Braggio M; Department of Diagnostics and Public Health, Verona, Italy.
Ceolan J; Minoia A; Villaboni S; Mazzi F; et al

BACKGROUND: Transfusion-dependent beta-thalassemia (TDT) is characterized
by reduced exercise capacity due to chronic hemolytic anemia, iron
overload cardiomyopathy, and potential skeletal muscle alterations. Early
cardiovascular and muscular dysfunction in the absence of cardiac iron
overload remains poorly characterized.

METHODS: In this exploratory study, 9 TDT patients without cardiac iron
overload and with normal body mass index (BMI) were matched with 9 healthy
controls. Cardiopulmonary exercise testing combined with lung ultrasound
(LUS-CPET) was used to assess exercise-induced lung congestion and
diastolic dysfunction. Serum biomarkers of endothelial activation (ICAM-1)
and muscle-metabolic function (FGF21, miR-577) were evaluated. Resting
echocardiography, handgrip strength, and body composition by bioelectrical
impedance analysis (BIA) were also assessed.

RESULTS: At rest, cardiac output and diastolic function were comparable
between groups. However, during LUS-CPET, TDT patients exhibited
significantly lower VO2max, O2 pulse, and chronotropic index, along with
increased B-lines, consistent with exercise-induced diastolic dysfunction.
TDT patients also showed reduced lean body mass and handgrip strength.
FGF21 levels were elevated at rest and post-exercise, whereas miR-577
levels were reduced. Post-exercise ICAM-1 levels were significantly higher
in TDT patients compared to controls.

CONCLUSIONS: LUS-CPET may represent a useful non-invasive approach to
identify early exercise-induced diastolic dysfunction in TDT patients
without cardiac iron overload. Altered FGF21 and miR-577 profiles suggest
the presence of metabolic dysregulation associated with early skeletal
muscle deconditioning.

Liu R; Beijing Friendship Hospital, China and other centres in USA and Brazil
Arena R; Santos-de-Araujo AD; Borghi-Silva A; Popovic D

Current Problems in Cardiology. 51(10):103399, 2026 Oct.

BACKGROUND: Atherosclerotic cardiovascular disease remains a leading cause
of morbidity and mortality worldwide. Established risk equations guide
prevention but rely mainly on static, clinic-based variables and
incompletely capture physical activity, sedentary behavior, and
cardiorespiratory fitness.

METHODS: This narrative review synthesizes evidence from epidemiological
studies, clinical trials, and methodological frameworks on the roles of
physical activity, sedentary behavior, and cardiorespiratory fitness in
cardiovascular risk prediction, with emphasis on digital phenotyping,
mechanistic exercise physiology, and multimodal clinical prediction
models.

RESULTS: Cardiorespiratory fitness reflects integrated physiological
reserve and is strongly associated with cardiovascular and all-cause
outcomes. Cardiopulmonary exercise testing extends fitness assessment by
identifying mechanisms of exercise limitation, including cardiac,
ventilatory, autonomic, pulmonary vascular, and peripheral contributors.
Wearable technologies provide longitudinal, real-world measures of
physical activity and sedentary behavior that complement static clinical
risk factors. Multimodal models integrating electronic health records,
electrocardiography, imaging, wearable signals, and exercise testing may
support more personalized and actionable risk stratification. However, the
current evidence base remains limited by insufficient external and
prospective validation, incomplete calibration reporting, limited
decision-analytic evaluation, and inadequate assessment of subgroup
performance and equity.

CONCLUSIONS: Physical activity and cardiorespiratory fitness should be
considered clinically relevant and modifiable phenotypes in contemporary
cardiovascular risk prediction. Future models should prioritize
standardized measurement, mechanistic validation of digital phenotypes,
calibration, external validation, subgroup evaluation, workflow
feasibility, and prospective evidence of clinical utility before
widespread implementation.

Wypyrsczyk L; Johannes Gutenberg-University Mainz,  Germany
Kuhn M; Dreismickenbecker E; Neu MA; et al

Pediatric Hematology & Oncology. 43(5):227-240, 2026 Aug.
Headings by Dr Older

Background The 6-min cycling test (6MCT), a submaximal endurance test, has not yet
been applied in pediatric oncology. This study evaluates its feasibility
and validity in 71 childhood cancer patients (9.6 +/- 4.0 years).
Methods For validation, 46 patients additionally underwent cardiopulmonary exercise
testing (CPET). Performance in the 6MCT (total revolutions) was correlated
with peak oxygen uptake (VO2peak) and peak work rate (WRpeak) using
Spearman’s correlation. Linear regressions assessed the predictive value
of VO2peak and WRpeak on 6MCT performance. Sixty-six participants (93%)
successfully completed the 6MCT, averaging 550 +/- 129 revolutions.
Results Revolutions correlated moderately with VO2peak (rho = 0.46, p = 0.001) and
strongly with WRpeak (rho = 0.64, p < 0.001). VO2peak significantly
predicted 6MCT performance (p = 0.001, R2 = 0.214), whereas WRpeak
explained more variance (p < 0.001, R2 = 0.488).
Conclusions The results demonstrate that the 6MCT is a feasible, valid endurance assessment in this
population, offering a promising alternative when gold standard testing is
not available.

Floriani AF; S. Valentino Hospital, Montebelluna, Italy.
Menzella F

Expert Review of Respiratory Medicine. 20(8):963-974, 2026 Aug.

INTRODUCTION: Persistent exertional dyspnea remains a major unmet need in
patients with difficult-to-treat and severe asthma, even in the era of
optimized inhaled therapy and biologics. Resting lung function and
inflammatory biomarkers often fail to explain exercise intolerance,
leading to empirical step-up therapy without clear physiological
justification.

AREAS COVERED: This review discusses the role of cardiopulmonary exercise
testing (CPET) in the evaluation of exertional dyspnea in
difficult-to-treat and severe asthma, within the treatable traits
framework. The review focuses on the main CPET-derived physiological
patterns, including ventilatory limitation, dynamic hyperinflation,
ventilatory inefficiency, dysfunctional breathing, deconditioning,
cardiovascular limitation, exercise-induced laryngeal obstruction, and
normal exercise physiology. It also examines how CPET may influence
step-up decisions, support trait-directed interventions, and inform
pharmacoeconomic considerations. A pragmatic clinical framework for
selective integration of CPET into severe asthma assessment is proposed.

EXPERT OPINION: CPET may represent a valuable physiological adjunct in
selected patients with difficult-to-treat or severe asthma and persistent
exertional dyspnea insufficiently explained by resting assessments. Its
integration into the assessment pathway may help contextualize symptoms,
distinguish asthma-driven exercise limitation from non-inflammatory or
non-asthmatic causes of dyspnea, and support more mechanism-based
management. However, current evidence supports CPET primarily as a tool
for physiological phenotyping and trait reclassification rather than as a
prospectively validated guide to treatment escalation, biologic
stewardship, or long-term outcome improvement.

Rojas Vega S; German Sport University Cologne, Germany,
Solera-Herrera A; Vafa R; Acero-Moreno D; et al

Journal of Diabetes Research. 2026(1):e1311227, 2026.

BACKGROUND: Diabetes is associated with an increased risk of cognitive
dysfunction. We are aimed at examining cognitive performance in people
with Type 2 diabetes mellitus (T2DM) and their correlation with physical
activity (PA)/fitness level and mood.

METHODS: A cross-sectional study involving 47 individuals with T2DM, 30
diabetes-free individuals (controls): ages of 40-65 years and without
dementia. Subjects were evaluated using a neuropsychological test battery
that included Stroop, VLMT, CORSI, TMT and neuropsychiatric scales. The
Global Physical Activity Questionnaire (GPAQ) was assessed. Physical
fitness was evaluated using a maximal cardiopulmonary exercise testing
(CPX).

RESULTS: Compared with controls, people with T2DM had lower
cardiorespiratory fitness (CRF) and more frequent cognitive performance
below 1 SD of the normative value. Those individuals with T2DM, who
displayed low fitness, showed significantly poorer cognitive inhibition
(Stroop, p < 0.001), processing speed (TMT-A, p < 0.001), cognitive
flexibility (TMT-B, p < 0.001), visuospatial memory (CORSI, p < 0.001) and
memory consolidation (VLMT, p < 0.001). Higher ventilatory and metabolic
CRF markers and higher PA levels correlated significantly with higher
cognitive performance. None of the neuropsychological or psychiatric
background variables correlated significantly with any of the cognitive
scales.

CONCLUSIONS: Individual CRF markers and PA levels correlated positively
with cognitive performance in people with T2DM and in nondiabetic
individuals. However, individuals with T2DM showed at least two to three
times more frequent cognitive performances more than 1 SD below norm as
compared with controls. Among people with T2DM, those with low aerobic
fitness/PA levels showed significantly lower cognitive performance,
especially in the attention-concentration, executive functioning, episodic
memory and visuospatial processing domains.

Morris TA; University of California San Diego, La Jolla, CA, USA
Dakaeva K; Alotaibi M; McGuire WC; et al

European Respiratory Journal. 68(2), 2026 Aug.

BACKGROUND: Chronic dyspnoea and exercise impairment are common after
acute pulmonary embolism (PE) but poorly characterised. We performed a
prospective observational study to validate an algorithm to diagnose
discrete post-PE outcomes, including chronic thromboembolism phenotypes.

METHODS: Six pulmonologists independently reviewed records from 150
consecutive patients >=3 months after acute PE who had undergone a
stepwise diagnostic algorithm (SEARCH), which incorporates Symptom
screening, cardiopulmonary Exercise testing, pulmonary Arterial perfusion
scans, Resting echocardiography, Confirmatory imaging, and Haemodynamic
measurements by rest and exercise right heart catheterisation (RHC).
Clinical data were reviewed after the first post-PE evaluation and then 6
months later.

RESULTS: Symptomatic recovery was most common and occurred in 66.2% of
patients during the final evaluation. Dyspnoea without discernible
physiological defects occurred in 2.1% and dyspnoea from alternative
diagnoses in 19.7%. Chronic thromboembolism phenotypes were diagnosed in
12.0% of patients. Chronic thromboembolism with ventilatory inefficiency
and/or small stroke volume augmentation during exercise was seen in 6.3%:
2.1% without pulmonary hypertension on RHC and 4.2% in whom RHC was not
performed. Chronic thromboembolic pulmonary hypertension and chronic
thromboembolism with exercise-induced pulmonary hypertension occurred in
2.1% and 3.5%, respectively. Krippendorff’s alpha among the readers was
0.984 (95% CI 0.9663-0.9960), signifying very high diagnostic reliability.
No patient developed chronic thromboembolism between the first and final
evaluations.

CONCLUSIONS: Dyspnoea from chronic thromboembolism is common after acute
PE, most of which is not associated with pulmonary hypertension. The
SEARCH protocol reliably identifies chronic thromboembolism phenotypes
after acute embolism. Validation of the SEARCH algorithm offers clinicians
a straightforward method to diagnose post-PE conditions that are rarely
distinguished clinically. Improved categorisation and definition of
post-PE conditions will enhance clinical follow-up and allow more precise
end-point adjudication in clinical trials of acute PE treatment.

Scussel A; Hospital de Clinicas de Porto Alegre, Brazil
Rodrigues NG; Santos AZ; Trombin LCB; et al

European Journal of Applied Physiology. 126(8):4567-4579, 2026 Aug.

PURPOSE: Smokers with preserved ratio impaired spirometry (PRISm) present
reduced forced expiratory volume in the first second (FEV1 < 80%
predicted) but preserved FEV1/forced vital capacity (FVC) >= 0.7. Although
they do not meet diagnostic criteria for chronic obstructive pulmonary
disease (COPD), they often report respiratory symptoms and exercise
intolerance. We aimed to compare sensory and physiological responses to
exercise between smokers with PRISm and matched healthy controls. Patients
with mild-to-moderate COPD were included as a reference group.

METHODS: In this cross-sectional study, smokers (> 10 pack-years) from a
specialized outpatient clinic were evaluated. Thirteen participants (11
females; 62.4 +/- 7.7 years) with PRISm and 13 age- and sex-matched
patients with mild-to-moderate COPD (FEV1/FVC < 0.7; FEV1 > 50% predicted)
underwent incremental cardiopulmonary exercise testing on a cycle
ergometer. Data from healthy nonsmoking controls were obtained from
previous studies.

RESULTS: PRISm and COPD groups had similarly reduced FEV1 (~ 72%
predicted) compared to controls (97% predicted), whereas FVC was lower in
PRISm (73% predicted) than in COPD and controls (~ 95% predicted). Both
patient groups showed higher ventilation, reduced ventilatory reserve, and
greater dyspnoea at a given submaximal workload versus controls. Increased
tidal volume/inspiratory capacity ratios were also observed, contributing
to greater dyspnoea for a given ventilation and lower peak work rate (42
+/- 16 vs. 68 +/- 11 vs. 94 +/- 17% predicted, respectively; all P <
0.05).

CONCLUSION: Smokers with PRISm exhibit increased dyspnoea and reduced
exercise tolerance compared to healthy controls, largely driven by
excessive ventilatory demand and reduced ventilatory capacity during
submaximal exercise.

Saito S; Faculty of Medicine,Hokkaido University, Sapporo,  Japan.
Temma T;  Watanabe M   Kadosaka T; et al

Heart Vessels Aug 5th 2026
Headings added by Dr Older

Keywords: Cardiac sympathetic nerve activity; Cardiac sympathoexcitation; T peak to T end interval; T peak to T end interval to Q-T end interval ratio; Ventricular sympathoexcitation.

Robbins JM; Beth Israel Deaconess Medical Center, Boston, MA USA
Benson M; Verkerke ARP; Tiwari G; et al

Circulation. 153(1):47-58, 2026 Jan 06.

BACKGROUND: Cardiorespiratory fitness is an integrative measure of
cardiometabolic health and predictor of survival, yet little is known
about its molecular underpinnings. Small molecule metabolites and lipids
are increasingly recognized as exercise-stimulated signaling molecules and
candidate molecular transducers of cardiorespiratory fitness.

METHODS: We performed nontargeted liquid chromatography mass
spectrometry-based plasma metabolomics in 654 participants (mean age, 35
years; 55% women) from the HERITAGE Family Study (Health, Risk Factors,
Exercise Training, and Genetics) who had cardiorespiratory fitness
(maximal oxygen uptake [VO2max]) measured by cardiopulmonary exercise
testing and underwent 20 weeks of supervised endurance training.
Metabolite-VO2max relationships were assessed using linear regression and
tested for replication in FHS (Framingham Heart Study) participants who
also underwent cardiopulmonary exercise testing. Metabolite relationships
with incident all-cause mortality ascertained in JHS (Jackson Heart Study)
and MESA (Multi-Ethnic Study of Atherosclerosis) were tested using Cox
regression. Experimental studies of cellular respiration and mitochondrial
function were performed in C2C12 myotubes.

RESULTS: An unknown mass spectrometry peak (mass-to-charge, 385.3056;
retention time, 3.69 minutes) had the strongest, positive relationship
with VO2max (mLxkg-1min-1) after adjustment for age, sex, race, and lean
body mass (beta=1.29; false discovery rate q=5.3×10-6); was identified as
N-palmitoyl glutamine (N-pal-gln) using tandem mass spectrometry and
bioinformatics; and was confirmed with an authentic chemical standard. The
biological role of N-pal-gln has not been described previously. The
relationship of N-pal-gln with VO2max was validated in 408 participants
from the FHS (beta=1.2; P=3.8×10-5), and its levels increased after
exercise training (log fold change=0.22; q=5.3×10-12). N-pal-gln levels
were inversely associated with all-cause mortality in JHS and MESA (hazard
ratio, 0.91 and 0.65 [P=0.029 and P=0.028], respectively). Previous
studies have shown that structurally related biochemicals modulate energy
homeostasis; thus, we performed mitochondrial experiments. N-pal-gln
administration led to a dose-dependent increase in mitochondrial:nuclear
DNA ratio compared with control treated cells (15% and 20% increases at
6.5 nM and 26 nM N-pal-gln, respectively [P=0.04 and P=0.02]) and improved
bioenergetics (N-pal-gln at 26 nM increased the phosphate:oxygen ratio
across ADP concentrations from 0 to 100 mcM; ANOVA P=0.0027).

CONCLUSIONS: We identified a novel, lipidated amino acid, N-pal-gln, that
is positively associated with VO2max, increases after regular aerobic
exercise, and is inversely associated with incident mortality. N-pal-gln
stimulates mitochondrial biogenesis and efficiency, demonstrating its
potential role as an exercise-stimulated transducer of cardiorespiratory
fitness.