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Aims: Individual prognostic assessment and disease evolution pathways are undefined in chronic heart failure (HF). The application of unsupervised learning methodologies could help to identify patient phenotypes and the progression in each phenotype as well as to assess adverse event risk., Methods and Results: From a bulk of 7948 HF patients included in the MECKI registry, we selected patients with a minimum 2-year follow-up. We implemented a topological data analysis (TDA), based on 43 variables derived from clinical, biochemical, cardiac ultrasound, and exercise evaluations, to identify several patients' clusters. Thereafter, we used the trajectory analysis to describe the evolution of HF states, which is able to identify bifurcation points, characterized by different follow-up paths, as well as specific end-stages conditions of the disease. Finally, we conducted a 5-year survival analysis (composite of cardiovascular death, left ventricular assist device, or urgent heart transplant). Findings were validated on internal (n = 527) and external (n = 777) populations. We analyzed 4876 patients (age = 63 [53-71], male gender n = 3973 (81.5%), NYHA class I-II n = 3576 (73.3%), III-IV n = 1300 (26.7%), LVEF = 33 [25.5-39.9], atrial fibrillation n = 791 (16.2%), peak VO 2 % pred = 54.8 [43.8-67.2]), with a minimum 2-year follow-up. Nineteen patient clusters were identified by TDA. Trajectory analysis revealed a path characterized by 3 bifurcation and 4 end-stage points. Clusters survival rate varied from 44% to 100% at 2 years and from 20% to 100% at 5 years, respectively. The event frequency at 5-year follow-up for each study cohort cluster was successfully compared with those in the validation cohorts (R = 0.94 and R = 0.84, P < 0.001, for internal and external cohort, respectively). Finally, we conducted a 5-year survival analysis (composite of cardiovascular death, left ventricular assist device, or urgent heart transplant observed in 22% of cases)., Conclusions: Each HF phenotype has a specific disease progression and prognosis. These findings allow to individualize HF patient evolutions and to tailor assessment., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: A sex-based evaluation of prognosis in heart failure (HF) is lacking., Methods and Results: We analyzed the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score registry, which includes HF with reduced ejection fraction (HFrEF) patients. A cross-validation procedure was performed to estimate weights separately for men and women of all MECKI score parameters: left ventricular ejection fraction (LVEF), hemoglobin, kidney function assessed by Modification of Diet in Renal Disease, blood sodium level, ventilation vs. carbon dioxide production slope, and peak oxygen consumption (peakVO 2 ). The primary outcomes were the composite of all-cause mortality, urgent heart transplant, and implant of a left ventricle assist device. The difference in predictive ability between the native and sex recalibrated MECKI (S-MECKI) was calculated using a receiver operating characteristic (ROC) curve at 2 years and a calibration plot. We retrospectively analyzed 7,900 HFrEF patients included in the MECKI score registry (mean age 61 ± 13 years, 6,456 men/1,444 women, mean LVEF 33% ± 10%, mean peakVO 2 56.2% ± 17.6% of predicted) with a median follow-up of 4.05 years (range 1.72-7.47). Our results revealed an unadjusted risk of events that was doubled in men compared to women (9.7 vs. 4.1) and a significant difference in weight between the sexes of most of the parameters included in the MECKI score. S-MECKI showed improved risk classification and accuracy (area under the ROC curve: 0.7893 vs. 0.7799, p  = 0.02) due to prognostication improvement in the high-risk settings in both sexes (MECKI score >10 in men and >5 in women)., Conclusions: S-MECKI, i.e., the recalibrated MECKI according to sex-specific differences, constitutes a further step in the prognostic assessment of patients with severe HFrEF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor RDP declared a past co-authorship with the author GP. The authors declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Grilli, Salvioni, Moscucci, Bonomi, Sinagra, Schaeffer, Campodonico, Mapelli, Rossi, Carriere, Emdin, Piepoli, Paolillo, Senni, Passino, Apostolo, Re, Santolamazza, Magri, Lombardi, Corrá, Raimondo, Cittadini, Iorio, Salzano, Lagioia, Vignati, Badagliacca, Passantino, Filardi, Correale, Perna, Girola, Metra, Cattadori, Guazzi, Limongelli, Parati, De Martino, Matassini, Bandera, Bussotti, Scardovi, Sciomer, Agostoni and MECKI Score Research Group.)

Aims: The Fick principle states that oxygen uptake (V̇O2) is cardiac output (Qc)*arterial-venous O2 content difference [ΔC(a-v)O2]. Blood flow distribution is hidden in Fick principle and its relevance during exercise in heart failure (HF) is undefined.To highlight the role of blood flow distribution, we evaluated peak-exercise V̇O2, Qc and ΔC(a-v)O2, before and after HF therapeutic interventions., Methods: Symptoms-limited cardiopulmonary exercise tests with Qc measurement (inert-gas-rebreathing) was performed in 234 HF patients before and 6 months after successful exercise training, cardiac-resynchronization therapy or percutaneous-edge-to-edge mitral valve repair., Results: Considering all tests (n=468) a direct correlation between peakV̇O2 and peakQc (R2=0.47) and workload (R2=0.70) were observed. Patients were grouped according to treatment efficacy in group 1 (peakV̇O2 increase >10%, n=93), group 2 (peakV̇O2 change between 0 and 10%, n=60) and group 3 (reduction in peakV̇O2, n=81). Post-treatment peakV̇O2 changes poorly correlated with peakQc and peakΔC(a-v)O2 changes. Differently, post-procedures peakQc vs. peakΔC(a-v)O2 changes showed a close negative correlation (R2=0.46), becoming stronger grouping patients according to peakV̇O2 improvement (R2=0.64, 0.79 and 0.58 in group 1, 2 and 3, respectively). In 76% of patients peakQc and ΔC(a-v)O2 changes diverged regardless of treatment., Conclusion: The bulk of these data suggests that blood flow distribution plays a pivotal role on peakV̇O2 determination regardless of HF treatment strategies. Accordingly, for assessing HF treatment efficacy on exercise performance the sole peakV̇O2 may be deceptive and the combination of V̇O2, Qc and ΔC(a-v)O2, must be considered., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: This overview of Cochrane Systematic Reviews (CSRs) reports on current evidence and its certainty of the effectiveness of interventions for the rehabilitation of people with ischemic heart disease (IHD), included in the World Health Organization Rehabilitation Programme Package of Interventions for Rehabilitation. Methods: We included all the CSRs relevant to people with IHD. We used a mapping synthesis to group outcomes and comparisons of included CSRs, indicating the effectiveness of interventions for rehabilitation and the certainty of evidence. Results: The evidence map included a total of 13 CSRs. The effect of the interventions varied across comparisons, and the certainty of evidence was inconsistent, ranging from high to very low. We found the best evidence for exercise-based cardiac rehabilitation in the reduction of fatal and non-fatal myocardial infarction and all-cause hospital admission up to 12 months follow-up. Also, combined interventions (work-directed interventions, physical conditioning interventions, and psychological interventions) reduce the days needed for returning to work. Conclusions: The current effect and certainty of evidence for several comparisons investigated support the role of exercise-based cardiac rehabilitation in the management of people with IHD, specifically reducing the risk of fatal and non-fatal myocardial infarction and hospitalisation. However, our findings highlight the lack of high-certainty evidence about hard endpoints, particularly total mortality. Future research should prioritise these primary endpoints to enhance the credibility of cardiac rehabilitation.

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.

Aims: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF)., Methods and Results: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis., Conclusions: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome., (© 2023 European Society of Cardiology.)

Fluid retention is a major determinant of symptoms in patients with heart failure (HF), and it is closely associated with prognosis. Hence, congestion represents a critical therapeutic target in this clinical setting. The first therapeutic strategy in HF patients with fluid overload is optimization of diuretic intervention to maximize water and sodium excretion. When diuretic therapy fails to relieve congestion, renal replacement therapy represents the only alternative option for fluid removal, as well as a way to restore diuretic responsiveness. On this background, the pathophysiology of fluid balance in HF is complex, with heart, kidney, and lung being deeply involved in volume regulation and management. Therefore, the interplay between these organs should be appreciated and considered when fluid overload in HF patients is targeted., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The evaluation of exercise capacity and cardiac output (QC) is fundamental in the management of patients with advanced heart failure (AdHF). QC and peak oxygen uptake (VO2) have a pivotal role in the prognostic stratification and in the definition of therapeutic interventions, including medical therapies and devices, but also specific treatments such as heart transplantation and left ventricular assist device (LVAD) implantation. Due to the intertwined relationship between exercise capacity and daily activities, exercise intolerance dramatically has impact on the quality of life of patients. It is a multifactorial process that includes alterations in central and peripheral haemodynamic regulation, anaemia and iron deficiency, pulmonary congestion, pulmonary hypertension, and peripheral O2 extraction. This paper aims to review the pathophysiological background of exercise limitations in HF patients and to examine the complex physiology of exercise in LVAD recipients, analysing the interactions between the cardiopulmonary system, the musculoskeletal system, the autonomic nervous system, and the pump. We performed a literature review to highlight the current knowledge on this topic and possible interventions that can be implemented to increase exercise capacity in AdHF patients-including administration of levosimendan, rehabilitation, and the intriguing field of LVAD speed changes. The present paper confirms the role of CPET in the follow-up of this peculiar population and the impact of exercise capacity on the quality of life of AdHF patients., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Venous thromboembolism (VTE) is an important complication in rehabilitation practice despite preventive measures. The management can be complicated because patients may have co-existing cardiovascular comorbidities., Objective: To assess the effects of antiplatelet agents in addition to current best medical practice (BMP) compared to current BMP (with or without placebo) for the treatment of deep venous thrombosis (DVT)., Methods: A summary of the Cochrane Review by Flumignan et al. (2022), with comments from a rehabilitation perspective., Results: The review included six studies with 1625 eligible participants, with data up to 37.2 months of follow-up. When used after standard initial treatment with anticoagulants, antiplatelet agents such as aspirin in addition to BMP, may reduce recurrence of DVT or pulmonary embolism, when compared to BMP plus placebo in a chronic DVT setting and there may be a lower risk for post-thrombotic syndrome in patients with acute DVT. There is no clear difference in side effects, major bleeding, or pulmonary embolism (PE) with the use of antiplatelet agents., Conclusion: Adding antiplatelet agents to standard anticoagulation treatment in patients with VTE could provide benefit without increasing risks in selected patient groups. However, high quality studies with a long-term follow up are needed, including patients in rehabilitation settings.

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.O 2 ; V.O 2 AT) has been reported as an absolute value (V.O 2 ATabs), as a percentage of predicted peak V.O 2 (V.O 2 AT%peak&#95;pred), or as a percentage of observed peak V.O 2 (V.O 2 AT%peak&#95;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.O 2 ATabs (mean ± SD, 823 ± 305 mL/min) and V.O 2 AT%peak&#95;pred (mean ± SD, 39.6 ± 13.9%), but not V.O 2 AT%peak&#95;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.O 2 ATabs (0.680) and V.O 2 AT%peak&#95;pred (0.688) performed similarly, whereas V.O 2 AT%peak&#95;obs (0.538) was significantly weaker (P < .001). Moreover, the V.O 2 AT%peak&#95;pred AUC value was the only one performing as well as the AUC based on peak V.O 2 (0.710), with an even a higher AUC (0.637 vs 0.618, respectively) in the group with severe HF (peak V.O 2  < 12 mL/min/kg). Finally, the combination of V.O 2 AT%peak&#95;pred with peak V.O 2 and V. per CO 2 production shows the highest prognostic power., Interpretation: In HF, V.O 2 AT%peak&#95;pred is the best way to report V.O 2 at AT in relationship to prognosis, with a prognostic power comparable to that of peak V.O 2 and, remarkably, in patients with severe HF., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Cardiopulmonary exercise testing is a prognostic tool in heart failure with reduced left ventricular ejection fraction (HFrEF). Prognosticating algorithms have been proposed, but none has been validated. In 2017, a predictive algorithm, based on peak oxygen consumption (VO 2 ), ventilatory response to exercise (ventilation [VE] carbon dioxide production [VCO2], the VE/VCO 2 slope), exertional oscillatory ventilation (EOV), and peak respiratory exchange ratio, was recommended, according treatment with β blockers: patients with HFrEF registered in the metabolic exercise test data combined with cardiac and kidney indexes (MECKIs) database were used to validated this algorithm. According to the inclusion/exclusion criteria, 4,683 MECKI patients with HFrEF were enrolled. At 3 years follow-up, the end point was cardiovascular death and urgent heart transplantation (cardiovascular events [CV]). CV events occurred in 25% in patients without β blockers, whereas those with β-blockers had 11% (p <0.0001). In patients without β blockers, 36%, 24%, and 7% CV events were observed in those with peak VO2 ≤10, with peak VO2 >10 <18, and with peak VO2 ≥18 ml/kg/min (p = 0.0001), respectively; in MECKI patients with peak VO2 ≤10 and patients with intermediate exercise capacity, a peak respiratory exchange ratio (≥1.15) and VE/VCO 2 slope (≥35) were diriment, respectively (p = 0.0001). EOV, when occurred, increased risk. In MECKI patients on β blockers, 29%, 17%, and 8% CV events were noticed in those with a peak VO2 ≤8, with peak VO2 = 8 to 12, and patients with peak VO2 ≥12 ml/kg/min, respectively (p = 0.0000); when EOV was monitored an increment of risk was witnessed. In conclusion, the outcome of this algorithm was confirmed with the MECKI cohort., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Intravenous iron therapy can improve symptoms in patients with heart failure, anaemia and iron deficiency. The mechanisms underlying such an improvement might involve chemoreflex sensing and nocturnal breathing patterns., Methods and Results: Patients with heart failure, reduced left ventricular ejection fraction, anaemia (haemoglobin <13 g/dl in men; <12 g/dl in women) and iron deficiency (ferritin <100 or 100-299 μg/L with transferrin saturation <20%) were 2:1 randomized to patient-tailored intravenous ferric carboxymaltose dose or placebo. Chemoreflex sensitivity cardiorespiratory sleep study, symptom assessment and cardiopulmonary exercise test were performed before and 2 weeks after the last treatment dose. Fifty-eight patients (38 active arm/20 placebo arm) completed the study. Intravenous iron was associated with less severe symptoms, higher haemoglobin (12.5 ± 1.4 vs. 11.7 ± 1.0 mg/dl, p < 0.05) and improved haematinic parameters. Ferric carboxymaltose improved the central hypercapnic ventilatory response (-25.8%, p < 0.05 vs. placebo), without changes in peripheral chemosensitivity. In particular, the central hypercapnic ventilatory responses passed from 4.6 ± 6.5 to 2.9 ± 2.9 L/min/mmHg after ferric carboxymaltose and from 4.4 ± 4.6 to 4.6 ± 3.9 L/min/mmHg after placebo (p treatment*condition  = 0.046). In patients presenting with sleep-related breathing disorder, apnoea-hypopnoea index was reduced with active treatment as compared to placebo (12 ± 11 vs. 19 ± 13 events/h, p < 0.05). After ferric carboxymaltose, but not after placebo, both peak oxygen uptake (VO 2 ) increased (Δ1.1 ± 2.0 ml/kg/min, p < 0.05) and VO 2 /workload slope was steeper (Δ0.67 ± 1.7 L/min/W, p < 0.01)., Conclusions: Intravenous ferric carboxymaltose improves the hypercapnic ventilatory response and sleep-related breathing disorders in patients with heart failure, anaemia and iron deficiency. These newly described findings, along with improved oxygen delivery to exercising muscles, likely contribute to the favourable effects of ferric carboxymaltose in anaemic patients with heart failure., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The battle against COVID-19 has entered a new phase with Rehabilitation Centres being among the major players, because the medical outcome of COVID-19 patients does not end with the control of pulmonary inflammation marked by a negative virology test, as many patients continue to suffer from long-COVID-19 syndrome. Exercise training is known to be highly valuable in patients with cardiac or lung disease, and it exerts beneficial effects on the immune system and inflammation. We therefore reviewed past and recent papers about exercise training, considering the multifactorial features characterizing post-COVID-19 patients' clinical conditions. Consequently, we conceived a proposal for a post-COVID-19 patient exercise protocol as a combination of multiple recommended exercise training regimens. Specifically, we built pre-evaluation and exercise training for post-COVID-19 patients taking advantage of the various programs of exercise already validated for diseases that may share pathophysiological and clinical characteristics with long-COVID-19.

Aims: Changes in peak exercise oxygen uptake (VO 2 ) 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, VO 2 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 O 2 content difference [ΔC(a-v)O 2 ]. 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 VO 2 was unchanged and ΔC(a-v)O 2 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 O 2 extraction behaviour. Direct rest and exercise CO should be measured to assess pMVR efficacy., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose of Review: Exercise causes various dynamic changes in all body parts either in healthy subject or in heart failure (HF) patients. The present review of current knowledge about HF patients with reduced ejection fraction focuses on dynamic changes along a "metabo-hemodynamic" perspective., Recent Findings: Studies on the dynamic changes occurring during exercise span many years. Thanks to the availability of advanced methods, it is nowadays possible to properly characterize respiratory, hemodynamic, and muscular function adjustments and their mismatch with the pulmonary and systemic circulations. Exercise is a dynamic event that involves several body functions. In HF patients, it is important to know at what level the limitation takes place in order to better manage these patients and to optimize therapeutic strategies.

In chronic heart failure, minute ventilation ( V ' E ) for a given carbon dioxide production ( V ' CO 2 ) 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 ' CO 2 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 ' CO 2 is extrapolated to 0, embeds information on exercise-induced dead space changes, while the analysis of end-tidal and arterial CO 2 pressures provides knowledge about reflex activities. The V ' E versus V ' CO 2 relationship has a relevant prognostic power either alone or, better, when included within prognostic scores. The V ' E versus V ' CO 2 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 ' CO 2 slope as percentage of the predicted value, due to age and gender interferences. Relevant attention is needed in V ' E versus V ' CO 2 analysis in the presence of heart failure comorbidities. Finally, V ' E versus V ' CO 2 abnormalities are relevant targets for treatment in heart failure., Competing Interests: Conflict of interest: P. Agostoni reports non-financial support from Menarini, grants from Daiichi Sankyo and Bayer; non-financial support from Novartis and Boehringer; and grants and non-financial support from Actelion, outside the submitted work. Conflict of interest: S. Sciomer has nothing to disclose. Conflict of interest: P. Palermo reports personal fees from Novartis and Malesci, outside the submitted work. Conflict of interest: M. Contini reports personal fees and non-financial support from Dompé Farmaceutici S.p.A. and personal fees from Novartis, outside the submitted work. Conflict of interest: B. Pezzuto has nothing to disclose. Conflict of interest: S. Farina has nothing to disclose. Conflict of interest: A. Magini has nothing to disclose. Conflict of interest: F. De Martino has nothing to disclose. Conflict of interest: D. Magrì has nothing to disclose. Conflict of interest: S. Paolillo has nothing to disclose. Conflict of interest: G. Cattadori has nothing to disclose. Conflict of interest: C. Vignati has nothing to disclose. Conflict of interest: M. Mapelli has nothing to disclose. Conflict of interest: A. Apostolo has nothing to disclose. Conflict of interest: E. Salvioni has nothing to disclose., (Copyright ©ERS 2021.)

Heart failure is a complex syndrome affecting several organs including kidney, lungs, liver, brain muscles and sympathetic system. Each of these organs might contribute to its severity and prognosis. The prognosis assessment is critical for a correct heart failure management. It has already been demonstrated that a single parameter is weaker for prognosis than different parameters combined. The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has been built and validated for heart failure with reduced ejection fraction (HFrEF) patients by considering cardiopulmonary exercise test data combined with clinical, laboratory and echocardiographic measurements. The betablockers treatment is a milestone in the HFrEF management. In the MECKI score database, the association of betablockers treatment with outcome has been investigated in different settings.

Background: Heart failure with midrange ejection fraction (HFmrEF) represents a heterogeneous category where phenotype, as well as prognostic assessment, remains debated. The present study explores a specific HFmrEF subset, namely those who recovered from a reduced EF (rec-HFmrEF) and, particularly, it focuses on the possible additive prognostic role of cardiopulmonary exercise testing., Methods and Results: We analyzed data from 4535 patients with HFrEF and 1176 patients with rec-HFmrEF from the Metabolic Exercise combined with Cardiac and Kidney Indexes database. The end point was cardiovascular death at 5 years. The median follow-up was 1343 days (25th-75th range 627-2403 days). Cardiovascular death occurred in 552 HFrEF and 61 rec-HFmrEF patients. The multivariate analysis confirmed an independent role of the MECKI score's variables in HFrEF (C-index = 0.744) whereas, in the rec-HFmrEF group, only age and peak oxygen uptake (pVO 2 ) remained associated to the end point (C-index = 0.745). A peak oxygen uptake of ≤55% of predicted and a ventilatory efficiency of ≥31 resulted as the most accurate cut-off values in the outcome prediction., Conclusions: Present data support the cardiopulmonary exercise test and, particularly, the peak oxygen uptake, as a useful tool in the rec-HFmrEF prognostic assessment. A peak VO 2 of ≤55% predicted and ventilatory efficiency of ≥31 might help to identify a high-risk rec-HFmrEF subgroup., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The prognostic role of diabetes mellitus (DM) in heart failure (HF) patients is undefined, since DM is outweighed by several DM-related variables when confounders are considered. We determined the prognostic role of DM, treatment, and glycemic control in a real-life HF population., Methods: 3927 HF patients included in the Metabolic Exercise Cardiac Kidney Index (MECKI) score database were evaluated with a median follow-up of 3.66 years (IQR 1.70-6.67). Data analysis considered survival between DM (n = 897) vs. non-DM (n = 3030) patients, and, in diabetics, between insulin (n = 304), oral antidiabetics (n = 479), and dietary only (n = 88) treatments. The role of glycemic control was evaluated grouping DM patients according to glycated hemoglobin (HbA1c): <7% (n = 266), 7.1-8% (n = 133), >8% (n = 149). All analyses were performed also adjusting for ejection fraction, renal function, hemoglobin, sodium, exercise peak oxygen uptake, and ventilation/carbon dioxide relationship slope. Study primary endpoint was the composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Secondary endpoints were cardiovascular and all causes death., Results: For all endpoints, upon adjustment for confounders, DM status and insulin treatment or dietary regimen were not significantly associated with adverse long-term prognosis compared to non-DM and oral antidiabetic treated patients, respectively. A worse prognosis was observed in HbA1c >8% patients (Log-Rank p < 0.001), even after correction for confounding factors. All results were replicated by hazard ratio analysis., Conclusion: In HF patients, DM, insulin treatment and dietary regimen are not adverse outcome predictors. The only condition related to long-term prognosis, considering potential confounders, is poor glycemic control., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) typically develop dyspnea and pulmonary congestion upon exercise. Lung ultrasound is a simple diagnostic tool, providing semiquantitative assessment of extravascular lung water through B-lines. It has been shown that patients with HFpEF develop B-lines upon submaximal exercise stress echocardiography; however, whether exercise-induced pulmonary congestion carries prognostic implications is unknown. This study aimed at evaluating the prognostic value of B-line assessment during exercise in patients with HFpEF., Methods: Sixty-one New York Heart Association class I to II patients with HFpEF underwent standard echocardiography, lung ultrasound (28-scanning point method), and BNP (B-type natriuretic peptide) assessment during supine exercise echocardiography (baseline and peak exercise). The primary end point was a composite of cardiovascular death or HF hospitalization at 1 year., Results: B-lines, E/e', and BNP significantly increased during exercise ( P <0.001 for all). By multivariable analysis, both peak (hazard ratio, 1.50 [95% CI, 1.21-1.85], P <0.001), and change (hazard ratio 1.34 [95% CI, 1.12-1.62], P =0.002) B-lines were retained as independent predictors of outcome (hazard ratios per 1 B-line increment), along with BNP and E/e' ratio. Importantly, adding peak B-line on top of a clinical model significantly improved prognostic accuracy (C-index increase, 0.157 [0.056-0.258], P =0.002) and net reclassification (continuous net reclassification improvement, 0.51 [0.09-0.74], P =0.016), with similar results for B-line change., Conclusions: Detection of exercise-induced pulmonary congestion by lung ultrasound is an independent predictor of outcome in patients with HFpEF; its use may help refining the routine risk stratification of these patients on top of well-established clinical variables.

Aims: Ventilation vs. carbon dioxide production (VE/VCO 2 ) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO 2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO 2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO 2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value., Methods and Results: We calculated the linear regressions between age and VE/VCO 2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13-83 years). We then applied age-adjusted and sex-adjusted formulas to predict VE/VCO 2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO 2 14.8 ± 4.9, mL/min/kg, VE/VCO 2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO 2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO 2 < 14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO 2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO 2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO 2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO 2 values. The 2-year survival prognostic power of VE/VCO 2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO 2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO 2 < 14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015)., Conclusions: The percentage of predicted VE/VCO 2 slope value strengthens the prognostic power of VE/VCO 2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO 2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Coronary artery disease is a major underlying etiology for heart failure. The role of coronary microvascular disease, and endothelial dysfunction, in the pathophysiology of heart failure is poorly appreciated. Endothelial dysfunction, induced by oxidative stress, contributes to the development of heart failure. Alterations of endothelial function and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure with both reduced and preserved ejection fraction. Indeed, an altered endothelium dependent vasodilatation, causing repeated episodes of ischemia/reperfusion, can induce a chronic stunned myocardium with systolic dysfunction and an increased diastolic stiffness with diastolic dysfunction. Moreover, the altered NO-cGMP pathway directly affects myocardial homeostasis. Endothelial dysfunction is associated with worse prognosis and higher rate of cardiovascular events. Potential therapeutic strategies targeting the NO-cGMP pathway in patients with HF will be discussed in this review article. Although clinical data are still inconclusive, the NO-cGMP pathway represents a promising target for therapy.

Aims: Exercise oscillatory ventilation (EOV) is a pivotal cardiopulmonary exercise test parameter for the prognostic evaluation of patients with chronic heart failure (HF). It has been described in patients with HF with reduced ejection fraction (<40%, HFrEF) and with HF with preserved ejection fraction (>50%, HFpEF), but no data are available for patients with HF with mid-range ejection fraction (40-49%, HFmrEF). The aim of the study was to evaluate the prognostic role of EOV in HFmrEF patients., Methods and Results: We analysed 1239 patients with HFmrEF and 4482 patients with HFrEF, enrolled in the MECKI score database, with a 2-year follow-up. The study endpoint was the composite of cardiovascular death, urgent heart transplant, and ventricular assist device implantation. We identified EOV in 968 cases (16% and 17% of cases in HFmrEF and HFrEF, respectively). HFrEF EOV+ patients were significantly older, and their parameters suggested a more severe HF than HFrEF EOV- patients. A similar behaviour was found in HFmrEF EOV+ vs. EOV- patients. Kaplan-Meier analysis, irrespective of ejection fraction, showed that EOV is associated with a worse survival, and that patients with HFrEF and HFmrEF EOV+ had a significantly worse outcome than the EOV- of the same ejection fraction groups. EOV-associated survival differences in HFmrEF patients started after 18 months of follow-up., Conclusion: Exercise oscillatory ventilation has a similar prevalence and ominous prognostic value in both HFmrEF and HFrEF patients, indicating a group of patients in need of a more intensive follow-up and a more aggressive therapy. In HFmrEF, the survival curves between EOV+ and EOV- patients diverged only after 18 months., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Heart failure (HF) is common in Type-2 diabetes mellitus (T2DM), and viceversa, leading to a mutual impact on prognosis. Knowledge about this complex interplay has dramatically changed recently, due to development of new glucose-lowering drugs, and to specific FDA and EMA Guidance mandating to perform cardiovascular outcome trials (CVOTs), aimed at establishing cardiovascular safety, for new anti-diabetic treatments before they enter the market. Such CVOTs have demonstrated that the effects of the new antidiabetic drugs on the mutual interactions between T2DM and HF may develop across different phases:Results of such trials can be summarized as: (a) all different classes of novel glucose-lowering drugs have good cardiovascular safety profile; (b) with respect to HF, DPP4 inhibitors might tend to increase risk; (c) sodium-glucose co-transporter 2 inhibitors (SGTLi), significantly reduce it; (d) glucagon-like peptide 1 receptor agonists (GLP1) tend to be neutral. These CVOTs data have led to guideline recommendations indicating appropriate therapy to T2DM patients with HF not at glycemic control target with metformin therapy., (Copyright © 2019. Published by Elsevier B.V.)

Aims: Exercise-derived parameters, specifically peak exercise oxygen uptake (peak VO 2 ) and minute ventilation/carbon dioxide relationship slope (VE/VCO 2 slope), have a pivotal prognostic value in heart failure (HF). It is unknown how the prognostic threshold of peak VO 2 and VE/VCO 2 slope has changed over the last 20 years in parallel with HF prognosis improvement., Methods and Results: Data from 6083 HF patients (81% male, age 61 ± 13 years), enrolled in the MECKI score database between 1993 and 2015, were retrospectively analysed. By enrolment year, four groups were generated: group 1 1993-2000 (n = 440), group 2 2001-2005 (n = 1288), group 3 2006-2010 (n = 2368), and group 4 2011-2015 (n = 1987). We compared the 10-year survival of groups and analysed how the overall risk (cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation) changed over time according to peak VO 2 and VE/VCO 2 slope and to major clinical and therapeutic variables. At 10 years, a progressively higher survival from group 1 to group 3 was observed, with no further improvement afterwards. A 20% risk for peak VO 2 15 mL/min/kg (95% confidence interval 16-13), 9 (11-8), 4 (4-2) and 5 (7-4) was observed in group 1, 2, 3, and 4, respectively, while the VE/VCO 2 slope value for a 20% risk was 32 (37-29), 47 (51-43), 59 (64-55), and 57 (63-52), respectively., Conclusions: Heart failure prognosis improved over time up to 2010 in a HF population followed by experienced centres. The peak VO 2 and VE/VCO 2 slope cut-offs identifying a definite risk progressively decreased and increased over time, respectively. The prognostic threshold of peak VO 2 and VE/VCO 2 slope must be updated whenever HF prognosis improves., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: The usefulness of β-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned., Methods and Results: We analyzed data from HF patients (958 patients (801 males, 84%, age 67 ± 11 years)) with AF enrolled in the MECKI score database. We evaluated prognosis (composite of cardiovascular death, urgent heart transplant, or left ventricular assist device) of patients receiving β-blockers (n = 777, 81%) vs. those not treated with β-blockers (n = 181, 19%). We also analyzed the role β1-selectivity and the role of daily β-blocker dose. To account for different HF severity, Kaplan-Meier survival curves were normalized for relevant confounding factors and for treatment strategies. Dose was available in 629 patients. Median follow-up was 1312 (577-2304) days in the entire population, 1203 (614-2420) and 1325 (569-2300) days in patients not receiving and receiving β-blockers. 224 (23%, 54/1000 events/year), 163 (21%, 79/1000 events/year), and 61 (34%, 49/1000 events/year) events were recorded, respectively. At 10-year patients treated with β-blockers had a better outcome (HR 0.447, p < 0.01) with no effects as regards β1selective drugs (53%) vs. β1-β2 blockers (47%). Survival improved in parallel with β-blocker dose increase (HR 0.296, 0.496, 0.490 for the high, medium, and low dose vs. no β-blockers, p < 0.0001)., Conclusion: HF patients with AF taking a β-blocker have a better outcome (with a survival improvement in parallel with daily dose but no differences as regards β1 selectivity) but this does not mean that β-blockers improve outcomes in these patients as we cannot control for all the potential confounders associated with β-blocker use., (Copyright © 2018. Published by Elsevier B.V.)

Aims: Mineralocorticoid receptor antagonists (MRAs) have been demonstrated to improve outcomes in reduced ejection fraction heart failure (HFrEF) patients. However, MRAs added to conventional treatment may lead to worsening of renal function and hyperkalaemia. We investigated, in a population-based analysis, the long-term effects of MRA treatment in HFrEF patients., Methods and Results: We analysed data of 6046 patients included in the Metabolic Exercise Cardiac Kidney Index score dataset. Analysis was performed in patients treated (n = 3163) and not treated (n = 2883) with MRA. The study endpoint was a composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Ten years' survival was analysed through Kaplan-Meier, compared by log-rank test and propensity score matching. At 10 years' follow-up, the MRA-untreated group had a significantly lower number of events than the MRA-treated group (P < 0.001). MRA-treated patients had more severe heart failure (higher New York Heart Association class and lower left ventricular ejection fraction, kidney function, and peak VO 2 ). At a propensity-score-matching analysis performed on 1587 patients, MRA-treated and MRA-untreated patients showed similar study endpoint values., Conclusions: In conclusion, MRA treatment does not affect the composite of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation in a real-life setting. A meticulous patient follow-up, as performed in trials, is likely needed to match the positive MRA-related benefits observed in clinical trials., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

The present update is dedicated to the evolution of the interaction between heart failure (HF) and exercise and how the scientific community has handled it. Indeed, on the one hand, HF is a leading cause of morbidity and mortality with a stable prevalence from 1998 onward varying between 6.3% and 13.3%. On the other hand, exercise is seen as a diagnostic and prognostic tool as well as a therapeutic intervention in chronic HF. More precisely, the knowledge, the clinical application, and the research interest on the mutual interactions between exercise and HF have different phases in disease progression: Before HF onset (past): exercise provides protective benefit in preventing HF (primary prevention). With HF present: exercise improvement with training provides benefits in HF (secondary prevention). The prediction of future in HF patients: exercise impairment, as a leading characteristic of HF, is used as a prognostic factor., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Risk stratification in heart failure (HF) is crucial for clinical and therapeutic management. A multiparametric approach is the best method to stratify prognosis. In 2012, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score was proposed to assess the risk of cardiovascular mortality and urgent heart transplantation. The aim of the present study was to compare the prognostic accuracy of MECKI score to that of HF Survival Score (HFSS) and Seattle HF Model (SHFM) in a large, multicentre cohort of HF patients with reduced ejection fraction., Methods and Results: We collected data on 6112 HF patients and compared the prognostic accuracy of MECKI score, HFSS, and SHFM at 2- and 4-year follow-up for the combined endpoint of cardiovascular death, urgent cardiac transplantation, or ventricular assist device implantation. Patients were followed up for a median of 3.67 years, and 931 cardiovascular deaths, 160 urgent heart transplantations, and 12 ventricular assist device implantations were recorded. At 2-year follow-up, the prognostic accuracy of MECKI score was significantly superior [area under the curve (AUC) 0.781] to that of SHFM (AUC 0.739) and HFSS (AUC 0.723), and this relationship was also confirmed at 4 years (AUC 0.764, 0.725, and 0.720, respectively)., Conclusion: In this cohort, the prognostic accuracy of the MECKI score was superior to that of HFSS and SHFM at 2- and 4-year follow-up in HF patients in stable clinical condition. The MECKI score may be useful to improve resource allocation and patient outcome, but prospective evaluation is needed., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: A reduced cardiac output (CO) response during exercise is a major limiting factor in heart failure (HF). Oxygen consumption (VO 2 ) is directly proportional to CO. Peripheral mechanisms via arteriovenous oxygen difference (Δ(a-v)O 2 ) play a pivotal role in chronic HF. We hypothesized a weak correlation between peak VO 2 and peak CO with a greater Δ(a-v)O 2 variability in most severe HF., Methods: We analyzed 278 HF patients (NYHA II-III) who performed maximal cardiopulmonary exercise test with non-invasive CO measurement by inert gas rebreathing., Results: Median peakVO 2 , CO and Δ(a-v)O 2 were 0.96 (0.78-1.28) L/min, 6.3 (5.1-8.0) L/min and 16.0 (14.2-18.0) mL/100mL respectively, with a linear relationship between VO 2 and CO: CO=5.3×VO 2 +1.13 (r 2 =0.705, p<0.001). Patients were grouped according to exercise limitation. Group 1 (101 patients) peakVO 2 <50% pred: peakVO 2 0.80 (0.67-0.94) L/min, peakCO 5.6 (4.7-6.5) L/min, peakΔ(a-v)O 2 14.8 (12.9-17.1) mL/100mL. Group 2 (89 patients) peakVO 2 ≥50-<65% pred: peakVO 2 1.02 (0.84-1.29) L/min, peakCO 6.4 (5.1-8.0) L/min, peakΔ(a-v)O 2 16.7 (15.0-18.5) mL/100mL. Group 3 (88 patients) peakVO 2 ≥65% pred: peakVO 2 1.28 (0.93-1.66) L/min, peakCO 8.0 (6.2-9.7) L/min, peakΔ(a-v)O 2 16.8 (14.6-18.3) mL/100mL. A peakVO 2 and peakCO linear relationship was observed in Group 1 (r 2 =0.381, p<0.001), Group 2 (r 2 =0.756, p<0.001) and Group 3 (r 2 =0.744, p<0.001)., Conclusions: With worsening HF we observed a progressive reduction of peak CO and peak VO 2 . However in most compromised patients also peripheral mechanisms play a role as indicated by reduced Δ(a-v)O 2 ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cardiac output is a key parameter in the assessment of cardiac function, and its measurement is fundamental to the diagnosis, treatment, and prognostic evaluation of all heart diseases. Until recently, cardiac output determination during exercise had been only possible through invasive methods, which were not practical in the clinical setting. Because [Formula: see text]o 2 is cardiac output times arteriovenous content difference, evaluation of cardiac output is usually included in its measurement. Because of the difficulty of directly measuring peak exercise cardiac output, indirect surrogate parameters have been proposed, but with only modest clinical usefulness. Direct measurement of cardiac output can now be made by several noninvasive techniques, such as rebreathing inert gases, impedance cardiology, thoracic bioreactance, estimated continuous cardiac output technology, and transthoracic echocardiography coupled to cardiopulmonary exercise testing, which allow more definitive results and better understanding of the underlying physiopathology.

Aims: The use of β-blockers represents a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF). Few studies have compared β-blockers in HFrEF, and there is little data on the effects of different doses. The present study aimed to investigate in a large database of HFrEF patients (MECKI score database) the association of β-blocker treatment with a composite outcome of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation, addressing the role of β-selectivity and dosage regimens., Methods and Results: In 5242 HFrEF patients, we investigated the role of: (i) β-blocker treatment vs. non-β-blocker treatment, (ii) β1-/β2-receptor-blockers vs. β1-selective blockers, and (iii) daily β-blocker dose. Patients were followed for 3.58 years, and 1101 events (18.3%) were observed; 4435 patients (86.8%) were on β-blockers, while 807 (13.2%) were not. At 5 years, β-blocker-patients showed a better outcome than non-β-blocker-subjects [hazard ratio (HR) 0.48, P < 0.0001], while also considering potential confounders. A comparable prognosis was observed at 5 years in the β1-/β2-receptor-blocker (n = 2219) vs. β1-selective group (n = 2216) (HR 0.95, P = ns). A better prognosis was observed in high-dose (>2 5 mg carvedilol equivalent daily dose, n = 1005) patients than in both medium dose (12.5-25 mg, n = 1431) and low dose (<12.5 mg, n = 1960) (HR 1.97, P < 0.001; HR 1.95, P = 0.001, respectively), with no differences between the last two groups (HR 0.84, P = ns)., Conclusion: In a large population of chronic HFrEF patients, β-blockers were associated with a more favourable prognosis without any difference between β1- and β2-receptor-blockers vs. β1-selective blockers. A better outcome was observed in subjects receiving a high daily dose., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: Cardiac output (Q˙) is a key parameter in the assessment of cardiac function, its measurement being crucial for the diagnosis, treatment, and prognostic evaluation of all heart diseases. Until recently, Q˙ determination at peak exercise has been possible through invasive methods, so that normal values were obtained in studies based on small populations., Methods: Nowadays, peak Q˙ can be measured noninvasively by means of the inert gas rebreathing (IGR) technique. The present study was undertaken to provide reference values for peak Q˙ in the normal general population and to obtain a formula able to estimate peak exercise Q˙ from measured peak oxygen uptake (V˙o 2 )., Results: We studied 500 normal subjects (age, 44.9 ± 1.5 years; range, 18-77 years; 260 men, 240 women) who underwent a maximal cardiopulmonary exercise test with peak Q˙ measurement by IGR. In the overall study sample, peak Q˙ was 13.2 ± 3.5 L/min (men, 15.3 ± 3.3 L/min; women, 11.0 ± 2.0 L/min; P < .001) and peak V˙o 2 was 95% ± 18% of the maximum predicted value (men, 95% ± 19%; women, 95% ± 18%). Peak V˙o 2 and peak Q˙ progressively decreased with age (R 2 , 0.082; P < .001; and R 2 , 0.144; P < .001, respectively). The V˙o 2 -derived formula to measure Q˙ at peak exercise was (4.4 × peak V˙o 2 ) + 4.3 in the overall study cohort, (4.3 × peak V˙o 2 ) + 4.5 in men, and (4.9 × peak V˙o 2 ) + 3.6 in women., Conclusions: The simultaneous measurement of Q˙ and V˙o 2 at peak exercise in a large sample of healthy subjects provided an equation to predict peak Q˙ from peak V˙o 2 values., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Backgrounds: Peak exercise cardiac output (CO) increase is associated with an increase of peak oxygen uptake (VO 2 ), provided that arteriovenous O 2 difference [Δ(Ca-Cv)O 2 ] does not decrease. At anaerobic threshold, VO 2 , is related to CO. We tested the hypothesis that, in heart failure (HF) patients with left ventricular assistance device (LVAD), an acute increase of CO obtained through changes in LVAD pump speed is associated with peak exercise and anaerobic threshold VO 2 increase., Methods: Fifteen of 20 patients bearing LVAD (Jarvik 2000) enrolled in the study successfully performed peak exercise evaluation. All patients had severe HF as shown by clinical evaluation, laboratory tests, echocardiography, spirometry with alveolar-capillary diffusion, and maximal cardiopulmonary exercise testing (CPET). CPETs with non-invasive CO measurements at rest and peak exercise were done on 2days at LVAD pump speed set randomly at 2 and 4., Results: Increasing LVAD pump speed from 2 to 4 increased CO from 3.4±0.9 to 3.8±1.0L/min (ΔCO 0.4±0.6L/min, p=0.04) and from 5.3±1.3 to 5.9±1.4L/min (ΔCO 0.6±0.7L/min, p<0.01) at rest and peak exercise, respectively. Similarly, VO 2 increased from 788±169 to 841±152mL/min (ΔVO 2 52±76mL/min, p=0.01) and from 568±116 to 619±124mL/min (ΔVO 2 69±96mL/min, p=0.02) at peak exercise and at anaerobic threshold, respectively. Δ(Ca-Cv)O 2 did not change significantly, while ventilatory efficiency improved (VE/VCO 2 slope from 39.9±5.4 to 34.9±8.3, ΔVE/VCO 2 -5.0±6.4, p<0.01)., Conclusions: In HF, an increase in CO with a higher LVAD pump speed is associated with increased peak VO 2 , postponed anaerobic threshold, and improved ventilatory efficiency., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Anemia is frequent in heart failure (HF), and it is associated with higher mortality. The predictive power of established HF prognostic parameters in anemic HF patients is unknown., Methods: Clinical, laboratory, echocardiographic and cardiopulmonary-exercise-test (CPET) data were analyzed in 3913 HF patients grouped according to hemoglobin (Hb) values. 248 (6%), 857 (22%), 2160 (55%) and 648 (17%) patients had very low (<11g/dL), low (11-12 for females, 11-13 for males), normal (12-15 for females, 13-15 for males) and high (>15) Hb, respectively., Results: Median follow-up was 1363days (606-1883). CPETs were always performed safely. Hb was related to prognosis (Hazard ratio (HR)=0.864). No prognostic difference was observed between normal and high Hb groups. Peak oxygen consumption (VO 2 ), ventilatory efficiency (VE/VCO 2 slope), plasma sodium concentration, ejection fraction (LVEF), kidney function and Hb were independently related to prognosis in the entire population. Considering Hb groups separately, peakVO 2 (very low Hb HR=0.549, low Hb HR=0.613, normal Hb HR=0.618, high Hb HR=0.542) and LVEF (very low Hb HR=0.49, low Hb HR=0.692, normal Hb HR=0.697, high Hb HR=0.694) maintained their prognostic roles. High VE/VCO 2 slope was associated with poor prognosis only in patients with low and normal Hb., Conclusions: Anemic HF patients have a worse prognosis, but CPET can be safely performed. PeakVO 2 and LVEF, but not VE/VCO 2 slope, maintain their prognostic power also in HF patients with Hb<11g/dL, suggesting CPET use and a multiparametric approach in HF patients with low Hb. However, the prognostic effect of an anemia-oriented follow-up is unknown., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Although cardiopulmonary exercise testing (CPET) is considered as an important tool in risk stratification of patients with heart failure (HF), prognostic data in the specific setting of Idiopathic Dilated Cardiomyopathy (iDCM) are still undetermined. The aim of the study was to test the prognostic value of CPET in a large cohort of iDCM patients., Methods and Results: We analyzed 381 iDCM patients who consecutively performed CPET. The study end-point was a composite of cardiovascular death/urgent heart transplantation (CVD/HTx). In the overall population the average values of peak oxygen consumption (peak VO 2 /kg) and percent-predicted peak VO 2 (peak VO 2 %) were 17.1±5.1ml/kg/min and 59±15%, respectively. Mean VE/VCO 2 slope was 29.8±6.1. During a median follow-up of 47months (interquartile range 23-84), 83 patients experienced CVD/HTx. Peak VO 2 % (Area Under the Curve [AUC] 0.74; 95% CI 0.71-0.85, p<0.001) and VE/VCO 2 slope (AUC 0.78; 95% CI 0.74-0.84, p<0.001) were more accurate in predicting CVD/HTx compared to peak VO 2 /kg (AUC 0.60; 95% CI 0.54-0.68, p=0.003) (p<0.001 for both comparisons). The most accurate threshold values for outcome prediction in our iDCM cohort were <60% for peak VO 2 % and >29 for VE/VCO 2 slope. At multivariable analysis peak VO 2 % and VE/VCO 2 slope were the strongest predictors of CVD/HTx, either as continuous and categorical variables, whereas peak VO 2 /kg was not independently related with prognosis., Conclusion: In a large population of iDCM patients peak VO 2 % and VE/VCO 2 slope emerged as the strongest prognostic CPET variables. Prospective studies will be necessary to confirm these data., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In heart failure (HF), women show better survival despite a comparatively low peak oxygen consumption (V˙o2): this raises doubt about the accuracy of risk assessment by cardiopulmonary exercise testing (CPET) in women. Accordingly, we aimed to check (1) whether the predictive role of well-known CPET risk indexes, ie, peak V˙o2 and ventilatory response (V˙e/V˙co2 slope), is sex independent and (2) if sex-related characteristics that impact outcome in HF should be considered as associations that may confound the effect of sex on survival., Methods: The study population consisted of 2985 patients with HF, 498 (17%) of whom were women, from the multicentre Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI): the end point was cardiovascular death within a 3-year period., Results: During the follow-up, 305 (12%) men and 39 (8%) women (P = 0.005) died, and female sex was linked to better survival on univariate analysis (P = 0.008) and independent of peak V˙o2 and V˙e/V˙co2 slope on multivariate analysis. According to propensity score matching for female sex to exclude a sex selection bias and sample discrepancy, 498 men were selected: the standardized percentage bias ranged from 20.8 (P < 0.0001) to 3.3 (P = 0.667). After clinical profile harmonizing, female sex was predictive of HF at univariate analysis., Conclusions: The low peak V˙o2 and female association with better outcome in HF might be counterfeit: the female prognostic advantage is lost when sex-specific differences are correctly taken into account with propensity score matching, suggesting that for an effective and efficient HF model, adjustment must be made for sex-related characteristics., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: Obesity has been found to be protective in heart failure (HF), a finding leading to the concept of an obesity paradox. We hypothesized that a preserved cardiorespiratory fitness in obese HF patients may affect the relationship between survival and body mass index (BMI) and explain the obesity paradox in HF., Methods and Results: A total of 4623 systolic HF patients (LVEF 31.5 ± 9.5%, BMI 26.2 ± 3.6 kg/m(2) ) were recruited and prospectively followed in 24 Italian HF centres belonging to the MECKI Score Research Group. Besides full clinical examination, patients underwent maximal cardiopulmonary exercise test at study enrolment. Median follow-up was 1113 (553-1803) days. The study population was divided according to BMI (<25, 25-30, >30 to ≤35 kg/m(2) ) and predicted peak oxygen consumption (peak VO2 , <50%, 50-80%, >80%). Study endpoints were all-cause and cardiovascular deaths including urgent cardiac transplant. All-cause and cardiovascular deaths occurred in 951 (28.6%, 57.4 per person-years) and 802 cases (17.4%, 48.4 per 1000 person-years), respectively. In the high BMI groups, several prognostic parameters presented better values [LVEF, peak VO2 , ventilation/carbon dioxide slope, renal function, and haemoglobin (P < 0.01)] compared with the lower BMI groups. Both BMI and peak VO2 were significant positive predictors of longer survival: both higher BMI and peak VO2 groups showed lower mortality (P < 0.001). At multivariable analysis and using a matching procedure (age, gender, LVEF, and peak VO2 ), the protective role of BMI disappeared., Conclusion: Exercise tolerance affects the relationship between BMI and survival. Cardiorespiratory fitness mitigates the obesity paradox observed in HF patients., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)