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Natriuretic peptides (NP) are recognized as the most powerful predictors of adverse outcomes in heart failure (HF). We hypothesized that a measure of functional limitation, as assessed by 6-min walking test (6MWT), would improve the accuracy of a prognostic model incorporating a NP. This was a multicenter observational retrospective study. We studied the prognostic value of severe functional impairment (SFI), defined as the inability to perform a 6MWT or a distance walked during a 6MWT < 300 m, in 1696 patients with HF admitted to cardiac rehabilitation. The primary outcome was 1-year all-cause mortality. After adjusting for the baseline multivariable risk model-including age, sex, systolic blood pressure, anemia, renal dysfunction, sodium level, and NT-proBNP-or for the MAGGIC score, SFI had an odds ratio of 2.58 (95% CI 1.72-3.88; p < 0.001) and 3.12 (95% CI 2.16-4.52; p < 0.001), respectively. Adding SFI to the baseline risk model or the MAGGIC score yielded a significant improvement in discrimination and risk classification. Our data suggest that a simple, 6MWT-derived measure of SFI is a strong predictor of death and provide incremental prognostic information over well-established risk markers in HF, including NP, and the MAGGIC score., (© 2024. The Author(s).)

Aims: Chronotropic incompetence (CI) is a strong predictor of outcome in heart failure with reduced ejection fraction, however no data on its clinical and prognostic impacts in heart failure with mildly reduced ejection fraction (HFmrEF) are available. Therefore, the study aims to investigate, in a large multicentre HFmrEF cohort, the prevalence of CI as well as its relationship with exercise capacity and its prognostic role over the cardiopulmonary exercise testing (CPET) parameters., Methods and Results: Within the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) database, we analysed data of 864 HFmrEF out of 1164 stable outpatients who performed a maximal CPET at the cycle ergometer and who had no significant rhythm disorders or comorbidities. The primary study endpoint was cardiovascular (CV) death. All-cause death was also explored. Chronotropic incompetence prevalence differed depending on the method (peak heart rate, pHR% vs. pHR reserve, pHRR%) and the cut-off adopted (pHR% from ≤75% to ≤60% and pHRR% ≤ 65% to ≤50%), ranging from 11% to 62%. A total of 84 (9.7%) CV deaths were collected, with 39 (4.5%) occurring within 5 years. At multivariate analysis, both pHR% [hazard ratio 0.97 (0.95-0.99), P < 0.05] and pHRR% [hazard ratio 0.977 (0.961-0.993), P < 0.01] were associated with the primary endpoint. A pHR% ≤ 75% and a pHRR% ≤ 50% represented the most accurate cut-off values in predicting the outcome., Conclusion: The study suggests an association between blunted exercise-HR response, functional capacity, and CV death risk among patients with HFmrEF. Whether the CI presence might be adopted in daily HFmrEF management needs to be addressed in larger prospective studies., 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.)

There is limited evidence regarding the prognostic value of the 6-minute walk test for patients with advanced heart failure (HF). Accordingly, we studied 260 patients presenting to inpatient cardiac rehabilitation (CR) with advanced HF. The primary outcome was 3-year all-cause mortality after discharge from CR. The association between 6-minute walk distance (6MWD) and the primary outcome was determined using the multivariable Cox regression analysis. To avoid collinearity, 6MWD at admission (6MWD adm ) to CR and 6MWD at discharge (6MWD disch ) from CR were analyzed separately. At multivariable analysis, 4 baseline characteristics (age, ejection fraction, systolic blood pressure, and blood urea nitrogen) were identified as prognostic of the primary outcome (baseline risk model). After adjusting for the baseline risk model, the hazard ratios of 6MWD adm and 6MWD disch modeled as per 50-m increase for the primary outcome were 0.92 (95% confidence interval [CI] 0.85 to 0.99, p = 0.035) and 0.93 (95% CI 0.88 to 0.99, p = -017), respectively. After adjusting for the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) score, the corresponding hazard ratios were 0.91 (95% CI 0.84 to 0.98, p = 0.017) and 0.93 (95% CI 0.88 to 0.99, p = 0.016). The addition of either 6MWD adm or 6MWD disch to the baseline risk model or the MAGGIC score yielded a statistically significant increase in global chi-square and in the net proportion of survivors reclassified downward. In conclusion, our data suggest that the distance covered during a 6-minute walk test predicts survival and provides incremental prognostic information on the top of well-established prognostic factors and the MAGGIC risk score in advanced HF., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diabetic patients frequently develop heart failure with preserved (HFpEF) or mid-range (HFmEF) cardiac ejection fractions. This condition may be secondary to diabetic cardiomyopathy or one of several relevant comorbidities, mainly hypertension. Several mechanisms link diabetes to HFpEF or HFmEF. Among these, non-enzymatic glycation of interstitial proteins, lipotoxicity, and endothelial dysfunction may promote structural damage and ultimate lead to heart failure. Findings from several large-scale trials indicated that treatment with sodium/glucose cotransporter 2 inhibitors (SGLT2-iss) resulted in significant improvements in cardiovascular outcomes in diabetic patients with high cardiovascular risk. However, there is currently some evidence that suggests a clinical advantage of using SGLT2-iss specifically in cases of HFpEF or HFmEF. Preclinical and clinical studies revealed that SGLT2-iss treatment results in a reduction in left ventricular mass and improved diastolic function. While some of the beneficial effects of SGLT2-iss have already been characterized (e.g., increased natriuresis and diuresis as well as reduced blood pressure, plasma volume, and arterial stiffness, and nephron-protective activities), there is increasing evidence suggesting that SGLT2-iss may have direct actions on the heart. These findings include SGLT2-iss-mediated reductions in the expression of hypertrophic foetal genes and diastolic myofilaments stiffness, increases in global phosphorylation of myofilament regulatory proteins (in HFpEF), inhibition of cardiac late sodium channel current and Na + /H + exchanger activity, metabolic shifts, and effects on calcium cycling. Preliminary data from previously published studies suggest that SGLT2-iss could be useful for the treatment of HFpEF and HFmEF. Several large ongoing trials, including DELIVER AND EMPEROR -preserved have been designed to evalute the efficacy of SGLT2-iss in improving clinical outcomes in patients diagnosed with HFpEF. The goal of this manuscript is to review the use of SGLT2-iss inhibitors for HFpEF or HFmEF associated with diabetes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is limited evidence regarding the effects of cardiac rehabilitation (CR) in patients with heart failure and preserved ejection fraction (HFpEF)., Methods: We studied 1784 patients admitted to inpatient CR. The patients were grouped into HFpEF (EF≥0.50), HF with mildly reduced EF (HFmrEF; EF 41-49), and HF with reduced EF (HFrEF; EF≤0.40). A standardized 6-min walking test was performed at admission and discharge. Measures of functional outcome were: (1) absolute increase in 6-min walking distance (6MWD) from admission to discharge >50 m and (2) increase in 6MWD to ≥300 among the patients who walked <300 m at admission., Results: After adjustment, the patients with HFpEF or HFmrEF were as likely as those with HFrEF to achieve an increase in 6MWD >50 m (odds ratio 0.95 [95%CI 0.71-1.24; p=0.648] and 1.04 [95%CI 0.77-1.41; p=0.769], respectively) or an increase in 6MWD to ≥300 m (odds ratio 0.79 [95%CI 0.51-1.23; p=0.299] and 0.65 [95%CI 0.38-1.12; p=0.118], respectively). The adjusted hazard ratio of 5-year mortality for patients who achieved an increase in 6MWD >50 m was 0.60 (95%CI 0.51-0.71; p<0.001) and that for patients who achieved an increase in 6MWD at discharge to ≥300 m 0.61 (95%CI 0.48-0.79; p<0.001). In each EF group, both outcomes remained independently associated with improved survival., Conclusions: Our data suggest that patients with HFpEF or HFmrEF are as likely as those with HFrEF to benefit from CR in terms of functional improvement. Functional improvement was independently associated with improved long-term survival, regardless of EF., Competing Interests: Declarations of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. 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: Predicting maximal heart rate (MHR) in heart failure with reduced ejection fraction (HFrEF) still remains a major concern. In such a context, the Keteyian equation is the only one derived in a HFrEF cohort on optimized β-blockers treatment. Therefore, using the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) data set, we looked for a possible MHR equation, for an external validation of Keteyien formula and, contextually, for accuracy of the historical MHR formulas and their relationship with the HR measured at the anaerobic threshold (AT)., Methods and Results: Data from 3487 HFrEF outpatients on optimized β-blockers treatment from the MECKI data set were analyzed. Besides excluding all possible confounders, the new equation was derived by using HR data coming from maximal cardiopulmonary exercise test. The simplified derived equation was [109-(0.5*age) + (0.5*HR rest) + (0.2*LVEF)-(5 if haemoglobin &lt;11 g/dL)]. The R2 and the standard error of the estimate were 0.24 and 17.5 beats min-1 with a mean absolute percentage error (MAPE) = 11.9%. The Keteyian equation had a slightly higher MAPE = 12.3%. Conversely, the Fox and Tanaka equations showed extremely higher MAPE values. The range 75-80% of MHR according to the new and the Keteyian equations was the most accurate in identifying the HR at the AT (MAPEs = 11.3-11.6%)., Conclusion: The derived equation to estimate the MHR in HFrEF patients, by accounting also for the systolic dysfunction degree and anaemia, improved slightly the Keteyian formula. Both formulas might be helpful in identifying the true maximal effort during an exercise test and the intensity domain during a rehabilitation programme., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In a previous study, we found that miR-150-5p was specifically downregulated in patients with advanced heart failure (HF). Here, we investigated the long-term prognostic potential of miR-150-5p., Methods: We studied optimally-treated HF outpatients with reduced ejection fraction. The primary outcome comprised the composite of death, urgent heart transplantation (HT) and ventricular assist device (VAD) implantation within 30 months. We used recursive partitioning analysis to identify the optimal log miR-150-5p cut-off. The association of log miR-150-5p with the primary outcome was examined using Cox regression analysis. We used the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score for adjustment in multivariable analysis. Finally, we compared the global fit of three models (MAGGIC score + miR-150-5p, MAGGIC score + NT-proBNP, and NT-proBNP + miR-150-5p) using Akaike Information Criterion., Results: Recursive partitioning analysis identified the value of -2.22 as the optimal cut-off for log miR-150-5p. Thirty-month survival free of urgent HT/VAD implantation was 31% among the patients with log miR-150-5p<-2.22 and 86% among those with log miR-150-5p>-2.22. Crude hazard ratio (HR) of the primary outcome for log miR-150-5p expression level <-2.22 was 6.70 (95% CI: 2.31-19.38; P<0.001). After adjusting for the MAGGIC score in multivariable analysis, the HR was 4.40 (95% CI: 1.52-12.77; P=0.006). Adding log miR-150-5p to the MAGGIC score led to an increase of 0.047 in C-index. The model combining miR-150-5p and MAGGIC score had a 73% likelihood of representing the best-fit model of those evaluated., Conclusions: Our data generate the hypothesis that miR-150-5p may represent a novel risk marker in HF with reduced ejection fraction.

Background: Poor functional status is highly prevalent among older patients hospitalized for HF and marks a downward inflection point in functional and prognostic trajectories. We assessed the prognostic value of 6-min walk test after transitional cardiac rehabilitation in older patients hospitalized for heart failure (HF)., Methods: We studied 759 patients aged ≥60 years who had been transferred to six inpatient rehabilitation facilities (IRF) from acute care hospitals after a hospitalization for acute HF. The primary outcome was 3-year all-cause mortality. We used multivariable Cox analysis to determine the association between 6-min walk distance (6MWD) at discharge from the IRFs and the primary outcome, adjusting for established predictors of death. The optimal cutoff for 6MWD was considered as the one that maximized the chi-square statistic., Results: Mean age was 75 ± 8 years. 6MWD significantly increased from admission to discharge (145 to 210 m; p < 0.001). The optimal cutoff for 6MWD was 198 m. After full adjustment, the hazard ratio for each 50 m-increase in discharge 6MWD was 0.90 (0.87-0.94; p < 0.001) and that for discharge 6MWD dichotomized at the optimal cutoff 0.48 (0.38-0.60; p < 0.001). The incidence rate of death/100 person-years for the patients who walked >198 m was 13.0 (10.0-15.5) compared with 30.8 (26.9-35.4) for those who walked <198 m. A statistically significant interaction of discharge 6MWD with left ventricular ejection fraction (EF) on the risk of death was observed (p value for interaction 0.047)., Conclusions: A rehabilitation intervention provided in the critical hospital-to-home transition period to older patients hospitalized for HF resulted in improved functional capacity. Increasing levels of functional capacity following rehabilitation were closely associated with decreasing risk of death; this association was significantly stronger for the subgroup with preserved EF., (© 2022 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Objective: To investigate the association of cardiac rehabilitation (CR) participation with all-cause mortality after a hospitalization for heart failure (HF) and to describe the characteristics and functional and clinical outcomes of HF patients undergoing inpatient CR., Design: Multicenter cohort study. The association between CR participation and all-cause mortality from discharge from the acute care setting was assessed using Cox regression analysis adjusting for established prognostic factors., Setting: Six inpatient rehabilitation facilities., Participants: A total of 3219 patients with HF admitted to inpatient CR between January 2013 and December 2016. Of these patients, 1455 had been transferred directly from acute care hospitals after a hospitalization for HF (CR-group 1) and 1764 had been admitted from the community due to worsening functional disability or worsening clinical conditions (CR-group 2). Serving as a control group were 633 patients not referred to CR after a hospitalization for HF served as control group (non-CR group)., Interventions: Cardiac rehabilitation., Main Outcome Measures: Long-term mortality. Secondary outcomes were: (1) change in functional capacity, as assessed by change in 6-minute walking distance from admission to discharge; (2) clinical outcomes of the index inpatient rehabilitation admission, including in-hospital mortality and unplanned readmission to the acute care., Results: Compared with the non-CR group, the adjusted hazard ratios of mortality at 1, 3, and 5 years for CR-group 1 patients were 0.82 (range, 0.68-0.97), 0.81 (range, 0.71-0.93), and 0.80 (range, 0.70-0.91). The 6-minute walking distance increased from 230-292 meters (P<.001), and 43.4% of the patients gained >50 m improvement. Overall, 2.5% of the patients died in hospital and 4.7% of the patients experienced unplanned readmissions to acute care, with significant differences between group 1 and group 2., Conclusions: Our data show that inpatient CR is effective in improving functional capacity and suggest that inpatient CR provided in the earliest period after a hospitalization for HF is associated with long-term improved survival., (Copyright © 2021 The American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic value of change in six-minute walking distance (6MWD) after treatment to predict mortality in heart failure (HF) remains a controversial issue. We assessed the prognostic value of rehabilitation-induced improvement in 6MWD in predicting mortality in patients with HF., Methods: We studied 2257 patients admitted to six inpatient rehabilitation facilities after a hospitalization for HF (N. 912) or because of worsening functional capacity and/or deteriorating clinical status (N. 1345). A six-minute walking test was performed at admission and discharge. The primary outcome was 3-year all-cause mortality after discharge from cardiac rehabilitation. We used multivariable Cox proportional hazard modeling to assess the association of increase in 6MWD with 3-year mortality, adjusting for established predictors of mortality., Results: 6MWD significantly increased by 61 m (p < .001) from admission to discharge and 969 patients (42.9%) achieved an increase in 6MWD >50 m. After full adjustment, an increase in 6MWD >50 m was associated with a 22% decreased risk for 3-year mortality (HR 0.78 [95% CI 0.68-0.91]; p = .002). When modeled as a continuous variable, improvement in 6MWD remained independently associated with decreased risk for 3-year mortality (HR per each 50 m increase: 0.92 [95% CI 0.88-0.96])., Conclusions: Rehabilitation-induced improvement in 6MWD was associated with a significantly reduced risk for 3-year mortality. Our data also suggest that an improvement in 6MWD of more than 50 m could represent a clinically meaningful endpoint of cardiac rehabilitation for patients with heart failure., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite improvements in pharmacotherapy, morbidity and mortality rates in community-based populations with chronic heart failure still remain high. The increase in medical complexity among patients with heart failure may be reflected by an increase in concomitant non-cardiovascular comorbidities, which are recognized as independent prognostic factors in this population. Heart failure and chronic kidney disease share many risk factors, and often coexist. The presence of kidney failure is associated with incremented risk of cardiovascular and non-cardiovascular mortality in heart failure patients. Chronic kidney disease is also linked with underutilization of evidence-based heart failure therapy that may reduce morbidity and mortality. More targeted therapies would be important to improve the prognosis of patients with these diseases. In recent years, serum uric acid as a determinant of cardiovascular risk has gained interest. Epidemiological, experimental and clinical data show that patients with hyperuricaemia are at increased risk of cardiac, renal and vascular damage and cardiovascular events. Moreover, elevated serum uric acid predicts worse outcome in both acute and chronic heart failure. While studies have raised the possibility of preventing heart failure through the use of uric acid lowering agents, the literature is still inconclusive on whether the reduction in uric acid will result in a measurable clinical benefit. Available evidences suggest that chronic kidney disease and elevated uric acid could worsen heart failure patients' prognosis. The aim of this review is to analyse a possible utilization of these comorbidities in risk stratification and as a therapeutic target to get a prognostic improvement in heart failure patients.

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.)

Objective: We investigated the performance of four prognostic tools in predicting 180-day mortality for patients admitted for acute decompensated heart failure (ADHF) by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) over a range of risk thresholds, in addition to discrimination and calibration., Study Design and Setting: We studied 1,458 patients. The risk assessment was performed using the Acute Decompensated Heart Failure National Registry (ADHERE) model and the Get With The Guidelines (GWTG), ADHF/NT-proBNP, and Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) risk scores., Results: C-statistics ranged from 0.727 for the ADHERE model to 0.767 for the ADHF/NT-proBNP score. The ADHF/NT-proBNP risk score, the ADHERE model, and the ASCEND risk score, but not the GWTG risk score, were also well calibrated. Sensitivity and PPV were modest at the >30% risk threshold and ranged from 55% for the ADHF/NT-proBNP risk score to 38.8% for the ADHERE model and from 46.7% for the ADHF/NT-proBNP risk score to 42.1% for the ASCEND risk score, respectively. There was a modest agreement between the risk scores in classifying the patients across risk strata or in classifying those who died as being at >30% risk of death., Conclusion: Although risk assessment tools work well for stratifying patients, their use in estimating the risk of mortality for individuals has limited clinical utility., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To assess the prevalence of diffuse idiopathic skeletal hyperostosis and its relationship with vascular risk factors among patients with congestive heart failure., Design: Population-based cross-sectional study., Participants: A total of 584 consecutive patients admitted to a Rehabilitative Cardiology Unit., Methods: Chi-square Automatic Interaction Detector (CHAID) decision tree analysis was used to build a predictive model., Results: The mean age (standard deviation) of the study population was 68.1 years (standard deviation 12.3), and 77.7% of the subjects were men. The overall prevalence of diffuse idiopathic skeletal hyperostosis in the cohort was 49.8%. Logistic regression analysis showed that age was a predictor of diffuse idiopathic skeletal hyperostosis (odds ratio: 1.034; 95% confidence interval 1.021-1.047, p < 0.001), with increasing odds ratios for increasing age tertiles. The CHAID prediction model identified 2 age "buckets": < 69 and ≥ 69 years. Patients ≥ 69 years had a diffuse idiopathic skeletal hyperostosis prevalence of 60.1%, compared with 39.2% among those < 69 years. Notably, body mass index was a predictor of diffuse idiopathic skeletal hyperostosis in this younger subset of patients (p = 0.028), with 2 body mass index "buckets", ≤ 23.3 and > 23.3 kg/m2, the latter showing more than twice the prevalence of diffuse idiopathic skeletal hyperostosis (43.2% vs 20%)., Conclusion: Diffuse idiopathic skeletal hyperostosis is extremely frequent among patients with congestive heart failure, with age and body mass index being the strongest predictors.

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.)

The increasing number of patients with heart failure HF and comorbidities is due to aging population and increase of life expectancy of patients with cardiovascular disease. Encouraging results derived by recent trials may suggest some comorbidities as new targets for new drugs, highlighting the need for a better understanding of the comorbidities' effects in HF patients and the need of a multidisciplinary approach for the management of chronic HF with comorbidities. We report a brief review about main cardiovascular and non-cardiovascular comorbidities in HF patients in order to update physicians and researchers engaged in the HF research or in "fight against heart failure.", Competing Interests: Declaration of Competing Interest The authors have no financial or other interest in the product or distributor of the product. Furthermore, they have no other kinds of associations, such as consultancies, stock ownership, or other equity interests or patent-licensing arrangements., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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.)

Objective: To measure competition amongst providers and to examine whether a correlation exists with hospitals mortality for congestive heart failure (CHF), acute myocardial infarction (AMI), isolated-coronary artery bypass graft (CABG) or valve surgery., Design: Cross-sectional study based on publically available data from the National Outcome Evaluation Program (Edition 2016) of the Italian Agency for Regional Health Services., Setting and Participants: Patients discharged during 2015 for CHF or AMI, and between 2014 and 2015 for cardiac surgery (respectively, from 662, 395 and 91 hospitals)., Main Outcome Measures: Risk-adjusted mortality rates at 30 days and measures of hospital competition for areas centred on hospital' location (fixed-radius 50-150 km, variable-radius to capture 10-30 hospitals and 6-10% of national volume). Competition was estimated as number of providers and Herfindahl-Hirschman Index (HHI)., Results: Indicators of competitions varied by condition and were sensitive to method used for the area definition. Hospital mortality after AMI and valve surgery increased with competition in areas identified by the variable-radius method (higher rates for a greater number of hospitals or lower HHIs). In area with fixed radius of 100-150 km, competition reduced mortality after CABG procedures (lower rates for a greater number of hospitals or smaller HHIs). Neither the number of hospitals nor HHI correlated with outcomes in CHF., Conclusions: The measures of hospital competition changed according to definition of local market and results in mortality correlations varied among conditions. Understanding the relationship between hospital competition and outcomes is important to identify strategies to improve quality of care., (© The Author(s) 2019. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Chronic obstructive pulmonary disease (COPD) is among the most common comorbidities in patients hospitalized with heart failure and is generally associated with poor outcomes. However, the results of previous studies with regard to increased mortality and risk trajectories were not univocal. We sought to assess the prognostic impact of COPD in patients admitted for acutely decompensated heart failure (ADHF) and investigate the association between use of β-blockers at discharge and mortality in patients with COPD., Methods: We studied 1530 patients. The association of COPD with mortality was examined in adjusted Fine-Gray proportional hazard models where heart transplantation and ventricular assist device implantation were treated as competing risks. The primary outcome was 5-year all-cause mortality., Results: After adjusting for establisked risk markers, the subdistribution hazard ratios (SHR) of 5-year mortality for COPD patients compared with non-COPD patients was 1.25 (95% confidence intervals [CIs] 1.06-1.47; p = .007). The relative risk of death for COPD patients increased steeply from 30 to 180 days, and remained noticeably high throughout the entire follow-up. Among patients with comorbid COPD, the use of β-blockers at discharge was associated with a significantly reduced risk of 1-year post-discharge mortality (SHR 0.66, 95%CIs 0.53-0.83; p ≤.001)., Conclusions: Our data indicate that ADHF patients with comorbid COPD have a worse long-term survival than those without comorbid COPD. Most of the excess mortality occurred in the first few months following hospitalization. Our data also suggest that the use of β-blockers at discharge is independently associated with improved survival in ADHF patients with COPD., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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.)

Palliative care is recognized as an approach that improves quality of life of patients and families facing life-threatening illnesses. This is achieved through prevention, early identification, assessment and treatment of symptoms and other psycho-social, spiritual and economic issues. Palliative care is not dependent on prognosis and can be delivered as "simultaneous care", together with disease-modifying treatments and adequate symptom relief. Palliative care relies on coordination across settings of care and offers open communication to patients and caregivers. Recently, there is increasing interest in the potential role of palliative care in refractory, advanced heart failure treated with optimal, maximized therapy.Heart failure is a chronic progressive syndrome characterized by periods of stability interrupted by acute exacerbations, usually leading to reduced functional status. It accounts for approximately one-third of deaths in industrialized countries and is a common cause of hospitalization. Fifty percent of patients with advanced heart failure die within 1 year of diagnosis and 50% of the remainder within 5 years. The trajectory of heart failure is often unpredictable and approximately 30% to 50% of patients die suddenly. Patients with heart failure suffer from numerous symptoms, often resistant to conventional treatments, frequently under-recognized and under-treated. Symptom assessment and control improve quality of life in patients with advanced heart failure; this can be managed at best by collaboration between specialistic teams.Although heart failure is a life-shortening condition, therapeutic and technological advances (such as left ventricular assist devices, coronary revascularization, percutaneous valve implantation, and implantable cardioverter defibrillators) can help healthcare professionals in the management of patients with advanced heart failure, improving global condition and reducing the risk of sudden death. On the other hand, it has to be acknowledged that management of cardiovascular implanted electronic devices towards end of life requires awareness of legal, ethical, religious principles regarding potential withdrawal of life-sustaining therapies.Adequate communication with patients regarding adverse events, end of life, benefits vs burdens of therapies and interventions, treatment preferences, and decision-making should be an issue in early stages of disease. The process of advanced care planning should be clearly documented and regularly reviewed.Barriers to the provision of palliative care in heart failure include clinical issues (disease trajectory), prognostic uncertainty, failure in identification of patients who need palliative care and timing of referral to specialist services, but also misconceptions of patients, families and sanitary staff regarding the role of palliative care, organization problems, and finally educational and time issues.This document focuses on the need of further, coordinated research and work-out on: (i) identification of heart failure patients eligible for palliative care, in terms of clinical and social-psychological issues, (ii) identification of trigger events and timing of referral; (iii) identification of adequate performance indicators/scales for measurement, assessment and follow-up of symptoms and quality of life in end-stage heart failure, including patient-reported outcome measures; (iv) treatment, care and organization strategies and models for advanced/end-stage heart failure ("care management"); and (v) implementation of knowledge and education of healthcare professionals in the fields of communication, ethics, and advanced care planning in heart failure.

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.)

Objective: The Kaplan-Meier method may overestimate absolute mortality risk (AMR) in the presence of competing risks. Urgent heart transplantation (UHT) and ventricular assist device implantation (VADi) are important competing events in heart failure. We sought to quantify the extent of bias of the Kaplan-Meier method in estimating AMR in the presence of competing events and to analyze the effect of covariates on the hazard for death and competing events in the clinical model of decompensated chronic heart failure with reduced ejection fraction (DCHFrEF)., Study Design and Setting: We studied 683 patients. We used the cumulative incidence function (CIF) to estimate the AMR at 1 year. CIF estimate was compared with the Kaplan-Meier estimate. The Fine-Gray subdistribution hazard analysis was used to assess the effect of covariates on the hazard for death and UHT/VADi., Results: The Kaplan-Meier estimate of the AMR was 0.272, whereas the CIF estimate was 0.246. The difference was more pronounced in the patient subgroup with advanced DCHF (0.424 vs. 0.338). The Fine-Gray subdistribution hazard analysis revealed that established risk markers have qualitatively different effects on the incidence of death or UHT/VADi., Conclusion: Competing risks analysis allows more accurately estimating AMR and better understanding the association between covariates and major outcomes in DCHFrEF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

: The right ventricle has become increasingly studied in cardiovascular research. In this article, we describe specific pathophysiological characteristics of the right ventricle, with special focus on functional and molecular modifications as well as therapeutic strategies in right ventricular dysfunction, underlining the differences with the left ventricle. Then we analyze the main imaging modalities to assess right ventricular function in different clinical settings. Finally, we acknowledge main therapeutic advances for treatment of right heart diseases.

Background: Still there is conflicting evidence about gender-related differences in prognosis among patients with heart failure. This prognostic uncertainty may have implications for risk stratification and planning management strategy. The aim of the present study was to explore the association between gender and one-year mortality in patients admitted with acute decompensated heart failure (ADHF)., Methods: We studied 1513 patients. The Cumulative Incidence Function (CIF) method was used to estimate the absolute rate of mortality, heart transplantation (HT)/ventricular assist device (VAD) implantation, and survival free of HT/VAD implantation at 1year. An interaction analysis was performed to assess the association between covariates, gender, and mortality risk. Propensity score matching and Cox regression were used to compare mortality rates in the gender subgroups., Results: The CIF estimates of 1-year mortality, HT/VAD implantation, and survival free of HT/VAD implantation at 1year were 33.1%, 7.0%, and 59.9% for women and 30.2%, 10.2%, and 59.6% for men, respectively. Except for diabetes, there was no significant interaction between gender, covariates, and mortality risk. In the matched cohort, the hazard ratio of death for women was 1.19 (95% confidence intervals [CIs]: 0.90-1.59; p=.202). After adjusting for age and baseline risk, the hazard ratio of death for women was 1.18 (95% CIs: 0.95-1.43; p=.127). The use of gender-specific predictive models did not allow improving the accuracy of risk prediction., Conclusions: Our data strongly suggest that women and men have comparable outcome in the year following a hospitalization for ADHF., (Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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.)

Optimal management of heart failure requires accurate risk assessment. Many prognostic risk models have been proposed for patient with chronic and acute heart failure. Methodological critical issues are the data source, the outcome of interest, the choice of variables entering the model, the validation of the model in external population. Up to now, the proposed risk models can be a useful tool to help physician in the clinical decision-making. The availability of big data and of new methods of analysis may lead to developing new models in the future.

Background: Circulating microRNAs (miRs) are promising biomarkers for heart failure (HF). Previous studies have provided inconsistent miR "signatures." The phenotypic and pathophysiologic heterogeneity of HF may have contributed to this inconsistency. In this study we assessed whether advanced HF (AHF) patients present a distinct miR signature compared with healthy subjects (HS) and mild to moderate HF (MHF) patients., Methods: The study consisted of 2 phases: a screening phase and a validation phase. In the screening phase, 752 miRs were profiled in HS and MHF and AHF patients (N = 15), using the real-time quantitative polymerase chain reaction (RT-qPCR) technique and global mean normalization. In the validation phase, the miRs found to be significantly dysregulated in AHF patients compared with both HS and MHF patients were validated in 15 HS, 25 patients with MHF and 29 with AHF, using RT-qPCR, and normalizing to exogenous (cel-miR-39) and endogenous controls., Results: In the screening phase, 5 miRs were found to be significantly dysregulated: -26a-5p; -145-3p; -150-5p; -485-3p; and -487b-3p. In the validation phase, miR-150-5p was confirmed to be significantly downregulated in AHF patients when compared with both HS and MHF patients, irrespective of the normalization method used. miR-26a-5p was confirmed to be significantly dysregulated only when normalized to cell-miR-39. Dysregulation of the other miRs could not be confirmed. miR-150-5p was significantly associated with maladaptive remodeling, disease severity and outcome., Conclusions: Our data suggest miR-150-5p as a novel circulating biomarker for AHF. The association of miR-150-5p with maladaptive remodeling, disease severity and outcome supports the pathophysiologic relevance of downregulated miR-150-5p expression to AHF., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Obesity has been suggested to confer a survival benefit in acute heart failure. The concentrations of NT-proBNP may be reduced in patients with high body mass index (BMI)., Objectives: To investigate the relationship among BMI, NT-proBNP, and mortality risk in decompensated chronic heart failure (DCHF)., Methods: This was a retrospective study. We studied 1001 patients with DCHF. Hazard ratios (HR) were calculated with Cox regression analysis., Results: During the 1-year follow-up, 295 patients died. Compared with normal-weight patients, the unadjusted HR for death were 1.02 (95% CIs 0.79-1.33; p = 0.862) for patients with a BMI of 25.0-29.9 kg/m 2 and 0.83 (95% CIs 0.61-1.12; p = 0.213) for patients with a BMI ≥ 30 kg/m 2 . NT-proBNP remained independently associated with mortality across the BMI categories. There was no statistically significant interaction between BMI and NT-proBNP levels for risk prediction., Conclusions: Obesity was not associated with mortality risk. NT-proBNP remained an independent prognostic factor across the BMI categories., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Acute heart failure is a common cause of hospitalization among older patients. Optimized risk stratification might improve the outcome for this subgroup of patients. Natriuretic peptides have been used in the diagnosis of heart failure and in evaluating the prognosis of patients hospitalized for heart failure. However, their utility in the elderly is still controversial., Objective: To evaluate long-term survival and prognostic factors for elderly patients hospitalized for acutely decompensated heart failure and evaluate the prognostic utility of NT-proBNP., Design: Retrospective, multicenter cohort study., Setting: Two Italian hospitals., Participants: Two hundred seventy-nine patients, aged >75 years; hospitalized for decompensation of chronic, established heart failure., Methods: Baseline clinical data were recorded at admission. The primary outcome was long-term mortality., Results: In-hospital, 12-month and 5-year mortality were, respectively, 10%, 36%, and 77%. NT-proBNP, eGFR, hemoglobin, diabetes, systolic blood pressure, and moderate to severe tricuspid regurgitation were independently associated with long-term prognosis and were entered into a multivariate model, with a C-index of 0.765 for the determination of high-risk patients. The C-index for NT-proBNP to predict mortality at 2 and 12 months was 0.740 and 0.756, respectively. The optimal cutoff point for predicting mortality at 2 and 12 months was 8,444 pg/mL (hazard ratio 5.33) and 8,275 pg/mL (hazard ratio 6.03), respectively., Conclusion: Elderly patients hospitalized for acutely decompensated heart failure had a poor long-term outcome, especially in the subgroup with reduced ejection fraction (EF). In addition to EF and comorbidities, NT-pro-BNP remained independently prognostic among elderly patients hospitalized with heart failure., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

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: To assess the impact of comorbidities on long-term all-cause mortality in patients hospitalized with exacerbated signs/symptoms of previously chronic stable HF (AE-CHF)., Methods: 1119 patients admitted for AE-CHF and with NT-proBNP levels >900pg/mL were enrolled. Univariable and multivariable Cox analyses were performed to assess the association of age, gender, hypertension, diabetes, obesity, atrial fibrillation, coronary heart disease (CHD), chronic obstructive pulmonary disease, previous cerebrovascular accidents, chronic liver disease (CLD), thyroid disease, renal impairment (RI), and anemia with 3-year all-cause mortality., Results: During the follow-up, 441 patients died and 126 underwent heart transplantation (HT) or ventricular assist device (VAD) implantation. 45.8% of the fatal events and 52.4% of HT/VAD implantations occurred within 180days after admission. Increasing age (p=.012), obesity (p=.037), atrial fibrillation (p=.030), CHD (p=.015), CLD (p=.001), RI (p<.001), and anemia (p<.001) were independently associated with 3-year all-cause mortality. Most of the prognostic impact of CHD, took place within the first 180days after admission. Male gender was associated with mortality beyond 180days. Compared with normal weight, obesity was associated with better overall survival. Obese patients, however, had significantly lower NT-proBNP concentrations and less frequently presented with hypotension, hyponatremia, and severe left ventricular systolic dysfunction, despite a similar prevalence of severe dyspnea at admission., Conclusions: Several comorbidities are associated with long-term risk of death in hospitalized patients with worsening HF, although the nature of this association does appear to be complex. Our data may help to raise awareness about the clinical relevance of comorbid conditions., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Although the prognostic value of right ventricular dysfunction in chronic heart failure (HF) has been studied extensively, it remains insufficiently characterized in the setting of acute decompensated HF (ADHF). We sought to assess whether measurement of tricuspid annular plane systolic excursion (TAPSE) or TAPSE-to-estimated pulmonary arterial systolic pressure (ePASP) ratio allows improvement of risk prediction in ADHF., Methods: Four hundred ninety-nine patients with ADHF were studied. Cox regression analyses were used to analyze the association of TAPSE and TAPSE-to-ePASP ratio with 1-year mortality and logistic regression analyses to analyze the association of the 2 variables of interest with adverse in-hospital outcome (AiHO) (in-hospital death plus worsening HF)., Results: During the 365-day follow-up, 143 patients (28.7%) died. At univariable analysis, both TAPSE (P = 0.026) and TAPSE-to-ePASP ratio (P < 0.0001) were significantly associated with 1-year mortality. At multivariable Cox analysis, age (P = 0.0270), ischemic heart disease (P = 0.020), systolic blood pressure (P = 0.006), log N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (P < 0.0001), serum sodium levels (P = 0.001), and hemoglobin levels (P = 0.001) at admission were independently associated with 1-year mortality. Adjusting for these covariates, neither TAPSE (P = 0.314) nor TAPSE-to-ePASP ratio (P = 0.237) remained independently associated with 1-year mortality. Eighty-three patients (16.6%) had an AiHO. At multivariable logistic regression analysis, the TAPSE-to-ePASP ratio was independently associated with an AiHO (P = 0.024). The association of TAPSE alone or ePASP alone was not statistically significant., Conclusions: Our data strongly suggest that early assessment of TAPSE or TAPSE-to-ePASP ratio does not improve prediction of 1-year mortality over other key risk markers in ADHF. Nonetheless, the TAPSE-to-ePASP ratio did appear to be independently associated with AiHO., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. 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.)

Objectives: To assess the incremental prognostic utility of discharge serum creatinine (SCr), systolic blood pressure (SBP), and NT-proBNP and sodium concentrations in hospitalized patients with acutely decompensated chronic heart failure., Background: Whether key prognostic variables at discharge provide incremental prognostic information beyond that provided by a model based on admission variables (referent) remains incompletely defined., Methods: The primary outcome was a composite of death, urgent heart transplantation, or ventricular assist device implantation at 1 year. The gain in predictive performance was assessed using C index, Bayesian Information Criterion, and Net Reclassification Improvement., Results: The best fit was obtained when discharge NT-proBNP was added to the referent model. No interaction between admission and discharge NT-proBNP was found. Discharge SCr, SBP, and sodium did not improve goodness-of-fit., Conclusions: Admission and discharge NT-proBNP provide complementary and independent prognostic information; as such, they should be taken into account concurrently., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score is a prognostic model to identify heart failure (HF) patients at risk for cardiovascular mortality (CVM) and urgent heart transplantation (uHT) based on 6 routine clinical parameters: hemoglobin, sodium, kidney function by the Modification of Diet in Renal Disease (MDRD) equation, left ventricle ejection fraction (LVEF), percentage of predicted peak oxygen consumption (VO2) and VE/VCO2 slope., Objectives: MECKI score must be generalizable to be considered useful: therefore, its performance was validated in a new sequence of HF patients., Methods: Both the development (MECKI-D) and the validation (MECKI-V) cohorts were composed of consecutive HF patients with LVEF <40% able to perform a symptom-limited cardiopulmonary exercise testing. The CVM or uHT rates were analyzed at one, two and three years in both cohorts: all patients with a censoring time shorter than the scheduled follow-up were excluded, while those with events occurring after 1, 2 and 3 years were considered as censored., Results: MECKI-D and MECKI-V consisted of 2009 and 992 patients, respectively. MECKI-V patients had a higher LVEF, higher peak VO2 and lower VE/VCO2 slope, higher prescription of beta-blockers and device therapy: after the 3-year follow-up, CVM or uHT occurred in 206 (18%) MECKI-D and 44 (13%) MECKI-V patients (p<0.000), respectively. MECKI-V AUC values at one, two and three years were 0.81 ± 0.04, 0.76 ± 0.04, and 0.80 ± 0.03, respectively, not significantly different from MECKI-D., Conclusions: MECKI score preserves its predictive ability in a HF population at a lower risk., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Atrial fibrillation (AF) is common in heart failure (HF). It is unclear whether AF has an independent prognostic role in HF. The aim of the present study was to assess the prognostic role of AF in HF patients with reduced ejection fraction (EF)., Methods: HF patients were followed in 17 centers for 3.15years (1.51-5.24). Study endpoints were the composite of cardiovascular (CV) death and heart transplant (HTX) and all-cause death. Data analysis was performed considering the entire population and a 1 to 1 match between sinus rhythm (SR) and AF patients. Match process was done for age±5, gender, left ventricle EF±5, peakVO2±3 (ml/min/kg) and recruiting center., Results: A total of 3447 patients (SR=2882, AF=565) were included in the study. Considering the entire population, CV death and HTX occurred in 114 (20%) AF vs. 471 (16%) SR (p=0.026) and all-cause death in 130 (23%) AF vs. 554 (19.2%) SR patients (p=0.039). At univariable Cox analysis, AF was significantly related to prognosis. Applying a multivariable model based on all variables significant at univariable analysis (EF, peakVO2, ventilation/carbon dioxide relationship slope, sodium, kidney function, hemoglobin, beta-blockers and digoxin) AF was no longer associated with adverse outcomes. Matching procedure resulted in 338 couples. CV death and HTX occurred in 63 (18.6%) AF vs. 74 (21.9%) SR (p=0.293) and all-cause death in 71 (21%) AF vs. 80 (23.6%) SR (p=0.406), with no survival differences between groups., Conclusion: In systolic HF AF is a marker of disease severity but not an independent prognostic indicator., (Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Chronic kidney disease is associated with sympathetic activation and muscle abnormalities, which may contribute to decreased exercise capacity. We investigated the correlation of renal function with peak exercise oxygen consumption (V̇O2) in heart failure (HF) patients. METHODS AND RESULTS: We recruited 2,938 systolic HF patients who underwent clinical, laboratory, echocardiographic and cardiopulmonary exercise testing. The patients were stratified according to estimated glomerular filtration rate (eGFR). Mean follow-up was 3.7 years. The primary outcome was a composite of cardiovascular death and urgent heart transplantation at 3 years. On multivariable regression, eGFR was predictor of peakV̇O2(P<0.0001). Other predictors were age, sex, body mass index, HF etiology, NYHA class, atrial fibrillation, resting heart rate, B-type natriuretic peptide, hemoglobin, and treatment. After adjusting for significant covariates, the hazard ratio for primary outcome associated with peakV̇O2<12 ml·kg(-1)·min(-1)was 1.75 (95% confidence interval (CI): 1.06-2.91; P=0.0292) in patients with eGFR ≥60, 1.77 (0.87-3.61; P=0.1141) in those with eGFR of 45-59, and 2.72 (1.01-7.37; P=0.0489) in those with eGFR <45 ml·min(-1)·1.73 m(-2). The area under the receiver-operating characteristic curve for peakV̇O2<12 ml·kg(-1)·min(-1)was 0.63 (95% CI: 0.54-0.71), 0.67 (0.56-0.78), and 0.57 (0.47-0.69), respectively. Testing for interaction was not significant., Conclusions: Renal dysfunction is correlated with peakV̇O2. A peakV̇O2cutoff of 12 ml·kg(-1)·min(-1)offers limited prognostic information in HF patients with more severely impaired renal function.

Background: The first few months after admission are the most vulnerable period in patients with acute decompensated heart failure (ADHF)., Methods and Results: We assessed the association of the updated ADHF/N-terminal pro-B-type natriuretic peptide (NT-proBNP) risk score with 90-day and in-hospital mortality in 701 patients admitted with advanced ADHF, defined as severe symptoms of worsening HF, severely depressed left ventricular ejection fraction, and the need for i.v. diuretic and/or inotropic drugs. A total of 15.7% of the patients died within 90 days of admission and 5.2% underwent ventricular assist device (VAD) implantation or urgent heart transplantation (UHT). The C-statistic of the ADHF/NT-proBNP risk score for 90-day mortality was 0.810 (95% CI: 0.769-0.852). Predicted and observed mortality rates were in close agreement. When the composite outcome of death/VAD/UHT at 90 days was considered, the C-statistic decreased to 0.741. During hospitalization, 7.6% of the patients died. The C-statistic for in-hospital mortality was 0.815 (95% CI: 0.761-0.868) and Hosmer-Lemeshow χ(2)=3.71 (P=0.716). The updated ADHF/NT-proBNP risk score outperformed the Acute Decompensated Heart Failure National Registry, the Organized Program to Initiate Lifesaving Treatment in Patients Hospitalized for Heart Failure, and the American Heart Association Get with the Guidelines Program predictive models., Conclusions: Updated ADHF/NT-proBNP risk score is a valuable tool for predicting short-term mortality in severe ADHF, outperforming existing inpatient predictive models.

Elevated heart rate could negatively influence cardiovascular risk in the general population. It can induce and promote the atherosclerotic process by means of several mechanisms involving endothelial shear stress and biochemical activities. Furthermore, elevated heart rate can directly increase heart ischemic conditions because of its skill in unbalancing demand/supply of oxygen and decreasing the diastolic period. Thus, many pharmacological treatments have been proposed in order to reduce heart rate and ameliorate the cardiovascular risk profile of individuals, especially those suffering from coronary artery diseases (CAD) and chronic heart failure (CHF). Ivabradine is the first pure heart rate reductive drug approved and currently used in humans, created in order to selectively reduce sinus node function and to overcome the many side effects of similar pharmacological tools (ie, β-blockers or calcium channel antagonists). The aim of our review is to evaluate the role and the safety of this molecule on CAD and CHF therapeutic strategies.

Background: The acute decompensated heart failure/N-terminal pro-B-type natriuretic peptide (ADHF/NT-proBNP) score is a validated risk scoring system that predicts mortality in hospitalized heart failure patients with a wide range of left ventricular ejection fractions (LVEFs). We sought to assess discrimination and calibration of the score when applied to patients with advanced decompensated heart failure (AHF)., Methods: We studied 445 patients hospitalized for AHF, defined by the presence of severe symptoms of worsening HF at admission, severely depressed LVEF, and the need for intravenous diuretic and/or inotropic drugs. The primary outcome was cumulative (in-hospital and post-discharge) mortality and post-discharge 1-year mortality. Separate analyses were performed for patients aged ≤ 70 years. A Seattle Heart Failure Score (SHFS) was calculated for each patient discharged alive., Results: During follow-up, 144 patients (32.4%) died, and 69 (15.5%) underwent heart transplantation (HT) or ventricular assist device (VAD) implantation. After accounting for the competing events (VAD/HT), the ADHF/NT-proBNP score's C-statistic for cumulative mortality was 0.738 in the overall cohort and 0.771 in patients aged ≤ 70 years. The C-statistic for post-discharge mortality was 0.741 and 0.751, respectively. Adding prior (≤6 months) hospitalizations for HF to the score increased the C-statistic for post-discharge mortality to 0.759 in the overall cohort and to 0.774 in patients aged ≤ 70 years. Predicted and observed mortality rates by quartiles of score were highly correlated. The SHFS demonstrated adequate discrimination but underestimated the risk. The ADHF/NT-proBNP risk calculator is available at http://www.fsm.it/fsm/file/NTproBNPscore.zip., Conclusions: Our data suggest that the ADHF/NT-proBNP score may efficiently predict mortality in patients hospitalized with AHF., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Renal dysfunction may confound the clinical interpretation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration. This study investigated whether renal dysfunction influences the prognostic accuracy of NT-proBNP in acute decompensated heart failure (ADHF)., Methods and Results: We studied 908 ADHF patients. The primary outcome was 12-month mortality. Interaction between estimated glomerular filtration rate (eGFR) and NT-proBNP in predicting mortality was tested with the likelihood ratio test. The patients were classified into 3 eGFR strata: ≥60, 30-59, and <30 ml·min(-1)·1.73 m(-2). Cox models were used to calculate the adjusted hazard ratios (HR) for NT-proBNP, modeled as a dichotomous or categorized variable, within each level of eGFR. NT-proBNP was categorized using optimal cut-offs defined in ROC analysis for each eGFR level. A total of 234 patients (25.8%) died. Testing for interaction was not significant (χ(2)=0.29; P=0.5928). The adjusted HR for NT-proBNP >5,180 pg/ml was 2.09 (P<0.001) in the highest, 1.7 (P<0.001) in the intermediate, and 3.33 (P=0.010) in the lowest eGFR level. The adjusted HR for NT-proBNP above the optimal cut-offs defined on ROC analysis were 1.5 (P=0.239), 2.2 (P<0.001), and 3.24 (P=0.002), respectively. The models incorporating NT-proBNP as a dichotomous or categorized variable had equivalent C-statistics., Conclusions: There was no evidence of interaction between eGFR and NT-proBNP in predicting mortality. The NT-proBNP cut-off of 5,180 ng/L provided independent prognostic information, irrespective of the level of residual renal function.

Background: NT-proBNP has been associated with prognosis in acute decompensated heart failure (ADHF). Whether NT-proBNP provides additional prognostic information beyond that obtained from standard clinical variables is uncertain. We sought to assess whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) determination improves risk reclassification of patients with ADHF and to develop and validate a point-based NT-proBNP risk score., Methods: This study included 824 patients with ADHF (453 in the derivation cohort, 371 in the validation cohort). We compared two multivariable models predicting 1-year all-cause mortality, including clinical variables and clinical variables plus NT-proBNP. We calculated the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI). Then, we developed and externally validated the NT-proBNP risk score., Results: One-year mortalities for the derivation and validation cohorts were 28.3% and 23.4%, respectively. Multivariable predictors of mortality included chronic obstructive pulmonary disease, estimated glomerular filtration rate, sodium, hemoglobin, left ventricular ejection fraction, and moderate to severe tricuspid regurgitation. Adding NT-proBNP to the clinical variables only model significantly improved the NRI (0.129; p=0.0027) and the IDI (0.037; p=0.0005). In the derivation cohort, the NT-proBNP risk score had a C index of 0.839 (95% CI: 0.798-0.880) and the Hosmer-Lemeshow statistic was 1.23 (p=0.542), indicating good calibration. In the validation cohort, the risk score had a C index of 0.768 (95% CI: 0.711-0.817); the Hosmer-Lemeshow statistic was 2.76 (p=0.251), after recalibration., Conclusions: The NT-proBNP risk score provides clinicians with a contemporary, accurate, easy-to-use, and validated predictive tool. Further validation in other datasets is advisable., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We built and validated a new heart failure (HF) prognostic model which integrates cardiopulmonary exercise test (CPET) parameters with easy-to-obtain clinical, laboratory, and echocardiographic variables., Background: HF prognostication is a challenging medical judgment, constrained by a magnitude of uncertainty., Methods: Our risk model was derived from a cohort of 2716 systolic HF patients followed in 13 Italian centers. Median follow up was 1041days (range 4-5185). Cox proportional hazard regression analysis with stepwise selection of variables was used, followed by cross-validation procedure. The study end-point was a composite of cardiovascular death and urgent heart transplant., Results: Six variables (hemoglobin, Na(+), kidney function by means of MDRD, left ventricle ejection fraction [echocardiography], peak oxygen consumption [% pred] and VE/VCO2 slope) out of the several evaluated resulted independently related to prognosis. A score was built from Metabolic Exercise Cardiac Kidney Indexes, the MECKI score, which identified the risk of study end-point with AUC values of 0.804 (0.754-0.852) at 1year, 0.789 (0.750-0.828) at 2years, 0.762 (0.726-0.799) at 3years and 0.760 (0.724-0.796) at 4years., Conclusions: This is the first large-scale multicenter study where a prognostic score, the MECKI score, has been built for systolic HF patients considering CPET data combined with clinical, laboratory and echocardiographic measurements. In the present population, the MECKI score has been successfully validated, performing very high AUC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: In patients with heart failure (HF), during maximal cardiopulmonary exercise test, anaerobic threshold (AT) is not always identified. We evaluated whether this finding has a prognostic meaning., Methods and Results: We recruited and prospectively followed up, in 14 dedicated HF units, 3058 patients with systolic (left ventricular ejection fraction <40%) HF in stable clinical conditions, New York Heart Association class I to III, who underwent clinical, laboratory, echocardiographic, and cardiopulmonary exercise test investigations at study enrollment. We excluded 921 patients who did not perform a maximal exercise, based on lack of achievement of anaerobic metabolism (peak respiratory quotient ≤1.05). Primary study end point was a composite of cardiovascular death and urgent cardiac transplant, and secondary end point was all-cause death. Median follow-up was 3.01 (1.39-4.98) years. AT was identified in 1935 out of 2137 patients (90.54%). At multivariable logistic analysis, failure in detecting AT resulted significantly in reduced peak oxygen uptake and higher metabolic exercise and cardiac and kidney index score value, a powerful prognostic composite HF index (P<0.001). At multivariable analysis, the following variables were significantly associated with primary study end point: peak oxygen uptake (% pred; P<0.001; hazard ratio [HR]=0.977; confidence interval [CI]=0.97-0.98), ventilatory efficiency slope (P=0.01; HR=1.02; CI=1.01-1.03), hemoglobin (P<0.05; HR=0.931; CI=0.87-1.00), left ventricular ejection fraction (P<0.001; HR=0.948; CI=0.94-0.96), renal function (modification of diet in renal disease; P<0.001; HR=0.990; CI=0.98-0.99), sodium (P<0.05; HR=0.967; CI=0.94-0.99), and AT nonidentification (P<0.05; HR=1.41; CI=1.06-1.89). Nonidentification of AT remained associated to prognosis also when compared with metabolic exercise and cardiac and kidney index score (P<0.01; HR=1.459; CI=1.09-1.10). Similar results were obtained for the secondary study end point., Conclusions: The inability to identify AT most often occurs in patients with severe HF, and it has an independent prognostic role in HF.

Recognition of the treatment gap in patients with heart failure (HF) led to the development of a set of process-of-care measures to improve the quality of care. To assess the association of established and emerging process-of-care measures with 1-year postdischarge survival, 496 patients with acute decompensated HF were studied. After adjustment for established prognostic factors, the relative risk (RR) for mortality in patients eligible for treatment was as follows: 0.49 (P < .001) for discharge prescription of renin-angiotensin system inhibitors (RAS-Is), 0.59 (P = .015) for β-blockers, 0.44 (P < .001) for combination therapy (ie, a β-blocker and a RAS-I), 0.87 (P nonsignificant) for aldosterone antagonists, and 0.49 (P nonsignificant) for planned cardioverter-defibrillator implantation. After adjustment for propensity scores, the RR was 0.49 (P < .001) for RAS-Is, 0.67 (P = .04) for β-blockers, and 0.57 (P < .001) for combination therapy. The data suggest that performance measures for RAS-Is, β-blockers, and combination therapy are strongly associated with improved 1-year survival.