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.
Publication Type

Mets G; Hospital for Sick Children Toronto Ontario Canada.
Bitterman Y; Mercer-Rosa L; Wald R; Friedberg MK

Journal of the American Heart Association. 14(23):e042371, 2025 Dec 02.

BACKGROUND: Right ventricular (RV) to pulmonary arterial coupling (RVPAc)
quantifies RV contractility in relation to its afterload but traditionally
requires high-fidelity catheter derived pressure-volume loops. We sought
to evaluate a noninvasive volume-based RVPAc parameter in children and
adults with repaired tetralogy of Fallot in relation to pulmonary
regurgitation (PR), RV outflow tract obstruction (RVOTO), and exercise
capacity.

METHODS: We retrospectively studied 92 pediatric and 105 adult patients
with repaired tetralogy of Fallot who had cardiovascular magnetic
resonance imaging and cardiopulmonary exercise testing within a 1-year
interval. RVPAc was calculated as the ratio of RV end-systolic volume over
stroke volume. RVOTO gradient was obtained by echocardiography; RV
ejection fraction, and PR fraction by cardiovascular magnetic resonance
imaging. Exercise capacity was measured as the percentage of predicted
peak oxygen consumption during cardiopulmonary exercise testing. Subgroups
were established depending on the combination of PR-RVOTO (cutoff defined
as PR >30% and RVOTO >25 mm Hg).

RESULTS: RVPAc was significantly higher in adult versus pediatric
patients (1.23 [1.03-1.48] versus 1.00 [0.88-1.15]; P<0.001). RVPAc was
comparable in the 4 pediatric hemodynamic subgroups (P=0.38) but tended to
be higher in adults with either RVOTO, PR, or RVOTO+PR (P=0.05). RVPAc
highly correlated with RVEF (r=-0.991, P<0.001) but was not associated
with percentage of predicted peak oxygen consumption.

CONCLUSIONS: Worse RVPAc in adult versus pediatric patients with repaired
tetralogy of Fallot may signify progressive RV-PA uncoupling with age- or
era-related effects. However, the clinical use of volumetric RVPAc in
repaired tetralogy of Fallot appears limited, as it does not provide
additional information over RVEF and is not associated with exercise
capacity.

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