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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
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.
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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
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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 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.
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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.
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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
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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).
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Table 5: Hemodynamic data at rest and during exercise
* 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
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
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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.
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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.
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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
** *
* *
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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
**
**
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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.
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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.
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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
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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.
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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
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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.
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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
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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.
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
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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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Version 2.0 Page 2 of 9 22-AUG-2012
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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Version 2.0 Page 3 of 9 22-AUG-2012
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
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.
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)
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?
01-11-2011
113
PAR-Q+
PARTICIPANT DECLARATION
NAME ____________________________________________________
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.
01-11-2011
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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
115
! 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
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! 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
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! 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
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RIGHT HEART HEMODYNAMICS AND ATRIAL FUNCTION DURING EXERCISE: The influence of chronic endurance exercise Case Report Form Subject No. _____
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
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June 13, 2013
R. Heart Hemo & Atr. Phasic Funct. – Technical Protocol Version 3.4
• 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
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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
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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
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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
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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
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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.