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Cardiopulmonary Exercise Testing (CPET) is the gold standard for the functional assessment in patients with heart failure (HF), providing objective parameters that reflect the integrated response of the cardiovascular, respiratory, and muscular systems, in addition several CPET-derived variables have shown independent prognostic value in patients with both reduced (HFrEF) and preserved ejection fraction (HFpEF) HF. This review aims to critically analyze the main CPET prognostic variables in heart failure, highlighting their underlying pathophysiological mechanisms, their predictive capacity for mortality and hospitalizations, and their integration into clinical decision-making models. Parameters such as peak oxygen uptake (VO2), minute ventilation/carbon dioxide production (VE/VCO2) slope, periodic breathing (or exercise oscillatory ventilation—EOV), anaerobic threshold (AT), oxygen pulse, and VO2/work slope provide complementary insights into clinical risk; moreover, the combination of multiple CPET variables allows for more accurate risk stratification compared to the isolated use of each parameter. Multiparametric prognostic models such as the Metabolic Exercise Cardiac Kidney Index (MECKI) score, the Seattle Heart Failure Model, and the Heart Failure Survival Score (HFSS) incorporate these variables alongside clinical and laboratory data to guide advanced management and therapeutic decisions, including heart transplantation or left ventricular assistant device (LVAD) implantation. For these reasons, CPET-derived variables are essential prognostic tools in heart failure. Beyond improving risk stratification, their integration into multiparametric models supports a more personalized therapeutic approach, including tailored pharmacological management.

ObjectivesIron deficiency (ID) is frequent in heart failure (HF). Among patients with HF and ID, those with impaired iron transport (IIT) (transferrin saturation (TSAT) <20%) have the worst ID phenotype. In HF, exercise limitation is mainly related to abnormality in oxygen delivery (VO2) and utilisation and/or to ventilation inefficiency. We evaluated whether it is possible to identify the leading cause of exercise limitation in patients with HF and IIT.DesignObservational study.SettingRetrospective study.ParticipantsWe analysed 1043 consecutive hospitalised patients with HF (66±14 years, 49.8% females) who underwent cardiopulmonary exercise test (CPET).Outcome measuresAssociations between CPET parameters and TSAT were explored using general linear models adjusted for potential confounders (haemoglobin, left ventricle ejection fraction, age, gender, C reactive protein, serum creatinine).ResultsWe observed that: (a) 413 patients with HF and IIT had worse functional capacity compared with non-IIT cases: peak VO2 (15±3 vs 16±6 mL/min/kg, p<0.0001) and ventilation/carbon dioxide relationship (VE/VCO2) slope (38±9 vs 33±8, p<0.0001); (b) VE/VCO2 values remained significantly different between IIT and non-IIT cases after adjusting for confounding variables including peak VO2; differently, peak VO2 after adjusting also for VE/VCO2 slope, resulted not different in IIT compared with non-IIT HF cases; (c) patients with both low peak VO2 (<14 mL/min/kg) and high VE/VCO2 (≥34) had a higher B-type natriuretic peptide (BNP), lower TSAT and higher MECKI (Metabolic Exercise combined with Cardiac and Kidney Index) score compared with patients with high peak VO2 and low VE/VCO2 (BNP 951±1041 vs 413±623 pg/mL (p<0.0001); TSAT 19.5%±10.5% vs 26.9%±10.2% (p<0.0001); MECKI score 14.8%±1.4% vs 1.2%±2.3% (p<0.0001).ConclusionsHigh VE/VCO2 slope is directly associated with IIT, independent of peak VO2, suggesting a pivotal role for ventilation inefficiency in exercise impairment in patients with IIT and HF. In patients with HF, the worst exercise performance is associated with low TSAT, high BNP and the highest MECKI score.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis if left untreated. Despite remarkable achievements in understanding disease pathophysiology, specific treatments, and therapeutic strategies, we are still far from a definitive cure for the disease, and numerous evidences have underlined the importance of early diagnosis and treatment to improve the prognosis. Cardiopulmonary exercise testing (CPET) is the gold standard for assessing functional capacity and evaluating the pathophysiological mechanisms underlying exercise limitation. As effort dyspnea is the earliest and one of the main clinical manifestations of PAH, CPET has been shown to provide valid support in early detection, differential diagnosis, and prognostic stratification of PAH patients, being a useful tool in both the first approach to patients and follow-up. The purpose of this review is to present the current applications of CPET in pulmonary hypertension and to propose possible future utilization to be further investigated.

Pulmonary arterial hypertension (PAH) is a rare condition characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. It primarily affects the pre-capillary pulmonary vascular system. The exact pathophysiological mechanisms underlying PAH are not entirely known. Environmental factors; genetic predisposition; mitochondrial and microRNA dysfunction; and inflammatory, metabolic, and hormonal mechanisms may be involved. A central role is played by the dysfunction of the pulmonary vascular endothelium. This alteration is characterized by a reduction in vasodilatory and antiproliferative factors such as prostacyclin and nitric oxide and an increase in vasoconstrictive and mitogenic substances such as endothelin and thromboxane A2. Such imbalance leads to a progressive increase in pulmonary vascular resistance. The aim of the present review is to focus on the vascular endothelium and its role as a potential therapeutic target in PAH.

Acute myocarditis (AM) is an inflammatory cardiac condition resulting from infections, toxic exposures, or immune-mediated mechanisms, with clinical presentations ranging from mild symptoms to heart failure (HF) or cardiogenic shock. Although viral infections remain the predominant cause, both the absolute prevalence and the relative distribution of different etiologies may change over time and across regions depending on endemic diseases. Immune checkpoint inhibitor (ICI)-associated myocarditis has emerged as a newly recognized entity, with diagnostic rates increasing in parallel with growing awareness and the expanding population of cancer patients eligible for ICI therapy. Additionally, genetic predisposition—particularly mutations linked to arrhythmogenic cardiomyopathy—is also being increasingly acknowledged as a susceptibility factor. Recent advances have markedly improved the diagnostic approach to AM. The availability of high-sensitivity cardiac troponins and the widespread use of cardiac magnetic resonance imaging (CMRI) have enhanced early detection and tissue characterization. CMRI, especially following the updated Lake Louise Criteria (2018), which incorporate T1 and T2 mapping, enables accurate assessment of myocardial inflammation and fibrosis. Endomyocardial biopsy (EMB) remains essential in complicated cases, particularly to identify histologic subtypes that may benefit from immunosuppressive therapy. Early EMB (within 48 h) has been associated with better outcomes in fulminant presentations. The use of immunohistochemistry with leukocyte-specific markers has further increased the sensitivity of EMB. Therapeutic strategies now integrate etiology-specific approaches. Immunosuppressive therapy is indicated for distinct histological forms such as eosinophilic (EM) and giant cell myocarditis (GCM) or cases associated with systemic autoimmune disease. Conversely, in most patients with acute myocarditis complicated by acute HF or cardiogenic shock, no specific treatment is currently recommended beyond evidence-based management of acute HF and general supportive therapy.

Evaluation of arterial carbon dioxide pressure (PaCO2) and dead space to tidal volume ratio (VD/VT) during exercise is important for the identification of exercise limitation causes in heart failure (HF). However, repeated sampling of arterial or arterialized ear lobe capillary blood may be clumsy. The aim of our study was to estimate PaCO2 by means of a non-invasive technique, transcutaneous PCO2 (PtCO2), and to verify the correlation between PtCO2 and PaCO2 and between their derived parameters, such as VD/VT, during exercise in HF patients. 29 cardiopulmonary exercise tests (CPET) performed on a bike with a ramp protocol aimed at achieving maximal effort in ≈10 min were analyzed. PaCO2 and PtCO2 values were collected at rest and every 2 min during active pedaling. The uncertainty of PCO2 and VD/VT measurements were determined by analyzing the error between the two methods. The accuracy of PtCO2 measurements vs. PaCO2 decreases towards the end of exercise. Therefore, a correction to PtCO2 that keeps into account the time of the measurement was implemented with a multiple regression model. PtCO2 and VD/VT changes at 6, 8 and 10 min vs. 2 min data were evaluated before and after PtCO2 correction. PtCO2 overestimates PaCO2 for high timestamps (median error 2.45, IQR −0.635–5.405, at 10 min vs. 2 min, p-value = 0.011), while the error is negligible after correction (median error 0.50, IQR = −2.21–3.19, p-value > 0.05). The correction allows removing differences also in PCO2 and VD/VT changes. In HF patients PtCO2 is a reliable PaCO2 estimation at rest and at low exercise intensity. At high exercise intensity the overall response appears delayed but reproducible and the error can be overcome by mathematical modeling allowing an accurate estimation by PtCO2 of PaCO2 and VD/VT.

In hypertrophic cardiomyopathy (HCM), cardiopulmonary exercise testing (CPET) is considered the gold standard for assessing exercise tolerance, with O 2 -pulse commonly used as a surrogate for stroke volume (SV). However, because SV reduction can be masked by increased oxygen extraction, direct non-invasive measurement of SV is valuable. This study involved 102 HCM patients (mean age 53 ± 16 years, 78% male), predominantly with a non-obstructive phenotype (74%), who underwent CPET with SV measurement using Physioflow (PF). Abnormal O 2 -pulse kinetics were observed in 12 patients, all confirmed by abnormal SV trends with PF. Additionally, PF identified another 28 patients with altered SV kinetics. Abnormal SV trends were associated with higher peak VE/VO 2 ratios (42.6 [37.4–47.5] vs. 38.0 [33.6–41.3]) and lower end-tidal CO 2 values (31.8 ± 4.9 vs. 34.3 ± 5.6 mmHg, p  < 0.05). Patients with greater SV growth during the final 25% of exercise showed improved anaerobic threshold VO 2 (49.8 ± 12.3% vs. 43.9 ± 15.2% predicted peak VO 2 ), VO 2 /work slope (10.2 ± 2.0 vs. 9.3 ± 1.3 mL/min/Watt), and peak PetCO 2 (34.5 ± 5.6 vs. 32.3 ± 5.2 mmHg), alongside a lower VE/VCO 2 slope (28.7 [24.9–31.0] vs. 31.3 [27.3–34.2], p  < 0.05). Integrating PF and CPET may enhance the detection of abnormal SV kinetics, which are associated with reduced functional capacity in HCM patients.

BackgroundCurrent guidelines recommend evaluating patients with ambulatory heart failure (HF) for heart transplantation if their peak oxygen consumption (peak VO2) is <12 mL/kg/min. However, these recommendations are based on decades-old data.MethodsWe retrospectively analysed 8060 patients with ambulatory HF with cardiopulmonary exercise testing (CPET) data. The primary analysis focused on 1218 patients with left ventricular ejection fraction <40% and peak VO2 <12 mL/kg/min, enrolled between 2010 and 2022. Survival outcomes (composite of death/left ventricular assist device/heart transplantation) were compared with those of heart transplantation recipients from the International Society for Heart and Lung Transplantation registry. Patients were stratified by ventilatory efficiency (ventilation versus CO2 production slope (VE/VCO2) >34 vs ≤34) and presence of exercise oscillatory ventilation. Survival analyses were performed using Kaplan-Meier curves compared with log-rank tests and Cox proportional hazards models, with heart transplantation survival curves reconstructed from aggregate data.ResultsPatients with peak VO2 <12 mL/kg/min demonstrated better survival than heart transplantation recipients, with survival curves intersecting at approximately 2.7 years. Among those with VE/VCO2 ≤34, 10-year mortality risk was halved (p<0.01), with survival curves crossing those of heart transplantation recipients around year 4. Absence of exercise oscillatory ventilation was similarly associated with a 50% lower long-term mortality. Combining VE/VCO2 and exercise oscillatory ventilation identified four distinct risk groups with significantly different 10-year outcomes (p<0.01). Patients with peak VO2 <12 mL/kg/min, VE/VCO2 ≤34 and no exercise oscillatory ventilation exhibited survival comparable to heart transplantation recipients at year 5.ConclusionsIn contemporary practice, a peak VO2 <12 mL/kg/min alone may not reliably identify patients with HF with sufficiently high short-term mortality to warrant heart transplantation referral. VE/VCO2 and exercise oscillatory ventilation provide important additional risk stratification, supporting re-evaluation of transplant referral criteria to reflect improved HF management and outcomes.

The mechanisms underlying the effects of dapagliflozin in heart failure with reduced ejection fraction (HFrEF) are not yet fully understood. This study aims to evaluate the effect of the drug on cardiorespiratory function by assessing alveolar–capillary membrane characteristics, sleep apnea, pulmonary and cardiac performance in stable HFrEF patients. Seventy-three patients with stable HFrEF were enrolled, with 66 completing the six-month follow-up. Analyses included assessment of the alveolar–capillary membrane by diffusion capacity, including its membrane diffusion and capillary volume components and measurements of proSP-B in the blood, an emerging biomarker of alveolar–capillary membrane function. Pulmonary function tests, overnight respiratory monitoring, and echocardiographic parameter collection were also conducted. After 6 months, a reduction in circulating proSP-B levels was observed (32.65 ± 13.36 at baseline vs. 30.86 ± 12.45 AU at 6 months, p for trend 0.0092), accompanied by improvements in echocardiographic parameters (left ventricle ejection fraction and pulmonary pressures). Pulmonary function tests and overnight respiratory monitoring showed no significant changes in lung diffusion, spirometry, or obstructive sleep apnea (apnea hypopnea index from 5.0 [1.1–16.6] at baseline to 6.2 [0.7–13.8]/h; p = n.s.). A significant reduction in central sleep apnea (CSA) was noted in the 13 patients with at least one CSA at baseline (15 [3–48] vs. 0 [0–18.5]/h, p = 0.017). Dapagliflozin demonstrates both hemodynamic and non-hemodynamic effects, particularly improving alveolar–capillary membrane function. This study highlights the multifactorial benefits of dapagliflozin in patients with stable HFrEF and the potential of proSP-B as a sensitive marker for evaluating therapeutic response.

AimsCardiopulmonary exercise testing (CPET) parameters are used for heart failure (HF) prognostication. While the ventilation to carbon dioxide production (VE/VCO2) slope ≥34 identifies high risk, patients with intermediate values remain heterogeneous. The VE/VCO2 Y-intercept, reflecting dead space ventilation at rest and its changes during effort, may refine prognostication.MethodsWe retrospectively analysed 2642 HF. Follow-up was 26 (9–63) months. The study endpoint was the composite of all-cause death, urgent transplant or left ventricular assist device implantation.ResultsMedian age was 62 (53–70) years and left ventricular ejection fraction (LVEF) 33% (27%–39%). 27% of patients were New York Heart Association class III–IV. During follow-up, 534 events occurred. Both VE/VCO₂ slope and peakVO₂ were associated with outcome in univariable and multivariable models (HR 1.04, 95% CI 1.03 to 1.06; HR 0.90, 95% CI 0.88 to 0.93, p<0.001, respectively). Y-intercept was not prognostic univariately but added independent value in multivariable models (HR 1.08, 95% CI 1.04 to 1.13, p<0.001). Prognosis and clinical profiles improved from group A (VE/VCO2 slope ≥34, n=858) to B (28–34, n=943) to C (<28, n=841). Group A versus C patients had lower LVEF (30% (25%–36%) vs 35% (30%–40%), ptrend<0.001), peakVO₂ (12.7 (10.06–15.3) vs 17.7 (14.6–21.6) mL/kg/min, ptrend<0.001) and higher N-terminal pro-B-type natriuretic peptide (1400 (572–3122) vs 454 (174–1081) pg/mL, ptrend<0.001). Only within group B, a high median Y-intercept (B1≥3.9 L/m) clearly identified patients with higher HF severity and worse survival than B2 (<3.9 L/m, log-rank p<0.001).ConclusionAn increase in the VE/VCO2 slope is associated with a progressive lower survival. Y-intercept enhances risk assessment in HF with intermediate VE/VCO₂ slope values.