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.

Burchert HH; Medical Faculty, University of Basel, Basel, Switzerland.
Stringer WW; Dash RK

Journal of Applied Physiology. 141(2):401-416, 2026 Aug 01.

Oxygen (O2) binding and release by hemoglobin (Hb) are governed by
cooperative interactions among its four subunits. During incremental
workload exercise, femoral venous oxyhemoglobin (O2Hb) saturation exhibits
a reproducible, momentary increase at the gas exchange
threshold-coinciding with the inflection point of the in vivo O2
nonequilibrium curve (ONC). This suggests a transient shift in Hb’s
binding dynamics. We hypothesized that at this threshold, Hb tetramers
carrying <=1 bound O2 become predominant. In this state, the last bound O2
promotes further cooperative binding, but its release confers no
cooperative advantage for unloading, biasing toward O2 rebinding. Using
the O2 equilibrium curve models of Dash et al. (Eur J Appl Physiol 116:
97-113, 2016) and Adair, we computed the distribution of Hb’s O2 ligation
states across 12 pooled mean femoral venous blood samples from incremental
workload cardiopulmonary exercise testing of five healthy male
participants. At the gas exchange threshold-where the ONC inflects and
flattens-tetramers with <=1 O2 indeed dominated. This ligation-state
distribution is consistent with Perrella et al.’s (J Biol Chem 274:
2605-2608, 1999) cryogenic resolution of native human Hb, which shows that
carbon monoxide-ligated Hb tetramers peak at ~15%-20% saturation, matching
femoral venous ranges at the gas exchange threshold. Our results suggest
that, at sufficiently low O2Hb saturation, Hb may favor O2 rebinding over
cooperative unloading. We propose that glycolytic proton production and
other Bohr effectors may counter this predicted binding bias supporting
continued O2 unloading. If confirmed, this mechanism unifies long-standing
controversies in O2 transport physiology, framing the Hb-Bohr system as a
proportional-integral controller of tissue oxygenation. NEW & NOTEWORTHY
Anaerobic metabolism is usually viewed as a fallback when oxygen delivery
becomes insufficient. Our analysis suggests a different role: it may
preserve oxygen delivery by correcting a hemoglobin-binding bias that
emerges at low oxyhemoglobin saturation. When hemoglobin tetramers carry
one or no oxygen molecules, the remaining bound oxygen can promote
cooperative rebinding but not cooperative release. Glycolytic proton
production and other Bohr effectors may counter

Schoffl I; Department of Pediatric Cardiology, Erlangen,Germany.
Trager E; Kessler L; Paech C;et al

Pediatric Exercise Science. 38(3):315-323, 2026 Aug 01.

PURPOSES: In pediatric cardiology, stress echocardiography is rarely used,
even though it is an established tool for investigating myocardial
dysfunction due to coronary insufficiency, a threat in children after
arterial switch operation (ASO) or Kawasaki disease (KD). This study
combines stress echocardiography with cardiopulmonary exercise testing in
this cohort.

METHOD: The participants in this study were recruited from a cohort of
patients after ASO or KD. An age- and sex-matched control group was
recruited from university students and school children from nearby
schools. All undertook a cardiopulmonary exercise testing either on a
tilt-recline cycle ergometer or on a treadmill with intermittent
echocardiography. The echocardiographic examination consisted of global
longitudinal strain measurements of the left ventricle as parameters of
left ventricular function. In addition to the standard cardiopulmonary
exercise parameters (peak oxygen consumption, peak heart rate, O2pulse,
oxygen uptake efficiency slope, VE/VCO2-slope, and others), the behavior
of the O2pulse before and after the end of exercise was evaluated.

RESULTS: Overall, 43 participants were recruited (20 ASO, mean age: 14.7
y, 8 females; 10 KD, mean age: 15.0 y, 3 females; 13 controls, mean age:
15.7 y, 5 females). The patients after ASO showed a significantly lower
peak cardiopulmonary function (VO2peak: 39.6 vs 45.9 mL/kg/min) than the
control group. When combined (KD and ASO patients), the first ventilatory
threshold as well as the decline of the O2pulse during recovery were
significantly lower than in the control group. There were no differences
with respect to the echocardiographic parameters.

CONCLUSION: The lower peak oxygen consumption observed in the ASO group
point to a lower cardiopulmonary function. The lower oxygen consumption at
first ventilatory threshold can be an indicator of poorer endurance. Even
though the ventricular function recorded using echocardiography showed no
significant decrease, the slower recovery of the O2pulse during recovery
could point to an impairment in cardiac output during exercise as the
O2pulse is a surrogate parameter of cardiac output at peak exercise

Reddy YNV; Department of Cardiovascular Medicine, Mayo Clinic, USA
Frantz RP; Miranda WR; Harada T; Kazui S; Borlaug BA

Comment by Dr Older
Sotatercept is available in Australia but NOT subsidised on PBS

Journal of the American College of Cardiology. 88(4):415-432, 2026 Jul 28.

BACKGROUND: Sotatercept is an activin ligand trap that markedly improves
exercise tolerance in patients with pulmonary arterial hypertension (PAH).

OBJECTIVES: The aim of this study was to determine the mechanisms of
these functional benefits.

METHODS: The effects of 24-week sotatercept treatment on central and
peripheral determinants of aerobic capacity, hemodynamic status,
cardiovascular function, and oxygen transport in patients with PAH were
comprehensively evaluated. Participants underwent blood volume
quantification, supine invasive cardiopulmonary exercise testing with
simultaneous echocardiography, single-leg exercise catheterization, and
exercise femoral venous blood sampling. Participants underwent 7 paired
hemodynamic assessments before and after sotatercept (rest, nitric oxide,
passive leg raise, 20-W exercise, peak exercise, repeat baseline, and
single-leg exercise).

RESULTS: Among 30 participants (mean age 49.3 +/- 13.5 years, 70% women),
sotatercept improved the primary endpoint of peak exercise mean pulmonary
artery (PA)/cardiac output (CO) (-2.1 mm Hg/L/min; 95% CI: -3.1 to -1.1 mm
Hg/L/min; P = 0.0003). Sotatercept reduced pulmonary vascular resistance
(-2.6 WU; 95% CI: -3.0 to -2.2 WU; P < 0.0001), mean PA pressure (-12.5 mm
Hg; 95% CI: -13.8 to -11.2 mm Hg; P < 0.0001), and right ventricular (RV)
work (-1.1 kg-m/min; 95% CI: -1.4 to -0.9 kg-m/min; P < 0.0001) and
improved RV-PA coupling across rest and exercise. Sotatercept reduced
systemic congestion, evidenced by decreases in N-terminal pro-B-type
natriuretic peptide (P < 0.0001), right atrial pressure (P = 0.04), and
blood volume (P < 0.0001). Increases in resting hemoglobin were observed
(1.7 g/dL; 95% CI: +1.1 to +2.2 g/dL; P < 0.0001) that were related to
reduction in plasma volume (P < 0.0001), as there was no effect on red
cell mass (P = 0.12). A decrease in resting CO was observed with
sotatercept (-0.58 L/min; 95% CI: -0.85 to -0.32 L/min; P < 0.0001), which
appeared to be related to the increase in hemoglobin. Despite lower
resting CO, CO reserve with exercise was enhanced (+0.74 L/min; 95% CI:
+0.15 to +1.32 L/min; P = 0.015), which was associated with improved
aerobic capacity (peak oxygen consumption; r = +0.69; 95% CI: +0.43 to
+0.84; P < 0.0001). Single-leg exercise performance also improved after
sotatercept. Sotatercept increased both convective oxygen delivery with
exertion (P = 0.002; interaction P = 0.018) and peripheral oxygen uptake
in skeletal muscle, as evidenced by an increase in arterial-femoral venous
O2 content difference across phases (+1.1 mL/dL; 95% CI: +0.7 to +1.4
mL/dL; P < 0.0001).

CONCLUSIONS: Sotatercept improves exercise tolerance in patients with PAH
through multiple, previously unappreciated mechanisms beyond the pulmonary
vasculature, including increased hemoglobin (driven in part by systemic
decongestion with hemoconcentration), which along with enhanced RV-PA
coupling and CO reserve increases skeletal muscle O2 delivery. The
increased O2 delivered occurs despite decreased RV work, with functional
benefits further enhanced by augmented skeletal muscle O2 use.
(Sotatercept on Central Cardiopulmonary Performance and Peripheral Oxygen
Transport During Exercise in Pulmonary Arterial Hypertension;

De Schutter S; GENCOR Department University of Antwerp, Belgium.
&other centres in Belgiujm
Pugliese NR; Meems LMG; Moura-Ferreira S; et al

Journal of the American Heart Association. 15(14):e050524, 2026 Jul 21.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a
heterogeneous disease characterized by exercise intolerance. Defining
pathophysiologically distinct subgroups allows more personalized therapy,
but efforts mainly relied on resting examinations. This study aimed to
define HFpEF phenotypes based on exercise limitations using combined
cardiopulmonary exercise testing with stress echocardiography.

METHODS: A total of 913 patients with HFpEF were recruited from 4
third-line centers and divided into derivation (n=623) and validation
cohorts (n=290). Unsupervised graph-based clustering of 61 cardiopulmonary
exercise testing with stress echocardiography variables was used to
identify HFpEF exercise phenotypes. Pathophysiological characteristics,
exercise capacity, and clinical outcomes were compared between phenotypes.

RESULTS: In the derivation cohort, cluster analysis identified 5 distinct
HFpEF exercise phenotypes characterized by specific exercise responses:
mild diastolic dysfunction (phenotype 1), impaired peripheral oxygen
extraction (phenotype 2), right ventricular-pulmonary artery uncoupling
(phenotype 3), reduced left ventricular systolic reserve (phenotype 4),
and chronotropic incompetence (phenotype 5). The composite outcome of
all-cause death and unplanned cardiovascular hospitalization differed
significantly across phenotypes, with phenotypes 2 (hazard ratio [HR],
1.76 [95% CI, 1.07-2.91]), 4 (HR, 2.15 [95% CI, 1.27-3.65]), and 5 (HR,
2.19 [95% CI, 1.33-3.61]) showing higher rates of the primary combined
outcome compared with phenotype 1. All phenotypes were replicated in the
validation cohort.

CONCLUSIONS: Deep phenotyping of the exercise response in patients with
HFpEF revealed 5 distinct phenogroups with marked differences in
pathophysiology, exercise performance, and clinical outcomes. This
subclassification may support more personalized therapeutic strategies and
improve risk stratification in HFpEF.

Smith JR; Department of Cardiovascular Medicine Mayo Clinic
Rochester MN. USA
Medina-Inojosa JR; Chacin Suarez AS; Taylor JL; et al

Journal of the American Heart Association. 15(14):e044403, 2026 Jul 21.

BACKGROUND: Cardiac rehabilitation (CR) leads to increased exercise
capacity (VO2peak) and risk reduction of major adverse cardiovascular
events (MACEs). Women exhibit blunted VO2peak improvements following CR.
The purpose was to examine sex differences in the clinical predictors of
VO2peak improvement and odds of MACEs following CR.

METHODS: From 1999 to 2017, all consecutive patients undergoing
cardiopulmonary exercise testing before and after CR were included. Sex
differences in peak exercise metrics in response to CR were compared.
Multiple logistic regression models were fit to assess clinical predictors
of VO2peak improvement (defined as >0% from pre-CR) and MACEs following CR
for men and women.

RESULTS: A total of 513 men and 158 women were included. Men had greater
increases in VO2peak than women following CR (P=0.001). For men,
independent predictors of VO2peak improvement following CR included higher
CR session attendance (odds ratio [OR], 1.04 [95% CI, 1.02-1.06]),
peripheral artery disease (OR, 0.47 [95% CI, 0.25-0.86]), and pre-CR
VO2peak (OR, 0.98 [95% CI, 0.97-0.99]) (all, P<0.02). Independent
predictors of lower odds of MACEs following CR in men included higher
number of CR sessions (OR, 0.97 [95% CI, 0.95-0.99]), pre-CR VO2peak (OR,
0.98 [95% CI, 0.97-0.99]), surgical CR indication (OR, 0.34 [95% CI,
0.18-0.68]), and no history of peripheral artery disease (OR, 2.94 [95%
CI, 1.60-5.38]) (all, P<0.02). For women, the selected clinical
characteristics were not statistically significant independent predictors
of VO2peak improvement or odds of MACEs (except for diabetes) following
CR.

CONCLUSIONS: These findings suggest that clinical predictors of VO2peak
improvement and odds of MACEs following CR are sex specific.

D’Ascenzi F (Chair); Sanz-de la Garza M (Co-chair); Many International Centres
Maestrini V; Cameli M; et al

European heart journal cardiovascular Imaging. 27(8):1449-1468, 2026 Jul 31.

Exercise imaging, particularly exercise stress echocardiography (ESE), has
become a pivotal non-invasive tool for evaluating cardiovascular function
in athletes and for distinguishing physiological adaptations from
pathological conditions. This Clinical Consensus Statement by the European
Association of Preventive Cardiology and the European Association of
Cardiovascular Imaging synthesizes current evidence and provides practical
guidance on indications, protocols, and interpretation of exercise imaging
modalities in both competitive and recreational athletes. The document
emphasizes the role of ESE in assessing cardiac reserve, unmasking
concealed cardiomyopathies, and stratifying risk in clinical scenarios
such as T-wave inversion, exercise-induced repolarization abnormalities,
and extreme ventricular remodelling. Special attention is given to imaging
protocols tailored to the athletic population, including dynamic
assessment of the right and left ventricles, atria, and valvular function
during various exercise modalities, highlighting the importance of the
functional evaluation in athletes and active individuals. Additionally,
the consensus explores the integration of advanced techniques such as
cardiopulmonary exercise testing and exercise cardiac magnetic resonance
imaging, highlighting their complementary roles in comprehensive
cardiovascular evaluation. The statement advocates for individualized
testing strategies that consider sport-specific demands, demographic
factors such as body size, sex, ethnicity, and the underlying pathology.
It also underscores the importance of exercise imaging in guiding sports
eligibility and in tailoring exercise prescription for competitive
athletes, as well as for patients willing to participate in recreational
sports or exercise programs. Copyright This article has been co-published
with permission in the European Journal of Preventive Cardiology and the
European Heart Journal – Cardiovascular Imaging. All rights reserved.
The European Society of Cardiology 2026. The articles are identical
except for minor stylistic and spelling differences in keeping with each
journal’s style. Either citation can be used when citing this article.

Guerrier K; Le Bonheur Children’s Hospital, Memphis, USA.
Bejnood A; Shyam S; Hyde RA; et al

Medical Sciences. 14(3), 2026 Jul 08.

BACKGROUND: Pectus excavatum (PEX) is the most common congenital chest
wall deformity and may result in cardiac compression and arrhythmias. The
relationship between structural severity and exercise-induced
electrocardiographic (ECG) abnormalities in pediatric patients remains
unclear.

METHODS: We performed a retrospective study of patients aged 10-19 years
that underwent standardized preoperative evaluation for PEX between 2015
and 2021, including ECG, transthoracic echocardiography (TTE), computed
tomography (CT), and cardiopulmonary exercise testing (CPET). PEX severity
was assessed using the Haller index (HI), while right ventricular (RV)
compression was evaluated on CT. Tricuspid valve annular size (TVAS) on
TTE was used as a surrogate marker of RV compression. Exercise-induced ECG
abnormalities, including premature ventricular complexes (PVCs), were
analyzed and correlated with HI, RV compression, and TVAS.

RESULTS: Among 124 patients (85% male; median age 15 years), 33%
exhibited exercise-induced ECG abnormalities, most commonly PVCs (24%
overall). PVC occurrence was not associated with Haller index severity (p
= 0.35) but was significantly associated with RV compression on CT (92.6%
vs. 62.1%, OR 7.64, p = 0.02). Patients with ECG abnormalities had
significantly smaller TVAS compared to those without (1.98 +/- 0.31 cm vs.
2.09 +/- 0.33 cm, p = 0.04). Although PVCs were more frequent in patients
with TVAS z-score <= -2.0, this did not reach statistical significance.

CONCLUSIONS: Exercise-induced ventricular ectopy in pediatric PEX is
associated with right ventricular compression rather than structural
severity as defined by HI. Echocardiographic measures such as TVAS may
serve as noninvasive markers of clinically significant compression. These
findings highlight the importance of cardiac-thoracic relationships in
predicting arrhythmic risk and suggest a potential for reversibility with
surgical correction.

Selvadurai Y; The Sydney Children’s Hospitals Network, Westmead, New
South Wales, Australia & Royal North Shore Hospital, St Leonards, New South
Wales, Australia.
Kennedy B; Mcbride J; Field P; et al

BMJ open respiratory research. 13(1), 2026 Jul 30.

BACKGROUND: Complicated pneumonia in children can result in an empyema.
The management options include chest drain insertion with fibrinolytic
therapy (CDF) and video-assisted thoracoscopic surgery (VATS) with
decortication. No studies have compared the long-term cardiopulmonary
impact of treatment interventions using sensitive static and dynamic
assessments of lung function.

AIM: To compare long-term cardiopulmonary function outcomes in children
with empyema treated with CDF with those who underwent VATS using highly
sensitive static and dynamic lung function measures.

METHODS: Children aged >8 years at the time of testing who were
previously hospitalised with empyema and treated with either CDF or VATS
were prospectively recruited. At one hospital, children were only treated
by VATS, whereas CDF was used exclusively at the other site. As both sites
belonged to the same network, all other aspects of treatment protocols
were identical, and clinicians worked across both sites. Healthy controls
were assessed as a comparison. Lung function testing included spirometry,
lung volumes, multiple-breath washout (lung clearance index), oscillometry
and cardiopulmonary exercise testing, all performed according to
international standards.

RESULTS: 51 children treated with CDF, 28 treated with VATS and 24
healthy controls participated in this study. Spirometry and lung clearance
index were normal across all groups. However, oscillometry revealed
significantly lower reactance in both treatment groups compared with
controls (respiratory system reactance at 5 Hz: CDF -2.54 (0.98), VATS
-4.08 (0.94), controls -0.24 (0.85)), with VATS showing greater
impairment. The ratio of minute ventilation to oxygen uptake was highest
in the VATS group compared with CDF and controls (39.7 (2.8), 36.8 (3.2)
and 32.2 (2.7), respectively).

CONCLUSION: Long-term pulmonary outcomes following both CDF and VATS were
generally reassuring. However, oscillometry and exercise testing revealed
subtle differences in ventilatory strategies, with children post-VATS
demonstrating mild residual impairment.

Siebold E; Division of Sport and Exercise Medicine, Basel, Switzerland.
Infanti L; Gruber HJ; Stehle GT;

European Journal of Applied Physiology. 126(7):4113-4126, 2026 Jul.

PURPOSE: Hematopoietic stem cell transplantation (HSCT) depends on
effective HSC mobilization with granulocyte colony-stimulating factor
(G-CSF), though some allogeneic donors experience severe side effects.
This study compares G-CSF and acute maximal exercise for HSC collection
and cellular composition in 10 healthy family donors, examining links to
donor fitness and recipient outcomes.

METHODS: Ten donors (3 females; 40.8 (18.3) years) and their recipients
(n = 8; 3 females; 47.5 (18.5) years) were enrolled. Donors completed
cardiopulmonary exercise testing with blood samples taken pre- and
post-exercise and on apheresis day for flow cytometric analysis.
Recipients were followed up on day ~ 30 post-transplant.

RESULTS: Exercise significantly increased circulating total CD34+ cells
(1.76-fold (0.51), p = 0.002) and select progenitor subsets (CD34+CD45dim,
1.74-fold (0.56), p = 0.006; and CD34+CD38+CD133+, 1.60-fold (0.46), p =
0.013), while other subsets showed no significant change (p > 0.05).
Compared with post-exercise, apheresis resulted in markedly higher
concentrations of total CD34+ cells (20.7-fold (9.7), p < 0.001) and all
measured subsets. The largest enrichments were observed in CD34+
CD38-CD133+ (52.7-fold (69.3) p = 0.005) and CD34+CD38+CD133+ (38.2-fold
(17.0), p < 0.001) populations. HSC collection at apheresis contained a
186.1-fold (72.3) elevation of immature granulocytes (p < 0.001) compared
to the acute exercise (1.5-fold (0.3)). The proportions of apoptotic CD34+
cells and their subpopulations were similar post-exercise to apheresis (p
> 0.05). Donor CD34+CD38- cell number was significantly negatively
associated with recipient engrafting CD34+CD45dimCD90+ cells/microl
(r=-0.70, p = 0.05, n = 8).

CONCLUSION: Exercise might complement pharmacological mobilization by
enhancing key HSC subgroups, improving collection quality, and supporting
transplantation success; future research should evaluate combined
approaches and the role of CRF in donor suitability and recipient
outcomes.