Lee S; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
Houstis NE; Cunningham TF; Brooks LC; Chen K; Slocum CL; Ostrom K; Birchenough C; Moore E;  Tattersfield H; Sigurslid H; Guo Y; Landsteiner I;
Rouvina JN; Lewis GD; Malhotra R;

JACC. Heart failure [JACC Heart Fail] 2025 Jun 10; Vol. 13 (8), pp. 102478.
Date of Electronic Publication: 2025 Jun 10.

Background: Iron is a critical factor in cardiac function, oxygen carrying capacity in the blood, and mitochondrial function in skeletal muscle, all of which are key elements of oxygen uptake and utilization during exercise. However, the impact of iron status on hemodynamic responses to exercise and component variables of peak oxygen consumption in patients with heart failure with preserved ejection fraction (HFpEF) is unknown.
Objectives: The authors sought to determine the relationship between markers of iron status and comprehensive exercise response patterns and clinical outcomes in patients with HFpEF.
Methods: Cardiopulmonary exercise testing using cycle ergometry with invasive hemodynamic assessment was performed in 372 patients with HFpEF. Serum iron, transferrin saturation (Tsat), hepcidin, and ferritin were measured at the time of cardiopulmonary exercise testing, and additionally the Tsat/hepcidin ratio was used as a measure of iron homeostasis and hepcidin dysregulation, with low values reflecting inappropriate elevation in hepcidin level relative to iron bioavailability.
Results: In this cohort, 66% had iron deficiency defined as ferritin <100 μg/L or ferritin 100-300 μg/L with Tsat <20%. Higher peak oxygen consumption was associated with higher Tsat% (ρ = 0.33; P < 0.0001), Tsat/hepcidin ratio (ρ = 0.23; P < 0.0001), and serum iron (ρ = 0.30; P < 0.0001) but was not associated with ferritin level. After adjustment for age, hypertension, diuretic use, hemoglobin level, and cardiac index at rest, the association between higher peak oxygen consumption with higher Tsat, Tsat/hepcidin, and iron remained significant (P ≤ 0.006 for all). Tsat, Tsat/hepcidin, and iron were also associated with lower pulmonary artery pressure/cardiac output slope and pulmonary capillary wedge pressure/cardiac output slope, whereas ferritin did not correlate with these exercise hemodynamic measures. Finally, Tsat independently predicted heart failure-free survival, with every higher tertile of Tsat corresponding to an HR of 0.60 (P = 0.002), whereas ferritin was not associated with outcomes.
Conclusions: In patients with HFpEF, Tsat%, but not ferritin levels, relates to more favorable overall metabolic and hemodynamic responses to exercise and better outcomes.
Competing Interests: Funding Support and Author Disclosures Support for this work was provided by the National Heart, Lung, and Blood Institute, including R01HL159514 (to Drs Lewis and Malhotra), R01HL131029 (to Dr Lewis), and R01HL151841 (to Dr Lewis). Drs Lewis and Malhotra have served as consultants for Pharmacosmos. Dr Lewis has served on the scientific advisory board for American Regent.

Weigelt A; Department of Pediatric Cardiology, University Hospital Erlangen,  Germany.
Akhundova G; Raming R; Tratzky JP; Regensburger AP; Kraus C; Waellisch W; Trollmann R; Woelfle J;Dittrich S; Heiss R; Knieling F; Schoeffl I;

European journal of pediatrics [Eur J Pediatr] 2025 Jun 10; Vol. 184 (7), pp. 413.
Date of Electronic Publication: 2025 Jun 10.

Few studies have examined post-COVID-19 sequelae in children, particularly regarding cardiopulmonary capacity. Longitudinal data are especially scarce. This study aimed to retest pediatric patients previously assessed in a cross-sectional design. In this longitudinal study, children meeting post-COVID-19 criteria and an age- and sex-matched control group underwent cardiopulmonary exercise testing at baseline and after 6 months. Thirteen of 20 post-COVID-19 children (mean age: 13.6 ± 2.6 years, 48% female) and 23 of 28 controls (mean age: 11.9 ± 3.1 years, 62% female) completed follow-up testing. All participants completed a maximal treadmill test. No significant differences were found in peak oxygen uptake ( INLINEMATH 39.5 ± 11.0 ml/kg/min vs. 45.5 ± 8.4 ml/kg/min; p = 0.101). Over 6 months, cardiopulmonary performance improved significantly across all subjects. Subgroup analysis showed improvements in both groups, although changes were not statistically significant. Oxygen pulse also proved to be significantly higher and the half-time recovery of INLINEMATH proved to be significantly longer after 6 months which was true for the overall group but not for the subgroups.
Conclusion: This is the first longitudinal study to reassess cardiopulmonary capacity in children with post-COVID-19. The initially reduced INLINEMATH normalized, and all children showed improved cardiopulmonary capacity after 6 months. The primary improvement was observed in the O ₂ pulse, a surrogate marker of stroke volume and, by extension, cardiac output. This finding suggests an enhancement in cardiovascular performance, reflecting improved central hemodynamic in all children 6 months after the pandemic. Deconditioning thus remains a plausible cause for the post-COVID-19 symptoms.
Trail Registration: ClinicalTrials.gov Identifier: NCT05445531.
What Is Known: • Children with post-COVID-19 (PASC) may exhibit reduced cardiopulmonary function (V̇O2 peak). Fatigue and exercise intolerance are common but poorly understood and objectified. • Previous studies have provided valuable cross-sectional insights but have yet to include longitudinal follow-up data.
What Is New: • First longitudinal CPET-based study reassessing children with PASC after 6 months. • Cardiopulmonary performance, including V̇O2 peak and O2 pulse, improved significantly over time, probably due to reversible deconditioning rather than organ damage.

Ferguson ON; Centre for Heart Lung Innovation, The University of British Columbia (UBC) and St. Paul’s Hospital (SPH), Vancouver, British Columbia, Canada; Jensen D; Guenette JA; Lewthwaite H;

Respiratory physiology & neurobiology [Respir Physiol Neurobiol] 2025 Jun 11; Vol. 336, pp. 104456.
Date of Electronic Publication: 2025 Jun 11.

Dyspnea, or breathlessness, is a complex, multidimensional symptom of breathing discomfort, which significantly impacts quality of life and clinical prognosis. While traditional assessments have primarily focused on breathlessness sensory intensity, this approach does not consider affective and/or qualitative dimensions. Growing evidence highlights the need for multidimensional assessment approaches that provide a more comprehensive understanding of breathlessness, particularly in the context of exercise. Cardiopulmonary exercise testing (CPET) provides a standardized physiological stimulus to assess breathlessness responses in real-time, offering valuable insights into its underlying mechanisms and response to therapeutic intervention. Normative reference equations can help identify abnormally high breathlessness intensity during CPET. This review examines current methodologies for multidimensional breathlessness assessment during exercise, including single-item rating scales, multidimensional tools, descriptor lists, and locus of symptom limitation. We also discuss best practices for linking breathlessness with physiological responses during CPET to enhance mechanistic understanding, inform targeted interventions, and evaluate interventional efficacy. Standardizing assessment approaches and ensuring transparent reporting are critical steps toward improving the clinical and research utility of exertional breathlessness assessments.

Kennouche D; Université Jean Monnet Saint-Etienne, Lyon 1, Saint-Etienne, FRANCE.
Foschia C; Brownstein CG; Gondin J; Lapole T; Rimaud D; Royer N; Thiery G;  Gauthier V; Giraux P; Oujamaa L; Sorg M; Vergès S; Doutreleau S; Marillier M; Prudent M; Bitker L; SFéasson L; Gergelé L; Stauffer E; Guichon C;

Medicine and science in sports and exercise [Med Sci Sports Exerc] 2025 Jun 13.
Date of Electronic Publication: 2025 Jun 13.

Purpose: Although most patients recover well from Covid-19 infection, this may not be the case of those who experienced severe dysfunction after being admitted to intensive care unit (ICU). This study aimed to assess the recovery of patients who experienced severe multiple dysfunctions after being admitted to intensive care unit (ICU) for Covid-19 infection.
Methods: Forty-seven patients hospitalized and mechanically ventilated in ICU for SARS-CoV-2 infection underwent evaluations at 4-8 weeks (T1) and 6 months (T2) post ICU discharge. Evaluations included questionnaires, lung function tests, incremental cardiopulmonary exercise testing, and neuromuscular function tests.
Results: From T1 to T2, the percentage of patients classified as fatigued decreased from 56% to 21% whereas forced vital capacity and the forced expiratory volume in one second increased by 13% and 8% (p < 0.05) to reach 93% and 95% of predicted values at T2, respectively. Peak work rate also increased from 97 to 135 W (+35 ± 32%, p < 0.001). Likewise, V̇O2peak increased from 18.3 to 21.6 ml/min/kg (+18 ± 27%, p < 0.001) to reach 72% of predicted values. Maximal strength and the number of contractions during the fatigability test increased between T1 and T2 by 41% and 39%, respectively (both p < 0.001).
Conclusions: Six months of recovery improved patients’ physical function and reduced fatigue.

Doi S; Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN, USA.
Tada A; Harada T; Naser JA; Ibe T; Smith JR; Reddy YNV;

European journal of heart failure [Eur J Heart Fail] 2025 Jun 18.
Date of Electronic Publication: 2025 Jun 18.

Aims: Oxygen consumption at peak exercise is widely used to assess functional impairment in heart failure with preserved ejection fraction (HFpEF), but few patients exercise to this intensity in daily living. Alternative metrics that quantify submaximal fitness may provide more patient-centred evaluations, but the pathophysiology of submaximal exercise intolerance in HFpEF is unexplored.
Methods and Results: Patients with HFpEF underwent invasive haemodynamic cardiopulmonary exercise testing with blood lactate measurement during exercise to volitional fatigue. Lactate threshold (LT) was defined as the exercise workload at which arterial lactate exceeded >2.0 mmol/L, taken as a measure of submaximal fitness. Of patients with HFpEF (n = 286), 194 (68%) reached LT at a workload of 40 W or less (LT ≤40 W), while 92 (32%) reached a workload exceeding 40 W at LT (LT >40 W). As compared to LT >40 W, patients with LT ≤40 W were more likely to be female, anaemic, and had greater pulmonary vascular disease (all p < 0.01). During 20 W exercise, participants with LT ≤40 W had higher pulmonary artery pressure, biventricular filling pressures, minute ventilation and respiratory drive, higher perceived dyspnoea and fatigue ratings, greater arterial-venous oxygen content difference, despite similar cardiac output and oxygen delivery. At peak exercise, most of these differences were no longer apparent. Findings were replicated using non-invasively-measured workload at ventilatory threshold.
Conclusions: Two-thirds of patients with HFpEF reach LT at workloads typical of activities of daily living. Patients with HFpEF and impaired submaximal fitness are more likely to be female, have greater pulmonary vascular disease and anaemia severity, and display greater haemodynamic, symptomatic, and ventilatory control abnormalities during low-level exercise, which are not apparent at maximal exertion. These findings have therapeutic implications and suggest a potentially important role for wider evaluation of submaximal fitness in addition to peak aerobic capacity.

Beaven ML; Curtin University, Perth, Australia.; The Kids Research Institute Australia, Perth, Australia & University Hospital of Wales, Cardiff, UK.
Gibbons JTD; Course CW; Kotecha SJ; Hixson T; Maiorana A; Zuidersma M; Kotecha S; Smith EF; Simpson SJ;

European respiratory review : an official journal of the European Respiratory Society [Eur Respir Rev] 2025 Jun 18; Vol. 34 (176).
Date of Electronic Publication: 2025 Jun 18 (Print Publication: 2025).

Rationale: Survivors of preterm birth (<37 weeks’ gestation) have low peak oxygen uptake, a global measure of aerobic fitness and an established predictor of increased morbidity and mortality. However, little is known about other cardiopulmonary outcome measures in this population. We addressed the hypothesis that preterm birth is associated with abnormal respiratory, cardiovascular and metabolic responses to exercise, as assessed by cardiopulmonary exercise testing, via a systematic review and meta-analysis.
Methods: Six databases were systematically searched up to 29 November 2024 (PROSPERO: CRD42022320775). Studies reporting cardiopulmonary outcome measures obtained during a standardised exercise test were included if they had preterm-born participants and matched term-born controls. The standardised mean difference (SMD) between pooled preterm-born and term-born cohorts was calculated using random-effects models for the meta-analysis.
Results: Of the 12 143 records identified, 47 cohorts were included in the final meta-analysis. At peak exercise, the preterm-born cohort (n=2149) demonstrated lower oxygen uptake (SMD -0.39, 95% CI -0.52 to -0.26), work rate (SMD -0.53, 95% CI -0.70 to -0.35), minute ventilation (SMD -0.43, 95% CI -0.60 to -0.26), tidal volume (SMD -0.38, 95% CI -0.62 to -0.15), oxygen pulse (SMD -0.47, 95% CI -0.75 to -0.19), heart rate (SMD -0.18, 95% CI -0.28 to -0.07), anaerobic threshold (SMD -0.29, 95% CI -0.49 to -0.08) and gas exchange efficiency (SMD 0.22, 95% CI 0.04 to 0.41), compared to the term-born cohort (n=1650).
Conclusions: In addition to a reduced peak oxygen uptake, survivors of preterm birth have impairments in the respiratory, cardiovascular and metabolic domains during cardiopulmonary exercise testing. Given that reduced aerobic capacity is associated with increased morbidity and mortality, exercise interventions that target cardiorespiratory fitness should be prioritised across the lifespan in those born preterm.

Papic V; Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland.
Ledergerber R; Roth R; Knaier R;

Pediatric research [Pediatr Res] 2025 Jun 19.
Date of Electronic Publication: 2025 Jun 19.

Background: Physiological responses to exercise differ between children and adults, but achieving maximal exertion in children complicates the interpretation of VO _2max . This study, therefore, examines age- and sex-related physiological differences in submaximal parameters during incremental exercise.
Methods: In this cross-sectional study, 24 children (7-11 years), 20 moderately trained adults (MTA), and 20 well-trained adults (WTA; 20-30 years) completed a maximal incremental exercise test on a cycle ergometer with continuous respiratory measurement. Linear regression models analysed age and sex differences in ventilatory thresholds (VT1, VT2) and oxygen uptake efficiency slope and plateau (OUES), with Cohen’s d effect sizes reported.
Results: Children showed higher body mass-adjusted VO ₂ at VT1 and VT2 (d = 0.58-0.66) compared to MTA, and slightly lower VT2 values than WTA (d = 0.35). Adults had higher absolute OUES (d = 0.37-1.45) and OUEP (d = 0.60-0.81), while children exhibited higher body mass-adjusted OUES (d = 0.87 - 1.80). Males had higher VO ₂ at VT2, OUES, and OUEP (d = 0.41-0.81), while females showed higher relative VO ₂ at VT1 and VT2 (d = 0.44-0.59) compared to males.
Conclusions: Children rely more on oxidative metabolism than adults. Maturation influences exercise efficiency more than body mass, underscoring physiological differences. These age- and sex-specific patterns call for longitudinal studies to further explore the roles of growth and training.
Impact: This study identifies clear physiological differences in submaximal CPET parameters between children and adults. It adds novel insight by including both ventilatory thresholds and oxygen uptake efficiency, adjusted for body mass and training status. The findings suggest children rely more on oxidative metabolism, emphasizing the importance of maturation on exercise efficiency and informing age- and sex-specific assessment protocols in pediatric exercise physiology.

Lewsey SC; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore,
Samuel TJ; Schär M; Sourdon J; Goldenberg JR; Yanek LR; Lai S; Steinberg AM; Bottomley PA; Gerstenblith G; Weiss RG;

Circulation. Heart failure [Circ Heart Fail] 2025 Jun 19, pp. e012512.
Date of Electronic Publication: 2025 Jun 19.

Background: Heart failure with preserved ejection fraction (HFpEF) is a systemic process with contributions from peripheral factors, including skeletal muscle (SM). Age-associated SM loss and impaired energy metabolism occur without heart failure, but the relative importance of changes in SM quantity versus metabolic quality in patients with HFpEF for exercise intolerance (EI) or outcomes has not been studied. We hypothesized that EI and subsequent clinical outcomes across the adult lifespan in patients with HFpEF are related to impaired SM energy metabolism rather than age-associated SM loss.
Methods: Patients with HFpEF (n=64; aged 34-86 years) with left ventricular ejection fraction ≥50% were stratified by age in a prospective study. They underwent 3T magnetic resonance imaging to measure calf muscle quantity and ³¹ P magnetic resonance spectroscopy to measure muscle high-energy phosphate metabolism during plantar flexion exercise.
Results: Older patients with HFpEF exhibited more severe EI, less calf muscle, faster exercise-induced high-energy phosphate decline, and worse SM energetics at fatigue than younger patients. EI correlated closely with muscle metabolic quality, not quantity. Neither magnetic resonance imaging exercise time, 6-minute walk distance, nor peak oxygen uptake at cardiopulmonary exercise testing on cardiopulmonary bicycle exercise testing correlated with calf SM area. In contrast, the 6-minute walk distance and peak oxygen uptake at cardiopulmonary exercise testing were inversely related to rapid exercise-induced high-energy phosphate decline and worse SM energetic profile at fatigue. Rapid exercise-induced high-energy phosphate decline and lower ATP at fatigue were associated with increased cardiovascular death and heart failure hospitalizations in univariate analysis over a median of 39.3 months.
Conclusions: EI in older patients with HFpEF is closely linked to age-associated abnormalities in SM energy metabolism, namely, rapid exercise-induced energetic decline and worse energetic profile at fatigue, and not SM quantity. Abnormal SM energy metabolism is associated with worse outcomes in patients with HFpEF in unadjusted analysis. These findings support SM energy metabolism as a barometer of systemic HFpEF severity and the pursuit of new SM metabolic modulators to reduce disabling EI and possibly adverse outcomes in patients with HFpEF.

Kramer M; Division of Pediatric Cardiology and Intensive Care, University Hospital, LMU Munich, 81377, Munich, Germany.
Li P; Langer M; Vilsmaier T; Sciuk F; Kolbinger B; Jakob A; Rogenhofer N; Dalla-Pozza R;Thaler C; Haas NA; Oberhoffer FS;

European journal of pediatrics [Eur J Pediatr] 2025 Jun 21; Vol. 184 (7), pp. 431.
Date of Electronic Publication: 2025 Jun 21.

Children conceived through assisted reproductive technologies (ART) potentially display an increased cardiovascular morbidity. Despite cardiorespiratory fitness (CRF) and muscle strength being key indicators of cardiovascular outcomes, they have not been investigated in ART offspring yet. This observational pilot cohort study aimed to evaluate CRF and muscle strength in ART participants and spontaneously conceived controls.
Anthropometric variables, diet quality, level of physical activity, and sedentary behavior were evaluated. Participants performed a 6-min walking test (6MWT) and a 20-m shuttle run test (20mSRT). 6MWT distance and the number of archived laps were assessed, the maximal oxygen uptake (V̇O2 _max ) was estimated, and pulse rate recovery was calculated. Maximal hand grip strength (HGS) was determined as a marker of muscle strength. Generalized linear models were used to adjust data for age, birthweight, and gestational age. Sixty-seven ART participants and 86 spontaneously conceived peers were included. Both groups did not differ significantly in age (11.3 (IQR 8.1-18.2) vs. 11.9 (IQR 8.7-18.3) years), gender ratio, anthropometric variables, diet quality, level of physical activity and sedentary behavior. The amount of 20mSRT laps (P _adj =0.02), estimated VO2 _max (45.0 (IQR 37.9-47.1) vs. 45.8 (IQR 43.1-48.0) ml·kg⁻ ¹ ·min⁻ ¹ , P _adj =0.04), and pulse rate recovery (P _adj =0.03) were significantly lower in ART participants after adjustment. HGS did not differ between groups.
Conclusion: This study indicates a significantly lower CRF in ART participants. Significant differences in muscle strength were not demonstrated between groups. Future studies should validate these results by using cardiopulmonary exercise testing for VO2 _max assessment.

Castiglione A; Department of Cardiology, Center for Congenital Heart Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
& many other centres in Switzerland
Schwerzmann M; Bouchardy J; Buechel RR; Engel R; Freese M; Gabriel H; Greutmann M; Heg D; Possner M; Ruperti-Repilado FJ; Rutz T; Schwitter J; Thomet C; Tobler D; Wilhelm M; Wustmann K; Schwitz F;

CJC pediatric and congenital heart disease [CJC Pediatr Congenit Heart Dis] 2024 Dec 12; Vol. 4 (2), pp. 81-91.
Date of Electronic Publication: 2024 Dec 12 (Print Publication: 2025).

Background: Adults with a transposition anatomy and a systemic right ventricle (RV) face long-term complications that may impact their quality of life (QoL). Few data are available regarding the QoL in this patient group and its evolution over time.
Methods: This study was performed in the SERVE trial’s (identifier: NCT03049540) prospective cohort of patients (n = 100) with congenitally corrected transposition of the great arteries (TGA) or dextro-TGA after the atrial switch procedure and a longitudinal follow-up of 3 years. We aimed to describe the longitudinal QoL levels and their predictors. QoL was assessed using the Linear Analog Scale. QoL parameters were collected at baseline, after 12 months, and after 36 months, together with clinical parameters and a questionnaire assessing general self-efficacy (GSE).
Results: The mean QoL on the Linear Analog Scale was 79.1 ± 13.6 at baseline, 75.5 ± 14.8 at 1 year, and 79.2 ± 13.6 at 3-year follow-up ( P  = 0.900). No significant differences in QoL were observed between congenitally corrected TGA or dextro-TGA patients. Cardiopulmonary exercise testing maximum work rate and maximum oxygen uptake, New York Heart Association class, end-diastolic RV volumes, N-terminal pro-B-type natriuretic peptide concentration, and GSE showed significant correlations with QoL levels. Multivariable regression analysis identified GSE value and New York Heart Association class ( r²  = 0.283, P < 0.001) as independent predictors of QoL at baseline.
Conclusions: Patients with a systemic RV reported a stable good QoL during 3 years of follow-up. Exercise capacity and self-efficacy were the only independent predictors of QoL.