Ambatipudi M; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, USA
Roshandelpoor A; Guseh JS; Kosyakovsky LB; Alotaibi M; Cheng S; Jain M; Lewis GD; Ho JE

Physiological Reports. 13(23):e70671, 2025 Dec.

The molecular mechanisms underlying the salutary effects of exercise
remain incompletely understood. Exerkines are signaling molecules with
autocrine, paracrine, or endocrine effects released in response to
exercise. Specific eicosanoids, small bioactive lipids, act as exerkines.
Using a mass spectrometry-based platform, we assayed eicosanoids and
related metabolites at rest and peak exercise in individuals undergoing
cardiopulmonary exercise testing (CPET). We examined changes in
metabolites with exercise and associations with cardiorespiratory fitness
measured by peak VO2 using multivariable linear regression. We studied 491
individuals (61% women, mean age 57 +/- 15). We found 523 (59%)
metabolites that dynamically changed with acute exercise (FDR q < 0.05).
Of these, 278 (53%) including linoleic acid and arachidonic acid
derivatives increased, and 245 (47%) decreased, including
trihydroxyoctadecenoic acids (triHOMEs) and omega-3 fatty acids. For 39
metabolites, the magnitude of exercise-induced change correlated with peak
VO2, including omega-3 and omega-6 fatty acids and linoleic, palmitic,
stearic, and arachidonic acid derivatives. We identified lipid metabolites
underlying metabolomic responses to acute exercise that relate directly to
cardiorespiratory fitness. Anti-inflammatory linoleic and arachidonic acid
derivatives increased with exercise, while pro-inflammatory and
pro-atherogenic triHOMEs decreased. Future studies may fully delineate
metabolomic contributions to the effects of exercise including chronic
exercise training.

Howie JO; Centre for Heart Rhythm Disorders, University of
Adelaide, Adelaide, Australia.
Dziano JK; Ariyaratnam JP; Abbas M; Kenny GT; Evans S;
Middeldorp ME; Emami M; Sanders P; Elliott AD

Heart Rhythm. 22(12):e1137-e1145, 2025 Dec.

BACKGROUND: Heart failure with preserved ejection fraction is common in
atrial fibrillation (AF), driven by an underlying left atrial (LA)
cardiomyopathy. We hypothesize that advancing age is a key risk factor for
the development of LA cardiomyopathy and heart failure with preserved
ejection fraction in patients with AF.

OBJECTIVE: This study aimed to determine the impact of age on invasive
and noninvasive measures of LA structure and function.

METHODS: Consecutive patients with symptomatic AF with preserved left
ventricular (LV) function undergoing catheter ablation were enrolled.
During ablation, invasive hemodynamic assessment was performed to quantify
LA pressure and stiffness. Noninvasive assessment included LA reservoir
strain and indexed volumes, LV global longitudinal strain, LV
end-diastolic volume, and natriuretic peptides. Functional capacity was
determined using cardiopulmonary exercise testing, and disease-specific
patient-reported symptoms were assessed. Results were adjusted for common
risk factors.

RESULTS: Of 125 patients, advancing age was associated with increased LA
pressure (beta = 0.08, P = .05) and stiffness (beta = 0.10, P = .002).
Patients older than 65 years had greater LA stiffness (P < .001), but no
difference in LA pressure (P = .11). Noninvasive measures revealed reduced
LA reservoir strain (beta = -0.37, P < .001), increased LA minimum (beta =
0.24, P < .001) and maximum volumes (beta = 0.24, P = .007), reduced LV
end-diastolic volume (beta = -0.63, P = .005), and increased natriuretic
peptides (beta = 12.8, P = .01) with age. Age was associated with reduced
peak oxygen consumption (beta = -0.15, P = .02), but not AF (beta = -0.01,
P = .66) or heart failure symptoms (beta = -0.13, P = .49).

CONCLUSION: In patients with symptomatic AF, aging is associated with LA
hemodynamic, structural, and functional impairments, suggestive of more
advanced LA disease. These age-related changes were confirmed with
exercise intolerance but not patient-reported symptoms.

Debo B; Ghent University Hospital, Ghent, Belgium.
Coomans I; Vandekerckhove K; De Groote K

European Journal of Pediatrics. 184(12):817, 2025 Dec 03.

Data on exercise capacity of pediatric patients with Turner syndrome (TS)
is scarce. This study was aimed at evaluating the cardiopulmonary response
to exercise in girls with TS aged 8 to 18 years. In this prospective,
single-center case-control cohort study girls with TS were matched to
healthy controls based on gender, age, and weight. All girls performed a
maximal incremental cardiopulmonary exercise test (CEPT) on an
electromagnetically braked cycle ergometer. Key variables measured
included peak oxygen uptake (VO2 peak) and maximal workload both expressed
as percentages of predicted values based on gender, age, and weight. O2
pulse is expressed in milliliters per heartbeat. Twenty-one girls with TS
were included and matched with 21 control patients. Girls with TS
demonstrated significantly lower VO2 peak values (% of predicted) compared
to controls (mean difference: – 10.3%, p = 0.014). Similarly, maximal
workload was significantly reduced in the TS group (mean difference: –
17.6%, p = 0.002). A general linear model confirmed that group status (TS
vs. control) was a significant predictor of both VO2 peak and maximal
workload, independent of age and weight. No significant differences were
observed in maximal heart rate or blood pressure between the two groups.
O2 pulse (ml/beat) was significantly lower in patients with TS (7.7 +/-
1.2 ml/beat) versus healthy controls (8.6 +/- 1.4 ml/beat, p = 0.03).
Conclusion: Girls with TS exhibit a reduced exercise capacity compared to
their healthy peers, as evidenced by lower VO2 peak, maximal workload and
O2 pulse during standardized CPET. Further research on pathophysiology,
evolution over time, and impact of targeted interventions is needed.

Selvaraj S; Division of Cardiology, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania, USA
Karaj A; Chirinos JA; Denney N; Grosso G; Fernando M; Chambers
K; Demastus C; Reddy R; Langham M; Kumar D; Maynard H; Pourmussa B;
Prenner SB; Cohen JB; Ischiropoulos H; Rickels MR; Poole DC; Church DD;
Wolfe RR; Kelly DP; Putt M; Margulies KB; Zamani P

JACC Heart Failure. 13(12):102435, 2025 Dec.

preserved ejection fraction (HFpEF) is multifactorial. Several
contributing pathways may be improved by ketone ester (KE).

OBJECTIVES: This study aims to determine whether KE improves exercise
tolerance in HFpEF.

METHODS: KETO-HFpEF (Ketogenic Exogenous Therapies in HFpEF) is a
randomized, crossover, placebo-controlled trial of acute KE dosing in 20
symptomatic HFpEF participants. Coprimary endpoints include peak oxygen
consumption (VO2) during incremental cardiopulmonary exercise testing and
time to exhaustion during an additional constant-intensity exercise (75%
peak workload) bout.

RESULTS: The average age was 71 +/- 8 years, 60% were women, and 65% were
White. KE did not improve peak VO2 (KE: 10.4 +/- 3.6 vs placebo: 10.5 +/-
4.0 mL/kg/min; P = 0.75). At rest, heart rate, biventricular systolic
function, and cardiac output (0.6 L/min [95% CI: 0.3-1.0 L/min]) were
greater with KE vs placebo, whereas total peripheral resistance (-3.2 WU
[95% CI: -5.2 to -1.2 WU]) and the arteriovenous oxygen content difference
(-0.7 mL of O2/dL blood [95% CI: -1.2 to -0.2 mL]) were lower. These
differences mostly disappeared during incremental exercise. KE did not
improve exercise endurance during the constant-intensity protocol (9.7 +/-
7.3 minutes vs 8.7 +/- 4.4 minutes; P = 0.51). In 6 participants receiving
6,6-2H2-glucose infusions during constant-intensity exercise, plasma
glucose appearance rate before and during exercise was lower with KE
(-0.24 mg/kg/min; P < 0.001). During both exercise protocols, KE lowered:
1) respiratory exchange ratios, demonstrating decreased systemic
carbohydrate use; 2) nonesterified fatty acids and glucose; and 3)
estimated left ventricular filling pressures (E/e’).

CONCLUSIONS: Despite robust ketosis, shifting substrate use away from
carbohydrates, and decreasing estimated left ventricular filling
pressures, acute KE supplementation did not improve peak VO2 or
constant-intensity exercise in HFpEF.

Nilo D; University of Campania “Luigi Vanvitelli”, Naples, Italy.
Gualdiero F; Russo V; Zielinska K; Sasso FC; Caturano A

Journal of Cardiovascular Pharmacology. 86(6):502-504, 2025 Dec 01.

ABSTRACT: Inflammation is increasingly recognized as a key mechanism
driving impaired cardiac function and reduced cardiorespiratory fitness in
heart failure. Interleukin-1 blockade with anakinra has shown consistent
anti-inflammatory effects but inconclusive benefits on functional capacity
in prior trials. In a pooled analysis of 73 patients, Hogwood et al
reported that anakinra reduced hsCRP and modestly improved peak VO 2
across both younger (<60 years) and older (>=60 years) patients, with no
difference in magnitude of benefit between age groups. These findings
indicate that the functional response to IL-1 inhibition is preserved
across age groups. Although the results are limited by small sample size,
heterogeneous treatment duration, and lack of placebo control, they
highlight the importance of age-stratified research and provide a
rational

Pedrosa B; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Daucourt C; Gremeaux V; Duscha BD; Coyne BJ; Kraus WE; Maletesta D; Borrani F; Baggish AL; Neyroud D

The impact of warm-up protocols on peak oxygen uptake (Vo2peak) during
cardiopulmonary exercise testing (CPET) remains unclear. This study
investigated the effect of warm-ups of different durations and intensities
on Vo2peak in healthy young adults during maximal-effort CPET cycle
ergometry.
Recreationally active participants (10 males, 4 females; 27 +/-
4 yr) performed five CPETs, each preceded by one of five randomized
conditions: 1) no warm-up (NWU), 2) short-duration/low-intensity (SD/LI)
warm-up (5 min at 0.5 W.kg-1), 3) long-duration/low-intensity (LD/LI)
warm-up (10 min at 0.5 W.kg-1), 4) short-duration/moderate-intensity
(SD/MI) warm-up (5 min at 1 W.kg-1), and 5) a long-duration/moderate-intensity
(LD/MI) warm-up (10 min at 1 W.kg-1).
No significant differences were found in Vo2peak, peak heart rate, maximal,
or submaximal power output across the different warm-up protocols (P >
0.05 for all comparisons), except for greater absolute HR and power output
observed at the first ventilatory threshold (VT1) following SD/MI versus
NWU (P < 0.05). Participant ratings of warm-up protocols indicated a
preference for shorter- and/or lower-intensity warm-ups.
Among healthy young adults, the inclusion of warm-up exercise before CPET has no
significant effects on maximal exercise parameters. These findings
question the necessity of warm-up before CPET and provide flexibility in
CPET warm-up protocol selection in this population. Recapitulation of this
study in alternative clinical and scientific populations is warranted.
NEW & NOTEWORTHY The impact of warm-up intensity and duration before maximal
effort cardiopulmonary exercise testing remains uncertain. Herein, we
investigated the effect of a 5- versus 10-min warm-up performed at low or
moderate intensity on maximal oxygen consumption. Compared with no
warm-up, these different warm-ups yielded similar peak oxygen uptake, peak
heart rate, and peak power output, thereby challenging the convention

Vecchiato M; Sports and Exercise Medicine Division, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy.
& Sports and Exercise Medicine Division, Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy.; Institute of Mountain Emergency Medicine, EURAC Research, Via Ipazia 2, 39100, Bolzano, Italy.
Borasio N; Scettri E; Cangialosi D;Palermi S;Savino S; Ermolao A; Neunhaeuserer D;

British medical bulletin [Br Med Bull] 2025 Sep 22; Vol. 156 (1).

Introduction: Hiking is an outdoor activity with not only significant health benefits but also associated risks, especially for individuals with cardiovascular conditions. Current trail recommendations lack personalization, potentially increasing the risk of adverse events during hiking.
Sources of Data: Prospective, cross-sectional study combining outpatient cardiopulmonary exercise testing with monitored outdoor hiking. Data were collected via portable gas analysis, heart rate monitors, and an official meteorological station.
Areas of Agreement: Hiking intensity and cardiorespiratory responses vary widely. Cardiovascular risk and trail slope were found to influence the exertion required to complete the hike.
Areas of Controversy: There is no consensus on how to standardize trail recommendations to account for individual variability.
Growing Points: Personalized hiking advice integrating individual fitness, cardiovascular risk, and trail features may enhance safety. Wearable technologies enable real-time adjustment of exertion levels.
Areas for Developing Research: New tools combining personal health data and environmental features to optimize hiking safety and accessibility should be implemented.

Schellenberg J; Sports and Rehabilitation Medicine, University Hospital Ulm, Leimgrubenweg 14, Ulm 89075, Germany.
& School of Sport Science, UiT the Arctic University of Norway, Tromsø, Norway.
Matits L; Kersten J; Bizjak DA; SKirsten J; Fremo T;Tjønna AE; Skovereng K; Sandbakk Ø; Aksetøy IA; Langlo KAR; Dalen H; Letnes JM;

European heart journal. Imaging methods and practice [Eur Heart J Imaging Methods Pract] 2025 Oct 30; Vol. 3 (4), pp. qyaf138.
Date of Electronic Publication: 2025 Oct 30 (Print Publication: 2025)

Aims: Left ventricular (LV) enlargement is a common training-induced adaptation in athletes, particularly in endurance sports. Previous research indicates that indexing LV volumes and mass to absolute peak oxygen uptake (VO₂ _peak ) better reflects physiological adaptation than traditional indexing to body surface area (BSA). Therefore, we investigated whether indexing LV end-diastolic volume (LVEDV) and mass to VO _2peak could eliminate differences in LV size among athletes from different sport categories (endurance, mixed, power, and technical).
Methods and Results: This analysis included 70 athletes from the multicenter COSMO-S in Germany and 15 elite endurance athletes from Norway. All participants (29 ± 8 years, 52 male) underwent echocardiography and cardiopulmonary exercise testing. In regression analyses, VO _2peak (L/min) accounted for a significantly greater proportion of the variance in LVEDV than BSA (R ² 0.64 vs. 0.19, P &lt; 0.001), while this difference was not significant for LV mass (R ² 0.54 vs. 0.36, P = 0.06). When indexed to BSA, both LVEDV and LV mass revealed significant differences across sports (both P ≤ 0.019), that disappeared when indexed to VO₂ _peak (all P ≥ 0.40). In a cohort of 12 dilated cardiomyopathy (DCM) patients serving as a pathological reference group, indexing LVEDV and LV mass to VO _2peak better differentiated DCM patients from athletes than indexing to BSA.
Conclusion: Indexing LV size to VO₂ _peak may provide a more physiological interpretation of cardiac adaptations in athletes and reduce sport-specific differences due to better consideration of training-induced adaptations. These findings should be replicated in larger cohorts and tested for the ability to detect subtle pathologies.

Looby M; Academic Surgery, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.; Southampton Complex Cancer and Exenteration Team (SCCET), University Hospital Southampton, Southampton, UK.
Matthews L; West CT; Khan K; Ansell G;Donovan K; Wood L;  Tapley P; Lewis R; Stoddard K; Grocott MPW; Jack S; Yano H; Levett D;Mirnezami A; West MA;

Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland [Colorectal Dis] 2025 Nov; Vol. 27 (11), pp. e70298.

Aim: Locally advanced pelvic malignancies, such as colorectal and anal cancers, can only be cured through multimodal cancer treatment including multi-visceral exenterative resections, which carry a high mortality and morbidity risk. Despite strong predictive abilities in other cancer cohorts, the combined prognostic value of body composition and cardiopulmonary exercise testing (CPET) for major in-hospital morbidity in patients undergoing exenterative surgery for advanced pelvic cancers has not been evaluated.
Method: A locally advanced colorectal and anal cancer cohort was derived from a prospectively maintained quaternary database. CPET was undertaken preoperatively, according to national guidelines. Skeletal muscle index (SMI) and radiation attenuation (SM-RA) were obtained from analysing L3 slices from preoperative computed tomography scans using SliceOmatic 5.0 and classified using predefined thresholds. Major morbidity was defined as Clavien-Dindo classification 3a or greater.
Results: From 247 patients (58% male, median age 60 years), 62.4% and 35.5% had locally advanced or recurrent disease respectively. Physical fitness variables were significantly reduced in low SMI or low SM-RA patients. In multivariate linear regression, SMI was strongly predictive of oxygen uptake at the anaerobic threshold (B = 0.013, p = 0.001) and at peak (B = 0.015, p = 0.002). 17.3% of all patients experienced a major postoperative complication. In multivariate analysis, reduced peak power output (&lt;1.5 W kg ^-1 ) was significantly associated with an increased risk of postoperative major morbidity (OR = 2.6, p = 0.012).
Conclusion: CPET may be predictive of in-hospital major morbidity in this cohort. The association of CPET with body composition necessitates further evaluation and external validation in a larger patient cohort, specifically interrogating their combined role in morbidity prediction and as a target for prehabilitation interventions.

Duarte ACB; Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE), Division of Respiratory Diseases Federal University of Sao Paulo; Brazil.
Lafetá ML; Verrastro CGY;Mancuso FJ; Tanni SE;Oliveira RKF; Ota-Arakaki JS; Ferreira EVM;

Pulmonary circulation [Pulm Circ] 2025 Nov 14; Vol. 15 (4), pp. e70198.
Date of Electronic Publication: 2025 Nov 14 (Print Publication: 2025).

During the COVID-19 pandemic, Brazil was one of the most affected countries. Patients presented higher risk of acute venous thromboembolism (VTE), in particular, pulmonary embolism (PE). However, long-term implications of these events remain unknown. A retrospective analysis from the FENIX study was conducted, and patients with COVID-19-related VTE during hospitalization were included. Further analysis, up to 6 months after the acute event, was performed exclusively in patients with PE. Persistence of dyspnea and exercise intolerance was evaluated through imaging, rest, and exercise functional tests. Cumulative incidence of VTE during hospitalization among COVID-19 survivors followed at the outpatient clinic was 17.7% ( n  = 75/423) and of acute PE was 9.9% ( n  = 42/423). Patients with PE were mostly male (66%), 56 ± 16 years old, and mainly classified as intermediate-low risk (74%). Dyspnea (mMRC≥ 1) up to 6 months of PE was present in 56% ( n  = 19/34), with a borderline association with parenchymal lung sequelae on chest CT scan ( p  = 0.069). Symptomatic patients upon follow-up presented lower FEV1 and FVC, as well as increased peak VD/VT ratio and ventilatory inefficiency. No signs of pulmonary hypertension (PH) were identified on echocardiogram (ECHO) and cardiopulmonary exercise testing (CPET). Persistence of dyspnea among post-PE related to COVID-19 was high. However, no cases of PH were found; follow-up findings may be related to pulmonary parenchymal and microvascular injury. Also, we cannot exclude association with long-COVID, in which pathophysiological mechanisms are multifactorial, involving chronic inflammatory changes and multiorgan dysfunction, highlighting the need for comprehensive evaluation of exercise intolerance through invasive CPET.