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.

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.

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.

Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients.

AIMS: The influence of permanent atrial fibrillation on exercise tolerance and cardio-respiratory function during exercise in heart failure (HF) is unknown. METHODS AND RESULTS: We retrospectively compared the results of 942 cardiopulmonary exercise tests, performed consecutively at seven Italian laboratories, in HF patients with atrial fibrillation (n = 180) and sinus rhythm (n = 762). By multivariable logistic regression analysis, peak VO(2) (OR 0.376, 95% CI 0.240-0.588, P < 0.0001), O(2)pulse (VO(2)/heart rate, HR) (OR 0.236, 95% CI 0.152-0.366, P < 0.0001), VCO(2) (OR 3.97, 95% CI 2.163-7.287, P < 0.0001), and ventilation (OR 1.38, 95% CI 1.045-1.821, P = 0.0231) were independently associated with atrial fibrillation. Anaerobic threshold (AT) was identified in 132 of 180 (73%) atrial fibrillation and in 649 of 762 (85%) sinus rhythm patients (P = 0.0002). By multivariable logistic regression analysis, only peak VO(2) (OR 0.214, 95% CI 0.155-0.296, P < 0.0001) was independently associated with unidentified AT. At AT, atrial fibrillation HF patients had higher HR (P < 0.0001) and higher VO(2) (P < 0.001) compared with sinus rhythm HF patients. Among AT variables, by multivariable logistic regression analysis, only HR was an independent predictor of atrial fibrillation. CONCLUSION: In HF patients with permanent atrial fibrillation, exercise performance is reduced as reflected by reduced peak VO(2). The finding of unidentified AT is associated with a poor performance. In atrial fibrillation patients, VO(2) is higher at AT whereas lower at peak. This last observation raises uncertainties about the use of AT data to define performance and prognosis of HF patients with atrial fibrillation.

Effects of trimetazidine on myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy.

AIMS: To determine whether short-term treatment with trimetazidine (TMZ), an antiischemic agent that directly inhibits fatty acid oxidation and results in stimulation of glucose oxidation, may improve myocardial perfusion and left ventricular systolic function in diabetic patients with ischemic cardiomyopathy. METHODS AND RESULTS: We studied 34 clinically stable patients with type 2 diabetes mellitus (DM) and documented multivessel coronary artery disease (29 men and 5 women, mean age 54 +/- 9 years) with depressed systolic function (left ventricular ejection fraction 38 +/- 6%). Patients were randomized into two groups. One group received TMZ (20 mg tid) for 3 months (n = 19), while another group received a placebo during the same period (n = 15). On study entry and at 3 months, all patients underwent a gated Single Photon Emission Computed Tomography (SPECT) myocardial scintigraphy with a 2-day stress(Bruce)-rest protocol (500 MBq tetrofosmin). At 3 months, TMZ-treated patients had a significant improvement in systolic wall thickening (P < 0.05) and ejection fraction (P = 0.007) as compared with control patients. These effects were more marked in patients with more severe reversible perfusion defects on initial evaluation and were not associated with changes in myocardial defects (P = 0.38). Total exercise time was also improved in TMZ-treated patients (20.5%, P < 0.05 vs. controls). CONCLUSIONS: In diabetic cardiomyopathy, short-term TMZ improved left ventricular systolic function and functional capacity despite no change in myocardial perfusion. These benefits were more evident in patients with more severe perfusion defects on initial evaluation, suggesting that chronic myocardial ischemia is a requirement for the effects of TMZ on left ventricular systolic performance.

Oxidative stress, endothelial function and coenzyme Q10.

Reactive oxygen species seem to play an important role in vascular homeostasis. In conditions of high oxidative stress, such as chronic heart failure and multiple coronary risk factors, the rate of inactivation of nitric oxide to peroxynitrite by superoxide anions may be reduced by CoQ10, which can also protect against nitrosative damage. CoQ10 may also influence vascular function indirectly via inhibition of oxidative damage to LDL. Patients with lower levels of extracellular superoxide dismutase (ecSOD) demonstrate greater improvements than patients with normal ec-SOD levels, suggesting that the higher the oxidative stress the greater the improvement in the endothelium-dependent relaxation after the administration of a compound with antioxidant properties like CoQ10. Future studies are needed to inquire whether these effects may translate into benefits in clinical practice.

Blood CoQ10 levels and safety profile after single-dose or chronic administration of PureSorb-Q40: animal and human studies.

Coenzyme Q10 (CoQ10) is known to be highly hydrophobic and, as such, insoluble in water: this leads to serious inconvenience when trying to incorporate it in food products. Its absorption is also known to be very limited. PureSorb-Q40 (P40) (Water-soluble type CoQ10 powder, CoQ10 content 40 w/w % was developed in order to improve its use with food products and to enhance its absorption. In the present study the absorption of this novel formulation was compared to a conventional lipid soluble CoQ10 by administering both products to rats and humans. Acute, single-administration studies in rats showed that P40 has a higher absorption, compared to lipid soluble CoQ10, both in prandial and fasting states. Similarly, single administration in humans revealed a higher absorption level for P40, taken in the fasting state or together with meals. In the rat study, no adverse effects were observed with P40 at doses up to 2,000 mg/kg in both sexes. In a double-blind, placebo controlled, comparative study conducted on 46 healthy volunteers and randomly divided into two groups, in the group receiving 900~mg of CoQ10 per day, for 4 consecutive weeks, the average level at two weeks was 8.79 +/- 3.34 microg/mL, similar to the corresponding level after 4 weeks (8.33 +/- 4.04 microg/mL). After 2 weeks of washout, serum CoQ10 level decreased to 1.30 +/- 0.49 microg/mL. P40 intake did not cause any significant changes in symptoms and clinical laboratory tests as assessed by physical, hematological, blood biochemical or urinalysis. Clinical examinations also did not reveal any abnormalities. The above blood (serum) CoQ10 level at 2 weeks after start of intake was compared with other reported values. The same dose of CoQ10 (900mg/day), when administered by softgel capsules yielded a plasma CoQ10 concentration of 3.6 microg/mL, while P40 levels were 8.79 +/- 3.34 microg/mL. These levels are remarkably high for instance when compared to the corresponding levels obtained, in patients affected by Parkinson's disease, with CoQ10 doses up to 2,400mg/day. A clinical study was conducted using doses of 300 mg/day and 600 mg/day, in patients affected by cardiovascular disease. Also in this case there was linearity in the response with the levels obtained by administering P40 at a dose of 100 and 900 mg/day.

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.

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.

Cardiovascular responses during recreational 5-a-side indoor-soccer.

The aims of this study were to examine the cardiovascular response to recreational 5-a-side indoor-soccer (5v5) matches (5v5 study, 5v5S, n=15) and to assess the validity of using heart rate (HR) to estimate oxygen uptake (VO(2)) demands during actual game-play (validity study, VS, n=16) in young subjects (age 16.8+/-1.5 years). Game responses during 5v5S were assessed during 30 min matches using short-range telemetry heart-rate monitors. In VS games (12 min), VO(2) and HR were monitored with a portable gas analyser (K4b(2), COSMED, Rome, Italy). Individual HR-VO(2) relationships were determined from a laboratory treadmill run to exhaustion (VS) and a multistage shuttle running fitness test (5v5S) using K4b(2). Results showed that 5v5 elicits 83.5+/-5.4 and 75.3+/-11.2% of HR(peak) and VO(2peak), respectively. Ninety-one percent of the playing time (30 min) was spent at HR higher than 70% of HR(peak). In VS match, gas analyses revealed that only 71% of HR variance was explained by VO(2) variations. However, playing at approximately 70% of HR(peak) elicited 51.6+/-11.2% of VO(2peak). Group actual versus predicted VO(2) values demonstrated no significant differences (p>0.05), however, large confidence limits were observed (+6.20 and -10.53 mlkg(-1)min(-1)). These results show that HR and VO(2) responses to recreational 5v5 soccer in young athletes are similar to the exercise intensities recommended by ACSM for promoting cardiovascular health and suggest that HR is valid to prescribe and monitor aerobic intermittent exercise. These results also show that HR measures are acceptable for estimating VO(2) during intermittent exercise when assessing large groups, but show that large estimation errors can occur at the individual level.

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.

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.

Clinical benefits of a metabolic approach in the cardiac rehabilitation of patients with coronary artery disease.

Patients referred for cardiac rehabilitation may benefit from combining trimetazidine with exercise training because both treatments produce synergic benefits on the cardiovascular system. There is evidence that trimetazidine improves left ventricular (LV) function in patients with ischemic and diabetic cardiomyopathy by shifting the cellular energy substrate reference from fatty acids to glucose oxidation, and that this effect is associated with a better outcome. Recently, results have demonstrated that trimetazidine improves radial artery endothelium-dependent relaxation related to its antioxidant properties. Similarly, exercise training has been demonstrated to improve diastolic filling and systolic function in patients with ischemic cardiomyopathy, in relation to enhanced perfusion and contractility of dysfunctional myocardium. Patients with viable myocardium, in theory, should have the greatest benefits because trimetazidine improves contractility of dysfunctional hibernating/stunned myocardium, whereas exercise has documented efficacy in improving endothelial vasomotor response of coronary arteries, stimulating coronary collateral circulation and small vessel growth, improving LV function, and increasing functional capacity. At present, there are no published reports about the efficacy of the combination of trimetazidine with exercise training. In this article, we discuss the rationale for using trimetazidine in cardiac rehabilitation, the identification of patients referred for cardiac rehabilitation who might benefit the most from the addition of trimetazidine to standard therapy, and the documented benefits.

[Hyperhomocysteinemia in pediatric age and nutritional aspects of folates: an early cardiovascular risk factor]. / Iperomocisteinemia in età evolutiva e aspetti nutrizionali dei folati: un fattore di rischio cardiovascolare precoce.

During the last decade, scientific evidence is mounting that elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischemic events. Despite this evidence, however, there are still concerns about the mechanisms(s) by which homocysteine exerts its pro-atherogenic effect, and it is unclear whether the decreased plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk. Experimental studies have shown that many possible mechanisms are implicated in the pro-atherogenic effect of homocysteine. Endothelial function is altered in subjects with hyperhomocysteinemia, and endothelial dysfunction is correlated with plasma levels of homocysteine. Exercise training reduces plasma levels of homocysteine and improves endothelial function, however without evidence of a better outcome. Larger studies are needed in order to demonstrate that the reduction of plasma levels of homocysteine by oral supplementation with folates and vitamins B6 and B12 translates into a decreased incidence of ischemic events, in particular in patients with documented coronary artery disease and ischemic encephalopathy.

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.

Effects of short-term moderate exercise training on sexual function in male patients with chronic stable heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) have sexual dysfunction that impairs quality of life. Recent trials have demonstrated that exercise training (ET) improves quality of life (QOL) of CHF patients, but it is not established whether this benefit may be associated with an improvement in sexual dysfunction. OBJECTIVE: To determine whether ET can improve sexual dysfunction in patients with CHF. METHODS: We prospectively studied 59 male patients (57+/-9 years) with stable CHF in sinus rhythm and without prostatic disease. Patients were randomized into two groups. A group (T, n = 30) underwent supervised cycle ergometer ET at 60% of peak VO2, three times a week, 60 min each session, for 8 weeks. A group (NT, n = 29) was not exercised. Medications were not changed during the study. On study entry and at 8 weeks all patients underwent a symptom-limited cardiopulmonary exercise testing, brachial artery endothelium-dependent (ED) and endothelium-independent (EI) vasomotor responses, QOL and sexual activity profile assessment (SAP) by questionnaire. RESULTS: At 8 weeks, no changes were observed in control patients. In trained patients, however, peak VO2 improved by 18% (P < 0.005) and was correlated with QOL (r = 0.80; P < 0.001). Flow-mediated dilation improved in trained patients (from 2.29+/-1.13% to 5.04+/-1.7%, P = 0.0001), while EI dilation (after 0.3 mg sublingual NTG) did not. In group T, all three domains (i.e. Domain 1=relationship with the partner; Domain 2 = quality of penile erection; Domain 3 = personal wellness) were significantly improved from baseline (total score patients: from 3.49+/-3.4 to 6.17+/-3.2, P < 0.001; partners: from 2.47+/-2.7 to 4.87+/-2.5, P < 0.001). Pre-post training change in SAP total score was correlated with changes in coronary risk profile (r = -0.49; P = 0.01), peak VO2 (r = 0.67; P < 0.001) and QOL (r = 0.73; P = 0.01). Multivariate analysis selected the improvement in ED-vasomotor response as the strongest independent predictor of SAP improvement (r = 0.63, P < 0.001). CONCLUSIONS: In stable CHF, cycle ergometer ET significantly improves brachial artery endothelial dysfunction, suggesting a systemic effect of leg exercise. This benefit was correlated with improvements in sexual activity.