Willixhofer, Robin;Ermolaev, Nikita;Kronberger, Christina;Eslami, Mahshid; et al

Circulation reports,2025 Jan 21

• Background: This study assessed the prognostic value of submaximal cardiopulmonary exercise testing (CPET) in cardiac amyloidosis and explored CPET as an alternative to the 6-min walk test (6MWT).
• Methods and Results: In this single-center prospective observational study, 160 patients with cardiac amyloidosis (87% male; mean age 78±7 years) were evaluated. A total of 145 performed maximum symptom limited CPET. The V̇E/V̇CO ₂ slope was 39±8, submaximal power output (SPO) was 24.75±11.50 W, and V̇O ₂ at anaerobic threshold (AT) was 8.13±2.29 mL/min/kg. During follow up, 34 (21.25%) patients died, and another 34 (21.25%) experienced heart failure (HF)-related hospitalization, with 15 (9.38%) patients experiencing both events. Univariate analysis showed that V̇E/V̇CO ₂ slope (hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.86-0.93; P<0.001) and SPO (HR 0.91; 95% CI 0.87-0.96; P<0.001) were predictors of mortality. In multivariate analysis, V̇E/V̇CO ₂ slope remained a significant predictor (HR 0.92; 95% CI 0.88-0.97; P<0.001) for both all-cause mortality and HF-related hospitalization independently. A SPO cut-off of <28 W predicted a worse outcome for both measures independently. Moderate correlations for V̇E/V̇CO ₂ slope (-0.56 [CI -0.67, -0.42]) and SPO (0.55 [CI 0.42, 0.67]) with 6MWT distance have been found.
• Conclusions: These findings highlight CPET parameters, particularly V̇E/V̇CO ₂ slope and SPO with a cut-off <28 W, as predictors of survival and HF-related hospitalization in cardiac amyloidosis.
• Competing Interests: R.B.E. received a research grant from AstraZeneca Austria. R.W. and N.E. have been reimbursed by Pfizer Austria for attending several conferences.

Santana,  J; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.;
Kim, D; Christle, J, et al

European journal of preventive cardiology,2025 Feb 07

• Aims: Cardiorespiratory fitness (CRF), measured by peak oxygen uptake (VO2peak), is a strong predictor of mortality. Despite its widespread clinical use, current reference equations for VO2peak show distorted calibration in obese individuals. Using data from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we sought to develop novel reference equations for VO2peak better calibrated for overweight/obese individuals – in both males and females, by considering body composition metrics.
• Methods: Graded treadmill tests from 6,836 apparently healthy individuals were considered in data analysis. We used the National Health and Nutrition Examination Survey equations to estimate lean body mass (eLBM) and body fat percentage (eBF). Multivariable regression was used to determine sex-specific equations for predicting VO2peak considering age terms, eLBM and eBF.
• Results: The resultant equations were expressed as VO2peak (male) = 2633.4 + 48.7✕eLBM (kg) – 63.6✕eBF (%) – 0.23✕Age2 (R2=0.44) and VO2peak (female) = 1174.9 + 49.4✕eLBM (kg) – 21.7✕eBF (%) – 0.158✕Age2 (R2=0.53). These equations were well-calibrated in subgroups based on sex, age and body mass index (BMI), in contrast to the Wasserman equation. In addition, residuals for the percent-predicted VO2peak (ppVO2) were stable over the predicted VO2peak range, with low CRF defined as < 70% ppVO2 and average CRF defined between 85-115%.
• Conclusions: The derived VO2peak reference equations provided physiologically explainable and were well-calibrated across the spectrum of age, sex and BMI. These equations will yield more accurate VO2peak evaluation, particularly in obese individuals.

Natalia, G; Almazov National Medical Research Center, Saint-Petersburg, Russia.
Lapshin, K; Berezina, A, et al.

Annals of thoracic medicine,2025 Jan-Mar

• Introduction: The choice of treatment strategy in patients with idiopathic pulmonary arterial hypertension (IPAH)/HPAH/DPAH (Hereditary pulmonary arterial hypertension/ Drug-induced pulmonary arterial hypertension) II-III functional class (FC) (WHO) based on an acute vasoreactive testing result (VRT). Positive VRT (VRT+) is an indication for calcium channel blockers therapy. Long-term vasoresponders demonstrate sustained low-risk status and the highest survival among all PH subtypes.
• The Study Aimed: To characterize VRT performance in IPAH patients and differences in presentation between patients with positive, negative VRT, and patients with not done VRT due to physicians’ decision.
• Methods: One hundred and sixty-six adult IPAH patients (44.2 ± 15.3 years, 34 males) comprised into prospective single-center study between 2008 and 2023 years. Inhaled iloprost was used for VRT. Positive VRT was defined with established Sitbon criteria. Standard baseline pulmonary arterial hypertension (PAH) evaluation including cardiopulmonary exercise test (CPET) was performed. Risk status was evaluated using ESC/ERS (European Society of Cardiology/European Respiratory Society) risk scale 2015. Survival was assessed with the Kaplan-Mayer method.
• Results: Eighty-five (51.2%) patients underwent VRT. VRT not done (ND VRT) due to the physicians’ decision in 26.7% patients, due to the technical inability in 15.4% and IV FC (WHO) in 16.2% patients. Positive VRT registered in 26 (15.6%) patients. Patients with negative VRT demonstrated worse hemodynamics and exercise tolerance, higher N-terminal pro-brain-type natriuretic peptide (NT-proBNP) level, and right heart dilatation compared with VRT+. Patients with ND VRT due to the physicians decision were often older than 60 years, had higher body mass index, symptoms of right heart failure, hemoptysis, arrhythmias, high NT-proBNP, and hemodynamic criteria of high risk in comparison with patients with done VRT. Some CPET parameters were similar between VRT + group and patients ND VRT group. Loss of vasoreactivity and PAH worsening were detected in 50% of VRT + patients in a 1.76 year of follow-up. Patients with vasoreactivity loss exhibited the criteria of intermediate risk at a baseline. Five-year survival was 97% in VRT + group in comparison with 61% in VRT – and 53% in ND VRT group.
• Conclusions: Physicians’ decision was the most common reason for not doing VRT in IPAH patients. Intermediate high-risk criteria presence at a baseline were associated with not done VRT due to physicians decision, negative VRT, and the vasoreactivity loss during the follow-up. CPET should be used more widely to detect the early signs of PAH progression in low risk or VRT + patients.

Wong, M; Asthma, Allergy and Clinical Immunology Service, Alfred Health, Australia.
Gardner, L; Denton, E, et al.

Journal of science and medicine in sport,2025 Feb

• Objectives: Abnormal breathlessness at maximal exercise may be caused by a range of conditions, including exercise-induced bronchospasm, breathing pattern disorder, or exercise-induced laryngeal obstruction. These three disorders may not be detected on standard cardiopulmonary exercise testing. The aim of this study was to describe diagnostic outcomes of an expanded protocol during cardiopulmonary exercise testing.
• Design: Retrospective cohort study.
• Methods: Patients presenting with abnormal breathlessness on maximal exercise underwent continuous laryngoscopy with cardiopulmonary exercise testing on a stationary cycle ergometer. Breathing pattern disorder was evaluated by video and ventilatory data. Pre- and post-exercise spirometry was performed.
• Results: 24 adult patients were evaluated; 10 were professional athletes. Mean age was 40 years (range 18-73). Nine of 24 (38 %) were diagnosed with exercise-induced laryngeal obstruction and referred for speech pathology. Six of these had supraglottic exercise-induced laryngeal obstruction; all were aged <30 years; 5/6 were professional athletes. One patient had breathing pattern disorder and was referred for physiotherapy; one had exercise-induced bronchospasm, requiring escalation of asthma medication; one had muscle tension dysphonia resulting in referral to an otolaryngologist who administered a laryngeal injection of botulinum toxin. A further four patients had unexplained lower maximal oxygen consumption with cardiac limitation and were referred for further cardiac investigation.
• Conclusions: In patients reporting abnormal breathlessness at maximal exercise, this expanded exercise protocol provided diagnostic information in 66.7 % cases which contributed to further personalised management.

Bokov, P; Hôpital Robert Debré, Service de Physiologie Pédiatrique, Paris, France
Dudoignon, B; Fikiri Bavurhe; R;Couque, N; et al

Pediatric research,2025 Jan

• Background: It has been stated that patients with congenital central hypoventilation syndrome (CCHS) do not perceive dyspnea, which could be related to defective CO ₂ chemosensitivity.
• Methods: We retrospectively selected the data of six-minute walk tests (6-MWT, n = 30), cardiopulmonary exercise test (CPET, n = 5) of 30 subjects with CCHS (median age, 9.3 years, 17 females) who had both peripheral (controller loop gain, CG0) and central CO ₂ chemosensitivity (hyperoxic, hypercapnic response test [HHRT]) measurement.
• Main Results: Ten subjects had no symptom during the HHRT, as compared to the 20 subjects exhibiting symptoms, their median ages were 14.7 versus 8.8 years (p = 0.006), their maximal PETCO ₂ were 71.6 versus 66.7 mmHg (p = 0.007), their median CO ₂ response slopes were 0.28 versus 0.30 L/min/mmHg (p = 0.533) and their CG0 values were 0.75 versus 0.50 L/min/mmHg (p = 0.567). Median dyspnea Borg score at the end of the 6-MWT was 1/10 (17/30 subjects >0), while at the end of the CPET it was 3/10 (sensation: effort). This Borg score positively correlated with arterial desaturation at walk (R = 0.43; p = 0.016) and did not independently correlate with CO ₂ chemosensitivities.
• Conclusion: About half of young subjects with CCHS do exhibit mild dyspnea at walk, which is not related to hypercapnia or residual CO ₂ chemosensitivity.
• Impact: Young subjects with CCHS exhibit some degree of dyspnea under CO ₂ exposure and on exercise that is not related to residual CO ₂ chemosensitivity. It has been stated that patients with CCHS do not perceive sensations of dyspnea, which must be tempered. The mild degree of exertional dyspnea can serve as an indicator for the necessity of breaks.

Khilzi, Pulmonology Department-Hospital del Mar Pulmonary Hypertension Unit Barcelona Spain.
Karys; Piccari, Lucilla; Franco, Gerard, et al.

Pulmonary circulation,2025 Feb 05Although current guidelines recommend standard cardiopulmonary exercise testing (CPET) to evaluate symptomatic patients after pulmonary embolism (PE), CPET with simultaneous echocardiography could provide relevant information to evaluate right ventricular-pulmonary arterial coupling.
AIMS
The aim of this study was to investigate exercise-induced changes in echocardiographic variables of RV function or RV- arterial coupling in patients with residual thrombotic defects at 3 months after PE.
METHODS
This retrospective study investigated patients with residual thromboembolic disease on V/Q scintigraphy with persistent symptoms despite adequate anticoagulation after 3 months of acute PE, and resting echocardiography with a low probability of PH. At rest and during exercise, CPET and doppler echocardiography were performed following a standard protocol. Forty-five patients were included, completing a follow-up period of at least 24 months. The mean (standard deviation) age was 63 (15) years, and 24 (53%) patients were male.
RESULTS
Four patients developed CTEPH after 2 years follow up. Correlation analyses showed that the peak TAPSE was significantly associated with peak workload ( r = 0.454, p = 0.003), peak VO ₂ ( r = 0.558, p < 0.001), VE/VECO ₂ (AT) ( r = -0.531, p < 0.001), and oxygen pulse ( r = 0.375, p = 0.02). TAPSE/PASP was only slightly associated with peak workload ( r = 0.300, p = 0.045). By contrast, the change on TAPSE (from rest to peak) was significantly correlate with peak oxygen uptake ( r = 0.491, p = 0.01). Also, reduced VO ₂ at AT and TAPSE/PASP was seen in patients with CTEPH. CPET with synchronic echocardiography could be a useful tool in early assessment of symptomatic patients with perfusion defects on imaging after 3 months of correctly treated PE.

T. Atanasovska, Melbourne Australia
T. Farr, R. Smith, A. C. Petersen, A. Garnham, M. J. Andersen, et al.

J Physiol 2024 Vol. 602 Issue 24 Pages 6849-6869

We investigated acute effects of the Na(+),K(+)-ATPase (NKA) inhibitor, digoxin, on muscle NKA content and isoforms, arterial plasma [K(+)] ([K(+)](a)) and fatigue with intense exercise.
In a randomised, crossover, double-blind design, 10 healthy adults ingested 0.50 mg digoxin (DIG) or placebo (CON) 60 min before cycling for 1 min at 60% V̇O2peak then at 95% V̇O2peak until fatigue. Pre- and post-exercise muscle biopsies were analysed for [(3)H]-ouabain binding site content without (OB-F(ab)) and after incubation in digoxin antibody (OB+F(ab)) and NKA alpha(1-2) and beta(1-2) isoform proteins. In DIG, pre-exercise serum [digoxin] reached 3.36 (0.80) nM [mean (SD)] and muscle NKA-digoxin occupancy was 8.2%. Muscle OB-F(ab) did not differ between trials, whereas OB+F(ab) was higher in DIG than CON (8.1%, treatment main effect, P = 0.001), whilst muscle NKA alpha(1-2) and beta(1-2) abundances were unchanged by digoxin. Fatigue occurred earlier in DIG than CON [-7.7%, 2.90 (0.77) vs. 3.14 (0.86) min, respectively; P = 0.037]. [K(+)](a) increased during exercise until 1 min post-exercise (P = 0.001), and fell below baseline at 3-10 (P = 0.001) and 20 min post-exercise (P = 0.022, time main effect). In DIG, [K(+)](a) (P = 0.035, treatment effect) and [K(+)](a) rise pre-fatigue were greater [1.64 (0.73) vs. 1.55 (0.73), P = 0.016], with lesser post-exercise [K(+)](a) decline than CON [-2.55 (0.71) vs. -2.74 (0.62) mM, respectively, P = 0.003]. Preserved muscle OB-F(ab) with digoxin, yet increased OB+F(ab) with unchanged NKA isoforms, suggests a rapid regulatory assembly of existing NKA alpha and beta subunits exists to preserve muscle NKA capacity. Nonetheless, functional protection against digoxin was incomplete, with earlier fatigue and perturbed [K(+)](a) with exercise.
KEY POINTS: Intense exercise causes marked potassium (K(+)) shifts out of contracting muscle cells, which may contribute to muscle fatigue. Muscle and systemic K(+) perturbations with exercise are largely regulated by increased activity of Na(+),K(+)-ATPase in muscle, which can be specifically inhibited by the cardiac glycoside, digoxin. We found that acute oral digoxin in healthy adults reduced time to fatigue during intense exercise, elevated the rise in arterial plasma K(+) concentration during exercise and slowed K(+) concentration decline post-exercise. Muscle functional Na(+),K(+)-ATPase content was not reduced by acute digoxin, despite an 8.2% digoxin occupancy, and was unchanged at fatigue. Muscle Na(+),K(+)-ATPase isoform protein abundances were unchanged by digoxin or fatigue. These suggest possible rapid assembly of existing subunits into functional pumps. Thus, acute digoxin impaired performance and exacerbated plasma K(+) disturbances with intense, fatiguing exercise in healthy participants. These occurred despite the preservation of functional Na(+),K(+)-ATPase in muscle.

Daza JF; University of Toronto, Toronto, Ontario, Canada
Chesney TR; Morales JF; Xue Y; Lee S; Amado LA; Pivetta B;
Mbadjeu Hondjeu AR; Jolley R; Diep C; Alibhai SMH; Smith PM; Kennedy ED;
Racz E; Wilmshurst L; Wijeysundera DN

Annals of Internal Medicine. 178(1):75-87, 2025 Jan.

BACKGROUND: Functional capacity is critical to preoperative risk
assessment, yet guidance on its measurement in clinical practice remains
lacking.
PURPOSE: To identify functional capacity assessment tools studied before
surgery and characterize the extent of evidence regarding performance,
including in populations where assessment is confounded by
noncardiopulmonary reasons.
DATA SOURCES: MEDLINE, EMBASE, and EBM Reviews (until July 2024).
STUDY SELECTION: Studies evaluating performance of functional capacity
assessment tools administered before elective noncardiac surgery to
stratify risk for postoperative outcomes.
DATA EXTRACTION: Study details, measurement properties, pragmatic
qualities, and/or clinical utility metrics.
DATA SYNTHESIS: 6 categories of performance-based tests and 5 approaches
using patient-reported exercise tolerance were identified. Cardiopulmonary
exercise testing (CPET) was the most studied tool (132 studies, 32 662
patients) followed by field walking tests (58 studies, 9393 patients)
among performance-based tests. Among patient-reported assessments, the
Duke Activity Status Index (14 studies, 3303 patients) and unstructured
assessments (19 studies, 28 520 patients) were most researched. Most
evidence focused on predictive validity (92% of studies), specifically
accuracy in predicting cardiorespiratory complications. Several tools
lacked evidence on reliability (test consistency across similar
measurements), pragmatic qualities (feasibility of implementation), or
concurrent criterion validity (correlation to gold standard). Only CPET
had evidence on clinical utility (whether administration improved
postoperative outcomes). Older adults (>=65 years) were well represented
across studies, whereas there were minimal data in patients with obesity,
lower-limb arthritis, and disability.
LIMITATION: Synthesis focused on reported data without requesting missing
information.
CONCLUSION: Though several tools for preoperative functional capacity
assessment have been studied, research has overwhelmingly focused on CPET
and only 1 aspect of validity (predictive validity). Important evidence
gaps remain among vulnerable populations with obesity, arthritis, and
physical disability.