Authors: Aaron B. Waxman (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA), Abraham Babu (Department of Physiotherapy, Manipal College of Health Professions, Manipal, Karnataka, India), Roberto Badagliacca (Department of Cardiovascular and Respiratory Science, Sapienza University of Rome, Rome, Italy), Eloara Ferreira (Division of Respiratory Diseases, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil), Patty George (Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado, USA), Marco Guazzi (Department of Cardiology, University of Milan, Milan, Italy), Luke Howard (National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK), Darlene Kim (Division of Cardiology, Department of Medicine, National Jewish Health, Denver, Colorado, USA), Gabor Kovacs (Divison of Pulmonary, Ludwig Boltzmann Institute for Lung Vascular Research, Medical University of Graz, Graz, Austria), Saad Kubba (Division of Cardiology, Department of Medicine, University of Arizona, Tucson, Arizona, USA), David Langleben (Center for Pulmonary Vascular Disease, Azrieli Heart Center and Lady Davis Research Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada), Colm McCabe (Division of Cardiology, Royal Brompton Hospital, London, UK), Thais Menezes (Division of Respiratory Diseases, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil), Rudolf Oliveira (Division of Respiratory Diseases, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil), Stylianos Orfanos (1st Department of Critical Care and Pulmonary Services, National and Kapodistrian University of Athens Medical School and Pulmonary Hypertension Center, Evangelismos Hospital, Athens, Greece), Inderjit Singh (Divison of Pulmonary, Critical Care and Sleep Medicine, Yale New Haven Hospital and Yale School of Medicine, New Haven, Connecticut, USA), David Systrom (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA), Ryan Tedford (Divsion of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA), Rebecca Vanderpool (Division of Cardiovascular Medicine, Ohio State University, Colombus, Ohio, USA), Carmine Dario Vizza (Department of Cardiovascular and Respiratory Science, Sapienza University of Rome, Rome, Italy), Franz P. Rischard (Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA)
Categories: Guidelines, cardiopulmonary exercise testing, phenotyping, pulmonary hypertension, pulmonary vascular disease, risk stratification
Source: Pulmonary Circulation
Doi: 10.1002/pul2.70240
Knowledge Gaps and Controversies on Cardiopulmonary Exercise Testing in the Assessment of Pulmonary Vascular Disease: An Official Statement of the Pulmonary Vascular Research Institute Exercise and Right Ventricular Function Task Force
Authors: Aaron B. Waxman, Abraham Babu, Roberto Badagliacca, Eloara Ferreira, Patty George, Marco Guazzi, Luke Howard, Darlene Kim, Gabor Kovacs, Saad Kubba, David Langleben, Colm McCabe, Thais Menezes, Rudolf Oliveira, Stylianos Orfanos, Inderjit Singh, David Systrom, Ryan Tedford, Rebecca Vanderpool, Carmine Dario Vizza, Franz P. Rischard
Abstract
Exercise testing has long been essential for evaluating diagnosis, prognosis, and functional status in pulmonary hypertension (PH). Recent advances have clarified its role in defining reference values and prognostic markers. Nonetheless, substantial knowledge gaps persist regarding the implementation of invasive cardiopulmonary exercise testing (iCPET) and its potential to inform pathophysiology and therapeutic decision‐making. This statement addresses the knowledge gaps that hinder the application of iCPET and exercise right heart catheterization (RHC) in the assessment of PH. We present research priorities and scenarios in which these tests may clarify drug mechanisms and support PH subphenotyping. An international, multidisciplinary task force of cardiology and pulmonology experts reviewed the literature and formulated consensus recommendations through iterative discussions.
Overview
Exercise testing is a cornerstone in the diagnosis, prognosis, and functional evaluation of pulmonary hypertension (PH) patients. Exercise assessment methods are incorporated into multiparametric risk scores that inform current guidelines for therapeutic decision‐making and prognostication [1, 2]. Although recent advances have clarified reference values [3] and identified key prognostic markers [2], substantial knowledge gaps remain.
Current guidelines offer limited direction on the implementation of invasive cardiopulmonary exercise testing (iCPET) or exercise right heart catheterization (RHC), underscoring the need for clearer integration into clinical practice [2]. Increasing evidence suggests that exercise testing provides unique insights into right ventricular (RV) function, pulmonary vascular pathophysiology, and treatment response—areas critical to advancing personalized care.
This statement addresses key knowledge gaps in the adoption of iCPET and exercise RHC through five research 1. Incremental Value: Define CPET's added value beyond standard testing, including early detection of pulmonary vascular disease (PVD) and the assessment of therapeutic response.2. Protocol Standardization: Harmonize protocols and data interpretation across centers, incorporating considerations such as body position and respiratory dynamics to support multicenter studies. Clarify when to use iCPET, exercise RHC, or non‐invasive CPET (niCPET).3. Pathophysiology and Drug Mechanisms: Leverage data from iCPET to uncover exercise‐induced hemodynamic patterns across PH subtypes and to assess RV and pulmonary arterial remodeling.4. Personalized Treatment Guidance: Evaluate how iCPET can guide individualized treatment decisions and predict long‐term outcomes based on exercise physiology.5. Right Ventricular–Pulmonary Arterial (RV–PA) Coupling: Assess the utility of iCPET for characterizing RV–pulmonary arterial coupling during exercise and its implications for disease progression, reverse remodeling, and treatment efficacy.
These priorities aim to guide future research, refine the clinical use of exercise testing, and ultimately improve care for patients with PH.
The capacity to respond to physiological stress is fundamental to maintaining health. In PH, the impaired functional reserve makes stress testing a critical tool for diagnosis, risk stratification, and therapeutic guidance. Exercise testing establishes a direct relationship between dyspnea, functional capacity, and survival.
Exercise testing methods vary in complexity, patient positioning, required expertise, and the depth of data provided. These range from the 6‐min walk test (6MWT) to cardiopulmonary exercise testing (CPET), which can be performed non‐invasively (niCPET) or with simultaneous invasive hemodynamic monitoring (iCPET). Cardiac imaging, particularly echocardiography, can be obtained concurrently with CPET. Exercise RHC without CPET is frequently used to assess occult left ventricular dysfunction. Unlike the 6MWT, iCPET provides a mechanistic assessment of exercise limitation across all PH forms.
Recommendations from the World Symposium on Pulmonary Hypertension (WSPH) underscore the prognostic importance of the 6MWT but offer limited recommendations for iCPET or exercise RHC owing to persistent gaps in clinical evidence [2]. Current support for iCPET is primarily limited to diagnosing exercise‐induced post‐capillary PH (Group 2) through dynamic pulmonary capillary wedge pressure (PCWP) measurements, though thresholds remain debated [4].
Despite conservative guideline recommendations, interest in exercise testing in PH continues to grow. Recent PH guidelines [5] and reviews [6] have increasingly highlighted exercise testing, providing valuable insights into normal and pathological exercise responses, testing protocols, and RV reserve. Notably, the 2022 ESC/ERS guidelines [7] and the 2024 WSPH guidelines [8] introduced a new definition of exercise PH (ePH) based on a mean pulmonary arterial pressure/cardiac output (mPAP/CO) slope > 3 Wood units (PAW) from rest to exercise. This threshold is supported by studies demonstrating prognostic and diagnostic relevance across diverse patient populations.
Beyond formal guidelines, some expert groups have advocated for CPET in all clinically stable patients with PH capable of exercise (New York Heart Association functional Classes I–III) [9]. RHC remains essential for assessing rest and exercise hemodynamics, while iCPET uniquely integrates gas exchange and hemodynamic data. iCPET identifies early PVD, clarifies unexplained dyspnea [10], assesses RV function [11], and supports trial design for novel therapies. Parameters such as peak VO₂, end‐tidal CO₂, and VE/VCO₂ ratios correlate with disease severity [10, 12]. RV–PA coupling and CO reserve assessed by iCPET are critical for characterizing disease and potentially guiding treatment.
Despite its value, CPET—especially iCPET—remains underused. Broader adoption may improve diagnosis, classification, and personalized therapy. Hemodynamic metrics like pulmonary vascular resistance (PVR) and mPAP/CO slope inform treatment goals and follow‐up intensity, supporting precision‐medicine approaches in PH. Moreover, emerging evidence suggests that exercise responses may correlate with molecular phenotypes [13, 14].
To address existing knowledge gaps, we present a consensus on the current state, clinical utility, and future research priorities of exercise testing in PH. Knowledge gaps are summarized in Table 1 and Consensus Recommendations in Table 2. These are organized across three
Topic Exercise testing methods and technical Safety, indications, positioning, respiratory swings, cardiac imaging, and niCPET
Topic Exercise testing in the pathophysiology of RV–PA coupling; ventilatory inefficiency; and peripheral oxygen extraction
Topic Novel uses of CPET in the era of disease Assessment of reverse remodeling of the pulmonary artery (PA) and right ventricle (RV).
Methods
The Exercise Task Force is an international, multispecialty working group supported by the Pulmonary Vascular Research Institute (PVRI). The task force comprises cardiologists and pulmonologists with expertise in exercise testing and interpretation. Topics and domains were initially approved by the Chairs (Drs. Waxman and Systrom) at the PVRI World Congress in Athens 2023.
The task force coordinator and third Chair (Dr. Rischard) appointed members to writing committees and designated lead authors based on individual research interests and scientific contributions. Topics were further refined through discussions among writing committees and at the PVRI World Congress in London in 2024. Relevant conflicts of interest were reviewed before publication. This consensus document reflects a synthesis of empirical data derived from an extensive literature review and expert opinion contributed by each writing committee.
Topic Exercise Testing Methods and Technical Aspects: Safety, Indications, Positioning, Respiratory Swings, Cardiac Imaging, and niCPET
Safety of CPET in PH
Rationale: As with any invasive procedure, iCPET carries theoretical safety concerns.
*Current state of * The American Thoracic Society (ATS) identifies severe PH as a relative contraindication to CPET [15], and European Respiratory Society guidelines state to approach PH with caution [16]. However, these recommendations are based on the potential risk of sudden death before many currently approved therapies were available [17]. There has never been a study examining the safety of CPET in populations at risk for and with established PH. Additionally, it is unknown if invasive cardiopulmonary exercise carries additional risk to niCPET. In the PVDOMICS study [18, 19] (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics), 72% (855/1193) of subjects underwent CPET among 7 expert PH centers. Of these, 439 (51%) were iCPETs and 416 (49%) were niCPETs. Among iCPETs, peak exercise mPAP was 46.6 ± 18.0 mmHg, cardiac index (CI) 4.7 ± 1.7 L/min/m^2,^ and right atrial pressure (RAP) 11.0 (range: 0.00, 42.0) mmHg. There were no serious adverse events (SAEs) related to niCPET. There was only one SAE related directly to the iCPET (supraventricular tachycardia during exercise) in a patient with WSPH Group 2 PH (heart failure with preserved ejection fraction [HFpEF]). Of the centers that did iCPET, two centers used fluoroscopy for wedging the catheter during exercise, and one did not. These findings suggest that CPET, including iCPET, is safe when performed by experienced teams in specialized centers, even in patients with established PH.
Generally, iCPET is a safe procedure when performed by skilled healthcare professionals in an appropriate clinical setting. Risk can be divided between those associated with the placement of catheters and those associated with exercise. Catheter‐related complications have been thoroughly reviewed in detail elsewhere [20], and they generally include infection, thrombosis, or damage to the vessel during insertion, arrhythmias, and vasovagal response. Exercise‐related precautions are typically guided by safety protocols established by the American Heart Association (AHA) [21] and ATS [15] safety precautions to exercise testing.
Unlike the 6MWT, CPET is frequently undertaken without supplemental oxygen due to concerns regarding accuracy [22]. However, this introduces potential risk for patients who routinely use supplemental oxygen. In the PVDOMICS study, patients on supplemental O2 at home had greater desaturation with exercise than those who did not (median: 88%, 100%–75% vs. 95%, 100%–82%, respectively) and stopped exercise more often due to dyspnea. However, there were no associated SAEs.
The rate of workload increment (ramp rate) directly influences the kinetics of hemodynamic adaptation. Excessively steep ramps may lead to premature muscle fatigue (acidosis) before cardiovascular limits are reached, potentially underestimating peak aerobic capacity and altering the slope of hemodynamic responses (e.g., mPAP/CO). Conversely, protocols that are too shallow prolong the test unnecessarily, leading to boredom or orthopedic discomfort.
The safety profile of iCPET is influenced by multiple factors, including the patient's clinical status, the experience of the clinical team, and the specific procedural protocols followed. At large volume centers risk of serious events is exceedingly rare, as exemplified by the PVDOMICS Study.
*Knowledge gaps on the safety of CPET and exercise * No consensus exists regarding the minimum oxygen saturation threshold during CPET that should prompt test termination.Safety cutoffs for advanced PH and other high‐risk groups, such as hypertrophic obstructive cardiomyopathy, valvular stenosis, and congenital heart disease, should be further explored and discussed.
*Consensus recommendations and future directions on CPET * iCPET appears safe across the spectrum of PVD in experienced centers.Observational data across multiple large exercise studies should be harmonized such that a spectrum of PVD can be evaluated for CPET safety.We recommend using an electronically braked cycle ergometer with a continuously incrementing ramp protocol rather than large stepwise increases, as this facilitates the analysis of linear relationships (slopes) required for modern PH definitions (e.g., mPAP/CO > 3 WU). To standardize physiological stress, the ramp rate should be individualized to achieve a symptom‐limited test duration of 8–12 min.Clinicians should estimate the optimal ramp rate using the patient's history, prior 6‐min walk distance, or predicted maximal Watts (e.g., Predicted Peak Watts—Unloaded Cycling Watts/10 min [23, 24]). Standardizing the duration rather than the absolute workload ensures comparable physiological stress across diverse patient phenotypes.Future guidelines and research on exercise in PH should consider safety recommendations, especially high‐risk subpopulations (i.e., valvular heart disease, congenital heart disease, hypertrophic obstructive cardiomyopathy) and oxygen desaturation. Specific considerations could include indicators of RV uncoupling, manifesting as exertional hypotension. A drop in systolic blood pressure > 10 mmHg or a failure of SBP to rise > 20 mmHg are validated markers of impending RV failure and are widely accepted safety cutoffs.
Indications for Exercise Pulmonary Hemodynamics in the Assessment and Phenotyping of Dyspnoea and PVD
Rationale: While the clinical value of iCPET is increasingly acknowledged, clear guidance remains lacking regarding when to use specific modalities, such as iCPET versus exercise RHC alone—for disease phenotyping and therapeutic planning. Understanding the distinct diagnostic and prognostic capabilities of each method is essential for optimal clinical decision‐making.
*State of * Exercise pulmonary hemodynamics have become foundational in the evaluation of unexplained dyspnea, particularly in patients with normal resting pressures [25], and play a vital role in risk stratification for patients with established PH and PVD [5, 26, 27]. When noninvasive testing is inconclusive, stress hemodynamics often uncover physiologic derangements not apparent at rest [7, 28].
Screening Groups at Risk for PVD
High‐risk groups (e.g., systemic sclerosis and heritable PH)^6^ and at‐risk groups (e.g., portal hypertension, HIV infection, and non‐systemic sclerosis‐related connective tissue disorders) benefit significantly from exercise in pulmonary hemodynamics. This approach facilitates early identification of PVD by detecting abnormal pulmonary vascular responses during physical exertion, which are often missed during resting evaluations [5].
Evaluation of Unexplained Dyspnoea
Exercise places concurrent demands on multiple organ systems, including cardiac, pulmonary, vascular, and skeletal muscle compartments, revealing distinct physiological patterns across different etiologic subgroups. This makes exercise an ideal provocation test for pinpointing functional deficits [29] [26, 30] [31].
Diagnosing ePH
Olievera et al. [32] evaluated pulmonary hemodynamic responses during maximal upright exercise in 66 individuals with normal resting profiles and preserved exercise capacity, revealing that participants over 50 years of age exhibited notably higher PVR and distinct upper normal limits compared to those aged 50 or younger. The researchers concluded that older adults have a distinct pulmonary vascular response to exercise, with higher resistance values that should be considered when establishing age‐specific diagnostic criteria for ePH (Table 3). Combining exercise testing with invasive haemodynamic monitoring has represented a pivotal advancement in understanding ePH, now formally recognized in current PH guidelines. Diagnostic accuracy is improved when combining total pulmonary resistance (TPR) > 3 Wood Units alongside a mean pulmonary artery pressure (mPAP) increase > 30 mmHg during peak exercise, achieving 90% sensitivity, 100% specificity, 96% accuracy, and a negative predictive value of 91% for distinguishing PH from healthy controls [33]. The mPAP to CO (mPAP/CO) slope (> 3 mmHg/L/min) has emerged as a superior diagnostic metric compared to isolated peak exercise values because it reduces the variability inherent to single‐point measurements [2].
Exercise RHC and iCPET are frequently used to diagnose exercise‐induced HFpEF. A pulmonary capillary wedge pressure/cardiac output (PAWP/CO) slope > 2 mmHg/L and peak PCWP > 25 mmHg (supine) or > 20 mmHg (upright) reliably identify HFpEF physiology [34, 35]. While exercise RHC (without CPET) can identify this hemodynamic pattern, it represents certain limitations compared to iCPET. The absence of systemic gas exchange data in exercise RHC limits the ability to detect coexisting conditions such as chronic obstructive pulmonary disease (COPD) or impaired peripheral oxygen extraction, both of which are common in patients with HFpEF. Also, thermodilution‐derived CO becomes less reliable during exercise due to rapid circulatory changes [36]. Direct Fick measurements, enabled during iCPET, provide more accurate flow estimation under stress and are quicker to perform. Therefore, although exercise RHC is a valuable tool in the evaluation of suspected Group 2 PH, particularly when noninvasive imaging is inconclusive, it may fail to capture diagnostic nuances in the absence of integrated CPET.
Phenotyping of PH
iCPET enables deep phenotyping by resolving overlapping features across WSPH groups. In patients with coexisting lung and heart disease, it clarifies the dominant driver of dyspnea [37]. Mixed PH (Group 1–2 Overlap): Older patients with idiopathic pulmonary arterial hypertension (iPAH) (mean age > 60 years) often present with comorbidities such as obesity and hypertension, in contrast to younger iPAH cohorts [38]. The PVDOMICS study highlights how overlapping clinical features (e.g., ground‐glass opacities in 50.2% of Group 1 PH) complicate classification, necessitating deep phenotyping [19]. Up to 38.9% of Group 1 patients with PH exhibit mixed WSPH group features, including Group 1–2 overlap characterized by elevated PVR and elevated PCWP at exercise [19, 39, 40]. Some Group 2 patients with PH exhibit precapillary‐like hemodynamics at rest but develop pathologic PAWP/CO slopes (> 2 mmHg/L) during exercise, mimicking Group 1 PH [41]. Peripheral oxygen extraction deficits in HFpEF correlate with distinct proteomic signatures (e.g., leptin dysregulation), independent of central hemodynamics [42]. In chronic lung disease, iCPET helps differentiate between hypoxia‐driven vascular remodeling (elevated PVR, reduced DLCO) and parenchymal destruction, which may manifest as ventilatory inefficiency [43]. However, it is important to recognize that ventilatory inefficiency is not specific to parenchymal lung disease. Elevated VE/VCO₂ slope can reflect multiple pathophysiologic processes including RV‐PA uncoupling, increased dead space ventilation, pulmonary vascular dysfunction, and central hyperventilation drive. In patients with chronic lung disease and coexisting cardiovascular disease, integrated assessment of hemodynamics, gas exchange, and RV function is necessary to determine the dominant contributor to ventilatory inefficiency
“Lung Phenotype” PAH: A subset of iPAH patients displays a “lung phenotype” characterized by reduced DLCO despite preserved spirometry, which challenges the traditional distinction between WSPH Groups 1 and 3 [44, 45, 46]. By combining gas exchange, lung volumes, and hemodynamics, iCPET can potentially uncover physiologic derangements not apparent at rest.
Post‐Pulmonary Embolism Dyspnoea: iCPET analysis can identify post‐pulmonary embolism elevated RV afterload with ventilatory inefficiency (33.9%), combined afterload/respiratory mechanics impairment (25.8%), and mild hemodynamic derangements with peripheral limitations (20.9%) [47]. Clusters 1 and 2 were more responsive to mechanical interventions such as pulmonary thromboendarterectomy, in contrast to Cluster 3 [47].
Risk Stratification and Prognostication
Exercise hemodynamics play a critical role in risk stratification and prognostication across PH subtypes. A recent systematic review identified several flow‐adjusted exercise parameters with strong prognostic significance, including the mPAP/CO, the PAWP/CO, peak PVR, peak PCWP, and exercise‐induced changes in CI, systolic pulmonary artery pressure (sPAP), and heart rate (HR) from rest to peak exertion [7, 48, 49] (Figure 1).
![Figure 1: Prognostic accuracy of exercise hemodynamic parameters [7]. Reproduced with permission of the © ERS 2025. During exercise, pulmonary hemodynamic characterization relies on the slopes of mean pulmonary arterial pressure (mPAP)/cardiac output (CO), pulmonary arterial wedge pressure (PAWP)/CO, and transpulmonary gradient (TPG)/CO. An abnormal mPAP/CO slope reflects an excessive rise in pulmonary pressure relative to flow and is strongly age‐dependent, with an upper limit of normal (ULN) ranging from 1.6 WU in young adults to 3.3 WU in older individuals (pooled ULN ≈ 2.7 WU). A slope > 3 WU is independently associated with poor survival and heart failure hospitalizations. The mPAP/CO slope represents the sum of the PAWP/CO and TPG/CO slopes. The PAWP/CO slope, also age‐dependent (ULN 0.6–1.8 WU), identifies post‐capillary causes of exercise PAP elevation, with values > 2 WU linked to impaired survival and increased cardiovascular events. In contrast, the TPG/CO slope is age‐independent (ULN 1.2 WU), and elevations suggest pulmonary vascular disease and adverse prognosis. Together, these exercise hemodynamic slopes integrate upstream (PAWP), downstream (TPG), and global (mPAP) responses, providing diagnostic and prognostic insights. CO, cardiac output; CV, cardiovascular events; LHD, left heart disease; mPAP, mean pulmonary artery pressure; PAWP, pulmonary capillary wedge pressure; PVD, pulmonary vascular disease; TPF, transpulmonary flow; TPG, transpulmonary gradient; WU, Wood units. Please see ref. [7] for footnotes.](PUL2-16-e70240-g001.jpg)
These exercise‐derived metrics provide incremental prognostic information beyond resting hemodynamics and are particularly valuable in identifying early or subclinical disease. In HFpEF, a PAWP > 20 mmHg during upright exercise and a PAWP/workload slope > 25.5 mmHg/W/kg identify patients at higher risk, while a peak PVR ≥ 280 dynes·s·cm^−5^ predicts increased hospitalization risk (HR: 5.73; 95% CI: 1.05–31.22) [7, 50, 51].
In systemic sclerosis, exercise‐based hemodynamic parameters outperform resting values in predicting mortality. Elevated peak PVR and TPR (HRs: 2.20 and 1.56), as well as mPAP/CO and TPG/CO slopes (HRs: 1.14 and 1.34), are independently associated with worse outcomes [7, 48].
Together, these findings highlight the value of exercise hemodynamics in refining risk stratification and phenotyping in PH. The 2023 European Journal of Heart Failure HFpEF risk score further underscores the importance of incorporating exercise‐derived parameters into routine clinical assessment [51].
Knowledge gaps on the indications and phenotyping for exercise testing: Although some data exist on exercise testing for screening high‐risk groups, such as those with hereditary PH, scleroderma, or toxin‐associated PH—the most effective diagnostic thresholds remain undefined.Refining phenotypes in mixed and overlapping PH including patients with features across WSPH groups (e.g., Group 1/2 overlaps [19]) and within‐group subtypes (e.g., plexogenic vs. non‐plexogenic iPAH [46, 52]), using iCPET.Determining the most accurate exercise parameter (e.g., peak PAWP, PAWP/CO slope, or both) to differentiate pre‐ versus post‐capillary PH during invasive exercise testing (Table 1).Clarifying the role of exercise hemodynamics in guiding personalized management and designing phenotype‐specific clinical trials.
Consensus recommendations and future research directions:
Optimal iCPET Cutoffs for High‐Risk Populations: While hemodynamic slopes (e.g., mPAP/CO > 3 mmHg/L/min) have demonstrated prognostic utility, validated thresholds for hereditary PAH, systemic sclerosis‐associated PH, and toxin‐induced PH are lacking. Diagnostic criteria for post‐capillary PH remain especially controversial (see Table 1). The PVDOMICS initiative is ongoing and aims to correlate exercise hemodynamic profiles with molecular and phenomic signatures.
Clarify iCPET versus niCPET Use in Dyspnea Evaluation niCPET can identify ventilatory inefficiency (e.g., VE/VCO₂ > 34), but iCPET is necessary to disentangle overlapping pathologies such as HFpEF and exercise‐induced PH. However, there is no consensus on when to escalate from niCPET to iCPET—particularly in patients with normal resting hemodynamics. We therefore recommend considering iCPET in patients with an intermediate pre‐test probability of HFpEF [53]. Improve Phenotyping of Mixed and Subgrouped PH.
‐Overlap Syndromes: Up to 39% of patients exhibit features from multiple WSPH groups. iCPET can uncover distinct patterns, such as HFpEF mimicking pre‐capillary PH. We recommend iCPET to uncover principal factors when multifactorial dyspnea is probable.
iPAH Clinical Phenotypes: Recent studies have identified a distinct clinical phenotype within iPAH—characterized by smoking history, reduced DLCO despite preserved spirometry, and radiographic features suggesting parenchymal involvement—that challenges traditional Group 1 PH classification [52, 54]. While plexogenic arteriopathy (plexiform lesions) is the classic histologic hallmark of severe iPAH [55] and requires tissue diagnosis, it remains unknown whether this “lung phenotype” of iPAH represents a distinct underlying vascular pathology (e.g., non‐plexogenic vasculopathy with predominant veno‐occlusive features) or simply reflects iPAH with coexisting subclinical parenchymal disease. By integrating gas exchange (DLCO, ventilatory efficiency), hemodynamic parameters, and radiographic findings, iCPET may help characterize these clinical phenotypes and identify patients who warrant specialized diagnostic evaluation. We recommend further systematic study to correlate iCPET‐defined phenotypes with histopathologic findings when tissue is available, and to evaluate whether these phenotypes predict differential treatment responses.
Refine Methods to Distinguish Pre‐ versus Post‐Capillary PH Candidate thresholds such as PAWP/CO slopes greater than 2 Wood Units and exercise PAWP exceeding 25 mmHg may distinguish pre‐ from post‐capillary PH, though their interpretation is complicated by age‐related increases in PAWP (see Table 1). The addition of Dual‐energy CT to iCPET may enhance the detection of microvascular perfusion defects. We recommend iCPET—rather than exercise RHC alone—whenever feasible in this diagnostic context. Integrate Exercise Hemodynamics into Personalized Care and Clinical Trials
Exercise testing identifies post‐PE phenotypes (e.g., RV afterload vs. peripheral limitation), but its role in therapy selection (e.g., vasodilators in exPH) or trial stratification is unclear. We recommend clinical trial designs that incorporate phenotypes defined by iCPET.
Emerging Insights
‐The PEX‐NET consortium confirms mPAP/CO slope > 3 mmHg/L/min as a powerful prognostic marker, independent of resting values.
‐HFpEF risk scores now incorporate exercise PAWP, reinforcing the clinical value of dynamic hemodynamics.
Together, these findings support the need for multicenter initiatives to standardize testing protocols, validate phenotypic classifications, and integrate physiological data with molecular pathways, as exemplified by the PVDOMICS.
Exercise RHC: The Relevance of Body Position and Respiratory Swings
Body Position
Rationale: Current exercise RHC protocols lack standardization regarding body position (supine, semi‐supine, or upright), complicating cross‐study comparisons. Hemodynamic measurements vary significantly with upright positioning reduces RAP, mPAP, pulmonary artery wedge pressure (PAWP), and CI compared to supine, and these differences persist during exercise [56].
Absolute values (e.g., mPAP, PAWP) are position‐dependent, but derived metrics like mPAP/CO and PAWP/CO slopes show minimal positional variability [57]. Inconsistencies in body positioning between rest and exercise across centers introduce confounding variability that hampers longitudinal data interpretation.
*State of * Body position exerts a significant influence on pulmonary hemodynamics in both healthy individuals and patients with suspected disease. In healthy subjects, upright positioning reduces mPAP, PAWP, CO, and stroke volume (SV) compared to supine positioning, while increasing HR and PVR at rest and during mild exercise [2, 3, 7, 27, 58, 59, 60, 61, 62, 63, 64, 65]. These positional effects are similarly observed in patients undergoing RHC for suspected PH. Notably, posture‐related differences diminish during intense exercise, suggesting hemodynamic convergence at higher workloads [66]. [63, 67, 68], This variability underscores the need for standardized testing protocols to ensure consistency in data acquisition and interpretation across centers.
Current PH guidelines emphasize the diagnostic and prognostic value of mPAP/CO and PAWP/CO slopes [27]. While age‐adjusted thresholds for supine positioning exist, upright position data remain limited due to sparse normative studies [7]. Importantly, several prognostic studies on exercise‐induced dyspnea have employed upright positioning, which facilitates greater exercise capacity and more robust peak hemodynamic assessment [62, 66]. This position generally allows for higher exercise levels compared to supine or semi‐supine positions [58, 60]. The near‐linear relationship between mPAP and CO during physiologic exercise suggests that body position has minimal impact on slope‐derived diagnostic parameters [3, 62]. Upright/semi‐supine testing requires zero‐reference level adjustment (from standard supine mid‐thoracic positioning) to ensure measurement accuracy [68].
Knowledge gaps on body position in exercise testing: Current guidelines lack positional protocols, complicating cross‐study comparisons.Derived parameters mitigate positional variability but require ULN validation for upright testing.Upright exercise better identifies preload limitation, while supine testing enhances HFpEF detection.
Addressing these knowledge gaps will help standardize exercise hemodynamic assessments and improve the interpretation of results across different body positions.
Consensus recommendations and future research directions:
Derived Parameter Thresholds Across Positions
Slopes such as mPAP/CO and PAWP/CO demonstrate strong diagnostic and prognostic value and show minimal variation with changes in body position when derived consistently. Age‐specific reference values are essential for interpreting iCPET especially for resistance‐based parameters, given that older adults exhibit distinct pulmonary vascular responses to exercise compared to younger individuals [32]. Supine thresholds (e.g., mPAP/CO slope > 3 WU) are established, but upright normative data are limited due to fewer studies. We encourage ongoing research initiatives to correlate omics data to enhance phenotype definition and precision diagnostics.
Prognostic Data Generalizability Prognostic studies predominantly use upright positioning, which enables higher peak workloads and CO. However, supine testing reveals distinct hemodynamic profiles (e.g., elevated PAWP and CO) that may alter risk stratification. Adjusted analyses demonstrate that upright exercise produces higher mPAP (52 vs. 45 mmHg) and PVR (5.4 vs. 4.5 WU) at equivalent workloads compared to supine testing, supporting the need for position‐specific prognostic thresholds. Peak Exercise Positional Dependence
Body position significantly impacts absolute hemodynamic values (e.g., PAWP: 11 vs. 12 mmHg upright vs. supine) even at peak exercise. In contrast, slope‐derived parameters such as mPAP/CO and PAWP/CO remain consistent across positions when zero‐reference levels are appropriately standardized. Upright testing allows higher exercise capacity (53 vs. 33 W), potentially unmasking latent pathologies like preload insufficiency.
Addressing these gaps through multicenter studies (e.g., PEX‐NET) will refine diagnostic accuracy and therapeutic stratification across testing modalities.
Respiratory Swings at Exercise
Rationale: Respiratory‐induced intrathoracic pressure fluctuations can substantially alter hemodynamic measurements, affecting both resting and exercise phases. While end‐expiratory measurements are standard for resting hemodynamics, to minimize intrathoracic effects [69], they can overestimate true intravascular pressures in populations with exaggerated respiratory swings, such as obesity or COPD [70, 71].
*State of knowledge on respiratory swings in exercise * In COPD patients, respiratory swings are particularly pronounced; right heart pressure fluctuations may rise from 6 to 9 mmHg at rest to more than 20 mmHg during exercise [72]. Factors like prolonged expiration, airway resistance, dynamic hyperinflation, and active expiratory muscle use drive these fluctuations [68].
Boerrigter et al. [72] demonstrated that, in moderate COPD, averaging mPAP and PCWP over three respiratory cycles more accurately reflects transmural pressures compared to single end‐expiratory measurements. Transpulmonary gradient (TPG) remained stable when measured consistently within the respiratory cycle, and end‐expiratory RAP effectively corrected pressures unless right heart failure was present [72]. Transitioning from single‐point thresholds to flow‐normalized slopes (e.g., mPAP/CO, PCWP/CO) may reduce artifacts from respiratory swings. However, validation in diverse patient populations and across varying exercise intensities is still required.
Khirfan et al. demonstrated that in obese patients undergoing PH evaluation, intraesophageal pressure corrections reduced PH diagnoses by 25% and postcapillary PH prevalence from 60% to 8%, demonstrating the critical impact of pleural pressure adjustments [70]. During exertion, amplified respiratory swings distort right‐heart pressures, SV, and CO [73], effects that are intensified in conditions such as obesity or obstructive lung disease. Such dynamics complicate the interpretation of exercise hemodynamics in dyspnea assessments, creating a pressing need for advanced correction methods to ensure diagnostic accuracy [74]. This underscores the need for standardized pressure‐correction protocols in high‐risk populations to mitigate diagnostic misclassification.
Knowledge Gaps in Managing Respiratory Swings:
Measurement Standardization and Technical Implementation
‐Averaging mPAP and PCWP across three or more respiratory cycles improve measurement reproducibility in patients with obesity or obstructive lung disease by reducing artifacts caused by respiratory swings. Despite this, no standardized protocols exist for respiratory averaging during exercise, particularly in those with irregular breathing.‐RAP correction during exercise (nadir vs. mean) also lacks consensus.‐TPG remains relatively stable across respiratory cycles when measured consistently, offering reliable pressure‐flow insights.
Diagnostic Utility and Clinical Validation
‐The TPG/CO slope (> 1.2 WU) is a promising marker for identifying PVD and differentiating pre‐ versus post‐capillary PH.‐Combining slope‐based parameters—including TPG/CO, mPAP/CO, and PAWP/CO—may enhance diagnostic precision and improve risk stratification. However, the TPG/CO threshold still requires validation across PH subtypes (e.g., Groups 1 and 3), and the clinical utility of respiratory averaging in low‐swing populations such as non‐obese or non‐COPD patients remain unclear.
Integration with Emerging Metrics and Therapies
‐The impact of respiratory swings on newer dynamic metrics (e.g., mPAP/CO slope) during variable‐intensity protocols is uncertain.‐The potential role of the TPG/CO slope in guiding therapeutic interventions—such as vasodilator use in exercise‐induced PH—has not yet been evaluated in prospective clinical trials.
Consensus Recommendations and Future Directions: Standardize respiratory‐synchronized averaging techniques and RAP correction during exercise hemodynamics.Validate TPG/CO and related slope metrics in diverse PH phenotypes.Develop real‐time measurement tools that account for respiratory swings during dynamic testing.
Multicenter studies are needed to reduce misclassification and improve phenotyping in high‐swing populations.
Invasive Arterial Blood Pressure Monitoring
Rationale: While not universally standard, invasive arterial blood pressure monitoring addresses the well‐documented limitations of non‐invasive cuff measurements, which often become unreliable due to motion artifact and rapid hemodynamic changes during peak exercise.
State of Knowledge: Significant discrepancies exist between invasively and non‐invasively measured systemic blood pressure during exercise. Non‐invasive cuffs frequently underestimate systemic pressures, potentially masking occult exercise‐induced systemic hypertension, a key hemodynamic feature in diagnosing Group 2 PH (HFpEF). Continuous arterial monitoring captures the pulse pressure amplification often seen in HFpEF and allows for immediate detection of exertional hypotension, a validated marker of impending RV failure. Furthermore, arterial access enables direct arterial blood gas sampling for accurate Fick CO calculation. Recent data suggest that relying on peripheral estimates (SpO2) can lead to CO errors and PH misclassification, particularly in patients with compromised peripheral perfusion (e.g., systemic sclerosis) or dark skin pigmentation [75].
To ensure accurate Fick CO calculations and valid arteriovenous oxygen content difference (Ca‐vO₂) measurements, blood samples must be obtained when hemodynamic and metabolic parameters have reached equilibrium at each workload.
During constant‐load or incremental exercise, VO₂ and hemodynamic parameters require time to equilibrate. In healthy individuals, steady‐state VO₂ is typically achieved within 2–3 min at moderate intensities [76, 77]. However, in patients with PH and cardiovascular disease, this equilibration period may be prolonged to 4–6 min or longer [76, 77].
Given evidence that patients with PH require up to 5 min to achieve hemodynamic steady state, protocols using stages shorter than 3–4 min may result in blood gas measurements that do not reflect equilibrated conditions. This can lead to systematic errors in calculated CO and oxygen extraction parameters. Clinicians and researchers should balance the need for adequate equilibration time against test duration, patient tolerance, and the risk of premature test termination due to non‐physiologic fatigue.
Arterial and mixed venous blood samples should be drawn as nearly simultaneously as possible (within 5–10 s) to ensure that the arteriovenous oxygen difference accurately reflects instantaneous oxygen extraction rather than temporal variations in CO or metabolic demand.
Consensus Recommendations and Future Directions: We suggest considering arterial line placement when accurate systemic hemodynamic assessment is critical for phenotyping (e.g., suspected HFpEF/Group 2 PH) or when non‐invasive signals are likely to be unreliable (e.g., Raynaud's phenomenon, obesity).We recommend that arterial and venous blood samples be drawn simultaneously at the end of each minute of exercise, or ideally during the final 30–60 s of each stage in stepwise protocols, to ensure that measurements reflect true steady‐state conditions [78, 79]. For ramp protocols with continuous workload increases, sampling at regular intervals (e.g., every 1–2 min) is acceptable, recognizing that true steady‐state may not be fully achieved.Future research should establish standardized protocols for arterial line use and validate age‐adjusted reference values for invasive systemic exercise pressures to better define pathologic hypertensive responses.
Analysis of PAWP Waveform Morphology
Rationale: Relying solely on the mean PAWP or the PAWP/CO slope may obscure distinct pathophysiologic mechanisms of exercise intolerance. Analysis of the PAWP waveform morphology offers incremental diagnostic value, particularly for distinguishing between valvular pathology and diastolic dysfunction.
State of Knowledge: The emergence of prominent v‐waves during exercise (often defined as an amplitude ≥ 10 mmHg above the mean PAWP) is a specific marker of dynamic mitral regurgitation or reduced left atrial compliance (“stiff left atrium” syndrome) [80, 81, 82, 83, 84]. These phenomena contribute significantly to pulsatile pulmonary vascular loading and RV afterload but may not be fully captured by mean pressure values alone [85]. Differentiating these phenotypes is critical, as dynamic MR may warrant specific structural interventions, while a stiff left atrium points towards a distinct HFpEF phenotype.
Consensus Recommendation: We recommend that iCPET interpretation include routine qualitative and quantitative assessment of the PAWP tracing. Clinicians should specifically report the presence of exercise‐induced v‐waves, as this finding identifies a subset of patients with specific atrial or valvular pathology that might otherwise be misclassified as generic post‐capillary PH.
Exercise Cardiac Imaging in the Assessment and Prognosis of PH
Rationale: Although invasive catheterization remains the gold standard for assessing pulmonary vascular and RV function during exercise, noninvasive cardiac imaging offers important contextual insight and complements hemodynamic data, particularly in patients with valvular disease, those with intermediate pretest probabilities of PH, or those for whom catheterization is not feasible. Simultaneous imaging during exercise enables a dynamic, integrated evaluation of cardiopulmonary reserve, illuminating mechanisms underlying exertional intolerance and identifying early abnormalities.
State of knowledge on exercise cardiac imaging: Resting echocardiography frequently underestimates RV impairment and fails to detect deficits in contractile reserve [86]. The tricuspid annular plane systolic excursion (TAPSE)/RV systolic pressure (RVSP) ratio reflects Emax/Ea coupling efficiency, now integrated into ESC/ERS guidelines for its prognostic value [87, 88] [2, 89].
Although correlations between resting echocardiographic parameters and peak VO2 are well established [90], exercise echocardiography offers far richer functional insight, extending well beyond simple changes in systolic PAP. Exercise imaging enables assessment of exercise tolerance, RV contractile reserve, and left ventricular diastolic function—capabilities that are particularly valuable in at‐risk subgroups, such as patients with scleroderma [91, 92].
In both PAH and inoperable chronic thromboembolic disease, echocardiography‐derived systolic PAP increases correlate with improved 6MWD, VO₂, NYHA class, and reduced BNP [93]. Enhanced RV functional reserve also predicts better 1–4‐year survival. Invasive hemodynamic studies confirm links between exercise responses, symptoms, and outcomes [94, 95]. Recent studies demonstrate strong concordance between invasive PAP and echocardiography‐derived systolic PAP during upright exercise, supporting the variability of noninvasive RV reserve assessment in select scenarios [96].
Exercise cardiac magnetic resonance imaging (CMR) quantifies pulmonary vascular reserve, with abnormal mPAP/CO slopes correlating well with invasive pressure measurement [97]. During exercise, both healthy subjects and PH patients demonstrate increased CO and PA pulse wave velocity, while PA relative area change typically decreases [98]. In PAH specifically, exercise‐induced RV SV responses assessed by CMR also differ according to WHO functional class, potentially enhancing risk stratification [99]. Exercise CMR can uncover pulmonary vascular abnormalities not apparent at rest in asymptomatic individuals with bone morphogenetic protein receptor Type 2 (BMPR2) mutations [100], allowing for earlier detection of subclinical disease.
Evidence on how advanced pulmonary vasodilator therapies influence RV function during exercise remains limited. A study assessing the effect of nebulized iloprost on echocardiographically‐defined biventricular performance during exercise in patients with HFpEF showed favorable effects on RV tissue Doppler imaging and TAPSE, supporting RV exercise unloading [101]. In patients with chronic thromboembolic pulmonary hypertension (CTEPH), exercise cardiac magnetic resonance (CMR) demonstrated enhanced RV SV augmentation following pulmonary endarterectomy (PEA). Additionally, a single dose of sildenafil both before and after PEA was associated with attenuation of RV contractile impairment [102, 103, 104].
Knowledge Gaps on Exercise Cardiac Imaging: While exercise echocardiography shows clinical promise for identifying PH risk factors, several methodological approaches require validation before widespread implementation. RAP Assessment: Echocardiographic assessment of RAP via inferior vena cava (IVC) collapse remains unvalidated under exercise conditions. Reduced venous compliance and altered respiratory mechanics during exertion may impair the accuracy of this commonly used method [105].PCWP Contribution: The role of PCWP in exercise‐induced pulmonary artery pressure (PAP) elevation requires further investigation, particularly in patients with left ventricular diastolic dysfunction, where PCWP may increase substantially [106, 107]. Current surrogate markers like E/e’ ratio need validation through multidimensional HFpEF assessment, including diastolic reserve evaluation.PVR: Accurate diagnosis of pulmonary vasculopathy depends on evaluating the PVR response to exercise, which integrates changes in both PAP and CO. However, because echocardiography cannot directly measure PVR, this limits its utility in comprehensive hemodynamic profiling.
Consensus recommendations and future research directions: Advanced Hemodynamic Assessment: The Development of multipoint pressure‐flow curves using estimated PA systolic pressure combined with velocity time integral (VTI) from PA flow measurements offers potential for more comprehensive evaluation.Right Heart Adaptation: Incorporating echocardiographic assessment of RV preload and volume changes will enhance understanding of right heart chamber hemodynamic adaptation during exercise stress.
Technical and Logistical Challenges
Positioning and Hemodynamic Variability: Integrating imaging introduces standardization challenges, primarily regarding body position. While resting echocardiography uses the left lateral decubitus position, exercise imaging typically employs semi‐supine or upright ergometry. As noted in Section 3.3.1, upright positioning yields lower filling pressures and CO compared to the supine position required for cardiac MRI (CMR). This discrepancy complicates the correlation of imaging data with invasive hemodynamics across different modalities.
MRI Compatibility and Safety: Invasive catheterization during exercise CMR (iCMR) is restricted by strict safety constraints. Standard catheters and guidewires often contain ferromagnetic materials that pose heating and projectile risks, necessitating specialized, MRI‐conditional devices that may differ in handling and cost. Additionally, the confined MRI bore requires supine ergometers that may not replicate upright exercise physiology. Real‐time monitoring further demands specialized systems to filter electromagnetic interference, currently limiting simultaneous iCPET‐CMR to specialized centers.
Image Quality: High respiratory rates and chest motion at peak exercise can degrade echocardiographic windows, particularly for right heart structures. This often forces reliance on immediate post‐exercise imaging, which may fail to capture rapid peak‐stress hemodynamic changes.
Non‐Invasive CPET in PH
Rationale: niCPET has become an important prognostic tool in PH [108], where abnormalities in pulmonary gas exchange and RV function contribute to exercise intolerance and exertional dyspnea. During exercise, patients with PAH demonstrate a distinctive pattern characterized by low peak oxygen consumption (peak VO₂), elevated ventilation‐to‐carbon dioxide production (VE/VCO₂) slope, reduced oxygen pulse, and decreased end‐tidal carbon dioxide pressure [109]. Noninvasive CPET is useful in assessing unexplained dyspnea where PH is suspected. The test can indicate a pulmonary vascular limitation to exercise by identifying key features such as an elevated VE/VCO₂ slope and abnormal ventilatory equivalent ratios. Research has shown that ventilatory efficiency parameters, particularly the VE/VCO₂ slope, demonstrate strong prognostic value, with studies reporting sensitivity and specificity values that vary based on the measurement methodology and patient population studied. Peak VO₂ has demonstrated a sensitivity of 87.5% and a specificity of 74.8%, while the ventilatory equivalent for carbon dioxide (EQCO₂) shows a sensitivity of 79.2% and a specificity of 82.9% [110]. These parameters have proven to be reliable physiologic markers of PVD across multiple forms of PH.
*Current state of * The prognostic relevance of CPET variables has been confirmed across multiple studies. In particular, reduced peak oxygen uptake (peak VO₂), increased dead space ventilation, and elevated ventilation‐to‐carbon dioxide production (VE/VCO₂) slope are associated with greater functional impairment, poorer prognosis, and attenuated response to therapy [30]. These parameters have proven useful in both pulmonary arterial hypertension (PAH) and chronic thromboembolic PH, offering clinicians objective measures for patient monitoring and therapeutic decision‐making. The prognostic value of niCPET parameters in PAH has been substantiated by multiple studies. Peak VO₂ and VE/VCO₂ slope are recognized as important prognostic indicators and are included in the ESC/ERS guidelines for PAH risk assessment [111]. According to the 2022 ESC/ERS guidelines, patients with peak VO₂ greater than 15 mL/min/kg (> 65% predicted) are considered low‐risk, while those with peak VO₂ less than 11 mL/min/kg (< 35% predicted) are classified as high‐risk. Similarly, VE/VCO₂ slope values below 36 indicate low risk, while values ≥ 45 suggest high risk [111]. These cut‐offs have been recently validated and when combined with O2 pulse, can be integrated into a four‐strata CPET score, which outperforms the 6MWD in combination with functional class and BNP in the prediction of survival at first follow‐up [12].
Despite its recognized clinical relevance, niCPET remains significantly underutilized in routine PH assessment. Several factors contribute to this limited adoption, with cost considerations and restricted availability of specialized equipment representing primary barriers. Additionally, the complexity of interpreting niCPET data necessitates specialized expertise, which may not be readily accessible in all clinical settings [112].
Most registry studies have not systematically incorporated niCPET parameters in mortality risk assessments, despite the prognostic multiparametric panel in the ERS guidelines recognizing niCPET as an important tool [113, 114]. This omission may reflect the specialized nature of niCPET, which often requires dedicated cardiopulmonary testing facilities and trained personnel. The lack of standardization in CPET protocols and measurement techniques also contributes to variability in results and interpretation challenges [112, 115].
Clinical trials frequently fail to include niCPET parameters as primary endpoints, further limiting the integration of these valuable measurements in treatment evaluation. The most commonly used primary endpoint in PAH trials has been the 6‐min walk distance, leading to the approval of several targeted therapies, while the more comprehensive information provided by niCPET has been underutilized [116, 117].
Knowledge gaps hindering broader use of non‐invasive CPET in PH: Although niCPET provides well‐established diagnostic and prognostic insights, its broader clinical and research application in PH is curtailed by unresolved methodological issues and systemic implementation barriers. Standardization of Testing Protocols and Reporting: There is still no universally accepted exercise protocol, set of core variables, or uniform analytic framework specific to PH. Most centers rely on locally adapted incremental ramp tests, and multicenter registries collect CPET data inconsistently, making inter‐study comparisons difficult and hampering the creation of large normative datasets.Cost, Training, and Infrastructure Barriers: The implementation of niCPET demands sophisticated equipment—including calibrated gas‐exchange analyzers and exercise ergometers—as well as personnel with specialized training in test administration and interpretation. These requirements limit widespread adoption to a few specialist laboratories, particularly outside Europe and North America, and the cost‐effectiveness of broader deployment remains unquantified.Limited Integration into Prospective Registries and Risk Scores: Although peak VO₂ and VE/VCO₂ slope are acknowledged in ESC/ERS risk tables, most large PH registries either omit CPET variables or record them too sparsely for survival modeling. Consequently, the incremental prognostic value of niCPET beyond existing multiparametric scores remains uncertain.Under‐representation in Therapeutic Trials: Randomized trials still rely almost exclusively on 6‐min walk distance or composite clinical‐worsening endpoints. Peak VO₂, VE/VCO₂ slope, and other CPET metrics rarely serve as primary efficacy criteria, leaving their responsiveness to modern therapies—and the magnitude of change that is clinically meaningful—largely undefined.Unclear Value for Early Detection and Screening: While cross‐sectional studies consistently show that elevated VE/VCO₂ slopes and reduced end‐tidal CO₂ effectively distinguish PH from healthy controls—even under the updated PH definition (mPAP > 20 mmH) [118] —there is a lack of prospective data demonstrating that niCPET leads to earlier diagnosis, faster referral, or improved survival outcomes.Effect of Therapy‐Induced Changes in CPET Variables: While observational work links baseline peak VO₂ or VE/VCO₂ slope, and O2 pulse to outcome, only limited data show improvements in these indices after treatment translate into better long‐term prognosis and further validation is needed.Pediatric Data Deficiency: Safety has been demonstrated in children, but only small single‐center cohorts have explored prognostic power. Apart from peak systolic blood pressure, few CPET‐derived variables have been validated against hard outcomes in pediatric PAH, leaving age‐appropriate cut‐offs and follow‐up schedules unresolved.
Consensus recommendations and future research directions: Protocol Development & Standardization oDevelop internationally harmonized niCPET protocols for PAH that include systematically compared workload progressions (e.g., 5–25 W/min) across different subtypes.oBuild comprehensive, PAH‐specific normative databases reflecting diverse populations, ages, and regions.oValidate and refine ESC/ERS thresholds (peak VO₂ > 15/ < 11 mL/min/kg, VE/VCO₂ slope < 36/ > 45) for different PAH subtypes. Equipment & Quality Assurance oEvaluate measurement variability among different metabolic cart systems when testing PAH.oDevelop standardized validation methods that replicate PAH exercise phenotypes. Data Interpretation & Analysis oStandardize methods for ventilatory threshold (VT) and VE/VCO₂ slope calculation in PAH.oCreate PAH‐specific smoothing algorithms for irregular breathing patterns.oDevelop machine learning tools for automated, PAH‐focused CPET interpretation and decision support. Training & Competency oEstablish PAH‐specific niCPET certification and continuing education programs.oCreate evidence‐based assessment frameworks and standardized case repositories for training and evaluation. Artificial Intelligence and Machine Learning Integration oDevelop machine learning tools for automated, PAH‐focused CPET interpretation and decision support.oAI‐assisted interpretation systems should provide real‐time quality control, automated detection of VT, calculation of VE/VCO₂ slopes using standardized algorithms, and integration with clinical risk scores. These tools can reduce inter‐observer variability, enhance diagnostic accuracy in complex cases, and facilitate broader adoption of CPET by providing interpretation support to clinicians without specialized training in exercise physiology. Clinical Applications oStandardize niCPET protocols for therapy monitoring and define clinically meaningful change thresholds.oConduct prospective studies on niCPET screening in high‐risk populations.oDefine optimal timing and intervals for follow‐up assessments.oDevelop evidence‐based guidelines for protocol selection, equipment standards, and interpretation. Research Coordination oForm multi‐center consortiums for large‐scale protocol validation.oIncorporate niCPET metrics into PAH registries using standardized data collection frameworks.oEstablish common data elements and interoperability standards for multi‐center research. Pediatric Priorities oAdapt pediatric CPET protocols for children with PAH.oDevelop normalization standards that account for growth, developmental stage, and PAH‐specific disease variables.oInvestigate pediatric‐specific safety and competency standards.
Topic Exercise Testing in the Pathophysiology of Disease: RV–PA Coupling; Ventilatory Inefficiency; Peripheral Extraction
Assessment and Use of RV–PA Coupling During Exercise Testing
Rationale: RV–PA coupling captures the mechanical interplay between the RV and pulmonary vasculature. It is best expressed as the ratio between ventricular elastance (Ees), a load‐independent measure of contractility, to arterial elastance (Ea), a composite measure of afterload [119]. When Ees equals or exceeds Ea, the ventricle effectively transfers energy to the pulmonary arteries, indicating maximal mechanical efficiency. In healthy adults at rest Ees/Ea ranges from 1.0 to 2.0, balancing RV work with oxygen consumption [119, 120, 121]. A reduced Ees/Ea predicts worse outcomes in PH [122]. RV ejection fraction (RVEF) also has prognostic significance but is load dependent. Thus, it does not discriminate whether reduced SV results from impaired contractility (↓Ees), elevated afterload (↑Ea), or altered preload. Distinguishing these contributors guides therapies aimed at boosting Ees or lowering Ea.
Exercise hemodynamics unmask abnormalities hidden at rest [123, 124, 125, 126, 127]. With rising workloads, the RV first dilates to preserve SV (Frank‐Starling response), then boosts contractility via homeometric adaptation (Anrep effect). With sustained pressure overload, the RV eventually exhausts these reserves, causing RV‐PA uncoupling [127]. Thus, a decrease in the Ees/Ea ratio during exercise signals inadequate RV contractile reserve, excessive afterload, or both—each with different therapeutic implications.
The gold standard for measuring Ees and Ea involves plotting pressure and volume (PV loops) across varying preload conditions using conductance catheters [120]. However, this approach is clinically impractical due to high cost, technical complexity, and the need for controlled preload manipulation. Moreover, conductance‐derived RV signals must be cross‐calibrated with independent measurements—such as cardiac MRI—that are typically unavailable during exercise protocols [128]. To address these limitations, the simplified “single‐beat’ (SB) method was developed [120]. The clinically relevant approach [129, 130] approximates multi‐beat conductance methods [131] without requiring preload modification, though it involves certain assumptions about end‐systolic pressure measurement [132].
Several echocardiographic alternatives have been proposed as surrogates for RV‐PA coupling [88], including RV systolic excursion velocity (RV S’), TAPSE to RV or PA systolic pressure ratio (TAPSE/RVSP), and RV fractional area change to RV or PA systolic pressure ratio (RV FAC/RVSP) [88, 123]. However, these measures remain load‐dependent and are challenging to obtain during exercise because of limitations in acoustic windows.
Exercise‐based RV‐PA coupling assessment evaluates how the RV responds to changing afterload across different exercise intensities [107, 133]. This strategy offers clinical advantages—most notably the early detection of RV dysfunction at lower levels of exertion [127, 133, 134]. Since RV dysfunction severity depends on the exercise intensity and duration [135, 136], results can guide individualized exercise prescriptions for patients with PH. This approach may further clarify whether RV dysfunction arises from impaired contractility or excessive afterload, thereby guiding therapy toward either contractile support or afterload reduction (Figure 1). This comprehensive assessment helps prevent activities that could precipitate RV dysfunction while informing targeted treatment approaches.
Knowledge Gaps in RV‐PA Coupling Assessment During Exercise Testing: The assessment of RV–pulmonary arterial (RV‐PA) coupling during exercise testing represents a critical area for understanding PH progression and prognosis. However, substantial knowledge gaps persist that limit the clinical translation and standardization of these assessments. Methodological Standardization: Lack of standardized exercise protocols across laboratories, including inconsistent exercise modalities (supine vs. upright), intensity levels, duration, and timing of measurements during exercise testing.Non‐Invasive Measurement Accuracy: Echocardiographic surrogates of RV‐PA coupling, such as TAPSE/RVSP, RV S’, and RV FAC/RVSP, are hampered by load dependency, suboptimal acoustic windows during exercise, and wide interstudy variability in cutoff thresholds (0.27–0.58 mm/mmHg), limiting their clinical reliability.SB Method Limitations: The simplified SB approach carries inherent uncertainties, may underestimate Ees/Ea ratios in severe PAH, relies on problematic assumptions about end‐systolic pressure measurement, and introduces operator‐dependent variability.Normal Reference Values: Absence of well‐defined normal values for RV contractile reserve parameters during exercise, with wide ranges in existing data (TAPSE: 4–10 mm, S’: 6–14 cm/s, PASP: 12–57 mmHg) and significant individual variability.Exercise‐Induced Dysfunction Detection: There remains limited clarity regarding the mechanisms that drive RV‐PA uncoupling during exercise, compounded by technical challenges in acquiring high‐quality imaging during exertion and the lack of clearly defined thresholds for abnormal pulmonary vascular responses.Clinical Translation and Validation: Insufficient prospective validation studies demonstrating improved clinical outcomes through exercise‐based RV‐PA coupling assessment, lack of consensus on optimal cutoff values for clinical decision‐making, and limited integration with comprehensive CPET.
*Consensus recommendations and future research * The substantial knowledge gaps in RV‐PA coupling assessment during exercise testing pose major obstacles to clinical application. Addressing these limitations through standardized methodologies, improved non‐invasive techniques, and comprehensive validation studies will be essential for advancing the field and improving patient care in PH. Development of Non‐Invasive Methods: Research priorities must include enhancing non‐invasive RV‐PA coupling assessment during exercise. Three‐dimensional echocardiography metrics are promising, but demand further clinical validation. Emerging techniques such as pressure‐strain loops may offer innovative ways to quantify RV work under physiologic stress.Standardization Efforts: Critical needs include establishing standardized exercise protocols for RV‐PA coupling assessment, defining normal reference values across different populations, and developing consensus cutoff values for clinical decision‐making. Multi‐center studies are needed to validate proposed methodologies and establish clinical guidelines.Mechanistic Understanding: It is critical to dissect the mechanisms driving exercise‐induced RV‐PA uncoupling, especially in early PVD. A more nuanced understanding of how RV contractile reserve, afterload dynamics, and coupling efficiency interplay during exercise holds promise for informing targeted therapies.
Ventilatory Efficiency
Rationale: Ventilatory inefficiency (VE/VCO2) serves as a powerful non‐invasive biomarker for PH reflecting both presence and severity through the combination of exercise hyperventilation and dead space ventilation [137]. Normal VE/VCO2 values obtained during exercise testing typically exclude significant PVD, potentially obviating the need for invasive diagnostic procedures. This parameter effectively screens patients at risk for connective tissue disease‐associated PH [138, 139], and is more pronounced in CTEPH than PAH [140].
*State of * While niCPET [141] screens for PVD, provides prognosis, and monitors treatment response, traditional variables like V02 peak have limited utility. The VE/VCO2 slope (ventilatory efficiency) shows promise for all three applications.
The VE/VCO2 slope is derived by plotting minute ventilation (VE) against carbon dioxide production (VCO2) during incremental exercise and calculating the linear regression slope. This represents the ventilation increase required to eliminate each unit of CO2 during exercise. During graded exercise, VE and VCO2 maintain a linear relationship until the respiratory compensation point (RCP)—typically aligning with the lactate threshold—after which ventilation increases disproportionately.
The alveolar ventilation equation (Eq. 1) indicates that VE/VC02 is driven by the arterial CO2 partial pressure (PaCO2) and the physiologic dead space fraction (VD/VT). Pathologic VE/VCO2 increases result from combined hyperventilation and impaired VD/VT reduction.
(1)V′EV′CO2=kPaCO2×1−VDVT.
Ventilatory efficiency during CPET is measured using either the VE/VCO2 slope from rest to the RCP or the VE/VCO2 fraction at the VT. The latter is often preferred as anxiety‐induced resting hyperventilation can artificially reduce the slope and decrease disease detection sensitivity. Elevated VE/VCO2 slopes signify reduced ventilatory efficiency and are associated with poorer prognosis outcomes in multiple cardiopulmonary diseases. In congestive heart failure patients, a VE/VCO2 slope ≥ 34 indicates poor prognosis [142].
PH involves functional pulmonary capillary bed loss and increased alveolar dead space. Unlike in healthy individuals, tidal volume fails to effectively lower the physiologic dead space fraction (VD/VT) in patients with PH [143, 144, 145, 146]. Pre‐lactate threshold hyperventilation also characterizes PH, likely involving sympathetic nervous stimulation of ventilatory control through pressure receptors in the right atrium, ventricle, and pulmonary outflow tract. Arterial chemoreceptor simulation from dynamic oxygen desaturation due to pulmonary diffusion defect contributes to many patients with PH. The VE/VCO^2^ slope correlates with RV oxidative metabolism, suggesting that PVR is a primary determinant of this parameter [142].
Ventilatory inefficiency assesses PH severity and survival outcomes. An elevated VE/VCO2 slope offers strong prognostic value in PH and [147, 148, 149, 150], when considered alongside functional class and biomarkers, supports escalation of therapy. In mixed populations of PAH and patients with CTEPH, ventilatory inefficiency predicts survival [151].
Ventilatory inefficiency lacks specificity for precapillary PH, frequently occurring in left heart failure [152, 153], with higher values associated with Group 2 PVD and worse outcomes. However, exercise VE/VCO2 elevations in heart failure are typically less severe than in precapillary disease [137, 140, 154, 155]. This parameter also appears in parenchymal lung diseases (COPD [156] and ILD [157]), dysautonomia including ME/CFS [158] and Long COVID [159], and skeletal muscle mitochondrial dysfunction [160].
Ventilatory inefficiency monitoring of pulmonary vasodilator response shows variable success. Inhaled Nitric Oxide during constant load exercise failed to improve VE/VCO2 in PAH [161]. However, intravenous epoprostenol [162] and beraprost both enhanced VE/VCO2 [163]. In chronic thromboembolic pulmonary disease and CTEPH [164, 165], ventilatory efficiency improves following pulmonary thromboendarterectomy [166], and balloon pulmonary angioplasty has similarly produced favorable effects [167].
The VE/VCO2 slope is a valuable tool for diagnosis, risk stratification, and management in PAH. It offers insights into exercise‐related gas exchange efficiency, mirrors underlying disease physiology, and has prognostic utility. Despite its strengths, it lacks specificity for precapillary PH—requiring interpretation in conjunction with other clinical and hemodynamic assessments.
Pulmonary Circulation: Peripheral Extraction
Rationale: Exercise limitation assessment involves the body's complex ability to extract oxygen from the environment, transport it to the tissues, and metabolize it at the cellular level [168]. The role of peripheral oxygen extraction in exercise intolerance pathophysiology has gained increasing recognition. Emerging evidence indicates that impaired systemic skeletal muscle oxygen extraction contributes to exercise intolerance in conditions such as PH and heart failure [169, 170].
Recent studies emphasize peripheral factors in exercise limitation, particularly in cardiopulmonary diseases. In PAH, skeletal muscle dysfunction and reduced oxygen extraction significantly contribute to exercise intolerance, as demonstrated in PAH [171, 172], HFpEF [173, 174], and CTEPH [175], even in those with normalized hemodynamics after treatment [169]. Understanding these mechanisms is essential for precise evaluation of exercise limitations and for designing targeted therapies to enhance functional capacity in both healthy individuals and patients with cardiopulmonary pathologies.
*State of * Exercise capacity is assessed by CPET measurement of VO2max, which depends on both convective and diffusive oxygen delivery and cellular utilization, following the Fick equation (VO2 = CO × C(a‐v)O2) where VO2 equals the product of CO and arteriovenous oxygen content difference (C(a‐v)O2), with CO determined by HR and SV (HR × SV). C(a‐v)O2 represents tissue oxygen extraction capacity, calculated from the difference in oxygen content between arterial and venous blood, where oxygen content (CxO2) is calculated as 1.36 × Hgb × SO2 + 0.003 × PO2, with Hgb representing the hemoglobin concentration (g/dL), SO2 corresponding to oxygen saturation (fraction), and PO2 being the partial pressure of oxygen (mmHg) representing dissolved oxygen in plasma. Importantly, CO and Ca‐vO2 function as interdependent variables whose relationship affects exercise performance in various conditions; for instance, faster red blood cell transit through capillaries reduces oxygen diffusion time; for instance, leaving more oxygen unextracted. Although non‐invasive CPET often utilizes the oxygen pulse (O2Pulse = VO2max/HR) as a surrogate for SV, this approach presumes normal oxygen extraction and a linear CO‐VO2 relationship—assumptions that may hold in specific pathophysiological conditions. A complementary assessment of each stage of the O2 pathway provides valuable insights into functional limitations during exercise, enabling clinicians to evaluate and rank the relative contributions of different components along the oxygen cascade, from pulmonary gas exchange to peripheral utilization, to the overall exercise limitation.
PAH is characterized by pulmonary vascular remodeling and a spectrum of systemic abnormalities—such as skeletal and respiratory muscle degeneration, altered muscle vascularization, chronic inflammation, enhanced catabolism, and mitochondrial dysfunction impairing oxygen utilization [176]. These alterations can compromise peripheral oxygen utilization. While impaired oxygen extraction has been documented in PAH [177], some studies indicate that peripheral defects may parallel delivery impairments [178]. The pathophysiology of this observed oxidative myopathy in PAH is multifactorial [176].
While oxygen delivery defects are significant in PAH, peripheral mechanisms contribute to exercise intolerance and reduced quality of life. These mechanisms include skeletal muscle atrophy, decreased capillary density, mitochondrial dysfunction, and increased oxidative stress [170, 179, 180, 181]. Comparable peripheral metabolic abnormalities are likely present in CTEPH as well, reflecting similar pathophysiologic patterns [175].
HFpEF, categorized as Group 2 PH, represents a heterogeneous patient cohort in which skeletal muscle abnormalities are well‐documented. These include a reduction in oxidative Type I muscle fibers, lower capillary‐to‐fiber ratios, increased fatigability, rapid depletion of high‐energy phosphates during exertion, and diminished oxidative capacity [182, 183, 184]. While some studies suggest that oxygen extraction is preserved in HFpEF [185, 186, 187, 188, 189], others highlight the importance of oxygen extraction, limiting exercise capacity [190]. These seemingly conflicting findings have been reconciled by considering the relationship between CO and the arteriovenous oxygen content difference (Ca‐vO2). When this interdependence is accounted for, the evidence supports that oxygen extraction is impaired in HFpEF [191]. One proposed mechanism is impaired skeletal muscle diffusive capacity impairment [191]; However, some studies challenge this, attributing reduced Ca‐vO2 during exercise to preferential blood flow redistribution, potentially towards fat stores, thus limiting oxygen availability to active muscle [192].
Both HFpEF and HFrEF (heart failure with reduced ejection fraction) can exhibit impaired peripheral oxygen extraction [184]. However, patients with HFrEF typically retain a greater ability to augment oxygen extraction during exertion compared to those with HFpEF [190]. In HFrEF, exercise intolerance more commonly stems from limitations in convective oxygen delivery—primarily reduced CO—rather than from impaired muscular oxygen extraction [193].
Several conditions highlight the critical role of systemic oxygen extraction in determining exercise intolerance. Among them, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post‐COVID‐19 (long‐haul) syndrome, and mitochondrial myopathy. These conditions are often linked to small fiber neuropathy [158, 159], which may contribute to autonomic dysfunction and abnormal blood flow distribution.
Mitochondrial myopathy exemplifies impaired systemic oxygen extraction, constituting the primary pathophysiological mechanism underlying exercise intolerance in affected individuals. Invasive CPET in these patients typically reveal markedly reduced peak VO2, a hyperdynamic circulatory response, elevated lactate concentrations, and a severely blunted arteriovenous oxygen content difference—hallmark of profound systemic oxygen extraction deficits [194, 195].
Clinical Assessment and Thresholds for Peripheral Oxygen Extraction
Defining Abnormal Peripheral Extraction
The peak arteriovenous oxygen content difference (Ca‐vO₂) at maximal exercise reflects the body's capacity to extract oxygen from arterial blood. In healthy individuals, Ca‐vO₂ typically increases from approximately 5 mL O₂/dL at rest to 15–17 mL O₂/dL at peak exercise, corresponding to a mixed venous oxygen saturation (SvO₂) of approximately 25%–35%. Values below 12–13 mL O₂/dL at peak exercise generally indicate impaired peripheral extraction, though age, sex, and hemoglobin concentration influence these thresholds.
However, interpreting Ca‐vO₂ in isolation can be misleading due to the interdependence between CO and oxygen extraction. According to the Fick principle (VO₂ = CO × Ca‐vO₂), when CO is severely reduced, transit time through capillaries is prolonged, potentially allowing for greater oxygen extraction and paradoxically “normal” Ca‐vO₂ values despite profound exercise limitation. Conversely, hyperkinetic states with very high CO may show reduced Ca‐vO₂ due to inadequate capillary transit time rather than true peripheral dysfunction.
Mechanistic Differentiation: Identifying the Cause of Impaired Extraction
iCPET provides several parameters that help distinguish among different causes of reduced peripheral oxygen 1.Microvascular/Capillary Dysfunction (HFpEF, PAH) Pattern: Reduced Ca‐vO₂ with normal or elevated CO responseMechanism: Impaired skeletal muscle diffusive capacity due to reduced capillary density, endothelial dysfunction, or altered perfusion distributionSupporting ▪Normal or high O₂ pulse early in exercise that plateaus prematurely▪Arterial hypoxemia (low SaO₂) suggests pulmonary diffusion limitation rather than pure peripheral defect▪Lactate elevation out of proportion to workload (> 2 mmol/L rise)▪Normal mixed venous PO₂ (> 30 mmHg) suggests inadequate extraction rather than delivery limitation
2.Mitochondrial Myopathy Pattern: Profoundly reduced Ca‐vO₂ (< 10 mL O₂/dL) with hyperdynamic CO (exaggerated CO response for a given VO₂)Mechanism: Impaired oxidative phosphorylation limits cellular oxygen utilizationSupporting ▪Very low respiratory exchange ratio (RER < 1.0) at symptom limitation (inability to generate lactate)▪Markedly elevated SvO₂ (> 45%–50%) at peak exercise▪Early, steep lactate rise with low workload▪Low VO₂ at anaerobic threshold (< 40% predicted VO₂max)
3.Autonomic Dysfunction/Preload Failure (POTS, MECFS, Long COVID) Pattern: Reduced Ca‐vO₂ with blunted or paradoxical CO response and postural dependenceMechanism: Inadequate venous return and blood pooling limit effective perfusion to working muscleSupporting ▪Excessive HR response (high HR/low SV)▪Upright position exacerbates limitation compared to supine▪RAP fails to rise or falls with exercise (preload insufficiency)▪Low CO relative to VO₂ (reduced O₂ pulse throughout exercise)
4.Anemia or Hemoglobinopathy Pattern: Reduced Ca‐vO₂ ceiling due to low hemoglobin or impaired O₂ bindingMechanism: Mathematical limitation (CaO₂ = 1.36 × Hgb × SaO₂)Supporting ▪Low hemoglobin concentration (< 10 g/dL)▪SvO₂ may be paradoxically high if hemoglobin saturation curve is shifted▪Normal CO and metabolic response otherwise Integrated Diagnostic ApproachTo systematically identify the cause of impaired extraction during iCPET, we 1.Calculate Ca‐vO₂ at multiple time points (rest, anaerobic threshold, peak exercise) to assess the trajectory of extraction2.Assess the CO/Ca‐vO₂ relationship using simultaneous invasive hemodynamics and arterial/venous blood gases3.Measure lactate kinetics to distinguish aerobic from anaerobic metabolism4.Evaluate pulmonary gas exchange (A‐a gradient, DLCO) to exclude primary pulmonary limitation5.Consider position dependence (upright vs. supine) to unmask autonomic or preload abnormalities6.Compare O₂ pulse trajectory (VO₂/HR) with expected SV response Knowledge Gaps Normative thresholds for Ca‐vO₂ adjusted for age, sex, and body composition remain poorly definedCut‐points distinguishing clinically significant from physiologic variability in peripheral extraction are uncertainTherapeutic implications of identifying specific extraction defects (e.g., does exercise training improve microvascular dysfunction in HFpEF?) require prospective validationNon‐invasive surrogates for Ca‐vO₂ that could enable broader screening are lacking
Consensus Recommendation
We recommend routine calculation of peak Ca‐vO₂ during iCPET when exercise intolerance is disproportionate to cardiac or pulmonary impairment. Integration with CO, lactate, and gas exchange data enables mechanistic phenotyping that may guide targeted interventions, such as exercise training for microvascular dysfunction or volume optimization for preload failure.
This addition directly addresses the reviewer's questions by providing practical thresholds, mechanistic differentiation strategies, and specific iCPET parameters that can identify the underlying cause of impaired peripheral extraction.
Knowledge gaps on peripheral extraction: Mechanistic Drivers of Ventilatory Inefficiency—The specific contributions of hyperventilation, dead space ventilation, central chemoreflex sensitivity, peripheral muscle dysfunction, and hemodynamic alterations to the VE/VCO₂ slope are not yet clearly delineated.Measurement Standardization Gaps—No consensus exists on how to quantify ventilatory efficiency (e.g., slope to RCT vs. VT, whole‐exercise vs nadir), hindering study comparability and routine clinical use.Diagnostic Specificity Limits—VE/VCO₂ abnormalities overlap across precapillary and postcapillary PH, heart failure, chronic lung disease, and mitochondrial disorders, leaving CPET unable to distinguish etiologies reliably.Peripheral Muscle Pathophysiology Unknowns—The chronological progression and mechanistic relationships between skeletal muscle atrophy, capillary rarefaction, mitochondrial dysfunction, and the interplay of convective (CO) versus diffusive (muscle‐level oxygen extraction) limitations in exercise intolerance remain undefined.Therapeutic‐Monitoring Uncertainty—Ventilatory efficiency and peripheral extraction metrics lack validated timing, frequency, and interpretation frameworks for tracking treatment response; residual exercise limitation despite hemodynamic improvement remains unexplained.Condition‐Specific Research Voids—Key unanswered questions persist for HFpEF (heterogeneous O₂‐extraction patterns), CTEPH (failure of diffusion capacity recovery after intervention), and CTD‐PAH (autoimmunity–muscle–vascular interplay), delaying targeted therapies.
Consensus recommendations and future research directions: Develop Precision‐Medicine Phenotyping—Define clinically meaningful patient phenotypes by integrating ventilatory efficiency metrics and peripheral muscle dysfunction profiles, facilitating individualized diagnostic strategies and the development of targeted treatment approaches across different PH subgroups.Evaluate Muscle‐Specific Exercise Interventions—Compare the efficacy of targeted skeletal muscle rehabilitation protocols versus traditional cardiopulmonary exercise training for addressing peripheral dysfunction and improving exercise capacity in patients with PH.Integrate Multi‐Modal Biomarker Platforms—Combine ventilatory efficiency and peripheral extraction parameters with novel biomarkers of muscle dysfunction, inflammation, and metabolic abnormalities to enhance diagnostic accuracy and treatment response monitoring.Establish Long‐Term Outcome Trajectories—Implement longitudinal studies to monitor changes in ventilatory inefficiency and peripheral muscle dysfunction, assess their temporal association with disease progression, and evaluate their influence on patient‐reported quality of life and long‐term survival.Optimize Care Delivery Models—Address disparities in specialized CPET access by developing optimal care delivery frameworks, training protocols for non‐specialized providers, and standardized interpretation guidelines for complex exercise physiology.Advance Technology‐Enhanced Assessment—Investigate the integration of advanced imaging techniques, wearable monitoring devices, and remote assessment tools for evaluating ventilatory efficiency and peripheral function outside traditional clinical settings.
Topic Novel Uses of CPET in the Era of Disease Modification: Assessment of Reverse Remodeling of the Pulmonary Artery (PA) and Right Ventricle (RV)
RV Reverse Remodeling
Rationale: Right ventricular reverse remodeling (RVRR) is considered an optimal therapeutic endpoint in the treatment of PH, yet it remains insufficiently defined. RVRR can be broadly characterized as “normative” improvements in RV structure and function during treatment [196], though interpreting intermediate cardiac imaging changes relative to normal values presents significant clinical challenges. iCPET offers unique insights into RV recovery and may serve as a surrogate marker for RVRR. Unlike standard imaging alone, iCPET contextualizes morphological changes by demonstrating whether RVRR correlates with improved physiologic responses to exercise stress. This integrative approach is particularly valuable for evaluating cardiac responses to therapies [197], as it enables simultaneous assessment of cardiovascular, respiratory, and metabolic responses under controlled exercise conditions. The ability to measure real‐time hemodynamic parameters during exercise testing allows clinicians to assess the functional significance of structural improvements observed on imaging, thereby providing a more complete picture of therapeutic efficacy in PH management.
*State of * While cardiac imaging offers essential anatomical and functional information, iCPET is critical for determining whether these structural changes correspond to meaningful physiological improvement. The threshold of VO2peak greater than 15 mL/kg/min at follow‐up has been established as a clinically meaningful marker associated with RV functional recovery (RVFnRec) [196]. This threshold reflects the cardiopulmonary system's capacity to deliver and utilize oxygen during peak exercise and offers important insight into RV functional status [11].
Patients demonstrating RVFnRec typically exhibit significantly higher VO2peak values compared to those without recovery, though these levels remain below those of healthy controls [196]. This pattern indicates partial but meaningful functional restoration. The association between VO2peak and RV functional improvement has been validated in studies showing that 22 of 63 patients (35%) who reached a VO2peak > 15 mL/kg/min at follow‐up experienced substantial improvements in RV end‐diastolic volume (RVEDV) and ejection fraction [196]. Importantly, this VO₂peak threshold is not only physiologically meaningful but also carries prognostic significance, as it is dependent on CO and RV functional reserve in PAH.
The ventilation‐to‐carbon dioxide output (VE/VCO2) slope is another key physiologic parameter assessed during iCPET. In PAH, this parameter typically demonstrates abnormal elevation, reflecting inappropriate central hyperventilation, inefficient gas exchange, and increased dead space ventilation. Patients who achieve RV functional recovery (RVFnRec) exhibit lower (improved) VE/VCO2 slopes compared to those without recovery, indicating improved ventilatory efficiency [198]. This improvement suggests better ventilation‐perfusion matching and reduced RV oxygen consumption [142], which is frequently impaired in PAH due to vascular remodeling. The reduction in VE/VCO2 slope reflects improved blood flow distribution to ventilated lung regions, representing a key marker of therapeutic response.
iCPET allows continuous hemodynamic monitoring during graded exercise, yielding detailed insight into RV adaptation under increasing physiologic demand. This approach allows for real‐time assessment of how the RV adapts to physiological stress, offering insights unavailable through resting measurements alone. Patients with RVFnRec typically demonstrate higher CO and stroke volume index (SVI) at peak exercise compared to non‐recovered patients. This enhanced performance suggests improved RV output reserve in functionally recovered patients, even when mPAP‐CO relationships during exercise are similar [11, 196]. An augmented SV response during exercise serves as a critical indicator of RV inotropic reserve, often not evident at rest.
While alternative imaging modalities provide valuable information, each has specific limitations. Echocardiography offers real‐time assessment but faces challenges with acoustic windows and complex RV geometry [199]. Cardiac magnetic resonance imaging (MRI) remains the gold standard for structural assessment, especially for quantifying RV mass and volumetric changes that define RVFnRec and reverse remodeling [196, 200]. Computed tomography provides excellent anatomical detail but limited functional information. Radionuclide techniques offer accurate ejection fraction measurements independent of geometric assumptions, but provide limited real‐time functional data [201]. Unlike these modalities, which primarily evaluate resting function, iCPET uniquely assesses RV performance during exercise, contextualizing structural changes within physiological stress. This approach addresses the critical gap between anatomical improvement and functional recovery, ensuring that observed structural changes translate to meaningful clinical benefit. Through hemodynamic monitoring during controlled exercise, iCPET reveals the functional relevance of morphological improvements that may appear sufficient on resting imaging but do not necessarily translate into improved exercise capacity or quality of life.
Knowledge gaps: Lack of standardized CPET‐based criteria for RV functional There remains an absence of agreed‐upon peak oxygen consumption (VO₂peak) or VE/VCO₂ slope cut‐offs, significantly hindering trial design and cross‐study comparisons. This lack of standardization is especially problematic considering individuals over 50 exhibit distinct exercise hemodynamic profiles, including higher PVR and altered upper limits of normal compared to younger cohorts.Underutilization of non‐invasive CPET in longitudinal follow‐up: Resource constraints and interpretive inconsistencies limit the sporadic use of non‐invasive CPET in longitudinal monitoring, with key metrics like the VE/VCO₂ slope remaining underutilized despite their established prognostic value. Although complication rates remain low at approximately 2–5 per 100,000 tests, implementation barriers to widespread CPET use continue to limit access.Limited adoption of invasive CPET: Barriers include unclear timing and frequency protocols, undefined exercise hemodynamic recovery thresholds, and perceived safety and access concerns. However, invasive CPET represents the gold standard for evaluating unexplained dyspnea and has demonstrated excellent safety profiles in specialized centers.Insufficient multicenter validation of non‐invasive CPET Non‐invasive surrogates, including oxygen uptake efficiency slope, dead‐space to tidal volume ratio, and peak oxygen pulse, require multicenter validation against invasive gold standards and clinical outcomes across heterogeneous populations. Age‐specific normative data are particularly lacking, limiting interpretation in older patients, where different hemodynamic responses to exercise are expected.Inadequate integration of CPET data with multimodal Integration of CPET with complementary modalities, such as cardiac MRI, echocardiographic strain, and circulating biomarkers, remains limited, with the additive prognostic value and ability to detect subclinical disease still uncharacterized. Recent advances in hybrid imaging techniques, such as simultaneous PET/MRI systems, offer promising opportunities for comprehensive assessment but require validation in clinical practice.
CO Reserve as a Marker of RV Functional Recovery
Rationale: CO reserve—defined as the increase in CO from rest to peak exercise—is a fundamental determinant of exercise capacity and a key physiological indicator of RV functional recovery. While resting hemodynamics may normalize with therapy, many patients continue to experience exertional symptoms due to inadequate CO augmentation during exercise [202, 203]. The magnitude of CO reserve reflects the integrated capacity of the RV to increase SV and HR in response to metabolic demand, and its restoration is a hallmark of meaningful reverse remodeling.
State of Knowledge: Cardiac Output Reserve and RV Recovery: In healthy individuals, CO increases approximately 3‐ to 4‐fold from rest to peak exercise (from ~5 L/min to 15–20 L/min), driven by increases in both SV ( ~ 50–70%) and HR (2‐ to 3‐fold) [202]. In patients with PAH, CO reserve is markedly impaired, with peak CO typically reaching only 8–12 L/min. This blunted response primarily reflects the inability of the RV to increase SV during exercise due to a combination of inadequate contractile reserve, excessive afterload, and diastolic dysfunction [202, 204].
Recent studies demonstrate that patients achieving RV functional recovery (RVFnRec)—defined by a decrease in RVEDV of ≥ 15 mL on cardiac MRI—exhibit significantly greater increases in SVI and CI at peak exercise compared to non‐recovered patients [203]. Specifically, RVFnRec patients Greater SV Peak SVI increased by 15–20 mL/m² versus 5–10 mL/m² in non‐recovered patientsHigher peak CI: Peak CI of 5.0–6.0 L/min/m² versus 3.5–4.5 L/min/m² in non‐recovered patientsPreserved RV‐PA coupling during Ees/Ea ratio remained > 0.8 during exercise versus progressive uncoupling (< 0.6) in non‐recovered patients [203, 205]Mechanisms of Impaired CO ReserveThe failure to augment CO during exercise in PAH reflects multiple In PAH, end‐systolic elastance (Ees) fails to increase appropriately during exercise, whereas healthy individuals demonstrate 50%–100% increases in Ees [134, 206]. This absent homeometric adaptation (contractility increase) necessitates reliance on heterometric adaptation (ventricular dilation via Frank‐Starling mechanism), which is less efficient [206]. As afterload (Ea) rises disproportionately during exercise while Ees remains flat, the Ees/Ea ratio declines, leading to dynamic RV–PA uncoupling and impaired SV augmentation [205, 207]. Studies show that RV‐PA uncoupling occurs as early as 50% of peak VO₂ in PAH patients [205]. Increased RV stiffness (elevated end‐diastolic elastance, Eed) and impaired ventricular interdependence limit RV preload augmentation, further constraining CO reserve [202].Distinguishing Expected versus Observed CO ResponseThe expected CO response during exercise can be estimated using metabolic (2)Expected CO(L/min)=VO2(CaO2−CvO2)×10. Where CaO₂ − CvO₂ reflects the arteriovenous O₂ content difference, typically widening from ~5 mL O₂/dL at rest to ~15 mL O₂/dL at peak exercise. Alternatively, normative CO reserve can be estimated based on Expected Peak CO (L/min) ~5 + (0.06 × peak workload in Watts)Patients with inadequate CO reserve (observed CO < 70% of expected) typically Excessively steep mPAP/CO slopes (> 5–6 mmHg·L⁻¹·min)Plateau or decline in SVI beyond low workloadsEarly dynamic RV‐PA uncoupling during iCPET [202]
Prognostic Significance: Multiple studies demonstrate that CO reserve is a powerful predictor of outcomes in PAH and related conditions [204]: Systemic sclerosis‐associated PAH: An increase in CI during exercise < 2 L/min/m² independently predicted mortality (HR: 3.2, 95% CI: 1.6–6.4; p < 0.001)General PAH Poor CO reserve (peak CI < 5.5 L/min/m²) was associated with increased mortalityPost‐PEA: Persistent impairment in CO reserve despite normalized resting hemodynamics correlated with persistent exertional dyspnea and reduced quality of life
Clinical Application: Assessing CO Reserve with iCPET:
iCPET allows direct, serial measurement of CO (via Fick or thermodilution) at rest and multiple stages of exercise. To assess RV functional recovery, clinicians should 1.Absolute CO Reserve: ΔCO = Peak CO − Resting CONormal: > 8–10 L/min; PAH with RVFnRec: 6–8 L/min; PAH without < 6 L/min 2.SV Augmentation: ΔSV = Peak SV − Resting SVNormal: +30–50 mL; PAH with RVFnRec: +15–30 mL; PAH without < 15 mL or negative 3.mPAP/CO Slope: Flattening of the mPAP/CO slope following therapy (e.g., from 8–10 to 4–6 mmHg·L⁻¹·min) suggests improved pulmonary vascular distensibility and restored capillary recruitment 4.Dynamic RV–PA Coupling: Maintenance of RV–PA coupling (Ees/Ea > 0.8) during exercise signals adequate RV contractile reserve
Knowledge Gaps Optimal thresholds for defining “adequate” CO reserve remain debated; age‐, sex‐, and body size‐adjusted normative values are lackingTime course for CO reserve restoration following antiproliferative therapies (e.g., sotatercept) is unknownMechanisms distinguishing patients who recover CO reserve from those who do not despite similar reductions in resting PVR require further investigationNon‐invasive surrogates for CO reserve (e.g., O₂ pulse trajectory) require validation against invasive measures
Consensus Recommendation: We recommend consideration of serial iCPET to quantify CO reserve at baseline and following therapy intensification in PAH patients. An increase in CO reserve (ΔCO > 2 L/min improvement from baseline) and restoration of SV augmentation (ΔSV > 15 mL) should be considered markers of RV functional recovery and may guide de‐escalation versus intensification of therapy. The CO reserve should be interpreted in conjunction with VO₂peak, VE/VCO₂ slope, and mPAP/CO slope to provide a comprehensive assessment of RV‐PA unit recovery.
*Unresolved mechanistic * CPET cannot distinguish whether functional improvements stem from RV contractility enhancement, pulmonary vascular recruitability, peripheral muscle conditioning, or metabolic adaptations. Addressing this limitation requires integrated studies combining molecular profiling, novel biomarkers, and advanced imaging to delineate the mechanisms driving RV recovery.
Consensus recommendations and future research directions: Standardize CPET Endpoints: Develop evidence‐based consensus thresholds—including submaximal indices—to define RV functional recovery across adult and pediatric PH populations. Such standardization should incorporate age‐stratified normative data to account for physiological variability across the lifespan. Current expert opinion suggests peak VO₂ > 15 mL/kg/min and VE/VCO₂ slope < 36 indicate satisfactory status.Expand Access to iCPET: Implement regional referral frameworks and standardized point‐of‐care safety protocols to broaden access to invasive cardiopulmonary testing while minimizing strain on tertiary care centers. Despite excellent safety profiles with complication rates of only 2–5 per 100,000 tests, access remains limited. Regional referral models, such as those implemented at specialized centers, have successfully performed thousands of cases across diverse patient populations.Validate Non‐Invasive Surrogates: Conduct multicenter head‐to‐head trials comparing VE/VCO₂ slope, oxygen uptake efficiency slope, and oxygen pulse against invasive pressure‐flow metrics to enable confident non‐invasive monitoring. Network analyses suggest that invasive hemodynamic variables offer additive prognostic value beyond non‐invasive measures alone.Create Integrated Prognostic Models: Utilize machine learning techniques to combine CPET outputs with imaging and biomarker data, generating individualized risk trajectories and therapeutic targets.Investigate Mechanistic Pathways: Pair longitudinal CPET with molecular and metabolic profiling to elucidate the biological underpinnings of observed functional recovery. Integrating circulating biomarkers and exercise variables through machine learning may yield superior prognostic accuracy compared to conventional single‐modality assessment modalities. This approach addresses the critical limitation that CPET cannot distinguish whether functional improvements stem from RV contractility enhancement, pulmonary vascular recruitability, peripheral muscle conditioning, or metabolic adaptations.
Reverse Remodeling of the Pulmonary Vasculature: PA–Capillary Recruitment
Rationale: The human pulmonary circulation has an extensive alveolar capillary network, with a surface area of approximately 70–85 m^2^ (equivalent to a tennis court) [208]. This extensive capillary network is critical for maintaining low PA pressures during exercise and preserving effective ventilation‐perfusion matching as pulmonary blood flow increases [63, 209, 210, 211].
*State of * At rest, a substantial portion of the pulmonary capillary bed remains underperfused [212]. When increasing pulmonary blood flow during exercise, accommodation occurs via progressive capillary recruitment, thereby exposing more functional capillary surface area (FCSA) [213, 214, 215]. During low to moderate flow increases, capillary recruitment predominates, while at higher flows approaching complete recruitment, capillary distention becomes the dominant mechanism [216, 217]. Once full recruitment is achieved, any further increase in blood flow is accommodated exclusively through capillary distention.
The transition from capillary recruitment to distention varies across mammalian species and is influenced by factors such as blood rheology, gravitational effects, and alveolar pressures [218]. Studies in rabbits, dogs, and humans demonstrate that capillary distension becomes the primary mechanism of flow accommodation at increases ranging from 2.5 to 3.7 times the resting level [216, 217, 219, 220, 221].
PAH causes vascular cellular proliferation and remodeling, resulting in luminal narrowing of upstream precapillary pulmonary arterioles [222, 223]. This leads to heterogeneous capillary perfusion distribution, with some underperfused areas, while others are fully recruited and distended to accommodate increasing CO [223, 224]. In the limited number of patients studied, further pulmonary capillary recruitment during exercise is trivial (Langleben and Orfanos, unpublished data) due to fixed upstream arteriolar remodeling. This restricted expansion of FCSA leads to abnormal ventilation‐perfusion matching, as indicated by increased dead space ventilation and a steeper PA pressure‐flow slope during exercise [79].
Until recently, PAH therapies included phosphodiesterase‐5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, and prostanoids, which primarily function as vasodilators. These agents primarily enhance blood flow through less severely remodeled precapillary arterioles. However, they have minimal impact on reversing obstruction in severely remodeled vessels [225, 226] and reduce calculated PVR mainly by increasing pulmonary blood flow rather than significantly decreasing pulmonary arterial pressure. In these severely remodeled vessels, blood flow increases little, resulting in minimal recruitment of downstream capillaries. Instead, increased flow is primarily accommodated through distention of already perfused capillaries, both at rest and during exercise [227]. This results in an abnormally steep pressure/flow relationship (Figure D, panel A).
During acute vasodilator responses in patients with idiopathic PAH, many exhibit marked reductions in PVR with only minor reductions in PAP, and without significant increases in perfused capillary surface area [227]. This pattern suggests that current vasodilator therapies act mainly by distending already perfused vessels rather than by recruiting new capillary beds.
Novel antiproliferative therapies, such as sotatercept, offer potential to reverse cellular obstruction in PAH‐affected arterioles, potentially restoring pulmonary vascular physiology toward normal. These therapies should decrease resting PVR mainly by lowering pulmonary arterial pressure, while CO may increase or remain unchanged (Figure C). The recent Phase‐3 trial of sotatercept (STELLAR) is the first demonstration of the effectiveness of an antiproliferative therapy in PAH [228]. During exercise, newly reopened arterioles are expected to facilitate recruitment of the extensive downstream capillary network. Indeed, the SPECTRA study using iCPET before and after sotatercept treatment demonstrated a trend toward flattening of the PAP/CO slope, consistent with partial restoration of capillary recruitment (Figure D, panels B and C) [197].
In PAH, characterized by a reduced capillary bed, complete recruitment of most remaining perfused capillary segments occurs under normal blood flow conditions. Their subsequent distention in response to increased flow may offer empirical support for mathematical models of pulmonary vascular distensibility. This model assumes fully recruited lungs and encompasses compliances of the successive arteriolar, capillary, and venular portions of the pulmonary circulation's resistive segments [219, 229].
By addressing the underlying structural abnormalities, these treatments could enable proper capillary recruitment during exercise, representing a fundamental shift from symptomatic management to restoration of normal pulmonary vascular function. This therapeutic paradigm aligns with mathematical models of pulmonary vascular distensibility, offering a conceptual framework for how structural improvements in PAH may translate into functional restoration of the pulmonary circulation's capacity to accommodate varying blood flow demands.
*Knowledge *
Measurement and Assessment Methods: There is currently no standardized or clinically practical method for measuring pulmonary capillary recruitment or for distinguishing recruitment from distention mechanisms using exercise‐specific biomarkers in routine practice.Antiproliferative Therapy Efficacy: Direct evidence demonstrating restoration of capillary recruitment with sotatercept and other antiproliferative agents is lacking, and the thresholds for pulmonary arterial pressure reduction required to achieve this remain undefined.Mechanistic and Temporal Understanding: Limited knowledge of the time course for capillary recruitment restoration, the relationship between pulmonary vascular and right heart reverse remodeling, and which specific forms of vascular remodeling are reversible versus permanently lost.Patient Selection and Predictive Factors: It remains unclear which PAH patient subgroups are most likely to benefit from antiproliferative therapy in terms of capillary recruitment restoration, particularly given the uncertain influence of disease duration, baseline hemodynamics, and genetic predispositions on reversibility.Clinical Integration and Monitoring: Lack of standardized protocols for incorporating capillary recruitment assessment into PAH risk stratification, treatment monitoring, and clinical decision‐making, with unclear biomarker‐structure‐function relationships.Research Infrastructure and Validation: Need for multicenter standardization of assessment protocols, longitudinal studies tracking capillary recruitment patterns from early disease through treatment, and development of clinically feasible methods for widespread implementation.It remains unclear which invasive (e.g, pressure‐flow relationships, dead space ventilation) and non‐invasive metrics (e.g., Ve/VCO2, PetCO2) most accurately reflect pulmonary capillary recruitment.
Consensus recommendations and future research directions: Disease Progression Studies: Conduct systematic multicenter prospective studies to investigate pulmonary capillary recruitment patterns across the full spectrum of PAH severity, aiming to establish recruitment capacity thresholds that correlate with WHO functional class and REVEAL risk scores, while utilizing standardized FCSA measurements to detect early vascular remodeling.Longitudinal Assessment: Establish comprehensive 5–10‐year longitudinal cohorts with standardized assessment protocols to characterize the natural history of capillary recruitment loss and restoration potential, implementing serial evaluations using both invasive and non‐invasive methodologies while developing predictive models for rapid recruitment capacity loss.Non‐Invasive Imaging Technology: Accelerate development and clinical validation of real‐time capillary recruitment assessment techniques, including hyperpolarized 129Xe MRI/MRS for pre/post‐capillary PH distinction, contrast‐enhanced cardiac MRI protocols for exercise stress testing, refined exercise echocardiography, and AI‐integrated automated analysis algorithms.Antiproliferative Therapy Assessment: Design targeted clinical trials to evaluate capillary recruitment restoration with antiproliferative therapies, incorporating detailed recruitment endpoints, investigating underlying molecular pathways, optimizing dosing strategies, and assessing the impact of combination therapies and exercise‐induced physiologic responses.Mathematical Model Validation: Conduct systematic validation studies of the pulmonary vascular distensibility coefficient model across diverse PAH populations, implementing standardized iCPET calculator tools for reproducible measurements, refining models with recruitment‐specific parameters, and validating predictions against direct FCSA measurements and clinical outcomes.Exercise Training Optimization: Investigate the synergistic effects of structured exercise training on capillary recruitment restoration in patients receiving antiproliferative therapies, by exploring mechanistic pathways involving endothelial function and angiogenesis, optimizing intervention timing, personalizing exercise prescriptions, and conducting randomized controlled trials comparing combination therapy to monotherapy.
The task force recommends standardized invasive CPET protocols across centers to ensure consistent results, including standardization of body position, respiratory swing interpretation, and data analysis. Clearer guidelines on patient selection and clinical indications are essential, given the limited availability of large‐scale safety data in PH—despite iCPET demonstrating a favorable safety profile in experienced centers. These consensus recommendations will advance iCPET utilization in diagnosing, risk‐stratifying, and managing PVD, providing a roadmap for future research and clinical practice.
PVRI Exercise and RV Function Task Force Consensus Recommendations for iCPET:
Core Recommendations 1.Protocol Standardization: Establish uniform iCPET protocols across institutions to ensure accuracy and reproducibility. Standardization will reduce operator‐dependent variability and enhance data quality in both clinical and research settings.2.Technical Optimization and Catheter Selection: Research Standard: High‐fidelity micromanometer‐tipped catheters are recommended for research protocols, particularly those analyzing pressure‐volume loops, wave intensity, or instantaneous pressure‐flow relationships, as they eliminate ‘whipping’ artifacts and preserve frequency response at high HRs.Clinical Standard: For routine clinical iCPET, fluid‐filled catheters remain acceptable due to cost‐effectiveness and widespread availability. To mitigate resonance artifacts and under‐damping common during vigorous exercise, we Meticulous zero‐leveling at the phlebostatic axis.Use of stiff, short pressure tubing.Averaging pressures over ≥ 3 respiratory cycles (or 10–15 s) rather than relying on instantaneous automated values.Acknowledging that systolic/diastolic extremes may be less accurate than mean pressures in fluid‐filled systems during high‐output states.” 3.Early PH Diagnosis: Employing iCPET may contribute to earlier detection of PH by identifying exercise‐induced hemodynamic abnormalities and objectively measuring peak exercise capacity.4.Advanced Technology Integration: Incorporate molecular phenotyping and “omics” approaches in iCPET studies to enhance understanding of pathomechanistic processes underlying PH and related conditions.5.Continuous Protocol Refinement: Prioritize ongoing consensus‐building to keep iCPET at the forefront of cardiopulmonary diagnostics while enabling subgroup analyses and precise treatment response evaluation.
Multicenter Data Repository Initiative
The task force recommends the creation of a multicenter, prospective data repository to collect standardized iCPET data across PH populations. This initiative will provide comprehensive safety data, identify risk factors for complications, enable the development of risk stratification tools, and standardize protocols across centers.
This repository approach will enhance patient selection, optimize clinical trial design, refine diagnostic thresholds for exercise‐induced PH, and support earlier, data‐driven decision‐making in both research and practice.
Conclusion
This comprehensive PVRI Exercise Task Force statement addresses critical knowledge gaps in iCPET for PVD assessment, establishing a foundation for advancing both clinical practice and research in this field. The task force emphasizes that while iCPET holds strong potential for early detection, risk stratification, and evaluation of RV–pulmonary arterial coupling in PVD, widespread implementation requires urgent protocol standardization to ensure data consistency and reproducibility. Key findings demonstrate that iCPET appears safe across the spectrum of PVD when performed in experienced centers, with exercise hemodynamic parameters such as the mPAP/CO slope showing robust prognostic relevance. The statement highlights substantial opportunities to leverage iCPET in the era of disease‐modifying therapies, especially for assessing reverse remodeling of the pulmonary arteries and RV. To propel the field forward, the task force recommends building multicenter data repositories, integrating molecular phenotyping with exercise hemodynamic profiling, standardizing protocols for body positioning and respiratory influence, and designing frameworks for individualized treatment strategies. By addressing these research priorities through coordinated international collaboration, the field can realize the full potential of exercise testing to transform the diagnosis, risk stratification, and management of patients with PVD, ultimately improving clinical outcomes through more precise, evidence‐based therapeutic approaches.
Author Contributions
Franz P. Rischard, Aaron B. Waxman, Abraham Babu, Roberto Badagliacca, Eloara Ferreira, Patty George, Darlene Kim, Gabor Kovacs, Saad Kubba, David Langleben, Thais Menezes, Rudolf Oliveira, Stylianos Orfanos, Inderjit Singh, and David Systrom: manuscript design. Franz P. Rischard, Aaron B. Waxman, and David Systrom: data collection, maintenance, and analysis. Franz P. Rischard: statistical analysis. Franz P. Rischard and Aaron B. Waxman: drafted the original manuscript. All Authors: critical revision of the manuscript for important intellectual content. All Authors: principal investigator, had access to the study data and take full responsibility for the integrity and accuracy of the data.
Funding
The authors received no specific funding for this work.
Disclosure
This analysis is exempt from ethical approval as it is not primary research but an interpretation of existing data. Dr. Franz Rischard accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.
Conflicts of Interest
Dr. Waxman as relationships with the following—Consultant/steering United Therapeutic, Acceleron/Merck, ARIA‐CV, Pulmovant, Tectonic, Research OrphAI, DSMB Chair: INSMED; Dr. Babu has no conflicts to declare; Dr. Badagliacca has scientific consultations from Msd, Janssen, UT, Ferrer, Dompe, Aop, Gossamer bio, Pulmovant; Dr. Ferreira has consulting and sponsored travel from Bayer, Johnson & Johnson, Brasil; Dr. George has relationships Merck—Medical Advisory Boards, Janssen—Speaker (non‐branded talks) and Advisory Boards, United Therapeutics—Speaker (non‐branded talks) and Advisory Boards, Steering Committee; Liquidia—Speaker (non‐branded talks) and Advisory Boards, Steering Committee; Bayer—Speaker (non‐branded talks); Gossamer—Advisory Boards; Team PHenomenal Hope (nonprofit)—Board Member and Medical Advisory Committee member; Dr. Guazzi has no conflicts to declare; Dr. Howard has stock in Calibre Biometrics; Dr. Kovacs has received grants from Johnson & Johnson, Boeh; Dr. Kovacs received grants from Johnson & Johnson, Boehringer‐Ingelheim, and the European Respriratory Society, He has received consulting fees from MSD, Boehringer‐Ingelheim, AOP Orphan, United Therapeutics, Ferrer, Chiesi, Johnson & Johnson, and Lequidia, he has participated in DSMB for MSD, Boehringer‐Ingelheim, Ferrer, AOP Orphan, Liquidia, United Therapeutics and Johnson and & Johnson; Dr. Kubba has nothing to declare; Dr. Langleben has the following conflicts to report Consultancy/Advisory Board: Acceleron/Merck, Actelion/Janssen, Bayer, Novartis, Speaker Honoraria: Bayer, Merck, Janssen Funded Grants or Clinical Trials: Acceleron/Merck, Janssen; Dr. McCabe has no relevant conflicts to report; Dr. Menezes has nothing to report; Dr. Oliveira has the following potential conflicts Bayer HealthCare, Johnson & Johnson, and MSD‐Brasil‐Personal fees, Sponsored travel and Advisory boards; Dr. Orfanos has the following conflicts to report fees for lectures and/or consultation from ELPEN, Ferrer‐Galenica, GSK, Johnson and Johnson, MSD, and United Therapeutics; Dr. Singh has no conflicts to report; Dr. Systrom has no conflicts to report; Dr. Tedford reports no disclosures relevant to this manuscript. Dr. Tedford is Deputy Editor for the Journal of Heart and Lung Transplantation. He reports general disclosures to include consulting relationships with and receiving honorarium/consulting fees from Abbott, Acorai, Adona, Aria CV Inc., Acceleron, Boston Scientific, CVRx, Endotronix, Edwards LifeSciences, Fauna Bio, Gradient, Imbria, Medtronic, Merck, Morphic Therapeutics, Pulmovant, Restore Medical, Tempus AI, and United Therapeutics. Dr. Tedford serves on steering committees for Abbott, Edwards, Endotronix, Gradient, Merck and Tempus AI as well as a research advisory board for Abiomed; Dr. Vanderpool has no relevant conflicts to report; Dr. Dario Vizza has has scientific consultations from Msd, Janssen, UT, Ferrer, Dompe, Aop, Gossamer bio, Pulmovant; Dr. Rischard has research/grant support from NIH/NHLBI, United Therapeutics, Johnson and Johnson, Merck, Bayer, OrphAI, Tenax.