Symptomatic post COVID patients have impaired alveolar capillary membrane function and high VE/VCO2.

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 (FEV1) 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, peakVO2 84 ± 18%pred, VE/VCO2 slope 112 [102-123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV1, Vcap and high VE/VCO2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO2 slope and low PeakVO2 and FEV1 while fatigability with high VE/VCO2 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/VCO2 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.

Beyond VO2: the complex cardiopulmonary exercise test.

Cardiopulmonary exercise test (CPET) is a valuable diagnostic tool with a specific application in heart failure (HF) thanks to the strong prognostic value of its parameters. The most important value provided by CPET is the peak oxygen uptake (peak VO2), the maximum rate of oxygen consumption attainable during physical exertion. According to the Fick principle, VO2 equals cardiac output (Qc) times the arteriovenous content difference [C(a-v)O2], where Ca is the arterial oxygen and Cv is the mixed venous oxygen content, respectively; therefore, VO2 can be reduced both by impaired O2 delivery (reduced Qc) or extraction (reduced arteriovenous O2 content). However, standard CPET is not capable of discriminating between these different impairments, leading to the need for 'complex' CPET technologies. Among non-invasive methods for Qc measurement during CPET, inert gas rebreathing and thoracic impedance cardiography are the most used techniques, both validated in healthy subjects and patients with HF, at rest and during exercise. On the other hand, the non-invasive assessment of peripheral muscle perfusion is possible with the application of near-infrared spectroscopy, capable of measuring tissue oxygenation. Measuring Qc allows, by having haemoglobin values available, to discriminate how much any VO2 deficit depends on the muscle, anaemia or heart.

Exercise oscillatory ventilation: the past, present, and future.

Exercise oscillatory ventilation (EOV) is a fascinating event that can be appreciated in the cardiopulmonary exercise test and is characterized by a cyclic fluctuation of minute ventilation, tidal volume, oxygen uptake, carbon dioxide production, and end-tidal pressure for oxygen and carbon dioxide. Its mechanisms stem from a dysregulation of the normal control feedback of ventilation involving one or more of its components, namely, chemoreflex delay, chemoreflex gain, plant delay, and plant gain. In this review, we intend to breakdown therapeutic targets according to pathophysiology and revise the prognostic value of exercise oscillatory ventilation in the setting of heart failure and other diagnoses.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Is red distribution width a valid tool to predict impaired iron transport in heart failure?

Background: Impaired iron transport (IIT) is a form of iron deficiency (ID) defined as transferrin saturation (TSAT) < 20% irrespective of serum ferritin levels. It is frequently observed in heart failure (HF) where it negatively affects prognosis irrespective of anaemia. Objectives: In this retrospective study we searched for a surrogate biomarker of IIT. Methods: We tested the predictive power of red distribution width (RDW), mean corpuscular volume (MCV) and mean corpuscular haemoglobin concentration (MCHC) to detect IIT in 797 non-anaemic HF patients. Results: At ROC analysis, RDW provided the best AUC (0.6928). An RDW cut-off value of 14.2% identified patients with IIT, with positive and negative predictive values of 48 and 80%, respectively. Comparison between the true and false negative groups showed that estimated glomerular filtration rate (eGFR) was significantly higher (p = 0.0092) in the true negative vs. false negative group. Therefore, we divided the study population according to eGFR value: 109 patients with eGFR ≥ 90 ml/min/1.73 m2, 318 patients with eGFR 60-89 ml/min/1.73 m2, 308 patients with eGFR 30-59 ml/min/1.73 m2 and 62 patients with eGFR < 30 ml/min/1.73 m2. In the first group, positive and negative predictive values were 48 and 81% respectively, 51 and 85% in the second group, 48 and 73% in the third group and 43 and 67% in the fourth group. Conclusion: RDW may be seen as a reliable marker to exclude IIT in non-anaemic HF patients with eGFR ≥60 ml/min/1.73 m2.

Does moderate hyperkalemia influence survival in HF? Insights from the MECKI score data base.

BACKGROUND: The prognostic role of moderate hyperkalemia in reduced ejection fraction (HFrEF) patients is still controversial. Despite this, it affects the use of renin-angiotensin-aldosterone system inhibitors (RAASi) with therapy down-titration or discontinuation. OBJECTIVES: Aim of the study was to assess the prognostic impact of moderate hyperkalemia in chronic HFrEF optimally treated patients. METHODS AND RESULTS: We retrospectively analyzed MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) database, with median follow-up of 4.2 [IQR 1.9-7.5] years. Data on K+ levels were available in 7087 cases. Patients with K+ plasma level ≥ 5.6 mEq/L and < 4 mEq/L were excluded. Remaining patients were categorized into normal >4 and < 5 mEq/L (n = 4826, 68%) and moderately high ≥5.0 and ≤ 5.5 mEq/L (n = 496, 7%) K+. Then patients were matched by propensity score in 484 couplets of patients. MECKI score value was 7% [IQR 3.1-14.1%] and 7.3% [IQR 3.4-15%] (p = 0.678) in patients with normal and moderately high K+ values while cardiovascular mortality events at two years follow-up were 41 (4.2%) and 33 (3.4%) (p = 0.333) in each group respectively. CONCLUSIONS: Moderate hyperkalemia does not influence patients' outcome in a large cohort of ambulatory HFrEF patients.

Exploring the Prognostic Performance of MECKI Score in Heart Failure Patients with Non-Valvular Atrial Fibrillation Treated with Edoxaban.

INTRODUCTION: Risk stratification in heart failure (HF) is essential for clinical and therapeutic management. The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score is a validated prognostic model for assessing cardiovascular risk in HF patients with reduced ejection fraction (HFrEF). From the validation of the score, the prevalence of HF patients treated with direct oral anticoagulants (DOACs), such as edoxaban, for non-valvular atrial fibrillation (NVAF) has been increasing in recent years. This study aims to evaluate the reliability of the MECKI score in HFrEF patients treated with edoxaban for NVAF. MATERIALS AND METHODS: This study included consecutive outpatients with HF and NVAF treated with edoxaban (n = 83) who underwent a cardiopulmonary exercise test (CPET). They were matched by propensity score with a retrospective group of HFrEF patients with NVAF treated with vitamin K antagonists (VKAs) from the MECKI score registry (n = 844). The study endpoint was the risk of cardiovascular mortality, urgent heart transplantation, or Left Ventricle Assist Device (LVAD) implantation. RESULTS: Edoxaban patients were treated with a more optimized HF therapy and had different clinical characteristics, with a similar MECKI score. After propensity score, 77 patients treated with edoxaban were successfully matched with the MECKI-VKA control cohort. In both groups, MECKI accurately predicted the composite endpoint with similar area under the curves (AUC = 0.757 vs. 0.829 in the MECKI-VKA vs. edoxaban-treated group, respectively, p = 0.452). The two populations' survival appeared non-significantly different at the 2-year follow-up. CONCLUSIONS: this study confirms the prognostic accuracy of the MECKI score in HFrEF patients with NVAF treated with edoxaban, showing improved predictive power compared to VKA-treated patients.

Impact of Sacubitril/Valsartan on surfactant binding proteins, central sleep apneas, lung function tests and heart failure biomarkers: Hemodynamic or pleiotropism?

Purpose: Little is known about the mechanism underlying Sacubitril/Valsartan effects in patients with heart failure (HFrEF). Aim of the study is to assess hemodynamic vs. non-hemodynamic Sacubitril/Valsartan effects by analyzing several biological and functional parameters. Methods: Seventy-nine patients (86% males, age 66 ± 10 years) were enrolled. At baseline and 6 months after reaching the maximum Sacubitril/Valsartan tolerated dose, we assessed biomarkers, transthoracic echocardiography, polysomnography, spirometry, and carbon monoxide diffusing capacity of the lung (DLCO). Results: Mean follow-up was 8.7 ± 1.4 months with 83% of patients reaching Sacubitril/Valsartan maximum dose (97/103 mg b.i.d). Significant improvements were observed in cardiac performance and biomarkers: left ventricular ejection fraction increased (31 ± 5 vs. 37 ± 9 %; p < 0.001), end-diastolic and end-systolic volumes decreased; NT-proBNP decreased (1,196 [IQR 648-2891] vs. 958 [IQR 424-1,663] pg/ml; p < 0.001) in parallel with interleukin ST-2 (28.4 [IQR 19.4-36.6] vs. 20.4 [IQR 15.1-29.2] ng/ml; p < 0.001) and circulating surfactant binding proteins (proSP-B: 58.43 [IQR 40.42-84.23] vs. 50.36 [IQR 37.16-69.54] AU; p = 0.014 and SP-D: 102.17 [IQR 62.85-175.34] vs. 77.64 [IQR 53.55-144.70] AU; p < 0.001). Forced expiratory volume in 1 second and forced vital capacity improved. DLCO increased in the patients' subgroup (n = 39) with impaired baseline values (from 65.3 ± 10.8 to 70.3 ± 15.9 %predicted; p = 0.013). We also observed a significant reduction in central sleep apneas (CSA). Conclusion: Sacubitril/Valsartan effects share a double pathway: hemodynamic and systemic. The first is evidenced by NT-proBNP, proSP-B, lung mechanics, and CSA improvement. The latter is confirmed by an amelioration of DLCO, ST-2, SP-D as well as by reverse remodeling echocardiographic parameters.

When Outcomes Diverge: Age and Cardiovascular Risk as Determinants of Mortality and ICU Admission in COVID-19.

BACKGROUND: Hospital mortality and admission to the Intensive Care Unit (ICU) are markers of disease severity in COVID-19 patients. Cardiovascular co-morbidities are one of the main determinants of negative outcomes. In this study we investigated the impact of cardiovascular co-morbidities on mortality and admission to the ICU in first-wave COVID-19 patients. METHODS: A multicenter, retrospective, cohort study. A total of 1077 patients were analyzed for mortality and ICU admission. Cardiovascular risk factors were explored as determinants of the outcomes after correction for other confounders. RESULTS: In the multivariable model, after correction for age, only a history of heart failure remained independently associated (p = 0.0013) with mortality (hazard ratio 2.22, 95% confidence interval 1.37 to 3.62). Age showed a mortality risk increase of 8% per year (hazard ratio 1.08, 95% confidence interval 1.05 to 1.10, p = 0.001). The transition from ward to the ICU had, as a single determinant, the age, but in a reversed fashion (hazard ratio 0.96, 95% confidence interval 0.94 to 0.98, p = 0.0002). CONCLUSIONS: Once adjusted for the main determinant of mortality (age) heart failure only remained independently associated with mortality. Admission to the ICU was less likely for elderly patients. This may reflect the catastrophic impact of the first wave of COVID-19 pandemic in terms of ICU bed availability in Lombardy, leading to a selection process for ICU admission.

Pick Your Threshold: A Comparison Among Different Methods of Anaerobic Threshold Evaluation in Heart Failure Prognostic Assessment.

BACKGROUND: In clinical practice, anaerobic threshold (AT) is used to guide training and rehabilitation programs, to define risk of major thoracic or abdominal surgery, and to assess prognosis in heart failure (HF). AT of oxygen uptake (V.O2; V.O2AT) has been reported as an absolute value (V.O2ATabs), as a percentage of predicted peak V.O2 (V.O2AT%peak_pred), or as a percentage of observed peak V.O2 (V.O2AT%peak_obs). A direct comparison of the prognostic power among these different ways to report AT is missing. RESEARCH QUESTION: What is the prognostic power of these different ways to report AT? STUDY DESIGN AND METHODS: In this observational cohort study, we screened data of 7,746 patients with HF with a history of reduced ejection fraction (< 40%) recruited between 1998 and 2020 and enrolled in the Metabolic Exercise Combined With Cardiac and Kidney Indexes register. All patients underwent a maximum cardiopulmonary exercise test, executed using a ramp protocol on an electronically braked cycle ergometer. RESULTS: This study considered 6,157 patients with HF with identified AT. Follow-up was median, 4.2 years (25th-75th percentiles, 1.9-5.0 years). Both V.O2ATabs (mean ± SD, 823 ± 305 mL/min) and V.O2AT%peak_pred (mean ± SD, 39.6 ± 13.9%), but not V.O2AT%peak_obs (mean ± SD, 69.2 ± 17.7%), well stratified the population regarding prognosis (composite end point: cardiovascular death, urgent heart transplant, or left ventricular assist device). Comparing area under the receiver operating characteristic curve (AUC) values, V.O2ATabs (0.680) and V.O2AT%peak_pred (0.688) performed similarly, whereas V.O2AT%peak_obs (0.538) was significantly weaker (P < .001). Moreover, the V.O2AT%peak_pred AUC value was the only one performing as well as the AUC based on peak V.O2 (0.710), with an even a higher AUC (0.637 vs 0.618, respectively) in the group with severe HF (peak V.O2 < 12 mL/min/kg). Finally, the combination of V.O2AT%peak_pred with peak V.O2 and V. per CO2 production shows the highest prognostic power. INTERPRETATION: In HF, V.O2AT%peak_pred is the best way to report V.O2 at AT in relationship to prognosis, with a prognostic power comparable to that of peak V.O2 and, remarkably, in patients with severe HF.

Exercise oxygen pulse kinetics in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Reduced cardiac output (CO) has been considered crucial in symptoms' genesis in hypertrophic cardiomyopathy (HCM). Absolute value and temporal behaviour of O2-pulse (oxygen uptake/heart rate (VO2/HR)), and the VO2/work relationship during exercise reflect closely stroke volume (SV) and CO changes, respectively. We hypothesise that adding O2-pulse absolute value and kinetics, and VO2/work relationship to standard cardiopulmonary exercise testing (CPET) could help identify more exercise-limited patients with HCM. METHODS: CPETs were performed in 3 HCM dedicated clinical units. We retrospectively enrolled non-end-stage consecutive patients with HCM, grouped according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuvre (72% of patients with LVOTO <30; 10% between 30 and 49 and 18% ≥50 mm Hg). We evaluated the CPET response in HCM focusing on parameters strongly associated with SV and CO, such as O2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise. RESULTS: We included 312 patients (70% males, age 49±18 years). Peak VO2 (percentage of predicted), O2-pulse and ventilation to carbon dioxide production (VE/VCO2) slope did not change across LVOTO groups. Ninety-six (31%) patients with HCM presented an abnormal O2-pulse temporal behaviour, irrespective of LVOTO values. These patients showed lower peak systolic pressure, workload (106±45 vs 130±49 W), VO2 (21.3±6.6 vs 24.1±7.7 mL/min/kg; 74%±17% vs 80%±20%) and O2-pulse (12 (9-14) vs 14 (11-17) mL/beat), with higher VE/VCO2 slope (28 (25-31) vs 27 (24-31)) (p<0.005 for all). Only 2 patients had an abnormal VO2/work slope. CONCLUSION: None of the frequently used CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal temporal behaviour of O2-pulse during exercise, which is strongly related to inadequate SV increase, correlates with reduced functional capacity (peak and anaerobic threshold VO2 and workload) and increased VE/VCO2 slope, identifying more advanced disease irrespectively of LVOTO.

Why Levosimendan Improves the Clinical Condition of Patients With Advanced Heart Failure: A Holistic Approach.

BACKGROUND: In advanced heart failure (HF), levosimendan increases peak oxygen uptake (VO2). We investigated whether peak VO2 increase is linked to cardiovascular, respiratory, or muscular performance changes. METHODS AND RESULTS: Twenty patients hospitalized for advanced HF underwent, before and shortly after levosimendan infusion, 2 different cardiopulmonary exercise tests: (a) a personalized ramp protocol with repeated arterial blood gas analysis and standard spirometry including alveolar-capillary gas diffusion measurements at rest and at peak exercise, and (b) a step incremental workload cardiopulmonary exercise testing with continuous near-infrared spectroscopy analysis and cardiac output assessment by bioelectrical impedance analysis.Levosimendan significantly decreased natriuretic peptides, improved peak VO2 (11.3 [interquartile range 10.1-12.8] to 12.6 [10.2-14.4] mL/kg/min, P < .01) and decreased minute ventilation to carbon dioxide production relationship slope (47.7 ± 10.7 to 43.4 ± 8.1, P < .01). In parallel, spirometry showed only a minor increase in forced expiratory volume, whereas the peak exercise dead space ventilation was unchanged. However, during exercise, a smaller edema formation was observed after levosimendan infusion, as inferable from the changes in diffusion components, that is, the membrane diffusion and capillary volume. The end-tidal pressure of CO2 during the isocapnic buffering period increased after levosimendan (from 28 ± 3 mm Hg to 31 ± 2 mm Hg, P < .01). During exercise, cardiac output increased in parallel with VO2. After levosimendan, the total and oxygenated tissue hemoglobin, but not deoxygenated hemoglobin, increased in all exercise phases. CONCLUSIONS: In advanced HF, levosimendan increases peak VO2, decreases the formation of exercise-induced lung edema, increases ventilation efficiency owing to a decrease of reflex hyperventilation, and increases cardiac output and muscular oxygen delivery and extraction.

Rest and exercise oxygen uptake and cardiac output changes 6 months after successful transcatheter mitral valve repair.

AIMS: Changes in peak exercise oxygen uptake (VO2 ) and cardiac output (CO) 6 months after successful percutaneous edge-to-edge mitral valve repair (pMVR) in severe primary (PMR) and functional mitral regurgitation (FMR) patients are unknown. The aim of the study was to assess the efficacy of pMVR at rest by echocardiography, VO2 and CO (inert gas rebreathing) measurement and during cardiopulmonary exercise test with CO measurement. METHODS AND RESULTS: We evaluated 145 and 115 patients at rest and 98 and 66 during exercise before and after pMVR, respectively. After successful pMVR, significant reductions in MR and NYHA class were observed in FMR and PMR patients. Cardiac ultrasound showed reverse remodelling (left ventricular end-diastolic volume from 158 ± 63 mL to 147 ± 64, P < 0.001; ejection fraction from 51 ± 15 to 48 ± 14, P < 0.001; pulmonary artery systolic pressure (PASP) from 43 ± 13 to 38 ± 8 mmHg, P < 0.001) in the entire population. These changes were significant in PMR (n = 62) and a trend in FMR (n = 53), except for PASP, which decreased in both groups. At rest, CO and stroke volume (SV) increased in FMR with a concomitant reduction in arteriovenous O2 content difference [ΔC(a-v)O2 ]. Peak exercise, CO and SV increased significantly in both groups (CO from 5.5 ± 1.4 L/min to 6.3 ± 1.5 and from 6.2 ± 2.4 to 6.7 ± 2.0, SV from 57 ± 19 mL to 66 ± 20 and from 62 ± 20 to 69 ± 20, in FMR and PMR, respectively), whereas peak VO2 was unchanged and ΔC(a-v)O2 decreased. CONCLUSIONS: These data confirm pMVR-induced clinical improvement and reverse ventricular remodelling at a 6-month analysis and show, in spite of an increase in CO, an unchanged exercise performance, which is achieved through a 'more physiological' blood flow distribution and O2 extraction behaviour. Direct rest and exercise CO should be measured to assess pMVR efficacy.

"You can leave your mask on": effects on cardiopulmonary parameters of different airway protective masks at rest and during maximal exercise.

During the COVID-19 pandemic, the use of protective masks has been essential to reduce contagions. However, public opinion is that there is an associated subjective shortness of breath. We evaluated cardiorespiratory parameters at rest and during maximal exertion to highlight any differences with the use of protective masks.12 healthy subjects performed three identical cardiopulmonary exercise tests, one without wearing a protective mask, one wearing a surgical mask and one with a filtering face piece particles class 2 (FFP2) mask. Dyspnoea was assessed using the Borg scale. Standard pulmonary function tests were also performed.All the subjects (40.8±12.4 years; six male) completed the protocol with no adverse events. Spirometry showed a progressive reduction of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) from no mask to surgical to FFP2 (FEV1: 3.94±0.91 L, 3.23±0.81 L, 2.94±0.98 L; FVC: 4.70±1.21 L, 3.77±1.02 L, 3.52±1.21 L; p<0.001). Rest ventilation, O2 uptake (V˙ O2 ) and CO2 production (V˙ CO2 ) were progressively lower, with a reduction in respiratory rate. At peak exercise, subjects had a progressively higher Borg scale when wearing surgical and FFP2 masks. Accordingly, at peak exercise, V˙ O2 (31.0±23.4 mL·kg-1·min-1, 27.5±6.9 mL·kg-1·min-1, 28.2±8.8 mL·kg-1·min-1; p=0.001), ventilation (92±26 L, 76±22 L, 72±21 L; p=0.003), respiratory rate (42±8 breaths·min-1, 38±5 breaths·min-1, 37±4 breaths·min-1; p=0.04) and tidal volume (2.28±0.72 L, 2.05±0.60 L, 1.96±0.65 L; p=0.001) were gradually lower. There was no significant difference in oxygen saturation.Protective masks are associated with significant but modest worsening of spirometry and cardiorespiratory parameters at rest and peak exercise. The effect is driven by a ventilation reduction due to increased airflow resistance. However, because exercise ventilatory limitation is far from being reached, their use is safe even during maximal exercise, with a slight reduction in performance.

Minute ventilation/carbon dioxide production in chronic heart failure.

In chronic heart failure, minute ventilation (V'E) for a given carbon dioxide production (V'CO2 ) might be abnormally high during exercise due to increased dead space ventilation, lung stiffness, chemo- and metaboreflex sensitivity, early metabolic acidosis and abnormal pulmonary haemodynamics. The V'E versus V'CO2 relationship, analysed either as ratio or as slope, enables us to evaluate the causes and entity of the V'E/perfusion mismatch. Moreover, the V'E axis intercept, i.e. when V'CO2 is extrapolated to 0, embeds information on exercise-induced dead space changes, while the analysis of end-tidal and arterial CO2 pressures provides knowledge about reflex activities. The V'E versus V'CO2 relationship has a relevant prognostic power either alone or, better, when included within prognostic scores. The V'E versus V'CO2 slope is reported as an absolute number with a recognised cut-off prognostic value of 35, except for specific diseases such as hypertrophic cardiomyopathy and idiopathic cardiomyopathy, where a lower cut-off has been suggested. However, nowadays, it is more appropriate to report V'E versus V'CO2 slope as percentage of the predicted value, due to age and gender interferences. Relevant attention is needed in V'E versus V'CO2 analysis in the presence of heart failure comorbidities. Finally, V'E versus V'CO2 abnormalities are relevant targets for treatment in heart failure.

Cardiac output changes during exercise in heart failure patients: focus on mid-exercise.

AIMS: Peak exercise oxygen uptake (VO2 ) and cardiac output (CO) are strong prognostic indexes in heart failure (HF) but unrelated to real-life physical activity, which is associated to submaximal effort. METHODS AND RESULTS: We analysed maximal cardiopulmonary exercise test with rest, mid-exercise, and peak exercise non-invasive CO measurements (inert gas rebreathing) of 231 HF patients and 265 healthy volunteers. HF patients were grouped according to exercise capacity (peak VO2  < 50% and ≥50% pred, Groups 1 and 2). To account for observed differences, data regarding VO2 , CO, stroke volume (SV), and artero-venous O2 content difference [ΔC(a-v)O2 ] were adjusted by age, gender, and body mass index. A multiple regression analysis was performed to predict peak VO2 from mid-exercise cardiopulmonary exercise test and CO parameters among HF patients. Rest VO2 was lower in HF compared with healthy subjects; meanwhile, Group 1 patients had the lowest CO and highest ΔC(a-v)O2 . At mid-exercise, Group 1 patients achieved a lower VO2 , CO, and SV [0.69 (interquartile range 0.57-0.80) L/min; 5.59 (4.83-6.67) L/min; 62 (51-73) mL] than Group 2 [0.94 (0.83-1.1) L/min; 7.6 (6.56-9.01) L/min; 77 (66-92) mL] and healthy subjects [1.15 (0.93-1.30) L/min; 9.33 (8.07-10.81) L/min; 87 (77-102) mL]. Rest to mid-exercise SV increase was lower in Group 1 than Group 2 (P = 0.001) and healthy subjects (P < 0.001). At mid-exercise, ΔC(a-v)O2 was higher in Group 2 [13.6 (11.8-15.4) mL/100 mL] vs. healthy patients [11.6 (10.4-13.2) mL/100 mL] (P = 0.002) but not different from Group 1 [13.6 (12.0-14.9) mL/100 mL]. At peak exercise, Group 1 patients achieved a lower VO2 , CO, and SV than Group 2 and healthy subjects. ΔC(a-v)O2 was the highest in Group 2. At multivariate analysis, a model comprising mid-exercise VO2 , carbon dioxide production (VCO2 ), CO, haemoglobin, and weight predicted peak VO2 , P < 0.001. Mid-exercise VO2 and CO, haemoglobin, and weight added statistically significantly to the prediction, P < 0.050. CONCLUSIONS: Mid-exercise VO2 and CO portend peak exercise values and identify severe HF patients. Their evaluation could be clinically useful.

How Patients With Heart Failure Perform Daily Life Activities: An Innate Energy-Saving Strategy.

BACKGROUND: Cardiopulmonary exercise test and 6-minute walking test are frequently used tools to evaluate physical performance in heart failure (HF), but they do neither represent activities of daily living (ADLs) nor fully reproduce patients' symptoms. We assessed differences in task oxygen uptake, both as absolute value and as percentage of peak oxygen consumption (peakVO2), ventilation efficiency (VE/VCO2 ratio), and dyspnea intensity (Borg scale) in HF and healthy subjects during standard ADLs and other common physical actions. METHODS: Healthy and HF subjects (ejection fraction <45%, stable conditions) underwent cardiopulmonary exercise test. All of them, carrying a wearable metabolic cart, performed a 6-minute walking test, two 4-minute treadmill exercises (at 2 and 3 km/h), and ADLs: ADL1 (getting dressed), ADL2 (folding 8 towels), ADL3 (putting away 6 bottles), ADL4 (making a bed), ADL5 (sweeping the floor for 4 minutes), ADL6 (climbing 1 flight of stairs carrying a load). RESULTS: Sixty patients with HF (age 65.2±12.1 years; ejection fraction 30.4±6.7%, peakVO2 14.2±4.0 mL/[min·kg]) and 40 healthy volunteers (58.9±8.2 years, peakVO2 28.1±7.4 mL/[min·kg]) were enrolled. For each exercise, patients showed higher VE/VCO2 ratio, percentage of peakVO2, and Borg scale value than controls, while absolute values of task oxygen uptake and exercise duration were lower and higher, respectively, in all activities, except for treadmill (fixed execution time and intensity). Differently from Borg Scale data, metabolic values and exercise time length changed in parallel with HF severity, except for ADL duration in very short (ADL3) and composite (ADL1) activities. Borg scale values correlated with percentage of peakVO2. CONCLUSIONS: During ADLs, patients self-regulated activities in parallel with HF severity by decreasing intensity (VO2) and prolonging the effort.

Roles of periodic breathing and isocapnic buffering period during exercise in heart failure.

In heart failure, exercise - induced periodic breathing and end tidal carbon dioxide pressure value during the isocapnic buffering period are two features identified at cardiopulmonary exercise testing strictly related to sympathetic activation. In the present review we analysed the physiology behind periodic breathing and the isocapnic buffering period and present the relevant prognostic value of both periodic breathing and the presence/absence of the identifiable isocapnic buffering period.

Sacubitril/valsartan use in a real-world population of patients with heart failure and reduced ejection fraction.

AIMS: Practice guidelines recommend sacubitril/valsartan for heart failure with reduced ejection fraction. The aim of our study was to describe the use of sacubitril/valsartan in real-world clinical practice to help identify patients best able to tolerate titration to higher doses. METHODS: We retrospectively analyzed clinical data for 201 patients with heart failure with reduced ejection fraction prescribed sacubitril/valsartan at our heart failure clinic (Centro Cardiologico Monzino) between September 2016/December 2018. Patients had a mean age of 67.2 years, mean left ventricular ejection fraction of 30.1%, New York Heart Association class II (65%), class III (35%), and poor cardiopulmonary exercise capacity. Median 2-year risk of death/urgent cardiac transplantation was 8.9% [Metabolic Exercise Cardiac Kidney Index (MECKI) score]. RESULTS: After a median follow-up of 230 (interquartile interval: 105-366) days, 57 patients achieved higher-dose sacubitril/valsartan, 103 tolerated medium/low doses, nine died, and 20 interrupted treatment. The highest dose of sacubitril/valsartan was reached by younger patients with better hemoglobin (Hb) levels, renal function, and blood pressure (BP). Patients continuing on sacubitril/valsartan had significantly higher serum Hb and sodium, better BP, and lower MECKI scores than patients who discontinued treatment or died during follow-up. Our patients were older and frailer than those in the pivotal PARADIGM-HF trial. CONCLUSION: In our experience, more than one-third of the patients were able to tolerate the higher dose of sacubitril/valsartan, and these patients were younger, had higher Hb, and better BP and renal function. MECKI score stratification was useful to discriminate patients who continued treatment from those who did not. Future prospective studies should test if these clinical variables can guide the up-titration of sacubitril/valsartan.