Giuseppe Reina

I.R.C.C.S. Policlinico San Donato, Milano, Lombardy, Italy

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Publications (13)90.15 Total impact

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    ABSTRACT: N-Terminal pro-brain natriuretic peptide (NT-proBNP) and cardiopulmonary exercise testing (CPET)-derived variables are gold standards for assessing prognosis in heart failure (HF) patients. We sought to refine cardiac events prediction by performing a combined analysis of NT-proBNP with markers of exercise ventilatory efficiency. A total of 260 stable HF patients underwent measurements of plasma NT-proBNP levels before, at peak exercise, and at 1-minute CPET recovery phase along with peak oxygen uptake (VO(2)), ventilation to CO(2) production (VE/VCO(2)) slope, and exercise periodic breathing (EPB) determinations. After a median follow-up period of 20.6 months, there were 54 cardiac-related deaths. Univariate analysis including NT-proBNP at rest, at peak exercise, and at 1 minute recovery, peak VO(2), VE/VCO(2) slope, and EPB showed NT-proBNP to be the strongest independent predictor with equivalent performance for rest, peak, and recovery levels. Thus, only NT-proBNP at rest was considered (Harrel C 0.783, 95% confidence interval [CI] 0.722-0.844) with VE/VCO(2) slope (Harrel C 0.720, 95% CI 0.646-0.794), EPB (Harrel C 0.685, 95% CI 0.619-0.751), and peak VO(2) (Harrel C 0.618, 95% CI 0.533-0.704). With bivariate stepwise analyses, NT-proBNP along with EPB emerged as the strongest prognosticators (Harrel C 0.800, 95% CI 0.737-0.862). In the refinement for robust outcome predictors in HF patients, NT-proBNP levels together with EPB led to the most powerful definition. VE/VCO(2) slope and peak VO(2) did not provide any prognostic adjunct. A biomarker/CPET approach seems very promising to warrant the continuous implementation in the prognostic work-up of HF patients.
    Journal of cardiac failure 04/2012; 18(4):313-20. · 3.25 Impact Factor
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    ABSTRACT: Cardiopulmonary exercise testing (CPET) provides powerful information on risk of death in heart failure (HF). We sought to define the relative and additive contribution of the 3 landmark (CPET) prognostic markers--peak oxygen consumption (VO₂), minute ventilation/carbon dioxide production (VE/VCO₂) slope, and exercise periodic breathing (EPB)-to the overall risk of cardiac death and to develop a prognostic score for optimizing risk stratification in HF patients. A total of 695 stable HF patients (average LVEF: 25 ± 8%) underwent a symptom-limited CPET maximum test after familiarization and were prospectively tracked for cardiac mortality. At multivariable Cox analysis EPB emerged as the strongest prognosticator. Using a statistical bootstrap technique (5000 data resamplings), point estimates, and 95% confidence intervals were obtained. Thirty-two configurations were adopted to classify patients into a given cell, according to EPB presence or absence and values of the 2 other covariates. Configurations without EPB and with VE/VCO₂ slope ≤30 were not significantly different from 0 (reference value). Statistical power of configurations increased with higher VE/VCO₂ slope and lower peak VO₂. This prompted us to formulate a score including EPB as a discriminating variable, the (P)e(R)i(O)dic (B)reathing during (E)xercise (PROBE), which ranges between -1 and 1, with zero as reference configuration, that would help to optimize the prognostic accuracy of CPET-derived variables. The greatest PROBE score impact was provided by EPB, followed by VE/VCO₂ slope, whereas peak VO₂ added minimal prognostic power. EPB with an elevated VE/VCO₂ slope leads to the highest and most precise PROBE score, whereas no additional risk information emerges when EPB is present with a peak VO₂ ≤10 mL O₂·kg⁻¹·min⁻¹. PROBE score appears to provide a step forward for optimizing CPET use in HF prognostic definition.
    Journal of cardiac failure 10/2010; 16(10):799-805. · 3.25 Impact Factor
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    ABSTRACT: Risk stratification for subsequent cardiovascular events following a myocardial infarction (MI) is an important area of research. Previous findings indicate flow-mediated dilatation (FMD) may be a valuable prognostic indicator. This study investigates the prognostic value of FMD in patients suffering an uncomplicated MI. One hundred and seventy nine post-MI patients [110 male/69 female, mean age: 64.8+/-10.0 years, ejection fraction: 51.9+/-12.2%] were included in this analysis. Ultrasound images of the brachial artery were used to determine FMD following reactive hyperemia. Subjects were tracked for subsequent cardiovascular events [myocardial infarction, heart failure, additional interventions (percutaneous coronary intervention, coronary artery bypass)] following data collection via medical chart review. There were 45 subsequent cardiovascular events during a mean tracking period of 13.7 (+/-9.5) months. Receiver operating characteristic (ROC) curve analysis revealed a diagnosis of diabetes (ROC area: 0.67, p=0.001, 95% confidence interval: 0.58-0.77) and percent change in arterial diameter (ROC area: 0.63, p=0.01, 95% confidence interval: 0.53-0.73, optimal threshold: <or=/>4.5%) were prognostically significant. Kaplan-Meier analysis revealed the event-free survival rate for subjects without diabetes and an arterial diameter change >4.5%, without diabetes and percent change in arterial diameter <or=4.5%, with diabetes and percent change in arterial diameter >4.5% and with diabetes and percent change in arterial diameter <or=4.5% was 88.7%, 78.4%, 67.7% and 38.5%, respectively (Log-rank: 24.9, p<0.0001). Non-invasive FMD is a potential risk factor after MI and may add information to conventional risk stratification. This will need to be tested in further studies.
    International journal of cardiology 01/2008; 132(1):45-50. · 6.18 Impact Factor
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    ABSTRACT: Statins represent a modern mainstay of the drug treatment of coronary artery disease and acute coronary syndromes. Reduced aerobic work performance and slowed VO(2) kinetics are established features of the clinical picture of post-myocardial infarction (MI) patients. We tested the hypothesis that statin therapy improves VO(2) exercise performance in normocholesterolaemic post-MI patients. According to a double-blinded, randomized, crossover and placebo-controlled study design, in 18 patients with uncomplicated recent (3 days) MI we investigated the effects of atorvastatin (20 mg day(-1)) on gas exchange kinetics by calculating VO(2) effective time constant (tau) during a 50-watt constant workload exercise, brachial artery flow-mediated dilatation (FMD) as an index of endothelial function, left ventricular function (echocardiography) and C-reactive protein (CRP, as an index of inflammation). Atorvastatin or placebo was given for 3 months each. Atorvastatin therapy significantly improved exercise VO(2) tau and FMD, and reduced CRP levels. We did not observe changes in cardiac contractile function and relaxation properties during all study periods in either group. In post-MI patients exercise performance is a potential additional target of benefits related to statin therapy. Endothelial function improvement is very likely implicated in this newly described therapeutic property.
    European Journal of Clinical Investigation 07/2007; 37(6):454-62. · 3.37 Impact Factor
  • Marco Guazzi, Giuseppe Reina
    Circulation 02/2007; 115(4):e54; author reply e55. · 15.20 Impact Factor
  • Medicine and Science in Sports and Exercise - MED SCI SPORT EXERCISE. 01/2007; 39.
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    ABSTRACT: Exercising muscle hypoperfusion stimulates afferents (metaboreceptors) involved in the regulation of ventilation. Atrial fibrillation (AF), particularly when combined with diseases causing endothelial (ED) impairment, such as hypertension (HP) and diabetes mellitus (DM), depresses the ED activity and enhances exercise hyperventilation. The relationship between these two functions and the underlying mechanisms have not been explored previously. In lone AF or AF associated with HP or DM (12 subjects in each cohort), we investigated the brachial artery flow-mediated dilatation (ED function) and ventilation during the recovery phase of handgrip (metaboreflex) exercise for subjects receiving placebo or oral vitamin C (double-blind crossover), both before and after cardioversion (CV) to sinus rhythm. Baseline ED impairment was increasingly more severe and the ergoreflex activity more pronounced in AF + HP and AF + DM compared with lone AF. Vitamin C and CV significantly improved both flow-mediated dilatation and metaboreflex activity in lone AF and AF + HP, and vitamin C did not produce any additive effect when administered after CV. In AF + DM, neither vitamin C nor CV was effective. This study provides the following information: AF generates oxidative injury, which is less when the arrhythmia is lone AF and greater when the arrhythmia is associated with HP. In DM, the oxidative injury generated by AF is refractory to a rather weak antioxidant, like vitamin C, or the baseline damage is such as to prevent any additive influence of AF. In AF, a cause-effect link exists between ED dysfunction and metaboreflex activity. Ventilatory advantages of CV seem to be inversely related with the extension of the underlying ED oxidative impairment.
    AJP Heart and Circulatory Physiology 12/2006; 291(5):H2396-402. · 4.01 Impact Factor
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    ABSTRACT: In heart failure (HF), changes in lung mechanics and gas diffusion are limiting factors to exercise. Their contribution to an increased exercise ventilation to CO2 production (VE/VCO2) slope is undefined. A total of 67 stable HF patients underwent cardiopulmonary exercise and pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), maximal voluntary ventilation (MVV), total lung capacity (TLC) and alveolar diffusing capacity with its subcomponents (alveolar-capillary membrane conductance (D(m)) and capillary blood volume (V(c))). Patients showed a mild restrictive pattern (FEV1=85+/-15% and FVC=75+/-13% of normal predicted) and a moderate D(m) reduction (32+/-12 ml min(-1) mm Hg(-1)). Average peak VO(2) was 15.6+/-4.0 ml min(-1) kg(-1) and the VE/VCO2 slope was 39.6+/-11.0. At simple Spearman correlation analysis, all variables, but V(c), correlated with peak VO2; only D(m) correlated with VE/VCO2 slope. At partial Spearman correlation, all variables lost the peak VO2 correlation, and D(m) still inversely correlated with VE/VCO2 slope (r=-0.35; p=0.005). In patients with a high VE/VCO2 slope (cutoff value 34), despite comparable lung volumes, D(m) was significantly more depressed (30+/-13 vs. 35+/-10 ml min(-1) mm Hg(-1); p<0.01). Pulmonary function tests and alveolar gas diffusing capacity poorly correlate with peak VO2. D(m) impairment rather than lung volumes correlates with exercise ventilation efficiency. This finding further adds to the pathophysiological relevance of an abnormal gas exchange in HF patients.
    European Journal of Heart Failure 11/2005; 7(6):1017-22. · 5.25 Impact Factor
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    ABSTRACT: In chronic heart failure (CHF) patients, the ventilation (Ve) needed to eliminate metabolically produced CO(2) during exercise (i.e. the Ve/Vco(2) slope) is a strong prognosticator. Ve/Vco(2) slope determinants are the dead space-tidal volume (Vd/Vt) ratio and the arterial CO(2) partial pressure (Paco(2)). We aimed at defining the respective prognostic role of these two variables. One hundred and twenty-eight stable CHF patients (average left ventricular ejection fraction 34+/-10%) underwent cardiopulmonary exercise testing and blood gas analysis. The prognostic relevance of the Ve/Vco(2) slope, Vd/Vt, and Paco(2) at peak exercise was evaluated by the Kaplan-Meier approach with log-rank testing and by multivariate Cox regression analysis. During a mean period of 31.3+/-20 months, 24 patients died from cardiac causes. In univariate analysis, predictors of death included the use of anti-aldosterone drugs, low peak Vo(2), peak Ve/Vo(2), peak Paco(2) and high Ve/Vco(2) slope, and peak Vd/Vt. Multivariate analysis identified a low peak Paco(2) (<35 mmHg) as the strongest independent prognostic indicator [hazard ratio 4.65, 95% confidence interval (CI) (1.695-12.751), P=0.003] that primarily accounts for the Ve/Vco(2) slope prognostic power. These findings imply that regulatory mechanisms involved in the tight control of ventilatory command and blood gas tension, rather than lung function abnormalities, play a critical pathophysiological role in the exercise ventilation inefficiency of CHF patients.
    European Heart Journal 03/2005; 26(5):472-80. · 14.72 Impact Factor
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    ABSTRACT: Chronic heart failure (CHF) may impair lung gas diffusion, an effect that contributes to exercise limitation. We investigated whether diffusion improvement is a mechanism whereby physical training increases aerobic efficiency in CHF. Patients with CHF (n = 16) were trained (40 min of stationary cycling, 4 times/wk) for 8 wk; similar sedentary patients (n = 15) were used as controls. Training increased lung diffusion (DlCO, +25%), alveolar-capillary conductance (DM, +15%), pulmonary capillary blood volume (VC, +10%), peak exercise O2 uptake (peak VO2, +13%), and VO2 at anaerobic threshold (AT, +20%) and decreased the slope of exercise ventilation to CO2 output (VE/VCO2, -14%). It also improved the flow-mediated brachial artery dilation (BAD, from 4.8 +/- 0.4 to 8.2 +/- 0.4%). These changes were significant compared with baseline and controls. Hemodynamics were obtained in the last 10 patients in each group. Training did not affect hemodynamics at rest and enhanced the increase of cardiac output (+226 vs. +187%) and stroke volume (+59 vs. +49%) and the decrease of pulmonary arteriolar resistance (-28 vs. -13%) at peak exercise. Hemodynamics were unchanged in controls after 8 wk. Increases in DlCO and DM correlated with increases in peak VO2 (r = 0.58, P = 0.019 and r = 0.51, P = 0.04, respectively) and in BAD (r = 0.57, P < 0.021 and r = 0.50, P = 0.04, respectively). After detraining (8 wk), DlCO, DM, VC, peak VO2, VO2 at AT, VE/VCO2 slope, cardiac output, stroke volume, pulmonary arteriolar resistance at peak exercise, and BAD reverted to levels similar to baseline and to levels similar to controls. Results document, for the first time, that training improves DlCO in CHF, and this effect may contribute to enhancement of exercise performance.
    Journal of Applied Physiology 11/2004; 97(5):1866-73. · 3.48 Impact Factor
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    ABSTRACT: It is debated whether in patients with chronic heart failure (CHF), aspirin may contrast the clinical benefits of angiotensin-converting enzyme inhibitors (ACEIs). Two major unresolved issues in patients with CHF are whether these agents together can affect mortality and whether the interaction is related with the dose of aspirin. We aimed at exploring these possibilities. We evaluated more than 4000 hospitalizations with a principal discharge diagnosis of CHF from January 10, 1990, to December 31, 1999. The final analysis was restricted to 344 patients taking ACEIs who satisfied the selection criteria, in whom reliable information was available concerning drug therapy during follow-up. In these patients, treatment included no aspirin in 235 (group 1), a low dose (< or =160 mg) in 45 (group 2), and a high dose (> or = 325 mg) in 64 (group 3). During a mean follow-up of 37.6 months, there were 84 (36%) deaths in group 1, 15 (33%) in group 2, and 35 (55%) in group 3. By the Kaplan-Meier approach, survival was similar in groups 1 and 2, and significantly (P =.009) worse in group 3 compared with groups 1 and 2. After adjusting for potential confounding factors (including treatment, cause of heart disease, age, smoking, and diabetes mellitus), a time-dependent multivariate Cox proportional hazards regression analysis showed that the combination of high-dose aspirin with an ACEI was independently associated with the risk of death (hazard ratio, 1.03; P =.01) and that the combination of low-dose aspirin with an ACEI was not (hazard ratio, 1.02; P =.18). These results support the possibility that in some patients with CHF who are taking an ACEI, a dose-related effect of aspirin may adversely affect survival.
    Archives of Internal Medicine 07/2003; 163(13):1574-9. · 11.46 Impact Factor
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    ABSTRACT: Lung dysfunction occurring in chronic heart failure worsens clinical status and exercise performance. The prognostic value of airway and alveolar function measurements in chronic heart failure has not been explored. We aimed to evaluate the prognostic value of lung function tests in a population of patients with stable chronic heart failure. One hundred and six stable chronic heart failure patients (whose left ventricular ejection fraction averaged 33 +/- 1%) underwent echocardiography, metabolic stress testing, assessment of pulmonary function at rest (by spirometry), of alveolar diffusing capacity (DLco) (with carbon monoxide technique) and of its membrane (DM) and capillary blood volume (Vc) components. Prognostic relevance of pulmonary variables was assessed by the Kaplan-Meier approach with log-rank testing and by Cox regression analysis. Cut-off values of lung parameters were based on the 33rd and 66th centiles. Seventeen patients died for cardiac reasons. Non-survivors compared to survivors showed lower forced expiratory volume in 1 s (2 X 1 +/- 0 X 1 vs 2 X 4 +/- 0 X 1 l; P<0 X 01), forced vital capacity (2 X 6 +/- 0 X 1 vs 2 X 9 +/- 0 X 1 l; P<0 X 01), maximal voluntary ventilation (80 X 7 +/- 2 X 5 vs 95 X 4 +/- 2 X 7 l; P<0 X 01), DLco (16 X 5 +/- 1 X 1 vs 19 X 3 +/- 0 X 6 ml . min(-1) . mmHg(-1); P<0 X 01) and DM (25 X 1 +/- 1 X 8 vs 31 X 9 +/- 1 X 5 ml . min(-1) . mmHg(-1); P<0 X 01). They also exhibited a smaller peak VO2 (14 X 6 +/- 0 X 7 vs 15 X 9 +/- 0 X 6 ml . min(-1) . kg(-1); P<0 X 05) and a steeper VE/VCO2 slope (45 X 0 +/- 1 X 7 vs 41 X 9 +/- 1 X 5; P<0 X 01). Multivariate analysis revealed that DM was the only independent predictor of cardiac death. Cases at high risk for adverse outcome were identified by a DM<24 X 7 ml . min(-1) . mmHg(-1). Patients receiving ACE-inhibitors presented with a higher DM (32 X 1 +/- 1 X 7 vs 27 X 9 +/- 1 X 7 ml . min(-1) . mmHg(-1), P<0 X 05) as well as a better Cox estimated survival rate. Impaired DM is a powerful independent predictor of worse prognosis in stable chronic heart failure and may be considered an additional index of disease severity, as well as a specific therapeutic target.
    European Heart Journal 03/2002; 23(6):467-76. · 14.72 Impact Factor
  • European Journal of Heart Failure 01/2000; 2. · 5.25 Impact Factor

Publication Stats

208 Citations
90.15 Total Impact Points

Institutions

  • 2012
    • I.R.C.C.S. Policlinico San Donato
      Milano, Lombardy, Italy
  • 2003–2012
    • University of Milan
      • • Department of Occupational and Environmental Health
      • • Institute of Human Physiology II
      Milano, Lombardy, Italy
  • 2005–2006
    • Azienda Ospedaliera San Paolo - Polo Universitario
      Milano, Lombardy, Italy
  • 2002
    • National Research Council
      Roma, Latium, Italy