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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.

Nasal and oral exclusive breathing modes have benefits and drawbacks during submaximal exercise. It is less known whether these responses would extend to anaerobic work performed at high intensity. The purpose of this study is to find the most efficient mode of breathing during different phases of a maximal exercise at cardiopulmonary exercise test (CPET). Healthy subjects were recruited to perform 4 maximal CPETs (standard conditions (STD), exclusively nasal breathing (eNAS), exclusively oral breathing (eOR), partial nasal breathing (pNAS) with just one blocked nostril) using the same ramp protocol on an electronically braked cycle ergometer. Before the exercise a standard spirometry was executed in the same order. Twelve healthy subjects (28.6 ± 5.2 y, 50% males) performed the 4 CPETs within one month. Variables were analysed at rest, at anaerobic threshold (AT), at intermediate exercise steps, and at peak. Compared to STD, eOR, and pNAS conditions, eNAS was associated with a significant lower peakVO2, peakVCO2, peak ventilation, respiratory rate, VE/VCO2 slope, respiratory exchange ratio, and workload (p < 0.05 for all). Moreover, peak inspiration and peak expiration time were augmented, while forced expiratory volume and vital capacity at rest were reduced. Only minor differences were detected at rest or AT. eNAS breathing Borg scale was higher in all phases of the exercise. In young healthy subjects, an exclusively nasal respiration induces significant impairment on peak exercise capacity at CPET due to ventilatory limitation, with only minor effects on metabolic parameters at rest and in submaximal effort.

Background Post COVID-19 syndrome is characterized by several cardiorespiratory symptoms but the origin of patients’ reported symptomatology is still unclear. Methods Consecutive post COVID-19 patients were included. Patients underwent full clinical evaluation, symptoms dedicated questionnaires, blood tests, echocardiography, thoracic computer tomography (CT), spirometry including alveolar capillary membrane diffusion (DM) and capillary volume (Vcap) assessment by combined carbon dioxide and nitric oxide lung diffusion (DLCO/DLNO) and cardiopulmonary exercise test. We measured surfactant derive protein B (immature form) as blood marker of alveolar cell function. Results We evaluated 204 consecutive post COVID-19 patients (56.5 ± 14.5 years, 89 females) 171 ± 85 days after the end of acute COVID-19 infection. We measured: forced expiratory volume (FEV 1 ) 99 ± 17%pred, FVC 99 ± 17%pred, DLCO 82 ± 19%, DM 47.6 ± 14.8 mL/min/mmHg, Vcap 59 ± 17 mL, residual parenchymal damage at CT 7.2 ± 3.2% of lung tissue, peakVO 2 84 ± 18%pred, VE/VCO 2 slope 112 [102–123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV 1 , Vcap and high VE/VCO 2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO 2 slope and low PeakVO 2 and FEV 1 while fatigability with high VE/VCO 2 slope. SPB was fivefold higher in post COVID-19 than in normal subjects, but not associated to any of the referred symptoms. SPB was negatively associated to Vcap. Conclusions In patients with post COVID-19, cardiorespiratory symptoms are linked to VE/VCO 2 slope. In these patients the alveolar cells are dysregulated as shown by the very high SPB. The Vcap is low likely due to post COVID-19 pulmonary endothelial/vasculature damage but DLCO is only minimally impaired being DM preserved.

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.

Background: Sodium/glucose cotransporter-2 inhibitors (SGLT2is), such as dapagliflozin and empagliflozin, are currently a standard therapy for heart failure (HF) patients. We report the real-world use of SGLT2is in a monocentric cohort of HF patients with reduced ejection fraction (HFrEF) and improved ejection fraction (HFimpEF), comparing patient characteristics and outcomes with those observed in large-scale randomized clinical trials (RCTs). Methods: We retrospectively analyzed a cohort of 370 stable patients with HFrEF or HFimpEF who initiated therapy with dapagliflozin or empagliflozin between June 2019 and November 2023. Baseline data, including medical history, concomitant diseases, therapy, laboratory tests, echocardiographic results and cardiopulmonary exercise tests (CPETs), were collected at the start of the therapy with SGLT2is. After a median period of 18 months, follow-up data on treatment adherence, adverse events, hospitalizations, and mortality were also reviewed. A comparison was made between patients taking dapagliflozin and those taking empagliflozin and then individual populations were compared with those from the trials. Results: Among 370 patients (81% HFrEF, 19% HFimpEF), 276 received dapagliflozin and 94 empagliflozin. Empagliflozin patients were older, had higher NYHA class and LVEF, and higher incidence of diabetes, while dapagliflozin users had greater use of sacubitril/valsartan and mineralocorticoid receptor antagonists. Both groups were older than the RCT cohorts. Dapagliflozin patients had LVEF comparable to DAPA-HF, while empagliflozin patients had higher LVEF than EMPEROR-Reduced. HF hospitalizations were more frequent in the real-world groups, but mortality was lower than in RCTs. The composite outcome of death and worsening HF was higher in the real-world dapagliflozin cohort vs. DAPA-HF but similar between the real-world empagliflozin cohort and EMPEROR-Reduced. Conclusions: In this real-world cohort, the use of empagliflozin was associated with cardio-nephro-metabolic comorbidities and dapagliflozin being prescribed more frequently for patients with isolated cardiac symptoms. While outcomes were generally favorable, they differed from those seen in RCTs, highlighting the importance of real-world data in understanding the practical application of these therapies.

In cardiac amyloidosis (CA) cardiopulmonary exercise testing (CPET) is underexplored. This study evaluated exercise limitations in CA using CPET, focusing on the ventilation‐to‐carbon dioxide production (VE/VCO2) slope and peak oxygen uptake (VO2). Seventeen studies involving 1505 patients were analyzed and systematically reviewed according to PRISMA reporting guidelines. Subgroup analyses assessed differences by diagnosis (ATTR vs. AL), CPET modality, and age. The cohort included 12% with AL, 80% with ATTR (23% hereditary [ATTRv], 70% wild‐type [ATTRwt], 7% unspecified), and 8% unidentified subtypes. VE/VCO2 slope was elevated across ATTR subgroups: 38.4 (95% CI: 36.9–40.0, I2 = 57%) in ATTRwt and 37.9 (95% CI: 35.1–40.7, I2 = 70%) in ATTRv. ATTR patients were older than AL patients by 9.0 years (95% CI: 0.4–17.6, I2 = 88%) and had a higher VE/VCO2 slope: 2.5 (95% CI: 0.2–4.8, I2 = 0%). CPET modality influenced peak VO2, which was lowest for treadmill exercise (13.7, 95% CI: 12.7–14.8, I2 = 0%, mL/min/kg) compared to upright cycle ergometry (14.7, 95% CI: 14.3–15.1, I2 = 33%) and semi‐recumbent cycle ergometry (14.5, 95% CI: 14.1–14.9, I2 = 28%). A high VE/VCO2 slope characterizes both ATTRwt and ATTRv, while AL patients are younger with lower VE/VCO2 slope levels. Peak VO2 in ATTR patients may depend on exercise modality. Exercise limitations and ventilatory efficiency in cardiac amyloidosis. This illustration summarizes CPET findings in cardiac amyloidosis. Patients with transthyretin amyloidosis, both wild‐type and variant, exhibit elevated VE/VCO₂ slopes, indicating ventilatory inefficiency. Light‐chain amyloidosis patients are younger and show comparatively lower VE/VCO₂ slopes. Peak VO₂ differs by CPET modality in ATTR patients, being lowest for treadmill. These findings emphasize disease mechanisms on ventilatory efficiency and the influence of CPET modality on exercise capacity. AL, amyloid light chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRv, variant transthyretin amyloidosis; ATTRwt, wild‐type transthyretin amyloidosis; CA, cardiac amyloidosis; CPET, cardiopulmonary exercise testing; VE, minute ventilation; VE/VCO₂ slope, ventilatory efficiency; VO₂, oxygen uptake.

BackgroundPersistent pulmonary dysfunction is common after COVID-19, yet traditional assessments using carbon monoxide diffusing capacity (DLCO) alone may miss alveolar-capillary impairment.ObjectiveTo determine whether combining nitric oxide (DLNO5s) and carbon monoxide (DLCO5s) diffusing capacities enhances detection of post-COVID-19 lung impairment and whether summed z-scores outperform individual measures in classifying affected individuals.Design and methodsWe conducted an individual participant data meta-analysis using hierarchical mixed-effects modelling. The dataset included 572 COVID-19 survivors and 72 matched controls from six European centres. Lung function metrics—including spirometry, total lung capacity, DLNO5s and DLCO5s—were standardised into z-scores. Logistic models were compared using Bayesian Information Criterion and Leave-One-Out Information Criterion. Classification accuracy was assessed with Matthews Correlation Coefficient (MCC) and net reclassification improvement (NRI). Principal Component Analysis examined score structures, and dyspnoea severity was correlated with z-scores. Assessments were conducted 32–575 days post-infection (median=130 days).ResultsThe number of days between SARS-CoV-2 diagnosis and testing did not affect any of the measured z‐scores. Summed DLNO5s + DLCO5s z-scores consistently outperformed individual metrics. The combined model improved MCC by 0.06 (95% CI 0.01 to 0.11) and NRI by 37% (95% CI 13 to 62%) over DLCO5s alone. The top model (summed DLNO5s + DLCO5s z-scores model) explained 10% of fixed and 59% of random variance. DLCO5s alone failed to identify reduced membrane diffusion in approximately 16% of cases. Dyspnoea severity was significantly associated with all diffusion indices (p<0.001), though combined scores showed no stronger correlation than single predictors.ConclusionSummed DLNO5s + DLCO5s z-scores enhance classification of post-COVID-19 pulmonary impairment beyond DLCO5s alone. The NO-CO double diffusion approach offers improved diagnostic discrimination between previously infected individuals and controls and aligns with symptom severity. These findings support broader clinical integration of combined diffusion metrics in post-COVID assessment.

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.