Category Archives: Publications

The cardiopulmonary exercise test grey zone; optimising fitness stratification by application of critical difference

Rose GA, Davies RG, Davison GW, et al.

Br J Anaesth. 2018;120(6):1187-1194.

BACKGROUND: Cardiorespiratory fitness can inform patient care, although to what extent natural variation in CRF influences clinical practice remains to be established. We calculated natural variation for cardiopulmonary exercise test (CPET) metrics, which may have implications for fitness stratification.
METHODS: In a two-armed experiment, critical difference comprising analytical imprecision and biological variation was calculated for cardiorespiratory fitness and thus defined the magnitude of change required to claim a clinically meaningful change. This metric was retrospectively applied to 213 patients scheduled for colorectal surgery. These patients underwent CPET and the potential for misclassification of fitness was calculated. We created a model with boundaries inclusive of natural variation [critical difference applied to oxygen uptake at anaerobic threshold (V O2-AT): 11 ml O2 kg(-1) min(-1), peak oxygen uptake (V O2 peak): 16 ml O2 kg(-1) min(-1), and ventilatory equivalent for carbon dioxide at AT (VE/VCO2-AT): 36].
RESULTS: The critical difference for V O2-AT, V O2 peak, and V E/V CO2-AT was 19%, 13%, and 10%, respectively, resulting in false negative and false positive rates of up to 28% and 32% for unfit patients. Our model identified boundaries for unfit and fit patients: AT <9.2 and >/=13.6 ml O2 kg(-1) min(-1), V O2 peak <14.2 and >/=18.3 ml kg(-1) min(-1), V E/V CO2-AT >/=40.1 and <32.7, between which an area of indeterminate-fitness was established. With natural variation considered, up to 60% of patients presented with indeterminate-fitness.
CONCLUSIONS: These findings support a reappraisal of current clinical interpretation of cardiorespiratory fitness highlighting the potential for incorrect fitness stratification when natural variation is not accounted for.

Dead-space ventilation is linked to exercise capacity and survival in distal chronic thromboembolic pulmonary hypertension.

Godinas L, Sattler C, Lau EM, Jaïs X, Taniguchi Y, Jevnikar M,
Weatherald J, Sitbon O, Savale L, Montani D, Simonneau G, Humbert
M, Laveneziana P, Garcia G.

J Heart Lung Transplant. 2017 Nov;36(11):1234-1242. doi:
10.1016/j.healun.2017.05.024. Epub 2017 May 22.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is frequently used for the
evaluation of patients with pulmonary hypertension (PH). Non-operable distal
chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique
subgroup of PH where microvascular disease resembling pulmonary arterial
hypertension (PAH) may predominate and efficacious medical therapy is now
available. However, little is known regarding the detailed CPET profile of
patients with distal CTEPH, and whether ventilation and gas exchange responses
are different from PAH.
METHODS: Forty-nine consecutive patients with non-operable distal CTEPH according
to multidisciplinary team assessment and 45 PAH patients underwent CPET and right
heart catheterization. Patients were followed up for a median of 3.2 years
(interquartile range: 1.8 to 4.4).
RESULTS: Pulmonary hemodynamics were similar in distal CTEPH and PAH groups, but
patients with distal CTEPH achieved a lower percent predicted peak oxygen
consumption (59 ± 13% vs 66 ± 14%, p < 0.05). At peak exercise, higher
physiologic dead-space fraction (VD/VT) (0.45 ± 0.07 vs 0.35 ± 0.07, p < 0.0001)
and higher arterial-to-end-tidal carbon dioxide gradient (9 ± 3 vs 5 ± 3 mm Hg, p
< 0.0001) were observed in distal CTEPH compared with PAH. Ventilatory
efficiency, expressed as VE/VCO2 slope, was also more impaired in distal CTEPH
(52.2 ± 10.1 vs 43.8 ± 8.4 liters/min, p < 0.0001). In the distal CTEPH group
only, higher VD/VT was associated with lower peak oxygen consumption (r = -0.46,
p = 0.003) and worse survival.
CONCLUSIONS: Compared with PAH, a distinct pattern of response to exercise was
observed in distal CTEPH, characterized by increased dead-space ventilation that
resulted in worse ventilatory efficiency and greater impairment of exercise
capacity. In distal CTEPH, dead-space ventilation correlated with exercise
capacity and was associated with survival.

Cardiopulmonary exercise testing as prognostic indicators: Comparisons among heart failure patients with reduced, mid-range and preserved ejection fraction.

Sato T, Yoshihisa A, Kanno Y, Suzuki S, Yamaki T, Sugimoto K,
Kunii H, Nakazato K, Suzuki H, Saitoh SI, Ishida T, Takeishi Y

Eur J Prev Cardiol. 2017 Dec;24(18):1979-1987.

We aimed to determine the differences of impact of cardiopulmonary exercise
testing (CPX) parameters on prognosis of heart failure with reduced left
ventricular ejection fraction (HFrEF), preserved ejection fraction (HFpEF) and
mid-range ejection fraction (HFmrEF).
We compared clinical
characteristics and CPX parameters among the three groups, and the value of each
CPX parameter to predict adverse cardiac events (cardiac deaths and
re-hospitalizations for heart failure), cardiac deaths and all-cause deaths.
Of 1190 patients, 41.9% had HFrEF, 36.8% had HFpEF and 21.3% had HFmrEF.
The patients in HFrEF group had higher rates of adverse cardiac events, cardiac
death and all-cause death than those of HFpEF and HFmrEF groups. In HFrEF, the
independent predictors of adverse cardiac events were peak oxygen consumption and
oxygen uptake efficiency slope, predictors of cardiac death were peak oxygen
consumption and oxygen uptake efficiency slope, and the predictor of all-cause
death was peak oxygen consumption. In HFpEF, the predictor of adverse cardiac
events was peak oxygen consumption, predictors of cardiac deaths and all-cause
deaths were peak oxygen consumption and exertional oscillatory ventilation. In
HFmrEF, predictors of adverse cardiac events were peak oxygen consumption and
oxygen uptake efficiency slope, and the predictor of cardiac deaths and all-cause
deaths was peak oxygen consumption.
Peak oxygen consumption is the
strong predictor for adverse events in all groups. Oxygen uptake efficiency slope
predicts adverse prognosis in HFrEF, but not in HFpEF. In contrast, exertional
oscillatory ventilation is the predictor only in HFpEF. Thus, different CPX
parameters may be able to differentially predict prognosis in HFrEF and HFpEF.
Those for predicting prognosis in HFmrEF may be intermediate between HFrEF and

Prognostic Value of Cardiopulmonary Exercise Testing in Heart Failure With Reduced, Midrange, and Preserved Ejection Fraction.

Nadruz W Jr, West E, Sengeløv M, Santos M, Groarke JD, Forman
DE, Claggett B, Skali H, Shah AM

J Am Heart Assoc. 2017 Oct 31;6(11)

BACKGROUND: This study aimed to compare the independent and incremental
prognostic value of peak oxygen consumption (VO2) and minute ventilation/carbon
dioxide production (VE/VCO2) in heart failure (HF) with preserved (HFpEF),
midrange (HFmEF), and reduced (HFrEF) ejection fraction (LVEF).
METHODS AND RESULTS: In 195 HFpEF (LVEF ≥50%), 144 HFmEF (LVEF 40-49%), and 630
HFrEF (LVEF <40%) patients, we assessed the association of cardiopulmonary
exercise testing variables with the composite outcome of death, left ventricular
assist device implantation, or heart transplantation (256 events; median
follow-up of 4.2 years), and 2-year incident HF hospitalization (244 events). In
multivariable Cox regression analysis, greater association with outcomes in HFpEF
than HFrEF were noted with peak VO2 (HR [95% confidence interval]: 0.76
[0.67-0.87] versus 0.87 [0.83-0.90] for the composite outcome,
Pinteraction=0.052; 0.77 [0.69-0.86] versus 0.92 [0.88-0.95], respectively for HF
hospitalization, Pinteraction=0.003) and VE/VCO2 slope (1.11 [1.06-1.17] versus
1.04 [1.03-1.06], respectively for the composite outcome, Pinteraction=0.012;
1.10 [1.05-1.15] versus 1.04 [1.03-1.06], respectively for HF hospitalization,
Pinteraction=0.019). In HFmEF, peak VO2 and VE/VCO2 slope were associated with
the composite outcome (0.79 [0.70-0.90] and 1.12 [1.05-1.19], respectively),
while only peak VO2 was related to HF hospitalization (0.81 [0.72-0.92]). In
HFpEF and HFrEF, peak VO2 and VE/VCO2 slope provided incremental prognostic value
beyond clinical variables based on the C-statistic, net reclassification
improvement, and integrated diagnostic improvement, with models containing both
measures demonstrating the greatest incremental value.
CONCLUSIONS: Both peak VO2 and VE/VCO2 slope provided incremental value beyond
clinical characteristics and LVEF for predicting outcomes in HFpEF.
Cardiopulmonary exercise testing variables provided greater risk discrimination
in HFpEF than HFrEF.

An official European Respiratory Society statement: pulmonary haemodynamics during exercise.

Kovacs G, Herve P, Barbera JA, Chaouat A, Chemla D, Condliffe R, Garcia G, Grünig E, Howard L, Humbert M, Lau E,
Laveneziana P, Lewis GD, Naeije R, Peacock A, Rosenkranz S, Saggar R, Ulrich S, Vizza D, Vonk Noordegraaf A,
Olschewski H.

Eur Respir J. 2017 Nov 22;50(5)
Erratum in
Eur Respir J. 2018 Jan 18;51(1):.

There is growing recognition of the clinical importance of pulmonary
haemodynamics during exercise, but several questions remain to be elucidated. The
goal of this statement is to assess the scientific evidence in this field in
order to provide a basis for future recommendations.Right heart catheterisation
is the gold standard method to assess pulmonary haemodynamics at rest and during
exercise. Exercise echocardiography and cardiopulmonary exercise testing
represent non-invasive tools with evolving clinical applications. The term
“exercise pulmonary hypertension” may be the most adequate to describe an
abnormal pulmonary haemodynamic response characterised by an excessive pulmonary
arterial pressure (PAP) increase in relation to flow during exercise. Exercise
pulmonary hypertension may be defined as the presence of resting mean PAP
<25 mmHg and mean PAP >30 mmHg during exercise with total pulmonary resistance
>3 Wood units. Exercise pulmonary hypertension represents the haemodynamic
appearance of early pulmonary vascular disease, left heart disease, lung disease
or a combination of these conditions. Exercise pulmonary hypertension is
associated with the presence of a modest elevation of resting mean PAP and
requires clinical follow-up, particularly if risk factors for pulmonary
hypertension are present. There is a lack of robust clinical evidence on targeted
medical therapy for exercise pulmonary hypertension.

Systolic Function of Right Ventricular Outflow Tract is a Better Predictor to Exercise Performance After Pulmonary Valve Replacement in Tetralogy of Fallot.

Li J, Luo S, Liu F, An Q

Pediatr Cardiol. 2017 Dec;38(8):1556-1561

Debate on the proper timing of pulmonary valve replacement (PVR) after repair of
tetralogy of Fallot is still continuing. We aim to clarify how the different
components of right ventricle (RV) changed with relieved volume overload in the
remodeling process after pulmonary valve replacement and gain a clear idea of the
relationship between different right ventricle components function and exercise
capacity after PVR in these patients. The medical records and results of cardiac
magnetic resonance imaging and cardiopulmonary exercise testing of 25 consecutive
eligible patients were reviewed. End-diastolic, end-systolic, and ejection
fraction (EF) were determined for the total RV and its components before and
after PVR. There was a marked increase in EF for the outlet after PVR
(39.5 ± 11.4 vs. 45.6 ± 12.7, P = 0.04); however, EF and volume change for the
other components showed no significant difference. Peak oxygen consumption (VO2)
correlated better with the RV outflow tract EF than with the EF of other
components of the RV or the global EF (r = 0.382, P = 0.018), and the time
interval between initial repair and PVR showed a significant correlation with
peak VO2 (r = -0.339, P = 0.037). Multivariate analysis showed the RV outflow
tract EF to be the only independent predictor of exercise capacity (β = 0.479;
P = 0.046). The systolic function of the RV outflow tract could be a reliable
determinant of intrinsic RV performance in repaired TOF (rTOF) patients and a
promising parameter for deciding timing of pulmonary valve replacement so as to
achieve the best possible exercise capacity in repaired TOF patients.

Importance of Non-invasive Right and Left Ventricular Variables on Exercise Capacity in Patients with Tetralogy of Fallot Hemodynamics.

Meierhofer C, Tavakkoli T, Kühn A, Ulm K, Hager A, Müller J,
Martinoff S, Ewert P, Stern H

Pediatr Cardiol. 2017 Dec;38(8):1569-1574.

Good quality of life correlates with a good exercise capacity in daily life in
patients with tetralogy of Fallot (ToF). Patients after correction of ToF usually
develop residual defects such as pulmonary regurgitation or stenosis of variable
severity. However, the importance of different hemodynamic parameters and their
impact on exercise capacity is unclear. We investigated several hemodynamic
parameters measured by cardiovascular magnetic resonance (CMR) and
echocardiography and evaluated which parameter has the most pronounced effect on
maximal exercise capacity determined by cardiopulmonary exercise testing (CPET).
132 patients with ToF-like hemodynamics were tested during routine follow-up with
CMR, echocardiography and CPET. Right and left ventricular volume data,
ventricular ejection fraction and pulmonary regurgitation were evaluated by CMR.
Echocardiographic pressure gradients in the right ventricular outflow tract and
through the tricuspid valve were measured. All data were classified and
correlated with the results of CPET evaluations of these patients. The analysis
was performed using the Random Forest model. In this way, we calculated the
importance of the different hemodynamic variables related to the maximal oxygen
uptake in CPET (VO2%predicted). Right ventricular pressure showed the most
important influence on maximal oxygen uptake, whereas pulmonary regurgitation and
right ventricular enddiastolic volume were not important hemodynamic variables to
predict maximal oxygen uptake in CPET. Maximal exercise capacity was only very
weakly influenced by right ventricular enddiastolic volume and not at all by
pulmonary regurgitation in patients with ToF. The variable with the most
pronounced influence was the right ventricular pressure.

Reference values for maximum work rate in apparently healthy Dutch/Flemish adults: data from the LowLands fitness registry

, , &

Acta Cardiologica Published online: 22 Jun 2018

Background: The peak oxygen uptake (VO2peak) test is the gold standard for cardiorespiratory fitness. However, the test is demanding, requiring sophisticated apparatus for measuring the oxygen uptake. Peak work rate (WRpeak) testing is a promising substitute for peak VO2peak testing. However, there is a paucity of research conducted to determine reference values (RVs) for WRpeak.

Methods: The database from the LowLands fitness registry was used, containing data from health checks from apparently healthy subjects among various professions. Exercise tests were performed using a cycle ergometer and a calibrated metabolic cart. Analysis was executed on 3463 subjects, 2868 male and 595 female. Reference values with corresponding centiles were developed using the LMS method.

Results: VO2peak and WRpeak where highly associated with Pearson’s correlation of 0.9 (p = .001). Weight, height, maximum heart rate, and the respiratory exchange ratio had a positive significant effect (p < .001) on WRpeak, and age a negative significant effect, in both males and females. The following formulas were computed for RVs:

Conclusions: WRpeak can be used as a substitute for VO2peak when a respiratory gas-analysis system is not available. This study provides RVs for WRpeak and WRpeak/kg in a healthy Dutch/Flemish adult population using cycle ergometry. Further research is needed to obtain RVs for elderly subjects, specific diseases, ethnicities and ergometers.

Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study

Duminda N Wijeysundera, PhD; Prof Rupert M Pearse, MD; Mark A Shulman, MPH; Tom E F Abbott, PhD; Elizabeth Torres, BMSc; Althea Ambosta, MA; Bernard L Croal, MD; Prof John T Granton, MD; Kevin E Thorpe, MMath; Prof Michael P W Grocott, MD; Catherine Farrington, BAppSc; Prof Paul S Myles, DSc; Prof Brian H Cuthbertson, MD

,on behalf of the

The Lancet Volume 391, No. 10140, p2631–2640, 30 June 2018



Functional capacity is an important component of risk assessment for major surgery. Doctors’ clinical subjective assessment of patients’ functional capacity has uncertain accuracy. We did a study to compare preoperative subjective assessment with alternative markers of fitness (cardiopulmonary exercise testing [CPET], scores on the Duke Activity Status Index [DASI] questionnaire, and serum N-terminal pro-B-type natriuretic peptide [NT pro-BNP] concentrations) for predicting death or complications after major elective non-cardiac surgery.


We did a multicentre, international, prospective cohort study at 25 hospitals: five in Canada, seven in the UK, ten in Australia, and three in New Zealand. We recruited adults aged at least 40 years who were scheduled for major non-cardiac surgery and deemed to have one or more risk factors for cardiac complications (eg, a history of heart failure, stroke, or diabetes) or coronary artery disease. Functional capacity was subjectively assessed in units of metabolic equivalents of tasks by the responsible anaesthesiologists in the preoperative assessment clinic, graded as poor (<4), moderate (4–10), or good (>10). All participants also completed the DASI questionnaire, underwent CPET to measure peak oxygen consumption, and had blood tests for measurement of NT pro-BNP concentrations. After surgery, patients had daily electrocardiograms and blood tests to measure troponin and creatinine concentrations until the third postoperative day or hospital discharge. The primary outcome was death or myocardial infarction within 30 days after surgery, assessed in all participants who underwent both CPET and surgery. Prognostic accuracy was assessed using logistic regression, receiver-operating-characteristic curves, and net risk reclassification.


Between March 1, 2013, and March 25, 2016, we included 1401 patients in the study. 28 (2%) of 1401 patients died or had a myocardial infarction within 30 days of surgery. Subjective assessment had 19·2% sensitivity (95% CI 14·2–25) and 94·7% specificity (93·2–95·9) for identifying the inability to attain four metabolic equivalents during CPET. Only DASI scores were associated with predicting the primary outcome (adjusted odds ratio 0·96, 95% CI 0·83–0·99; p=0·03).


Subjectively assessed functional capacity should not be used for preoperative risk evaluation. Clinicians could instead consider a measure such as DASI for cardiac risk assessment.


Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.