Multiparametric prognostic scores in chronic heart failure with reduced ejection fraction: a long-term comparison

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

The appearance of levator ani muscle abnormalities in magnetic resonance images after vaginal delivery.

OBJECTIVE: To describe the appearance and occurrence of abnormalities in the levator ani muscle seen on magnetic resonance imaging (MRI) in nulliparous women and in women after their first vaginal birth. METHODS: Multiplanar proton density magnetic resonance images were obtained at 0.5-cm intervals from 80 nulliparous and 160 vaginally primiparous women. These had been previously obtained in a study of stress incontinence, and half the primiparas had stress incontinence. All scans were reviewed independently by at least two examiners blinded to parity and continence status. RESULTS: No levator ani defects were identified in nulliparous women. Thirty-two primiparous women (20%) had a visible defect in the levator ani muscle. Defects were identified in the pubovisceral portion of the levator ani in 29 women and in the iliococcygeal portion in three women. Within the pubovisceral muscle, both unilateral and bilateral defects were found. The extent of abnormality varied from one individual to the next. Of the 32 women with defects, 23 (71%) were in the stress incontinent group. CONCLUSION: Abnormalities in the levator ani muscle are present on MRI after a vaginal delivery but are not found in nulliparas

Myeloperoxidase-Related Chlorination Activity Is Positively Associated with Circulating Ceruloplasmin in Chronic Heart Failure Patients: Relationship with Neurohormonal, Inflammatory, and Nutritional Parameters

RATIONALE: Heart failure (HF) is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. Both chlorinating and peroxidase cycle of Myeloperoxidase (MPO) contribute to oxidative and nitrosative stress and are involved in tyrosine nitration of protein. Ceruloplasmin (Cp) has antioxidant function through its ferroxidase I (FeOxI) activity and has recently been proposed as a physiological defense mechanism against MPO inappropriate actions. OBJECTIVE: We investigated the relationship between plasma MPO-related chlorinating activity, Cp and FeOxI, and nitrosative stress, inflammatory, neurohormonal, and nutritional biomarkers in HF patients. METHODS AND RESULTS: In chronic HF patients (n = 81, 76 ± 9 years, NYHA Class II (26); Class III (29); Class IV (26)) and age-matched controls (n = 17, 75 ± 11 years, CTR), plasma MPO chlorinating activity, Cp, FeOxI, nitrated protein, free Malondialdehyde, BNP, norepinephrine, hsCRP, albumin, and prealbumin were measured. Plasma MPO chlorinating activity, Cp, BNP, norepinephrine, and hsCRP were increased in HF versus CTR. FeOxI, albumin, and prealbumin were decreased in HF. MPO-related chlorinating activity was positively related to Cp (r = 0.363, P < 0.001), nitrated protein, hsCRP, and BNP and inversely to albumin. CONCLUSIONS: Plasma MPO chlorinated activity is increased in elderly chronic HF patients and positively associated with Cp, inflammatory, neurohormonal, and nitrosative parameters suggesting a role in HF progression

Anaerobic threshold and respiratory compensation point identification during cardiopulmonary exercise tests in chronic heart failure

BACKGROUND: We evaluated the prognostic meaning of the simple presence or absence of identifiable anaerobic threshold (AT) and respiratory compensation point (RCP) at cardiopulmonary exercise tests (CPETs) performed with a maximal incremental exercise protocol.METHODS: In the present multicenter study, we retrospectively analyzed data in 1,995 patients with heart failure with reduced ejection fraction (HFrEF). All underwent clinical and laboratory evaluation, echocardiography, and maximal CPET at baseline. The analysis was performed according to absence of identified AT and RCP (group 1: n = 292; 15%), presence of AT but absence of identified RCP (group 2: n = 920; 46%), and presence of both AT and RCP (group 3: n = 783; 39%). The study end point was the composite of cardiovascular mortality, urgent heart transplant, and left ventricular assist device implantation.RESULTS: Median follow-up was 2.97 years (interquartile range, 1.50-5.35 years). Eighty-seven (30%), 169 (18%), and 111 (14%) events were observed in groups 1, 2, and 3, respectively (P = .025). Compared with results in group 3 (patients with the best survival), the likelihood of reaching the study end point increased 2.7 times when neither AT nor RCP were identified (hazard ratio, 2.74) and 1.4 times when only AT was identified (hazard ratio, 1.4). Moreover, adding the presence or absence of identified AT and RCP improved the prognostic power of peak oxygen uptake because a significant reclassification was obtained.CONCLUSIONS: AT and RCP identification has a potential role in the prognostic stratification of HFrEF

Isocapnic buffering period: from physiology to clinics

13BACKGROUND: During cardiopulmonary exercise test, the isocapnic buffering period ranges between anaerobic threshold (AT) and respiratory compensation point (RCP). We investigated whether oxygen uptake (VO2) increase during the isocapnic buffering period (ΔVO2AT-RCP) is related to heart failure severity and prognosis. METHODS: We retrospectively analysed reduced ejection fraction heart failure patients who attained RCP at cardiopulmonary exercise test. The study endpoint was the composite of cardiovascular mortality and urgent heart transplantation/left ventricular assist device implantation. Hazard ratio was assessed to identify the increase of risk associated with ΔVO2AT-RCP (below and above the median of ΔVO2AT-RCP). RESULTS: AT and RCP were both identified in 782 (39.2%) out of 1995 reduced ejection fraction heart failure cases. Left ventricular ejection fraction and peak VO2 were 33 ± 9% and 16.5 ± 4.5 mL/kg per min (61 ± 16% of predicted value), suggesting moderate heart failure. At five years, endpoint did not vary between patients below and above the median ΔVO2AT-RCP (3.85 mL/min per kg (25-75th interquartile range = 2.69-5.46)). ΔVO2AT-RCP correlated with several parameters associated to heart failure prognosis, such as peak VO2, VE/VCO2 slope, brain natriuretic peptide and left ventricular ejection fraction. The ΔVO2AT-RCP value was associated with prognosis at univariate but not at multivariable analysis, where only VE/VCO2 slope endured. CONCLUSION: ΔVO2AT-RCP correlates with several parameters linked to heart failure severity. Isocapnic buffering period stratifies heart failure patients, but not more than other prognostic indices.reservedmixedCarriere, Cosimo; Corrà, Ugo; Piepoli, Massimo; Bonomi, Alice; Salvioni, Elisabetta; Binno, Simone; Magini, Alessandra; Sciomer, Susanna; Pezzuto, Beatrice; Gentile, Piero; Schina, Mauro; Sinagra, Gianfranco; Agostoni, PiergiuseppeCarriere, Cosimo; Corrà, Ugo; Piepoli, Massimo; Bonomi, Alice; Salvioni, Elisabetta; Binno, Simone; Magini, Alessandra; Sciomer, Susanna; Pezzuto, Beatrice; Gentile, Piero; Schina, Mauro; Sinagra, Gianfranco; Agostoni, Piergiusepp

Low Serum Ferroxidase I Activity Is Associated With Mortality in Heart Failure and Related to Both Peroxynitrite-Induced Cysteine Oxidation and Tyrosine Nitration of Ceruloplasmin

RATIONALE: Ceruloplasmin antioxidant function is mainly related to its ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite, whose production is increased in heart failure (HF), can affect ceruloplasmin antioxidant function through amino acid modification. OBJECTIVE: We investigated the relationship between FeOxI and ceruloplasmin tyrosine and cysteine modification and explored in a cohort of patients with HF the potential clinical relevance of serum FeOxI. METHODS AND RESULTS: In patients with chronic HF (n=96, 76 ± 9 years; New York Heart Association class, 2.9 ± 0.8) and age-matched controls (n=35), serum FeOxI, FeOxII, ceruloplasmin, nitrotyrosine-bound ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were measured, and the patients were followed up for 24 months. Ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were increased in HF versus controls. FeOxI was decreased in HF (-20%) and inversely related to nitrotyrosine-bound ceruloplasmin (r, -0.305; P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared with middle-higher tertiles. FeOxI emerged as a mortality predictor (hazard ratio, 2.95; 95% confidence intervals [1.29-6.75]; P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, estimated glomerular filtration rate, and high-sensitivity C-reactive protein. In experimental settings, peroxynitrite incubation of serum samples and isolated purified ceruloplasmin reduced FeOxI activity while increasing ceruloplasmin tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented peroxynitrite-induced FeOxI drop, tyrosine nitration, and cysteine oxidation; flavonoid(-)-epicatechin, which prevented ceruloplasmin tyrosine nitration but not cysteine oxidation, partially impeded peroxynitrite-induced FeOxI drop. CONCLUSIONS: Reduced activity of serum FeOxI is associated with ceruloplasmin nitration and reduced survival in patients with HF. Both ceruloplasmin tyrosine nitration and cysteine thiol oxidation may be operant in vivo in peroxynitrite-induced FeOxI activity inhibition

Anaerobic Threshold and Respiratory Compensation Point Identification During Cardiopulmonary Exercise Tests in Chronic Heart Failure

BACKGROUND: We evaluated the prognostic meaning of the simple presence or absence of identifiable anaerobic threshold (AT) and respiratory compensation point (RCP) at cardiopulmonary exercise tests (CPETs) performed with a maximal incremental exercise protocol. METHODS: In the present multicenter study, we retrospectively analyzed data in 1,995 patients with heart failure with reduced ejection fraction (HFrEF). All underwent clinical and laboratory evaluation, echocardiography, and maximal CPET at baseline. The analysis was performed according to absence of identified AT and RCP (group 1: n = 292; 15%), presence of AT but absence of identified RCP (group 2: n = 920; 46%), and presence of both AT and RCP (group 3: n = 783; 39%). The study end point was the composite of cardiovascular mortality, urgent heart transplant, and left ventricular assist device implantation. RESULTS: Median follow-up was 2.97 years (interquartile range, 1.50-5.35 years). Eighty-seven (30%), 169 (18%), and 111 (14%) events were observed in groups 1, 2, and 3, respectively (P = .025). Compared with results in group 3 (patients with the best survival), the likelihood of reaching the study end point increased 2.7 times when neither AT nor RCP were identified (hazard ratio, 2.74) and 1.4 times when only AT was identified (hazard ratio, 1.4). Moreover, adding the presence or absence of identified AT and RCP improved the prognostic power of peak oxygen uptake because a significant reclassification was obtained. CONCLUSIONS: AT and RCP identification has a potential role in the prognostic stratification of HFrEF

Prealbumin improves death risk prediction of BNP-added Seattle Heart Failure Model: results from a pilot study in elderly chronic heart failure patients.

Background: An accurate prognosis prediction represents a key element in chronic heart failure (CHF) management. Seattle Heart Failure Model (SHFM) prognostic power, a validated risk score for predicting mortality in CHF, is improved by adding B-type natriuretic peptide (BNP). We evaluated in a prospective study the incremental value of several biomarkers, linked to different biological domains, on death risk prediction of BNP-added SHFM. Methods: Troponin I (cTnI), norepinephrine, plasma renin activity, aldosterone, high sensitivity-C reactive protein (hs-CRP), tumor necrosis factor-α :(TNF-α), interleukin 6 (IL-6), interleukin 2 soluble receptor, leptin, prealbumin, free malondialdehyde, and 15-F2t-isoprostane were measured in plasma from 142 consecutive ambulatory, non-diabetic stable CHF (mean NYHA-class 2.6) patients (mean age 75 ± 8 years). Calibration, discrimination, and risk reclassification of BNP-added SHFM were evaluated after individual biomarker addition. Results: Individual addition of biomarkers to BNP-added SHFM did not improve death prediction, except for prealbumin (HR 0.49 CI: (0.31-0.76) p = 0.002) and cTnI (HR 2.03 CI: (1.20-3.45) p = 0.009). In fact, with respect to BNP-added SHFM (Harrell's C-statistic 0.702), prealbumin emerged as a stronger predictor of death showing the highest improvement in model discrimination (+ 0.021, p = 0.033) and only a trend was observed for cTn I (+ 0.023, p = 0.063). These biomarkers showed also the best reclassification statistic (Integrated Discrimination Improvement-IDI) at 1-year (IDI: cTnI, p = 0.002; prealbumin, p = 0.020), 2-years (IDI: cTnI, p = 0.018; prealbumin: p = 0.006) and 3-years of follow-up (IDI: cTnI p = 0.024; prealbumin: p = 0.012). Conclusions: Individual addition of prealbumin allows a more accurate prediction of mortality of BNP enriched SHFM in ambulatory elderly CHF suggesting its potential use in identifying those at high-risk that need nutritional surveillance

Regional differences in exercise training implementation in heart failure: findings from the Exercise Training in Heart Failure (ExTraHF) survey

Exercise training programmes (ETPs) are a crucial component in cardiac rehabilitation in heart failure (HF) patients. The Exercise Training in HF (ExTraHF) survey has reported poor implementation of ETPs in countries affiliated to the European Society of Cardiology (ESC). The aim of the present sub-analysis was to investigate the regional variations in the implementation of ETPs for HF patients.Background Exercise training programmes (ETPs) are a crucial component in cardiac rehabilitation in heart failure (HF) patients. The Exercise Training in HF (ExTraHF) survey has reported poor implementation of ETPs in countries affiliated to the European Society of Cardiology (ESC). The aim of the present sub-analysis was to investigate the regional variations in the implementation of ETPs for HF patients. Methods and results The study was designed as a web-based survey of cardiac units, divided into five areas, according to the geographical location of the countries surveyed. Overall, 172 centres replied to the survey, in charge of 78 514 patients, differentiated in 52 Northern (n = 15 040), 48 Southern (n = 27 127), 34 Western (n = 11 769), 24 Eastern European (n = 12 748), and 14 extra-European centres (n = 11 830). Greater ETP implementation was observed in Western (76%) and Northern (63%) regions, whereas lower rates were seen in Southern (58%), Eastern European (50%) and extra-European (36%) regions. The leading barrier was the lack of resources in all (83-65%) but Western region (37%) where patients were enrolled in dedicated settings and specialized units (75%). In 40% of centres, non-inclusion of ETP in the national or local guideline pathway accounted for the lack of ETP implementation. Conclusion Exercise training programmes are poorly implemented in the ESC affiliated countries, mainly because of the lack of resources and/or national and local guidelines. The linkage with dedicated cardiac rehabilitation centres (as in the Western region) or the model of local rehabilitation services adopted in Northern countries may be considered as options to overcome these gaps

Sacubitril/valsartan reduces indications for arrhythmic primary prevention in heart failure with reduced ejection fraction: insights from DISCOVER-ARNI, a multicenter Italian register

Aims This sub-study deriving from a multicentre Italian register [Deformation Imaging by Strain in Chronic Heart Failure Over Sacubitril-Valsartan: A Multicenter Echocardiographic Registry (DISCOVER)-ARNI] investigated whether sacubitril/valsartan in addition to optimal medical therapy (OMT) could reduce the rate of implantable cardioverter-defibrillator (ICD) indications for primary prevention in heart failure with reduced ejection fraction (HFrEF) according to European guidelines indications, and its potential predictors. Methods In this observational study, consecutive patients with HFrEF eligible for sacubitril/valsartan from 13 Italian centres and results were included. Lack of follow-up or speckle tracking data represented exclusion criteria. Demographic, clinical, biochemical, and echocardiographic data were collected at baseline and after 6 months from sacubitril/valsartan initiation. Of 351 patients, 225 (64%) were ICD carriers and 126 (36%) were not ICD carriers (of whom 13 had no indication) at baseline. After 6 months of sacubitril/valsartan, among 113 non-ICD carriers despite having baseline left ventricular (LV) ejection fraction (EF) &lt;_ 35% and New York Heart Association (NYHA) class = II–III, 69 (60%) did not show ICD indications; 44 (40%) still fulfilled ICD criteria. Age, atrial fibrillation, mitral regurgitation &gt; moderate, left atrial volume index (LAVi), and LV global longitudinal strain (GLS) significantly varied between the groups. With receiver operating characteristic curves, age &gt;_ 75 years, LAVi &gt;_ 42 mL/m2 and LV GLS &gt;_-8.3% were associated with ICD indications persistence (area under the curve = 0.65, 0.68, 0.68, respectively). With univariate and multivariate analysis, only LV GLS emerged as significant predictor of ICD indications at follow-up in different predictive models. Conclusions Sacubitril/valsartan may provide early improvement of NYHA class and LVEF, reducing the possible number of implanted ICD for primary prevention in HFrEF. Baseline reduced LV GLS was a strong marker of ICD indication despite OMT. Early therapy with sacubitril/valsartan may save infective/haemorrhagic risks and unnecessary costs deriving from ICDs