Knuiman P; Straw S; Gierula J; Koshy A; Roberts LD; Witte KK; Ferguson C; Bowen TS;

ESC heart failure [ESC Heart Fail] 2021 Feb 20. Date of Electronic Publication: 2021 Feb 20.

Aims: Heart failure with reduced ejection fraction (HFrEF) induces skeletal muscle mitochondrial abnormalities that contribute to exercise limitation; however, specific mitochondrial therapeutic targets remain poorly established. This study quantified the relationship and contribution of distinct mitochondrial respiratory states to prognostic whole-body measures of exercise limitation in HFrEF.
Methods and Results: Male patients with HFrEF (n = 22) were prospectively enrolled and underwent ramp-incremental cycle ergometry cardiopulmonary exercise testing to determine exercise variables including peak pulmonary oxygen uptake (V̇O _2peak ), lactate threshold (V̇O _2LT ), the ventilatory equivalent for carbon dioxide (V̇ _E /V̇CO _2LT ), peak circulatory power (CircP _peak ), and peak oxygen pulse. Pectoralis major was biopsied for assessment of in situ mitochondrial respiration. All mitochondrial states including complexes I, II, and IV and electron transport system (ETS) capacity correlated with V̇O _2peak (r = 0.40-0.64; P < 0.05), V̇O _2LT (r = 0.52-0.72; P < 0.05), and CircP _peak (r = 0.42-0.60; P < 0.05). Multiple regression analysis revealed that combining age, haemoglobin, and left ventricular ejection fraction with ETS capacity could explain 52% of the variability in V̇O _2peak and 80% of the variability in V̇O _2LT , respectively, with ETS capacity (P = 0.04) and complex I (P = 0.01) the only significant contributors in the model.
Conclusions: Mitochondrial respiratory states from skeletal muscle biopsies of patients with HFrEF were independently correlated to established non-invasive prognostic cycle ergometry cardiopulmonary exercise testing indices including V̇O _2peak , V̇O _2LT , and CircP _peak . When combined with baseline patient characteristics, over 50% of the variability in V̇O _2peak could be explained by the mitochondrial ETS capacity. These data provide optimized mitochondrial targets that may attenuate exercise limitations in HFrEF.

T. Takken, C.F. Mylius, D. Paap, W. Broeders, H.J. Hulzebos, M. Van Brussel & B.C. Bongers

Expert Review of Cardiovascular Therapy,
DOI: 10.1080/14779072.2019.1627874
https://doi.org/10.1080/14779072.2019.1627874

Introduction: Reference values for cardiopulmonary exercise testing (CPET) parameters provide the
comparative basis for answering important questions concerning the normalcy of exercise responses in
patients, and significantly impacts the clinical decision-making process.
Areas covered: The aim of this study was to provide an updated systematic review of the literature on
reference values for CPET parameters in healthy subjects across the life span.
A systematic search in MEDLINE, Embase, and PEDro databases were performed for articles describing
reference values for CPET published between March 2014 and February 2019.
Expert opinion: Compared to the review published in 2014, more data have been published in the last
five years compared to the 35 years before. However, there is still a lot of progress to be made. Quality
can be further improved by performing a power analysis, a good quality assurance of equipment and
methodologies, and by validating the developed reference equation in an independent (sub)sample.
Methodological quality of future studies can be further improved by measuring and reporting the level
of physical activity, by reporting values for different racial groups within a cohort as well as by the
exclusion of smokers in the sample studied. Normal reference ranges should be well defined in
consensus statements.

Papp D; Takken T;

December 2014. Expert Review of Cardiovascular Therapy 12(12):1439-53

Reference values (RV) for cardiopulmonary exercise testing (CPET) provide the comparative basis for answering important questions concerning the normality of exercise response in patients and significantly impacts the clinical decision-making process. The aim of this study is to systematically review the literature on RV for CPET in healthy adults. A secondary aim is to make appropriate recommendations for the practical use of RV for CPET. Systematic searches of MEDLINE, EMBASE and PEDro databases up to March 2014 were performed. In the last 30 years, 35 studies with CPET RV were published. There is no single set of ideal RV; characteristics of each population are too diverse to pool the data in a single equation. Therefore, each exercise laboratory must select appropriate sets of RV that best reflect the characteristics of the population/patient tested, and equipment and methodology utilized.

JONATHAN WAGNER, MAX NIEMEYER, DENIS INFANGER, TIMO HINRICHS, LUKAS STREESE,
HENNER HANSSEN1 JONATHANMYERS, ARNO SCHMIDT-TRUCKSÄSS and RAPHAEL KNAIER

Med. Sci. Sports Exerc., Vol. 52, No. 9, pp. 1915–1923, 2020.

Purpose: To determine age-dependent cutoff values for secondary exhaustion criteria for a general population free
of exercise limiting chronic conditions; to describe the percentage of participants reaching commonly used exhaustion criteria during a cardiopulmonary exercise test (CPET); and to analyze their oxygen uptake at the respective criteria to quantify the impact of a given criterion on the respective oxygen uptake (V˙O2) values.
Methods: Data from the COmPLETE-Health Study were analyzed involving participants from 20 to 91 yr of age. All underwent a CPET to maximal voluntary exertion using a cycle ergometer. To determine new exhaustion criteria, based on maximal respiratory exchange ratio (RERmax) and age-predicted maximal HR (APMHR), one-sided lower tolerance intervals for the tests confirmingV˙O2 plateau status were calculated using a confidence level of 95% and a coverage of 90%.
Results: A total of 274 men and 252 women participated in the study. Participants were nearly equally distributed across age decades from20 to >80 yr. A V˙O2 plateauwas present in 32%. There were only minor differences in secondary exhaustion criteria between participants exhibiting a V˙O2 plateau and participants not showing a V˙O2 plateau. New exhaustion criteria according to the tolerance intervals for the age group of 20 to 39 yr were: RERmax ≥ 1.13, APMHR210 − age ≥ 96%, and APMHR208 × 0.7 age ≥ 93%; for the age group of 40 to 59 yr: RERmax ≥ 1.10, APMHR210 − age ≥ 99%, and APMHR208 × 0.7 age ≥ 92%; and, for the age group of 60 to 69 yr: RERmax ≥ 1.06, APMHR210 − age ≥ 99%, and APMHR208 × 0.7 age ≥ 89%.
Conclusions: The proposed cutoff values for secondary criteria reduce the risk of underestimating V˙02max. Lower values would increase false-positive results, assuming participants are exhausted although, in fact, they are not.

Karsten Königstein, Sebastian Abegg, Andrea N Schorn, Ines C Weber, Nina Derron,
Andreas Krebs, Philipp A Gerber, Arno Schmidt-Trucksass and Andreas T Güntner

J. Breath Res. 15 (2021) 016006

Exhaled breath acetone (BrAce) was investigated during and after submaximal aerobic exercise as a
volatile biomarker for metabolic responsiveness in high and lower-fit individuals in a prospective
cohort pilot-study. Twenty healthy adults (19–39 years) with different levels of cardiorespiratory
fitness (VO2peak), determined by spiroergometry, were recruited. BrAce was repeatedly measured
by proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS) during 40–55 min
submaximal cycling exercise and a post-exercise period of 180 min. Activity of ketone and fat
metabolism during and after exercise were assessed by indirect calorimetric calculation of fat
oxidation rate and by measurement of venous β-hydroxybutyrate (βHB). Maximum BrAce ratios
were significantly higher during exercise in the high-fit individuals compared to the lower-fit group
(t-test; p = 0.03). Multivariate regression showed 0.4% (95%-CI = −0.2%–0.9%, p = 0.155)
higher BrAce change during exercise for every ml kg−1 min−1 higher VO2peak. Differences of BrAce
ratios during exercise were similar to fat oxidation rate changes, but without association to
respiratory minute volume. Furthermore, the high-fit group showed higher maximum BrAce
increase rates (46% h−1) in the late post-exercise phase compared to the lower-fit group
(29% h−1). As a result, high-fit young, healthy individuals have a higher increase in BrAce
concentrations related to submaximal exercise than lower-fit subjects, indicating a stronger
exercise-related activation of fat metabolism.

Jonathan Wagner, Raphael Knaier, Karsten Königstein, Christopher Klenk, Justin Carrard, Eric Lichtenstein,
Hubert Scharnagl, Winfried März, Henner Hanssen, Timo Hinrichs, Arno Schmidt-Trucksäss and Konstantin Arbeev

Frontiers in Physiology | www.frontiersin.org December 2020 | Volume 11 | Article 596240

Background: Aging and changing age demographics represent critical problems of our
time. Physiological functions decline with age, often ending in a systemic process that
contributes to numerous impairments and age-related diseases including heart failure
(HF). We aimed to analyze whether differences in composite measures of physiological
function [health distance (HD)], specifically physical fitness, between healthy individuals
and patients with HF, can be observed.
Methods: The COmPLETE Project is a cross-sectional study of 526 healthy participants
aged 20–91 years and 79 patients with stable HF. Fifty-nine biomarkers characterizing
fitness (cardiovascular endurance, muscle strength, and neuromuscular coordination)
and general health were assessed. We computed HDs as the Mahalanobis distance
for vectors of biomarkers (all and domain-specific subsets) that quantified deviations
of individuals’ biomarker profiles from “optimums” in the “reference population”
(healthy participants aged <40 years). We fitted linear regressions with HD outcomes
and disease status (HF/Healthy) and relevant covariates as predictors and logistic
regressions for the disease outcome and sex, age, and age2 as covariates in the base
model and the same covariates plus combinations of one or two HDs.
Results: Nine out of 10 calculated HDs showed evidence for group differences between
Healthy and HF (p  0.002) and most models presented a negative estimate of the
interaction term age by group (p < 0.05 for eight HDs). The predictive performance of
the base model for HF cases significantly increased by adding HD General health or
HD Fitness [areas under the receiver operating characteristic (ROC) curve (AUCs) 0.63,
0.89, and 0.84, respectively]. HD Cardiovascular endurance alone reached an AUC of
0.88. Further, there is evidence that the combination of HDs Cardiovascular endurance
and General health shows superior predictive power compared to single HDs.
Conclusion: HD composed of physical fitness biomarkers differed between healthy
individuals and patients with HF, and differences between groups diminished with
increasing age. HDs can successfully predict HF cases, and HD Cardiovascular
endurance can significantly increase the predictive power beyond classic clinical
biomarkers. Applications of HD could strengthen a comprehensive assessment of
physical fitness and may present an optimal target for interventions to slow the decline
of physical fitness with aging and, therefore, to increase health span.

Jonathan Wagner, Max Niemeyer, Denis InfangerID, Timo Hinrichs,Clement Guerra, Christopher Klenk,
Karsten Ko¨nigsteinID, Christian Cajochen, Arno Schmidt-Trucksa, Raphael KnaierID

https://doi.org/10.1371/journal.pone.0245306

Objective
This study compared the robustness of a V_ O2-plateau definition and a verification-phase
protocol to day-to-day and diurnal variations in determining the true V_ O2max. Further, the
additional value of a verification-phase was investigated.
Methods
Eighteen adults performed six cardiorespiratory fitness tests at six different times of the day
(diurnal variation) as well as a seventh test at the same time the sixth test took place (dayto-
day variation). A verification-phase was performed immediately after each test, with a
stepwise increase in intensity to 50%, 70%, and 105% of the peak power output.
Results
Participants mean V_ O2peak was 56 ± 8 mL/kg/min. Gwet’s AC1 values (95% confidence
intervals) for the day-to-day and diurnal variations were 0.64 (0.22, 1.00) and 0.71 (0.42,
0.99) for V_ O2-plateau and for the verification-phase 0.69 (0.31, 1.00) and 0.07 (−0.38, 0.52),
respectively. In 66% of the tests, performing the verification-phase added no value, while, in
32% and 2%, it added uncertain value and certain value, respectively, in the determination
of V_ O2max.
Conclusion
Compared to V_ O2-plateau the verification-phase shows lower reliability, increases costs
and only adds certain value in 2% of cases.

JONATHAN WAGNER, RAPHAEL KNAIER, DENIS INFANGER, KARSTEN KÖNIGSTEIN,
CHRISTOPHER KLENK, JUSTIN CARRARD, HENNER HANSSEN, TIMO HINRICHS,
DOUGLAS SEALS, and ARNO SCHMIDT-TRUCKSÄSS

Med. Sci. Sports Exerc., Vol. 53, No. 1, pp. 26–37, 2021.

Purpose: Cardiopulmonary exercise testing (CPET) is an importantmeasurement in clinical practice,
and its primary outcome, maximal oxygen uptake (V˙O2peak), is inversely associated with morbidity and mortality. The purposes of this study are to provide CPET reference values for maximal and submaximal parameters across the adult age spectrum of a healthy European cohort, to compare V˙O2peak values with other reference data sets, and to analyze the associations between physical activity (PA) levels and CPET parameters.
Methods: In this cross-sectional study, we prospectively recruited 502 participants (47% female) from 20 to 90 yr old. The subjects a CPET on a cycle ergometer using a ramp protocol. PA was objectively and continuously measured over 14 d using a triaxial accelerometer. Quantile curves were calculated for CPET parameters. To investigate the associations between CPET parameters and PA levels, linear regression analysis was performed. Results: V˙O2peak values observed in the group of 20–29 yr were 46.6 ± 7.9 and  39.3 ± 6.5 mL·kg−1⋅min−1 for males and females, respectively. On average, each age category (10-yr increments) showed a 10% lower V˙O2peak relative to the next younger age category. V˙O2peak values of previous studies were on average 7.5 mL·kg−1⋅min−1 (20%) lower for males and 6.5 mL·kg−1⋅min−1 (21%) lower for females. There was strong evidence supporting a positive association between theV˙O2peak (mL·kg−1⋅min−1) and the level of habitual PA performed at vigorous PA (estimate, 0.26; P < 0.001].
Conclusion: Maximal and submaximal CPET reference values over a large age range are novel, and differences to other studies are clinically highly relevant. Objectively measured vigorous-intensity PA showed a strong positive association with higher V˙O2peak and other performance-related CPET parameters, supporting
the implementation of higher-intensity aerobic exercise in health promotion.

Franssen WMA; Keytsman C; Marinus N; Verboven K; Eijnde BO; van Ryckeghem L; Dendale P; Zeevaert R;
Hansen D;

Journal of sport and health science [J Sport Health Sci] 2021 Jan 30. Date of Electronic Publication: 2021 Jan 30.

Background: Adults with obesity may display disturbed cardiac chronotropic responses during cardiopulmonary exercise testing (CPET), which relates to poor cardiometabolic health and an increased risk for adverse cardiovascular events. It is unknown whether cardiac chronotropic incompetence (CI) during maximal exercise is already present in obese adolescents and, if so, how that relates to cardiometabolic health.
Methods: Sixty-nine obese adolescents (body mass index (BMI) standard diviation score (SDS) 2.23 ± 0.32, age: 14.1 ± 1.2 years) and 29 lean adolescents (BMI SDS: -0.16 ± 0.84, age: 14.0 ± 1.5 years) performed a maximal CPET from which indicators for peak performance were determined. The resting heart rate (HR) and peak HR were used to calculate the maximal chronotropic response index. Biochemistry (lipid profile, glycemic control, inflammation, and leptin) was studied in fasted blood samples and during an oral glucose tolerance test within obese adolescents. Regression analyses were applied to examine associations between the presence of CI and blood or exercise capacity parameters, respectively, within obese adolescents.
Results: CI was prevalent in 32 out of 69 obese adolescents (46%) and 3 out of 29 lean adolescents (10%). C-reactive protein was significantly higher in obese adolescents with CI compared to obese adolescents without CI (p = 0.012). Furthermore, peak oxygen uptake and peak cycling power output were significantly reduced (p < 0.05) in obese adolescents with CI vs. obese adolescents without CI. The chronotropic index was independently related to blood total cholesterol (standardized coefficient (SC) β =-0.332; p = 0.012) and C-reactive protein concentration (SC β =-0.269; p = 0.039).
Conclusion: CI is more common in the current cohort of obese adolescents, and is related to systemic inflammation and exercise intolerance.