Pietro Palermo

Synergistic efficacy of enalapril and losartan on exercise performance and oxygen consumption at peak exercise in congestive heart failure

Oxygen consumption at peak exercise (peak VO2) is a strong independent predictor of the outcome in congestive heart failure (CHF). Renin-angiotensin system inhibition with either ACE or AT1 receptor blockers is effective on peak VO2. We evaluated whether mechanisms are similar for the 2 categories of drugs and whether their combination is able to produce a synergistic effect. Twenty CHF patients were randomized to receive, in a double-blind fashion, placebo + placebo (P+P), enalapril (20 mg/day) + placebo (E+P), losartan (50 mg/day) + placebo (L+P), and enalapril + losartan (E+L) or the same preparations in a reverse order, each for 8 weeks. Two patients did not complete the trial. Pulmonary function, cardiopulmonary exercise test, plasma neurohormones, and quality of life were assessed at the end of each treatment. Compared with P+P, E+P, and L+P similarly (16% and 15%, respectively) and significantly (p <0.01) augmented peak VO2. Enalapril improved lung function (reduced slope of ventilation vs carbon dioxide production and dead space to tidal volume ratio, and increased alveolar membrane conductance and tidal volume). Losartan likely activated the exercising muscle perfusion (raised delta VO2/delta work rate, which is a measure of aerobic work efficiency). In combination, they further increased peak VO2, 10% from E+P (p <0.05) and 11% from L+P (p <0.05). Compared with run-in, E+P and L+P significantly reduced plasma norepinephrine by 70 +/- 14 pg/ml and 100 +/- 16 pg/ml and aldosterone by 1.6 +/- 0.7 ng/dl and 1.6 +/- 0.8 ng/dl. These changes were significantly greater when the drugs were combined (140 +/- 20 pg/ml for norepinephrine, and 5.6 +/- 0.9 ng/dl for aldosterone). Quality-of-life score did not improve significantly at each treatment step. Thus, lorsartan and enalapril similarly increased peak VO2 in CHF patients, but mediators of this effect were, at least in part, different therapeutic targets that may be synergistic when the 2 drugs are combined.

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.

Work-rate affects cardiopulmonary exercise test results in heart failure

Cardiopulmonary exercise test (CPET) is used to evaluate patients with chronic heart failure (HF) usually by means of a personalized ramp exercise protocol. Our aim was to evaluate if exercise duration or ramp rate influences the results.

Lack of improvement of lung diffusing capacity following fluid withdrawal by ultrafiltration in chronic heart failure

OBJECTIVES We sought to investigate the possibility that lung diffusing capacity reduction observed in chronic heart failure is reversible in the short term. BACKGROUND Mechanical properties of the lung usually ameliorate with antifailure treatment including drugs, ultrafiltration and heart transplantation, whereas lung diffusion rarely improves. METHODS We studied the mechanical properties of the lung (pulmonary function tests with determination of alveolar volume, extravascular lung fluids and lung tissue), lung diffusion for carbon monoxide (DLco), including membrane diffusing capacity (Dm), pulmonary capillary blood volume (Vc) and pulmonary hemodynamics, in 28 patients with stable chronic heart failure, before a single session of extracorporeal ultrafiltration (3,973 +/- 2200 ml) and four days thereafter. Lung mechanics and diffusion were also evaluated in 18 normal subjects. RESULTS Vital capacity, forced expiratory volume (1 s) and maximal voluntary ventilation were lower in patients when compared with normal subjects, and increased after ultrafiltration from 2.1 +/- 0.7 to 2.5 +/- 0.7(1)*, 1.7 +/- 0.5 to 2.0 +/- 0.6(1)* and 67 +/- 25 to 79 +/- 26 (1/min)*, respectively (* p < 0.02 vs. pre-ultrafiltration). Post-ultrafiltration alveolar volume was augmented, while lung tissue, body weight (approximately 6 kg), chest X-ray extravascular lung water score and pulmonary vascular pressure were reduced. Heart dimensions (echocardiography) remained unchanged. DLco, Dm and Vc were 29.0 +/- 5.0 ml/min/mm Hg, 47.0 +/- 11.0 ml/min/mm Hg, 102 +/- 20 ml in normal subjects and 17.1 +/- 4.0#, 24.1 +/- 6.5#, 113 +/- 38 and 17.0 +/- 5.0#, 24.8 +/- 7.9#, 100 +/- 39 in patients before and after ultrafiltration, respectively (# = p < 0.01 vs. controls). CONCLUSIONS In chronic heart failure, ultrafiltration improves volumes and mechanical properties of the lung by reducing lung fluids. Diffusion is unaffected by ultrafiltration, suggesting that, in chronic heart failure, the alveolar-capillary membrane abnormalities are fluid-independent.

Lung function with carvedilol and bisoprolol in chronic heart failure: Is β selectivity relevant?

Carvedilol is a β‐blocker with similar affinity for β1‐ and β2 receptors, while bisoprolol has higher β1 affinity. The respiratory system is characterized by β2‐receptor prevalence. Airway β receptors regulate bronchial tone and alveolar β receptors regulate alveolar fluid re‐absorption which influences gas diffusion.

Carvedilol reduces exercise-induced hyperventilation: A benefit in normoxia and a problem with hypoxia

To evaluate whether carvedilol influences exercise hyperventilation and the ventilatory response to hypoxia in heart failure (HF).

Does lung diffusion impairment affect exercise capacity in patients with heart failure

Objective: To determine whether there is a relation between impairment of lung diffusion and reduced exercise capacity in chronic heart failure. Design: 40 patients with heart failure in stable clinical condition and 40 controls participated in the study. All subjects underwent standard pulmonary function tests plus measurements of resting lung diffusion (carbon monoxide transfer, Tlco), pulmonary capillary volume (Vc), and membrane resistance (Dm), and maximal cardiopulmonary exercise testing. In 20 patients and controls, the following investigations were also done: (1) resting and constant work rate Tlco; (2) maximal cardiopulmonary exercise testing with inspiratory O2 fractions of 0.21 and 0.16; and (3) rest and peak exercise blood gases. The other subjects underwent Tlco, Dm, and Vc measurements during constant work rate exercise. Results: In normoxia, exercise induced reductions of haemoglobin O2 saturation never occurred. With hypoxia, peak exercise uptake (peak V̇o2) decreased from (mean (SD)) 1285 (395) to 1081 (396) ml/min (p < 0.01) in patients, and from 1861 (563) to 1771 (457) ml/min (p < 0.05) in controls. Resting Tlco correlated with peak V̇o2 in heart failure (normoxia < hypoxia). In heart failure patients and normal subjects, Tlco and peak V̇o2 correlated with O2 arterial content at rest and during peak exercise in both normoxia and hypoxia. Tlco, Vc, and Dm increased during exercise. The increase in Tlco was greater in patients who had a smaller reduction of exercise capacity with hypoxia. Alveolar–arterial O2 gradient at peak correlated with exercise capacity in heart failure during normoxia and, to a greater extent, during hypoxia. Conclusions: Lung diffusion impairment is related to exercise capacity in heart failure.

Circulating Plasma Surfactant Protein Type B as Biological Marker of Alveolar-Capillary Barrier Damage in Chronic Heart Failure

Background—Surfactant protein type B (SPB) is needed for alveolar gas exchange. SPB is increased in the plasma of patients with heart failure (HF), with a concentration that is higher when HF severity is highest. The aim of this study was to evaluate the relationship between plasma SPB and both alveolar-capillary diffusion at rest and ventilation versus carbon dioxide production during exercise. Methods and Results—Eighty patients with chronic HF and 20 healthy controls were evaluated consecutively, but the required quality for procedures was only reached by 71 patients with HF and 19 healthy controls. Each subject underwent pulmonary function measurements, including lung diffusion for carbon monoxide and membrane diffusion capacity, and maximal cardiopulmonary exercise test. Plasma SPB was measured by immunoblotting. In patients with HF, SPB values were higher (4.5 [11.1] versus 1.6 [2.9], P=0.0006, median and 25th to 75th interquartile), whereas lung diffusion for carbon monoxide (19.7±4.5 versus 24.6±6.8 mL/mm Hg per min, P<0.0001, mean±SD) and membrane diffusion capacity (28.9±7.4 versus 38.7±14.8, P<0.0001) were lower. Peak oxygen consumption and ventilation/carbon dioxide production slope were 16.2±4.3 versus 26.8±6.2 mL/kg per min (P<0.0001) and 29.7±5.9 and 24.5±3.2 (P<0.0001) in HF and controls, respectively. In the HF population, univariate analysis showed a significant relationship between plasma SPB and lung diffusion for carbon monoxide, membrane diffusion capacity, peak oxygen consumption, and ventilation/carbon dioxide production slope (P<0.0001 for all). On multivariable logistic regression analysis, membrane diffusion capacity (&bgr;, −0.54; SE, 0.018; P<0.0001), peak oxygen consumption (&bgr;, −0.53; SE, 0.036; P=0.004), and ventilation/carbon dioxide production slope (&bgr;, 0.25; SE, 0.026; P=0.034) were independently associated with SPB. Conclusion—Circulating plasma SPB levels are related to alveolar gas diffusion, overall exercise performance, and efficiency of ventilation showing a link between alveolar-capillary barrier damage, gas exchange abnormalities, and exercise performance in HF.

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.