M. Lokietek, A. Marionneau, S. Lecoq, S. Henni, M. Houle and P. Abraham

Respir Physiol Neurobiol 2026 Vol. 343 Pages 104573

BACKGROUND AND OBJECTIVE: During cardiopulmonary exercise testing (CPET), the alveolar-arterial oxygen gradient varies with exercise intensity, but direct assessment is limited by the invasiveness of arterial sampling. End-tidal oxygen pressure (PETO(2)) and transcutaneous oxygen pressure (PtcO(2)) may provide non-invasive estimates of alveolar and arterial oxygen pressures. This study aimed to identify the statistical model that best characterize the relationship between the end-tidal to transcutaneous oxygen pressure gradient (ET-tcDO(2)) and oxygen uptake (VO(2)) in apparently healthy individuals. METHODS: This retrospective study analyzed medical records (n = 68) from incremental CPETs performed with PtcO(2) monitoring. Breath‑by‑breath PETO(2) and VO(2) data from CPET tests were also extracted. The relationship between ET‑tcDO(2) and VO(2) was then characterized using functional data analysis (FDA) and polynomial regression models of increasing degree.
RESULTS: FDA demonstrated high modeling accuracy (adjusted R(2) = 0.96). ET-tcDO2 decreased at onset of exercise, until VO2 = 1.26 L/min, and then increased until maximal exercise. Among polynomial regression models, the polynomial of the third degree best described this relationship (adjusted R(2) = 0.48). At the individual level, most responses followed a polynomial of the third degree, with 75% of participants exhibiting an adjusted R(2) above 0.7.
CONCLUSION: Continuous PtcO(2) monitoring enables detailed characterization of exercise-induced alveolar-arterial gas exchange in apparently healthy individuals. ET-tcDO(2) follows a polynomial of the third-degree during CPET. The combined use of PETO(2) and PtcO(2) may offer a simple, non-invasive approach for assessing alveolar-arterial gas exchange in routine clinical practice that should be further investigated.

Lin KY; Department of Paediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Bucha A; McSweeney K; Wade KL; Karaj A; Tamaroff J; O’Malley S;
Chung NM; Cilenti NA; Wanner J; Adzika GK; Mesaros C; Blair IA;
Rojsajjakul T; Serai S; Farmer J; Bryant K; Lu Y; Harhay MO; Weber DR;
Paridon SM; Seifert EL; Putt ME; Zamani P; Baur JA; Lynch DR; McCormack SE

Lancet Neurology. 25(5):469-481, 2026 May.

BACKGROUND: Friedreich’s ataxia is a rare, chronic, progressive,
neurodegenerative condition affecting multiple organ systems, including
neurological, musculoskeletal, cardiac, and endocrine systems, and is
marked by low cardiopulmonary fitness. We tested the effect of exercise
and NAD+ precursor supplementation with nicotinamide riboside, which have
each shown benefits in animal and early clinical studies, on
cardiopulmonary fitness in individuals with Friedreich’s ataxia.

METHODS: This 12-week, outpatient, phase 2, single-site (Children’s
Hospital of Philadelphia, Philadelphia, PA, USA), randomised, 2 x 2
factorial clinical trial recruited individuals aged 10-40 years with an
ejection fraction of 45% or greater who were able to exercise. A
computer-generated randomisation sequence was developed by the trial
statistician. Random allocation was age-stratified (<18 years vs >=18
years) to one of four groups: placebo and no exercise with attention
control (weekly phone calls; henceforth placebo only), nicotinamide
riboside and no exercise with attention control (henceforth nicotinamide
riboside only), placebo and exercise (exercise only), and nicotinamide
riboside and exercise (combination therapy). Individualised exercise plans
were developed by the exercise physiologist (three aerobic and two
resistance training sessions weekly), performed at the individual’s home,
and overseen remotely (telephone check-ins by the physiologist).
Weight-based dosing of nicotinamide riboside or placebo was 300 mg (1
capsule) for weights of 24 kg up to 48 kg, 600 mg (2 capsules) for weight
48 kg up to 72 kg, and 900 mg (3 capsules) for weights of over 72 kg. The
primary outcome was change in peak VO2 (L/min) during cardiopulmonary
exercise testing at 12 weeks versus baseline, and the effect of treatment
group was assessed in a statistical model accounting for age
(stratification variable), sex, and baseline peak VO2. Stage 1 analysis
tested the difference between each active treatment versus the control
group, and stage 2 analysis (if combination therapy was effective) tested
the difference between combination treatment and exercise alone;
family-wise type 1 error was maintained <0.05. Analyses were by
intention-to-treat. Adverse events were recorded systematically. This
trial is registered with ClinicalTrials.gov (NCT04192136) and is complete.

FINDINGS: Between Sept 3, 2020, and April 23, 2025, we enrolled 74
individuals, of whom 66 met the eligibility criteria and were randomly
allocated to the four study groups. All participants completed the study.
33 (50%) were children (aged 10-17 years) and 33 (50%) were adults (aged
>=18 years); 37 (56%) were male and 29 (44%) were female. Least mean
squares for the change in peak VO2 in L/min were -0.05 (95% CI -0.16 to
0.06) for the 17 participants in the control group; 0.06 (-0.05 to 0.17)
for the 17 participants in the nicotinamide riboside and no exercise
group; 0.11 (0.00 to 0.22) for the 16 participants in the placebo and
exercise group; and 0.16 (0.05 to 0.27) for the 16 participants in the
nicotinamide riboside and exercise group. Differences between active
treatment and the control group were 0.10 (95% CI -0.05 to 0.26;
padjusted=0.188) for nicotinamide riboside and no exercise; 0.16 (0.00 to
0.31; padjusted=0.103) for placebo and exercise; and 0.21 (0.05 to 0.36;
padjusted=0.0299) for nicotinamide riboside and exercise in combination.
Combination therapy was not statistically different from exercise alone
(difference -0.05 ([95% CI -0.10 to 0.21]; p=0.49). Adverse events were
all mild or moderate, and included gastrointestinal symptoms, falls, upper
respiratory infections, and skin rashes. At least one moderate adverse
event of interest in these categories was reported by seven (41%)
participants in the control group; six (35%) in the nicotinamide riboside
and no exercise group; three (19%) in the placebo and exercise group; and
four (25%) in the nicotinamide plus exercise group.

INTERPRETATION: The combination of nicotinamide riboside plus exercise
for 12 weeks was safe and increased cardiopulmonary fitness in children
and adults with Friedreich’s ataxia. Longer studies are needed to
establish whether adding nicotinamide riboside to exercise could be
considered as part of a long-term, comprehensive treatment approach.

Yang F;  Air Force Health Care Center for Special Services, Hangzhou, China.
Tan W; Tian Y; Wu Q; Feng X; Hu G; Li O

Physiological Reports. 14(8):e70864, 2026 Apr.
Headings added by Dr Older

AIM
To evaluate altitude-stratified differences in static lung function,
aerobic capacity, and exercise physiology under standardized normoxic
conditions, and identify multiple predictors of peak oxygen uptake (VO2)
reduction among asymptomatic men after prolonged residence at varying
altitudes.
METHODS
We conducted a cross-sectional study of 103 asymptomatic men
stratified by residential altitude: low (<2500 m; n = 35), high (2500-3500
m; n = 32), and very high (>3500 m; n = 36). All underwent spirometry,
fasting blood tests, and symptom-limited cardiopulmonary exercise testing
(CPET) in normoxia.
RESULTS
Multiple linear regression identified independent
predictors of peak VO2/kg. Very high-altitude residents had significantly
lower peak VO2/kg (-13.4 mL.min-1.kg-1 vs. low altitude, p < 0.001),
reduced oxygen pulse, and impaired small-airway function (MMEF, FEF75; p <
0.05), despite preserved ventilatory efficiency (VE/VCO2 slope, p =
0.782). Hemoglobin was elevated at higher altitudes; triglycerides were
higher only above 3500 m. Age (beta = -0.285), regular exercise (>=3
sessions/week; beta = +3.648), and very high-altitude residence (beta =
-13.370) independently predicted peak VO2/kg (all p < 0.001; R2 = 0.739).
CONCLUSIONS
Residence above 3500 m causes persistent cardiopulmonary impairment driven
by circulatory limitations and smoking, despite preserved ventilatory
efficiency. Normoxic assessment identifies regular exercise (>=3
sessions/week) as a key countermeasure against altitude-induced
deconditioning. Prioritizing smoking cessation and mandatory exercise
programs is therefore recommended for long-term health in high-altitude
personnel.

Cloud JA; The Ohio State University, Columbus, USA.
Howe IA; Kraemer WJ; Volek JS; Hayes JP; Hayes SM

Scientific Reports. 16(1), 2026 Mar 11.

Tasks associated with unilateral patterns of functional magnetic resonance
imaging (fMRI) activation often demonstrate bilateral activation with
aging (hemispheric asymmetry reduction). We examined relationships between
the modifiable lifestyle variable cardiorespiratory fitness (CRF),
hemispheric asymmetry reduction, and visuomotor task performance in
middle-aged and older adults. Sixty-four participants aged 35-86 years
completed progressive, maximal cardiopulmonary exercise testing to assess
VO2peak and a standardized test of motor coordination, the Grooved
Pegboard Test. fMRI was acquired during a visuomotor task requiring a
right-hand motor response. The relationships between hemispheric asymmetry
during the fMRI task, CRF, and performance on simple (fMRI task) and
complex (Grooved Pegboard Test) motor tasks were examined. Age moderated
the relationship between CRF (VO2peak) and hemispheric asymmetry. Among
middle-aged adults, greater VO2peak was associated with more hemispheric
asymmetry; no association was observed in older adults. Age marginally
moderated the relationship between hemispheric asymmetry and Grooved
Pegboard performance. Among middle-aged adults, greater hemispheric
asymmetry was marginally associated with better performance; among older
adults, reduced asymmetry showed a trending association with better
performance. These findings highlight age-related differences in the
relationship between CRF, behavioral performance, and fMRI activation and
emphasize the importance of investigating brain function, cognition, and
age across the adult lifespan.

Willixhofer R; Centro Cardiologico Monzino, IRCCS Milan Italy.
Mapelli M; Baracchini N; Campana N; Capovilla TM; Nava A;
Salvioni E; Vignati C; Rubbo FM; Magri D; Fiori E; Pezzuto B; Mattavelli
I; Apostolo A; Palermo P; Campodonico J; Contini M; Costantino S; Carriere
C; Tavcar I; Rossi M; Cadeddu Dessalvi C; Merlo M; Sinagra G; Agostoni P

Journal of the American Heart Association. 15(8):e046438, 2026 Apr 21.

BACKGROUND: The RoMa classification, based on peak heart rate and oxygen
pulse derived from cardiopulmonary exercise testing, was recently proposed
to stratify patients with hypertrophic cardiomyopathy by physiological
reserve during exercise. We aimed to externally validate RoMa in an
independent multicenter cohort with hypertrophic cardiomyopathy and assess
its association with long-term clinical outcomes.

METHODS: In this retrospective multicenter cohort study patients with
hypertrophic cardiomyopathy, undergoing cardiopulmonary exercise testing,
were consecutively enrolled. Patients were enrolled regardless of left
ventricular outflow tract obstruction and were naive to disease-specific
therapy (eg, mavacamten). Patients were categorized into RoMa I to IV
based on percentage of predicted heart rate and oxygen pulse. The primary
end point was a composite of all-cause and cardiovascular death, sudden
cardiac death, or aborted sudden cardiac death, heart failure-related
hospitalization, stroke, systemic embolism, surgical myectomy, and heart
transplantation.

RESULTS: The study included 292 patients (age 51 [36-63] years, 70% male
sex, 30% with obstructive left ventricular outflow tract). Functional
capacity declined hierarchically across RoMa groups (peak oxygen uptake
29.2 to 17.9 mL/kg/min; P-trend <0.001). During follow-up (=6 years), 68
composite events occurred. Kaplan-Meier analysis showed significant
differences in event-free survival across groups (log-rank P=0.019). In
multivariable analysis, RoMa II to IV compared with RoMa I were
independently associated with higher hazard ratios (HRs) for the composite
outcome (HRs, 3.89-5.37; all P<0.05), whereas genotype, LVEF <50%, male
sex, and left ventricular outflow tract obstruction were not predictive.

CONCLUSIONS: The RoMa classification independently predicts long-term,
clinically relevant outcomes in hypertrophic cardiomyopathy regardless of
left ventricular outflow tract obstruction and may provide a novel
approach to risk stratification.

Boccia G; University of Torino, 10043 Orbassano, Italy.
Beratto L; Tarperi C; Rainoldi A; Calliera C; Ierace D; Satolli
MA; Bo S; Costelli P

Medical Sciences. 14(2), 2026 Apr 07.

BACKGROUND: Patients with pancreatic cancer (PC) commonly present with
reduced aerobic fitness, sarcopenia, and malnutrition, which may increase
perioperative risk and compromise access to chemotherapy treatments.
Although exercise-based prehabilitation can improve physical fitness, its
implementation is often limited by short diagnostic-to-surgery intervals
and treatment-related toxicity.

METHODS: We conducted a pilot prospective pretest-posttest feasibility
study in Torino, Italy. Patients with PC undergoing neoadjuvant
chemotherapy prior to surgery were offered a 4-week, partially supervised,
home-based bimodal exercise prehabilitation program (single-arm design)
combining remotely monitored high-intensity interval training (HIIT) on a
cycle ergometer with functional and resistance exercises. The primary
outcome was adherence to prescribed exercise frequency, intensity, and
duration, objectively assessed via remote monitoring. Secondary outcomes
included cardiorespiratory fitness (CPET), muscle function, body
composition, fatigue, quality of life, and circulating inflammatory
markers.

RESULTS: From July 2022 to February 2024, 23 patients were screened; 15
were eligible and 10 enrolled. Four participants discontinued the
intervention (two due to asthenia/fatigue, one due to chemotherapy-related
adverse events, and one for organizational reasons), leaving six
participants who completed the program. Among completers, fatigue and
quality of life did not change meaningfully. Aerobic capacity and muscle
function outcomes were generally stable, with few pre-post changes
exceeding the minimum clinically important difference (MCID) thresholds
used. Body composition markers and the assessed circulating
cytokines/chemokines remained unchanged except for IL-6 levels, which
decreased significantly (p < 0.05).

CONCLUSIONS: A partially supervised, home-based HIIT-based
prehabilitation program is feasible for a subset of PC patients undergoing
neoadjuvant therapy, but a substantial attrition rate suggests the need
for more flexible symptom-adapted prescriptions and enhanced supportive
strategies.

(Obstructive sleep apnoea) Definition of OSA by Dr Older

Mouraux S; Department of Medicine, University of Lausanne
Lechartier B; Imler T; von Garnier C; Heinzer R; Vollenweider
P; Preisig M; Solelhac G; Touilloux B

Chest. 169(4):1091-1100, 2026 Apr.

BACKGROUND: Dyspnea increases mortality and remains unexplained in 15% of
patients. Although OSA is linked to reduced exercise capacity during
cardiopulmonary exercise testing, the association between dyspnea and OSA
remains uncertain.

RESEARCH QUESTION: Is there an association between exertional dyspnea and
OSA in the general population? What are the polysomnographic OSA-related
measures associated with exertional dyspnea?

STUDY DESIGN AND METHODS: We used data from a prospective cohort study of
the general population conducted in an urban area. Participants underwent
polysomnography and completed a respiratory questionnaire. Logistic
regression models were used to determine the association between
self-reported dyspnea (modified Medical Research Council Dyspnea scale >=
1) and OSA categories or apnea-hypopnea index (AHI) cutoffs. We performed
an adjusted model for sex, BMI, age, FEV1, psychiatric disorders, cardiac
and respiratory disorders, and smoking history.

RESULTS: We included 1,200 participants (mean age, 62.1 years; 54%
female), of whom 515 (42.9%) reported exertional dyspnea. The adjusted
model revealed a positive association between exertional dyspnea and AHI
>= 15 events/h (OR, 1.57; 95% CI, 1.13-2.19), AHI >= 30 events/h (OR,
1.72; 95% CI, 1.06-2.78), moderate OSA (OR, 1.60; 95% CI, 1.04-2.46), and
severe OSA (OR, 2.25; 95% CI, 1.28-3.96). Moreover, in the adjusted model,
dyspnea was associated with AHI, respiratory disturbance index,
respiratory pulse wave amplitude drop index, sleep apnea-specific
pulse-rate response, respiratory arousal index, and oxygen desaturation
index 3%.

INTERPRETATION: Our results suggest that exertional dyspnea is associated
with moderate and severe OSA, potentially due to heightened autonomic and
cortical responses to increased respiratory efforts. Further research is
needed to assess the effectiveness of OSA treatment on dyspnea in patients
with OSA.

Moncion K; School of Physical & Occupational Therapy, McGill University, Quebec, CANADA
Rodrigues L; DE Las Heras B; Wiley E; Sikorska K; Cristini J;
Allison EY; Eng JJ; Tang A; Roig M

Medicine & Science in Sports & Exercise. 58(5):1073-1084, 2026 May 01.

BACKGROUND: Accurate assessment of cardiorespiratory fitness is a critical
component of cardiopulmonary exercise testing (CPET) and prescription for
people with stroke. However, post-stroke disability and neuromuscular
impairments are common and may disproportionately affect females
throughout the continuum of recovery. There is a need to evaluate
alternative whole-body CPET protocols and to characterize the sex-specific
CPET responses throughout the continuum of stroke recovery.

PURPOSE: To characterize the sex-specific CPET responses on a whole-body
recumbent stepper CPET using American College of Sports Medicine (ACSM)
criteria in people with subacute (7-90 d) and chronic (>=6-60 months)
stroke.

METHODS: Participants underwent a whole-body recumbent stepper
symptom-limited CPET. Each CPET was assessed for ventilatory threshold
(VT), peak oxygen uptake ( ) and ACSM maximal oxygen uptake criteria,
including respiratory exchange ratio >=1.10; plateau, heart rate (HR)
within 10 beats of HRmax, and ratings of perceived exertion (RPE) >=17/20
or >=7/10. Sex differences by stroke chronicity were evaluated via t
tests, rank-sum tests, chi 2 , or Fisher exact tests.

RESULTS: In total, 145 participants underwent a symptom-limited CPET. In
subacute stroke ( n = 69), no sex differences were found for VT or ( P >
0.05), but females were more likely to achieve a plateau ( P = 0.002). In
chronic stroke ( n = 76), no sex differences were observed for VT or
criteria ( P > 0.05), but females had lower ( P = 0.002). Irrespective of
sex, achieving the RPE ( n = 41 subacute [61%], n = 38 chronic [54%]) or
respiratory exchange ratio criteria ( n = 28 subacute [41%], n = 39 [51%])
was the most commonly met ACSM criteria.

CONCLUSIONS: This whole-body CPET protocol is appropriate for eliciting
peak and maximal efforts in people post-strok

Filakovszky A; Department of Anesthesiology and Critical Care Linz, Austria.
Brat K; Tschoellitsch T; Bartos S; Mazur A; Meier J; Olson L;
Cundrle I

Thorax. 81(5):474-482, 2026 Apr 16.

RATIONALE: Despite significant advances in patient care and outcomes,
criteria for cardiopulmonary exercise testing (CPET) in risk
stratification guidelines for lung resection have not been updated in over
a decade. We hypothesised that CPET no longer holds additional predictive
value for postoperative complications.

METHODS: In this secondary analysis, we included lung resection
candidates from two prospective, multicentre studies eligible for CPET and
assessed with preoperative pulmonary function tests (PFTs) and arterial
blood gas analysis. Postoperative pulmonary (PPCs) and cardiovascular
complications (PCCs) were documented during hospitalisation. We trained
five types of machine learning models applying nested cross-validation to
predict complications and compared predictive performance based on four
metrics, including area under the receiver operating characteristic curve
(AUC-ROC).

RESULTS: A total of 497 patients were included. PPCs developed in 71
(14%) patients. Adding CPET parameters to PFTs and baseline clinical data
did not improve the ability of models to predict PPCs in unselected
patients (AUC-ROC=0.72-0.78; p=0.47), nor in those meeting American
College of Chest Physicians (ACCPs) (n=236; AUC-ROC=0.64-0.78; p=0.70) or
European Respiratory Society/European Society of Thoracic Surgery
(ERS/ESTS) criteria (n=168; AUC-ROC=0.59-0.76; p=0.92). PCCs developed in
90 (18%) patients. CPET parameters likewise did not improve model
performance for the prediction of PCCs in unselected patients
(AUC-ROC=0.65-0.73; p=0.96), nor in the ACCP (AUC-ROC=0.61-0.73; p=0.82)
or ERS/ESTS subgroups (AUC-ROC=0.62-0.69; p=0.87).

CONCLUSIONS: In contemporary surgical practice, CPET did not improve the
predictive performance of machine learning models for PPCs or PCCs in
patients with an indication based on established guidelines or in those
without. The role of CPET in preoperative risk stratification for lung
resection should be re-evaluated.

Caligiuri SPB; Department of Health Sciences, Virginia USA
Ravandi A; Aukema HM; Shah AH

American Journal of Physiology – Heart & Circulatory Physiology.
330(5):H1466-H1478, 2026 May 01.

The Fontan procedure enhances systemic oxygenation and survival in
patients with complex congenital heart defects not amenable to
biventricular repair. Despite these improvements, individuals with Fontan
circulation often develop progressive multisystem dysfunction, the
biochemical underpinnings of which remain poorly understood. Oxylipins are
bioactive lipid mediators implicated in cardiovascular disease and
represent targetable pathways that may contribute to the pathophysiology
of the Fontan state. The study aims to quantify plasma oxylipins in
individuals with Fontan circulation, compared with matched controls, and
assess correlations with hemodynamic function and exercise capacity. A
total of 20 adult patients with Fontan circulation and 20 matched controls
underwent assessment of body composition, frailty, cardiopulmonary
exercise testing, and noninvasive hemodynamic evaluation. Absolute plasma
oxylipin concentrations were measured using triple quadrupole HPLC-MS/MS.
Compared with controls, Fontan participants exhibited significantly
increased (34%) total plasma oxylipin concentrations, with a 42% elevation
in omega-6 fatty acid-derived oxylipins. Among these, metabolites
generated via the 15-lipoxygenase (15-LOX) pathway were elevated by 52%.
In addition, product-to-substrate ratios reflecting putative soluble
epoxide hydrolase (sEH) activity for omega-6 fatty acids were nearly
threefold higher in the Fontan group. Several oxylipins derived from
omega-3 and omega-6 fatty acids, including those generated by 15-LOX and
sEH pathways, demonstrated significant correlations with key clinical
parameters, including resting and exercise hemodynamics, ventilatory
efficiency, and peak oxygen consumption (Vo2). Individuals with Fontan
circulation exhibit marked alterations in circulating oxylipins,
particularly those involving omega-6 fatty acid metabolism via 15-LOX and
sEH. These findings offer mechanistic insights and identify potentially
modifiable targets. NEW & NOTEWORTHY Fontan patients exhibit a distinct
oxylipin signature characterized by markedly elevated total and
omega-6-derived oxylipins, including increased 15-LOX activity and higher
sEH product-to-substrate ratios, alongside reduced omega-3 species such as
20-hydroxydocosahexanoic acid (20-HDoHE) and
17,18-dihydroxyeicosatetraenoic acid (DiHETE). Elevated omega-6 oxylipins
correlated with poorer exercise capacity, greater frailty, and impaired
hemodynamics, whereas omega-3 oxylipins showed the opposite trend. These
findings identify oxylipin dysregulation as a central metabolic hallmark
and potential therapeutic target in Fontan circulation.