Combining Ubiquinol With a Statin May Benefit Hypercholesterolaemic Patients With Chronic Heart Failure.

Heart failure (HF) is one of the most common causes of death in Western society. Recent results underscore the utility of coenzyme Q10 (CoQ10) addition to standard medications in order to reduce mortality and to improve quality of life and functional capacity in chronic heart failure (CHF). The rationale for CoQ10 supplementation in CHF is two-fold. One is the well-known role of CoQ10 in myocardial bioenergetics, and the second is its antioxidant property. Redox balance is also improved by oral supplementation of CoQ10, and this effect contributes to enhanced endothelium-dependent relaxation. Previous reports have shown that CoQ10 concentration is decreased in myocardial tissue in CHF and by statin therapy, and the greater the CoQ10 deficiency the more severe is the cardiocirculatory impairment. In patients with CHF and hypercholesterolaemia being treated with statins, the combination of CoQ10 with a statin may be useful for two reasons: decreasing skeletal muscle injury and improving myocardial function. Ubiquinol, the active reduced form of CoQ10, presents higher bioavailability than the oxidised form ubiquinone, and should be the preferred form to be added to a statin. The combination ezetimibe/simvastatin may have advantages over single statins. Since ezetimibe reduces absorption of cholesterol and does not affect CoQ10 synthesis in the liver, the impact of this combination on CoQ10 tissue levels will be much less than that of high dose statin monotherapy at any target low density lipoprotein-cholesterol (LDL-C) level to be reached. This consideration makes the ezetimibe/statin combination the ideal LDL-lowering agent to be combined with ubiquinol in CHF patients. However, particular caution is advisable with the use of strategies of extreme lowering of cholesterol that may negatively impact on myocardial function. All in all there is a strong case for considering co-administration of ubiquinol with statin therapy in patients with depressed or borderline myocardial function.

The Role of Gas Exchange Variables in Cardiopulmonary Exercise Testing for Risk Stratification and Management of Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is common in the developed world and results in significant morbidity and mortality. Accurate risk assessment methods and prognostic variables are therefore needed to guide clinical decision making for medical therapy and surgical interventions with the ultimate goal of decreasing risk and improving health outcomes. The purpose of this review is to examine the role of cardiopulmonary exercise testing (CPET) and its most commonly used ventilatory gas exchange variables for the purpose of risk stratification and management of HFrEF. We evaluated five widely studied gas exchange variables from CPET in HFrEF patients based on nine previously used systematic criteria for biomarkers. This paper provides clinicians with a comprehensive and critical overview, class recommendations and evidence levels. Although some CPET variables met more criteria than others, evidence supporting the clinical assessment of variables beyond peak V̇O2 is well-established. A multi-variable approach also including the V̇E-V̇CO2 slope and EOV is therefore recommended.

Mineralocorticoid receptor antagonists for heart failure: a real-life observational study.

AIMS: Mineralocorticoid receptor antagonists (MRAs) have been demonstrated to improve outcomes in reduced ejection fraction heart failure (HFrEF) patients. However, MRAs added to conventional treatment may lead to worsening of renal function and hyperkalaemia. We investigated, in a population-based analysis, the long-term effects of MRA treatment in HFrEF patients. METHODS AND RESULTS: We analysed data of 6046 patients included in the Metabolic Exercise Cardiac Kidney Index score dataset. Analysis was performed in patients treated (n = 3163) and not treated (n = 2883) with MRA. The study endpoint was a composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Ten years' survival was analysed through Kaplan-Meier, compared by log-rank test and propensity score matching. At 10 years' follow-up, the MRA-untreated group had a significantly lower number of events than the MRA-treated group (P < 0.001). MRA-treated patients had more severe heart failure (higher New York Heart Association class and lower left ventricular ejection fraction, kidney function, and peak VO2 ). At a propensity-score-matching analysis performed on 1587 patients, MRA-treated and MRA-untreated patients showed similar study endpoint values. CONCLUSIONS: In conclusion, MRA treatment does not affect the composite of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation in a real-life setting. A meticulous patient follow-up, as performed in trials, is likely needed to match the positive MRA-related benefits observed in clinical trials.

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.

Prognostic role of ß-blocker selectivity and dosage regimens in heart failure patients. Insights from the MECKI score database.

AIMS: The use of ß-blockers represents a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF). Few studies have compared ß-blockers in HFrEF, and there is little data on the effects of different doses. The present study aimed to investigate in a large database of HFrEF patients (MECKI score database) the association of ß-blocker treatment with a composite outcome of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation, addressing the role of ß-selectivity and dosage regimens. METHODS AND RESULTS: In 5242 HFrEF patients, we investigated the role of: (i) ß-blocker treatment vs. non-ß-blocker treatment, (ii) ß1-/ß2-receptor-blockers vs. ß1-selective blockers, and (iii) daily ß-blocker dose. Patients were followed for 3.58 years, and 1101 events (18.3%) were observed; 4435 patients (86.8%) were on ß-blockers, while 807 (13.2%) were not. At 5 years, ß-blocker-patients showed a better outcome than non-ß-blocker-subjects [hazard ratio (HR) 0.48, P < 0.0001], while also considering potential confounders. A comparable prognosis was observed at 5 years in the ß1-/ß2-receptor-blocker (n = 2219) vs. ß1-selective group (n = 2216) (HR 0.95, P = ns). A better prognosis was observed in high-dose (>2 5 mg carvedilol equivalent daily dose, n = 1005) patients than in both medium dose (12.5-25 mg, n = 1431) and low dose (<12.5 mg, n = 1960) (HR 1.97, P < 0.001; HR 1.95, P = 0.001, respectively), with no differences between the last two groups (HR 0.84, P = ns). CONCLUSION: In a large population of chronic HFrEF patients, ß-blockers were associated with a more favourable prognosis without any difference between ß1- and ß2-receptor-blockers vs. ß1-selective blockers. A better outcome was observed in subjects receiving a high daily dose.

Frailty and cardiac rehabilitation: A call to action from the EAPC Cardiac Rehabilitation Section.

Frailty is a geriatric syndrome characterised by a vulnerability status associated with declining function of multiple physiological systems and loss of physiological reserves. Two main models of frailty have been advanced: the phenotypic model (primary frailty) or deficits accumulation model (secondary frailty), and different instruments have been proposed and validated to measure frailty. However measured, frailty correlates to medical outcomes in the elderly, and has been shown to have prognostic value for patients in different clinical settings, such as in patients with coronary artery disease, after cardiac surgery or transvalvular aortic valve replacement, in patients with chronic heart failure or after left ventricular assist device implantation. The prevalence, clinical and prognostic relevance of frailty in a cardiac rehabilitation setting has not yet been well characterised, despite the increasing frequency of elderly patients in cardiac rehabilitation, where frailty is likely to influence the onset, type and intensity of the exercise training programme and the design of tailored rehabilitative interventions for these patients. Therefore, we need to start looking for frailty in elderly patients entering cardiac rehabilitation programmes and become more familiar with some of the tools to recognise and evaluate the severity of this condition. Furthermore, we need to better understand whether exercise-based cardiac rehabilitation may change the course and the prognosis of frailty in cardiovascular patients.

Heart failure and anemia: Effects on prognostic variables.

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 (VO2), ventilatory efficiency (VE/VCO2 slope), plasma sodium concentration, ejection fraction (LVEF), kidney function and Hb were independently related to prognosis in the entire population. Considering Hb groups separately, peakVO2 (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/VCO2 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. PeakVO2 and LVEF, but not VE/VCO2 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.

Exercise tolerance can explain the obesity paradox in patients with systolic heart failure: data from the MECKI Score Research Group.

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

Sex Profile and Risk Assessment With Cardiopulmonary Exercise Testing in Heart Failure: Propensity Score Matching for Sex Selection Bias.

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.

The metabolic exercise test data combined with Cardiac And Kidney Indexes (MECKI) score and prognosis in heart failure. A validation study.

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.

Exercise Performance Is a Prognostic Indicator in Elderly Patients With Chronic Heart Failure--Application of Metabolic Exercise Cardiac Kidney Indexes Score.

BACKGROUND: In patients with chronic heart failure (HF) the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score, is a predictor of cardiovascular death and urgent heart transplantation. We investigated the relationship between age, exercise tolerance and the prognostic value of the MECKI score. METHODS AND RESULTS: We analyzed data from 3,794 patients with chronic systolic HF. The primary endpoint was a composite of cardiovascular death and urgent heart transplantation. Older patients had higher prevalence of comorbidities and lower exercise performance compared with younger subjects (peak V̇O2, 925 vs. 1,351 L/min; P<0.0001; V̇E/V̇CO2slope, 33.2 vs. 28.3; P>0.0001). The rate of the primary endpoint was 19% in the highest age quartile and 14% in the lowest quartile. At multivariable analysis, the independent predictors of the primary endpoint were left ventricular ejection fraction (LVEF), eGFR, peak V̇O2, serum Na(+)and the use of ß-blockers in patients aged ≥70 years, and LVEF, eGFR and peak V̇O2in younger subjects. The MECKI risk score increased across age subgroups, but on receiver operating characteristic curve analysis its prognostic power was similar in both patients aged ≥70 and <70 years. CONCLUSIONS: Older patients with HF are a high-risk population with lower exercise performance. The MECKI score increased according to age and maintained its prognostic value also in older patients.

Prognostic role of atrial fibrillation in patients affected by chronic heart failure. Data from the MECKI score research group.

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.

Renal function and peak exercise oxygen consumption in chronic heart failure with reduced left ventricular ejection fraction.

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.

Deceptive meaning of oxygen uptake measured at the anaerobic threshold in patients with systolic heart failure and atrial fibrillation.

BACKGROUND: Oxygen uptake at the anaerobic threshold (VO2AT), a submaximal exercise-derived variable, independent of patients' motivation, is a marker of outcome in heart failure (HF). However, previous evidence of VO2AT values paradoxically higher in HF patients with permanent atrial fibrillation (AF) than in those with sinus rhythm (SR) raised uncertainties. DESIGN: We tested the prognostic role of VO2AT in a large cohort of systolic HF patients, focusing on possible differences between SR and AF. METHODS: Altogether 2976 HF patients (2578 with SR and 398 with AF) were prospectively followed. Besides a clinical examination, each patient underwent a maximal cardiopulmonary exercise test (CPET). RESULTS: The follow-up was analysed for up to 1500 days. Cardiovascular death or urgent cardiac transplantation occurred in 303 patients (250 (9.6%) patients with SR and 53 (13.3%) patients with AF, p = 0.023). In the entire population, multivariate analysis including peak oxygen uptake (VO2) showed a prognostic capacity (C-index) similar to that obtained including VO2AT (0.76 vs 0.72). Also, left ventricular ejection fraction, ventilation vs carbon dioxide production slope, ß-blocker and digoxin therapy proved to be significant prognostic indexes. The receiver-operating characteristic (ROC) curves analysis showed that the best predictive VO2AT cut-off for the SR group was 11.7 ml/kg/min, while it was 12.8 ml/kg/min for the AF group. CONCLUSIONS: VO2AT, a submaximal CPET-derived parameter, is reliable for long-term cardiovascular mortality prognostication in stable systolic HF. However, different VO2AT cut-off values between SR and AF HF patients should be adopted.

Cardiopulmonary exercise testing is more accurate than ECG-stress testing in diagnosing myocardial ischemia in subjects with chest pain.

BACKGROUND: Cardiopulmonary exercise stress testing (CPET) is used to grade the severity of heart failure and to assess its prognosis. However it is unknown whether CPET may improve diagnostic accuracy of standard ECG stress testing to identify or exclude obstructive coronary artery disease (O-CAD) in patients with chest pain. METHODS: We prospectively studied 1265 consecutive subjects (55 ± 8 years, 156 women) who were evaluated with ECG stress testing (ET) for chest pain. No one had a documented O-CAD. All patients performed an incremental CPET with ECG recordings on an electronically braked cycle ergometer. RESULTS: Of 1265 patients, 73 had a positive CPET and 1192 had a negative CPET. Seventy-three patients with a positive CPET and 71 patients with a negative CPET agreed to undergo nuclear SPECT imaging and coronary angiography. Follow-up lasted 48 ± 7 months. As compared with ET, sensitivity, specificity, PPV and NPV were all improved significantly (ET: 48%, 55%, 33%, 95%; CPET: 88%, 98%, 73%, 99%, respectively, P<0.001). Patients with both peak VO2>91% of predicted VO2 max and absence of VO2-related signs of myocardial ischemia had no evidence of O-CAD in 100% of cases. Cardiac events occurred in 32 patients with a positive CPET and 8 patients with a negative CPET (log rank 18.2, P<0.0001). CONCLUSIONS: In patients with chest pain, CPET showed a better diagnostic and predictive accuracy than traditional ET to detect/exclude myocardial ischemia. Its use should be encouraged among physicians as a first line diagnostic tool in clinical practice.

Prognostic value of indeterminable anaerobic threshold in heart failure.

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.

Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study.

OBJECTIVES: The aim of this cohort study was to retrospectively evaluate, in patients with chronic heart failure (CHF), the long term effect of trimetazidine (TMZ) on morbidity and mortality. BACKGROUND: Previous small studies in patients with CHF have shown that TMZ can improve left ventricular function, exercise capacity and NYHA class compared to placebo. However, no data on the effects of TMZ on survival in patients with CHF have ever been produced. METHODS: In this international multicentre retrospective cohort study data from 669 patients were analyzed. 362 patients were on TMZ due to symptom persistence despite up-titration of optimal CHF therapy, while the remaining patients continued conventional CHF therapy alone. Propensity score analysis was performed in order to minimize selection bias between the two groups. RESULTS: Kaplan-Meier analysis for global mortality showed 11.3% improved global survival (p=0.015) and 8.5% improved survival for cardiovascular (CVD) death (p=0.050) in the TMZ group. Cox regression analysis for global mortality showed a significant risk reduction for TMZ treated patients with a hazard ratio (HR)=0.189 (confidence interval - CI 95%: 0.017-0.454; p=0.0002). TMZ also showed a good risk reduction profile for CVD death causes (HR=0.072, CI 95%: 0.019-0.268, p=0.0001). The rate of hospitalization for cardiovascular causes was reduced by 10.4% at 5 years (p<0.0005) with increased hospitalization-free survival of 7.8 months. CONCLUSION: TMZ is effective in reducing mortality and event-free survival in patients with CHF. The addition of TMZ on top of optimal medical therapy improves long term survival in CHF patients.

Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: a multiparametric approach to heart failure prognosis.

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.

10-year exercise training in chronic heart failure: a randomized controlled trial.

OBJECTIVES: This study investigated the effect of a very long-term exercise training program is not known in chronic heart failure (CHF) patients. BACKGROUND: We previously showed that long-term moderate exercise training (ET) improves functional capacity and quality of life in New York Heart Association class II and III CHF patients. METHODS: We studied 123 patients with CHF whose condition was stable over the previous 3 months. After randomization, a trained group (T group, n = 63) underwent a supervised ET at 60% of peak oxygen consumption (Vo(2)), 2 times weekly for 10 years, whereas a nontrained group (NT group, n = 60) did not exercise formally. The ET program was supervised and performed mostly at a coronary club with periodic control sessions twice yearly at the hospital's gym. RESULTS: In the T group, peak Vo(2) was more than 60% of age- and gender-predicted maximum Vo(2) each year during the 10-year study (p < 0.05 vs. the NT group). In NT patients, peak Vo(2) decreased progressively with an average of 52 ± 8% of maximum Vo(2) predicted. Ventilation relative to carbon dioxide output (VE/Vco(2)) slope was significantly lower (35 ± 9) in T patients versus NT patients (42 ± 11, p < 0.01). Quality-of-life score was significantly better in the T group versus the NT group (43 ± 12 vs. 58 ± 14, p < 0.05). During the 10-year study, T patients had a significant lower rate of hospital readmission (hazard ratio: 0.64, p < 0.001) and cardiac mortality (hazard ratio: 0.68, p < 0.001) than controls. Multivariate analysis selected peak Vo(2) and resting heart rate as independent predictors of events. CONCLUSIONS: Moderate supervised ET performed twice weekly for 10 years maintains functional capacity of more than 60% of maximum Vo(2) and confers a sustained improvement in quality of life compared with NT patients. These sustained improvements are associated with reduction in major cardiovascular events, including hospitalizations for CHF and cardiac mortality.