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.

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.