Lim, Kenneth; Division of Nephrology & Hypertension, Indiana University School of Medicine, Indianapolis, IN, USA.
Campos, Monique;Moe, Sharon

Kidney360,2025 Dec 15

Cardiovascular outcome trials are challenging to conduct in patients with CKD. Despite this, well-designed randomized controlled trials are critical to inform optimal management strategies and improve clinical care. Unfortunately, many cardiovascular outcome trials in nephrology have not demonstrated a treatment benefit. Contributing to this are the difficulties associated with endpoint selection and the limitations of many traditional endpoints such as resting left ventricular geometric measures and circulating biomarkers in patients with CKD, which are well known to be a major impediment to the conduct of cardiovascular trials in this population. The emergence of state-of-the-art Cardiopulmonary Exercise Testing (CPET) technology in nephrology has taken center stage in this field due to the possibilities and solutions afforded by CPET-derived functional endpoints. CPET is a powerful tool that incorporates ventilatory gas exchange measurements during graded exercise and robustly quantifies VO2Peak, the gold standard index for cardiovascular functional capacity. The use of functional endpoints such as VO2Peak is a critical mechanism to promote patient-centered clinical trials in patients with CKD. Furthermore, the Food and Drug Administration (FDA) has now approved both drugs and devices that have utilized VO2Peak as an endpoint outside of nephrology. With accumulating scientific evidence base supporting the rationale for CPET-derived endpoints in patients with CKD, the potential use of VO2Peak in clinical trials as a basis for regulatory approval creates an exciting opportunity in nephrology.

Moncion, Kevin; Montreal Center for Interdisciplinary Research in Rehabilitation (CRIR), Laval, Quebec, CANADA.
Rodrigues, Lynden ;De Las Heras, Bernat; Wiley, Elise; et al

Medicine and science in sports and exercise,2025 Dec 16

• Background: Accurate assessment of cardiorespiratory fitness is a critical component of cardiopulmonary exercise testing (CPET) and prescription for people with stroke. However, post-stroke disability and neuromuscular impairments are common and may disproportionately affect females throughout the continuum of recovery. There is a need to evaluate alternative whole-body CPET protocols and to characterize the sex-specific CPET responses throughout the continuum of stroke recovery.
• Purpose: To characterize the sex-specific CPET responses on a whole-body recumbent stepper CPET using American College of Sports Medicine (ACSM) criteria in people with subacute (7-90 days) and chronic (≥6-60 months) stroke.
• Methods: Participants underwent a whole-body recumbent stepper symptom-limited CPET. Each CPET was assessed for ventilatory threshold (VT), peak oxygen uptake (V̇O2peak) and ACSM maximal oxygen uptake V̇O2max criteria including respiratory exchange ratio [RER] ≥1.10; V̇O2 plateau, heart rate [HR] within 10 beats of HRmax, and ratings of perceived exertion [RPE] ≥17/20 or ≥7/10. Sex differences by stroke chronicity were evaluated via ttests, ranksum tests, Chi-squared, or Fisher’s exact tests.
• Results: In total, 145 participants underwent a symptom limited CPET. In subacute stroke (n=69), no sex differences were found for VT or V̇O2peak (p>0.05), but females were more likely to achieve a V̇O2 plateau (p=0.002). In chronic stroke (n=76), no sex differences were observed for VT or V̇O2max criteria (p>0.05), but females had lower V̇O2peak (p=0.002). Irrespective of sex, achieving the RPE (n=41 subacute [61%], n=38 chronic [54%]) or RER criteria (n=28 subacute [41%], n=39 [51%]) were the most commonly met ACSM criteria.
• Conclusions: This whole-body CPET protocol is appropriate for eliciting peak and maximal efforts in people post-stroke, however, clinicians should consider biological sex and stroke chronicity.

Carlén, Anna; Faculty of Sport Sciences, University of Granada, Granada, Spain.
Sánchez-Aranda, Lucía; Solis-Urra, Patricio; Coca-Pulido, Andrea; et al

European journal of preventive cardiology,2025 Dec 16

• Aim: Patients with coronary artery disease (CAD) are at risk of accelerated cognitive decline. We aimed to explore how different cardiorespiratory fitness (CRF) indicators associate with brain structure and cognitive function in these patients.
• Methods: We studied 105 stable CAD patients (62.1±6.6 years, 21% female), using baseline data from the randomized controlled Heart-Brain trial. Time-to-exhaustion (TTE), peak oxygen uptake (VO2peak), ventilatory anaerobic threshold (VAT), oxygen uptake efficiency slope (OUES), peak O2-pulse and 60-s heart rate recovery (HRrec) were determined from cardiopulmonary exercise tests. From magnetic resonance imaging, we extracted brain volumes (total-, grey-, and white matter volumes [TBV, GMV and WMV]) and hippocampal volume (HV), and calculated the difference between estimated and chronological brain age (brainPAD). Episodic memory, processing speed, working memory, executive function/attentional control and general cognition were evaluated.
• Results: TTE, VO2peak and OUES were positively associated with TBV (βstd 0.15 to 0.19, p<0.05) and HV (βstd 0.23 to 0.36, p<0.05). Higher OUES, HRrec and O2-pulse were associated with lower brainPAD (βstd -0.23 to -0.32, p<0.05). Higher VAT was associated with better working memory (βstd=0.26, p=0.023), and higher OUES with better executive function/attentional control (βstd=0.20, p=0.021). Hippocampal atrophy was more prevalent in lower vs middle/upper VO2peak tertile (p=0.001).
• Conclusion: In CAD patients, both maximal and submaximal CRF-indicators were associated with larger brain volumes, with stronger region-specific association with HV, and younger physiological appearance of the brain, while associations with cognitive functions were fewer and weaker. Our findings support CRF as a biomarker of structural brain health in CAD patients.

Beke, Nóra; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.
Jockers, Xenia; Hernádfői, Márk; Kói, Tamás; et al

Pediatric research,2025 Dec 17

• Background: Anthracycline-induced cardiotoxicity is a major concern in childhood cancer survivors. Detecting subclinical cardiac dysfunction early is critical, but the accuracy of current diagnostic tools is uncertain.
• Methods: We performed a systematic review and meta-analysis of studies evaluating the prognostic accuracy of echocardiography, serum biomarkers, microRNAs (miRNAs), and artificial intelligence (AI) models in predicting chemotherapy-induced cardiotoxicity in pediatric patients. Seventy-three studies were included in the qualitative synthesis, and ten in the meta-analysis. Quality was assessed using the QUAPAS tool (CRD42023485629).
• Results: AI-based models showed the highest pooled predictive performance area under the curve (AUC)~0.80, despite significant heterogeneity (I² = 93%). Global longitudinal strain (GLS) had moderate accuracy (AUC~0.72). Cardiac biomarkers like troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) showed variable sensitivity and specificity, largely influenced by timing and thresholds. Preliminary evidence on miRNAs was promising but lacked standardization. Additional methods (e.g., cardiac MRI, cardiopulmonary exercise testing (CPET)) were excluded from meta-analysis due to methodological variability.
• Conclusion: No single modality reliably detects early cardiotoxicity. Promising tools like AI models and miRNAs need further validation. A multimodal diagnostic strategy combining imaging, biomarkers, and clinical data may be the most effective approach. Standardized definitions and protocols are urgently needed.
• Impact: Early detection of chemotherapy-induced cardiotoxicity in children remains unresolved. Multimodal assessment is most effective because no single test is sufficiently reliable. There are critical methodological gaps and heterogeneity that impede standardization in pediatric cardio-oncology. AI and microRNAs are promising but still unvalidated tools. The findings guide future clinical monitoring strategies and support standardized multimodal diagnostic algorithms.

D’Ambrosio, Paolo; Department of Medicine, The University of Melbourne, Parkville, VIC, Australia and many other centres
De Paepe, Jarne; Spencer, Luke W;Ohanian, Monique; et al

Circulation,2025 Dec 18

• Background: Sinus bradycardia is a well-recognized physiological adaptation in endurance athletes, primarily attributed to sinus node remodeling or increased vagal modulation. Although genetic influences on resting heart rate (HR) have been observed, the genetic contribution to athletic bradycardia has not been elucidated.
• Methods: We phenotyped current and former elite endurance athletes in the Pro@Heart cohort study using multimodal cardiac imaging, cardiopulmonary exercise testing, and Holter monitoring. Genetic susceptibility to bradycardia was assessed using a validated HR-associated polygenic risk score (HR-PRS), in which lower scores are associated with a lower HR, and compared with healthy nonathletic controls. Clinical and genetic features of bradycardic endurance athletes with minimum HR ≤40 bpm on a Holter monitor (bradycardic athletes [BAs]) were compared with non-BAs). A healthy cohort of nonathletes from the ASPREE study (Aspirin in Reducing Events in the Elderly) were used for genetic comparisons.
• Results: Among 465 endurance athletes (median age, 23 [18-49] years, 75% men), 175 (38%) had a minimum HR on a Holter monitor ≤40 bpm, of whom 7 (2% of total) had a HR ≤30bpm. Pauses ≥2 s were observed in 115 (25%) athletes, of whom 12 (3% of total) had pauses ≥3 s. Mobitz I second-degree atrioventricular block was observed in 15 (3% of total) athletes. BAs were younger and fitter and exhibited greater athletic cardiac remodeling than non-BAs. Mean HR-PRS was significantly lower in all athletes compared with ASPREE nonathletes ( P <0.001) and in BAs compared with non-BAs ( P =0.006). When the distribution of HR-PRS within our athletic cohort was considered, athletes with scores in the bottom quartile had a lower minimum HR (median HR, 41 [35-45] bpm versus 45 [40-49] bpm, P <0.001) and higher bradycardia burden (14 [2-37]% versus 2 [0%-25]%, P <0.001) than those with scores in the top quartile. After adjusting for age, sex, fitness, and indexed right atrial volume, HR-PRS was independently associated with lower minimum HR and increased the odds of resting bradycardia by 2-fold (odds ratio [OR], 2.2 [95% CI, 1.3-3.9]; P= 0.004). Neither bradycardia nor pauses were associated with increased risk of adverse outcomes over 5.5 years.
• Conclusions: Resting bradycardia (HR ≤40 bpm) and pauses of 2 to 3 s are present in a significant proportion of endurance athletes and are well tolerated. Our data suggest that both fitness and genetic variation contribute to sinus node function in endurance athletes. Intriguingly, HR-PRS differed between athletes and nonathletes, raising the possibility that genetics may be a determinant of athleticism.

Miki, Keisuke; Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka, Japan
Nishijima, Ryosuke ;Sugisawa, Kenta; Nagata, Yuka;

BMC pulmonary medicine,2025 Dec 18

• Background: Oxygen uptake (V’ _O2 ) obtained from expiratory gas analysis is generally calculated using minute ventilation (V’ _E ) and the inspired‒expired mean oxygen (O ₂ ) concentration difference (ΔF _O2 ) during cardiopulmonary exercise testing (CPET). We have reported that ΔF _O2 , which is associated with ventilatory efficiency, is independent of V’ _E at peak exercise and affects exercise tolerance in respiratory diseases other than idiopathic pulmonary fibrosis (IPF). We hypothesized that similar results are obtained in IPF, and that ΔF _O2 is a prognostic factor for survival in IPF.
• Methods: Forty-three patients with IPF, who underwent CPET with blood gas analysis were enrolled from our database.
• Results: At peak exercise, ΔF _O2 was strongly correlated with variables related to ventilatory efficiency, i.e., V’ _E /carbon dioxide output (V’ _CO2 ) ratio at the nadir during exercise (r=‒0.91) and correlated well with peak V’ _O2 (r = 0.67), but it was independent of V’ _E (r = 0.24) at peak exercise. Two multivariate Cox proportional hazards models with adjustment for age, including the previously reported prognostic factors, showed that ΔF _O2 at peak exercise was a stronger predictor of survival than (1) peak V’ _O2 , V’ _E at peak exercise in a first analysis (hazard ratio: 0.195, 95% CI 0.070 to 0.500; p = 0.0005) and (2) than tidal volume at peak exercise, body mass index, and arterial oxygen tension (PaO ₂ )-slope, i.e., the decrease in PaO ₂ per the increase in V’ _O2 during exercise in a second analysis (hazard ratio: 0.437, 95% CI 0.201 to 0.958; p = 0.0389).
• Conclusions: These results show that ∆F _O2 at peak exercise, which is correlated with ventilatory efficiency related to carbon dioxide clearance, is independent of ventilatory ability and is a stronger prognostic factor for survival than physiological ventilatory impairments with hypoxemia in IPF. CPET is essential for evaluating exercise alveolar O ₂ extraction and guiding the optimal management of patients with IPF.

Cohen, Robyn T; Department of Pediatrics, Boston Medical Center, Boston, Massachusetts, USA.
Hankins, Jane S; Ness, Kirsten K; Hsu, Lewis L; et al

American journal of hematology,2025 Dec 20

Abstract

• Sickle cell anemia (SCA) leads to reduced physical functioning and cardiopulmonary fitness. Prior studies suggest that airway hyperresponsiveness to bronchoprovocation testing is common in SCA, but the prevalence of exercise-induced bronchospasm (EIB) is understudied. We hypothesized that EIB is more common in children with SCA than in controls. Non-asthmatic subjects 10-21 years old with SCA and race-matched controls underwent (1) maximal Cardiopulmonary Exercise Testing (CPET) by cycle ergometry and (2) a Controlled Intensity Interval Test (CIIT) consisting of eight bouts of constant workload cycling, randomized to 50% (moderate) or 70% (vigorous) of peak workload. Spirometry was performed pre/post CPET and CIIT. Multivariable logistic regression models tested associations between SCA status and EIB in response to CPET and CIIT. Compared to controls, subjects with SCA demonstrated lower hemoglobin, reduced baseline spirometry values, and decreased CPET maximal workload. Baseline lower airway obstruction and completion rates for CPET and CIIT were similar between groups. No adverse events occurred. The percentage of participants who met criteria for EIB did not differ between subjects and controls after CPET (21% vs. 26%, p = 0.537) or CIIT (32% vs. 17%, p = 0.126). In adjusted models, SCA status was not associated with EIB after CPET or CIIT. EIB was not more common in subjects with SCA versus controls after maximal CPET or submaximal exercise challenge of longer duration. Further research is needed to inform the development of exercise guidelines and to better understand the effects of exercise on airway dynamics in SCA.

Wikner, Anna; Department of Public Health and Clinical Medicine, Umeå University, 901 87 Umeå, Sweden.
Rinnström, Daniel;Johansson, Karna;Bergman, Frida; et al

Cardiology in the young,2025 Dec 22

• Background: Impaired muscle function, aerobic capacity, and fatigue are common in individuals with Fontan circulation. Knowledge regarding the effects of strength training in this population is limited. Therefore, the study aimed to investigate the effects of strength training on dynamic muscle function, aerobic capacity, and fatigue in adults with Fontan circulation compared to matched controls.
• Methods: In this pilot non-randomised controlled trial, nine patients with Fontan circulation (median age 28.9 years [IQR: 23.4-35.0], 44.4% women) and nine age- and sex-matched controls completed a 10-week strength training intervention. Dynamic muscle function was assessed through shoulder flexion, heel rise, elbow flexion, and knee extension tests. Aerobic capacity was evaluated using cardiopulmonary exercise testing, and fatigue using the questionnaire Multidimensional Fatigue Inventory . All assessments were conducted pre – and post -intervention. Within-group changes were analysed using the Wilcoxon signed rank test and between-group differences using the Mann-Whitney U test.
• Results: Patients showed improvements in all muscle function tests post-intervention (shoulder flexions 39.3% [IQR: 18.9-69.7], p = 0.008; heel rise 26.7% [IQR:17.5-58.1], p = 0.008; elbow flexions 57.1% [IQR: 50.0-173.8], p = 0.007; knee extensions 66.7% [24.3-92.9], p = 0.008). The improvements were at comparable levels to controls. Only controls reported reduced fatigue (-19.4% [IQR: -28.7, -10.5], p = 0.01), while patients showed no change (-5.9% [IQR: -25.5, 3.2], p = 0.1). Aerobic capacity remained unchanged. No severe adverse events occurred.
• Conclusion: Strength training is safe and improves dynamic muscle function in patients with Fontan circulation, with changes comparable to those of healthy controls. However, the effect of strength training on fatigue and aerobic capacity requires further investigation.

McCarthy OM; Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark
Brødsgaard RB; Tawfik S; Lundemose SB; Lindkvist EB; Naaman SH; Hansen CS; Bracken RM; Nørgaard K

Diabetologia [Diabetologia] 2025 Dec 09.
Date of Electronic Publication: 2025 Dec 09.

• Aims/hypothesis: The aim of this work was to compare the cardiopulmonary, sympathoadrenal and metabolic responses to physical exercise in adults with type 1 diabetes with or without cardiovascular autonomic neuropathy (CAN).
• Methods: Data collected during a graded maximal exercise test (GXT) from 24 participants with type 1 diabetes and CAN were compared against 24 matched control individuals without CAN (NO CAN). Throughout exercise, integrated cardiopulmonary variables were obtained continuously via spiroergometry. Plasma concentrations of adrenaline (epinephrine), noradrenaline (norepinephrine), glucose (PG) and lactate (PLa) were measured in 3 min intervals during exercise as well as at the peak workload. Data were assessed via independent t tests and two-factor ANOVAs with significance accepted at p≤0.05.
• Results: Participants with CAN displayed a reduced INLINEMATH (CAN 19.6 ± 5.4 vs NO CAN 27.5 ± 7.8 ml kg ^-1 min ^-1 ) as well as attenuations in several other cardiopulmonary, lactate and exercise performance variables during GXT. Peak catecholamine concentrations were lower in CAN vs NO CAN (AD 0.17 ± 0.12 vs 0.38 ± 0.27 ng/ml, p=0.002; NAD 1.86 ± 1.04 vs 2.85 ± 1.23 ng/ml, p=0.007) as were the magnitudes of change in hormonal concentrations from rest to peak workloads (adrenaline Δ +0.13 ± 0.12 vs Δ +0.32 ± 0.24 ng/ml, p=0.005; noradrenaline Δ +1.33 ± 0.89 vs Δ +2.33 ± 1.30 ng/ml, p=0.005). PG concentrations throughout exercise were similar between groups and remained unchanged from rested values irrespective of CAN status.
• Conclusions/interpretation: In adults with type 1 diabetes, CAN was associated with exercise intolerance characterised by impairments in various cardiopulmonary, sympathoadrenal system and metabolic responses to GXT. These data support uncovering the presence of CAN when prescribing a personalised physical training plan.

Moura-Ferreira S; Department of Cardiology and Jessa & Science, Jessa Hospital, Hasselt, Belgium
Pugliese NR; Milani M; Taddei S; Jacobs A; De Biase N; Dhont S; Falter M; Bekhuis Y; L’Hoyes W; Hoedemakers S; Droogmans S;
Cosyns B; Jasaityte R; Claessen G; Del Punta L; Herbots L; De Carlo M; Mazzola M; Bertrand PB; Falcetta G; Debonnaire P; Masi S; Verwerft J

Circulation. 152(23):1594-1607, 2025 Dec 09.

METHODS: Between January of 2019 and December of 2023, 211 patients
assigned to a derivation cohort (64+/-12 years of age, 40% women) and 146
patients assigned to a validation cohort (66+/-13 years of age, 39%
women), all of whom had moderate or severe primary mitral regurgitation,
no or discordant symptoms, and no left ventricular systolic dysfunction or
atrial fibrillation, underwent semisupine cycle-ergometry cardiopulmonary
exercise testing combined with exercise echocardiography. TAPSE/sPAP was
measured at rest and at intermediate (defined as the first ventilatory
threshold) and peak exercise. The primary end point was a composite of
cardiovascular death, unplanned cardiovascular hospitalizations, and new
atrial fibrillation.

RESULTS: In the derivation cohort, 48 patients reached the composite
outcome (median follow-up, 24 months [interquartile range, 12-51]).
Intermediate and peak exTAPSE/sPAP were strongly correlated (r=0.84;
P<0.001), with intermediate exTAPSE/sPAP offering superior feasibility
(98% versus 92%) with comparable prognostic accuracy to peak exTAPSE/sPAP
(area under the receiver operating characteristic curve, 0.794
[0.730-0.849] versus 0.765 [0.698-0.823]) and therefore was used as the
exercise TAPSE/sPAP measure. Patients with a reduced rest TAPSE/sPAP
(cutoff 0.8 mm/mm Hg) and intermediate exTAPSE/sPAP (cutoff 0.6 mm/mm Hg)
had a lower event-free survival (log-rank P<0.0001). Intermediate
exTAPSE/sPAP and percent-predicted peak VO2 were independently associated
with the primary end point (hazard ratio, 0.64 [0.51-0.80] per 0.1 mm/mm
Hg increase [P<0.001] and hazard ratio, 2.03 [1.05-3.93] if <80% [P=0.04],
respectively) and had incremental prognostic value beyond age, left atrial
volume index, mitral regurgitation severity, rest TAPSE/sPAP, and mitral
valve intervention (time-dependent covariable). Similar results were found
when rest and intermediate exTAPSE/sPAP were included in the multivariable
model as categorical measures. Validation in an independent cohort
confirmed the consistent and robust performance of both multivariable
models, irrespective of whether TAPSE/sPAP was modeled as a continuous or
categorical variable.

CONCLUSIONS: Exercise right ventricular-pulmonary arterial coupling,
particularly intermediate exTAPSE/sPAP, is a robust and feasible measure
independently associated with adverse outcomes, and provides prognostic
information beyond resting variables and cardiorespiratory fitness,
potentially refining risk stratification and guiding management in
patients with primary mitral regurgitation.
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