Critser PJ; Department of Cardiology, Boston Children’s Hospital, Boston, MA.
Buchmiller TL; Gauvreau K; Zalieckas JM; Sheils CA; Visner GA;
Shafer KM; Chen MH; Mullen MP

Journal of Pediatrics. 271:114034, 2024 Aug.

OBJECTIVE: To determine the prevalence of exercise-induced pulmonary
hypertension (PH) among long-survivors of congenital diaphragmatic hernia (CDH)
repair.

STUDY DESIGN: This is a single-center, retrospective cohort study of CDH
survivors who underwent exercise stress echocardiography (ESE) at Boston
Children’s Hospital from January 2006 to June 2020. PH severity was
assessed by echocardiogram at baseline and after exercise. Patients were
categorized by right ventricular systolic pressure (RVSP) after exercise:
Group 1 – no or mild PH; and Group 2 – moderate or severe PH (RVSP >= 60
mmHg or >= 1/2 systemic blood pressure).

RESULTS: Eighty-four patients with CDH underwent 173 ESE with median age
8.1 (4.8 – 19.1) years at first ESE. Sixty-four patients were classified
as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate
to severe PH after exercise was found in 8 (10%) patients with no or mild
PH at rest. Exercise-induced PH was associated with larger CDH defect
size, patch repair, use of ECMO, supplemental oxygen at discharge, and
higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen
saturation, and lower percent predicted FEV1, and FEV1/FVC ratio were
associated with Group 2 classification. ESE changed management in 9/11
Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing
cardiac catheterization after ESE.

CONCLUSIONS: Among long-term CDH survivors, 10% had moderate-severe
exercise-induced PH on ESE, indicating ongoing pulmonary vascular
abnormalities. Further studies are needed

Singh I; Division of Pulmonary, Critical Care, New Haven, CT, USA
Waxman AB

European Respiratory Journal. 64(1), 2024 Jul.

BACKGROUND: The direct Fick principle is the standard for calculating
cardiac output (CO) to detect CO-dependent conditions like exercise
pulmonary hypertension (ePH). Fick COarterial incorporates arterial
haemoglobin (Hba) and oxygen saturation (S aO2 ) with oxygen consumption
from exercise testing, while Fick COnon-arterial substitutes mixed venous
haemoglobin (Hbmv) and peripheral oxygen saturation (S pO2 ) in the
absence of an arterial line. The decision to employ an arterial catheter
for exercise testing varies, and discrepancies in oxygen saturation and
haemoglobin between arterial and non-arterial methods may lead to
differences in Fick CO, potentially affecting ePH classification.

METHODS: We performed a retrospective analysis of 296 consecutive
invasive cardiopulmonary exercise testing (iCPET) studies comparing oxygen
saturation from pulse oximetry (S pO2 ) and radial arterial (S aO2 ), Hba
and Hbmv, and CO calculated with arterial (COarterial) and non-arterial
(COnon-arterial) values. We assessed the risk of misclassification of pre-
and post-capillary ePH and data loss due to inaccurate S pO2 .

RESULTS: When considering all stages from rest to peak exercise, Hba and
Hbmv demonstrated high correlation, while S pO2 and S aO2 as well as
COarterial and COnon-arterial demonstrated low correlation. Data loss was
significantly higher across all stages of exercise for S pO2 (n=346/1926
(18%)) compared to S aO2 (n=17/1923 (0.88%)). We found that pre- and
post-capillary ePH were misclassified as COnon-arterial data (n=7/41
(17.1%) and n=2/23 (8.7%), respectively). Patients with scleroderma and/or
Raynaud’s (n=11/33 (33.3%)) and black patients (n=6/19 (31.6%)) had more S
pO2 data loss.

CONCLUSION: Reliance upon S pO2 during invasive exercise testing results
in the misclassification of pre- and post-capillary ePH, and unmeasurable
S pO2 for black, scleroderma and Raynaud’s patients can preclude accurate
exercise calculations, thus limiting the diagnostic and prognostic value
of invasive exercise testing without an arterial line.

de Souza IPMA; Cardio Pulmonar Hospital, Salvador, Bahia,Brazil
Ramos JVSP; da Silveira AD; Stein R; Ribeiro RS; Pazelli AM;
de Oliveira QB; Darze ES; Ritt LEF

PURPOSE: The objective of this study was to evaluate the independent and
added value of a cardiopulmonary exercise test (CPX) to New York Heart
Association (NYHA) functional analysis in patients with heart failure (HF)
and ejection fraction (EF) <50%.
METHODS: Patients (n = 613) with HF and EF < 50% underwent CPX and were
followed for 28 +/- 17 mo with respect to primary outcomes (death or heart
transplantation).
RESULTS: Mean patient age was 56 +/- 12 yr, and 64% were male. Most
patients were classified as NYHA class II (41%). The composite rate of
primary outcomes was 12%; death occurred in 9%, and heart transplant in
4%. Independent predictors of primary outcomes were: EF (HR = 0.95: 95%
CI, 0.92-0.98; P = .001) and NYHA (HR = 2.06: 95% CI, 1.54-2.75; P <
.0001). When added to the model, peak oxygen uptake (V O2peak ) was an
independent predictor (HR = 0.90: 95% CI, 0.84-0.96; P = .001), as was the
percentage of predicted V O2peak (HR = 0.03: 95% CI, 0.007-0.147; P <
.001), minute ventilation/carbon dioxide production slope (HR = 1.02: 95%
CI, 1.01-1.04; P = .012), and CPX score (HR = 1.16: 95% CI, 1.06-1.27; P =
.001).
CONCLUSIONS: CPX variables were independent predictors of HF prognosis,
even when controlled by NYHA functional class. Despite being independent
predictors, the value added to NYHA classification was modest and lacked
statistical significance.

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.