Grech J;  National Heart, Lung, and Blood Institute, Framingham, MA.
Thibord F;Chan M; Lachapelle A; Spartano N; Chen MH; Nayor M;Johnson AD;

Medicine and science in sports and exercise [Med Sci Sports Exerc] 2024 Jun 24.
Date of Electronic Publication: 2024 Jun 24.

Purpose: Platelets are key mediators in cardiovascular disease (CVD). Low cardiorespiratory fitness (CRF) is a risk factor for CVD. The purpose of our study was to assess if CRF associates with platelet function.
Methods: Platelet assays and cardiopulmonary exercise testing were conducted in the Framingham Heart Study (n = 3,014). Linear mixed effects models estimated associations between CRF (assessed by peak oxygen uptake [VO2]), and multiple platelet reactivity assays. Models were adjusted for multiple medications, risk factors, relatedness and prevalent CVD.
Results: Nineteen associations passed the significance threshold in the fully adjusted models, all indicating higher CRF associated with decreased platelet reactivity. Significant traits spanned multiple platelet agonists. Strongest associations were observed in Multiplate whole blood testing after TRAP-6 (e.g., velocity, beta = -0.563, 95% CI [-0.735,-0.391], p = 1.38E-10), ADP (e.g., velocity, beta = -0.514, 95% CI [-0.681,-0348], p = 1.41E-09), collagen (e.g., velocity, beta = -0.387, 95% CI [-0.549,-0.224], p = 3.01E-06), ristocetin (e.g., AUC, beta = -0.365, 95% CI [-0.522,-0.208], p = 5.17E-06) and arachidonic acid stimulation of platelets (e.g., velocity, beta = -0.298, 95% CI [-0.435,-0.162], p = 3.39E-04), and light transmission aggregometry (LTA) after ristocetin stimulation (e.g., max aggregation, beta = -0.362, 95% CI [-0.540,-0.184], p = 6.64E-05). One trait passed significance threshold in the aspirin sub-sample (LTA ristocetin primary slope, beta = -0.733, 95% CI [-1.134,-0.333], p = 3.30E-04), and another in a model including von Willebrand Factor levels as a covariate (U46619, a thromboxane receptor mimetic, AUC in the Optimul assay, beta = -0.36, 95%CI [-0.551,-0.168], p = 2.35E-04). No strong interactions were observed between the associations and sex, age or body mass index in formal interaction analyses.
Conclusions: Our findings build on past work that shows CRF to be associated with reduced CVD by suggesting decreased platelet reactivity may play a mechanistic role. We found significant associations with multiple platelet agonists, indicating higher CRF may globally inhibit platelets; however, given multiple strong associations after TRAP-6 and ADP stimulation, PAR-1 and purinergic signaling may be most heavily involved. This is notable since each of these receptor pathways are tied to anti-coagulant (DOACs/thrombin inhibitors) and anti-platelet therapies (P2Y12/PAR1/PAR4 inhibitors) for CVD prevention.
Competing Interests: Conflict of Interest and Funding Source: This research was primarily supported by a special Population Sciences funding award to A.D.J. from the National Heart, Lung, and Blood Institute (NHBLI) Intramural Research program. The Framingham Heart Study (FHS) acknowledges the support of Contracts NO1-HC-25195, HHSN268201500001I, and 75N92019D00031 from the NHLBI and NHLBI grants HL107385, HL126136, HL93328, HL142983, HL143227, HL131532, and R01HL131029 for this research. The authors declared no competing interests for this work.

enmassaoud A; Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
Geraci O; Martel M;Awasthi R; Barkun J; Chen T; Edgar L; Sebastiani G; Carli F; Bessissow A

BMJ open [BMJ Open] 2024 Jun 25; Vol. 14 (6), pp. e081362.
Date of Electronic Publication: 2024 Jun 25.

Introduction: Patients with cirrhosis awaiting liver transplantation (LT) are often frail, and malnourished. The period of time on the waitlist provides an opportunity to improve their physical fitness. Prehabilitation appears to improve the physical fitness of patients before major surgery. Little is known about prehabilitation in patients with cirrhosis. The aim of this feasibility study will be to investigate the feasibility, safety, and effectiveness of a multimodal prehabilitation programme in this patient population.
Methods and Analysis: This is an open-label single-arm feasibility trial recruiting 25 consecutive adult patients with cirrhosis active on the LT waiting list of the McGill University Health Centre (MUHC). Individuals will be excluded based on criteria developed for the safe exercise training in patients with cirrhosis. Enrolled individuals will participate in a multimodal prehabilitation programme conducted at the PeriOperative Programme complex of the MUHC. It includes exercise training with a certified kinesiologist (aerobic and resistance training), nutritional optimisation with a registered dietician and psychological support with a nurse specialist. The exercise training programme is divided into an induction phase with three sessions per week for 4 weeks followed by a maintenance phase with one session every other week for 20 weeks. Aerobic training will be individualised based on result from cardiopulmonary exercise testing (CPET) and will include a high-intensity interval training on a cycle ergometer. Feasibility, adherence and acceptability of the intervention will be assessed. Adverse events will be reviewed before each visit. Changes in exercise capacity (6-minute walk test, CPET, liver frailty index), nutritional status and health-related quality of life will be assessed during the study. Post-transplantation outcomes will be recorded.

Foulkes SJ; College of Health Sciences, University of Alberta, Edmonton, Alberta, Canada and University of Melbourne, Melbourne, Victoria, Australia.
Haykowsky MJ; Kistler PM; McConell G; Trappe S; HHargreaves M; Costill D; La Gerche A;

Journal of applied physiology (Bethesda, Md. : 1985) [J Appl Physiol (1985)] 2024 Jun 27.
Date of Electronic Publication: 2024 Jun 27.

In a 77-year-old former world-record holding male marathoner (2:08:33.6) this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac structure, function and the trajectory of functional capacity (determined by maximal oxygen consumption, V̇O ₂ max) throughout the adult lifespan. As a competitive runner, our athlete (DC) reported performing up to 150-300 miles/wk of moderate-to-vigorous exercise, and sustained 10-15 hours/wk of endurance exercise after retirement from competition. DC underwent maximal cardiopulmonary exercise testing in 1970 (aged 27yrs), 1991 (aged 49yrs) and 2020 (aged 77yrs) to determine V̇O ₂ max. At his evaluation in 2020, DC also underwent comprehensive cardiac assessments including resting echocardiography, and resting and exercise cardiac magnetic resonance to quantify cardiac structure and function at rest and during peak supine exercise. DC’s V̇O ₂ max showed minimal change from 27yrs (69.7mL/kg/min) to 49yrs (68.1mL/kg/min), although it eventually declined by 36% by the age of 77yrs (43.6mL/kg/min). DC’s V̇O ₂ max at 77yrs, was equivalent to the 50 ^th percentile for healthy 20-29 year-old males and 2.4 times the requirement for maintaining functional independence. This was partly due to marked ventricular dilatation (left-ventricular end-diastolic volume: 273mLs), which facilitates a large peak supine exercise stroke volume (200mLs) and cardiac output (22.2L/min). However, at the age of 78 years, DC developed palpitations and fatigue, and was found to be in atrial fibrillation requiring ablation procedures to revert his heart to sinus rhythm. Overall, this life study of a world champion marathon runner exemplifies the substantial benefits and potential side effects of many decades of intense endurance exercise.

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.