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Pulmonary Vascular Mechanics in Long-Standing Male Endurance Athletes at Rest and During Exercise
by
Taylor Gray
A thesis submitted in conformity with the requirements for the degree of Master of Science
Graduate Department of Exercise Sciences University of Toronto
© Copyright by Taylor Gray 2013
ii
Pulmonary Vascular Mechanics in Long-Standing Male
Endurance Athletes at Rest and During Exercise
Taylor Gray
Master of Science
Graduate Department of Exercise Sciences University of Toronto
2013
Abstract
This study examined right-ventricular-pulmonary arterial (RV-PA) coupling and pulmonary
vascular mechanics during acute exercise in 12 middle-aged men with a long-standing history of
endurance training. Subjects underwent simultaneous right-heart catheterization and
echocardiography, with measures obtained at steady state heart rates of 100, 130 and 150
beats/min. Subjects were highly trained and displayed RV remodeling of endurance-trained
athletes. During exercise at 100 beats/min, systolic, diastolic, and mean pulmonary artery
pressure increased significantly from rest, as did pulmonary capillary wedge pressure. The slope
of pooled mean pulmonary pressure indexed to cardiac output was 1.436 mmHg⋅min-1⋅L-1 with a
distensibility index of 0.112 ± 0.048 mmHg-1. The pulmonary arterial elastance-RV end-systolic
elastance ratio (Ea:Ees) decreased from rest to exercise at 130 beats/min (P < 0.01). These
results suggest that Ea:Ees becomes favourable for RV function during exercise, indicative of a
pulmonary vasculature that is highly distensible and well matched to RV output.
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Acknowledgments
I would like to begin by sincerely thanking everyone who played a part in the successful
completion of this research project. This project was truly a collaborative effort that would not
have been possible without the untiring and passionate work of all involved. The mentorship of
my supervisor and thesis committee, and the assistance from my lab mate Stephen Wright and
the hospital technicians and staff made this study a unique learning experience and a joy to be
apart of. I am also indebted to our study participants whose enthusiasm and curiosity gave me an
intangible satisfaction that results alone cannot impart.
I would like to acknowledge my supervisor Dr. Jack Goodman for his guidance throughout this
academic endeavour and his continued efforts to develop and hone my skills as a researcher and
an academic. I have greatly benefited from his extensive knowledge within this field and his
ability to foster critical thinking and attention to detail across all scopes. I would also like to
thank my graduate committee members, Dr. Susanna Mak and Dr. Scott Thomas for their
expertise and valuable contributions to this project. I owe much of this project’s feasibility to
Dr. Susanna Mak, and her relentless progression of research within this field. Her devotion to
her work is truly inspiring. I would also like to thank my lab members and fellow graduate
students for their generous support whenever requested.
Lastly, I would like to extend a special thanks to my family members and friends for their
unwavering support. I owe my deepest gratitude to my parents, who have done everything they
could to help me succeed throughout my entire post-secondary education. Your unconditional
love and support is very special to me and I cherish it deeply.
iv
Table of Contents
Acknowledgments .......................................................................................................................... iii
Table of Contents ........................................................................................................................... iv
List of Tables ............................................................................................................................... viii
List of Figures ................................................................................................................................ ix
List of Appendices .......................................................................................................................... x
List of Abbreviations ..................................................................................................................... xi
Chapter 1 Introduction ................................................................................................................. 1
1.1 Rationale ............................................................................................................................. 1
1.2 Objectives ............................................................................................................................ 3
1.3 Hypotheses .......................................................................................................................... 3
Chapter 2 Supplemental Review of Literature .......................................................................... 5
2.1 The Athlete’s Heart: Cardiac Remodeling .......................................................................... 5
2.1.1 Exercise as a Stimulus for Cardiac Remodeling ..................................................... 5
2.1.1.1 Sport-Specific Adaptations ....................................................................... 7
2.1.2 Left Ventricular Remodeling .................................................................................. 7
2.1.2.1 Characteristic Remodeling ....................................................................... 7
2.1.2.2 Younger versus Older Athletes ................................................................. 9
2.1.3 Right Ventricular Remodeling .............................................................................. 10
2.1.3.1 Morphology of the Right Ventricle ........................................................ 10
2.1.3.2 Characteristic Remodeling ..................................................................... 11
2.1.3.3 Functional Differences in Trained Individuals ....................................... 12
2.2 Pulmonary Hemodynamics at Rest ................................................................................... 13
2.2.1 Components of Arterial Load in the Pulmonary Circulation ................................ 13
v
2.2.1.1 Pulmonary Vascular Resistance ............................................................. 13
2.2.1.2 Pulmonary Vascular Compliance ........................................................... 15
2.2.2 Non-Invasive and Invasive Assessment of Pulmonary Pressures: ........................ 16
2.2.2.1 Non-Invasive Doppler Echocardiography .............................................. 16
2.2.2.2 Invasive Right Heart Catheterization ..................................................... 18
2.2.3 Pulmonary Hemodynamics in Untrained Individuals ........................................... 19
2.2.4 Pulmonary Hemodynamics in Trained Individuals .............................................. 21
2.3 Pulmonary Hemodynamics During Exercise .................................................................... 22
2.3.1 Response to Increased Right Ventricular Output .................................................. 22
2.3.2 Pulmonary Vascular Resistance ............................................................................ 23
2.3.2.1 Pressure-Flow Relations During Exercise (mPAP – Q Plot) ................. 24
2.3.2.2 Pulmonary Vascular Distensibility ......................................................... 24
2.3.3 Pulmonary Hemodynamics in Untrained Individuals ........................................... 25
2.3.3.1 Pulmonary Hemodynamics During Aerobic Exercise ............................ 26
2.3.3.2 Intermittent Exercise ............................................................................... 28
2.3.3.3 Resistance Exercise ................................................................................ 28
2.3.4 Trained Individuals ............................................................................................... 29
2.3.5 Potential Mechanisms of Elevated Pressures in Trained ...................................... 34
2.4 Right Ventricular Function During Exercise .................................................................... 35
2.4.1 Right Ventricular-Pulmonary Arterial Coupling .................................................. 35
2.4.2 RV Performance During Acute Exercise .............................................................. 37
2.4.3 Prolonged Endurance Exercise ............................................................................. 38
2.5 Clinical Relevance and Insight ......................................................................................... 39
2.6 Conclusion ........................................................................................................................ 39
Chapter 3 Manuscript for Journal Submission ....................................................................... 41
3.1 Introduction ....................................................................................................................... 41
vi
3.2 Methods ............................................................................................................................. 43
3.2.1 Study Population ................................................................................................... 43
3.2.2 Experimental Design ............................................................................................. 44
3.2.3 Maximal Oxygen Consumption ............................................................................ 44
3.2.4 Echocardiographic Measures ................................................................................ 45
3.2.5 Right Heart Catheterization .................................................................................. 47
3.2.6 Statistical Analysis ................................................................................................ 50
3.3 Results ............................................................................................................................... 51
3.3.1 Study Population ................................................................................................... 51
3.3.2 Left Atrial and Left Ventricular Morphology ....................................................... 52
3.3.3 Right Atrial and Right Ventricular Morphology ................................................... 53
3.3.4 Resting Pulsed-wave Doppler and Tissue Doppler Imaging ................................ 54
3.3.5 Hemodynamic Measures by Right Heart Catheterization ..................................... 56
3.3.6 Pressure – Flow Relationship ................................................................................ 61
3.3.7 Right Ventricular – Pulmonary Arterial Coupling ................................................ 62
3.4 Discussion ......................................................................................................................... 67
3.4.1 Cardiac Morphology and Function ....................................................................... 67
3.4.2 Hemodynamic Measures ....................................................................................... 69
3.4.3 Pressure-Flow Relationship .................................................................................. 71
3.4.4 Right-Ventricular – Pulmonary Arterial Coupling ............................................... 72
3.4.5 Clinical Implications ............................................................................................. 74
3.4.6 Limitations ............................................................................................................ 75
3.4.7 Conclusion ............................................................................................................ 77
Chapter 4 General Discussion, Future Perspectives and Conclusions ................................... 78
4.1 Study Limitations .............................................................................................................. 78
4.1.1 Study Design and Subject Population ................................................................... 78
vii
4.1.2 Catheterization and Hemodynamic Measures ....................................................... 79
4.1.3 Echocardiography ................................................................................................. 80
4.2 Future Perspectives ........................................................................................................... 81
4.3 Study Conclusions ............................................................................................................. 83
References ..................................................................................................................................... 85
Appendices .................................................................................................................................. 100
Copyright Acknowledgements .................................................................................................... 133
viii
List of Tables
Table 1. Baseline characteristics 52
Table 2. Left atrial and left ventricular morphology 53
Table 3. Right atrial and right ventricular morphology 54
Table 4. Resting pulsed-wave Doppler and tissue Doppler measures 55
Table 5. Hemodynamic data at rest and during exercise 58
Table 6. Systemic pressure, oxygen saturation and transpulmonary pressure gradient 59
Table 7. Hemodynamic variables at exercise of 100 beats/min stratified by subjects with
mPAP ≥ 30 and < 30mmHg 60
ix
List of Figures
Figure 1. Percent increases in pulmonary artery systolic pressure (PASP) and systemic
blood pressure (SBP) across age quartiles compared to the youngest quartile 20
Figure 2. Calculated PASP response to incremental exercise for athletes vs. nonathletes 30
Figure 3. Submaximal exercise protocol performed during right heart catheterization 49
Figure 4. Mean pulmonary artery pressure and cardiac output coordinates for each
subject at rest-supine, 100 and 130 beats/min 61
Figure 5. Changes in right ventricular end-systolic elastance (Ees) and pulmonary
arterial elastance (Ea) at rest supine and during exercise of 100 and 130 beats/min 63
Figure 6. Right ventricular-pulmonary arterial coupling as quantified as Ea:Ees at rest
supine and during exercise of 100 and 130 beats/min 64
Figure 7. Right ventricular stroke work index at rest supine and during exercise of
100 and 130 beats/min 64
Figure 8. Relationship between the ratio of pulmonary arterial elastance and right
ventricular end-systolic elastance (Ea:Ees) and mean pulmonary artery pressure (mPAP) 65
Figure 9. Relationship between pulmonary artery systolic pressure (PASP) at exercise
of 150 beats/min and right ventricular (RV) diastolic area index at rest 66
Figure 10. Relationship between pulmonary artery systolic pressure (PASP) at exercise
of 150 beats/min and right ventricular (RV) systolic area index at rest 66
x
List of Appendices
Appendix 1. Recruitment Poster 100
Appendix 2. Written Informed Consent Form 101
Appendix 3. Physical Activity Readiness Questionnaire (PAR-Q+) 110
Appendix 4. Lifetime Total Physical Activity Questionnaire 114
Appendix 5. Case Report Form 119
Appendix 6. Right-Heart Catheterization Technical Protocol 127
xi
List of Abbreviations
1RM 1 repetition max
2DSE 2-dimensional strain echocardiography
A Late ventricular filling
A’ Late diastolic annular velocity
AF Atrial fibrillation
ASE American Society of Echocardiography
beats/min Beats per minute
C Pulmonary arterial compliance
E Early ventricular filling
E/E’ Ratio of peak early diastolic filling to early diastolic annular tissue velocity
E’ Early diastolic annular velocity
EA Endurance trained individual
Ea Pulmonary arterial elastance
EDV End-diastolic volume
Ees Right ventricular end-systolic elastance
EIPAH Exercise-induced pulmonary arterial hypertension
EPIH Exercise-induced pulmonary hemorrhage
FAC Fractional area change
HR Heart rate
HRmax Maximal heart rate
IGF-I Insulin-like growth factor-I
Kpm Kilopond-meter
LV Left ventricle
xii
LVOT Left ventricular outflow tract
MET Metabolic equivalent of task
mPAP Mean pulmonary artery pressure
mRAP Mean right atrial pressure
MRI Magnetic resonance imaging
PADP Pulmonary artery diastolic pressure
PASP Pulmonary artery systolic pressure
PCWP Pulmonary capillary wedge pressure
PVR Pulmonary vascular resistance
Q Cardiac output
R Vessel resistance
RAP Right atrial pressure
RHC Right heart catheter
RPM Revolutions per minute
RV Right ventricle
RVOTVTI Right ventricular outflow tract time-velocity integral
RV-PA Right-ventricular-pulmonary arterial
RVSP Right ventricular systolic pressure
S’ Strain
SaO2 Arterial oxygen saturation
SBP Systemic blood pressure
SR Strain rate
SV Stroke volume
SvO2 Mixed venous oxygen saturation
TAPSE Tricuspid annular plane systolic excursion
TDI Tissue Doppler imaging
xiii
TRV Tricuspid regurgitant velocity
VO2max Maximal oxygen consumption
VO2peak Peak oxygen consumption
W Watts
1
Chapter 1 Introduction
1
1.1 Rationale
Exercise training is associated with functional improvements in cardiac performance at rest and
during exercise to meet an increased oxygen demand within the working skeletal muscle [1]. A
hallmark feature of endurance-trained athletes is a larger left ventricular (LV) end-diastolic
volume (EDV) that increases stroke volume (SV) secondary to Frank-Starling mechanism [2].
Following exercise training, cardiac output (Q) at rest and during submaximal exercise is
unchanged as stroke volume is increased and heart rate (HR) is proportionally decreased [3, 4].
Therefore, trained individuals have increase output from the ventricles during rest and exercise
compared to untrained individuals. In addition, when exercise training is sufficiently intense and
sustained, it may induce morphological adaptations. Morphological adaptations within the left
ventricle (LV) have been well documented and include increases in mass, cavity size, and wall
thickness [5, 6].
In comparison to the LV, the right ventricle (RV) has been less studied, however recent literature
has suggested that the RV in highly trained individuals undergoes remodeling that is proportional
to the LV [7-12]. As a result, stroke volume is increased to the low-pressure pulmonary
circulation downstream to the RV. During exercise, there is an increase in mean pulmonary
artery pressure (mPAP) [13]. However, limited data suggests that endurance trained individuals
(EA) may have disproportionally elevated pulmonary artery pressures at both rest and exercise
despite a similar resting cardiac output [5]. During exercise, untrained individuals show only
2
modest increases in mPAP due to a balanced reduction in pulmonary vascular resistance (PVR)
secondary to a well-matched, compliant pulmonary vasculature [14]. However, trained
individuals in a small data set have demonstrated exaggerated increases in both stroke volume
and pulmonary pressures [15-17]. It remains unknown if these increases in pulmonary pressures
reflect a higher RV stroke volume or is secondary to down-stream elevations in left atrial
pressure or a failure to adequately reduce pulmonary vascular resistance.
The elevated resting and exercise pulmonary pressures observed in trained athletes may be linked
to the unique anatomy and physiology of a remodeled RV. In contrast to the conical shape of the
LV, the RV is more triangular with a cavity that is crescent shaped in cross-section, formed by
the concave free wall and the convex interventricular septum that wraps around the LV [18].
The free wall of the RV is also much thinner than the LV reflecting the lower pressure of right
side of the heart in comparison to the left [19]. As a result of these morphological differences,
the RV has a lower volume to surface ratio than the LV, is more compliant and is likely more
vulnerable to chronic remodeling due to volume-overload rather than pressure overload [20].
Therefore, during acute exercise the RV afterload may be disproportionally greater than the LV
due to the Law of Laplace, given the comparatively large EDV but thinner walls. Consequently,
it remains unknown if the pulmonary vasculature accommodates the output of an enlarged RV
during exercise.
The consequences of long-standing athletic training and associated changes in pulmonary and
RV physiology are clinically relevant given the 2-to-10-fold increase in atrial fibrillation (AF)
incidence in endurance-trained individuals compared to untrained. While the mechanisms
explaining this increased risk remain unclear, chronic right ventricular and atrial remodeling may
be contributing factors. In addition, the acute response to intensive exercise training may
3
produce substrates that are pro-arrhythmic, including elevated RV and pulmonary pressures [21].
The health benefits of exercise training are obtainable with more modest levels of exercise,
however the potential negative cardiovascular consequences of long-term excessive endurance
exercise remain unknown [22]. Therefore, this study aimed to characterize the right-heart
hemodynamics and pulmonary vascular mechanics in response to a bout of acute exercise and
the influence of RV remodeling secondary to chronic endurance exercise training.
1.2 Objectives
1) To assess and quantify the morphological adaptations within the right heart of middle
aged (45-65 years) men with a long-standing history of endurance exercise training (EA).
2) To characterize the pulmonary hemodynamic response to acute exercise in middle-aged
male EA individuals.
3) To characterize pulmonary artery-RV coupling at rest and during exercise in middle-aged
male EA individuals.
1.3 Hypotheses
1) Increased cavity size and linear dimensions will be observed in long-standing EA.
2) Long-standing EA will have elevated pulmonary artery pressures at rest and during
exercise relative to established normal values, and will be correlated to right ventricular
size.
4
3) EA will demonstrate a disproportionate increase in mean pulmonary artery pressure
indexed to cardiac output during submaximal exercise, relative to established normal
values in untrained individuals.
5
Chapter 2 Supplemental Review of Literature
2
2.1 The Athlete’s Heart: Cardiac Remodeling
2.1.1 Exercise as a Stimulus for Cardiac Remodeling
Endurance exercise involves an increased demand for oxygen within the working skeletal
muscle. To meet this demand, the heart is capable of significant increases (5-6 fold) in Q, the
product of HR and SV [23]. As intensity increases, HR increases in proportion to exercise
intensity, contributing significantly to the increase in cardiac output at high intensities following
the asymptotic pattern of SV that often occurs before maximal exercise is achieved. With
endurance exercise training, cardiac remodeling occurs as an adaptation to intermittent elevations
in loading conditions that enhance Q [24].
Physiological hypertrophy can be defined as a normal increase in cardiac size associated with
normal or improved function, generally considered to be a favourable adaptation. This includes
normal postnatal growth, pregnancy-induced and exercise-induced hypertrophy [25, 26].
Increased venous return to the heart during exercise provides the stimulus for molecular
signaling of eccentric physiological cardiac hypertrophy [25]. In response to volume overload
during exercise, cardiac myocytes are subject to mechanical stretch and humoral factors that bind
to receptors and initiate intracellular signaling pathways associated with cell hypertrophy [25].
Insulin-like growth factor-I (IGF-I) is essential for normal postnatal cardiac growth and appears
to be involved in exercise induced physiological hypertrophy. IGF-I is released in response to
exercise [27, 28] and has shown to be elevated in the plasma of endurance athletes compared to
6
sedentary individuals [29]. Furthermore, genetic mouse models overexpressing IGF-I have
shown cardiac hypertrophy due to increased myocyte size with no histopathology [30].
Downstream, IGF-I activates the phosphoinositide 3-kinase p110α subunit leading to protein
kinase B phosphorylation and subsequent initiation of protein synthesis [31]. Cardiac myocytes
also directly detect mechanical stretch and deformation that occurs with volume overload [31] to
activate the process of cardiac hypertrophy [32]. These alterations in response to exercise alter
both the organization of the sarcomere structure and the biochemical milieu [33]. Calcium
uptake in the sarcoplasmic reticulum cardiac myocytes is augmented in endurance-trained
individuals [34, 35], which enhances diastolic relaxation and increases EDV. In addition to the
physiological hypertrophy that enhances SV via Frank-Starling mechanisms, chronic endurance
exercise has also been shown to increase myocardial contractility, independent of preload [29,
36, 37] providing further augmentation of stroke volume compared to untrained individuals.
Studies of trained individuals have shown continued increases in SV throughout incremental
exercise to VO2max that are not observed in untrained individuals [38-41]. The likely mechanism
for the enhanced SV with endurance training is a more rapid diastolic filling time [42], an
increased LV end-diastolic volume [43] and greater myocardial contractility [37]. These
adaptations occur without an increase maximal heart rate [44]. Endurance-trained individuals
have shown to be able to increase their SV throughout incremental exercise due to a progressive
utilization of the more energy-efficient Frank-Starling mechanism [37]. This adaptation is
advantageous during exercise, as increasing SV by increasing myocardial contractility works by
increasing intracellular calcium, and is an energy-dependent mechanism.
7
2.1.1.1 Sport-Specific Adaptations
The so-called ‘athlete’s heart’ is characterized by a resting bradycardia, increased ventricular
mass, wall thickness, and cavity dimensions compared to non-athletes [10]. Morganroth et al.
[1] were the first to characterize two distinct types of cardiac remodeling depending on the type
of exercise training performed. Endurance exercise that is characterized by dynamic movement
of skeletal muscle involves sustained increases in Q creating primarily a volume-loading
condition within the heart [45]. Conversely, strength training involves primarily static
contractions that are characterized by significant increases in peripheral vascular resistance with
only modest elevations in cardiac output, thus creating primarily a pressure-loading situation
[26]. Volume-loading is associated with eccentric hypertrophy, involving increases in wall
thickness and cavity dilation, whereas pressure-loading is associated with concentric hypertrophy
defined by increases in myocardial mass and wall thickness, but lacking the cavity dilation
observed in eccentric hypertrophy [1, 46, 47]. While Morganroth’s hypothesis has remained
largely accepted, it is now recognized that pure volume- or pressure-loading does not occur
during any type of exercise. Acute bouts of aerobic exercise induces slight increases in systemic
blood pressure during exercise [47], and acute bouts of strength training sessions involve modest
increases in Q [48]. Thus, the assessment of cardiac remodeling amongst different athletes of
various disciplines has generated disparate results.
2.1.2 Left Ventricular Remodeling
2.1.2.1 Characteristic Remodeling
In a meta-analysis of 1451 male athletes between the ages of 18 and 40, distinct patterns of left
ventricular remodeling reflecting different types of training were observed [47], similar to those
8
proposed by Morganroth. Endurance-trained athletes showed significant increases in all
measurements of LV dimensions, without any significant differences in function compared to
controls as measured by ejection fraction, fractional shortening, and Doppler blood flow ratio of
early to late diastolic filling (E/A) [47]. Conversely, strength-trained athletes demonstrated
slight increases in LV internal diameter and large increases in LV wall thickness. In a large
multi-sport assessment of elite Italian athletes, Pelliccia et al. [2] reported a range of left
ventricular end-diastolic diameters normalized for body surface area from 43-70mm (mean,
55mm) in men. While most of these athletes remain within the normal reference range, 14% of
athletes showed marked LV dilation greater than 60mm, defined as mildly abnormal [49]. These
athletes tended to have a greater body surface area and were involved in certain endurance sports
such as cycling and cross-country skiing.
The individual response to prolonged exercise training is not uniform due to number of
contributing factors. Based on the observed LV remodeling by Pelliccia et al. [2], it was
suggested that 75% of the variability in LV cavity size was explained by body size (50%), type
of sport (14%), gender (7%) and age (4%), leaving 25% unexplained and potentially due to
genetic factors [50]. Baggish et al. [24] determined the effect of exercise training on cardiac
structure and function using echocardiography following 90 days of competitive athletics in
university students. With no effort made to control training regimes, individuals involved in
endurance sports (rowing) experienced significant increases in measures of LV structure
including internal end-diastolic diameter, end-diastolic and -systolic volume, and mass. These
results suggest that athletic exercise training had a causal role in cardiac remodeling. In contrast
to the approach of uncontrolled and genuine athletic training, Spence et al. [6] used a
longitudinal and randomized study of distinct and controlled endurance- and strength-training
programs. Cardiac measures were assessed using magnetic resonance imaging (MRI) to
9
overcome the geometrical assumptions necessary in echocardiography. Following 6 months of
training, the randomized group performing endurance exercise showed a significant increase in
LV mass (9.3 grams), with no increase observed in the strength-training group. LV end-diastolic
volume approached a significant increase in the endurance group, which lead to an unchanged
ratio of LV mass:LV end-diastolic volume, reflecting an eccentric pattern of hypertrophy [6].
This observation confirmed the Morganroth hypothesis to a large extent, indicating that LV
remodeling is dependent on the type of exercise performed. These adaptations are considered to
be physiological and beneficial given that most LV dimensions remain within the upper limits of
normal ranges, and systolic and diastolic function are augmented during exercise [2].
2.1.2.2 Younger versus Older Athletes
Aging is associated with reduced functional capacity of the cardiovascular system and an
increased risk for cardiovascular disease [51]. The effects of long-term exercise training on
cardiac remodeling in middle-aged individuals has been examined in a number of studies [52-
54]. Compared to age-matched controls, veteran male athletes ranging in age from 50-67 years,
demonstrated significantly larger indexed LV end-diastolic and -systolic volumes, wall thickness
during diastole, and SV as measured by cardiac MRI [54], and similar to reported studies using
echocardiography [52, 53]. These data demonstrate that continuous exercise training throughout
life maintains cardiac remodeling. However, in comparison to younger athletes, indexed LV
end-diastolic and -systolic volumes were lower in veteran athletes. Interestingly, LV mass was
not different between any of the groups, possibly reflecting the increased prevalence of LV
hypertrophy that is associated with aging [51]. Nishimura et al. [53] compared male professional
cyclists ranging in age from 20-49 years using echocardiography and found the oldest age group
(40-49 years) had greater interventricular septum, LV posterior wall thickness, and LV mass
10
compared to younger age cohorts of cyclists. LV end-diastolic dimensions and volumes were not
different between any of the age groups of athletes, and thus the significant finding was a greater
LV wall thickness demonstrated in older athletes. Results from Heath et al. [52] involving
master athletes ranging in age from 50-72 showed no significant differences in wall thickness or
LV mass compared to younger athletes. While comparison of young and older athletes has
produced conflicting results, all veteran/master athletes in the above-mentioned studies show
increased measures of LV dimension compared to age-matched untrained controls.
2.1.3 Right Ventricular Remodeling
2.1.3.1 Morphology of the Right Ventricle
In comparison to the left ventricle, the right ventricle (RV) has been understudied when assessing
cardiac structure and function. This is partly attributable to the difficulty in fully visualizing the
complex geometry of the RV with echocardiography [18, 55-58]. In contrast to the conical shape
of the LV, the RV is more triangular with a cavity that is crescent shaped when observed in
cross-section, formed by the concave free wall and the convex interventricular septum that wraps
around the LV [18]. The cavity can be separated into 3 distinct regions: the smooth muscular
inflow, the trabecular apical region and the outflow [59]. Due to this complex shape, there are
limited data defining the normal dimensions of RV size and volume [5, 59]. The free wall of the
RV is much thinner (3-5 mm reference range) [58, 59] than the LV (6-10 mm reference range as
measured by posterior wall thickness) [47, 49] reflecting the lower pressure of the RV in
comparison to the LV [19]. As a result of these morphological differences, the RV has a lower
volume to surface ratio than the LV, which gives the RV a greater compliance than the LV. This
11
also reflects the RVs predilection to more readily adapt to volume, rather than pressure overload
[20].
2.1.3.2 Characteristic Remodeling
The use of MRI has allowed for more reliable determinations of RV structure and is considered
the gold standard, however the use of echocardiography is common due to its low-cost
accessibility. Due to the RVs crescent shape, the density of trabeculae, and its anatomical
position beneath the sternum, echocardiographic images are more difficult to accurately obtain
than in the LV. Imaging of the RV in endurance trained athletes has suggested that the
adaptations in RV morphology that occur with training are proportional to the observed changes
in LV morphology, reflecting a balanced enlarged heart [7, 9, 10, 12, 60]. Using MRI, Scharhag
et al. [7] examined RV hypertrophy in 21 well-trained male endurance athletes (mean age 27 ± 4
years) of various exercise disciplines and a control group of healthy untrained males matched for
body size. Imaging demonstrated that LV and RV masses were significantly increased in
endurance athletes (36 ± 14% and 37 ± 17%, respectively), however the ratio of LV-to-RV mass
was similar for athletes and control subjects. Furthermore, in athletes, LV-EDV and RV-EDV
were significantly greater compared with control subjects, yet the LV-EDV-to-RV-EDV ratio did
not differ between athletes and control subjects. These results reflect a balanced biventricular
hypertrophy and dilation in the athletic heart, with functional consequences of an increased LV
and RV stroke volume, resulting from a greater EDV [7]. RV cavity size assessed by linear
dimensions of the basal, mid-ventricle and base-to-apex was shown to be significantly greater in
a large study of endurance trained athletes compared to controls [5]. Similar cardiac remodeling
was observed in a group of 26 premium triathletes competing at national and international levels
for more than 6 years [11]. Indexed RV end-diastolic volumes were significantly greater in
12
athletes than control subjects, resulting in elevated stroke volume. However, the LV-to-RV
ratios for end-diastolic volume and myocardial mass were comparable in triathletes and controls
reflecting a balanced hypertrophy. Furthermore, a remodeling index calculated as myocardial
mass/end-diastolic volume for both the LV and RV was similar between athletes and controls.
Thus, while the athletes had significantly lower resting heart rates, this is offset by increases in
stroke volume that are attributable to greater end-diastolic volumes of the hypertrophied
ventricles and not due to an increase in ejection fraction.
2.1.3.3 Functional Differences in Trained Individuals
The data describing RV function in trained individuals is scarce due to the difficulties in
quantifying volume, particularly using echocardiography [61, 62]. Due to the ellipsoid shape,
there is limited data regarding the normal dimensions of the RV compared to the relatively
predictable LV shape [59]. Thus, while normal values for volume and function have been
established in the LV, the RV is limited to surrogate measures when using echocardiography
[19]. Compared to untrained individuals, there are discrepant findings as to whether RV systolic
function in endurance-trained athletes is improved [24, 61, 63, 64], unchanged [10, 11, 60, 65],
or reduced [66, 67] at rest and whether RV diastolic function is improved [24, 62, 63, 68] or
unchanged [10, 64, 65] at rest in exercise-trained individuals. Although some studies of RV
function at rest have shown depressed measures, it is unlikely these findings are of clinical
relevance or are considered deleterious. A more valid assessment of the athletic heart may be
conducted during exercise when the loading conditions of the heart are increased.
13
2.2 Pulmonary Hemodynamics at Rest
2.2.1 Components of Arterial Load in the Pulmonary Circulation
In healthy humans, the pulmonary circulation is characterized by high flow and low pressure
resulting in a reduced resistance for ejection of blood relative to the LV, thereby allowing the RV
to operate at a low energy cost [69]. The pulmonary circulation is functionally coupled to the
RV. Pulmonary artery pressure is generated as blood is ejected from the RV during systole and
is determined by the amount of blood flowing through the pulmonary circulation, the intrinsic
properties of the pulmonary vasculature, and the downstream pressure in the left atrium [70]. It
is these components that contribute to the arterial load on the RV. As a low-pressure system, the
pulmonary circulation is sensitive to mechanical increases in stress. Although both the
pulmonary and systemic circulatory systems transport an equal amount of blood, altered loading
conditions have a significant impact on the right ventricular-pulmonary arterial system compared
to that of the LV, due to this difference in pressure [69]. As a result, load changes within the
pulmonary arterial circulation may have significant consequences on RV work and function [71].
2.2.1.1 Pulmonary Vascular Resistance
To determine the functional state of the pulmonary circulation, pulmonary vascular resistance
(PVR) is calculated as the difference between mean pulmonary artery pressure (inflow pressure;
mPAP) and pulmonary artery wedge pressure as an estimate of left atrial pressure (outflow
pressure; PCWP), divided by the mean flow measured as cardiac output (Q) (Equation 1) [69].
Equation 1: PVR = (mPAP – PCWP) / Q
14
In order to increase blood flow through the vessel system, either resistance can be reduced, or the
pressure gradient can be increased. Vessel resistance (R) can be determined from Poiseuille’s
equation, which states that R is directly proportional to the length of the vessel and the viscosity
of the blood, and inversely proportional to the radius to the fourth power (r4). Although the
intact human vasculature does not conform exactly to the assumptions of this equation, it
illustrates that vessel resistance is highly sensitive to small changes in radius within the small
arteries of the pulmonary arterial tree that account for a large proportion of the resistance through
this circulatory system [72]. Correspondingly, PVR is an important measure of pulmonary
circulatory function that integrates the intrinsic properties of the pulmonary vasculature,
downstream pressures, and blood flow [69]. However, this component of arterial load assumes a
steady blood flow, thus ignoring the pulsatile load that is generated by the cardiac cycle.
Both invasive and non-invasive methods have been used to calculate PVR. Non-invasive
calculation using echocardiography uses the ratio of TRV/RVOTTVI, where TRV is the peak
tricuspid regurgitant velocity (in meters per second), and RVOTTVI is the right ventricular
outflow tract time-velocity integral (in centimeters) [59]. Since PVR is directly related to
changes in pressure and inversely related to transpulmonary flow, TRV and RVOTTVI can be
used as correlates of these variables, respectively. A ratio of TRV/RVOTTVI less than 0.2 is
indicative of a low PVR [73]. However, as with most non-invasive assessments limitations to
this technique exist relating to the difficulty in obtaining accurate measures, especially during
exercise when heart rate and pulmonary pressures are increased significantly. While
echocardiography derived PVR has been validated [73], invasive hemodynamic measurements
during right-heart catheterization provide a more accurate and reliable determination of PVR.
Invasively, PVR can be calculated with 3 variables measured with a balloon-tipped catheter and
applied to Equation 1. This represents a more accurate measure of the pressure difference across
15
the pulmonary circulation and directly reflects the amount of blood flow through the system.
From equation 1, PVR is expressed in the units of mmHg L-1min-1, which can be converted into
dynes/s/cm-5 by multiplying by 80. The dyne is a unit of force required to accelerate a 1 gram
mass at a rate of 1 cm per second squared. A normal, invasively measured PVR is 120
dynes/s/cm-5 in healthy untrained individuals [59].
2.2.1.2 Pulmonary Vascular Compliance
Compliance (C) of the pulmonary circulation reflects the buffering of pulsatile blood flow
generated during each cardiac cycle. This component is related to arterial wall elasticity and
vessel size and can be represented by the ratio of SV to pulse pressure of systolic and diastolic
pulmonary pressures [71] (Equation 2). This provides a measure of how much the pulmonary
arterial tree will dilate and accommodate flow with each contraction of the RV [74].
Equation 2: C = SV/ (PASP – PADP)
A compliant arterial tree allows the arteries to expand passively during systole due to their elastic
properties, which then recoil during diastole [71]. This reduces the workload on the right heart,
as not all blood is sent downstream into the resistance vessels at once [74]. Rather, blood is
stored in the compliant arteries and released during diastole resulting in constant blood flow
throughout the cardiac cycle. The effect of this is seen in the difference between systolic and
diastolic pressures in the pulmonary artery, where diastolic pressure decreases much less
compared to that of the right ventricle [71].
16
2.2.2 Non-Invasive and Invasive Assessment of Pulmonary Pressures:
2.2.2.1 Non-Invasive Doppler Echocardiography
Non-invasive measurements using Doppler echocardiography have assessed pulmonary artery
pressures across a range of subject populations. Transthoracic Doppler echocardiography
provides a reliable estimate of pulmonary artery systolic pressures (PASP) by measuring the
tricuspid regurgitant velocity (TRV) and mean right atrial pressure (mRAP) and applying these
to the simplified Bernoulli equation (Equation 3):
Equation 3: PASP = ([TRV]2 x 4) + mRAP
Tricuspid regurgitant velocity provides an estimate of PASP due to the pressure gradients that
exist between the RV and RA. In the presence of tricuspid regurgitation, the gradient across the
tricuspid valve from the right ventricle to the right atrium can be estimated from the peak
velocity of the systolic tricuspid regurgitant jet velocity [75, 76] and provides an indirect
measure of right ventricular systolic pressure (RVSP) [77]. In the absence of a significant
gradient across the pulmonary valve and RV outflow tract, RVSP provides an approximation of
PASP [78]. With normal RVSP and tricuspid regurgitation present, only small pressure
gradients between the RV and RA exist and a low velocity of the regurgitant jet would be
expected, however when RVSP is elevated, higher systolic tricuspid gradients exist and a higher
regurgitant jet velocity is anticipated [76]. This non-invasive estimation is also dependent on
right atrial pressure (RAP), which is added to the tricuspid regurgitant jet velocity product [78].
Estimated pressure at rest using the TRV has shown to correlate closely with directly measured
PASP, with r values of .90 [77] and .97 [78] reported. However, there are several limitations
17
when using Doppler-derived estimates of PASP. Firstly, not all individuals with normal
pulmonary artery pressures have a measurable or high quality TR jet that allows for an
estimation of PASP [78]. Secondly, the addition of mRAP is a possible source of variation
between reported estimates of PASP. Although mRAP can be estimated from the height of
jugular vein distension [79] or from the respiratory variation in the diameter of the inferior vena
cava [5, 80], an assumed mRAP of 5 mmHg [70] or 10 mmHg [81] is often used for all subjects,
which limits the comparison of pulmonary hemodynamics between studies. Despite a high
correlation of these two measures, accuracy is better represented by the frequency in which
Doppler echocardiography may overestimate and underestimate pulmonary artery pressure [82].
Fisher et al. [83], reported both overestimation (by +19 ± 11 mmHg) and underestimation (by -30
± 16 mmHg) using Doppler echocardiography with the magnitude of underestimation being
greater, despite a similar frequency (16 vs. 15 instances, respectively).
Using the estimated PASP, mean pulmonary artery pressure (mPAP) can be calculated. It has
been shown that PASP accounts for 98% of the variability in mPAP and thus, single-pressure
models have been derived that does not require a diastolic pulmonary artery pressure
measurement. The Chemla formula (Equation 4) has shown to accurately predict mPAP across a
wide pressure range [84], and has been validated using echocardiography [85].
Equation 4: mPAP = 0.61 x PASP + 2 mmHg
While the use of echocardiography provides reliable estimates of pulmonary artery pressures, its
use in the diagnosis of pulmonary hypertension has been recommended as a screening tool, with
right-heart catheterization necessary to confirm diagnosis.
18
2.2.2.2 Invasive Right Heart Catheterization
Invasive, right-heart catheterization provides a direct measure of pulmonary artery pressure by
placing a catheter directly in the pulmonary artery and is considered the gold standard. The
pressure generated by the right ventricle during contraction is transmitted to the catheter tip
placed in the pulmonary artery, which records PASP. Because the pulmonic valve is open during
systole, PASP provides an estimate of RV systolic pressure because there is a common chamber.
During diastole, the catheter tip measures pulmonary artery diastolic pressure (PADP), however
the pulmonic valve closes while the RV continues to relax, and as a result, RV diastolic pressure
is lower than the diastolic pressure in the pulmonary artery. By obtaining systolic and diastolic
pulmonary pressures, mPAP can be accurately estimated using a standard formula (Equation 5)
[86].
Equation 5: mPAP = (2/3 PADP) + (1/3 PASP)
Typically, catheterization required cannulation of a central site, however insertion using
peripheral sites has become more prevalent in recent years and minimizes the risk of damaging
major vascular structures. Peripheral venous insertion techniques have been described
previously [87], but in brief, the insertion site is sterilized and locally anesthetized and the
selected vein is cannulated. A guide wire is then advanced under ultrasound guidance, followed
by placement of the sheath that allows for catheterization. Catheter tip location can be
determined by fluoroscopy or by visualizing the typical waveforms and pressures that represent
specific locations within the heart [88]. Once in place, a continuous thermodilution Swan-Ganz
catheter is capable of measuring RAP, PASP, PADP and cardiac output. By inflating the
ballooned-tip Swan-Ganz in the pulmonary artery to create a wedge, RV pressure is blocked and
the pulmonary capillary wedge pressure (PCWP) is measured, reflecting the left atrial filling
19
pressure [88]. Although automatic calculations of PCWP can be performed with currently
available catheter technology, measurements of PCWP averaged over 4 end-expiratory cycles
has shown better accuracy and reliability in reflecting left atrial filling pressures, by minimizing
the inaccuracies due to fluctuating intrathoracic pressures [89]. The direct assessment of
intracardiac pressures and the ability to measure cardiac output makes right heart catheterization
a powerful tool in the assessment of the heart’s ability to function.
2.2.3 Pulmonary Hemodynamics in Untrained Individuals
Resting pulmonary hemodynamics is influenced by several factors including age, sex, and
training status [81]. In the largest study to date on the pulmonary hemodynamics in healthy
individuals, Kovacs et al. [13] summarized 47 studies using right heart catheterization involving
data from 1,187 individuals. Results indicated that resting mPAP was independent of sex, but
slightly influenced by age and posture. In the supine position, mPAP was 14.0 ± 3.3 mmHg, and
13.8 ± 3.1 mmHg when upright. Pulmonary arterial wedge pressure was slightly lower in the
upright versus supine position (5.9 ± 2.8 and 8.0 ± 2.9 mmHg, respectively), which likely reflects
the reduced cardiac output in the upright posture secondary to a reduced venous return.
Although the mPAP differences amongst the age groups were small, mPAP was significantly
higher in subject’s ≥50 years of age compared to younger subjects. Mean values of mPAP were
14.7 ± 4.0, 12.9 ± 3.0 and 12.8 ± 3.1 mmHg, in subjects aged ≥ 50, 30-50 and < 30 years,
respectively.
The effect of age on pulmonary artery pressures is further highlighted in the study by Lam et al.
[70] involving a random sample of individuals aged ≥ 45 years from the general population. The
tricuspid regurgitation jet of 1413 subjects showed a slight but significant increase in PASP with
age in both men and women. The absolute increase in PASP was smaller in the lower-pressured
20
pulmonary circulation compared to that of the high-pressure systemic circulation, however the
percent increase relative to the youngest age quartile showed remarkable similarity between the
pulmonary and systemic circulations (Figure 1).
Figure 1. Percent increases in pulmonary artery systolic pressure (PASP) and systemic blood
pressure (SBP) across age quartiles compared to the youngest quartile [70].
The increase in PASP was associated with an increase in pulse pressure and estimated left heart
filling pressures, which suggests that age-associated vessel stiffening and diastolic dysfunction
may be contributing factors, similar to the age-related increase in systemic blood pressure [70].
The reference range for PASP derived from Doppler echocardiography was determined by
McQuillan et al. [81] from 3790 normal subjects in terms of atrial and ventricular dimension and
function assessed by echocardiography. Mean PASP from all subjects was 28.3 ± 4.9 mmHg
with a 95% confidence interval of 18.7, 37.9 mmHg. Similar to other studies involving a large
number of subjects, age showed an independent association with PASP, with an average increase
in PASP of 0.8 mmHg per decade. BMI also showed an independent association with PASP and
is likely explained by an increased cardiac output that is associated with obesity [90].
21
2.2.4 Pulmonary Hemodynamics in Trained Individuals
The physiological range of PASP and mPAP has been reported across a range of clinical
demographics and healthy subjects [13, 70, 81], however data on highly-trained individuals is
limited [16, 17, 91-93]. The equine literature has documented the significant increases in mPAP
that occur in highly trained hearts of thoroughbred horses during exercise. In conditioned horses,
Q may exceed 250 L⋅min-1 at maximal exercise creating significantly elevated loading conditions
in the equine RV compared to other mammals [94]. As a result, extraordinary increases in
mPAP have been reported, with values reaching 80 mmHg [95]. Exercise-induced pulmonary
hemorrhage (EPIH) occurs in over 40 percent of horses raced [95] and may partly be explained
by these extreme elevations in pulmonary pressures causing pulmonary capillary stress failure
[94]. Interestingly, Young et al. [94] observed a positive association between EIPH and RV
internal diameter at diastole and systole, which suggests that the factors resulting in EIPH, may
also affect RV remodeling. RV chamber dilation is likely the result of an in increase in volume
loading rather than pressure, and the increase in cardiac output may explain the elevated
pulmonary pressures observed during exercise.
Due to the hemodynamic alterations that occur with endurance training, trained individuals have
a greater RV EDV and SV. Whether these adaptations result in an increased pulmonary artery
pressure at rest due to a higher volume of blood flowing through the pulmonary circulation
remains uncertain. D’Andrea et al. [92] reported resting PASP in 615 athletes (strength and
endurance trained; mean age 28.4 ± 10.1 years) with intensive training for 15-20 hours/week for
more than 4 years, compared to 230 untrained subjects matched for sex and age using Doppler
echocardiography. Endurance-trained individuals showed significantly increased PASP
compared to strength-trained individuals and controls (26.1 ± 0.5, 19.4 ± 8.1, 17.6 ± 4.6 mmHg,
22
respectively), calculated from peak TRV by applying the simplified Bernoulli equation, with
RAP measured by the inferior vena cava respiratory index. These results support earlier findings
by Bossone et al. [16] who compared 26 varsity male hockey players (mean age 20.3 ± 1.7 years)
at rest and exercise to 14 normally active males (mean age 18.9 ± 0.9 years). Doppler
echocardiography showed a significant increase in PASP at rest in the athlete group compared to
non-athletes.
Conflicting results have also been reported by Janosi et al. [93] who found no difference in
resting PASP measuring by pulmonary artery catheter between a group of young male water-
polo players, and a group of medical students. However, this study failed to mention the training
status of medical students and did not report on the intensity of exercise performed by the athlete
group, and so comparison as an athlete vs. non-athlete group is limited. In addition, earlier work
by Bevegard et al. [91] who studied 8 male elite Swedish cyclists (mean age 21.5 years; range
17-28), found no difference in mPAP at rest when compared to earlier published data from two
studies of similar design involving normal non-athletic subjects [96, 97].
2.3 Pulmonary Hemodynamics During Exercise
2.3.1 Response to Increased Right Ventricular Output
With the onset of exercise, Q increases linearly with exercise intensity to meet the demand for
oxygen within the working skeletal muscle. In humans, significantly increased HR and SV in
both the LV and RV reflect the 5-6-fold increase in Q that occurs during vigorous exercise.
Contributory mechanisms include increase Frank-Starling mechanism due to increased venous
return, and increased inotropic state brought about by greater sympathetic activity [98]. This
23
increase in Q results in a normal physiological increase in PASP [99], since pulmonary pressures
are partly determined by the amount of blood flowing through the pulmonary circulation.
2.3.2 Pulmonary Vascular Resistance
A moderate decrease in PVR is seen during exercise in healthy normal subjects. Expanding on
earlier work examining the pulmonary pressure response to exercise [13], Kovacs et al. [14]
reviewed all right heart catheterization data on PVR in 222 healthy subjects at rest and exercise.
The changes in PVR during exercise reflect the intrinsic properties of the pulmonary circulation,
with age and disease explaining the differing responses of pulmonary pressure during exercise.
Subjects aged 24-50 years had a mean resting mPAP of 13.9 ± 2.9 mmHg with a PVR of 69 ± 28
dynes/s/cm-5 in the supine position. With exercise, an 85% increase in cardiac output was
associated with a 41% increase in mPAP and a 12% decrease in PVR. In subjects greater than 50
years old, resting mPAP and PVR was slightly higher than younger subjects and in response to
exercise an initial increase in Q by 71% was associated with a 66% increase in mPAP and a 19%
decrease in PVR. This decrease in PVR in aged subjects was not significantly greater than
younger subjects, and thus the increase in mPAP with exercise in aged individuals may be partly
explained by a less compliant pulmonary system, including higher resting PVR values in older
individuals [14]. In general, upright posture causes an increase in PVR and a decrease in mPAP.
The suggested explanation for the increased resting PVR is related to a smaller amount of
perfused lung vessels when upright. Upon exercise, upright posture is associated with a marked
decrease in PVR. At high exercise intensities, changes in PVR occur independent of body
position [69], with a decrease in PVR attributable to passive recruitment and distension of a
normally compliant pulmonary circulation with additional flow-mediated dilation [100].
24
2.3.2.1 Pressure-Flow Relations During Exercise (mPAP – Q Plot)
When multiple simultaneous pulmonary artery pressure and cardiac output measures are taken
during exercise, the slope and linearity of the relationship between pressure and flow can be
examined. Plotting mPAP against Q is a measure of the resistance through the pulmonary
circulation with increases in steady flow, as reflected by cardiac output. When multiple points
are generated, the slope of this line demonstrates the flow-dependency of pulmonary pressures
and represents how mPAP is affected by every 1 litre per minute increase in Q. The slope of this
ratio has been reported across a range of flow states in healthy young individuals performing
various exercise protocols, yielding an average slope of ~1 mmHg per litre of Q in this
population [101-103]. Aging has shown to be associated with a slight increase in this slope [103,
104], reflecting the increased resistive and less compliant pulmonary vasculature. The mPAP-Q
relationship during exercise has yet to be examined in middle-aged endurance trained
individuals.
2.3.2.2 Pulmonary Vascular Distensibility
The slope of mPAP-Q plots is most often described by a linear approximation, however a slight
curvilinearity of this relationship can be observed with as little as 4-5 coordinates [105]. This
curvilinearity may be explained by the distensibility of the thin-walled pulmonary resistive
vessels reflecting the mechanical properties of stretch with increases in flow [106]. With
increases in blood flow through the pulmonary circulation, the increase in pulmonary vascular
pressure results in distension of the resistive vessels, further decreasing pulmonary vascular
resistance, significantly augmenting pulmonary flow that yields a net increase in vascular
pressure [107]. Distensibility (α) is defined as the fractional change in vessel diameter per unit
25
change in pressure and in vivo measurements of several mammalian species have shown
consistency with a calculated value of ~ 0.02 [108, 109]. A simplistic model was developed by
Linehan et al. [107] to describe this distension coefficient in pulmonary vessels with increases in
flow (Equation 6).
Equation 6: mPAP = [(1 + αLAP)5 + 5αRoQ]⅕ - 1 α
Where mPAP is mean pulmonary artery pressure, LAP is left atrial pressure measured by PCWP,
Ro is pulmonary vascular resistance, and Q is cardiac output. Solving for α over several
coordinates provides a calculation of the pulmonary vascular distensibility. The pulmonary
vascular distensibility coefficient (α) in younger healthy humans is approximately 0.02, which
translates to a 2% change in vessel diameter per mmHg of mean pressure increase [102, 106].
This value of 0.02 and its effect on mPAP-Q relationship can be appreciated when compared to
different values of α (0.01 to 0.10) modeled to mPAP and Q at a constant LAP, assuming a linear
relationship between mPAP and Q as was demonstrated by Naeije et al. [110]. The pulmonary
vascular distensibility coefficient has yet to be calculated in endurance trained individuals and it
remains unknown if these individuals have an increased capacity for distension with significant
increases in Q that occur during exercise.
2.3.3 Pulmonary Hemodynamics in Untrained Individuals
The pulmonary pressure response to exercise in healthy untrained individuals has been well-
studied due to the use of healthy control groups in comparison with disease states in which
pulmonary hemodynamics are assessed with exercise stress testing. However, due to
methodological differences, results are often difficult to compare especially when considering
the wide variations in exercise protocols.
26
2.3.3.1 Pulmonary Hemodynamics During Aerobic Exercise
Kovacs et al. [13] summarized 47 studies of right-heart catheter derived measures of pulmonary
hemodynamics. Data were stratified for sex, age, body position and exercise intensity, and
provides a significant understanding of the factors involved in the pulmonary hemodynamic
response to exercise. During upright exercise, mPAP at rest was 13.8 ± 3.1 mmHg, which
increased to 20.8 ± 4.0 during slight exercise, and 25.6 ± 5.6 during maximal exercise. When
stratified by age, mPAP was significantly higher at rest in subjects aged ≥ 50 years compared
with younger subjects aged 30-50 years (14.7 ± 4.0 vs. 12.9 ± 3.0 mmHg, respectively). The
elevated pulmonary pressure in aged subjects was further exaggerated during slight exercise with
mean values of 29.4 ± 8.4 and 20.0 ± 4.7 mmHg, in subjects ≥ 50 years and those 30-50 years,
respectively. Using non-invasive Doppler derived measures, Argiento et al. [103] measured the
pulmonary hemodynamic response to cycling in a semi-recumbent position in healthy men and
women with mean ages of 38 ± 14 and 37 ± 13 years, respectively. During exercise at an
average work rate of 175 W, calculated mPAP (using the simplified Bernoulli equation and
Chemla formula), increased from 15.5 ± 2.6 at rest to 36.0 ± 5.9 mmHg in men, and from 15.1 ±
2.9 to 30.5 ± 7.2 mmHg in women. The greater increase in mPAP observed in men may be
explained by the higher cardiac output achieved at peak exercise. Interestingly, in subjects aged
> 50 years, resting and exercise mPAP was significantly elevated compared to younger subjects,
despite a similar cardiac output at rest and lower output during exercise [103]. These results may
be explained by the increased mean left atrial pressure and increased pulmonary vascular
resistance in the aged subjects, however the non-invasive echocardiographic estimation of these
parameters limits this conclusion.
27
As many studies have shown, age appears to be an independent factor affecting pulmonary
hemodynamics during both rest and exercise. This was addressed explicitly by Mahjoub et al.
[111] using non-invasive assessment of the PASP response to exercise in healthy individuals of
various ages. In their study, 36 women and 34 men with at least 10 subjects in each 10-year age
range beginning at 20-30 and up to 70-80 years were analyzed. Similar to the results shown by
Kovacs et al. [13], PASP reached a higher value in individuals above 60 years, than in
individuals aged from 20-59 (56 ± 9 vs. 49 ± 7 mmHg, respectively). Using the Chemla
equation this yields an average mPAP of 36.2 and 31.9 mmHg for the older and younger
subjects, respectively. These peak PASP values on exercise were significantly elevated
compared to resting means for all subjects (27 ± 4 mmHg, mPAP = 18.5 mmHg). In an invasive
study by Tolle et al. [99] examining exercise-induced pulmonary arterial hypertension, the
normal control group (mean age 45.9 ± 14.9) had a mPAP of 13.9 ± 2.9 mmHg at rest. During
incremental cycling, this pressure increased to 27.4 ± 3.7 mmHg at an average work rate of 155.5
± 43.1 W. This group was compared to subjects with exercise-induced pulmonary arterial
hypertension (EIPAH) (mean age 58.8 ± 15.1), defined as normal mPAP at rest but greater than
30 mmHg with exercise, who demonstrated an increase in resting mPAP of 18.6 ± 3.2 to 36.6 ±
5.7 mmHg, with an average peak work rate of 90.3 ± 41.7 W. The significantly elevated
pulmonary pressures observed in the EIPAH can be largely attributable to greater PVR during
exercise in these subjects. Normal subjects had a calculated PVR of 62 ± 20 dynes/sec/cm-5,
whereas the EIPAH group had a value of 161 ± 60, which is likely due to the greater increase in
cardiac output observed in the normal group during exercise.
28
2.3.3.2 Intermittent Exercise
Although the typical exercise protocol for the assessment of pulmonary hemodynamics and
cardiac function during exercise involves a graded increase in workload, various exercise
protocols have also been employed. Intermittent/interval exercise involving repeated bouts of
high intensity work alternating with relief consisting of a rest or light work period allows for the
achievement of more time spent near maximal oxygen consumption where energy expenditure is
greatest. The pulmonary hemodynamic response in healthy subjects to strenuous intermittent
cycling exercise was examined with right-heart catheterization by Lonsdorfer-Wolf et al. [101].
Healthy males (mean age 38 ± 5 years) first performed an incremental exercise test to determine
work rates for the intermittent exercise. During incremental exercise, mPAP showed a usual
increase from 13.5 ± 2.0 to 26.5 ± 5.6 mmHg at peak exercise. During incremental exercise with
a total duration of 30 minutes, mPAP increased immediately and peak values were seen during
the first 5 minutes of exercise (24.0 ± 5.0 mmHg). Thereafter mPAP decreased significantly
with the last value measured as 19.5 ± 2.0 mmHg. The likely mechanism for this decrease was
the stable Q that occurred during the intermittent protocol due to an increase in HR, and a
decrease in SV and further reinforces the strong relationship between pulmonary pressures and
Q.
2.3.3.3 Resistance Exercise
Although exercise prescriptions have generally advocated for dynamic lower-limb exercise
involving large muscle mass, complimentary resistance exercise has become increasingly
prescribed due to benefits related to muscular strength, cardiovascular function, coronary risk
factors, and psychological health [112]. The acute hemodynamic response to resistance exercise
29
was investigated by Fowler et al. [113] using invasive catheterization in patients referred for
investigation of shortness of breath with unknown etiology and were considered to have EIPAH.
Resting mPAP had a median of 19 mmHg (interquartile range of 16-20) that increased to 36
mmHg during peak exercise on cycle ergometer. During resistance exercise involving lower-
limb extensor muscle, mPAP increased to a median value of 25 mmHg and during both 40% and
60% 1 repetition max (1RM) and 26 mmHg during 1RM. From these results, the authors
concluded that the higher hemodynamic response at VO2peak compared to 1RM, likely reflects
the continuous nature of aerobic exercise and the associated increase in cardiac output.
2.3.4 Trained Individuals
The pulmonary hemodynamic response to exercise in trained athletes is limited to a small
number of studies involving primarily younger athletes below the age of 40. One of the most
salient changes in cardiac function with endurance training is a pronounced resting bradycardia
[114]. The reduction in resting HR is offset by an increase in SV to maintain Q with the increase
in resting SV secondary to an increase in EDV [11, 43, 115]. This increase in RV output is a
common hypothesis for the increased pulmonary pressures observed in athletes [15-17].
In a simple study by Bossone et al. [16], the tricuspid regurgitation peak velocity in male NCAA
Division 1 varsity hockey players (mean age 20.3 ± 1.7 years) was compared to normally active
males (mean age 18.9 ± 0.9 years); the estimated PASP showed significant differences between
athletes and nonathletes over all workloads of recumbent cycling (Figure 3.)
30
Figure 2. Calculated PASP response to incremental exercise for athletes vs. nonathletes. PASP
was significantly higher in athletes at each stage [16].
A partial explanation given for this observation was the disproportional increase in LV SV in
athletes [16]. Due to the limitations of non-invasive echocardiographic assessment, other
potential contributory mechanisms such as increased left atrial pressure and changes in PVR
were not obtained. Using a similar approach, Bidart et al. [15] studied the mechanisms of the
increase in PASP during exercise in highly conditioned endurance athletes with an average 14.4
± 4.4 hours/week of training (mean age 38.7 years), recruited from cycling and triathlon clubs.
During recumbent cycling to a peak work rate of 350 W, while maintaining a cadence of 70 rpm,
calculated PASP increased significantly in athletes from 19.4 to 54.8 mmHg. Using the
assumptions of the Chemla equation, this can be calculated as a mPAP of 35.4 mmHg, which is
significantly greater than the reported mPAP during maximal exercise by Kovacs et al. [13]
involving normal healthy individuals. To explore the mechanism of this pressure elevation, PVR
was calculated as the ratio of TRV/RVOTTVI. The mean resting value for the athletes was
calculated as 0.13 m/s/cm, which increased slightly to 0.15 m/s/cm during exercise. It has been
suggested that TRV/RVOTTVI values less than 0.2 indicate normal PVR, and while athletes
31
remained below this reference range, the slight increase conflicts with the observed PVR
response to exercise in normal untrained individuals [14] and in part, may potentially reflect the
inaccuracies of echocardiographic imaging during high intensity exercise.
In the largest study to date on the pulmonary hemodynamic response to exercise in highly trained
endurance athletes, La Gerche et al. [17] used combined cardiac magnetic resonance imaging and
echocardiography to examine loading conditions within the RV of 39 athletes during exercise.
Endurance athletes (mean age 36 ± 8 years) performing 16 ± 5 hours/week of various endurance
disciplines and had significantly greater RV mass, EDV and SV than nonathletes. Incremental
exercise was performed on a semi-supine cycle ergometer until exhaustion with PASP measured
every 2 minutes. At peak exercise, with an average work rate of 283 ± 34 W and heart rate 149 ±
14 beats/min, PASP reached an average value of 61.1 ± 12.7 in athletes, which was significantly
greater than the increase in nonathletes (47.0 ± 6.5 mmHg). Interestingly, resting PASP was not
different between groups, despite significantly greater RV stroke volume but similar cardiac
output in the athlete group. The augmented cardiac output in the athlete group during exercise is
a likely mechanism for the exaggerated PASP observed in athletes, however the relative
contributions of left atrial pressure and PVR were not assessed.
To explore the relationship of right ventricular systolic pressure (RVSP) to aerobic exercise
capacity, Moller et al. [116] used echocardiographic measures of RVSP in 108 healthy subjects
aged 13 to 25. Non-invasive echocardiographic calculation of RVSP by measurement of TRV
jet reflects, but does not equal PASP in the absence of an obstructed right ventricular outflow
tract. Like most studies of this design, RVSP is calculated using the modified Bernoulli
equation, and can be equated with non-invasive studies reporting PASP. Though not explicitly
recruited as a specific study group, athletes were defined as having Z-scores higher than 2.0
32
based on initial cardiopulmonary exercise test of aerobic capacity. This yielded 13 athletes, 8 of
which were aged 16-18 years of age. Thus, while considered athletes based on aerobic capacity,
the morphological characteristics of the so-called ‘athletic heart’ were likely not present in these
subjects making comparison with the results of the previously mentioned studies dubious.
Despite these differences, during incremental exercise to a target heart rate of 160 beats/min,
maximal RVSP had a median of 55.5 mmHg and the difference between athletes and nonathletes
was significantly different. Moller et al. [116] also categorized subjects as normal and abnormal
responders based on RVSP during exercise with a cut off value of > 50 mmHg defining
abnormal. With this cut-off value, 67% of athletes and only 8% of normally trained subjects
were defined as abnormal responders. Thus, despite the high variability of RVSP response to
exercise, athletes with high aerobic capacity often show an abnormally high response.
Although echocardiography has been validated as a reliable method for estimating pulmonary
pressures, right heart catheterization remains the gold standard during rest and exercise. Invasive
monitoring overcomes the limitations of echocardiography related to the assumptions that
indirectly obtained right ventricular pressures reflect the pressures in the pulmonary arteries,
however studies using this methodology in highly trained athletes are limited. In a
catheterization study focused on the behaviour of stroke volume during heavy exercise, Bevegard
et al. [91] reported pulmonary artery pressures in 8 well-trained cyclists with a mean age of 21.5
± 4.2 years. Both recumbent and upright-sitting cycling was performed at 2 workloads of 800
kpm/min and 1600 kpm/min, the latter derived from a work rate determined to achieve a heart
rate of 170 beats/min. During recumbent cycling, mPAP increased from 13.6 ± 2.0 to 24.8 ± 5.1
to 28.6 ± 5.5 mmHg at rest, first and second workload respectively. During upright-sitting
cycling, mPAP increased from 13.0 ± 1.7 to 22.6 ± 4.4 to 27.6 ± 4.8 mmHg at rest, first and
second workload respectively. Comparison to two previous studies of normal individuals using
33
the same protocol [96, 97] showed a similar mPAP at rest between athletes and nonathletes,
however during exercise the mPAP was significantly greater in the athletes, with mPAP
measured at the second workload reaching 18.3 ± 3.5 mmHg in nonathletes during recumbent
cycling [96]. During exercise, the stroke volume was 15-30 ml larger in the athletic group,
which represents the main difference between the athletes and nonathletes studied. No
difference in the resistance of the pulmonary circulation was observed between the two groups,
and thus the increase in stroke volume is a likely explanation for the elevations in mPAP seen in
athletes.
While most of the reported findings on the pulmonary pressure response to exercise in athletes
has shown elevations greater than normal healthy controls, conflicting results were observed by
Janosi et al. [93] using right-heart catheterization. Male water-polo players (mean age 18 ± 3
years) were compared with medical students (mean age 22 ± 1 years) with unspecified training
status, however no indication was made that they were performing any considerable amount of
athletic training. The exercise protocol involved an initial workload of 25 W, with progressive
increases of 25 W every 6 minutes. Water-polo players had mPAP during exercise of 16.7
mmHg and untrained medical students had an average of 19.9 mmHg. These relatively low
measures of mPAP reflect the low PASP that was observed. Exercise PASP was 31.3 ± 2.2 and
32.6 ± 5.5 mmHg in water-polo players and medical students, respectively. An explanation for
these low values may lie in the exercise protocol. Water-polo players reached an average
working capacity of 200 W, which would require 48 minutes of cycling given the 6-minute
stages of the exercise protocol. This is a significantly longer duration of exercise than other
reported studies which generally have durations no longer than 20 minutes. The duration of
exercise may have implications for RV function and pressures, given evidence of prolonged
34
exercise inducing a reduction in RV performance [117-120]. Furthermore, Q and PVR during
exercise were not reported, making any explanation of these results difficult to interpret.
The results of the study by Janosi et al. [93] underscore the difficulties in comparing exercise
studies with different protocols. Absolute measures of mPAP or PASP can be misinterpreted
without knowledge of cardiac output. Since pulmonary pressures are highly dependent on the
regional blood flow, determination of the change in mPAP relative to the change in cardiac
output (mPAP/Q) provides a more complete description of the pulmonary hemodynamic
response to exercise. For this reason, invasive catheterization derived measures of pulmonary
hemodynamics are preferable because this relationship can be accurately determined.
Furthermore, precise measures of PVR can be obtained allowing the researcher to quantify the
changes in flow and pressure throughout the pulmonary circulation in response to exercise.
2.3.5 Potential Mechanisms of Elevated Pressures in Trained
Potential mechanisms for increased pulmonary pressures in athletically trained individuals may
be related to the functional consequences of morphological remodeling within the atria and
ventricles. Long-term endurance training elicits morphological remodeling in the atria with
increased reservoir volume. Increased left atrial pressure during exercise has been shown by
indirect measurement of PCWP [121, 122]. The increase in PCWP during exercise was less in
athletes versus control subjects in the study by Bevegard et al. [91]. Although this seems to
contrast what would be expected in athletes with large SV, a lower PCWP would cause an
increase in PVR if all other variables were constant based on Equation 1. A simple explanation
for the increased pulmonary pressures in athletes has been the increased SV that results from
cardiac remodeling. Since PASP is generated as the RV ejects blood during systole, a greater
volume of blood expelled by the ventricle should cause an increase in pressure, unless vascular
35
compliance accommodates this increased blood flow. To better assess this pressure-flow
relationship, indexing the exercise-induced increase in pulmonary pressure to increases in blood
flow (mPAP/Q) may be useful, however this ratio has not been compared in trained and
untrained individuals. Furthermore, the current literature is limited to younger athletes, and the
influence of chronic long-standing endurance training on pulmonary pressures in middle-aged
individuals has not been documented.
2.4 Right Ventricular Function During Exercise
Despite the proportional left- and right-heart remodeling that has been suggested with endurance
training, hemodynamic differences exist between the two sides due to the underlying physiology.
The relative workload of the RV at rest is considerably lower than that of the LV due to the
minimal afterload caused by the low-pressure pulmonary circulation. However, with increasing
exercise intensity, RV systolic pressures increase resulting in a greater increase in coronary
perfusion, oxygen extraction, and RV afterload relative to the LV [123]. While conflicting
resting measures of RV function in trained athletes have been reported, exercise data may
provide a more valuable measure of RV function when the work requirements are at its greatest.
2.4.1 Right Ventricular-Pulmonary Arterial Coupling
The morphological and physiological changes that occur in the RV with long-standing endurance
exercise training may have important consequences on the tightly coupled downstream low-
pressure pulmonary circulation. Measurement of the coupling between pump function and
arterial load provides insight into the mechanics and efficiency of these two systems. RV end-
systolic elastance (Ees) is used as a parameter of RV contractility (Equation 7) and arterial
36
elastance (Ea) represents all elements of total ventricular afterload to provide an index of arterial
load (Equation 8) [124, 125].
Equation 7: Ees = (PASP x 0.9) / RV end-systolic volume
Equation 8: Ea = ((PASP x 0.9) – PCWP) / SV
Right ventricular-pulmonary arterial (RV-PA) coupling is quantified as the ratio of Ea to Ees.
Optimal coupling occurs with a ratio of 1.0, when the ventricle and arterial system have equal
elastance allowing for maximum energy transfer. Under control conditions the RV has been
shown to operate at maximum efficiency and submaximal work output producing a ratio of < 1.0
[126]. During exercise, changes in this ratio can be used to assess the response in the pulmonary
arterial system to increases in volume loading within the RV. A decrease in the Ea:Ees ratio
with exercise indicates favourable coupling between the RV and pulmonary vasculature. Sanz et
al. [127] observed a significantly greater Ea:Ees ratio in individuals with pulmonary
hypertension compared to controls. The increased ratio was the result of an increased Ea and a
decreased Ees, secondary to increased afterload that occurs with pulmonary hypertension. Latus
et al. [124] demonstrated impaired RV-PA coupling at rest in tetralogy of Fallot patients with
significant RV volume overload. Despite increased contractility with dobutamine infusion,
Ea:Ees ratio remained significantly increased (2.74 ± 3.08) indicating an uncoupled pulmonary
arterial response to chronic volume overload. While RV-PA coupling has been quantified in
pathological volume overload, changes in coupling have yet to be examined in physiological
volume overload that occurs with exercise.
37
2.4.2 RV Performance During Acute Exercise
Data on RV function during acute aerobic exercise in trained individuals are limited. This is
partly attributable to the marked changes in ventricular loading that occur during exercise. These
loading conditions convolute the assessment of contractility by echocardiography due to the
inherent geometrical assumptions that are necessary. La Gerche et al. [66] used strain rate
imaging to assess RV function in endurance-trained athletes during an acute bout of incremental
exercise. Using 2D speckle-tracking, strain rate increased with exercise similarly in both athletes
and nonathletes, however the increases in the basal segment of the RV were greater in
nonathletes compared to athletes. The explanation for this reduced strain rate in athletes is the
tight coupling between RV elastance (a measure of contractility) and pulmonary arterial
elastance (a measure of RV afterload) [128]. Arterial elastance is inversely proportional to
stroke volume when pressures are comparable [20, 129], and thus the greater stroke volume in
athletes, may imply that athletes can maintain RV output, with lower contractility [66].
Furthermore, there is more volume at the base of the RV and so a lesser degree of deformation
may be required to generate the same stroke volume, which explains the results of reduced basal
strain rate in athletes [66].
Biventricular function has also been examined following a short bout of high-intensity interval
exercise. Scott et al. [130] compared endurance-trained men to normally active men with an
exercise protocol requiring subjects to work at a 100% power-output workload for 1 minute,
followed by 2 minutes of active recovery, for a total of 15 times. The design of the exercise was
to elicit a cardiac stimulus similar to interval training performed by endurance subjects and
normally active individuals (ex. soccer or hockey). Endurance athletes showed impaired LV
diastolic function as indicated by a reduced interval between twisting and peak circumferential
38
strain rate. The only functional parameter reported in the RV was a significantly reduced
ejection fraction after exercise in the endurance athletes that was not observed in the normally
trained. Due to the lack of correlation between RV function and HR or RV EDV, the authors
hypothesized these functional impairments may be related to an alteration in intrinsic RV
function, reflecting the response of the RV to increased right-sided pressures [130]. Despite
these differences between athletes and nonathletes in response to exercise, further research is
necessary to delineate the mechanisms of the observed differences. Whether these measures
truly reflect RV ‘dysfunction’ is unlikely given that athletes typically achieve higher work rates
and maximal oxygen consumption during short bouts of exercise compared to untrained.
However the implications of these differences remains unknown.
2.4.3 Prolonged Endurance Exercise
Functional abnormalities have been observed in athletes following prolonged bouts of endurance
exercise [117-120, 131-134], however the significance of these impairments remains speculative.
The effect of prolonged aerobic exercise on cardiac function has received increasing attention
due to cases of sudden cardiac death in mass-participation events [135]. In addition, there are
limited but intriguing data describing a 2-to-10 fold increase in atrial fibrillation (AF) incidence
observed in athletes with a long-standing history of intensive, frequent endurance exercise [136].
Following prolonged endurance events, RV ejection fraction was shown to decrease relative to
baseline measures due to increased RV volumes, while LV ejection fraction was preserved [131,
134]. RV function assessed by echocardiographic strain analysis has demonstrated reduced LV
and RV systolic function that was independent of exercise intensity (60 or 80% VO2max)
following 150 minutes of exercise [117]. Furthermore, dobutamine stress following prolonged
exercise showed an intensity-mediated decline in myocardial β-adrenergic receptor sensitivity for
39
LV and RV contractility [117, 118]. Following an ultra-endurance triathlon, RV fractional area
change and tricuspid annular plane systolic excursion (TAPSE), a measure of RV longitudinal
systolic function, were reduced due to an increase in RV systolic area [131].
2.5 Clinical Relevance and Insight
Endurance exercise training is associated with well-established cardiovascular benefits [137-
139]. However, an emerging body of evidence suggests that long-standing chronic vigorous
endurance training, considered to be ‘excessive’, may have negative cardiovascular
consequences [22]. Intensive endurance exercise training induces cardiac remodeling and acute
physiological responses that may act as pro-arrhythmic substrates, particularly for AF [135, 136,
140-144]. While the possible mechanisms explaining this increased risk remain speculative,
right ventricular and atrial enlargement may be contributing factors [141, 145, 146], in addition
to acutely elevated RV and pulmonary pressures during exercise that may lead to chronic
elevations at rest [22]. Our understanding of these conditions are limited in part, to predictive
measures of pulmonary pressures from echocardiography at rest and a paucity of data obtained
during exercise using high-fidelity, intra-cardiac monitoring in highly-trained athletes with a
long-standing history of endurance training.
2.6 Conclusion
In summary, our understanding of the pulmonary pressure response to exercise has been largely
limited to estimate measures derived from echocardiography. Chronic endurance exercise
training has been associated with cardiac remodeling resulting in a significantly enlarged RV.
Using echocardiography, the complex geometry of the RV is a limiting factor in assessment of
volume and function in normal individuals due to the necessary geometrical assumptions that do
40
not apply in the RV, as they do for the LV. The remodeled hearts of highly trained athletes may
further convolute this assessment. Catheterization derived measures of right-heart and
pulmonary pressures provide a more accurate and reliable means of assessing pressures. In
addition, simultaneous measurement of cardiac output would allow for a more comprehensive
understanding of the right heart and pulmonary hemodynamic response to exercise, particularly
in athletes with greater end-diastolic volumes with large cardiac output states during exercise.
Whether or not the pulmonary vasculature accommodates the increased output of blood from the
RV associated with cardiac remodeling remains unknown.
41
Chapter 3 Manuscript for Journal Submission
3This chapter contains a modified version of a manuscript to be submitted for publication.
3.1 Introduction
The pulmonary arterial circulation is a highly compliant, low-pressure system that is functionally
coupled to the right ventricle (RV). Athletes engaging in frequently intense endurance exercise
have shown to demonstrate bi-ventricular remodeling resulting in RV enlargement that is
proportional to changes observed in the left ventricle (LV) [7, 9-12]. As a result of these
morphological adaptations, endurance athletes (EA) demonstrate an increase in both left and
right ventricular end-diastolic volume (EDV) [7, 11, 147, 148], a hallmark feature that increases
stroke volume (SV) secondary to Frank-Starling mechanism [2]. While RV adaptations are the
result of physiological hypertrophy that has been associated with normal [10, 11, 60, 65] or
improved function considered to be a favourable adaptation [24, 61, 63, 64], the downstream
consequences in the pulmonary circulation remain largely unknown, particularly during exercise
when the pulmonary circulation must accommodate large increases in stroke volume.
While limited data suggest that EA have elevated pulmonary artery pressures (PAP) at rest and
during exercise compared to untrained, most data are derived non-invasively by
echocardiography [15-17]. In addition, these measures have been reported as absolute values
without respect to changes in flow (Q). However, a more complete description of the resistive
index within the vasculature is derived by indexing changes in mean PAP (mPAP) to changes in
Q, since pulmonary pressures are dependent on the flow of blood through the pulmonary
42
circulation. Additionally, this accounts for any interindividual variability in peak exercise work
rate. Linear pressure-flow relationships have been previously reported in healthy individuals
across a wide range of flows with a slope of approximately 1 mmHg⋅min-1⋅L-1 being reported
[101-103]. However, pressure-flow data on EA has not been established.
The pulmonary arterial system is functionally coupled to the RV, which generates pulsatile blood
flow with each contraction. Measurement of the coupling between pump function and arterial
load provides insight into the mechanics and efficiency of these two systems, and has been
quantified as the ratio of pulmonary arterial elastance (Ea) to RV end-systolic elastance (Ees)
[126, 149]. Impaired right-ventricular-pulmonary arterial (RV-PA) coupling has been observed
in disease states that produce significant RV volume [124] and afterload [127], however RV-PA
coupling has yet to be quantified during acute aerobic exercise in EA, a cohort that may exhibit
excessive RV afterload during exercise. Therefore, we sought to characterize RV morphology in
long-standing EA and investigate the exercise-induced increase in PAP by examining pressure-
flow relationship and RV-PA coupling at rest and during submaximal exercise using right heart
catheterization. We hypothesized that EA would demonstrate right atrial (RA) and RV
remodeling characterized by increased cavity size and linear dimensions, manifested by elevated
PAP at rest and during exercise compared to established normal values. We also hypothesized
that EA will have a greater increase in mPAP relative to increases in Q during submaximal
exercise, reflecting sub-optimal RV-PA coupling.
43
3.2 Methods
3.2.1 Study Population
We recruited 12 middle-aged men (age range 45-65 years) who responded to advertisements to
local running and cycling clubs with a history and actively engaging in endurance exercise
training and endurance competitions. All participants were normotensive (blood pressure <
140/90 mmHg), non-obese (BMI < 30 kg⋅m-2), non-diabetic, non-smokers, and had no history of
cardiovascular disease, prior diagnosis of coronary artery disease or cardiomyopathy, significant
valvular disease, diagnosis or treatment of any ventricular or supraventricular arrhythmias. In
addition, subjects were excluded if they were taking any cardioactive medication, had a current
viral or chronic illness, or a history or diagnosis of sleep disorders and/or sleep apnea or prior
exposure to chemotherapy. The criteria for endurance trained subjects required life-long
participation in prolonged, intensive endurance exercise of vigorous intensity or greater, defined
as: runners or triathletes who compete and train year-round, participate in one or more marathons
and/or triathlons per year and with weekly running mileage greater than 35 km or cycling more
than 6 hours per week, performed regularly throughout the year, minimum of 20 years. Our
study population consisted of 3 cyclists, 3 runners and 6 mixed cyclists and runners. The
selection of both runners and triathletes provided a range of high-volume training with similar
patterns of cardiac adaptation and remodeling [47]. Exercise history was confirmed with the
Lifetime Total Physical Activity Questionnaire [150], as well as an Internet search of endurance
competition registration and completion times. Informed written consent and the Physical
Activity Readiness Questionnaire for Everyone (PAR-Q+) was successfully completed by all
subjects prior to participation. The study procedures were reviewed and approved in full by the
hospital and university research ethics boards.
44
3.2.2 Experimental Design
Subjects underwent a comprehensive cardiac assessment including electrocardiography (ECG),
echocardiography (ECHO) and right heart catheterization (RHC) to obtain resting and exercise
data. A 12-lead ECG reading was obtained at rest, as well as baseline 2-dimensional (2D) and
Doppler ECHO with subjects in a supine position to assess cardiac structure and function. RHC
was performed via peripheral venous cannulation with hemodynamic measures recorded at rest
and during a submaximal exercise protocol, with simultaneous ECHO. On a separate visit
separated by at least five days and no more than two weeks, subjects underwent a maximal
graded exercise test to determine maximal oxygen consumption (VO2peak) in addition to
anthropometric measures. Resting blood pressure and heart rate was recorded as the average of 5
measurements using an automatic blood pressure device (BpTRU Vital Signs Monitor BPM-100,
BpTRU Medical Devices, Coquitlam BC, Canada). Percent body fat was estimated using
bioimpedance analysis (Hydra 4200 Bio-Impedance Analyser, XiTRON Technologies, San
Diego, CA) and was calculated as fat-free mass divided by total body weight.
3.2.3 Maximal Oxygen Consumption
Peak oxygen consumption (VO2peak) was determined by indirect calorimetry obtained during a
standard graded exercise test on a cycle ergometer (Examiner WLP-904, Lode B.V., Groningen,
Netherlands) using a calibrated metabolic cart (Moxus Modular Metabolic System, Applied
Electrochemistry Incorporated, Pittsburgh, PA). Heart rate was monitored throughout exercise
using a Polar Wireless Heart Rate System (Polar Electro Inc., Lake Success, NY) with a Polar
transmitter (Polar T61-Coded) strapped to the chest immediately inferior to the pectoral muscles
and transmitted wirelessly and displayed in real-time using a Polar receiver integrated with
45
Moxus software. Following a 3-minute warm-up at 25W, workload was increased to 50W and
then increased by 50W every two minutes until 200W, after which workload was increased by
25W every minute until subjects reached exhaustion. Breath-by-breath measurement of expired
gases was collected and recorded as 15-second averages to determine VO2peak. Achievement of
VO2peak was confirmed based on standard criteria: plateau of VO2 despite an increase in work
rate, RER > 1.15, achievement of age predicted maximal heart rate (HRmax ± 10 beats/min). If
none of these criteria were met, VO2peak was recorded as the highest VO2 obtained during the test.
3.2.4 Echocardiographic Measures
Baseline ECHO images were acquired with subjects lying supine and oriented in a left lateral
decubitus position. Subsequent resting and submaximal exercise ECHO were acquired with
subjects in a semi-upright (45°) position with the imaging bed laterally tilted to achieve a left
lateral decubitus position. ECHO was performed on a commercially available system (GE Vivid
7 Dimension & Imaging System; GE healthcare, Canada) with a phased array M4S probe. All
imaging and analysis was done in accordance with the American Society of Echocardiography
Guidelines [49, 59]. Post-process imaging was done offline by a single trained observer on a
proprietary workstation (GE Healthcare, EchoPAC, Version 11).
M- and B-Mode Measurements
Standard 2D images were acquired, including apical (2- and 4 chamber) and parasternal (long-
and short-axis) views. Parasternal long-axis was used to determine LV internal dimension
during diastole (LVIDd) and systole (LVIDs), the interventricular septum during diastole (IVSd),
LV posterior wall thickness during diastole (LVPWDd), and LV outflow tract diameter during
systole (LVOT). 2D images of left atrial (LA), right atrial (RA), and LV and RV area were made
46
from apical 4- and 2-chamber views. LV end-diastolic and end-systolic volume was measured in
apical 4- and 2-chamber views and used to determine ejection fraction and SV using a modified
bi-plane Simpson method.
RA area was measured in apical 4-chamber view by tracing, beginning at the plane of the
tricuspid annulus, and along the interatrial septum, superior and anterolateral walls of the RA,
with the maximal long-axis distance being parallel to the interatrial septum. RV linear
dimensions at end diastole were measured in apical 4-chamber view. RV size was assessed with
linear dimensions using multiple acoustic windows according to American Society of
Echocardiography (ASE) guidelines for RV analysis. RV basal, mid-cavity and longitudinal
diameter was determined from a 4-chamber apical view. RV end-diastolic and end-systolic
cavity area was measured and used to calculate RV fractional area change (FAC).
Doppler Analysis
Pulsed-wave Doppler interrogation of mitral and tricuspid inflow was used for the quantification
of regurgitation and blood flow. LV outflow tract velocity time integral was acquired and
multiplied by LV outflow tract area to calculated LV stroke volume. LV stroke volume was
multiplied by heart rate to calculate Q. Tissue Doppler imaging of the RV free wall was assessed
from the apical 4- chamber view by placing the sample volume at the tricuspid annulus. Indices
of diastolic function (E, A and E/A) in the mitral and tricuspid valves were recorded by placing
the sample volume at the tip of the valve.
47
3.2.5 Right Heart Catheterization
Procedure
Each subject was instrumented with a Swan-Ganz catheter inserted via peripheral venous
cannulation. Under direct ultrasound guidance using a standard ultrasound machine (Site-Rite 5
Ultrasound System; Bard Access Systems, Salt Lake City, UT), the cephalic and basilic vein was
identified. The vein chosen was typically the larger of the two and deemed to be the easiest to
cannulate. The relationship of the chosen vein to the brachial artery was noted, and the
procedure was performed following routine clinical practice guidelines, ensuring sterility. Heart
rate was continuously monitored with 5 lead ECG. The subject’s arm was prepped from the
axilla to the antecubital fossa with antiseptic solution and then draped in a sterile fashion. The
site was anesthetized with local anesthetic and an 18-gauge 3.8cm Seldinger needle (Argon
Medical Devices) was visualized and advanced. A 145cm long J-wire guide wire was advanced
under fluoroscopy followed by placement of an 8-Fr venous sheath, allowing insertion of a
continuous thermodilution Swanz-Ganz catheter (Swan-Ganz CCOmbo Pulmonary Artery
Catheter; Edwards Lifesciences, Irvine, CA). The catheter tip was positioned in the pulmonary
artery under fluoroscopy with inspection of waveforms to ensure accurate positioning. The
catheter was connected to a Vigilance II Monitor (Edwards Lifesciences, Irvine, CA) to display
continuous cardiac output, mixed venous oxygen saturation (SvO2), and RV EDV. Arterial
oxygen saturation (SpO2) was measured with a pulse oximeter finger probe and SvO2 was
measured with a sample drawn from the tip of the pulmonary artery catheter to reflect the
average amount of oxygen remaining after all tissues in the body have removed O2 from the
hemoglobin. Pressure waveforms were recording using a Mac-Lab Hemodynamic Recording
System (GE Healthcare) with simultaneous heart rate recordings.
48
Exercise Protocol
Upon successful cannulation and supine resting hemodynamic measurements, subjects were
transferred to a specialized cycle ergometer (Ergoselect 1000 L; Ergoline, Bitz, Germany) and
positioned semi-upright to 45° with a slight lateral tilt for optimal ECHO imaging. The pressure
transducers were set at the level of the right atrium. Semi-upright hemodynamic and ECHO
measurements were acquired 7 minutes after positioning and recorded as semi-upright resting
measurements. Subsequently, a submaximal exercise protocol was initiated. Subjects exercised
at 3 target heart rates (100, 130 and 150 beats/min) and simultaneous ECHO and hemodynamic
catheter measurements were obtained during each (Figure 3). Work rate was increased over a 2-
minute period to achieve steady state heart rate before measurements at desired heart rates were
acquired. Hemodynamic measurements were taken at consistent time points of 6 minutes and 50
seconds during each progressive heart rate. To prevent peripheral muscular fatigue during the
final exercise stage, a recovery stage with a workload of 75 watts and duration of 3 minutes
occurred prior to measurements at 150 beats/min. Subjects were instructed to maintain a cycling
cadence greater than 70 revolutions per minute. Blood pressure measurements were recorded
during each exercise stage with a Tango+ automated blood pressure monitor (SunTech Medical,
Morrisville, NC).
49
Figure 3: Submaximal exercise protocol performed during right heart catheterization. RHC,
right-heart catheterization measurements; ECHO, echocardiographic measures; bpm, beats per
minute
Pressure Analysis and Calculations
Analysis of mPAP, pulmonary artery systolic pressure (PASP), pulmonary artery diastolic
pressure (PADP), mean right atrial pressure (RAP) and mean pulmonary capillary wedge
pressure (PCWP) was performed with automated measures from the Mac-Lab Hemodynamic
Recording System. These measures were acquired over a digital caliper of 10 cardiac cycles.
The mean value of the pressure waveform is obtained by adding together all the data points then
dividing by the period of time over which the data is obtained. The systolic point is obtained by
finding the maximum point in the systolic phase of the beat and the diastolic point is obtained by
finding the minimum point in the diastolic phase of the beat. PVR was calculated as (mPAP-
PCWP)/Q. Pulmonary arterial compliance (C) was calculated as SV/(PASP-PADP). Pulmonary
arterial elastance (Ea) was calculated as ((PASP x .9) – PCWP)/SV and right ventricular end-
systolic elastance (Ees) was calculated as (PASP x.9)/RV end-systolic volume. RV end-systolic
50
volume was calculated by dividing stroke volume over RV diastolic area minus RV systolic area
to generate a conversion factor. RV area was then multiplied by this conversion factor to
calculate an RV volume. RV stroke work index (RV SWI) was calculated as (mPAP-RAP) x SV
index x 0.0136, where RAP is mean right atrial pressure and SV index is stroke volume indexed
to BSA, calculated with the DuBois formula. The slope of all mPAP-Q coordinates from rest
and exercise data was calculated by linear regression and each mPAP-Q point was fitted to the
equation:
mPAP = [(1 + αLAP)5 + 5αRoQ]⅕ - 1 α
where LAP is PCWP and Ro is PVR, to calculate α, the distensibility index representing the %
change in vessel diameter, per mmHg increase in mean pulmonary pressure [107].
3.2.6 Statistical Analysis
Statistical analysis for each dependent variable was performed using one-way repeated measures
Analysis of Variance (ANOVA) with within-subjects effects representing exercise stage (rest
semi-upright, 100 beats/min, 130 beats/min, and 150 beats/min). Linear regression was used to
determine the slope of mPAP-Q coordinates. All comparisons are based on a probability of type
1 error set at 0.05. Statistically significant differences from main effect results from ANOVA
were compared post-hoc using Bonferroni-corrected t-tests. Results are reported as mean ± SD.
All analysis was performed using SPSS 20.0 for Windows (SPSS Inc., Chicago, Illinois).
51
3.3 Results
3.3.1 Study Population
Baseline characteristics of the study population are described in Table 1. All subjects completed
the study protocol with no serious adverse events. There were no significant differences in
height or body mass between visits (74.8 ± 8.6 kg and 177.7 ± 3.8 cm at catheterization vs. 75.9
± 8.3 kg and 177.1 ± 3.7 cm at peak oxygen consumption). The average VO2peak achieved by all
participants falls above the 80th percentile for men aged 40-49 and 50-59 years, and above the
90th percentile for men aged 60+ years according to values set by the American College of Sports
Medicine Guidelines for Exercise Testing and Prescription (6th edition).
52
Table 1: Baseline characteristics
Variable Average ± SD Range
Age (y) 55 ± 6 45 – 65
Height (m) 1.77 ± 0.04 1.71 – 1.82
Weight (kg) 75.9 ± 8.3 67 – 90.5
Body Mass Index (kg/m2) 24.2 ± 2.1 21.7 – 28.2
Body Surface Area (m2) 1.93 ± 0.12 1.79 – 2.09
Percent Body Fat 15.3 ± 6.3 2.3 – 22.5
Resting HR (beats/min) 55 ± 10 43 – 79
Resting SBP (mmHg) 117 ± 14 101 – 142
Resting DBP (mmHg) 76 ± 9 65 – 88
Exercise Measures
Maximum HR (beats/min) 160 ± 12 134 – 173
Peak Power Output (Watts) 331 ± 40 275 – 400
VO2peak (mL⋅kg-1⋅min-1) 46.6 ± 8.9 35.9 – 66.5
HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure
3.3.2 Left Atrial and Left Ventricular Morphology
Anatomical-M mode and 2D ECHO measures of left atrial and left ventricular morphology at
rest in the supine position are shown in Table 2.
53
Table 2: Left atrial and left ventricular morphology
Variable Average ± SD Range
LA ESD (mm) 35.6 ± 3.4 30.0 – 41.0
LA maximal volume index (ml) 47.8 ± 10.7 33.0 – 65.0
LVIDd (mm) 46.9 ± 3.1 40.0 – 51.0
LVIDs (mm) 29.3 ± 2.2 27.0 – 34.0
IVSd (mm) 11.5 ± 1.0 0.9 – 13.0
LVPWd (mm) 8.0 ± 0.7 7.0 – 9.0
LV Mass (g) 158.7 ± 23.6 106.0 – 195.0
LV Mass Index (g/m2) 83.0 ± 13.4 59.9 – 102.1
LVOT (mm) 20.6 ± 0.9 19.5 – 22.4
LV EDV (ml) 113.3 ± 9.9 100.0 – 137.0
LV ESV (ml) 39.8 ± 3.6 34.0 – 48.0
LV SV (ml) 73.4 ± 7.6 61.0 – 89.0
LV EF (%) 64.7 ± 2.3 61.0 – 68.8
LA ESD, left atrial end-systolic diameter; LA maximal volume index, left atrial volume in systole; LVIDd, left ventricular internal dimension in diastole; LVIDs, left ventricular internal dimension in systole; IVSd, interventricular septum dimension in diastole; LVPWd, left ventricular posterior wall thickness in diastole; LV mass, left ventricular mass; LV mass index, left ventricular mass divided by body surface area; LVOT, left ventricular outflow tract diameter in systole; LV EDV, left ventricular end-diastolic volume; LV ESV, left ventricular end-systolic volume; LV SV, left ventricular stroke volume; LV EF, left ventricular ejection fraction.
3.3.3 Right Atrial and Right Ventricular Morphology
Right atrial and right ventricular morphology data are presented in Table 3. Resting RV end-
diastolic and end-systolic areas were in the upper-range of reference values [59], as were basal
54
and mid-cavity linear dimensions of RV size. These measures reflect an increased RV cavity
size in EA individuals. Indices of systolic function (RV FAC, TAPSE) were within normal
limits.
Table 3: Right atrial and right ventricular morphology
Variable Average ± SD Range
RA end-systolic area (cm2) 23.2 ± 4.1 18.6 – 30.4
RA maximal volume (ml) 87.5 ± 38.0 59.0 – 191.0
RA minimal volume (ml) 39.3 ± 16.4 18.9 – 71.7
RA pre-contraction volume (ml) 52.6 ± 21.2 28.0 – 102.0
RV basal diameter (mm) 44.2 ± 4.9 34.8 – 53.2
RV mid cavity diameter (mm) 29.2 ± 2.5 25.0 – 34.5
RV longitudinal diameter (mm) 74.6 ± 5.8 61.4 – 84.0
RV end-diastolic area (cm2) 22.0 ± 2.5 17.0 – 24.9
RV end-systolic area (cm2) 12.2 ± 2.1 7.0 – 14.5
RV FAC (%) 43.4 ± 2.6 40.0 – 48.0
TAPSE (cm) 2.3 ± 0.3 1.7 – 2.8
RA, right atrial; RV, right ventricular; RV FAC, RV fractional area change; TAPSE, tricuspid annular plane systolic excursion.
3.3.4 Resting Pulsed-wave Doppler and Tissue Doppler Imaging
Pulsed-wave Doppler and tissue Doppler imaging of the transmitral valve, and tissue Doppler
imaging of the tricuspid valve at rest are shown in Table 4.
55
Table 4: Resting pulsed-wave Doppler and tissue Doppler measures
Variable Average ± SD Range
Mitral Inflow
E (cm/s) 71.7 ± 11.4 56.0 – 100.0
A (cm/s) 50.8 ± 14.2 32.0 – 82.0
E/A ratio 1.5 ± 0.6 0.9 – 2.9
IVRT (msec) 75.2 ± 28.0 24.0 – 101.0
DT (msec) 201.4 ± 23.8 158.5 – 240.0
Mitral Valve Annular Velocities
E’ lateral (cm/s) 11.7 ± 2.5 7.0 – 14.0
A’ lateral (cm/s) 8.4 ± 2.2 5.0 – 13.0
S’ lateral (cm/s) 9.1 ± 2.6 5.0 – 15.0
E’ septal (cm/s) 8.8 ± 2.0 6.0 – 12.0
A’ septal (cm/s) 8.7 ± 1.8 6.0 – 11.0
S’ septal (cm/s) 7.4 ± 1.5 6.0 – 11.0
E’ average (cm/s) 10.3 ± 1.9 6.5 – 13.0
E/E’ ratio 7.2 ± 1.5 5.5 – 10.9
Tricuspid Valve Annular Velocities
E’ lateral (cm/s) 12.2 ± 2.7 8.0 – 17.0
A’ lateral (cm/s) 13.2 ± 4.5 7.0 – 21.0
S’ lateral (cm/s) 12.3 ± 0.9 11.0 – 14.0
E, peak early filling velocity; A, late diastolic filling velocity; E/A ratio, Doppler blood flow ratio describing ratio of early to late diastolic filling; IVRT, isovolumic relaxation time; DT, deceleration time; E’, early diastolic annular velocity; A’, late diastolic annular velocity; S’, systolic myocardial velocity; E’ average, average of E’ lateral and E’ septal as a measure of global early diastolic annular velocity; E/E’ ratio, ratio of peak early diastolic filling to early diastolic annular tissue velocity as a surrogate for left atrial pressure.
56
3.3.5 Hemodynamic Measures by Right Heart Catheterization
Invasive pressure measurements in all but one subject were attainable at a heart rate of 150
beats/min. At supine rest, PASP, PADP and mPAP were within normal limits, as was PCWP
and RAP (Table 4). No significant differences in any dependent variable in Table 5 were
observed when subjects transferred from supine to a semi-upright position. Upon exercise, all
measured pressures increased significantly (P < 0.01) at 100 beats/min. The average workload at
100, 130, and 150 beats/min was 84.6 ± 30.0, 166.4 ± 23.4, and 189.5 ± 41.8 watts, respectively.
These wattages correspond to the average work rate when pressure measurements were acquired.
In most subjects, the work rate required to achieve steady state heart rate at targeted heart rates,
was higher than the eventual work rate at which pressure measurements were recorded, this was
due to a drift in heart rate throughout the exercise stage and an adjustment to work rate to
maintain steady state heart rate.
With increasing exercise intensity, no significant changes in pressures were observed at 130
beats/min compared to 100 beats/min, or at 150 beats/min compared to 130 beats/min or 100
beats/min. Heart rate was significantly different at each preceding exercise stage and compared
to both resting conditions (P < 0.001). Cardiac output data was available at rest-supine and
exercise at 100 and 130 beats/min and was significantly different at each stage (Table 5) (P <
0.001).
Changes in systemic blood pressure, oxygen saturation and transpulmonary pressure
gradients at rest semi-upright and throughout exercise are shown in Table 6. A normal blood
pressure response to exercise was observed and the arterial oxygen saturation (SaO2) declined
significantly from rest compared to exercise at 130 and 150 beats/min, although the absolute
change was relatively small. The observed mixed venous oxygen saturation (SvO2) at rest is
57
within the expected normal range and the significant decline that occurred from rest to exercise
at 150 beats/min reflects an increase in oxygen consumption.
At maximum exercise (150 beats/min), 7 subjects had a PASP ≥ 40mmHg, 5 of which
who also had mPAP ≥ 30 mmHg. At a lower exercise intensity (100 beats/min), 8 subjects had a
PASP ≥ 40 mmHg, and 7 subjects had a mPAP ≥ 30 mmHg. When separating individuals with
mPAP ≥ 30 mmHg at 100 beats/min, significant differences were observed in mPAP, PASP,
TPG, each being augmented in those with mPAP ≥ 30 mmHg. Pulmonary resistive vessel
distensibility (α) was significantly lower in individuals with mPAP ≥ 30 mmHg at 100 beats/min
(Table 7). There were no significant differences in age between the groups. RV diastolic area
index at rest in individuals with mPAP ≥ 30 mmHg was not significantly different than those
with mPAP < 30 mmHg (11.1 ± 1.2 vs. 12.1 ± 1.7 cm2/m2, P = 0.45, respectively), nor was
arterial systolic blood pressure at 100 beats/min (176.8 ± 18.4 vs. 159.8 ± 11.5 mmHg, P = 0.13,
respectively).
58
Table 5: Hemodynamic data at rest and during exercise
Variable Rest Supine 100 beats/min 130 beats/min 150 beats/min
RAP (mmHg) 6.8 ± 2.1 8.6 ± 4.4 7.0 ± 4.7 7.8 ± 5.6
PASP (mmHg) 26.1 ± 5.9 46.2 ± 12.8** 44.3 ± 12.4** 45.6 ± 12.4**
PADP (mmHg) 8.2 ± 3.3 17.5 ± 5.1** 16.9 ± 6.7** 17.5 ± 7.2**
mPAP (mmHg) 15.8 ± 4.1 31.6 ± 7.5** 30.3 ± 8.4** 30.5 ± 8.8**
PCWP (mmHg) 10.4 ± 3.2 18.5 ± 3.1** 14.8 ± 6.0** 17.3 ± 8.4
HR (beats/min) 50.3 ± 6.2 102.1 ± 2.5** 130.2 ± 4.1**† 149.0 ± 5.3**‡
Q (L⋅min-1) 3.8 ± 0.5 9.3 ± 1.4** 13.7 ± 1.5**† -
C (ml⋅mmHg-1) 4.5 ± 1.2 3.5 ± 1.0* 4.2 ± 1.3 -
PVR (dyn⋅s⋅cm-5) 114.6 ± 53.8 109.6 ± 46.4 91.6 ± 26.5 -
* P < 0.05: compared to rest ** P < 0.01: compared to rest † P < 0.05: 130 beats/min vs. 100 beats/min ‡ P < 0.01: 150 beats/min v. 130 beats/min
RAP, mean right atrial pressure; PASP, pulmonary artery systolic pressure; PADP, pulmonary artery diastolic pressure; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; HR, heart rate; Q, cardiac output; C, pulmonary arterial compliance; PVR, pulmonary vascular resistance.
59
Table 6: Systemic pressure, oxygen saturation and transpulmonary pressure gradients
Variable Rest Semi-Upright 100 beats/min 130 beats/min 150 beats/min
Systolic BP (mmHg)
132.8 ± 19.3 168.3 ± 17.0** 194.1 ± 26.1** 204.7 ± 23.0**
Diastolic BP (mmHg)
79.7 ± 5.5 81.9 ± 13.0 86.9 ± 19.2 83.8 ± 15.9
SaO2 99.4 ± 0.5 96.8 ± 4.5 96.7 ± 2.1* 95.5 ± 2.2**
SvO2 75.6 ± 4.9 42.6 ± 7.4** 38.4 ± 13.5** 29.7 ± 7.1**§
TPG (mmHg) 5.7 ± 1.8 13.1 ± 4.9** 15.6 ± 4.4**† 12.1 ± 6.4*
DPG (mmHg) -1.3 ± 2.1 -1.0 ± 3.2 2.2 ± 4.2 0.2 ± 4.9
* P < 0.05: compared to rest semi-upright ** P < 0.01: compared to rest semi-upright † P<0.05: 130 beats/min vs. 100 beats/min § P < 0.01: 150 beats/min vs. 100 beats/min
Systolic BP, systolic blood pressure; diastolic BP, diastolic blood pressure; SaO2, arterial oxygen saturation; SvO2, mixed venous oxygen saturation; TPG, transpulmonary pressure gradient; DPG, diastolic-to-wedge pressure gradient.
60
Table 7. Hemodynamic variables at exercise of 100 beats/min stratified by subjects with mPAP ≥ 30 and < 30 mmHg.
Exercise @ 100 beats/min
Variable mPAP ≥ 30 mmHg n = 7
mPAP < 30 mmHg n = 5 P value*
Age (years) 55.9 ± 6.1 53.0 ± 6.2 ns
mPAP (mmHg) 36.7 ± 5.0 24.4 ± 2.6 < 0.0033
PASP (mmHg) 54.4 ± 9.9 34.6 ± 4.1 < 0.0033
PADP (mmHg) 20.3 ± 4.8 13.6 ± 2.3 ns
PCWP (mmHg) 20.6 ± 1.3 15.6 ± 2.6 ns
SV (ml) 78.9 ± 8.7 73.0 ± 3.9 ns
TPG (mmHg) 16.1 ± 4.1 8.8 ± 1.5 < 0.0033
DPG (mmHg) -0.3 ± 4.0 -2.0 ± 1.6 ns
C (ml⋅mmHg-1) 3.0 ± 0.9 4.2 ± 0.8 ns
PVR (dyn⋅s⋅cm-5) 132.9 ± 50.9 81.7 ± 18.9 ns
Ea (mmHg⋅ml-1) 0.30 ± 0.12 0.17 ± 0.05 ns
Ees (mmHg⋅ml) 0.75 ± 0.46 0.48 ± 0.16 ns
Ea:Ees 0.48 ± 0.32 0.37 ± 0.10 ns
RV SWI (g/m2/beat) 17.3 ± 4.2 12.7 ± 2.1 ns
α (mmHg-1) 0.069 ± 0.008 0.099 ± 0.013 < 0.0033
* Bonferonni corrected P value = 0.0033
mPAP, mean pulmonary artery pressure; PASP, pulmonary artery systolic pressure; PADP, pulmonary artery diastolic pressure; PCWP, pulmonary capillary wedge pressure; SV, stroke volume; TPG, transpulmonary pressure gradient; DPG, diastolic-to-wedge pressure gradient; C, pulmonary arterial compliance; PVR, pulmonary vascular resistance; Ea, pulmonary arterial elastance; Ees, right ventricular end-systolic elastance; Ea:Ees, right ventricular-pulmonary arterial coupling ratio; RV SWI, right ventricular stroke work index; α, pulmonary resistive vessel distensibility index
61
3.3.6 Pressure – Flow Relationship
Linear regression of the pooled mPAP-Q data showed an average slope of 1.436
mmHg⋅min-1⋅L-1 with an intercept of 12.8 mmHg and a correlation coefficient R2 value of 0.40
(Figure 4). The average α for all subjects was calculated as 0.112 ± 0.048 mmHg-1, suggesting
an 11.2% change in the diameter of the resistive vessels per mmHg of mPAP. Baseline α (0.159
± 0.042) was significantly elevated compared to exercise at 100 (0.083 ± 0.019, P < 0.01) and
130 beats/min (0.092 ± 0.025, P <0.01)
Figure 4. Mean pulmonary artery pressure and cardiac output coordinates for each subject at rest supine, 100 and 130 beats/min. Linear equation of this relationship; y=1.436x + 12.8, R2=0.40. mPAP: mean pulmonary artery pressure.
62
3.3.7 Right Ventricular – Pulmonary Arterial Coupling
RV end-systolic elastance and pulmonary arterial elastance during exercise are shown in
Figure 5. Data are available from rest supine, 100 beats/min and 130 beats/min. The Ea:Ees
declined significantly from rest to 130 beats/min (0.72 ± 0.21 to 0.37 ± 0.10, P < 0.01).
Although Ea:Ees declined from rest to 100 beats/min (0.72 ± 0.21 to 0.44 ± 0.25), this change
was not statistically significant, nor was the decrease from 100 to 130 beats/min (Figure 6). This
decline in Ea:Ees was due to an increase in Ees from rest to 130 beats/min (0.26 ± 0.08 to 0.70 ±
0.30 mmHg⋅ml-1, P < 0.01), compared to a modest increase in Ea from baseline to 130 beats/min
(0.17 ± 0.04 to 0.23 ± 0.08 mmHg⋅ml-1, P < 0.05). No significant differences were observed in
Ea or Ees from 100 to 130 beats/min. RV SWI showed a similar pattern to Ees during exercise
with a significant increase from rest supine to 100 beats/min (5.00 ± 1.36 to 15.17 ± 4.06
g/m2/beat, P < 0.01), and a significant increase from rest to 130 beats/min (5.00 ± 1.36 to 19.27 ±
4.09 g/m2/beat, P < 0.01), but no significant difference between 100 and 130 beats/min (Figure
7). Figure 8 shows the relationship between Ea:Ees and mPAP to be curvilinear, with concavity
to the pressure axis. Figure 9 and 10 show the relationship between RV area index in diastole
and systole at rest supine and PASP at 150 beats/min.
63
Figure 5. Changes in right ventricular end-systolic elastance (Ees) and pulmonary arterial elastance (Ea) at rest supine and during exercise of 100 and 130 beats/min. Ees increased significantly from rest to 100 beats/min (P < 0.05) and was significantly increased at 130 beats/min compared to rest (P < 0.01). Ea displayed a similar trend increasing significantly from rest supine to 100 beats/min (P < 0.05) and was significantly increased at 130 beats/min compared to rest (P < 0.05). Neither variable was significantly different at 130 beats/min compared to 100 beats/min. * P < 0.05: compared to rest supine ** P < 0.01: compared to rest supine
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Rest Supine 100 beats/min 130 beats/min
mm
Hg⋅
ml-1
Ees
Ea
** *
* *
64
Figure 6. Right ventricular-pulmonary arterial coupling quantified as Ea:Ees at rest supine and during exercise of 100 and 130 beats/minute. Ea:Ees declined significantly from baseline to 130 beats/min (P < 0.01) due to a significant increase in Ees compared to Ea. The decline in Ea:Ees from baseline to 100 beats/min was not statistically significant.
** P < 0.01: compared to rest supine
Figure 7: Right ventricular stroke work index at rest supine and during exercise of 100 and 130 beats/minute.
** P < 0.01: compared to rest supine
0.0
0.2
0.4
0.6
0.8
1.0
Rest Supine 100 beats/min 130 beats/min
Ea:
Ees
**
0
10
20
30
Rest Supine 100 beats/min 130 beats/min
g/m
2 /bea
t
**
**
65
Figure 8. Relationship between the ratio of pulmonary arterial elastance and right ventricular end-systolic elastance (Ea:Ees) and mean pulmonary artery pressure (mPAP). The exponential regression trendline (y=0.674e-0.014x) approached statistical significance (P = 0.055). R2 = 0.11.
66
Figure 9. Relationship between pulmonary artery systolic pressure (PASP) at exercise of 150 beats/min and right ventricular (RV) diastolic area index at rest supine. PASP at 150 beats/min showed significant negative correlation with RV diastolic area at rest, r = -0.79, P < 0.01, n=11.
Figure 10. Relationship between pulmonary artery systolic pressure (PASP) at exercise of 150 beats/min and right ventricular (RV) systolic area index at rest supine. PASP at 150 beats/min showed significant negative correlation with RV systolic area at rest, r = -0.66, P < 0.05, n=11.
67
3.4 Discussion
To the best of our knowledge, this is the first study to characterize pulmonary pressures and RV-
PA coupling during exercise in long-standing EA using right heart catheterization. RV
dimensions and pulmonary pressures at rest were in the upper-high normal range and consistent
with previous studies of endurance-trained individuals [5, 17, 132]. We also report a finding of
pulmonary pressures during exercise that were elevated to an upper-high normal range, but not
considered to be excessive. This pressure response was contrary to our hypothesis and likely due
to the favourable RV-PA coupling and vascular mechanics that were observed during exercise.
These results suggest that long-standing EA have a pulmonary vasculature that is highly
compliant and well matched to the RV volume output during exercise.
3.4.1 Cardiac Morphology and Function
Our observation of enlarged RA and RV cavity size in EA is consistent with a considerable body
of literature describing cardiac remodeling in endurance-trained individuals [7, 10, 92, 147]. In
our population of EA, RV end-diastolic and end-systolic area was in the upper-high normal range
(mean, 95% confidence interval) of established American Society of Echocardiography (ASE)
values, but below upper reference values [59]. Linear dimensions of basal and mid-cavity RV
cavity size were also in the upper-high end of reference values and similar to those reported
previously [151]. The values we report for RV longitudinal diameter fall within established
normal values and lower than the mean for EA established by Oxborough et al. [152]. However,
we cannot discern whether this reflects a divergent pattern of RV remodeling in our older cohort
of EA or simply a bias of underestimating longitudinal diameter. Marked RA cavity dilation was
also observed, as the average area was above the upper reference value of RA end-systolic area
68
established by the ASE. Indices of systolic function were also consistent with previous
literature, as RV FAC and TAPSE were comparable to reference values for control individuals
[5].
Measures of left atrial and ventricular size were within normal limits of established reference
values of untrained individuals [49]. The ratio between ventricular septal and LV posterior free
wall thickness was 1.43 in our study population, which is above the criteria ratio of >1.3 for
confirming the presence of LV hypertrophy. However, pulsed-wave Doppler and tissue Doppler
indices of diastolic and systolic function were within normal limits, likely reflecting
physiological hypertrophy, as opposed to pathological [153]. Our findings suggest greater
relative RV structural changes compared to the LV and this is similar to observations in a
middle-aged cohort of athletes made by La Gerche et al. [17]. This contradicts previous MRI
findings that have involved younger athletes and warrants further attention.
Previous work has demonstrated that endurance training alters transmitral filling at rest
compared to controls with reductions in late filling (A) [154, 155], and augmentations in early
filling (E) [156, 157]. With increasing age, the mitral E velocity and E/A ratio decrease, whereas
DT and A velocity increase [158]. Our results suggest that long-standing endurance training may
attenuate the age-associated decrease in early filling as we observed resting global diastolic
function (E/A ratio of 1.5 ± 0.6) well within the normal range. Enlargement of the left and right
atria is a consistent finding in endurance trained individuals [8, 9] and was similarly observed in
our population, suggesting atrial remodeling with improved diastolic function.
69
3.4.2 Hemodynamic Measures
Previous non-invasive studies have demonstrated elevated pulmonary artery pressure in younger
(<40 years) EA at rest and during exercise compared to untrained controls. The proposed
mechanisms include a training-induced increase in stroke volume, an increase in left atrial
pressure, or a failure to adequately reduce pulmonary vascular resistance [16]. Our data are
consistent with previous findings demonstrating increased pulmonary pressures at rest in the
upper-high normal range compared to established normal values [13]. During submaximal
exercise, pulmonary pressures increased significantly during a low intensity exercise stage
corresponding to 25.2 ± 8.7 % of subject’s average maximal work rate (100 beats/min).
Contrary to our hypothesis and previous literature, no further increase in pulmonary pressure was
observed with increasing exercise intensity. Well-conditioned athletes in our study were capable
of reaching PASP > 50mmHg at a low exercise intensity, which is consistent with
echocardiographic studies reporting upper-reference values in this range, at higher exercise
intensities [15-17]. Our pressure measurements were recorded at consistent time intervals after a
steady-state heart rate was established, therefore creating stability in pressures when recordings
were made.
Our direct measures of pulmonary pressure from RHC overcome the inherent technical
limitations associated with ECHO-derived pressures and provide additional measures of PCWP
and PADP. Compared to established normal values, a slightly elevated PCWP at rest was
observed that might have contributed to the elevated PASP we observed at rest, since SV was in
the normal range. The resting bradycardia observed in our subjects likely contributed to the low
cardiac output seen at rest and as a result, PVR was elevated at rest, which may further explain
the slight elevation in PASP. At exercise of 130 beats/min, there was no further augmentation of
70
PCWP compared to the increase we observed at 100 beats/min, which may have played a
significant part in the plateau of PASP. Tedford et al. [159] demonstrated that elevations in
PCWP lower pulmonary vascular compliance, leading to augmentation of PASP and thus mPAP.
We observed the same effect as subjects transitioned from rest to exercise at 100 beats/min, as
PCWP significantly increased and pulmonary compliance decreased significantly. Interestingly,
at 130 beats/min, further changes were not observed for either PCWP or compliance. These
findings highlight the importance of PCWP on the pulsatile RV load and suggest a preservation
of compliance during exercise in EA, after an initial reduction at the onset of exercise. These
findings are in agreement with Tedford et al. [159] who reinforced the notion of a hyperbolic
dependence between resistance and compliance within the pulmonary circulation, and showed
that change in this relationship result from elevated PCWP, which augments right ventricular
pulsatile load.
The transpulmonary pressure gradient (TPG) has often been used for the detection of intrinsic
pulmonary vascular disease, with a cut off of 12 mmHg at rest as clinical criteria for concluding
out of proportion pulmonary hypertension (defined as a mPAP higher than expected from an
upstream transmission of PCPW secondary to intrinsic changes in vascular structure [105]).
That TPG at rest was well within normal limits and the significant increase that occurred with
exercise reflects an increase in both mPAP and PCWP. The utility of TPG has been challenged
however, and recommendations for the preferred use of diastolic-to-wedge gradient have been
made. We observed no significant difference in DPG between conditions and the negative
values we report may be explained by catheter artifact.
71
3.4.3 Pressure-Flow Relationship
Previous, non-invasive echocardiography studies that report absolute PASP measurements
without respect to changes in flow are limited in their interpretation, as pulmonary pressures are
flow-dependent. The acute pressure response to exercise is best described in relation to flow as
this also accounts for interindividual variability in peak exercise intensity. Our linear
approximation of the pulmonary vascular pressure-flow relationship revealed an average slope of
1.44 mmHg⋅min-1⋅L-1, demonstrating the flow-dependency of pulmonary pressures and a well-
preserved mPAP-Q slope in EA subjects. This value is below that reported by Argiento et al.
[103] in a range of healthy young to middle-aged adults, with a slope of 1.51 ± 0.54 mmHg⋅min-
1⋅L-1, and are in agreement with several previous studies yielding a reference range slope of 0.5
to 3 mmHg⋅min-1⋅L-1, with slope > 3 corresponding to a diagnosis of exercise-induced pulmonary
hypertension [110]. However, examination of this slope reveals concavity to the flow axis
reflecting pulmonary resistive vessels that become more distensible with increased flow [106].
Our data support this curvilinearity as we calculated an average distensibility index (α) of 0.112
± 0.048 mmHg-1, or an 11.2% change in resistive vessel diameter per mmHg increase in mPAP.
Argiento et al. [102] calculated a α of 0.017 ± 0.018 mmHg-1 in 25 healthy volunteers, and a α of
0.013 ± 0.010 mmHg-1 in 124 healthy volunteers, none of who were considered to be athletes.
Previous studies reveal a α of roughly 2 mmHg-1 in most mammalian species [106, 107]. To the
best of our understanding, the present study is the first to calculate a distensibility index in EA
and our data suggests training increases the capacity for a decrease in pulmonary vascular
resistance with exercise. The high degree of distensibility within the resistive vessels of the
pulmonary vasculature in EA may help accommodate the increase in blood flow during exercise
to prevent excessive pressurization. This α value is on the upper-end of values modeled by
72
Naeije et al. [110], but interestingly we observed an almost 50% decrease in α from rest to
exercise (0.159 ± 0.042 to 0.083 ± 0.019 mmHg-1), similar to that observed by Argiento et al.
[103], reflecting a decrease in vascular compliance with increased distending pressure.
The change in pulmonary vascular compliance during exercise appears to reflect changes
within the smaller pulmonary resistive vessels, as opposed to the large pulmonary artery. The
distensibility index (α) represents changes in pulmonary resistive arteriole compliance that is
likely due to both mechanical properties of arterial wall elasticity and endothelial-dependent
vasodilation associated with increases in shear stress with increased blood flow. The high α
value we calculated suggests that EA have an increased capacity for decreasing resistance within
the smaller resistance arterioles, which function to control blood pressure with vascular smooth
muscle cellular activity, and where much of the resistance to flow occurs. In contrast, the large
pulmonary artery serves to transport the pressure energy and momentum of blood, which is
reflected by compliance (SV/(PASP-PADP)). In our EA population, compliance showed a
significant decrease at exercise of 100 beats/min, followed by a slight elevation at 130 beats/min
that was not statistically significant. From these two measures, it appears that small vessel
compliance changes are the more important mechanism in EA that may contribute to
accommodating increased blood flow and maintenance of pulmonary pressures during exercise.
3.4.4 Right-Ventricular – Pulmonary Arterial Coupling
Our combined echocardiography and catheterization measures provide novel data on the
coupling between right ventricular pump function and pulmonary vascular mechanics in EA.
The significant decline in Ea:Ees from rest to exercise at 130 beats/min indicates favourable RV-
PA coupling during exercise that may explain the stabilization of pulmonary pressures with
increasing exercise intensity beyond 100 beats/min. Previous employment of Ea:Ees analysis
73
has been limited to disease populations in resting state. Sanz et al. [127] observed a significantly
greater Ea:Ees ratio in individuals with pulmonary hypertension compared to controls (median
1.26 vs. 0.37) and Latus et al. [124] observed an elevated Ea:Ees ratio (2.99 ± 2.77) at rest in
tetralogy of Fallot patients with significant RV volume overload. RV-PA coupling has also
previously been described as the ratio of Ees-to-Ea, with an optimal ratio ≈ 1.5, allowing for flow
output at a minimal amount of energy cost [128]. Though we report RV-PA coupling as an
Ea:Ees ratio, when expressing our data as Ees:Ea, the average ratio at rest was 1.60 ± 0.66,
indicating optimal coupling in our study population.
Our observation of a significant reduction in Ea:Ees from rest to exercise at 130 beats/min was
due to a significant increase in RV contractility, as measured by Ees, compared to a significant
but modest absolute increase in pulmonary arterial elastance from rest to exercise at 130
beats/min. A key observation was that Ea showed relatively no change from exercise at 100
beats/min to 130 beats/min (0.47 ± 0.25 to 0.46 ± 0.17 mmHg/ml/), despite a significant increase
in stroke volume, which may explain the plateau in PASP, PADP, mPAP that occurred
throughout increasing exercise intensity. Taken together, the significant increase in Ees and
decline in Ea:Ees indicate favourable RV-PA coupling in EA during acute exercise.
The adaptations to long-standing endurance exercise training appear to induce a compliant
pulmonary vasculature that is well matched in mechanics and accommodation to increases in
blood flow during exercise. Further support of this association is shown by the high negative
correlation between PASP at 150 beats/min and RV diastolic area index at rest (Figure 9). This
is contrary to our hypothesis and challenges the assertion that augmented RV size is associated
with disproportionate increases in pulmonary artery systolic pressure during exercise. From
74
these data, it appears that exercise training may lead to well-matched adaptation of the
pulmonary circulation.
3.4.5 Clinical Implications
Exercise-induced pulmonary arterial hypertension has been defined as mPAP > 30 mmHg during
exercise. Naeije et al. [110] expanded on this criterion, defining it as an exercise-induced
increase in mPAP greater than 30 mmHg at a Q less than 10 L⋅min-1. It was estimated by Kovacs
et al. [13] that nearly half of subjects aged > 50 years would develop mPAP > 30 mmHg during
slight exercise. This is congruent with our data as we observed 7 subjects with mPAP ≥ 30
mmHg during exercise at 100 beats/min, 4 of whom had a cardiac output less than 10 L⋅min-1
(Table 7). Interestingly, none of these 4 subjects showed any further increase in mPAP with
increased exercise intensity, despite an increase in cardiac output, yet all tended to have a higher
mPAP at rest than those subjects with mPAP < 30 mmHg at 100 beats/min. The difference
between groups in Table 7 appears to be partially mediated by differences in pulmonary vascular
mechanics, as individuals with mPAP ≥ 30 mmHg had a significantly decreased distensibility
index. Furthermore, these individuals also had a higher PCWP, which is transmitted upstream
and likely contributed to the increase in PVR and decrease in compliance within this group.
Aside from mechanisms related to pulmonary vascular mechanics, individuals with mPAP ≥ 30
mmHg also had higher systemic systolic blood pressure, although this was not statistically
significantly, potentially due to the small sample size within groups. This observation is of
importance however and suggests that endurance athletes with higher pulmonary pressures
during exercise may also have a higher systemic blood pressure response to exercise. Thus the
mechanisms involved in the vascular response to exercise may be similar with the systemic and
pulmonary circulations. This may have important clinical implications as exaggerated systolic
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blood pressure during maximal exercise defined as 210 mmHg or greater, has been found to be a
future predictor of hypertension and cardiovascular mortality [160].
In addition, attaining a PASP > 40 mmHg during exercise is considered abnormal [161, 162]. In
our subject population, 8 subjects reached a PASP ≥ 40 mmHg at 100 beats/min. Are these
individuals ‘abnormal’? We would suggest these subjects are physiologically-adapted,
particularly given a reduction in Ea:Ees from rest to exercise at 100 beats/min, and a high α value
at rest and exercise. These data suggest that the criteria for exercise-induced pulmonary
hypertension may not be applicable in EA individuals, as they appear to undergo RV remodeling
that is associated with favourable mechanical adaptations within the pulmonary vasculature
during exercise. Therefore, a further broadening of the criteria used to define a pathological
response to exercise is warranted.
3.4.6 Limitations
Our study is not without limitations. We did not include an age-matched control group of
untrained individuals, which limits our interpretation of the effects of long-standing endurance
training on the acute pulmonary pressure response to exercise and the observed RV-PA coupling.
Instead, our comparisons were made against previous literature involving younger cohorts of
trained and untrained individuals. Despite this limitation, our mPAP-Q results were within
normal physiological ranges and showed similar trends to untrained individuals, but with
favourable increases. Due to limitations with cardiac output determinations from continuous
thermodilution, echocardiographic measures were used to determine cardiac output during
exercise; imaging quality was not reliable beyond exercise at 130 beats/min, limiting the mPAP-
Q relationship and RV-PA coupling data to this level of exercise. Although Q estimated from
LVOT diameter and LVOTvti tends to underestimate cardiac output [163], an overestimation
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would cause the mPAP-Q slope to decrease and α to increase, and therefore the improved
measures we observed in EA are likely true physiological adaptations and not the result of an
overestimated cardiac output. Finally, MRI remains the gold standard for assessing RV
morphology. Our echocardiography measures were limited to linear dimensions and cavity areas
and likely underestimates MRI-derived RV volumes [164]. Estimation of RV end-systolic
volume for the calculation of RV end-systolic elastance was made by assuming that the RV area
during end-diastole and end-systole are representative of volume without a change in geometric
shape of the RV from diastole to systole, and we used a conversion factor to account for the
assumption that LV and RV stroke volume were the same in the absence of pulmonary shunting
(stroke volume/(RV diastolic area index - RV systolic area index)) and then multiplied to RV
diastolic area index and RV systolic area index to estimate respective volumes. These
assumptions rely on accurate determinations of RV area and although they do not permit
comparison to RV volumes derived from MRI, they are useful for observing the relative changes
from rest to exercise within our subject population.
A further limitation to our results and interpretation of pulmonary mechanics is the lack of lung
volume measurements in our subjects. Lung volume has shown to have drastic effects on
pulmonary vascular resistance, as the change in volume from residual capacity to total capacity
can increase by as much as 2-3 times [165]. Functional residual capacity is the volume of the
lung at the end of normal exhalation after a normal tidal volume and represents the lung volume
in which total pulmonary vascular resistance is at its lowest point. Both increases and decreases
in lung volume away from residual capacity cause an increase in pulmonary vascular resistance
by different mechanisms, creating a U-shape relationship between lung volume and pulmonary
vascular resistance [166]. An increase in lung volume would cause an increase in alveolar
compression of small intra-alveolar vessels causing an increase in small vessel pulmonary
77
vascular resistance. Whether lung volume in our subject population had any influence on
pulmonary mechanics is unknown and whether this had any effect in individuals with mPAP ≥
30 mmHg at exercise of 100 beats/min is worth questioning.
3.4.7 Conclusion
Long-standing endurance exercise training is associated with RV dimensions and pulmonary
pressures at rest that fall within the upper-high normal range. During exercise, a significant
increase in pulmonary pressures was observed at low exercise intensity, with no further increases
in pressure, despite an increase in exercise intensity and stroke volume. This response to acute
exercise appears to be mediated by a well-preserved mPAP-Q slope and a high degree of
distensibility within the pulmonary resistive vessels. Furthermore, RV-PA coupling becomes
favourable for RV function during exercise in EA suggesting a pulmonary vasculature that
becomes well adapted to accommodate increases in RV stroke work during exercise.
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Chapter 4 General Discussion, Future Perspectives and Conclusions
4
4.1 Study Limitations
4.1.1 Study Design and Subject Population
We conducted both study visits within two weeks as to avoid any potential de-training or hyper-
training that could potentially occur within a short period of time. Although we designed the
study in this fashion, we had no control over the amount of training that subjects performed
between visits, though most reported a level that was consistent with their training prior to be
involved in the study. Subjects performed a single maximal exercise test and many were
unfamiliar with the equipment and nature of the test. Though VO2peak was not a primary
endpoint measure, reported values may have been increased had subjects been re-tested after an
initial familiarization test.
Our age range for participation was selected to include a population with accumulated endurance
exercise training of at least 20 years. Thus, 45 years was set as our lower age limit to achieve
this criterion, and 65 as our upper age limit to yield a demographic following accepted
definitions of middle-aged [167, 168]. Since targeted heart rates were used to define exercise
intensity during our catheterization exercise protocol, this age gap likely had a significant effect
on the maximal heart rate elicited during exercise. Heart rate was used as an exercise intensity
rather than work rate so that comparable R-R intervals (and hemodynamic loading) occurred
when intracardiac pressures were measured. This also provided the advantage of creating
ventricular filling and ejection times that were similar, apart from between-subject differences in
79
diastolic filling and systolic ejection times. Our eventual selection of intensity defined by
absolute heart rate was also influenced by future endeavours to compare athletic populations to
untrained individuals where comparable R-R intervals would be advantageous, rather than
absolute work rate. However, for the purpose of the current study, these heart rate intensities
meant that older subjects were exercising at a higher relative intensity, closer to their peak heart
rate, than our younger subjects.
4.1.2 Catheterization and Hemodynamic Measures
We chose to perform the right-heart catheterization via the arm as this approach was considered
to be the safest and most ethical approach to performing an invasive procedure on a healthy
subject population. Access through the arm rather than the larger internal jugular vein or femoral
approach minimizes the already low risk of damaging major vascular structures. Also, access
through the arm permits the least complications in having subject’s exercise while catheterized.
Although this approach has been well described and performed previously, we had 6 subjects
that we were unable to successfully cannulate due to obstructive valve structures or tortuous vein
architecture.
The pressure measurements reported are computer-generated averages over a specific timeframe
identified as a ‘snapshot’. The computer software discerns systolic and diastolic pressures as
high and low points and a- and v-waveforms of RA and PCWP from the corresponding ECG
tracing. Though our reported measures were acquired during steady state exercise, large
variations in intrathoracic pressure occur with increased respiratory volume, creating a sinusoid
pattern of pulmonary pressures. Due to the difficulty in discerning end-expiratory pressures, our
reported pressures are averages taken over a time period which may include several end-
expiratory and end-inspiratory time points, particularly at high exercise intensities when
80
breathing rate is increased. Thus, true end-expiratory PASP may be elevated compared to our
reported values. However, a slight underestimation of PASP would have no effect on measures
of RV-PA coupling from rest to exercise since PASP is used in the equation of both Ea and Ees.
Therefore our absolute values of Ea and Ees may be slightly underestimated compared to Ea and
Ees at end-expiratory, but the within-subject effect that was observed would remain unchanged.
4.1.3 Echocardiography
There are inherent limitations associated with ECHO derived measures that must be
acknowledged, particularly for the assessment of the RV. Our measures of mPAP-Q relationship
and RV-PA coupling are highly dependent on accurate volume assessments, in which MRI
remains the gold standard. Our use of 2D and pulsed-wave Doppler has shown clinical utility and
accuracy but exercise volumes should be further validated with 3D ECHO.
It is important to acknowledge that our measures of cardiac output at rest and during exercise
were acquired in different postures. Resting cardiac output was measured in the supine position,
and exercise cardiac output in the semi-upright position after subjects underwent a passive
change in posture (head-up tilt to 45°). A sudden change in posture evoked by active standing
induces several physiological responses, as there is a rapid parasympathetic withdrawal, leading
to an almost immediate increase in heart rate. The sympathetic response to gravitational stimulus
occurs over a longer time period but results in a decreased venous return. The change in posture
for our subjects occurred gradually as to ensure the subject’s arm and distal catheter was not
disturbed. The slower change in orthostatic stress that occurred as our subjects went from supine
to semi-upright, may explain why we observed only a slight increase in heart rate (50.3 ± 6.2 to
53.7 ± 6.8 beats/min) and systemic blood pressure (systolic; 127.4 ± 17.0 to 132.8 ± 19.3 mmHg,
diastolic; 75.8 ± 5.8 to 79.7 ± 5.5 mmHg).
81
Kovacs et al. [13] concluded that resting pulmonary pressures are slightly influenced by posture
(supine versus upright), though we observed no significant differences in any pressure
measurement in supine versus semi-upright. Typically, Q in the supine position exceeds upright
values, however the values we report were lower than values reported in healthy individuals
measured by RHC. This may be a product of our ECHO derived Q and may explain why PVR
was higher at rest than data from previous studies. However, our observation of a low Q at rest
is unlikely to have any significant effect on the linear slope of mPAP-Q coordinates in EA as an
underestimation of Q would likely persist when measured during exercise. Furthermore, the
relationship between mPAP and Q has shown to be independent of body position due to
increases in Q, associated with full recruitment of the pulmonary circulation [102]. Thus, it is
unlikely there were any postural effects on our observed pressure response during acute
submaximal exercise.
4.2 Future Perspectives
As stated previously, data from several investigators has shown elevated pulmonary pressures in
endurance-trained individuals at rest and during exercise. These studies have involved younger
cohorts with a predominantly male population. Our study is limited in that we do not have an
age-matched control group in which comparisons can be made, and future work in this regard is
warranted for two reasons: firstly, it would provide data on the influence of long-standing
exercise training on the acute pulmonary artery pressure response to exercise versus an untrained
population, or those engaged in only moderate amounts of exercise. Secondly, it would provide
important information on the age-related changes in RV morphology and pulmonary artery
pressure. D’Andrea et al. [5] demonstrated that RV basal diameter and RA area were
significantly associated with advanced age. We report values of these two measures that are
82
above established reference values, however without a control group, we can not conclude if
these differences are the product of aging, training, or a combination of both. It has also been
demonstrated that mPAP is significantly higher in subjects aged ≥ 50 years, with a similar trend
persisting during exercise [13]. Furthermore, subjects aged > 50 years have shown to have a
slightly higher resting PVR compared to subjects aged ≤ 50 years [14].
We demonstrated the utility of a rather novel method of quantifying right-ventricular pulmonary
arterial coupling with RHC and ECHO indices in EA. Previous work employing this
methodology has involved subject populations including pulmonary hypertension and Tetralogy
of Fallot. While these studies have included control groups, further work is needed to establish
normal values for these measures at rest and during acute exercise. Additionally, our study
population was limited to males given the sex differences that have been associated with
cardiovascular aging [169] and the greater prevalence of males competing in endurance events
[145]. Sex hormones play a role in the disparate cardiac remodeling that occurs with aging
between sexes, as females exhibit concentric remodeling, while males display a more eccentric
pattern of remodeling [170], but whether these remodeling phenotypes have any dissimilar
effects on RV-PA coupling is unknown. To this end, the study of females may offer insights
about the factors contributing to abnormal hemodynamic responses to exercise stress in the
absence of significant cardiac remodeling [171, 172].
In an attempt to dissociate exercise-induced adaptations in RV function from RV pathology,
recent work from La Gerche and colleagues has established an appreciable insight in to the role
that exercise training plays on RV function [17, 66, 173]. During exercise, pulmonary pressures,
wall stress, RV stroke work, perfusion, and contractility all increase. This creates an ideal
condition to assess RV function in EA as greater demands in work are required, and potential
83
functional limitations become more apparent. However, this assessment proved to be
challenging. The difficulty in imaging the RV with ECHO becomes further intensified with
exercise, which La Gerche et al. [66] reported when attempting to obtaining strain and strain rate
at high exercise intensities. Our ECHO parameters of RV function are limited to resting
measures, however our combined ECHO and RHC measures provide a unique measure of RV
function in addition to pulmonary arterial load. The refinement of ECHO methodology in
combination with RHC measures for the assessment of RV function during exercise is paramount
for establishing normal values in EA and across other demographics.
4.3 Study Conclusions
To the best of our knowledge, this is the first study to describe the acute pulmonary pressure
response to aerobic exercise in a population of longstanding EA using right-heart catheterization.
We confirm our first hypothesis of RV remodeling in EA, as we observed RA cavity dilation and
RV area and linear dimensions in the upper high reference range, and consistent with previous
echocardiography studies of endurance individuals. We also observed normal systolic function at
rest in EA as measured by RV FAC and TAPSE, which has been previously reported. These
results suggest that long-standing endurance training is associated with RV remodeling coupled
with normal function that is comparable to younger cohorts of trained individuals. Our second
hypothesis stated that long-standing EA would have elevated pulmonary artery pressures at rest
and during exercise compared to establish normal values, and correlated to RV size. While we
observed pulmonary pressures at rest that are considered to be in the upper-high normal range,
we can only speculate this to be a consequence of training, as age-associated increases in
pulmonary pressures may be partly responsible. However, we reject our hypothesis that
pulmonary pressures are exaggerated in EA during exercise, as there was no significant increase
84
in any pressure variable after the initial onset of exercise. Most notably, we reject our hypothesis
that pulmonary pressures during exercise are correlated to right ventricular size as we expected a
positive association between RV diastolic area index at rest and PASP at 150 beats/min, but
rather a significant negative correlation existed, where individuals with the largest RV diastolic
area at rest had lower PASP at 150 beats/min. Thirdly, we hypothesized that EA would
demonstrate a greater increase in mPAP relative to the increase in cardiac output during
submaximal exercise, reflected by the slope of mPAP-Q coordinates. With an observed slope of
1.436 mmHg⋅min-1⋅L-1, we reject this hypothesis and conclude that EA have a well-preserved
slope that falls within physiological normal range. This suggests training is also associated with
the adaptive capacity to decrease pulmonary vascular resistance with increased flow, further
supported by the high average α value we report, indicating a high distensibility within the
pulmonary resistive vessels of highly-trained endurance athletes.
Evidence supporting our conclusions comes from novel RV-PA coupling data showing a decline
in Ea:Ees from baseline to exercise at 130 beats/min. This response favours RV function and
therefore suggests that the RV may actually become ‘unloaded’ during exercise, relative to the
pulmonary arterial load. This is contrary to our hypotheses and the conclusion of previous
studies, but may explain the plateau in pulmonary pressures with increasing exercise intensity.
To conclude, the pulmonary vasculature in EA appears to be well adapted to accommodate
increases in flow, and is associated with favourable RV-PA coupling during exercise.
85
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Appendices
Appendix 1. Recruitment Poster
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Appendix 2. Written Informed Consent Form
Version 2.1 Page 1 of 9 10-OCT-2012
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Title Right heart hemodynamics and atrial phasic function during
exercise: the influence of chronic endurance training Investigator Dr. Jack Goodman (T) 416-978-6095 Co-Investigators Dr. Susanna Mak, Dr. Filipe Fusch, Taylor Gray, Steve
Wright Introduction You are being asked to take part in a research study. Please read this explanation about the study and its risks and benefits before you decide if you would like to take part. You should take as much time as you need to make your decision. You should ask the study doctor or study staff to explain anything that you do not understand and make sure that all of your questions have been answered before signing this consent form. Before you make your decision, feel free to talk about this study with anyone you wish. Participation in this study is voluntary. Background It is becoming increasingly recognized that cardiac enlargement is associated with longstanding athletic training. The heart is a muscular pump consisting of four hollow chambers: 2 atrial chambers (which receive blood returning from the body and the lungs), and 2 ventricles (which send blood away from the heart). Highly trained endurance athletes exhibit altered cardiac function at rest, driven by increased stroke volumes (the volume of blood pumped from one ventricle during each heart beat), and reduced heart rate. This effect is exaggerated during submaximal exercise, where increased stroke volumes can largely be explained by an increase in volume within the ventricles at the end of the diastole (the period of time when the heart is filling with blood). This increase in volume of blood stretches the wall of the ventricle causing the cardiac muscle contract more forcefully, a mechanism known as the Frank-Starling mechanism. Altered function of the atria may be responsible for the improved diastolic filling of the ventricles during exercise; however, in the right heart, increased ventricular stroke volume may cause an increase in lung artery pressure that is greater in trained athletes. The lung artery carries blood from the right ventricle to the lungs to become oxygenated. This study is designed to examine the effect of exercise on atrial function and lung pressures and the influence of long term endurance training on the cardiac response to exercise.
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Purpose The purposes of this study is to examine the effect of short-duration submaximal exercise on atrial, right ventricular, and pulmonary function in untrained and highly trained males; and to observe the influence of long-term endurance training on cardiac and pulmonary function at rest and during submaximal exercise. You have been asked to take part in this research study because you have expressed an interest in furthering the understanding of the training differences in heart function. There are 2 groups we wish to enroll, both involving males between the ages of 45-65 years, with 12 participants in each group The first group includes men with a long-standing history of competitive endurance exercise training. The second group includes recreationally active individuals, not training for or competing in endurance events. You will undergo the same tests and measures regardless of which group you are in. Study Design In order for us to understand the mechanisms responsible for the behavior of the heart in highly trained and recreationally trained men we must be able to accurately assess the pressures inside your heart at rest and during exercise. The current experiment is an observational study using a cross-sectional design. There will be 2 visits during this study, with the first visit taking approximately 1 hour, and the second approximately 3 hours. The 2 visits will take place within one week of each other. Study Visits and Procedures Visit 1: Screening/Baseline During the screening/baseline visit, you will meet with one of our graduate students involved with this study who will show you the laboratory space and explain the research procedures during each visit. Your height, weight, heart rate, seated blood pressure, and anthropometrics will be measured. These procedures are part of the standard-of-care with research of this nature. Additionally, a Physical Activity Readiness Questionnaire and Lifetime Total Physical Activity Questionnaire will be completed, which is done soley for the purpose of this study to examine your exercise history. You may refuse to answer any questions asked. The results of the tests/questions at the screening visit help the researchers to decide whether you can continue in this study. You will then be familiarized with a cycle ergometer used to determine your maximal oxygen consumption (VO2max). Once accustomed to the cycle, you will be equipped with a Polar heart rate monitor and a mouthpiece/headset attached to a metabolic cart. A maximal exercise test will then be performed using standard lab protocol, and the metabolic cart will measure breath-by-breath recordings of gas volumes and concentrations. The exercise protocol is designed to take no longer than 15 minutes and the total duration of this visit will be approximately 1 hour. The results of this test will be used to establish the workload during the exercise protocol used in Visit 2.
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Visit 2: Cardiac Assessment The second visit will take place at the Clinical Cardiovascular Research Laboratory of Mount Sinai Hospital and will involve insertion of a right-heart catheter (RHC). When you arrive on the morning of the study visit, we will need to place a sheath (a hollow plastic tube with a one-way valve) in your arm vein to allow us to measure the pressures on the right sided pumping chamber of the heart. The pressure measurement is often done in patients with heart failure but in your case it is to allow us to obtain accurate pressures inside your heart. Usually it is performed by placement of a catheter (a long, thin hollow plastic tube that can measure pressure) into the right side of your heart and also into the large lung blood vessels. This test is mostly performed from a large vein of the leg (femoral vein) or the neck (internal jugular vein) following administration of local anesthetic or freezing because these are relatively large blood vessels and relatively easy to access. However, in this study it is performed through the arm under direct ultrasound guidance because of the lower risk of injury to major arteries and nerves. We will place an ultrasound probe on your arm and this will help us identify the precise location of the vein. We have already safely used this approach in a safety study of 10 patients prior to commencing this study. We will also insert a small cannula (plastic tube) into your radial (wrist) artery, which will allow us to continuously and accurately measure your blood pressure throughout the study. Similar to the venous sheath insertion, we will freeze the skin before inserting the cannula. You may feel some discomfort during this procedure. You will then undergo a short but detailed ultrasound (pictures taken using sound waves) assessment of your heart, which will allow us to measure the function of your heart. This initial setup process with pressure measurement, wrist monitor, and echocardiogram may take up to 1-1.5 hours. With you lying on your back in a semi-supine position (shown in figure below), you will be fitted to a specialized bed-bicycle, which consists of a separate ergometer/bike and a computer display that contains preset and customizable exercise protocols, in which workload is increased in stages. To maintain cadence (rhythm) during exercise, the computer has a light indicator which indicates whether you are pedaling too fast or too slow to produce the desired workload.
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During exercise, you will be monitored continuously by 12 lead electrocardiogram (ECG). In this test patches attached by wires to a machine will be put on your chest, so that the machine can record the pattern of your heart beats. In some cases we may need to trim or shave your body hair. We will also monitor your heart and lung pressures, blood pressure as well as heart ultrasound for measurement of heart volumes and function. The test will be stopped if you notice fatigue, any chest pain, or shortness of breath. The test will also be stopped if there is a fall in your blood pressure of more than 10 mm Hg from baseline or if your blood pressure is less than 90 mm Hg. The study protocol will consist of 5 stages, including a resting stage, a 2-minute warm-up stage, and three 5-minute stages of submaximal exercise at step-wise increasing intensities based on achieving a heart rate of 100, 130 and 150 beats per minute. In each of the resting and submaximal exercise stages, following 2-minutes to achieve steady state, data collection will begin. Intracardiac and pulmonary pressures will be acquired from the the catheter located in your heart. Echocardiographic assessment will be performed by a trained sonographer. The risk for healthy volunteers is minimal. Among a large series of subjects without known disease, there were approximately < 1 to 5 serious complications (including heart attack or other events requiring hospitalization) and 0.5 deaths for every 10,000 tests performed. As stated, during each of these stages we will obtain readings from your heart, the arterial line as well as information from brief echocardiographic assessments. You will not feel any discomfort during these measurements. Overall, this entire visit duration is expected to last 2-3 hours from start to finish. If at any stage of the study you feel unwell or would like us to stop, then please let us know and no further test will be performed and we will remove all lines. Once the exercise protocol is complete, all lines will be removed. Once all lines are removed (arm vein sheath and the wrist cannula) and you have had a chance to rest and ask any questions about the procedures, you are free to leave. You will be given ample time to review these procedures to make sure you understand what is involved before we commence the study procedure. Calendar of Visits Boxes marked with an X show what will happen at each visit:
Visit Questionnaire Exercise ECG Ultrasound Catheterization Time
Screening/Baseline X X 1 hour
Cardiac Assessment X X X X 3 hours
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Reminders It is important to remember the following things during this study:
• You should not consume any food, caffeine or alcohol after 9 pm on the night before your study visits (12 hours prior to visit)
• Do not take medications before visits • No prolonged exercise on day before study visits • Tell study staff anything about your health that has changed • Tell your study team if you change your mind about being in this study
Risks Related to Being in the Study There are risks associated with this study. We will take every precaution to ensure that the risk you are exposed to and development of any possible adverse event are minimized. During Visit 2 we will use ultrasound and fluoroscopy guidance to ensure that we will obtain venous access as quickly and safely as possible. If in the instance that we cannot successfully access your arm vein on 3 attempts (including an attempt on your other arm), we will stop the study and you will still be remunerated for your time even though we won’t be proceeding with the other study procedures. There are no additional risks to pressure measurements from the arm approach. The risk of local bruising is similar to RHC from the neck or the leg. The risk of blood clots and bleeding are less than 1% and are more easily managed than those arising from the leg or the neck. The risk of nerve damage, and catheter related infection is rare and less than 1%.
The risk related to pressure measurement is minimal with no serious complications arising since commencement of this practice at our Catheterization Laboratory. Extra-systoles (extra heart beats) occur frequently, but do not cause significant consequences and are fully reversible by withdrawing the catheter. Risks related to exercise is also very low. In the case of undiagnosed coronary artery disease, you may notice chest discomfort during exercise and there may be electrocardiographic abnormalities that we can detect on the monitor. In such circumstances, we will stop the exercise and let you recover. You will be excluded from further participation but you will be reimbursed for the $250.00 In addition, appropriate and timely further investigations will be arranged for you to further assess your symptoms and to rule out any underlying coronary artery disease you may have. You may feel some local discomfort when we administer freezing to your wrist before we insert a small sheath inside your wrist (radial) artery, which will help us continuously monitor your blood pressure during the research procedure. Once the sheath is in you will not feel any further discomfort. There may be local bruising that develops where the sheath was inserted. The risk associated with causing damage to the wrist artery and bleeding is rare at about 1%.
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Fluoroscopy (or x-rays) may be used to guide RHC placement if we have difficulty placing the RHC into the lung blood vessels. We expect that fluoroscopy use will be minimal as in most cases the RHC will float into the lung blood vessels quite easily. If we have to use fluoroscopy, you will be exposed to minimal amounts of radiation of less than 1 millisievert (mSv) equivalent to less than a third of the background radiation dose you are exposed to in a year (3mSv) or less radiation than you would receive on a transatlantic commercial airplane flight.
Please feel free to notify the study investigators during the procedure at any time you feel unwell or if you experience any discomfort (chest pain, palpitations or shortness of breath). If for any reason we feel that you should not proceed further with the research study because of development of symptoms or an unexpected reaction, you will still be remunerated $250.00 for your travel and time for this study visit. We do not expect to find any abnormal findings with RHC and exercise challenges. In the rare instance that abnormal findings are found, for example, the discovery of high lung pressures or abnormal heart function, we will disclose these findings to you and will arrange timely appropriate follow-up for any abnormal findings. The investigators of this study are all cardiologists who are trained in further investigations and management of any abnormal cardiac findings. There will be no cost to you as a result of tests required for the follow-up of any abnormal/incidental findings. We will also relay any abnormal findings to your family physician.
Benefits to Being in the Study You will not receive any direct benefit from being in this study. Information learned from this study may help further our understanding of the effect of acute submaximal exercise on atrial, right ventricular, and pulmonary function and the influence of chronic endurance exercise on these responses.
Voluntary Participation Your participation in this study is voluntary. You may decide not to be in this study, or to be in the study now and then change your mind later. You may leave the study at any time without affecting your future care. You may refuse to answer any question you do not want to answer, or not answer an interview question by saying “pass”. We will give you new information that is learned during the study that might affect your decision to stay in the study. Alternatives to Being in the Study You do not have to join this research study if you do not wish.
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Confidentiality If you agree to join this study, the study doctor and his/her study team will look at your personal health information and collect only the information they need for the study. Personal health information is any information that could be used to identify you and includes your:
• name, • address, • date of birth, • new or existing medical records, that includes types, dates and results of medical
tests or procedures. The information that is collected for the study will be kept in a locked and secure area by the study doctor for 7 years. Only the study team or the people or groups listed below will be allowed to look at your records. Your participation in this study also may be recorded in your medical record at this hospital. Representatives of the Mount Sinai Hospital Research Ethics Board may look at the study records and at your personal health information to check that the information collected for the study is correct and to make sure the study followed proper laws and guidelines. All information collected during this study, including your personal health information, will be kept confidential and will not be shared with anyone outside the study unless required by law. You will not be named in any reports, publications, or presentations that may come from this study. If you decide to leave the study, the information about you that was collected before you left the study will still be used. No new information will be collected without your permission. In Case You Are Harmed in the Study If you become ill, injured or harmed as a result of taking part in this study, you will receive care. The reasonable costs of such care will be covered for any injury, illness or harm that is directly a result of being in this study. In no way does signing this consent form waive your legal rights nor does it relieve the investigators, sponsors or involved institutions from their legal and professional responsibilities. You do not give up any of your legal rights by signing this consent form.
Expenses Associated with Participating in the Study
You will not have to pay for any of the procedures involved with this study. You will be reimbursed $250.00 for transportation and time upon completion of both study visits. If you wish to voluntarily withdraw from the study at any point and for any reason after completion of Visit 1, you will receive $25.00 remuneration for your time. Should you experience an adverse response during Visit 1 (ex. injury) that prevents you from completing the visits, you will receive $25.00 but no further compensation. If you must involuntarily
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withdraw during Visit 2 (ie. if a vein cannot be successfully cannulated), you will be entitled to full compensation ($250.00). Conflict of Interest All of the people involved with this study have an interest in completing this study. Their interests should not influence your decision to participate in this study. You should not feel pressured to join this study. Questions About the Study
If you have any questions, concerns or would like to speak to the study team for any reason, please call: Dr. Jack Goodman at 416-978-6095 If you have any questions about your rights as a research participant or have concerns about this study, call Ronald Heslegrave, Ph. D., Chair of the Mount Sinai Hospital Research Ethics Board (REB) or the Research Ethics office number at 416-586-4875. The REB is a group of people who oversee the ethical conduct of research studies.These people are not part of the study team. Everything that you discuss will be kept confidential.
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Consent This study has been explained to me and any questions I had have been answered. I know that I may leave the study at any time. I agree to take part in this study. Print Study Participant’s Name Signature Date (You will be given a signed copy of this consent form) My signature means that I have explained the study to the participant named above. I have answered all questions.. Print Name of Person Obtaining Consent Signature Date Was the participant assisted during the consent process? YES NO If YES, please check the relevant box and complete the signature space below:
The person signing below acted as a translator for the participant during the consent process and attests that the study as set out in this form was accurately translated and has had any questions answered. Print Name of Translator Signature Date Relationship to Participant Language
The consent form was read to the participant. The person signing below attests that the study as set out in this form was accurately explained to, and has had any questions answered.
Print Name of Witness Signature Date Relationship to Participant
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Appendix 3. Physical Activity Readiness Questionnaire (PAR-Q+)
PAR-Q+The Physical Activity Readiness Questionnaire for Everyone
Regular physical activity is fun and healthy, and more people should become more physically active every day of the week. Being more physically active is very safe for MOST people. This questionnaire will tell you whether it is necessary for you to seek further advice from your doctor OR a quali!ed exercise professional before becoming more physically active.
YES NOPlease read the 7 questions below carefully and answer each one honestly: check YES or NO.
1) Has your doctor ever said that you have a heart condition OR high blood pressure?
4) Have you ever been diagnosed with another chronic medical condition (other than heart disease or high blood pressure)?
5) Are you currently taking prescribed medications for a chronic medical condition?
7) Has your doctor ever said that you should only do medically supervised physical activity?
2) Do you feel pain in your chest at rest, during your daily activities of living, OR when you do physical activity?
3) Do you lose balance because of dizziness OR have you lost consciousness in the last 12 months? Please answer NO if your dizziness was associated with over-breathing (including during vigorous exercise).
6) Do you have a bone or joint problem that could be made worse by becoming more physically active? Please answer NO if you had a joint problem in the past, but it does not limit your current ability to be physically active. For example, knee, ankle, shoulder or other.
GENERAL HEALTH QUESTIONS
Start becoming much more physically active – start slowly and build up gradually.
Follow Canada’s Physical Activity Guidelines for your age (www.csep.ca/guidelines).
You may take part in a health and !tness appraisal.
If you have any further questions, contact a quali!ed exercise professional such as a Canadian Society for Exercise Physiology - Certi!ed Exercise Physiologist® (CSEP-CEP) or a CSEP Certi!ed Personal Trainer® (CSEP-CPT).
If you are over the age of 45 yr and NOT accustomed to regular vigorous to maximal e"ort exercise, consult a quali!ed exercise professional (CSEP-CEP) before engaging in this intensity of activity.
If you answered NO to all of the questions above, you are cleared for physical activity.Go to Page 4 to sign the PARTICIPANT DECLARATION. You do not need to complete Pages 2 and 3.
If you answered YES to one or more of the questions above, COMPLETE PAGES 2 AND 3.
Delay becoming more active if:You are not feeling well because of a temporary illness such as a cold or fever - wait until you feel better
You are pregnant - talk to your health care practitioner, your physician, a quali!ed exercise professional, and/or complete the ePARmed-X+ at www.eparmedx.com before becoming more physically active
Your health changes - answer the questions on Pages 2 and 3 of this document and/or talk to your doctor or quali!ed exercise professional (CSEP-CEP or CSEP-CPT) before continuing with any physical activity program.
Copyright © 2011 PAR-Q+ Collaboration 1 / 401-11-2011
111
1. Do you have Arthritis, Osteoporosis, or Back Problems?
1a. Do you have di!culty controlling your condition with medications or other physician-prescribed therapies? (Answer NO if you are not currently taking medications or other treatments)
1b. Do you have joint problems causing pain, a recent fracture or fracture caused by osteoporosis or cancer, displaced vertebra (e.g., spondylolisthesis), and/or spondylolysis/pars defect (a crack in the bony ring on the back of the spinal column)?
1c. Have you had steroid injections or taken steroid tablets regularly for more than 3 months?
If the above condition(s) is/are present, answer questions 1a-1c If NO go to question 2
2. Do you have Cancer of any kind?If the above condition(s) is/are present, answer questions 2a-2b
3. Do you have Heart Disease or Cardiovascular Disease? This includes Coronary Artery Disease, High Blood Pressure, Heart Failure, Diagnosed Abnormality of Heart Rhythm
If the above condition(s) is/are present, answer questions 3a-3e
If the above condition(s) is/are present, answer questions 4a-4c4. Do you have any Metabolic Conditions? This includes Type 1 Diabetes, Type 2 Diabetes, Pre-Diabetes
5. Do you have any Mental Health Problems or Learning Di!culties? This includes Alzheimer’s, Dementia, Depression, Anxiety Disorder, Eating Disorder, Psychotic Disorder, Intellectual Disability, Down Syndrome)
If the above condition(s) is/are present, answer questions 5a-5b
If NO go to question 3
If NO go to question 4
If NO go to question 5
If NO go to question 6
2a. Does your cancer diagnosis include any of the following types: lung/bronchogenic, multiple myeloma (cancer of plasma cells), head, and neck?
2b. Are you currently receiving cancer therapy (such as chemotheraphy or radiotherapy)?
3a. Do you have di!culty controlling your condition with medications or other physician-prescribed therapies? (Answer NO if you are not currently taking medications or other treatments)
3b. Do you have an irregular heart beat that requires medical management? (e.g., atrial "brillation, premature ventricular contraction)
3c. Do you have chronic heart failure?
3d. Do you have a resting blood pressure equal to or greater than 160/90 mmHg with or without medication? (Answer YES if you do not know your resting blood pressure)
3e. Do you have diagnosed coronary artery (cardiovascular) disease and have not participated in regular physical activity in the last 2 months?
4a. Is your blood sugar often above 13.0 mmol/L? (Answer YES if you are not sure)
4b. Do you have any signs or symptoms of diabetes complications such as heart or vascular disease and/or complications a#ecting your eyes, kidneys, and the sensation in your toes and feet?
4c. Do you have other metabolic conditions (such as thyroid disorders, pregnancy-related diabetes, chronic kidney disease, liver problems)?
5a. Do you have di!culty controlling your condition with medications or other physician-prescribed therapies? (Answer NO if you are not currently taking medications or other treatments)
5b. Do you ALSO have back problems a#ecting nerves or muscles?
PAR-Q+YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
FOLLOW-UP QUESTIONS ABOUT YOUR MEDICAL CONDITION(S)
YES NO
YES NO
YES NO
Copyright © 2011 PAR-Q+ Collaboration 2 / 401-11-2011
112
If the above condition(s) is/are present, answer questions 6a-6d
If the above condition(s) is/are present, answer questions 7a-7c
If the above condition(s) is/are present, answer questions 8a-8c
If you have other medical conditions, answer questions 9a-9c
If NO go to question 7
If NO go to question 8
If NO go to question 9
If NO read the Page 4 recommendations
PAR-Q+
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
YES NO
Copyright © 2011 PAR-Q+ Collaboration 3 / 4
GO to Page 4 for recommendations about your current medical condition(s) and sign the PARTICIPANT DECLARATION.
6. Do you have a Respiratory Disease? This includes Chronic Obstructive Pulmonary Disease, Asthma, Pulmonary High Blood Pressure
6a. Do you have di!culty controlling your condition with medications or other physician-prescribed therapies? (Answer NO if you are not currently taking medications or other treatments)
6b. Has your doctor ever said your blood oxygen level is low at rest or during exercise and/or that you require supplemental oxygen therapy?
6c. If asthmatic, do you currently have symptoms of chest tightness, wheezing, laboured breathing, consistent cough (more than 2 days/week), or have you used your rescue medication more than twice in the last week?
6d. Has your doctor ever said you have high blood pressure in the blood vessels of your lungs?
7. Do you have a Spinal Cord Injury? This includes Tetraplegia and Paraplegia
7a. Do you have di!culty controlling your condition with medications or other physician-prescribed therapies? (Answer NO if you are not currently taking medications or other treatments)
7b. Do you commonly exhibit low resting blood pressure signi"cant enough to cause dizziness, light-headedness, and/or fainting?
7c. Has your physician indicated that you exhibit sudden bouts of high blood pressure (known as Autonomic Dysre#exia)?
8. Have you had a Stroke? This includes Transient Ischemic Attack (TIA) or Cerebrovascular Event
8a. Do you have di!culty controlling your condition with medications or other physician-prescribed therapies? (Answer NO if you are not currently taking medications or other treatments)
8b. Do you have any impairment in walking or mobility?
8c. Have you experienced a stroke or impairment in nerves or muscles in the past 6 months?
9. Do you have any other medical condition not listed above or do you have two or more medical conditions?
9a. Have you experienced a blackout, fainted, or lost consciousness as a result of a head injury within the last 12 months OR have you had a diagnosed concussion within the last 12 months?
9b. Do you have a medical condition that is not listed (such as epilepsy, neurological conditions, kidney problems)?
9c. Do you currently live with two or more medical conditions?
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PAR-Q+
PARTICIPANT DECLARATION
NAME ____________________________________________________
SIGNATURE ________________________________________________
SIGNATURE OF PARENT/GUARDIAN/CARE PROVIDER ____________________________________________________________________
DATE _________________________________________
WITNESS ______________________________________
Copyright © 2011 PAR-Q+ Collaboration 4 / 4
For more information, please contact
Key References
www.eparmedx.com or Canadian Society for Exercise Physiology
www.csep.ca
1. Jamnik VJ, Warburton DER, Makarski J, McKenzie DC, Shephard RJ, Stone J, and Gledhill N. Enhancing the e!ectiveness of clearance for physical activity participation; background and overall process. APNM 36(S1):S3-S13, 2011.2. Warburton DER, Gledhill N, Jamnik VK, Bredin SSD, McKenzie DC, Stone J, Charlesworth S, and Shephard RJ. Evidence-based risk assessment and recommendations for physical activity clearance; Consensus Document. APNM36(S1):S266-s298, 2011.
Citation for PAR-Q+Warburton DER, Jamnik VK, Bredin SSD, and Gledhill N on behalf of the PAR-Q+ Collaboration.The Physical Activity Readiness Questionnaire (PAR-Q+) and Electronic Physical ActivityReadiness Medical Examination (ePARmed-X+). Health & Fitness Journal of Canada 4(2):3-23, 2011.
If you answered NO to all of the follow-up questions about your medical condition, you are ready to become more physically active - sign the PARTICIPANT DECLARATION below:
If you answered YES to one or more of the follow-up questions about your medical condition: You should seek further information before becoming more physically active or engaging in a "tness appraisal. You should complete the specially designed online screening and exercise recommendations program - the ePARmed-X+ at www.eparmedx.com and/or visit a quali"ed exercise professional (CSEP-CEP) to work through the ePARmed-X+ and for further information.
It is advised that you consult a quali"ed exercise professional (e.g., a CSEP-CEP or CSEP-CPT) to help you develop a safe and e!ective physical activity plan to meet your health needs.
You are encouraged to start slowly and build up gradually - 20-60 min of low to moderate intensity exercise, 3-5 days per week including aerobic and muscle strengthening exercises.
As you progress, you should aim to accumulate 150 minutes or more of moderate intensity physical activity per week.
If you are over the age of 45 yr and NOT accustomed to regular vigorous to maximal e!ort exercise, consult a quali"ed exercise professional (CSEP-CEP) before engaging in this intensity of activity.
Please read and sign the declaration below:
If you are less than the legal age required for consent or require the assent of a care provider, your parent, guardian or care provider must also sign this form.
I, the undersigned, have read, understood to my full satisfaction and completed this questionnaire. I acknowledge that this physical activity clearance is valid for a maximum of 12 months from the date it is completed and becomes invalid if my condition changes. I also acknowledge that a Trustee (such as my employer, community/!tness centre, health care provider, or other designate) may retain a copy of this form for their records. In these instances, the Trustee will be required to adhere to local, national, and international guidelines regarding the storage of personal health information ensuring that they maintain the privacy of the information and do not misuse or wrongfully disclose such information.
Delay becoming more active if:
You are not feeling well because of a temporary illness such as a cold or fever - wait until you feel better
You are pregnant - talk to your health care practitioner, your physician, a quali"ed exercise professional, and/or complete the ePARmed-X+ at www.eparmedx.com before becoming more physically active
Your health changes - talk to your doctor or quali"ed exercise professional (CSEP-CEP) before continuing with any physical activity program.
You are encouraged to photocopy the PAR-Q+. You must use the entire questionnaire and NO changes are permitted.The PAR-Q+ Collaboration, the Canadian Society for Exercise Physiology, and their agents assume no liability for persons who undertake physical activity. If in doubt after completing the questionnaire, consult your doctor prior to physical activity.
The PAR-Q+ was created using the evidence-based AGREE process (1) by the PAR-Q+ Collaboration chaired by Dr. Darren E. R. Warburton with Dr. Norman Gledhill, Dr. Veronica Jamnik, and Dr. Donald C. McKenzie (2). Production of this document has been made possible through "nancial contributions from the Public Health Agency of Canada and the BC Ministry of Health Services. The views expressed herein do not necessarily represent the views of the Public Health Agency of Canada or BC Ministry of Health Services.
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Appendix 4. Lifetime Total Physical Activity Questionnaire
! 1
The Lifetime Total Physical Activity Questionnaire
Friedenreich, C. M., K. S. Courneya, et al. (1998). The lifetime total physical activity questionnaire: development and reliability. Med Sci Sports Exerc 30(2): 266-274.
The next section will be about your physical activity patterns over your lifetime. Specifically, I will be asking you about your occupational, household and exercise/sports activities. Occupational Activities Starting with your occupational activities, please tell me what jobs (paid or volunteer) that you have done at least 8 hours a week for four months of the year over your lifetime. We will start with your first job and end with the job that you had in your reference year. Please describe the job that you had, the age that you started working at this job and the age when you ended doing this particular job. For each job we also need to know the number of years, the number of months per year, the number of days per week, the number of hours per day and the intensity of the job. No. Description of Occupational
Activity Age Started
Age Ended
No. of months/year
No. of days/week
Time per day Intensity of Activity (1,2,3,4)* Hours Minutes
* Intensity of occupational activity defined as 1 = jobs that require only sitting with minimal walking 2 = jobs that require a minimal amount of physical effort such as standing and slow walking with no increase in heart rate and no perspiration 3 = jobs that require carrying light loads (5-10 lbs), continuous walking, mainly indoor activity that would increase the heart rate slightly and cause light perspiration 4 = jobs that require carrying heavy loads (>10 lbs), brisk walking, climbing, maily outdoor activity, that increase the heart rate substantially and cause heavy sweating
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! 2
Household Activities
Now I am going to ask you to report what household and gardening activities that you have done over your lifetime. Again, we will start with your past activity and then continue up to your reference year. Please include only those activities that you have done at least 7 hours per week for 4 months of the year. It may help you to consider what a typical day is for you. Then think about how many hours of household and gardening or yard work you do in a typical day. For seasonal activities, such as gardening, you can report those separately from all other household activities that are done all year.
No. Age Started
Age Ended
No. of months/year
No. of days/week Time per day
Hours per day spent in activities that were in category:*
Hours Minutes 2 3 4
* Intensity of household activity defined as 1 = activities that can be done while sitting 2 = activities that require minimal effort such as those done standing, sitting or with slow walking, that do not require much physical effort 3 = activities that are not exhausting, that increase the heart rate slightly and that may cause some light perspiration 4 = activities that increase the heart rate and cause heavy sweating such as those requiring lifting, moving heavy objects, rubbing vigorously for fairly long periods
! !
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! 3
Exercise/Sports Activities
Now I would like to know all your exercise or sports activities that you did during your lifetime starting with childhood and continuing to your reference year. Please report the activities that you have done at least2 hours per week for at least 4 months of the year. Please tell us what exercise and sports activities you have done at least 10 times during your lifetime. Besides sports and exercise, we are also interested in knowing whether you walked or biked to work. If you have done this, please report all the information as for the other sports activities. Please begin by telling me the activities that you did during your school years including your physical education (gym) classes.
No. Description of Exercise/Sports Activity
Age Started
Age Ended Frequency of
Activity Time/Day
Intensity of Leisure Activity (2, 3 or 4)*
Day
Wee
k
Mon
th
Yea
r
Hours Minutes 2 3 4
* Intensity of exercise/sports activity defined as 1 = activities that are done sitting 2 = activities that require minimal effort 3 = activities that are not exhausting, that increase the heart rate slightly and that may cause some light perspiration 4 = activities that increase the heart rate and cause heavy sweating
117
! 4
ESTIMATION OF OUTCOME VARIABLES
a) Average number of hours per week spent in occupational activity over lifetime = Equation 1A. The average number of hours per week spent in occupational activity over a lifetime was estimated separately for sedentary, light, moderate, and heavy occupational activity.
Equation 1A:
b) Average number of hours per week spent in household activity over lifetime = Equation 1B. Average number of hours per week spent in household activity over lifetime was estimated separately for light, moderate, and heavy household activity.
Equation 1B
c) Average number of hours per week spent in exercise/sports activities over lifetime =
If respondent reported per day: Equation 1C
118
! 5
If respondent reported per week: Equation 1D
If respondent reported per month: Equation 1E
If respondent reported per year: Equation 1F
119
Appendix 5. Case Report Form
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 1 of 8 Nov 13, 2012
CASE REPORT FORM
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE
REB #: 12-0171-A
STUDY SITE: Mt. Sinai Hospital/University of Toronto
PRINCIPAL INVESTIGATOR: Jack Goodman CO-INVESTIGATORS: Susanna Mak Taylor Gray Steve Wright
Subject Initials:
Subject Study Group:
Subject Number:
I am confident that the information supplied in this case record form is complete and accurate data. I confirm that the study was conducted in accordance with the protocol and any protocol amendments and that written informed consent was obtained prior to
the study.
Investigator’s Signature:
Date of Signature: ________________________ DD/MM/YYY
120
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 2 of 8 Nov 13, 2012
Inclusion Criteria: Yes No
1. Subject is a healthy male between the ages of 45-65 years
2. Has subject willing given written informed Consent
3. For RT subjects a. Subject is recreationally active in regular mild-to-
moderate aerobic exercise no more than 4 days per week
a. b. c. d.
e. f.
b. Subject has no experience in prolonged activities of aerobic competition in the past 5 years
4. For ET subjects a. Minimum 20 years participation in year-round
intensive endurance exercise b. c.
Exclusion Criteria: Yes No
1. Prior diagnosis of any of the following a. Coronary artery disease
b. Cardiomyopathy
c. Significant valvular disease
d. Ventricular or supraventricular arrhythmias
e. Hypertension
f. Heart failure
g. Diabetes
h. Current or chronic illness
2. Use of any cardioactive drugs
3. BMI > 25 kg/m2
4. Current smoker
5. Recreational drug use
6. Excessive alcohol consumption (>2 drinks/day)
7. History or diagnosis of sleep disorders and/or sleep apnea
121
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 3 of 8 Nov 13, 2012
Visit 1: Screening/Baseline Date: __________________
DD/MM/YYY Demographic Data
Age (yrs): _______ Height (cm): ________ Weight (kg): __________ Body Mass Index: (BMI = (weight [kg])/ (height [m])2: ___________ Resting blood pressure: __________ Resting heart rate (bpm): __________
Body Composition: Bioelectrical Impedance Analysis E: ________ I : _________ T: ________ L: _________ % Body Fat _______ �
� Questionnaires Yes No Par-Q+ Completed ������ Lifetime Total Physical Activity Questionnaire Completed ������������
122
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 4 of 8 Nov 13, 2012
Maximal Exercise Test
Measurement* Rest* Max*Predicted*Max*
%*Predicted*Max*
Work%(Watts)% %% %% %% %%Heart%Rate% %% %% %% %%VO2%(ml/min)% %% %% %% %%VO2/kg%(ml/kg/min)% %% %% %% %%%% %% %% %% %%Minute%Ventilation%(L/min)% %% %% %% %%FVC%(Forced%vital%capacity)% %% %% %% %%PEF%(Peak%expiratory%flow)%% %% %% %% %%Tidal%volume% %% %% %% %%Respiratory%Rate% %% %% %% %%RER% %% %% %% %%
Estimated Workrate to Achieved Desired HR During Visit 2 Exercise Protocol
Heart Rate Estimated Workrate (W)
100 bpm
130 bpm
150 bpm
123
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 5 of 8 Nov 13, 2012
Visit 2: Catheterization Date: __________________ DD/MM/YYYY
Protocol*Conditions* Rest%(supine)%
Rest**(semiGsupine)%
100bpm*Exercise*
130*bpm*Exercise*
150*bpm*Exercise*
Vitals* %%SBP% %% %% %% %% %%DBP% %% %% %% %% %%MAP% %% %% %% %% %%Heart%Rate% %% %% %% %% %%
Exercise*Protocol* %%Work%Rate%(Watts)% %% %% %% %% %%Time%Commenced% %% %% %% %% %%
RHC* %%mRA%pressure% %% %% %% %% %%mRV%pressure% %% %% %% %% %%PASP% %% %% %% %% %%PADP% %% %% %% %% %%mPAP% %% %% %% %% %%CO%(Thermodilution)% %% %% %% %% %%CO%(NICOM)% %% %% %% %% %%Cardiac%Index%
(Thermodilution)% %% %% %% %% %%PVR%% %% %% %% %% %%mPCWP% %% %% %% %% %%SvO2% % % % % %Pulse%oximeter%O2%sat.%% % % % % %
Echocardiography* %%Chamber*Size* %%RV%mid%cavity%diameter% %% %% %% %% %%RV%basal%diameter% %% %% %% %% %%RV%longitudinal%diameter% %% %% %% %% %%RVOT%proximal%diameter% %% %% %% %% %%RVOT%distal%diameter% %% %% %% %% %%RV%subcostal%wall%
thickness% %% %% %% %% %%RV%FAC% %% %% %% %% %%3D%RV%EDV%indexed%
(mL/m^2)% %% %% %% %% %%% %% %% %% %% %%
124
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 6 of 8 Nov 13, 2012
3D%RV%ESV%indexed%(mL/m^2)%LA%maximal%volume%
% % % % %LA%preGcontraction%volume%
% % % % %LA%minimal%volume%% % % % %
125
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 7 of 8 Nov 13, 2012
!
! %%Rest*(supine)%
Rest%%(semiGsupine)%
100bpm*Exercise%
130*bpm*Exercise%
150*bpm*Exercise%
Hemodynamic*Assessment*
%
TRV%%
% % % %IVC%diameter%
%% % % %
RV*Function* %2D%peak%strain%
rate%at%the%base%% %%%
%% %% %%2D%peak%strain%
rate%at%the%mid%cavity%% %%
%
%% %% %%2D%peak%strain%
rate%at%the%apex%% %%%
%% %% %%2D%peak%strain%at%
the%base%% %%%
%% %% %%2D%peak%strain%at%
the%mid%cavity% %%%
%% %% %%2D%peak%strain%at%
the%apex%%% %%%
%% %% %%Global%peak%strain%
rate%%
%
% % %Global%peak%strain%%%
%% % %LA*Function% %
2D%peak%positive%strain%
%
%
% % %2D%peak%negative%strain%
%
%
% % %2D%total%strain%%
%% % %2D%early%diastolic%
strain%rate%%
%
% % %2D%late%diastolic%strain%rate%
%
%
% % %2D%systolic%strain%rate%
%
%
% % %Peak%AVP%displacement%(Lat)%
%
%
% % %Peak%AVP%displacement%(Sept)%
%
%
% % %% % % % % %
126
RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
Version 1.2 Page 8 of 8 Nov 13, 2012
Peak%AVP%displacement%(Inf)%
%
%
% % %Mitral*Function*(PW*Doppler)%
%
%
% % %EGwave%velocity%%
%% % %AGwave%velocity%
%%
% % %E/A%Ratio%%
%% % %IVRT%
%%
% % %EGwave%deceleration%time%
%
%
% % %% %
%% % %
127
Appendix 6. Right-Heart Catheterization Technical Protocol
June 13, 2013
R. Heart Hemo & Atr. Phasic Funct. – Technical Protocol Version 3.4
1 Right Heart Hemodynamics and Left Atrial Phasic Function During Exercise:
The Influence of Chronic Endurance Training Purpose: To examine the hemodynamic and echocardiographic response to incremental semi-supine cycling exercise. Hypotheses: Exercise will elicit an increase in pulmonary artery pressure associated with right heart cardiac output. Atrial filling will be acutely improved related to atrioventricular plane displacement. Equipment: • Ergoselect table • 5-lead ECG • Non-invasive BP monitor • 8-Fr venous sheath • 0.035-145 cm Long J-wire with 1.5mm J • 18g X 1 1/2” Seldinger needle (Argon) • Tourniquet (Sarstedt) • 1x Swan sleeve, omit if patient very tall • 2x Right Heart kits • 2x COBE stopcocks • 1x 500cc heparin flush bags • 2x fluid administration sets • 2x flush devices • 4x NICOM stickers • Swan-Ganz CCOmbo Volumetrics PA catheter (CO, SvO2, RAP, PAP) • Vigilance II SvO2/CCO monitor • Sterile towel drapes for left antecubital fossa • Site-rite portable ultrasound (Site-rite 5, Bard); sterile and non-sterile U/S gel • NICOM Non-invasive cardiac output monitor and electrodes • Tango BP monitor • Non-invasive pulse oximetry finger probe or disposable finger sensor • Blood tubes: 2 Lavender top Preparation: • Prepare flush line/pressure bag for the RA and PA ports • Place 500 cc bag of NS in heater over night • Synchronize clocks (GE/Vigilance/NICOM/Tango) • Cover Ergo Select with sheet • Place handle on left side to drive table • Prepare blood tubes for the following conditions:
- baseline Hgb/Hct - post procedure Hgb/Hct
128
June 13, 2013
R. Heart Hemo & Atr. Phasic Funct. – Technical Protocol Version 3.4
2 Measures: • Hematocrit (Hct) • Hemoglobin (Hb) • Plasma volume (PV) • Blood pressure (Systolic, Diastolic, MAP) • RA, PA (Systolic, Diastolic, Mean), PAWP (a-wave, v-wave) • CO (CCOmbo continuous thermo; NICOM) • SV/SvO2/RV EF (CCOmbo) • SpO2 (Non-invasive pulse oximetry – finger probe) • Echocardiographic Images In Cath Lab Bay
• Subject arrives at cath lab following 12hr fasting • 12 lead ECG completed • Subject weighed • Start IV • Baseline Echo in the Bay Procedure: • Subject lies supine on cath table • Fully drape subject • Use good technique to apply ECG electrodes, prepping with sandpaper and alcohol swab • Apply electrodes anteriorly with (2) RA (2) LA (2) LL (1) RL and (1) ground • BP cuff around patient’s right arm • Place Site-Rite on left side of table and Vigilance II on right side of table (will need
to be moved after subject is transferred to Ergoselect) • Clip transducers on Right side of table • Place Ergoselect out of the way on right side of table • Notify Joan to come to cath lab in 15min
o Prep and drape left anticubital access o Apply tourniquet loosely o Tighten tourniquet o Anesthetize site with local anesthesia o Prep ultrasound head with transducer jelly o Cannulate vein and advance 8-Fr sheath as per routine
• Position Swan-Ganz catheter and connect PA line to transducer • Monitor PA port while subject is transferred from bed to Ergoselect • Bring Ergoselect adjacent to cath table • Transfer subject to Ergoselect • Move the Ergoselect away from cath table • Move the Vigilance II monitor and place the Vivid machine beside the Ergoselect • Attach electrical ports to Vigilance II monitor and calibrate using in vivo
instructions. o If Unit fails to calibrate, use baseline PA Sat and Hgb from sample sent
pre-procedure o Slave ECG into Vigilance using phono to phono cable from back of
Vigilance to top of Defibrillator
129
June 13, 2013
R. Heart Hemo & Atr. Phasic Funct. – Technical Protocol Version 3.4
3 • Place BP Tango cuff on opposite arm from Swan. Import ECG by slaving from T
connector beneath cath lab table • Move arm-table and board to left side of Ergoselect • Connect RA and PA to transducers and set up flush • Secure RA/PA ports to medial side of black arm board • Electrodes for NICOM placed anteriorly – make sure left inferior doesn’t obstruct
apical window • Assign someone to annotate NICOM machine Student responsibilities: Sam will adjust resistance on the bike, initiate Tango BP recordings and chart NICOM CO and Tango measurements Steve or delegate will print out snapshot of Vigilance and write arterial saturation and exercise stage on it Steve or delegate will annotate exercise stage on NICOM at the beginning of each stage Taylor will hydrate the subject
130
June 13, 2013
R. Heart Hemo & Atr. Phasic Funct. – Technical Protocol Version 3.4
4 Research Protocol:
TIME (min.sec)
REST - ACTION
0.00 Change phase to Rest – Semi-upright Incline table to 45’ and annotate on NICOM
0.00 Start timer when all equipment calibrated and sonographer happy with her window
0.30 Sonographer to begin image acquisition
3.50 Record RA/PA
4.00 Record Wedge Pressure Print off CCO snapshot and write SaO2 from Maclab on printout Record SBP/DBP/MAP/HR Record NICOM CO Blood draw – mixed Venous sample
4.10 Conclude resting semi upright measures
TIME (min.sec)
EXERCISE - ACTION
0.00 Change phase to Exercise Stage 1 and annotate on NICOM Commence Exercise Stage 1 – Increasing WR to 100bpm and annotate on NICOM
1.50 Record RA/PA 2.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP/MAP/HR Record NICOM CO
3.00 Change phase to Exercise Stage 2 Commence Exercise Stage 2 - Steady State @ 100bpm and annotate on NICOM
3.00 Joan begins image acquisition 6.50 Record RA/PA 7.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP/MAP/HR Record NICOM CO
8.00 Conclude exercise Stage 2 when sonographer finished
0.00 Change phase to Exercise Stage 3
Commence Exercise Stage 3 – Increasing WR to 130bpm and annotate on NICOM 1.50 Record RA/PA 2.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP/MAP/HR Record NICOM CO
3.00 Change phase to Exercise Stage 4 Commence Exercise Stage 4 - Steady State @ 130bpm and annotate on NICOM
3.00 Joan begins image acquisition 6.50 Record RA/PA 7.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP/MAP/HR Record NICOM CO
8.00 Conclude exercise Stage 4 when sonographer finished
131
June 13, 2013
R. Heart Hemo & Atr. Phasic Funct. – Technical Protocol Version 3.4
5
0.00 Change phase to Hysteresis
0.00 Commence Hysteresis Stage Decreasing WR to and annotate on NICOM 1.50 Record RA/PA
2.00 Record Wedge Pressure
Print off CCO snapshot and write SaO2 from Maclab on printout Record SBP/DBP/MAP/HR Record NICOM CO
0.00 Change phase to Exercise Stage 5 Commence Exercise Stage 5 – Increasing WR to 150bpm and annotate on NICOM
1.50 Record RA/PA 2.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP/MAP/HR Record NICOM CO
3.00 Change phase to Exercise Stage 6 Commence Exercise Stage 6 - Steady State @ 150bpm and annotate on NICOM
3.00 Joan begins image acquisition 6.50 Record RA/PA 7.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP/MAP/HR Record NICOM CO
7.10 Conclude Study when sonographer finished - Cool down 25W
Mass Pre: _____kg Mass Post: _____kg
• Remove Swan-Ganz catheter • Draw post–exercise Hct from side arm of sheath • Transfer subject to recovery area and remove #8-Fr Sheath • Weigh subject post-exercise, dry and without electrodes PRIOR to rehydrating • Discharge from Cath Lab
132
June 13, 2013
R. Heart Hemo & Atr. Phasic Funct. – Technical Protocol Version 3.4
6
MEASUREMENTS
TIME (min.sec)
EXERCISE - ACTION
0.00 Change phase to Exercise Stage 1 Commence Exercise Stage 1 – Increasing WR to 100bpm and annotate on NICOM
1.50 Record RA/PA 2.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP __________ HR _____ SpO2 _____ Record NICOM CO __________ WR _____
3.00 Change phase to Exercise Stage 2 Commence Exercise Stage 2 - Steady State @ 100bpm and annotate on NICOM
3.00 Joan begins image acquisition 6.50 Record RA/PA 7.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP __________ HR _____ SpO2 _____ Record NICOM CO __________ WR _____
0.00 Change phase to Exercise Stage 3 Commence Exercise Stage 3 – Increasing WR to 130bpm and annotate on NICOM
1.50 Record RA/PA 2.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP __________ HR _____ SpO2 _____ Record NICOM CO __________ WR _____
3.00 Change phase to Exercise Stage 4 Commence Exercise Stage 4 - Steady State @ 130bpm and annotate on NICOM
3.00 Joan begins image acquisition 6.50 Record RA/PA 7.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP __________ HR _____ SpO2 _____ Record NICOM CO __________ WR _____
0.00 Change phase to Hysteresis Commence Hysteresis Stage – decreasing WR and annotate on NICOM
1.50 Record RA/PA 2.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP __________ HR _____ SpO2 _____ Record NICOM CO __________ WR _____
0.00 Change phase to Exercise Stage 5 Commence Exercise Stage 5 – Increasing WR to 150bpm and annotate on NICOM
1.50 Record RA/PA 2.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP __________ HR _____ SpO2 _____ Record NICOM CO __________ WR _____
3.00 Change phase to Exercise Stage 6 Commence Exercise Stage 6 - Steady State @ 150bpm and annotate on NICOM
3.00 Joan begins image acquisition 6.50 Record RA/PA 7.00 Record Wedge Pressure, Print off CCO snapshot with SaO2, Record SpO2
Record SBP/DBP __________ HR _____ SpO2 _____ Record NICOM CO __________ WR _____
7.10 Conclude Study - Cool down 25W
133
Copyright Acknowledgements
The following figures in the supplemental review of literature were reproduced from previously
published work. Copyright permissions were obtained from the respective publishers.
Figure 1 was reproduced from:
Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ, Redfield MM. Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation 2009: 119(20): 2663-2670. Reproduced with permission from © Wolters Kluwer Health.
Figure 2 was reproduced from:
Bossone E, Rubenfire M, Bach DS, Ricciardi M, Armstrong WF. Range of tricuspid regurgitation velocity at rest and during exercise in normal adult men: implications for the diagnosis of pulmonary hypertension. J Am Coll Cardiol 1999: 33(6): 1662-1666. Reproduced with permission from © Elsevier.
