Elisabetta Salvioni

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.

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.

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.

Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: The CARNEBI trial

BACKGROUND Several β-blockers, with different pharmacological characteristics, are available for heart failure (HF) treatment. We compared Carvedilol (β1-β2-α-blocker), Bisoprolol (β1-blocker), and Nebivolol (β1-blocker, NO-releasing activity). METHODS Sixty-one moderate HF patients completed a cross-over randomized trial, receiving, for 2 months each, Carvedilol, Nebivolol, Bisoprolol (25.6 ± 12.6, 5.0 ± 2.4 and 5.0 ± 2.4 mg daily, respectively). At the end of each period, patients underwent: clinical evaluation, laboratory testing, echocardiography, spirometry (including total DLCO and membrane diffusion), O2/CO2 chemoreceptor sensitivity, constant workload, in normoxia and hypoxia (FiO2=16%), and maximal cardiopulmonary exercise test. RESULTS No significant differences were observed for clinical evaluation (NYHA classification, Minnesota questionnaire), laboratory findings (including kidney function and BNP), echocardiography, and lung mechanics. DLCO was lower on Carvedilol (18.3 ± 4.8*mL/min/mmHg) compared to Nebivolol (19.9 ± 5.1) and Bisoprolol (20.0 ± 5.0) due to membrane diffusion 20% reduction (*=p<0.0001). Constant workload exercise showed in hypoxia a faster VO2 kinetic and a lower ventilation with Carvedilol. Peripheral and central sensitivity to CO2 was lower in Carvedilol while response to hypoxia was higher in Bisoprolol. Ventilation efficiency (VE/VCO2 slope) was 26.9 ± 4.1* (Carvedilol), 28.8 ± 4.0 (Nebivolol), and 29.0 ± 4.4 (Bisoprolol). Peak VO2 was 15.8 ± 3.6*mL/kg/min (Carvedilol), 16.9 ± 4.1 (Nebivolol), and 16.9 ± 3.6 (Bisoprolol). CONCLUSIONS β-Blockers differently affect several cardiopulmonary functions. Lung diffusion and exercise performance, the former likely due to lower interference with β2-mediated alveolar fluid clearance, were higher in Nebivolol and Bisoprolol. On the other hand, Carvedilol allowed a better ventilation efficiency during exercise, likely via a different chemoreceptor modulation. Results from this study represent the basis for identifying the best match between a specific β-blocker and a specific HF patient.

Effects of β-blockers on ventilation efficiency in heart failure

BACKGROUND Hyperventilation and consequent reduction of ventilation (VE) efficiency are frequently observed during exercise in heart failure (HF) patients, resulting in an increased slope of VE/carbon dioxide (VE/Vco(2)) relationship. The latter is an independent predictor of HF prognosis. beta-Blockers improve the prognosis of HF patients. We evaluated the effect on the efficiency of VE of a beta(1)-beta(2) unselective (carvedilol) versus a beta(1) selective (bisoprolol) beta-blocker. METHODS We analyzed consecutive maximal cardiopulmonary exercise tests performed on 572 clinically stable HF patients (New York Heart Association class I-III, left ventricle ejection fraction < or =50%) categorized in 3 groups: 81 were not treated with beta-blocker, 304 were treated with carvedilol, and 187 were treated with bisoprolol. Clinical conditions were similar. RESULTS The VE/Vco(2) slope was lower in carvedilol- compared with bisoprolol-treated patients (29.7 +/- 0.4 vs 31.6 +/- 0.5, P = .023, peak oxygen consumption adjusted) and with patients not receiving beta-blockers (31.6 +/- 0.7, P = .036). Maximum end-tidal CO(2) pressure during the isocapnic buffering period was higher in patients treated with carvedilol (39.0 +/- 0.3 mm Hg) than with bisoprolol (37.2 +/- 0.4 mm Hg, P < .001) and in patients not receiving beta-blockers (37.2 +/- 0.5 mm Hg, P = .001). CONCLUSIONS Reduction of hyperventilation, with improvement of VE efficiency during exercise (reduction of VE/Vco(2) slope and increase of maximum end-tidal CO(2) pressure), is specific to carvedilol (beta(1)-beta(2) unselective blocker) and not to bisoprolol (beta(1)-selective blocker).

Role of Alveolar β2-Adrenergic Receptors on Lung Fluid Clearance and Exercise Ventilation in Healthy Humans

Background In experimental conditions alveolar fluid clearance is controlled by alveolar β2-adrenergic receptors. We hypothesized that if this occurs in humans, then non-selective β-blockers should reduce the membrane diffusing capacity (DM), an index of lung interstitial fluid homeostasis. Moreover, we wondered whether this effect is potentiated by saline solution infusion, an intervention expected to cause interstitial lung edema. Since fluid retention within the lungs might trigger excessive ventilation during exercise, we also hypothesized that after the β2-blockade ventilation increased in excess to CO2 output and this was further enhanced by interstitial edema. Methods and Results 22 healthy males took part in the study. On day 1, spirometry, lung diffusion for carbon monoxide (DLCO) including its subcomponents DM and capillary volume (VCap), and cardiopulmonary exercise test were performed. On day 2, these tests were repeated after rapid 25 ml/kg saline infusion. Then, in random order 11 subjects were assigned to oral treatment with Carvedilol (CARV) and 11 to Bisoprolol (BISOPR). When heart rate fell at least by 10 beats·min−1, the tests were repeated before (day 3) and after saline infusion (day 4). CARV but not BISOPR, decreased DM (−13±7%, p = 0.001) and increased VCap (+20±22%, p = 0.016) and VE/VCO2 slope (+12±8%, p<0.01). These changes further increased after saline: −18±13% for DM (p<0.01), +44±28% for VCap (p<0.001), and +20±10% for VE/VCO2 slope (p<0.001). Conclusions These findings support the hypothesis that in humans in vivo the β2-alveolar receptors contribute to control alveolar fluid clearance and that interstitial lung fluid may trigger exercise hyperventilation.

Relationship of resting hemoglobin concentration to peak oxygen uptake in heart failure patients

Anemia is frequent in chronic heart failure (HF). To calculate what change in peak oxygen uptake (

Ambulatory Blood Pressure in Untreated and Treated Hypertensive Patients at High Altitude: The High Altitude Cardiovascular Research–Andes Study

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Acute high-altitude exposure reduces lung diffusion: Data from the HIGHCARE Alps project

O2) should be expected in the event of changes in hemoglobin concentration, we studied the correlation between peak

Severe heart failure prognosis evaluation for transplant selection in the era of beta-blockers: role of peak oxygen consumption.

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