Pandit A; Biomedical Research Center, Baton Rouge,  USA.
Gupta M; Arabie DA; Milton P; Elbatreek M; Goodchild T; Lefer
DJ; Francis J; Moll D; Allerton TD

Obesity. 34(5):984-996, 2026 May.

Heart failure with preserved ejection fraction (HFpEF) now represents the
dominant form of heart failure in the United States. Approximately 80% of
HFpEF patients also live with obesity. This review highlights the central
role of obesity in driving the pathophysiology and clinical presentation
of HFpEF, particularly exercise intolerance, which is the hallmark symptom
of heart failure. We summarize evidence that obesity promotes early
concentric remodeling, diastolic dysfunction, and atrial enlargement while
reducing the diagnostic utility of natriuretic peptides. We also examine
how cardiopulmonary exercise testing (CPET), the gold standard for
assessing exercise capacity, reveals obesity-related impairments in peak
oxygen uptake, chronotropic response, and pulmonary pressures. Beyond
cardiac contributions, obesity amplifies peripheral drivers of exercise
intolerance, including vascular stiffening, endothelial dysfunction,
impaired skeletal muscle oxygen utilization, mitochondrial dysfunction,
and myosteatosis. We also discuss new evidence that the chronic
inflammatory response can drive central and peripheral dysfunction
(systemic fibrosis and skeletal muscle atrophy) to reduce functional
capacity in HFpEF. Together, these findings position obesity as a central,
modifiable determinant of HFpEF and underscore the need for mechanistic
studies targeting skeletal muscle, vascular, and inflammatory pathways.

Tsai YL; Veterans General Hospital, Taichung City, Taiwan.
Chang KM; Chin CS; Hsu CY; Yu YH; Cheng YY; Fu PK

Respirology. 31(5):498-508, 2026 May.

BACKGROUND AND OBJECTIVE: Our previous study demonstrated that a summed
score derived from six cardiopulmonary exercise testing (CPET) parameters
could predict 1-year mortality in patients with interstitial lung disease
(ILD). However, its long-term prognostic value across different ILD
aetiologies remains unclear. This study aimed to assess the predictive
performance of CPET-derived parameters for long-term outcomes in patients
with idiopathic pulmonary fibrosis (IPF) and connective tissue
disease-associated ILD (CTD-ILD).

METHODS: In this prospective cohort study, 210 patients newly diagnosed
with ILD between 2018 and 2022 at a tertiary medical centre underwent
CPET. A CPET-derived summed score was evaluated for its association with a
composite outcome of all-cause mortality or lung transplantation. Cox
regression and receiver operating characteristic curve analyses were used
to examine predictive ability and identify the optimal cutoff value.
Kaplan-Meier survival analysis and log-rank tests compared event-free
survival in IPF and CTD-ILD patients.

RESULTS: A summed score incorporating five CPET-derived variables was an
independent predictor of the composite outcome. Patients with scores of
2-5 had markedly lower event-free survival (44.2%) than those with scores
of 0-1 (88.3%). The score demonstrated consistent predictive value in both
IPF and CTD-ILD.

CONCLUSION: The CPET-derived summed score is a useful prognostic tool for
predicting all-cause mortality or the need for lung transplantation in
newly diagnosed ILD patients. It also retains predictive accuracy for
long-term outcomes in both IPF and CTD-ILD. External validation in other
ILD subtypes is warranted.

Billany RE; Division of Cardiovascular Sciences,, Leicester, UK.
Vadaszy N; Burns S; Chowdhury R; Ford EC; Mubaarak Z;
Sohansoha GK; Yeo JL; Dattani A; Cowley AC; Gulsin GS; Bishop NC; Smith
AC; McCann GP; Graham-Brown MP

Clinical Rehabilitation. 40(5):587-602, 2026 May.

Objectives (1) Explore the effects of a 12-week home-based rehabilitation
programme on cardiorespiratory fitness in kidney transplant recipients;
(2) Compare cardiorespiratory fitness parameters in kidney transplant
recipients and age-sex matched healthy volunteers to aid the justification
for routine rehabilitation programmes.
Design  Pilot randomised controlled
trial with nested case-control. Setting Home-based rehabilitation;
hospital-based outcome assessments. Participants Pilot randomised
controlled trial: 50 stable kidney transplant recipients (>1 year
post-transplant) (randomised 1:1; n = 25 control and n = 25 intervention).
Nested case-control: 30 kidney transplant recipients and 30 healthy
volunteers. InterventionA 12-week home-based aerobic and resistance
rehabilitation programme or guideline-directed care control.Main
measuresCardiorespiratory fitness measured by cardiopulmonary exercise
testing.
Results Pilot randomised controlled trial: After adjusting for
baseline, follow-up values were significantly greater in intervention
compared to control for peak oxygen uptake (VO2peak) mL/kg/min, (+1.50, p
= .03) and maximum workload (+8 W, p = .04) but not VO2peak L/min or
variables at the gas exchange threshold. Higher frequency of aerobic
exercise sessions was associated with greater improvements in
cardiorespiratory fitness (R2 = .252, p = .040). Nested case-control:
VO2peak was reduced in kidney transplant recipients compared to healthy
volunteers (18.81 +/- 4.61 vs 24.06 +/- 5.72 mL/kg/min; p < .01), as was
VO2 at the gas exchange threshold (11.70 +/- 2.67 vs 14.47 +/- 3.39
mL/kg/min; p < .01).
Conclusions A 12-week home-based rehabilitation
programme induced a significant improvement in some cardiorespiratory
fitness variables and higher frequency of aerobic exercise associated with
greater improvements. Cardiorespiratory fitness is significantly impaired
in kidney transplant recipients compared to age-sex-matched healthy
volunteers. Together, these findings highlight the clinical importance of
promoting aerobic exercise and the integration of rehabilitation
programmes into routine care for this population.

Robin Willixhofera, Marlus Karstena,b, Arianna Galottaa, Elisabetta Salvionia, Carlo Vignatia,
Alice Bonomia, Anna Apostoloa, Mauro Continia, Pietro Palermoa, Jeness Campodonicoa,
Beatrice Pezzutoa, Stefania Farinaa, Massimo Mapellia, Irene Mattavellia, Piergiusepe Agostonia,c,*

a) Centro Cardiologico Monzino IRCCS, Milan,
b) Cardiovascular Health and Exercise Research Group (GEPCardio), Department of
Physiotherapy, Graduate Program in Physiotherapy, Santa Catarina State University (UDESC),
Florianopolis, Santa Catarina, Brazil
c) Department of Clinical Sciences and Community Health, Cardiovascular Section, University of
Milan, 20122 Milan, Italy.

Paper not yet published but accepted for publication

Background

Cardiopulmonary exercise testing (CPET) is the gold standard for assessing exertional dyspnea,
providing peak oxygen uptake (VO2), and the VE/VCO2 slope. Different metabolic carts may
introduce systematic variability, confounding longitudinal assessments and multicenter trials.
We evaluated intra-device reliability and inter-device comparability of CPET parameters.

Methods
In this prospective, single-center, within-subject, repeated-measures, multi-device comparison
study 34 healthy adults (35±11 years; 59% males) completed eight CPETs: two per cart, on four
systems (MGC Ultima™ CPX, COSMED Quark CPET™, Schiller PowerCube® Ergo, Vyaire
Vyntus™ CPX). Tests used randomized order, ramp protocols on cycle ergometer, and
standardized calibration, masks, and timing (2–10 days apart; within 40 days). Breath by breath
data were 10-second averaged. Analyses included paired tests for intra-device reliability, repeated-
measures ANOVA for inter-device comparisons, and iso-workload evaluation at 25–100% of
lowest peak workload (ISO-Wpeak).

Results
Intra-device reliability was high, with no significant differences in VO2, heart rate or workload at
anaerobic threshold (AT), respiratory compensation point (RCP) or peak. Minor variances
occurred in resting VO2 (COSMED: 56ml/min, p=0.0427) and peak ventilation (Medical Graphic
9 l/min, p<0.05). Inter-device comparability showed no differences in peak VO2 and the VE/VCO2
slope calculated up to the RCP. The VE/VCO2 slope assessed as the full slope however, showed
significant differences between machines (p=0.0048). Across standardized ISO-Wpeak (25%,
50%, 75%, and 100% of ISO-Wpeak), VO2 values were largely comparable between devices, with
significant differences only for VO2 (ml/kg/min) at 25% ISO-Wpeak (p=0.022).

Conclusion
Under standardized conditions, the tested metabolic carts yield comparable values both for intra-
device reliability and inter-device comparability.

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.