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ONLINE APPENDIX
Approach to Utilizing CPET in Heart Failure Patients
Historically, challenges to performing CPET have included the need for specialized equipment
(i.e. a metabolic cart), long metabolic cart “warm-up” times, the need to perform routine
equipment calibration, and the lack of standardized lab accreditation and staff competency
assessment. In addition, the lack of formal training of health professionals in CPET interpretation
limits the comfort level of physicians in interpreting gas exchange patterns. Fortunately, modern
metabolic carts that measure gas exchange from expired breaths during exercise are now widely
commercially available, calibrate in minutes, and have software systems that facilitate pattern
recognition. Furthermore, the physiologic and prognostic significance of gas exchange patterns
has come into clearer focus through a growing body of work in applied CPET that has been
endorsed by scientific statements.(1-3)
A 5-minute period of resting gas exchange measurement permits the patient to become
accustomed to breathing into the mouthpiece without hyperventilation, which can confound
subsequent exercise gas exchange measurements. Low initial work rate is critical to avoid rapid
cessation of exercise in patients with HF. We recommend an initial 3 minute period of unloaded
exercise (0 Watts) in order to quantify the isolated metabolic cost of moving the legs (i.e. internal
work) prior to measurement of VO2-work rate relationships during incremental ramp exercise
(i.e. external work). Because the linearity of O2 uptake during exercise is used to ascertain the
ventilatory threshold(4) and to determine a cardiovascular basis for exercise intolerance, it is
important to be confident of the linearity of the work rate profile that yielded the response.(5)
For cycle ergometry, a ~10 W/min increment is usually appropriate based on previous studies in
1
HF demonstrating achieved workloads of 50-80 Watts which translates to the desired duration of
testing (8-11min) shown to optimize peak VO2 measurement.(6) Treadmill protocols should also
consist of a gradual increment in speed and grade with an ~10 W/min ramp (for a 70 kg
individual), which is the case for the modified Naughton Protocol used in the HF ACTION
trial(7) and a customized HF protocol currently used by the NHLBI Heart Failure Network.(8)
Of note, treadmill testing, compared to cycle ergometry, results in 7-11% higher peak VO2
values because of activation of more muscle mass with treadmill exercise.(9)
The individualized gradual incremental ramp (5-25 W/min) and patient-limited nature of
CPET makes the procedure feasible and safe even in patients with advanced cardiovascular
diseases, as recently shown by 0.045-0.16% adverse event rates (primarily ventricular
tachyarrhythmias) and no deaths in the investigation of over 9000 CPETs performed in
populations enriched for heart failure.(10,11)
Approach to Measuring Oxygen Uptake, Ventilatory Efficiency, and EOV
The O2 uptake at the VT is a reflection of the anaerobic threshold whereby skeletal
muscle begins to undergo anaerobic glycolysis to meet metabolic demands. Anaerobic glycolysis
produces lactic acid that requires buffering from bicarbonate, which results in a sharp increment
in VCO2 out of proportion to VO2, thereby creating a divergence in the VCO2-VO2 relationship
that is detectable by the V-slope method. Limitations of the VT measurement include moderate
inter-observer and intra-observer variability(12,13) due to difficulty ascertaining VT in some HF
patients, particularly those with a high degree of oscillatory ventilation.(1) In recent data from
the MECKI (Metabolic Exercise, Cardiac, Kidney Index) study, 9.4% of patients with HFrEF did
not have an identifiable VT and failure to detect a VT was an independent predictor of the
composite endpoint of cardiovascular death and urgent cardiac transplantation.(14)
2
Ventilatory efficiency assesses the increase in minute ventilation (VE) relative to work
rate, VO2, or VCO2, and is most commonly calculated as the linear regression slope of VE versus
VCO2 throughout exercise.(1) HF patients (predominantly HFrEF) with a normal VE/VCO2 slope
had an 18-month survival of 95% compared to a survival rate of 69% in those with an abnormal
slope.(15) When compared to other CPET variables in one study of 142 HFrEF patients,
VE/VCO2 slope was the strongest predictor of event-free survival in a multivariate model that
included peak VO2, LVEF, age, total lung capacity, and NYHA class.(16) In addition to patients
with LV systolic dysfunction, patients with HFpEF often have abnormal VE/VCO2 slope and, in
one study of HFpEF patients, VE/VCO2 slope was a stronger predictor of survival than peak
VO2.(17)
Although ventilatory efficiency is an important gas exchange variable used to detect
cardiopulmonary abnormalities and predict outcome in disease states, it does not distinguish
between different causes of dyspnea and abnormal functional capacity. Increased VE/VCO2 slope
is observed in HF, COPD (in the absence of CO2 retention),(18,19) and PAH.(20,21) The partial
pressure of end-tidal CO2 (PETCO2), which similarly reflects PaCO2 and VD/VT, augments with
exercise up until the VT in normal individuals. In one study, PETCO2 was found to be most
severely reduced in PAH, intermediately reduced in HF, and least reduced in COPD.(22)
However, given that the underlying determinants of PETCO2 and VE/VCO2 slope are the same, it
is likely that the two variables have similar diagnostic and prognostic capabilities. PETCO2 is
lower in patients with HF (HFrEF and HFpEF) than normal patients at rest, is tightly correlated
with cardiac output and cardiac index, and decreases as NYHA class increases.(23,24)
Furthermore, exercise PETCO2 predicts cardiac-related events in HF patients independent of peak
VO2.(25)
3
EOV has been defined differently in a nonstandardized fashion, based on somewhat
arbitrary criteria. Oscillations in VE exhibit a characteristic cycle length or period (i.e. time from
nadir to nadir for respective oscillations in VE) and amplitude (i.e. the difference between the
peak VE during an oscillation and the average of the VE of the two surrounding nadirs in
VE).(26,27) Some studies(28,29) have defined EOV as oscillations in VE with a cycle length of 
1 min, an amplitude of >15% of resting VE, and a duration of EOV encompassing >60% of total
exercise time. In 510 apparently healthy subjects undergoing CPET, EOV was present in 17% of
individuals and was found to be more prevalent in females and diabetics and associated with
poorer CPET performance.(30)
Despite the clear association between EOV and poor prognosis in HF, the mechanistic
basis for EOV remains unclear. As with any feedback control system, oscillatory waves in
ventilation may arise from: 1) delay in information transfer (i.e. reduced cardiac output resulting
in increased circulation time);(31,32) 2) increase in controller gain (i.e. increased
chemosensitivity to PaCO2 and PaO2),(33,34) or 3) reduction in system damping (i.e. baroreflex
impairment, Fig. 3).(27) Our group and others have linked EOV to circulatory delay by
measuring cardiac index (CI) during exercise.(35) We found that the amplitude and cycle length
of oscillations were inversely related to exercise CI (r=-0.60 and r=-0.71, respectively, both
P0.001). HF subjects with EOV cycle length > 1 minute, which is readily recognizable during
non-invasive CPET, demonstrated markedly limited augmentation in CI in response to exercise
(i.e. <2 L/min/m2) and changes in EOV amplitude and cycle length over time were inversely
related to changes in exercise CI.(35)
CPET-based Multivariate Models for Prognostication in Heart Failure
4
In studies examining the relative predictive value of multiple CPET variables for clinical
outcomes, EOV and VE/VCO2 slope are consistently retained in multivariate Cox regression
models whereas peak VO2 is not.(3,36,37) In 508 HFrEF patients, Sun et al.(37) found that when
EOV was observed along with an elevated VE/VCO2 slope, the odds ratio for 6-month mortality
increased 4-fold. A CPET score utilizing VE/VCO2 slope ≥34 (7 points), HR recovery ≤6 bpm
(5 points), OUES ≤1.4 (3 points), resting PETCO2 <33 mmHg (3 points), and a peak VO2 ≤14
mL/kg/min (2 points) has been validated to predict transplant/MCS-free survival in HF (HFpEF
and HFrEF) patients better than peak VO2 alone, with a summed score > 15 indicating the
poorest prognosis.(38,39) The use of this CPET score is helpful in risk stratifying Weber class B
HF patients (with peak VO2 16-20 ml/kg/min) into low risk and higher risk subgroups.(40)
In a recent study examining the prognostic value of combining biomarkers and CPET
parameters, NT-proBNP levels in combination with EOV emerged as the most powerful
predictor of cardiovascular death in 260 stable HFrEF patients.(41) This study and others have
found that combining information obtained from CPET with other clinical and laboratory data
can enhance prognostic determination. The MECKI score (Metabolic Exercise, Cardiac, Kidney
Index) is a risk model derived from a study of >2700 HFrEF patients that relies on six
independent predictors including peak VO2, VE/VCO2 slope, LVEF, renal function, hemoglobin,
and serum sodium levels. This score that combines CPET parameters with other indices serves as
a strong predictor of 2-year cardiovascular death or urgent cardiac transplant and has emerged as
a useful prognostic tool for HFrEF patients.(42)
CPET with Imaging
5
Imaging modalities such as echocardiography and radionuclide ventriculography have
been combined with CPET to provide additional insights into cardiac performance during
exercise. The use of Doppler echocardiography combined with CPET in 459 patients with HF
(both HFrEF and HFpEF) to determine the TAPSE-pulmonary artery systolic pressure (PASP)
relationship demonstrated that the TAPSE/PASP ratio during exercise was a strong predictor of
clinical outcome independent of other CPET ventilation parameters.(43) A TAPSE< 16 mm and
PASP ≥ 40 mm Hg in the presence of EOV identified patients with highest cardiac risk. In
another investigation, simultaneous exercise echocardiography with CPET identified the right
ventricular-pulmonary vascular unit as the primary determinant of the ∆VO2/∆work rate
relationship (i.e. aerobic efficiency) in 136 patients with exertional dyspnea.(44)
To determine the extent of LV recovery and candidacy for LVAD explantation,
echocardiography at low device speeds plays a central role in assessing for normalization of
aortic valve opening time, LVEF > 0.45, and LV end-diastolic dimension (LVEDD) < 6 cm.(45)
However, these parameters do not assess the reserve capacity of the heart during activity. As a
result, our laboratory and others measure serial values of CO and PAWP as well as peak VO2
during incremental ramp exercise at low LVAD speeds to assess intrinsic LV reserve capacity. A
peak VO2 in excess of 16 ml/kg/min is the one CPET variable that has been incorporated into
assessment algorithms as a threshold for LVAD removal,(46) although an appropriate CO
augmentation and PAWP response (i.e. PAWP<20 mmHg and PAWP-CO slope <2
mmHg/L/min) increases confidence that LV reserve capacity has been restored. Further work is
required to validate the use of CPET in determining the appropriate timing of LVAD
explantation.
6
First-pass radionuclide ventriculography provides a noninvasive method to assess left and
right ventricular volume and ejection fraction at rest and with exercise, which permits estimation
of cardiac output and stroke volume during CPET.(47) The assessment of resting and peak stroke
volume can aid in the diagnosis of disorders of abnormal ventricular compliance such as diastolic
HF. In patients with HFrEF, a ventriculographic RVEF <0.40 at rest and during exercise
independently predicts HF mortality.(48) The addition of invasive hemodynamic measurements
of “forward” Fick CO and ventriculographic “total CO” with CPET also allows for the
determination of valvular regurgitant fractions during exercise.
The addition of invasive hemodynamic measurements and radionuclide ventriculography
with CPET allows for the determination of the relative contributions of heart rate, stroke volume,
and peripheral oxygen extraction augmentation to peak VO2. Ideally, treatment of patients with
HF will target and optimize all three components of peak VO2 commensurate with the degree of
abnormality in each.
7
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17
CPET
Description and Physiologic
Variable
Relevance
Measurement Methodology
Required
%CV,
Threshold
Prognostic
Exercise
Relation to for
Significance in
Duration
pVO2*
Abnormal
Heart Failure
Maximum
4-7% (50-
<80%
HR 1.13-1.27 for
53)
predicted
mortality per 1
O2
utilization
Peak VO2
Aerobic capacity, gold standard
Highest VO2 (average over
indicator of maximum
30s) occurring in final minute
cardiorespiratory fitness.
of max. exercise (49)
ml/kg/min decrease
(54); +1ml/kg/min
leads to an 8%
reduction in CV
death & HF
hospitalization (55)
O2 uptake
Upon initiation of exercise, Phase 1
Mean response time (MRT)
Onset
VO2 kinetics reflect CO increase,
(56) is 63% of duration to
Kinetics
Phase 2 reflect peripheral muscle
reach steady state VO2. Slow ↑
18
3 min
5-7%
r=-0.37 (56)
MRT>60 sec 2.6-fold increased
mortality after 10
years (57)
adaptation, slow kinetics --> higher
reflects impaired metabolic
O2 debt
adaptation to exercise.
Anaerobic
Limit of aerobic metabolism during
V-slope method (slope of
threshold
60% Max
2-7%
<40% peak
<11ml/kg/min
exercise, reflects metabolic switch to regression of breath by breath
(51,53,59)
predicted
confers 5.3x
anaerobic metabolism
variable
VO2
increased mortality
CO2 production vs. O2
consumption) (58)
O2 pulse
(60)
Reflects premature leveling or fall in Slope of VO2 versus heart rate Maximum
7% (51)
Plateau
stroke volume in response to exercise relationship (61-63)
r=0.69
pattern
4%
<8.5
Flattening pattern
r=0.49
ml/min/W
associated with 25%
(64,65)
reduced peak VO2
(i.e. cardiac ischemia, RV
uncoupling)
Aerobic
Reflects metabolic cost (in terms of
O2 consumption/Work (W)
efficiency
O2 uptake) of performing external
during incremental exercise
work aerobically.
(58)
6 min
(44)
Ventil.
19
Patterns
Ventilatory Measure of ventilation required to
efficiency
exchange 1 L/min of CO2; reflects
Slope of least-squares
6 min
regression of total minute
5 % (51)
VE/ VCO2
6-fold higher
r=0.45 (56)
slope >34
mortality at 18
right ventricular-pulmonary vascular ventilation VE against CO2
months if >34 in HF
function + neural reflexes controlling production (66)
(15)
ventilatory drive
Oscillatory
A distinct form of periodic breathing 3+ contiguous, regular
ventilation
that reflects circulatory delay relative oscillations in VE with
to metabolic needs during exercise.
6 min
NA
Present
3-fold higher
mortality (>20% 1-yr
amplitude ≥ 25% of VE,
mortality) (26,31)
persisting for ≥ 60% of
exercise (37)
O2 +
Ventilatory
O2 uptake
O2 uptake relative to ventilation
VO2/logVE slope
6 min
Efficiency
(VE); a higher value reflects
(51,67,68)
slope
improved adaptation of the
r=0.83(68)
20
2-7%
<1.47
2-fold higher
mortality (69)
(OUES)
cardiopulmonary circuit to oxygenate
and deliver blood for a given VE
Supplementary Table. Cardiopulmonary exercise testing gas exchange patterns and their significance
%CV indicates coefficient of variance. *r values reflect the correlation coefficient between values of the displayed variable and
values of peak VO2.
21