis), cardiac hemodynamics (impedance
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cardiography) and left frontal cerebral oxygenation-perfusion (near-infrared spectroscopy) were
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measured continuously during and after a maximal ergocycle test. Results: Compared to AMHC,
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& peak, maximal cardiac index (CI max), and maximal ventilatory variables HTR had a lower VO 2
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(P<0.05). Cerebral oxygenation/perfusion was lower during exercise (∆O2 Hb: 50 and 75% of
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& peak, ∆tHb: 100% of VO & peak; P<0.05) and recovery in HTR (∆O2 Hb: min 2 to 5; ∆tHb: VO 2 2
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min 1 to 5; P<0.05) as compared to AMHC. End tidal pressure of CO2 was lower during exercise
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vs. AMHC (P<0.0001). In HTR, CI max was positively correlated with exercise cerebral
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hemodynamics (R=0.54 to 0.60, P<0.01). Conclusions: In HTR, COP was reduced during
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exercise and recovery vs. AMHC, potentially due to a combination of blunted cerebral
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vasodilatation by CO2, cerebrovascular dysfunction, reduced cardiac function and medication.
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& peak observed in HTR was mainly due to reduced maximal ventilation and CI. In Impaired VO 2
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HTR, COP is impaired and is correlated to cardiac function, potentially impacting their cognitive
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function. Therefore, we need to study which interventions (e.g., exercise training) are most
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effective for improving and/or normalizing COP during and after exercise in HTR.
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Key words: cardiopulmonary exercise test, cerebral oxygenation-perfusion, cardiac output,
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recovery, heart transplant recipients.
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Introduction
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Heart transplantation is an accepted therapeutic intervention for select patients with advanced
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heart failure. This intervention improves their survival 1, quality of life and ability to return to
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& peak) remains 40 to 60 % lower in heart transplant work 2. However, peak oxygen uptake ( VO 2
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recipients (HTR) compared to healthy aged-matched subjects
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limitation during exercise includes chronotropic incompetence due to cardiac denervation, a
63
diastolic dysfunction
64
& peak in HTR peripheral vascular factors are also limiting VO 2
65
effects of immunosuppressive agents and/or corticosteroids 7. Previous studies in patients with
66
valvular disease demonstrated lower cerebral oxygenation (assessed by near-infra red
67
spectroscopy: NIRS) during a maximal incremental exercise compared to healthy controls,
68
& peak and ventilatory threshold 8. Similarly, patients cerebral oxygenation being related to VO 2
69
with chronic heart failure showed lower cerebral oxygenation/perfusion (NIRS) during exercise 9,
70
10
71
peak
72
disease, decreased cerebral oxygenation was shown to be an independent predictor of future
73
cardiovascular deaths 11 and to be related in part to cerebral arteriosclerosis 12. In addition, studies
74
with small sample sizes have demonstrated a restored cerebral blood flow (at rest: measured by
75
echography) after transplantation
76
but may not be fully restored in the long term as compared to AMHC
77
their daily activities and their quality of life. At present, it is unknown if HTR have an impaired
78
cerebral oxygenation-perfusion (COP) during and after exercise (vs. AMHC) and if exercise
79
(including their daily activities) would chronically expose them to a reduced cerebral
80
& peak) and preserved central oxygenation. Additionally, it is unclear if a higher fitness level ( VO 2
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. In HTR, central factors for this
, and a 30 to 40 % reduction of maximal cardiac output 7. In addition,
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10
. Finally, in patients with coronary heart
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. Cognitive function is also improved after transplantation, 16
, potentially affecting
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hemodynamic function are protective factors that are associated with better COP during and after
82
exercise.
83
Therefore, the aims of this work were: 1) To compare cerebral oxygenation-perfusion (COP),
84
& peak in heart transplant recipients (HTR) vs. aged-matched central hemodynamics and VO 2
85
healthy controls (AMHC) during exercise and recovery. 2) To study the relationships between
86
& peak in HTR and AMHC. cerebral oxygenation-perfusion, central hemodynamic and VO 2
87
Methods
88
Subjects
89
A total of 53 adults were recruited from the Cardiovascular Prevention and Rehabilitation Centre
90
of the Montreal Heart Institute, including 26 HTR (age: 27 to 76 years) and 27 AMHC (age: 26 to
91
85 years). For AMHC, inclusion criteria were: age >18 years, no evidence of coronary heart
92
disease (CHD), ability to perform a maximal incremental exercise test and at most one following
93
cardiovascular risk factor (dyslipidemias, hypertension or overweight) and/or its medication 17-19.
94
The exclusion criteria for AMHC were: recent acute coronary syndrome (<3 months), significant
95
resting ECG abnormality, history of ventricular arrhythmias or congestive heart failure, stroke,
96
uncontrolled hypertension, recent coronary bypass surgery (<3 months), recent percutaneous
97
transluminal coronary angioplasty (<6 months), left ventricular ejection fraction <45%,
98
pacemaker or implantable cardioverter defibrillator, recent modification of medication (<2
99
weeks), and musculoskeletal conditions making exercise on ergocycle difficult or contraindicated.
100
In AMHC, 1 subject was treated for dyslipidemia (statin) and one for hypertension (calcium
101
channel blocker) (table S1). In HTR, inclusion criteria were: age >18 years, to have undergone a
102
heart transplantation, to be in a stable clinical condition including optimal medication and with no
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cardiac allograft rejection and to be able to perform a maximal incremental exercise test 17-19. All
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subjects provided written informed consent and the protocol was approved by the local Ethics
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Committee. All subjects underwent a baseline evaluation that included a medical history, physical
106
examination with measurement of height and weight, body composition (bioimpedance, Tanita,
107
model BC418, Japan) and fasting blood sample (glucose and lipid profile)
108
performed a maximal cardiopulmonary exercise test (CPET) with gas exchange analysis on
109
ergocycle
110
central hemodynamics (impedance cardiography) were measured continuously
111
Maximal cardiopulmonary exercise testing
112
This test was performed on an ergocycle (Ergoline 800S, Bitz, Germany), with an individualized
113
protocol that included a 3 min warm up at 20 Watts, followed by a power increase of 10 to 20
114
Watts/min until exhaustion at a pedaling speed > 60 rpm
115
continuously at rest, during exercise, and after exercise cessation using a metabolic system
116
(Oxycon Pro, Jaegger, Germany) as previously published
117
details).
118
Cerebral oxygenation/perfusion
119
Cerebral oxygenation/perfusion was measured using a near-infrared spectroscopy (NIRS) system
120
(Oxymon Mk III, Artinis Medical, Netherlands) during maximal exercise and recovery
121
Two optodes were placed on the left prefrontal cortical area between Fp1 and Fp3, according to
122
the modified international EEG 10-20 system 20, 23-25 (see supplemental text for details).
123
Central hemodynamics
124
Central hemodynamics were measured continuously at rest, during exercise and recovery using
125
an impedance cardiography device (PhysioFlow®, Enduro model, Manatec, France)
126
noninvasive technique has proven to be valid, accurate, and reproducible at rest and during
127
exercise in healthy subjects and cardiac patients
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. All subjects
18
. During CPET, cerebral oxygenation-perfusion (near-infra red spectroscopy) and 17, 20
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17, 18
. Gas exchange was measured
(see supplemental text for
20, 23, 24
.
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17, 26-28
. This
26-31
. Data were averaged every 15 consecutive
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heartbeats for cardiac index (CI: in L/min/m2, stroke volume index (SVi: in mL/m2), heart rate (in
129
beats/min), end diastolic and systolic volume index (EDVi and ESVi: in mL/m2), and systemic
130
vascular resistance index (SVRi: in dynes/s/cm5/m2) 17. C(a-v)O2 was calculated according to the
131
& /cardiac output. Fick principle: C(a-v)O2 = VO 2
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Statistical analysis
134
Results are presented as mean ± standard deviation except where otherwise indicated. Statistical
135
analysis was performed using Statview software 5.0 (SAS, Cary, USA). Normal Gaussian
136
distribution of the data was verified by the Shapiro–Wilk test. A Student's unpaired t-test
137
was used to compare cardiopulmonary and cardiac hemodynamic function variables
138
between HTR and AMHC. A two-way ANOVA with repeated measure for time (group ×
139
time) was performed to compare NIRS variables (∆O2Hb, ∆HHb and ∆tHb) during
140
exercise and recovery between HTR and AMHC. All post-hoc tests were Bonferroni
141
corrected. Statistical significance was set at P<0.05 level for all analyses. Relationships
142
& peak, CI max and NIRS maximal variables (∆O2Hb, ∆HHb, ∆tHb) during between VO 2
143
exercise were assessed with a Pearson coefficient of correlation (R).
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Results
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Clinical characteristics
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Clinical characteristics of AMHC and HTR subjects are described in supplemental text and in
148
Table S1. As expected, medication usage was higher in HTR vs. AMHC with a large
149
proportion of patients taking immunosuppressive agents (100%), statins (95%), 7
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antiplatelet agents (80%), calcium channels blockers (70%) and angiotensin II receptor
151
antagonist (50%). As well, compared to AMHC, HTR had a larger BMI, and a greater
152
total and trunk fat mass (P<0.05). Compared to AMHC, HTR had a higher fasting
153
glycemia, total and LDL-cholesterol (P<0.0001).
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154 Cardiopulmonary exercise testing variables
156
The cardiopulmonary exercise testing variables in AMHC and HTR subjects are described
157
in supplemental text and in Table S2. Compared to AMHC, HTR had a higher resting HR
158
& and SBP (P<0.05). Compared to AMHC, HTR had a lower VO 2 and power at ventilatory
159
threshold (VT) and peak exercise (P<0.0001). Compared to AMHC, HTR had a lower V
160
E peak, % V E peak predicted, tidal volume and breathing frequency at peak effort
161
(P<0.05). At peak effort, HTR had a lower peak HR, heart rate reserve, arteriovenous
162
difference, CImax, SVi and SVRi (P<0.05). Compared to AMHC, HTR had a higher
163
& peak was related to V Emax, CImax and C(a-v)O2 ESVi (P<0.05). In AMHC, VO 2
164
whereas, in HTR, it was related to
165
materials).
166
Left prefrontal NIRS variables during exercise and recovery
167
Figures 1 and 2 describe left prefrontal NIRS variables during exercise and recovery in AMHC
168
& and HTR subjects. During exercise, HTR had lower values for ∆O2Hb (at 50% and 75% of VO 2
169
& peak, P<0.05) and ∆Hb diff. (at 50% to 75% of VO & peak, P<0.05), ∆tHb (at 100% of VO 2 2
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.
.
V Emax and CImax (Table S3, supplementary
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peak, P<0.05) vs. AMHC. During recovery, HTR had lower values for ∆O2Hb, ∆Hb diff. (from 2
171
to 5 min, P<0.05) and ∆tHb (from 1 to 5 min, P<0.05) vs. AMHC.
172
End tidal pressure of CO2 , blood pressure and cardiac index during exercise and
173
recovery
174
Figures 3 and 4 describe end tidal pressure of CO2 (PETCO2), SBP, DBP and CI during exercise
175
and recovery in AMHC and HTR subjects. During exercise, HTR had lower values for
176
PETCO2 at each intensities (Fig 3 a) as compared to AMHC. During exercise, SBP and
177
DBP were not different between both groups (Fig 3 b and c). Finally, HTR had lower
178
& peak (Fig 3 d) as compared to values for cardiac index from 25% to 100% of VO 2
179
AMHC. During recovery, HTR had lower values for PETCO2 at 4 min (Fig 4 a) as
180
compared to AMHC. During recovery, HTR had lower values for SBP at 0 and 1 min
181
(Fig 4 b) as compared to AMHC. During recovery, DBP was not different between
182
groups (Fig 4 c). Finally, during recovery, HTR had lower values for cardiac index at 0, 1
183
and 2 min (Fig 4 d) as compared to AMHC.
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& peak, CI max, and left prefrontal NIRS variables Relationships between VO 2
186
& peak, CI max and left prefrontal NIRS Table S4 presents the relationships between VO 2
187
variables (NIRS maximal values during exercise: ∆O2Hb, ∆HHb, ∆tHb) in all subjects, AMHC
188
& peak was positively correlated with ∆O2 Hb and ∆tHb. In HTR, only and HTR. In AMHC, VO 2
189
CI max positively correlated with ∆O2Hb, ∆HHb and ∆tHb.
190
Discussion
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The main findings of this study were that: 1) Compared to AMHC, HTR had a reduced cerebral
192
& peak) and perfusion (∆tHb: 100 % of VO & peak) oxygenation (∆O2Hb: 50 and 75% of VO 2 2
193
during exercise. 2) However, cerebral oxygenation/perfusion was impaired during exercise
194
recovery (∆O2Hb: 2nd to 5th min; ∆tHb: 1st to 5th min) in HTR as compared to AMHC. 3) In HTR,
195
PETCO2 during exercise and central hemodynamics (CI) during exercise and recovery were both
196
reduced vs. AMHC. 4) Cerebral hemodynamics (∆O2Hb, ∆tHb) was positively correlated with
197
& peak in AMHC and with maximal cardiac output (CI max) in HTR. In addition, the findings VO 2
198
& peak in HTR as compared to AMHC might originates from support that the impairment of VO 2
199
altered ventilation and central hemodynamics. To the best of our knowledge, this study is the first
200
to integrate simultaneous measures of cerebral oxygenation/perfusion, cardiac hemodynamics and
201
& peak during exercise in HTR and the first to examine cerebral oxygenation/perfusion during VO 2
202
recovery from maximal exercise in HTR.
203
& peak values of HTR obtained in our study is in agreement with previous The reduced VO 2
204
studies
205
chronotropic incompetence (cardiac denervation), reduced cardiac output, reduced cardiac
206
compliance and diastolic dysfunction 3, 6, 7, 32, 33. Our central hemodynamics results confirm some
207
of those mechanisms: chronotropic incompetence (reduced % HR reserve), reduced cardiac
208
output (CImax), reduced ejection fraction and higher end systolic volume. We also showed that
209
& peak was related to maximal cardiac index in HTR. In addition, we the reduced VO 2
210
demonstrated a reduced arterio-venous difference [(C(a-v)O2)] during exercise in HTR vs.
211
& peak. These AMHC, underlying also a peripheral limitation origin for the reduced VO 2
212
peripheral limitations in HTR have been previously described and they include skeletal muscle
213
myopathy, impaired muscle metabolism, blood flow and vascular dilatation
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. This reduction has been attributed in part to central limitations including
4, 5, 7
. We also
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214
demonstrated an impaired maximal ventilation and its components (tidal volume and respiratory
215
frequency at peak effort) in HTR, in agreement with one previous study
216
explained by ventilatory muscle deconditioning, abnormal and/or intrapulmonary pressure. In
217
& peak in HTR, underlying its important addition, maximal ventilation was related to VO 2
218
contribution to reduced maximal aerobic capacity in HTR. An increased systemic vascular
219
resistance was found in HTR that could explain in part a higher end systolic volume as compared
220
to AMHC. Previous studies have documented negative vascular effects of immunosuppressive
221
agents that include hypertension, endothelial and microvascular dysfunction 7, 35.
222
Our results demonstrated that HTR had a lower cerebral oxygenation (∆O2 Hb) (at 50 and 75 %
223
& peak) and perfusion (∆tHb: 100% of VO & peak) during exercise vs. AMHC. As well, of VO 2 2
224
HTR did present a reduced cerebral oxygenation (∆O2 Hb: from 2 to 5 min) and perfusion (∆tHb:
225
from 1 to 5 min) during recovery as compared to AMHC. In addition, we showed that PETCO2
226
and cardiac output were reduced during exercise in HTR as compared to AMHC. During
227
exercise, those two important factors (PETCO2 and CI) might have greatly contributed to
228
difference in cerebral oxygenation/perfusion between groups. During exercise, PETCO2 generally
229
& peak in AHMC, and CO2 is known to be a powerful cerebral increases up to 50% of VO 2
230
& peak vasodilator, as shown by our data and those of others group 36. From 75 to 100% of VO 2
231
(both groups), PETCO2 decreases and was shown to be accompanied by a cerebral
232
vasoconstriction and thus as reduction of cerebral oxygenation/perfusion
233
& peak, and could reflect a more blunted cerebral does not increase from 0 to 50% of VO 2
234
vasodilatation by CO2. The mechanisms of this blunted cerebral vasodilatation by CO2 in HTR
235
vs. AMHC are not clear, but might result from a reduced lung and chest wall compliance,
236
respiratory muscle fatigue and differences in chemosensitivity 39. Our results agree with previous
237
studies in patients with valvular disease and heart failure (NHYA class III) that demonstrated a
34
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, that could be
36-38
. In HTR, PETCO2
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238
reduced cerebral oxygenation/perfusion (∆O2 ∆HHb, ∆tHb: left prefrontal NIRS) during exercise
239
compared to aged matched healthy controls
240
immunosuppressive agents and/or corticosteroids could have deleterious effects on cerebral
241
endothelial and microvascular functions in HTR, and could also have also influenced our cerebral
242
oxygenation/perfusion results 7. However, differences in cerebral oxygenation/perfusion during
243
exercise may differ according to the patients studied. In a study by Fu and colleagues, with a
244
similar design, they showed similar values of cerebral oxygenation/perfusion (∆O2, ∆tHb: left
245
prefrontal NIRS) between heart failure patients (NHYA class II) and AMHC 9. We showed that
246
brain perfusion (∆tHb) only differed at peak effort in HTR, and that this function was not
247
different for other exercise intensities. For NIRS variables, an important inter-individual
248
variability (high standard deviation) during exercise was observed, potentially explained that
249
∆tHb only differed at maximal intensity. As well, at peak effort, an important contribution of the
250
sympathetic tone on heart rate may have contributed to this difference. Similarly, one study
251
demonstrated that cerebral blood flow (measured by transcranial Doppler) was similar between
252
HTR and AMHC during incremental exercise 39. In that study, sample size was low (n=7, in each
253
& peak vs. HTR, and transcranial Doppler was used to assess group), AMHC had similar VO 2
254
cerebral blood flow, potentially explaining differences with our results
255
etiology of heart disease, patient’s aerobic capacity and cardiac function are important factors
256
accounting for the different findings seen across studies. Major differences in cerebral
257
oxygenation/perfusion and cardiac output in HTR were observed during recovery (lower values).
258
This agrees with a previous study in heart failure patients
259
oxygenation (∆O2Hb),perfusion (∆tHb) and cardiac function were reduced vs. AMHC. As
260
suggested, cardiac output is a major contributor to cerebral oxygenation/perfusion post-exercise
261
independently of PaCO2, and is reduced in HTR during recovery
262
overshoot phenomenon has been previously suggested as a factor implicated in higher ∆O2Hb
8-10
39
. We believe that the
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10
where post-exercise cerebral
10, 38
. An hemodynamic
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10
263
observed during recovery in AMHC as compared to heart failure patients
. Because cardiac
264
function during recovery is also regulated by the autonomic nervous system and metabolic
265
mediators (i.e: NO, adenosine), those factors could also be implicated in the differences observed
266
between the HTR and AMHC
267
to cerebral oxygenation/perfusion (∆O2Hb, ∆tHb) in AMHC and that maximal cardiac output was
268
correlated to cerebral hemodynamics (∆O2Hb, ∆HHb, ∆tHb) in HTR during exercise. These
269
& peak and maximal cardiac output were findings align with Fu et al. who demonstrated that VO 2
270
related to cerebral perfusion (∆tHb) in healthy controls and patients with chronic heart failure 9.
271
Clinical implications of our findings are that HTR with an impaired cardiac function could suffer
272
from cerebral hemodynamic dysfunction during and more particularly after an exercise period
273
10
274
their lifespan to preserve their aerobic fitness, cardiac and cerebrovascular function.
275
Our study has limitations, including the enrolment of fit healthy subjects and stable HTR
276
recruited in a single centre, hence inducing a potential recruitment bias. It is important to note that
277
& peak predicted), which could have amplified our AMHC were high fit subjects (141 % of VO 2
278
differences in most exercise variables as compared to an age-matched sedentary sample. Heart
279
transplant recipients were also primarily male, undergoing optimal or near-optimal medical
280
therapy and our results may differ in women HTR and/or in other HTR in the real-world setting.
281
As well, cerebral oxygenation and perfusion were assessed non-invasively using NIRS at the left
282
prefrontal area level implicating a very limited spatial resolution and a relatively superficial brain
283
tissue measurement (light penetration ≈ 2.25 cm). Therefore, our results may differ from other
284
more invasive and global measurement of brain oxygenation and perfusion (ex: catheters,
285
transcranial Doppler) or from other brain regions. Finally, as recently suggested 43, cerebral NIRS
286
O2Hb and tHb signals can be contaminated by extracranial tissues (particularly scalp blood flow)
& peak was correlated . In addition, we demonstrated that VO 2
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8-
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. This also underlies the clinical importance for HTR to remain physically active throughout
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during exercise. The AMHC exercised longer and to a greater absolute work rate so they might
288
have had a greater skin temperature response. Therefore, to minimize factors influencing skin
289
blood flow, we have attempted to standardize the thermo neutral environment (room temperature
290
: 20°C) and we have used a more important interoptode distance (4.5 cm) to allow deeper light
291
penetration into intracranial tissues 37, 44, 45.
292
Conclusions
293
We demonstrate that HTR may be exposed to cerebral hemodynamic dysfunction during and/or
294
after an exercise period as compared to AMHC. In HTR, this cerebral hemodynamic dysfunction
295
was mainly due to a blunted cerebral vasodilatation by CO2 and to a reduced cardiac function. As
296
well, HTR with poor cardiac function seem to be more susceptible to this dysfunction. In
297
perspective, future studies in HTR exploring the potential relation between cerebral
298
oxygenation/perfusion during exercise and cognitive function would be of important clinical
299
interest. As well, future studies particularly in HTR are required to document the optimal aerobic
300
& exercise training program (intensity, duration, frequency) that would optimally improve VO 2
301
peak, cardiac output, and cerebral oxygenation-perfusion.
302
Funding sources: ÉPIC Foundation, Montreal Heart Institute Foundation.
303
Disclosures: none
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Northridge DB, Findlay IN, Wilson J, Henderson E, Dargie HJ. Non-invasive determination of cardiac output by Doppler echocardiography and electrical bioimpedance. Br Heart J. 1990;63:93-97. Scherhag A, Pfleger S, Garbsch E, Buss J, Sueselbeck T, Borggrefe M. Automated impedance cardiography for detecting ischemic left ventricular dysfunction during exercise testing. Kidney Blood Press Res. 2005;28:77-84. Carter R, Al-Rawas OA, Stevenson A, McDonagh T, Stevenson RD. Exercise responses following heart transplantation: 5 year follow-up. Scott Med J. 2006;51:6-14. Givertz MM, Hartley LH, Colucci WS. Long-term sequential changes in exercise capacity and chronotropic responsiveness after cardiac transplantation. Circulation. 1997;96:232-237. Marzo KP, Wilson JR, Mancini DM. Effects of cardiac transplantation on ventilatory response to exercise. Am J Cardiol. 1992;69:547-553. Hoorn EJ, Walsh SB, McCormick JA, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med. 2011;17:1304-1309. Fisher JP, Hartwich D, Seifert T, et al. Cerebral perfusion, oxygenation and metabolism during exercise in young and elderly individuals. J Physiol. 2013;591:1859-1870. Brugniaux JV, Marley CJ, Hodson DA, New KJ, Bailey DM. Acute exercise stress reveals cerebrovascular benefits associated with moderate gains in cardiorespiratory fitness. J Cereb Blood Flow Metab. 2014;34:1873-1876. Ogoh S, Ainslie PN. Cerebral blood flow during exercise: mechanisms of regulation. J Appl Physiol (1985). 2009;107:1370-1380. Smirl JD, Haykowsky MJ, Nelson MD, Altamirano-Diaz LA, Ainslie PN. Resting and exercise cerebral blood flow in long-term heart transplant recipients. J Heart Lung Transplant. 2012;31:906-908. Chirpaz-Oddou MF, Favre-Juvin A, Flore P, et al. Nitric oxide response in exhaled air during an incremental exhaustive exercise. J Appl Physiol (1985). 1997;82:1311-1318. Perini R, Orizio C, Comande A, Castellano M, Beschi M, Veicsteinas A. Plasma norepinephrine and heart rate dynamics during recovery from submaximal exercise in man. Eur J Appl Physiol Occup Physiol. 1989;58:879-883. Watson RD, Hamilton CA, Jones DH, Reid JL, Stallard TJ, Littler WA. Sequential changes in plasma noradrenaline during bicycle exercise. Clin Sci (Lond). 1980;58:37-43. Miyazawa T, Horiuchi M, Komine H, Sugawara J, Fadel PJ, Ogoh S. Skin blood flow influences cerebral oxygenation measured by near-infrared spectroscopy during dynamic exercise. Eur J Appl Physiol. 2013;113:2841-2848. Tagougui S, Fontaine P, Leclair E, et al. Regional cerebral hemodynamic response to incremental exercise is blunted in poorly controlled patients with uncomplicated type 1 diabetes. Diabetes Care. 2015;38:858-867. Germon TJ, Evans PD, Barnett NJ, Wall P, Manara AR, Nelson RJ. Cerebral near infrared spectroscopy: emitter-detector separation must be increased. Br J Anaesth. 1999;82:831-837.
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Figures Legend:
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Figure 1 a-d: Brain near-infrared spectroscopy (NIRS) variables during exercise in aged
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matched healthy controls (AMHC) and heart transplant recipients (HTR). ANOVA p
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value: A (intensity), B (group), C (interaction). Post hoc group effect: *= P<0.05, O2Hb :
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oxyhemoglobin, HHb : desoxyhemoglobin, tHb : total hemoglobin, Hb Diff. : differential
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hemoglobin.
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Figure 2 a-d: Brain near-infrared spectroscopy (NIRS) variables during recovery in aged
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matched healthy controls (AMHC) and heart transplant recipients (HTR). ANOVA p
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value: A (time), B (group), C (interaction). Post hoc group effect: *= P<0.05, † = P<0.01,
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‡= P<0.001, O2Hb : oxyhemoglobin, HHb : desoxyhemoglobin, tHb : total hemoglobin,
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Hb Diff. : differential hemoglobin.
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Figures 3 a-d: End tidal pressure of CO2 (PETCO2), systolic blood pressure (SBP), diastolic
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blood pressure (DBP) and cardiac index during exercise in aged matched healthy controls
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(AMHC) and heart transplant recipients (HTR). ANOVA p value: A (intensity), B
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(group), C (interaction). Post hoc group effect: *= P<0.05, † = P<0.01, §= P<0.0001.
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Figures 4 a-d: End tidal pressure of CO2 (PETCO2), systolic blood pressure (SBP), diastolic
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blood pressure (DBP) and cardiac index during recovery in aged matched healthy controls 18
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(AMHC) and heart transplant recipients (HTR). ANOVA p value: A (time), B (group), C
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(interaction). Post hoc group effect: *= P<0.05, † = P<0.01.
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Supplementary Materials Maximal cardiopulmonary exercise testing
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The calibrations of the flow module and gas concentration were performed according to manufacturer recommendations. Data were measured every four respiratory cycles during testing and then averaged every 15 sec for minute ventilation (VE, in L/min BTPS),
L/mim, STPD)
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& , in L/min, STPD), and carbon dioxide production (VCO2, in oxygen uptake ( VO 2 . The exercise test lasted until the attainment of one of two primary
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maximal criteria: (1) a plateau of despite an increase in work rate 21, (2) R.E.R > 1.1, or one of the two secondary maximal criteria: (3) measured maximal heart rate attaining 95% of age-predicted maximal heart rate, (4) inability to maintain the cycling cadence, (5) subject exhaustion with cessation caused by fatigue and/or other clinical symptoms
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(dyspnea, abnormal BP responses) or ECG abnormalities that required exercise cessation . The ventilatory threshold was determined using a combination of the V-slope,
ventilatory equivalents, and end-tidal oxygen pressure methods
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The highest
value
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reached during the exercise phase of each test was considered as the peak and peak power
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output (PPO) was defined as the power output reached at the last fully completed stage 17,
Cerebral oxygenation/perfusion During exercise test, optodes were secured with a tensor bandage wrapped around the forehead, a neoprene pad (with two holes for optodes) was place between the skin and the optodes plastic holder and ambient room light (dimmer) was reduced 20, 24. To correct for scattering of photons in the tissue, a differential path-length factor of 5.93 was used for
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the calculation of absolute concentration changes with an interoptode distance of 45 mm 25
. Two wavelengths (780 and 855 nm) were used during NIRS measurement. Data were
sampled at 10 Hz during the rest period (3 min), the exercise phase and the 5-min
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recovery period. Data were displayed in real time and stored on disk for off-line analysis. Raw NIRS signals were filtered via the oxysoft/DAQ software (Artinis Medical, Netherlands) using a running average function with a filter width of 1. Thereafter, NIRS
statistical treatment
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signals were exported into excel files with the oxysoft/DAQ software at 0.2 Hz for . Relative concentration changes (∆µM) were measured from
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resting baseline of oxyhaemoglobin (∆O2Hb), deoxyhaemoglobin (∆HHb), total haemoglobin (∆tHb = O2Hb + HHb), and differential haemoglobin (∆Hb diff. = ∆O2Hb ∆HHb). The baseline period was set at the end of the 3-min resting period, defined as 0 µM 20, 23, 24. Cerebral oxygenation was represented by the oxyhaemoglobin (∆O2Hb) and
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cerebral perfusion by the total haemoglobin (∆tHb) measured in the left prefrontal cortex.
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Table S1: Clinical characteristics of aged-matched healthy controls (AMHC) and heart transplant recipients (HTR).
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Blood analysis Fasting glucose (mmol/l) Total cholesterol (mmol/l) HDL-cholesterol (mmol/l) LDL- cholesterol (mmol/l)
P value
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0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (4%) 1 (4%) 0 (0%) 0 (0%)
26 (100%) 5 (25%) 1 (5%) 16 (80%) 10 (50%) 19 (95%) 14 (70%) 1 (5%) 2 (10%)
4.95 ± 0.34 5.01 ± 0.82 1.60 ± 0.48 3.04 ± 0.70
6.16 ± 1.23 3.95 ± 0.73 1.63 ± 0.94 1.85 ± 0.51
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Medication Immunosuppressive agents Beta–blockers ACE inhibitors Antiplatelet agents Angiotensin receptor blockers Statins Calcium channel blockers Anticoagulants Spironolactone
HTR (n = 26) 58 ± 11 169 ± 7 3 (12%) 76 ± 14 27 ± 5 84 ± 12 58 ± 9 19 ± 8 11 ± 5 51 ± 11 8±5
0.6991 0.1498
0.0746 0.0027 0.1647 0.7793 0.0072 0.0042
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Age (years) Height (cm) Female (n and %) Body mass (kg) BMI (kg/m2) WC (cm) LBM (kg) TFM(kg) Trunk FM (kg) Age at trans. (years) Years post trans. (years)
AMHC (n = 27) 57 ± 15 172 ± 8 5 (19%) 70 ± 8 24 ± 2 88 ± 7 57 ± 9 14 ± 4 8±3 -
<0.0001 <0.0001 0.9225 <0.0001
BMI: body mass index, WC: waist circumference, LBM: lean body mass, TFM: total fat mass, FM: fat mass, trans.: transplantation, ACE: angiotensin–converting enzyme.
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Table S2: Cardiopulmonary exercise testing data in aged-matched healthy controls
At peak effort
& peak (ml/min/LBM) VO 2 & VO peak (ml/min/kg) 2
& plateau (%) VO 2 & peak predicted (%) % VO 2 Power (Watts) .
.
V E max (l/min) .
ANOVA P value
65 ± 11 117 ± 9 71 ± 7
87 ± 13 125 ± 16 74 ± 9
<0.0001 0.0324 0.2150
31 ± 8
15 ± 5
<0.0001
61 ± 22
<0.0001
168 ± 55
50 ± 10
28 ± 7
<0.0001
41 ± 10
21 ± 7
<0.0001
88
76
0.2461
141 ± 20
77 ± 24
<0.0001
226 ± 72 3329 ± 930
90 ± 43 1810 ± 499
<0.0001 <0.0001
1.17 ± 0,07 107 ± 34
1.13 ± 0.08 66 ± 16
0.1310 <0.0001
152 ± 31
95 ± 25
<0.0001
2.63 ± 0,57 40 ± 10 163 ± 16 105 ± 15 182 ± 19 78 ± 10 -22 ± 9 18 ± 4 55 ± 4 9±1 61 ± 10 92 ± 14 37 ± 14 1028 ± 172
1.89 ± 0.50 35 ± 5 127 ± 21 55 ± 29 172 ± 24 78 ± 10 -7 ± 10 13 ± 4 52 ± 7 7±2 53 ± 16 106 ± 35 54 ± 36 1402 ± 406
<0.0001 0.0243 <0.0001 <0.0001 0.1227 0.8929 <0.0001 0.0003 0.0364 <0.0001 0.0540 0.0833 0.0348 <0.0001
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V CO2 (ml/min) R.E.R
HTR (n = 26)
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% V E max predicted (%) VT max (l) Bf (breaths/min) HRmax (bpm) HR reserve (%) SBP max (mm Hg) DBP max (mm Hg) HRR at 1 min (bpm) C(a-v)O2 (ml O2 /100 ml blood) SVi (ml/m2) CI (l/min/m2) EF (%) EDVi (ml/m2) ESVi (ml/m2) SVRi (dynes.s/cm5/m2)
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At ventilatory threshold & (ml/min/kg) VO 2 Power (Watts)
AMHC (n = 27)
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Cardiopulmonary and hemodynamic variables Rest HR (bpm) SBP (mm Hg) DBP (mm Hg)
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(AMHC) and heart transplant recipients (HTR).
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HR: heart rate, SBP: systolic blood pressure, DBP: diastolic blood pressure, LBM: lean body mass, R.E.R: respiratory exchange ratio, VT: volume tidal, Bf: breathing frequency, HR: heart rate, HRR: heart rate recovery, C(a-v)O2 : arteriovenous difference, SVi: stroke
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volume index, CI: cardiac index, EF: ejection fraction, EDVi: end diastolic volume index,
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ESVi: end systolic volume index, SVRi: systemic vascular resistance index.
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& peak, V Emax, CImax and C(a-v)O2 in agedTable S3: Correlation between VO 2 matched healthy controls (AMHC) and heart transplant recipients (HTR).
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& peak (ml/min/LBM) VO 2 AMHC
R=0.68, p<0.0001
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V Emax
R=0.51, p=0.0051
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CImax C(a-v)O2
R=0.85, p<0.0001
HTR
R=0.69, p=0.0004
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CImax
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C(a-v)O2
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V Emax
R=0.66, p=0.0014 R=0.11, p=0.6469
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& peak (ml/min/kg), maximal cardiac index (CI max) Table S4. Relationship between VO 2 and brain NIRS parameters in all subjects, in aged-matched healthy controls (AMHC)
All subjects (n = 53)
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and heart transplant recipients (HTR).
∆ HHb
& peak (ml/min/kg) VO 2
R = 0.33, P = 0.0133
R = 0.19, P = 0.1450
R = 0.35, P = 0.0077
CI max
R = 0.36, P = 0.0057
R = 0.37, P = 0.0047
R = 0.44, P = 0.0006
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∆ O2Hb
∆ tHb
AMHC (n = 32) ∆ O2Hb
R = 0.35, P = 0.0458
CI max
R = 0.27, P = 0.1301
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& peak (ml/min/kg) VO 2
∆ HHb
∆ tHb
R = 0.29, P = 0.1038
R = 0.47, P = 0.0058
R = 0.28, P = 0.1154
R = 0.34, P = 0.0522
HTR (n = 21) ∆ HHb
∆ tHb
& peak (ml/min/kg) VO 2
R = 0.17, P = 0.4214
R = -0.03, P = 0.8635
R = 0.09, P = 0.6780
CI max
R = 0.54, P = 0.0099
R = 0.55, P = 0.0078
R = 0.60, P = 0.0028
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∆ O2Hb
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CI max: maximal cardiac index, O2Hb : oxyhemoglobin, HHb : desoxyhemoglobin, tHb :
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total hemoglobin.