Panza L; Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.
Piamonti D; Palange P;

Expert review of respiratory medicine [Expert Rev Respir Med] 2024 Jun 27, pp. 1-13.
Date of Electronic Publication: 2024 Jun 27.

Introduction: Cardiopulmonary exercise testing (CPET) is nowadays used to study the exercise response in healthy subjects and in disease. Ventilatory efficiency is one of the main determinants in exercise tolerance, and its main variables are a useful tool to guide pathophysiologists toward specific diagnostic pathways, providing prognostic information and improving disease management, treatment, and outcomes.
Areas Covered: This review will be based on today’s available scientific evidence, describing the main physiological determinants of ventilatory efficiency at rest and during exercise, and focusing also on how CPET variables are modified in specific diseases, leading to the possibility of early diagnosis and management.
Expert Opinion: Growing knowledge on CPET interpretation and a wider use of this clinical tool is expected in order to offer more precise diagnostic and prognostic information to patients and clinicians, helping in the management of therapeutic decisions. Future research could be able to identify new and more simple markers of ventilatory efficiency, and to individuate new interventions for the improvement of symptoms, such as exertional dyspnea.

Agostoni P; Centro Cardiologico Monzino, IRCCS, Milano, Italy.;
Cattadori G; Vignati C; Apostolo A; Farina S; Salvioni E; Di Marco S; Sonaglioni A; Nodari S; Marenzi G; Schmidt-Trucksäss A; Myers J;

European journal of preventive cardiology [Eur J Prev Cardiol] 2024 Jun 27.
Date of Electronic Publication: 2024 Jun 27.

Aims: The Fick principle states that oxygen uptake (V̇O2) is cardiac output (Qc)*arterial-venous O2 content difference [ΔC(a-v)O2]. Blood flow distribution is hidden in Fick principle and its relevance during exercise in heart failure (HF) is undefined.To highlight the role of blood flow distribution, we evaluated peak-exercise V̇O2, Qc and ΔC(a-v)O2, before and after HF therapeutic interventions.
Methods: Symptoms-limited cardiopulmonary exercise tests with Qc measurement (inert-gas-rebreathing) was performed in 234 HF patients before and 6 months after successful exercise training, cardiac-resynchronization therapy or percutaneous-edge-to-edge mitral valve repair.
Results: Considering all tests (n=468) a direct correlation between peakV̇O2 and peakQc (R2=0.47) and workload (R2=0.70) were observed. Patients were grouped according to treatment efficacy in group 1 (peakV̇O2 increase >10%, n=93), group 2 (peakV̇O2 change between 0 and 10%, n=60) and group 3 (reduction in peakV̇O2, n=81). Post-treatment peakV̇O2 changes poorly correlated with peakQc and peakΔC(a-v)O2 changes. Differently, post-procedures peakQc vs. peakΔC(a-v)O2 changes showed a close negative correlation (R2=0.46), becoming stronger grouping patients according to peakV̇O2 improvement (R2=0.64, 0.79 and 0.58 in group 1, 2 and 3, respectively). In 76% of patients peakQc and ΔC(a-v)O2 changes diverged regardless of treatment.
Conclusion: The bulk of these data suggests that blood flow distribution plays a pivotal role on peakV̇O2 determination regardless of HF treatment strategies. Accordingly, for assessing HF treatment efficacy on exercise performance the sole peakV̇O2 may be deceptive and the combination of V̇O2, Qc and ΔC(a-v)O2, must be considered.

Miller PE; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Gajjar P; Mitchell GF; Khan SS; Vasan RS; Larson MG; Lewis GD; Shah RV;Nayor M;

ESC heart failure [ESC Heart Fail] 2024 Jun 28.
Date of Electronic Publication: 2024 Jun 28.

Aims: New tools are needed to identify heart failure (HF) risk earlier in its course. We evaluated the association of multidimensional cardiopulmonary exercise testing (CPET) phenotypes with subclinical risk markers and predicted long-term HF risk in a large community-based cohort.
Methods and Results: We studied 2532 Framingham Heart Study participants [age 53 ± 9 years, 52% women, body mass index (BMI) 28.0 ± 5.3 kg/m ² , peak oxygen uptake (VO ₂ ) 21.1 ± 5.9 kg/m ² in women, 26.4 ± 6.7 kg/m ² in men] who underwent maximum effort CPET and were not taking atrioventricular nodal blocking agents. Higher peak VO ₂ was associated with a lower estimated HF risk score (Spearman correlation r: -0.60 in men and -0.55 in women, P < 0.0001), with an observed overlap of estimated risk across peak VO ₂ categories. Hierarchical clustering of 26 separate CPET phenotypes (values residualized on age, sex, and BMI to provide uniformity across these variables) identified three clusters with distinct exercise physiologies: Cluster 1-impaired oxygen kinetics; Cluster 2-impaired vascular; and Cluster 3-favourable exercise response. These clusters were similar in age, sex distribution, and BMI but displayed distinct associations with relevant subclinical phenotypes [Cluster 1-higher subcutaneous and visceral fat and lower pulmonary function; Cluster 2-higher carotid-femoral pulse wave velocity (CFPWV); and Cluster 3-lower CFPWV, C-reactive protein, fat volumes, and higher lung function; all false discovery rate < 5%]. Cluster membership provided incremental variance explained (adjusted R ² increment of 0.10 in women and men, P < 0.0001 for both) when compared with peak VO ₂ alone in association with predicted HF risk.
Conclusions: Integrated CPET response patterns identify physiologically relevant profiles with distinct associations to subclinical phenotypes that are largely independent of standard risk factor-based assessment, which may suggest alternate pathways for prevention.

Yang L; Guangdong Cardiovascular Institute, Guangdong Province, 510100, China.
Luo D; Huang T; Li X; Zhang G; Zhang C; Fei H;

BMC pulmonary medicine [BMC Pulm Med] 2024 Jun 28; Vol. 24 (1), pp. 306.
Date of Electronic Publication: 2024 Jun 28.

Background: For patients with congenital heart disease-related pulmonary arterial hypertension (CHD-PAH), cardiopulmonary exercise testing (CPET) can reflect cardiopulmonary reserve function. However, CPET may not be readily accessible for patients with high-risk conditions or limited mobility due to disability. Echocardiography, on the other hand, serves as a widely available diagnostic tool for all CHD-PAH patients. This study was aimed to identify the parameters of echocardiography that could serve as indicators of cardiopulmonary function and exercise capacity.
Methods: A cohort of 70 patients contributed a total of 110 paired echocardiogram and CPET results to this study, with 1 year interval for repeated examinations. Echocardiography and exercise testing were conducted following standardized procedures, and the data were collected together with clinically relevant indicators for subsequent statistical analysis. Demographic comparisons were performed using t-tests and chi-square tests. Univariate and multivariate analyses were conducted to identify potential predictors of peak oxygen uptake (peak VO ₂ ) and the carbon dioxide ventilation equivalent slope (VE/VCO ₂ slope). Receiver operating characteristic (ROC) analysis was used to assess the performance of the parameters.
Results: The ratio of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) was found to be the only independent indicator significantly associated with both peak VO ₂ and VE/VCO ₂ slope (both p < 0.05). Additionally, left ventricular ejection fraction (LVEF) and right ventricular fractional area change (FAC) were independently correlated with the VE/VCO ₂ slope (both p < 0.05). TAPSE/PASP showed the highest area under the ROC curve (AUC) for predicting both a peak VO ₂  ≤ 15 mL/kg/min and a VE/VCO ₂ slope ≥ 36 (AUC = 0.91, AUC = 0.90, respectively). The sensitivity and specificity of TAPSE/PASP at the optimal threshold exceeded 0.85 for both parameters.
Conclusions: TAPSE/PASP may be a feasible echocardiographic indicator for evaluating exercise tolerance.

Rissanen A;  Foundation for Sports and Exercise Medicine (HULA), Helsinki, Finland
Mikkola T; Gagnon D; Lehtonen E; Lukkarinen S; Peltonen J;

Physiol. Meas. 45 (2024) 055028

Objective. Maximal O2 uptake ( ˙VO2max) reflects the individual’s maximal rate of O2 transport and
utilization through the integrated whole-body pathway composed of the lungs, heart, blood,
circulation, and metabolically active tissues. As such, ˙VO2max is strongly associated with physical
capacity as well as overall health and thus acts as one predictor of physical performance and as a
vital sign in determination of status and progress of numerous clinical conditions. Quantifying the
contribution of single parts of the multistep O2 pathway to ˙VO2max provides mechanistic insights
into exercise (in)tolerance and into therapy-, training-, or disuse-induced adaptations at individual
or group levels. We developed a desktop application (Helsinki O2 Pathway Tool—HO2PT) to
model numerical and graphical display of the O2 pathway based on the ‘Wagner diagram’
originally formulated by Peter D. Wagner and his colleagues. Approach. The HO2PT was developed
and programmed in Python to integrate the Fick principle and Fick’s law of diffusion into a
computational system to import, calculate, graphically display, and export variables of the Wagner
diagram. Main results. The HO2PT models O2 pathway both numerically and graphically according
to the Wagner diagram and pertains to conditions under which the mitochondrial oxidative
capacity of metabolically active tissues exceeds the capacity of the O2 transport system to deliver O2
to the mitochondria. The tool is based on the Python open source code and libraries and freely and
publicly available online for Windows, macOS, and Linux operating systems.
Significance. The HO2PT offers a novel functional and demonstrative platform for those interested
in examining ˙VO2max and its determinants by using the Wagner diagram. It will improve access to
and usability of Wagner’s and his colleagues’ integrated physiological model and thereby benefit
users across the wide spectrum of contexts such as scientific research, education, exercise testing,
sports coaching, and clinical medicine.

Bondar G; David Geffen School of Medicine, University of California Los Angeles Medical Center, Los Angeles,
Mahapatra AD; Bao TM; Silacheva I; Hairapetian A; Vu T; .Su S; Katappagari A; Galan L; Chandran J; Adamov R; Mancusi L; Lai I;Rahman A; Grogan T;
Hsu JJ; Cappelletti M;Ping P;Elashoff D; Reed EF; Deng M

Journal of clinical medicine [J Clin Med] 2024 May 29; Vol. 13 (11).
Date of Electronic Publication: 2024 May 29.

Background : Cardiorespiratory fitness positively correlates with longevity and immune health. Regular exercise may provide health benefits by reducing systemic inflammation. In chronic disease conditions, such as chronic heart failure and chronic fatigue syndrome, mechanistic links have been postulated between inflammation, muscle weakness, frailty, catabolic/anabolic imbalance, and aberrant chronic activation of immunity with monocyte upregulation. We hypothesize that (1) temporal changes in transcriptome profiles of peripheral blood mononuclear cells during strenuous acute bouts of exercise using cardiopulmonary exercise testing are present in adult subjects, (2) these temporal dynamic changes are different between healthy persons and heart failure patients and correlate with clinical exercise-parameters and (3) they portend prognostic information.
Methods : In total, 16 Heart Failure (HF) patients and 4 healthy volunteers (HV) were included in our proof-of-concept study. All participants underwent upright bicycle cardiopulmonary exercise testing. Blood samples were collected at three time points (TP) (TP1: 30 min before, TP2: peak exercise, TP3: 1 h after peak exercise). We divided 20 participants into 3 clinically relevant groups of cardiorespiratory fitness, defined by peak VO ₂ : HV ( n = 4, VO ₂ ≥ 22 mL/kg/min), mild HF (HF1) ( n = 7, 14 < VO ₂ < 22 mL/kg/min), and severe HF (HF2) ( n = 9, VO ₂ ≤ 14 mL/kg/min).
Results : Based on the statistical analysis with 20-100% restriction, FDR correction ( p -value 0.05) and 2.0-fold change across the three time points (TP1, TP2, TP3) criteria, we obtained 11 differentially expressed genes (DEG). Out of these 11 genes, the median Gene Expression Profile value decreased from TP1 to TP2 in 10 genes. The only gene that did not follow this pattern was CCDC181 . By performing 1-way ANOVA, we identified 8/11 genes in each of the two groups (HV versus HF) while 5 of the genes ( TTC34 , TMEM119 , C19orf33 , ID1 , TKTL2 ) overlapped between the two groups. We found 265 genes which are differentially expressed between those who survived and those who died.
Conclusions : From our proof-of-concept heart failure study, we conclude that gene expression correlates with VO ₂ peak in both healthy individuals and HF patients, potentially by regulating various physiological processes involved in oxygen uptake and utilization during exercise. Multi-omics profiling may help identify novel biomarkers for assessing exercise capacity and prognosis in HF patients, as well as potential targets for therapeutic intervention to improve VO ₂ peak and quality of life. We anticipate that our results will provide a novel metric for classifying immune health.

MacNamara JP; Division of Cardiovascular Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Turlington WM;Dias KA; Hearon CM Jr; Ivey E; Delgado VA; Brazile TL; Wakeham DJ;Turer AT;Link MS;Levine BD; Sarma ;

Echocardiography (Mount Kisco, N.Y.) [Echocardiography] 2024 Jun; Vol. 41 (6), pp. e15857.

Background: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM.
Methods: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (ED _exc ) and systole (S _exc ) and compared between groups. Peak oxygen uptake (peak V̇O ₂ ) (Douglas bags), cardiac index (C ₂ H ₂ rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O ₂ , peak cardiac index, and peak SVi.
Results: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O ₂ and stroke volume reserve were lower in patients with HCM (Peak VO ₂ Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O ₂ (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001).
Conclusion: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.

Hock J; Deutsches Herzzentrum München, Technische Universität München.
Brudy L; Willinger L; Hager A; Ewert P;Oberhoffer-Fritz R; Müller J

The American journal of cardiology [Am J Cardiol] 2024 Jun 17.
Date of Electronic Publication: 2024 Jun 17.

Sedentary lifestyle is reported to be associated with diminished exercise capacity resulting in increased cardiovascular risk in adults with congenital heart disease (CHD). This cross-sectional study examined the association between objectively measured physical activity (PA) and exercise capacity in children and adolescents with CHD. Therefore, 107 patients (13.0 ± 2.7 years, 41 girls) with various CHD performed a cardiopulmonary exercise test (CPET) to quantify their peakV’O2. Moderate-to-vigorous physical activity (MVPA) and daily step count were assessed with “Garmin vivofit jr.®” for 7 consecutive days. For association between PA and (sub-) maximal exercise capacity Spearman’s correlation was performed. CHD patients showed almost normal values compared to reference (79.5 ± 17.2% [31.6-138.1] %peakV’O2 predicted) with roughly normal ventilatory anaerobic thresholds (50.6±14.0% [20.3-97.9] %VATV’O2). Step counts are below recommendations (9,304 ± 3,792 steps/day [1,701-20,976]), whereas MVPA data are above recommendations for children with ≥ 60min/day (83.6 ± 34.6 min/day [10.1-190.9]). Spearman’s Rho showed significant positive correlations to VATV’O2 (r=0.353, p<0.001), and %VATV’O2 (r=0.307, p=0.001) with similar results regarding MVPA (VATV’O2: r=0.300, p=0.002, and %VATV’O2: r=0.270, p=0.005). Concluding, submaximal exercise capacity and PA correlate positively making both assessments relevant in a clinical setting – PA in the context of cardiovascular prevention and peakV’O2 as the strongest predictor for morbidity and mortality.

Habedank D;  DRK Kliniken Berlin Köpenick Berlin Germany.; University Medicine Greifswald Greifswald Germany.
Ittermann T; Kaczmarek S; Stubbe B; Heine A; Obst A; Ewert R;

Pulmonary circulation [Pulm Circ] 2024 Jun 17; Vol. 14 (2), pp. e12398.
Date of Electronic Publication: 2024 Jun 17 (Print Publication: 2024).

Parameters of cardiopulmonary exercise testing significantly discriminate between healthy subjects and patients with pulmonary hypertension (PH), also according to the new 2022 definition of pulmonary hypertension (mean pulmonary arterial pressure mPAP > 20 mmHg). The cut-offs indicating on PH were peakVO ₂  ≤ 16.7 mL/min/kg (Youden-Index YI = 0.79), p _et CO ₂ @AT ≤ 34 mmHg (YI = 0.67), and VE/VCO ₂ @AT ≤ 30 (YI = 0.76).

Cavero-Redondo I;  Universidad de Castilla-La Mancha, Cuenca, 16001, Spain.; Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile.
Saz-Lara A; Bizzozero-Peroni B; Núñez-Martínez L; Díaz-Goñi V; Calero-Paniagua I; Matínez-García I; Pascual-Morena

Sports medicine – open [Sports Med Open] 2024 Jun 18; Vol. 10 (1), pp. 74.
Date of Electronic Publication: 2024 Jun 18.

Background: Heart diseases, particularly heart failure, significantly impact patient quality of life and mortality rates. Functional capacity assessment is vital for predicting prognosis and risk in these patients. While the cardiopulmonary exercise test is considered the gold standard, the 6-minute walk test has emerged as a more accessible alternative. However, the screening accuracy and optimal cut-off points of the 6-minute walk test for detecting severely reduced functional capacity in cardiac pathologies, including heart failure with preserved ejection fraction, are unclear. The study aimed to analyse the diagnostic accuracy of the 6-minute walk test for detecting reduced functional capacity, defined as VO _2max  < 14 ml/kg/min, compared with the cardiopulmonary exercise test in participants with heart failure with preserved ejection fraction using data from the “Ejercicio en Insuficiencia Cardiaca con Fracción de Eyección Preservada” (ExIC-FEp) trial; and to compare these results with previous studies investigating the screening accuracy for assessing functional capacity of the 6-minute walk test in participants with other chronic cardiac pathologies through a meta-analysis.
Results: The ExIC-FEp trial involved 22 participants with heart failure with preserved ejection fraction, who were not treated with beta-blockers, using the cardiopulmonary exercise test, specifically VO _2max, as the reference test. The 6-minute walk test had a sensitivity of 70%, a specificity of 80%, and an area under the curve of 76% in the ExIC-FEp trial. Five studies were included in the meta-analysis showing a sensitivity of 79%, a specificity of 78%, and an area under the curve of 85%.
Conclusion: In conclusion, the 6-minute walk test holds promise as a screening tool for assessing functional capacity in heart failure with preserved ejection fraction and chronic heart diseases, with a VO _2max  < 14 ml/kg/min as a reference point. It demonstrates moderate to good screening accuracy. However, the screening accuracy and optimal cut-off points of the 6-minute walk test for detecting severely reduced functional capacity, regardless of aetiology, are unclear.