Author Archives: Paul Older

Oxygen uptake at aerobic threshold is inversely associated with fatal cardiovascular and all-cause mortality events.

Kunutsor SK, Kurl S, Khan H, Zaccardi F, Rauramaa R, Laukkanen

Ann Med. 2017 Dec;49(8):698-709. doi: 10.1080/07853890.2017.1367958. Epub 2017
Aug 22

PURPOSE: We aimed to assess the associations of oxygen uptake at aerobic
threshold (VO2 at AT) with cardiovascular and all-cause mortality.
DESIGN: VO2 at AT was assessed in 1663 middle-aged men in a cohort study. Hazard
ratios (HRs) were calculated for sudden cardiac death (SCD), fatal coronary heart
disease (CHD) and cardiovascular disease (CVD) and all-cause mortality.
RESULTS: During a median follow-up of 25.6 years, 138 SCDs, 209 fatal CHDs, 333
fatal CVDs and 719 all-cause mortality events occurred. On adjustment for
established risk factors, the HRs (95% CIs) for SCD, fatal CHD, fatal CVD and
all-cause mortality were 0.48 (0.28-0.82), 0.48 (0.31-0.74), 0.57 (0.41-0.79) and
0.66 (0.53-0.82), respectively comparing extreme quartiles of VO2 at AT. On
further adjustment for peak VO2, the HRs were 0.87 (0.48-1.56), 0.83 (0.52-1.34),
0.91 (0.63-1.30) and 0.88 (0.69-1.12), respectively. Addition of VO2 at AT to a
standard CVD mortality risk prediction model was associated with a C-index change
of 0.0085 (95% CI: -0.0002-0.0172; p = .05) at 25 years.
CONCLUSIONS: VO2 at AT is inversely associated with cardiovascular and all-cause
mortality events, but the associations are partly dependent on peak VO2. VO2 at
AT may improve the prediction of the long-term risk for CVD mortality. KEY
MESSAGES Oxygen uptake at aerobic threshold (VO2 at AT), a cardiopulmonary
exercise testing parameter, may be a useful prognostic tool for adverse clinical
outcomes in the general population. In a population-based prospective cohort
study of men, VO2 at AT was inversely associated with cardiovascular and
all-cause mortality events and improved the prediction of cardiovascular
mortality. In populations who cannot achieve maximal VO2, VO2 at AT may serve as
a useful prognostic tool; however, further studies are warranted.

Cardiopulmonary Exercise Testing in Pediatrics.

Takken T, Bongers BC, van Brussel M, Haapala EA, Hulzebos EHJ

Ann Am Thorac Soc. 2017 Jul;14(Supplement_1):S123-S128. doi:

Aerobic fitness is an important determinant of overall health. Higher aerobic
fitness has been associated with many health benefits. Because myocardial
ischemia is rare in children, indications for exercise testing differ in children
compared with adults. Pediatric exercise testing is imperative to unravel the
physiological mechanisms of reduced aerobic fitness and to evaluate intervention
effects in children and adolescents with a chronic disease or disability.
Cardiopulmonary exercise testing includes the measurement of respiratory gas
exchange and is the gold standard for determining aerobic fitness, as well as for
examining the integrated physiological responses to exercise in pediatric
medicine. As the physiological responses to exercise change during growth and
development, appropriate pediatric reference values are essential for an adequate
interpretation of the cardiopulmonary exercise test.

Inspiratory Muscle Training Is Associated With Improved Inspiratory Muscle Strength, Resting Cardiac Output, and the Ventilatory Efficiency of Exercise in Patients With a Fontan Circulation.

Laohachai K, Winlaw D, Selvadurai H, Gnanappa GK, d’Udekem
Y, Celermajer D, Ayer J

J Am Heart Assoc. 2017 Aug 21;6(8). pii: e005750. doi: 10.1161/JAHA.117.005750.

BACKGROUND: Patients with a Fontan circulation have reduced exercise capacity and
respiratory muscle strength. Inspiratory muscle training (IMT) improves exercise
capacity and quality of life in adults with heart failure. We assessed whether
6 weeks of a home-based program of IMT improves inspiratory muscle strength and
the ventilatory efficiency of exercise in adolescent patients with a Fontan
METHODS AND RESULTS: Twenty-three adolescent participants (aged 16±2 years) with
a Fontan circulation underwent 6 weeks of IMT for 30 minutes daily. Respiratory
muscle strength (maximal inspiratory pressure and expiratory pressure), lung
function, and exercise capacity (cardiopulmonary exercise testing) were assessed.
Fourteen of 23 participants also underwent exercise cardiac magnetic resonance
imaging to examine the effects of IMT on cardiac output and systemic and
pulmonary blood flow. Six weeks of IMT improved maximal inspiratory pressure by
36±24 cm H2O (61±46%) with no change in maximal expiratory pressure. Ventilatory
efficiency of exercise improved after 6 weeks of IMT (from 34.2±7.8 to 32.2±5.6,
P=0.04). In those who underwent exercise cardiac magnetic resonance imaging, IMT
increased resting cardiac output (from 4.2±1.2 to 4.5±1.0 L/min, P=0.03) and
ejection fraction (from 50.1±4.3 to 52.8±6.1%, P=0.03).
CONCLUSIONS: Six weeks of IMT is associated with improved inspiratory muscle
strength, ventilatory efficiency of exercise, and resting cardiac output in young
Fontan patients. IMT may be a simple beneficial addition to the current
management of Fontan patients, potentially reducing exercise intolerance and
long-term morbidity and mortality.

Evidence on Exercise Training in Pulmonary Hypertension.

Babu AS, Arena , Morris NR.

Adv Exp Med Biol. 2017;1000:153-172. doi: 10.1007/978-981-10-4304-8_10.

Pulmonary hypertension (PH) is a chronic, debilitating condition which gravely
affects exercise tolerance and quality of life. Though most therapies focus
purely on medical intervention, there is a growing body of evidence to suggest
the role and benefits of exercise training. This chapter discusses the various
physiological basis for exercise intolerance observed in PH and highlights the
rationale for exercise training. Recent evidence related to exercise training is
summarized and potential pathways to suggest adaptations to exercise training are
put forward. While keeping the paper applicable to clinicians, details on
evaluating exercise intolerance, prescribing exercise and setting up
rehabilitation centers for PH are discussed.

Testing physical function in children undergoing intense cancer treatment-a RESPECT feasibility study.

Nielsen MKF;Christensen JF; Frandsen TL; Thorsteinsson T; Andersen LB; Christensen KB; Nersting J; Faber M; Schmiegelow K; Larsen HB;

Pediatric Blood & Cancer [Pediatr Blood Cancer] 2018 May 09, pp. e27100. Date of Electronic Publication: 2018 May 09.

Background: The physical function of children with cancer is reduced during treatment, which can compromise the quality of life and increase the risk of chronic medical conditions. The study, “REhabilitation, including Social and Physical activity and Education in Children and Teenagers with cancer” ( NCT01772862) examines the efficacy of multimodal rehabilitation strategies introduced at cancer diagnosis. This article addresses the feasibility of and obstacles to testing physical function in children with cancer.
Methods: The intervention group comprised 46 males and 29 females aged 6-18 years (mean ± SD: 11.3 ± 3.1 years) diagnosed with cancer from January 2013 to April 2016. Testing at diagnosis and after 3 months included timed-up-and-go, sit-to-stand, flamingo balance, handgrip strength, and the bicycle ergometer cardiopulmonary exercise test (CPET).
Results: Of the 75 children, 92% completed a minimum of one test; two children declined testing and four were later included. Completion was low for CPET (38/150, 25%) but was high for handgrip strength (122/150, 81%). Tumor location, treatment-related side effects, and proximity to chemotherapy administration were primary obstacles for testing physical function. Children with extracranial solid tumors and central nervous system tumors completed significantly fewer tests than those with leukemia and lymphoma. Children with leukemia demonstrated reduced lower extremity function, that is, 24% reduction at 3 months testing in timed-up-and-go (P = 0.005) and sit-to-stand (P = 0.002), in contrast with no reductions observed in the other diagnostic groups.
Conclusion: Children with cancer are generally motivated to participate in physical function tests. Future studies should address diagnosis specific obstacles and design testing modalities that facilitate physical function tests in this target group.

Reliability of repeated arm-crank cardiopulmonary exercise tests in patients with small abdominal aortic aneurysm.

Durrand JW; Wagstaff K; Kasim A; Cawthorn L; Danjoux GR; Kothmann E

Anaesthesia [Anaesthesia], ISSN: 1365-2044, 2018 May 04

Arm-crank ergometry may be useful in patients unable to pedal, for instance due to peripheral arterial disease. Twenty participants with small abdominal aortic aneurysm undertook two serial arm-crank tests and then a pedal test, four of whom had indeterminate anaerobic thresholds, precluding analysis. The mean (SD) peak arm and leg oxygen consumptions in 16 participants were 13.71 (2.62) .min-1 and 16.82 (4.44) .min-1 , with mean (SD) individual differences of 3.11 (2.48) .min-1 , p = 0.0001. The respective values at the anaerobic thresholds were 7.83 (1.58) ml O2 .kg-1 .min-1 and 10.09 (3.15) ml O2 .kg-1 .min-1 , with mean (SD) individual differences of 2.26 (2.34) ml O2 .kg-1 .min-1 , p = 0.0001. The correlation coefficients (95%CI) for peak oxygen consumption and anaerobic threshold were 0.88 (0.62-1.0) and 0.70 (0.32-1.0). There were no significant differences in serial arm-crank tests, with intracluster correlations (95%CI) of 0.87 (0.86-0.88) and 0.65 (0.61-0.69) for peak oxygen consumption and anaerobic threshold, respectively.

Short-term preoperative exercise therapy does not improve long-term outcome after lung cancer surgery: a randomized controlled study

Karenovics W, Licker M, Ellenberger C, Christodoulou M, Diaper J,
Bhatia C, Robert J, Bridevaux PO, Triponez F

Eur J Cardiothorac Surg. 2017 Jul 1;52(1):47-54. doi: 10.1093/ejcts/ezx030

OBJECTIVES: Poor aerobic fitness is a potential modifiable risk factor for
long-term survival and quality of life in patients with lung cancer. This
randomized trial evaluates the impact of adding rehabilitation (Rehab) with
high-intensity interval training (HIIT) before lung cancer surgery to enhance
cardiorespiratory fitness and improve long-term postoperative outcome.
METHODS: Patients with operable lung cancer were randomly assigned to usual care
(UC, n  = 77) or to intervention group (Rehab, n  = 74) that entailed HIIT that
was implemented only preoperatively. Cardiopulmonary exercise testing (CPET) and
pulmonary functional tests (PFTs) including forced vital capacity (FVC), forced
expiratory volume (FEV 1 ) and carbon monoxide transfer factor (KCO) were
performed before and 1 year after surgery.
RESULTS: During the preoperative waiting time (median 25 days), Rehab patients
participated to a median of 8 HIIT sessions (interquartile [IQ] 25-75%, 7-10). At
1 year follow-up, 91% UC patients and 93% Rehab patients were still alive ( P
= 0.506). Pulmonary functional changes were non-significant and comparable in
both groups (FEV 1 mean -7.5%, 95% CI, -3.6 to -12.9 and in KCO mean 5.8% 95% CI
0.8-11.8) Compared with preoperative CPET results, both groups demonstrated
similar reduction in peak oxygen uptake (mean -12.2% 95% CI -4.8 to -18.2) and in
peak work rate (mean -11.1% 95% CI -4.2 to -17.4).
CONCLUSIONS: Short-term preoperative rehabilitation with HIIT does not improve
pulmonary function and aerobic capacity measured at 1 year after lung cancer

Measuring Cardiac Output during Cardiopulmonary Exercise Testing.

Vignati C, Cattadori G

Ann Am Thorac Soc. 2017 Jul;14(Supplement_1):S48-S52. doi:

Cardiac output is a key parameter in the assessment of cardiac function, and its
measurement is fundamental to the diagnosis, treatment, and prognostic evaluation
of all heart diseases. Until recently, cardiac output determination during
exercise had been only possible through invasive methods, which were not
practical in the clinical setting. Because [Formula: see text]o2 is cardiac
output times arteriovenous content difference, evaluation of cardiac output is
usually included in its measurement. Because of the difficulty of directly
measuring peak exercise cardiac output, indirect surrogate parameters have been
proposed, but with only modest clinical usefulness. Direct measurement of cardiac
output can now be made by several noninvasive techniques, such as rebreathing
inert gases, impedance cardiology, thoracic bioreactance, estimated continuous
cardiac output technology, and transthoracic echocardiography coupled to
cardiopulmonary exercise testing, which allow more definitive results and better
understanding of the underlying physiopathology.

Periodic Breathing during Incremental Exercise.

Agostoni P, Corrà U, Emdin M

Ann Am Thorac Soc. 2017 Jul;14(Supplement_1):S116-S122. doi:

Periodic breathing during incremental cardiopulmonary exercise testing is a
regularly recurring waxing and waning of tidal volume due to oscillations in
central respiratory drive. Periodic breathing is a sign of respiratory control
system instability, which may occur at rest or during exercise. The possible
mechanisms responsible for exertional periodic breathing might be related to any
instability of the ventilatory regulation caused by: (1) increased circulatory
delay (i.e., circulation time from the lung to the brain and chemoreceptors due
to reduced cardiac index leading to delay in information transfer), (2) increase
in controller gain (i.e., increased central and peripheral chemoreceptor
sensitivity to arterial partial pressure of oxygen and of carbon dioxide), or (3)
reduction in system damping (i.e., baroreflex impairment). Periodic breathing
during exercise is observed in several cardiovascular disease populations, but it
is a particularly frequent phenomenon in heart failure due to systolic
dysfunction. The detection of exertional periodic breathing is linked to outcome
and heralds worse prognosis in heart failure, independently of the criteria
adopted for its definition. In small heart failure cohorts, exertional periodic
breathing has been abolished with several dedicated interventions, but results
have not yet been confirmed. Accordingly, further studies are needed to define
the role of visceral feedbacks in determining periodic breathing during exercise
as well as to look for specific tools for preventing/treating its occurrence in
heart failure.

Cardiopulmonary Exercise Testing: Basics of Methodology and Measurements

Mezzani A

Ann Am Thorac Soc. 2017 Jul;14(Supplement_1):S3-S11. doi:

Cardiopulmonary exercise testing adds measurement of ventilation and volume of
oxygen uptake and exhaled carbon dioxide to routine physiological and performance
parameters obtainable from conventional exercise testing, furnishing an
all-around vision of the systems involved in both oxygen transport from air to
mitochondria and its use during exercise. Peculiarities of cardiopulmonary
exercise testing methodology are the use of ramp protocols and calibration
procedures for flow meters and gas analyzers. Among the several parameters
provided by this technique, peak oxygen uptake, first and second ventilatory
thresholds, respiratory exchange ratio, oxygen pulse, slope of ventilation
divided by exhaled carbon dioxide relationship, exercise oscillatory ventilation,
circulatory power, and partial pressure of end-tidal carbon dioxide are among the
most relevant in the clinical setting. The choice of parameters to be considered
will depend on the indication to cardiopulmonary exercise testing in the
individual subject or patient, namely, exercise tolerance assessment, prognostic
stratification, training prescription, treatment efficacy evaluation, diagnosis
of causes of unexplained exercise tolerance reduction, or exercise
(patho)physiology evaluation for research purposes. Overall, cardiopulmonary
exercise testing is a methodology now widely available and supported by sound
scientific evidence. Despite this, its potential still remains largely underused.
Strong efforts and future investigations are needed to address these issues and
further promote the use of cardiopulmonary exercise testing in the clinical and
research setting.