Anna Apostolo

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.

Electrophysiological characteristics and outcome in patients with idiopathic right ventricular arrhythmia compared with arrhythmogenic right ventricular dysplasia

Background: Idiopathic right ventricular arrhythmias (IRVA) are responsive to medical and ablative treatment and have a benign prognosis. Arrhythmias caused by right ventricular dysplasia (ARVD) are refractory to treatment and may cause sudden death. It is difficult to distinguish between these two types of arrhythmia. Objective: To differentiate patients with IRVA and ARVD by a conventional electrophysiological study. Methods: 56 patients with a right ventricular arrhythmia were studied. They had no history or signs of any cardiac disease other than right ventricular dysplasia. They were classified as having IRVA (n = 41) or ARVD (n = 15) on the basis of family history, ECG characteristics, and various imaging techniques. They were further investigated by standard diagnostic electrophysiology. Results: The two groups were clearly distinguished by the electrophysiological study in the following ways: inducibility of ventricular tachycardia by programmed electrical stimulation with ventricular extrastimuli (IRVA 3% v ARVD 93%, p < 0.0001); presence of more than one ECG morphology during tachycardia (IRVA 0% v ARVD 73%, p < 0.0001); and fragmented diastolic potentials during ventricular arrhythmia (IRVA 0% v ARVD 93%, p < 0.0001). Data from the clinical follow up in these patients supported the diagnosis derived from the electrophysiological study. Conclusions: Patients with IRVA or ARVD can be distinguished by specific electrophysiological criteria. A diagnosis of ARVD can be made reliably on the basis of clinical presentation, imaging techniques, and an electrophysiological study.

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).

Mechanisms of Periodic Breathing During Exercise in Patients With Chronic Heart Failure

BACKGROUND Periodic breathing (PB) in heart failure (HF) is attributed to many factors, including low cardiac output delaying the time it takes pulmonary venous blood to reach the central and peripheral chemoreceptors, low lung volume, lung congestion, augmented chemoreceptor sensitivity, and the narrow difference between eupneic carbon dioxide tension and apneic/hypoventilatory threshold. METHODS AND RESULTS We measured expired gases, ventilation, amplitude, and duration of PB in 23 patients with PB during progressive exercise tests done with 0 mL, 250 mL, or 500 mL of added dead space. Periodicity of PB remained constant despite heart rate, oxygen consumption, and minute ventilation increasing. Within each PB cycle, starting from the beginning of exercise, the largest (peak) tidal volume approached maximum observed tidal volume, while the smallest (nadir) tidal volume increased as exercise power output increased. PB ceased when nadir tidal volume reached peak tidal volume. End-tidal carbon dioxide increased with added dead space, and PB ceased progressively earlier during the exercise done with increased dead space. CONCLUSION Circulatory delay does not contribute to the PB observed in exercising HF patients. The pattern of gradually increasing nadir tidal volume during exercise and the effect of dead space on both PB ceasing and end-tidal carbon dioxide suggest that low tidal volume and carbon dioxide apnea threshold are important contributors to PB that occurs during exercise in HF.

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.

Impact of chronic obstructive pulmonary disease on exercise ventilatory efficiency in heart failure

BACKGROUND Heart failure (HF) and chronic obstructive pulmonary disease (COPD) coexistence increases morbidity and mortality. The intercept of ventilation (VEint) on the VE vs. carbon dioxide production (VCO2) relationship during exercise has been found to vary in proportion with dead space (VD) in HF. Considering that increased VD is the key pathophysiological abnormality in COPD but a secondary finding in HF we hypothesized that a high VEint would be useful in suggesting COPD as HF co-morbidity. Our aim was to assess whether an elevated VEint suggests the presence of COPD in HF. METHODS In a multicenter retrospective study, the VE-VCO2 relationship was analyzed both as slope and intercept in HF (n = 108), HF-COPD (n = 106) and COPD (n = 95). Patients with pulmonary arterial hypertension (PAH) (n = 85) and healthy subjects (HF) (n = 56) served as positive and negative controls relative to VE-VCO2 abnormalities, respectively. RESULTS Slope and VEint varied in opposite directions in all groups (p < 0.05) being VE-VCO2 slope highest and lowest in PAH and healthy subjects, respectively. No slope differences were observed among HF, HF-COPD and COPD (32 ± 7, 31 ± 7, and 31 ± 6, respectively). VEint was higher in HF-COPD and COPD compared to HF, PAH and controls (4.8 ± 2.4 L/min, 5.9 ± 3.0 L/min, 3.0 ± 2.6L/min, 2.3 ± 3.3 L/min and 3.9 ± 2.5L/min, respectively; p < 0.01). A VEint ≥ 4.07 L/min identified patients with high probability of having COPD or HF-COPD (sensitivity of 71.6% and specificity of 72.0%). CONCLUSION These data provide novel evidence that a high VEint (≥ 4.07 L/min) should be valued to suggest coexistent COPD 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).