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.

Simonenko M;   Russia. Belgium. Italy. Germany. Spain. France. Sweden. Romania. Leeds, UK. Australia. The Netherlands. Slovenia. Portugal. Israel. Poland. Kazakhstan. Switzerland. Serbia
Hansen D; Niebauer J; Volterrani M; Adamopoulos S; Amarelli C; Ambrosetti M;  Anker SD; Bayes-Genis A; Gal TB;Bowen TS; Cacciatore F; Caminiti G; Cavaretta E; Chioncel O; Coats AJS;  Cohen-Solal A; D’Ascenzi F; de Pablo Zarzosa C; Gevaert AB; Gustafsson F; Kemps H; Hill L; SJaarsma T;Jankowska E; Joyce E;Krankel N;Lainscak M;Lund LH; Moura B; Nytrøen K; Osto E; Piepoli M;
Potena L;Rakisheva A; Rosano G; Savarese G;Seferovic PM; Thompson DR; Thum T; Van Craenenbroeck EM;

European journal of heart failure [Eur J Heart Fail] 2024 Jun 19.
Date of Electronic Publication: 2024 Jun 19.

Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients’ physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.

Vishram-Nielsen JKK; Peter Munk Cardiac Centre, Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.; and Department of Cardiology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Scolari FL;Steve Fan CP; Moayedi Y;Ross HJ; Manlhiot C; Allwood MA; Alba AC; Brunt KR; Simpson JA; Billia F

CJC open [CJC Open] 2024 Jan 24; Vol. 6 (5), pp. 745-754.
Date of Electronic Publication: 2024 Jan 24 (Print Publication: 2024).

Background: Diaphragm atrophy can contribute to dyspnea in patients with heart failure (HF) with its link to central neurohormonal overactivation. HF medications that cross the blood-brain barrier could act centrally and improve respiratory function, potentially alleviating diaphragmatic atrophy. Therefore, we compared the benefit of central- vs peripheral-acting HF drugs on respiratory function, as assessed by a single cardiopulmonary exercise test (CPET) and outcomes in HF patients.
Methods: A retrospective study was conducted of 624 ambulatory adult HF patients (80% male) with reduced left ventricular ejection fraction ≤ 40% and a complete CPET, followed at a single institution between 2001 and 2017. CPET parameters, and the outcomes all-cause death, a composite endpoint (all-cause death, need for left ventricular assist device, heart transplantation), and all-cause and/or HF hospitalizations, were compared in patients receiving central-acting (n = 550) vs peripheral-acting (n = 74) drugs.
Results: Compared to patients who receive peripheral-acting drugs, patients who receive central-acting drugs had better respiratory function (peak breath-by breath oxygen uptake [VO ₂ ], P  = 0.020; forced expiratory volume in 1 second [FEV1], P  = 0.007), and ventilatory efficiency (minute ventilation / carbon dioxide production [VE/VCO ₂ ], P < 0.001; end-tidal carbon dioxide tension [PETCO ₂ ], P  = 0.015; and trend for forced vital capacity [FVC], P  = 0.056). Many of the associations between the CPET parameters and drug type remained significant after multivariate adjustment. Moreover, patients receiving central-acting drugs had fewer composite events ( P  = 0.023), and HF hospitalizations ( P  = 0.044), although significance after multivariant correction was not achieved, despite the hazard ratio being 0.664 and 0.757, respectively.
Conclusions: Central-acting drugs were associated with better respiratory function as measured by CPET parameters in HF patients. This could extend to clinically meaningful composite outcomes and hospitalizations but required more power to be definitive in linking to drug effect. Central-acting HF drugs show a role in mitigating diaphragm weakness.

Kershner CE; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Hardie WD; Chin C; Opotowsky AR; Aronoff EB; Mays WA; Knecht SK; TPowell AW

Frontiers in surgery [Front Surg] 2024 May 20; Vol. 11, pp. 1356501.
Date of Electronic Publication: 2024 May 20 (Print Publication: 2024).

Introduction: Patients with congenital heart disease (CHD) often have pulmonary abnormalities and exercise intolerance following cardiac surgery. Cardiac rehabilitation (CR) improves exercise capacity in patients with CHD, but minimal study has been performed to see if resting and dynamic pulmonary performance improves following CR in those with prior cardiac surgery.
Methods: This was a retrospective cohort study of all patients who completed ≥12 weeks of CR from 2018 through 2022. Demographic, cardiopulmonary exercise test (CPET), spirometry, 6-minute walk, functional strength measures, and outcomes data were collected. Data are presented as median[IQR]. A Student’s t -test was used for comparisons between groups and serial measurements were measured with a paired t -test. A p  < 0.05 was considered significant.
Results: There were a total of 37 patients [age 16.7 (14.2-20.1) years; 46% male] included. Patients with prior surgery ( n  = 26) were more likely to have abnormal spirometry data than those without heart disease ( n  = 11) (forced vital capacity [FVC] 76.7 [69.1-84.3]% vs. 96.4 [88.1-104.7]%, p  = 0.002), but neither group experienced a significant change in spirometry. On CPET, peak oxygen consumption increased but there was no change in other pulmonary measures during exercise. Percent predicted FVC correlated with hand grip strength ( r  = 0.57, p  = 0.0003) and percent predicted oxygen consumption ( r  = 0.43, p  = 0.009). The number of prior sternotomies showed negative associations with both percent predicted FVC ( r  = -0.43, p  = 0.04) and FEV ₁ ( r  = -0.47, p  = 0.02).
Discussion: Youth and young adults with a prior history of cardiac surgery have resting and dynamic pulmonary abnormalities that do not improve following CR. Multiple sternotomies are associated with worse pulmonary function.

Piamonti D; Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.
Panza L; Flore R;Baccolini V;Pellegrino D; Sanna A;Lecci A;Lo Muzio G; Angelone D; Mirabelli FM; Morviducci M;Onorati P; Messina E;Panebianco V; Catalano C; Bonini M; Palange P

Respiratory physiology & neurobiology [Respir Physiol Neurobiol] 2024 May 31; Vol. 327, pp. 104285.
Date of Electronic Publication: 2024 May 31.

Background: Long COVID is defined as persistency of symptoms, such as exertional dyspnea, twelve weeks after recovery from SARS-CoV-2 infection.
Objectives: To investigate ventilatory efficiency by the use of cardiopulmonary exercise testing (CPET) in patients with exertional dyspnea despite normal basal spirometry after 18 (T ₁₈ ) and 36 months (T ₃₆ ) from COVID-19 pneumonia.
Methods: One hundred patients with moderate-critical COVID-19 were prospectively enrolled in our Long COVID program. Medical history, physical examination and lung high-resolution computed tomography (HRCT) were obtained at hospitalization (T ₀ ), 3 (T ₃ ) and 15 months (T ₁₅ ). All HRCTs were revised using a semi-quantitative CT severity score (CSS). Pulmonary function tests were obtained at T ₃ and T ₁₅ . CPET was performed in a subset of patients with residual dyspnea (mMRC ≥ 1), at T ₁₈ and at T ₃₆ .
Results: Remarkably, at CPET, ventilatory efficiency was reduced both at T ₁₈ (V’ _E /V’CO ₂ slope = 31.4±3.9 SD) and T ₃₆ (V’ _E /V’CO ₂ slope = 31.28±3.70 SD). Furthermore, we identified positive correlations between V’ _E /V’CO ₂ slope at T ₁₈ and T ₃₆ and both percentage of involvement and CSS at HRCT at T ₀ , T ₃ and T ₁₅ . Also, negative linear correlations were found between V’ _E /V’CO ₂ slope at T ₁₈ and T ₃₆ and DL _CO at T ₃ and T ₁₅ .
Conclusions: At eighteen months from COVID-19 pneumonia, 20 % of subjects still complains of exertional dyspnea. At CPET this may be explained by persistently reduced ventilatory efficiency, possibly related to the degree of lung parenchymal involvement in the acute phase of infection, likely reflecting a damage in the pulmonary circulation.