Filippo M. Sarullo

Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend?

The aim of the present study was to evaluate the effects of a normal-sodium (120 mmol sodium) diet compared with a low-sodium diet (80 mmol sodium) on readmissions for CHF (congestive heart failure) during 180 days of follow-up in compensated patients with CHF. A total of 232 compensated CHF patients (88 female and 144 male; New York Heart Association class II-IV; 55-83 years of age, ejection fraction <35% and serum creatinine <2 mg/dl) were randomized into two groups: group 1 contained 118 patients (45 females and 73 males) receiving a normal-sodium diet plus oral furosemide [250-500 mg, b.i.d. (twice a day)]; and group 2 contained 114 patients (43 females and 71 males) receiving a low-sodium diet plus oral furosemide (250-500 mg, b.i.d.). The treatment was given at 30 days after discharge and for 180 days, in association with a fluid intake of 1000 ml per day. Signs of CHF, body weight, blood pressure, heart rate, laboratory parameters, ECG, echocardiogram, levels of BNP (brain natriuretic peptide) and aldosterone levels, and PRA (plasma renin activity) were examined at baseline (30 days after discharge) and after 180 days. The normal-sodium group had a significant reduction (P<0.05) in readmissions. BNP values were lower in the normal-sodium group compared with the low sodium group (685+/-255 compared with 425+/-125 pg/ml respectively; P<0.0001). Significant (P<0.0001) increases in aldosterone and PRA were observed in the low-sodium group during follow-up, whereas the normal-sodium group had a small significant reduction (P=0.039) in aldosterone levels and no significant difference in PRA. After 180 days of follow-up, aldosterone levels and PRA were significantly (P<0.0001) higher in the low-sodium group. The normal-sodium group had a lower incidence of rehospitalization during follow-up and a significant decrease in plasma BNP and aldosterone levels, and PRA. The results of the present study show that a normal-sodium diet improves outcome, and sodium depletion has detrimental renal and neurohormonal effects with worse clinical outcome in compensated CHF patients. Further studies are required to determine if this is due to a high dose of diuretic or the low-sodium diet.

Medium term effects of different dosage of diuretic, sodium, and fluid administration on neurohormonal and clinical outcome in patients with recently compensated heart failure.

Studies have shown that patients with compensated heart failure (HF) receiving high diuretic doses associated with normal sodium diet and fluid intake restrictions demonstrated significant reductions in readmissions and mortality compared with those who received low-sodium diets, and over a 6-month observation period, a reduction in neurohormonal activation was also observed. The aim of this study was to evaluate the effects of different sodium diets associated with different diuretic doses and different levels of fluid intake on hospital readmissions and neurohormonal changes after 6-month follow-up in patients with compensated HF. Four hundred ten consecutive patients with compensated HF (New York Heart Association class II to IV) aged 53 to 86 years, with ejection fractions <35% and serum creatinine <2 mg/dl, were randomized into 8 groups: group A (n = 52): 1,000 ml/day of fluid intake, 120 mmol/day, and 250 mg furosemide twice daily; group B (n = 51): 1,000 ml/day of fluid intake, 120 mmol/day, and 125 mg furosemide twice daily; group C (n = 51): 1,000 ml/day fluid intake, 80 mmol/day, and 250 mg furosemide twice daily; group D (n = 51): 1,000 ml/day fluid intake, 80 mmol/day, and 125 mg furosemide twice daily; group E (n = 52): 2,000 ml/day fluid intake, 120 mmol/day, and 250 mg furosemide twice daily; group F (n = 50): 2,000 ml/day fluid intake, 120 mmol/day, and 125 mg furosemide twice daily; group G (n = 52): 2,000 ml/day fluid intake, 80 mmol/day, and 250 mg furosemide twice daily; and group H (n = 51): 2,000 ml/day fluid intake, 80 mmol/day, and 125 mg furosemide twice daily. All patients received the treatments >or=30 days after discharge and for 180 days afterward. Signs of HF, body weight, blood pressure, heart rate, laboratory parameters, electrocardiograms, echocardiograms, brain natriuretic peptide, aldosterone, and plasma renin activity were examined at baseline and 180 days later. Group A showed the best results, with a significant reduction (p <0.001) in readmissions, brain natriuretic peptide, aldosterone, and plasma renin activity compared with the other groups during follow-up (p <0.001). In conclusion, these data suggest that the combination of a normal-sodium diet with high diuretic doses and fluid intake restriction, compared with different combinations of sodium diets with more modest fluid intake restrictions and conventional diuretic doses, leads to reductions in readmissions, neurohormonal activation, and renal dysfunction.

Six-Month Echocardiographic Study in Patients With Submassive Pulmonary Embolism and Right Ventricle Dysfunction: Comparison of Thrombolysis With Heparin

Introduction:The aim of this study was to assess the effect of thrombolysis versus heparin treatment on echocardiographic parameters and clinical outcome, during hospitalization and within the first 180 days after admission, in patients with first episode of submassive pulmonary embolism (SPE) and right ventricle dysfunction (RVD). Methods:Consecutive patients (age, 18–75 years) with a first episode of SPE, symptoms onset since no more than 6 hours, normal blood pressure (>100 mm Hg), echocardiographic evidence of RVD and positive lung spiral computed tomography were double-blind randomized: 1 group received 100 mg of alteplase (10-mg bolus, followed by a 90-mg intravenous infusion over a period of 2 hours), while the other group received matching placebo. In addition to alteplase or placebo, both groups received an unfractionated heparin treatment. Echocardiogram was performed at admission, at 24, 48 and 72 hours, at discharge and at 3 and at 6 months after randomization. Results:Seventy-two patients were included into the study; 37 were assigned to thrombolysis and 35 to placebo. Both groups were well matched with regard to features and clinical presentation. Thrombolysis group showed a significant early improvement of RV function compared with heparin group, and this improvement was observed also during the follow-up (180 days). The same group also showed significant reduction in clinical events during the hospitalization and follow-up. Conclusions:Our data suggest that, in hemodynamically stable patients with SPE, thrombolysis shows an earliest reduction of RVD and a more favorable trend in clinical outcome, so, it could merit consideration in SPE.

Effects of Ivabradine and Ranolazine in Patients With Microvascular Angina Pectoris

Patients with microvascular angina (MVA) often have persistence of symptoms despite full classical anti-ischemic therapy. In this study, we assessed the effect of ivabradine and ranolazine in MVA patients. We randomized 46 patients with stable MVA (effort angina, positive exercise stress test [EST], normal coronary angiography, coronary flow reserve <2.5), who had symptoms inadequately controlled by standard anti-ischemic therapy, to ivabradine (5 mg twice daily), ranolazine (375 mg twice daily), or placebo for 4 weeks. The Seattle Angina Questionnaire (SAQ), EuroQoL scale, and EST were assessed at baseline and after treatment. Coronary microvascular dilation in response to adenosine and to cold pressor test and peripheral endothelial function (by flow-mediated dilation) were also assessed. Both drugs improved SAQ items and EuroQoL scale compared with placebo (p <0.01 for all), with ranolazine showing some more significant effects compared with ivabradine, on some SAQ items and EuroQoL scale (p <0.05). Time to 1-mm ST-segment depression and EST duration were improved by ranolazine compared with placebo. No effects on coronary microvascular function and on flow-mediated dilation were observed with drugs or placebo. In conclusion, ranolazine and ivabradine may have a therapeutic role in MVA patients with inadequate control of symptoms in combination with usual anti-ischemic therapy.

Short-Term Effects of Hypertonic Saline Solution in Acute Heart Failure and Long-Term Effects of a Moderate Sodium Restriction in Patients With Compensated Heart Failure With New York Heart Association Class III (Class C) (SMAC-HF Study)

Introduction:Hypertonic saline solution (HSS) and a moderate Na restriction plus high furosemide dose showed beneficial effects in compensated heart failure (HF), in short and long terms. The study was aimed to verify the effects of this combination on hospitalization time, readmissions and mortality in patients in New York Heart Association (NYHA) class III. Method:Chronic ischemic or nonischemic cardiomyopathy uncompensated patients with HF in NYHA III functional class with ejection fraction <40%, serum creatinine <2.5 mg/dL, blood urea nitrogen <60 mg/dL and reduced urinary volume were single-blind randomized in 2 groups: the first group received a 30-minute intravenous infusion of furosemide (250 mg) plus HSS (150 mL) twice daily and a moderate Na restriction (120 mmol); the second group received furosemide intravenous bolus (250 mg) twice a day, without HSS and a low Na diet (80 mmol); both groups received a fluid intake of 1000 mL/d. After discharge, the HSS group continued with 120 mmol Na/d; the second group continued with 80 mmol Na/d. Results:A total of 1771 patients (881 HSS group and 890 without HSS group) met inclusion criteria: the first group (881 patients), compared with the second (890 patients), showed an increase in diuresis and serum Na levels, a reduction in hospitalization time (3.5 + 1 versus 5.5 + 1 days, P < 0.0001) and, during follow-up (57 + 15 months), a lower rate in readmissions (18.5% versus 34.2%, P < 0.0001) and mortality (12.9% versus 23.8%, P < 0.0001); the second group also showed a significant increase in blood urea nitrogen and serum creatinine. Conclusion:This study suggests that in-hospital HSS administration, combined with moderate Na restriction, reduces hospitalization time and that a moderate sodium diet restriction determines long-term benefit in patients with NYHA class III HF.

Effect of physical training on exercise capacity, gas exchange and N-terminal pro-brain natriuretic peptide levels in patients with chronic heart failure

Background Decreased exercise capacity is the main factor restricting the daily life of patients with chronic heart failure. N-terminal pro-brain natriuretic peptide (NT pro-BNP) is strongly related to the severity of and is an independent predictor of outcome in chronic heart failure. Design The study aimed to evaluate the effect of exercise training on functional capacity and on changes in NT pro-BNP levels and to assess the effect of exercise training on quality of life. Materials and methods Sixty patients (45 men/15 women, mean age 52.7 years; ±5.3 SD), with stable heart failure (45 ischaemic/hypertensive and 15 idiopathic patients), in New York Heart Association (NYHA) functional class II (n = 35) to III (n = 25), with an ejection fraction less than 40%, were randomly assigned to a training (n = 30) and a control group (n = 30). The training group (30 patients) performed 3 months of supervised physical training programme using a bicycle ergometer for 30 min three times a week at a load corresponding to 60–70% of their oxygen consumption (Vo2) peak. The control group did not change their previous physical activity. A graded maximal exercise test with respiratory gas analysis and an endurance test with constant workload corresponding to 85% of the peak oxygen load at the baseline and after 3 months were performed, and at the same times NT pro-BNP levels were measured. Results The exercise capacity increased from 15.8 (±2.3 SD) to 29.9 (±2.1 SD) min (P<0.0001) and the peak Vo2 tended to improve from 14.5 (±1.4 SD) to 17.7 (±2.6 SD) ml/kg per min (P<0.0001) during the supervised training period. Vo2 at the anaerobic threshold increased from 12.9 (±1.0 SD) to 15.5 (±1.7 SD) ml/kg per min (P<0.0001). NT pro-BNP levels decreased from 3376 (±3133 SD) to 1434 (±1673 SD) pg/ml (P=0.043). The positive training effects were associated with an improvement in the NYHA functional class. Conclusion Physical training of moderate intensity significantly improves the exercise capacity and neurohormonal modulation in patients with chronic heart failure. This is associated with an alleviation of symptoms and improvement in quality of life.

Spinal cord stimulation for the treatment of refractory angina pectoris: a multicenter randomized single-blind study (the SCS-ITA trial).

&NA; Spinal cord stimulation (SCS) is believed to be effective in treating refractory angina. The need for SCS‐related chest paresthesia, however, has hitherto made impossible placebo‐controlled trials. Subliminal (non paresthesic) SCS, however, might be also effective on anginal pain. In this trial we compared subliminal SCS with paresthesic SCS and with sham SCS. Twenty‐five refractory angina patients, who had never received SCS before, underwent SCS device implantation and were randomized to three groups: paresthesic SCS (group PS; n = 10), subliminal SCS (group SS; n = 7) or “sham” SCS (group NS; n = 8). After 1 month group NS patients were randomized to either group PS or SS. After 1 month, changes in angina episodes (p = 0.016), nitroglycerin use (p = 0.015), angina class (p = 0.02), quality of life score (p = 0.05), and items 2 (p = 0.008) and 3 (p = 0.009) of Seattle angina questionnaire differed significantly among groups. Group PS showed significant improvement in outcomes compared to group NS, whereas there were no significant differences between groups SS and NS; furthermore, only nitroglycerin use differed significantly between groups PS and SS. At 3 months, a significant difference between groups PS and SS was observed in angina attacks (p = 0.002), but not in other variables. Thus, in this study, paresthesic, but not subliminal SCS was superior to sham SCS in improving clinical status in refractory angina patients. The lack of significant differences between PS and SS groups in this small study suggests that a possible role for subliminal SCS in individual patients deserves to be assessed in larger trials with appropriate statistical power.

Impact of ‘‘Off-Label’’ Use of Ivabradine on Exercise Capacity, Gas Exchange, Functional Class, Quality of Life, and Neurohormonal Modulation in Patients With Ischemic Chronic Heart Failure

Background: Epidemiologic studies indicate that elevated heart rate (HR) is an independent risk factor for mortality and morbidity in patients (pts) with chronic heart failure (CHF). Clinical trials with β-blockers suggest that HR reduction is an important mechanism of their benefit in pts with stable CHF. Pharmacologic inhibition of the If current now provides the opportunity of pure HR reduction. The purpose of this study was to evaluate the impact of ‘‘Off-Label’’ use of ivabradine on exercise capacity, gas exchange, functional class, quality of life, and neurohormonal modulation in pts with ischemic CHF. Methods: Between January 2008 and June 2008, a graded maximal exercise test with respiratory gas analysis and an endurance test with constant workload corresponding to 85% of the peak VO2 at the baseline and after 3 months were performed, and at the same times, N-terminal probrain natriuretic peptide (NT-proBNP) levels were also measured, in 60 pts (45 M, 15 F, mean age 52.7 ± 5.3 years), with stable ischemic CHF, New York Heart Association (NYHA) functional classes II (n = 35)—III (n = 25), with left ventricular ejection fraction (LVEF) ≤ 40%, randomized to a ‘‘off-label’’ ivabradine use (n = 30) and a control group (n = 30). Results: The exercise capacity increased from 14.8 ± 2.5 to 28.2 ± 3.5 min (P < .0001) and the peak oxygen consumption tended to improve from 13.5 ± 1.3 to 17.9 ± 2.4 mL/kg per minute (P < .0001) in ivabradine group. Oxygen consumption at the anaerobic threshold (AT) increased from 11.9 ± 1.4 to 15.3 ± 1.4 mL/kg per minute (P < .0001). NTproBNP levels decreased from 2356 ± 2113 pg/mL to 1434 ± 1273 pg/mL (P = .045). No significant differences were found in control group at 3 months. The positive ivabradine effects were also associated with an improvement in the NYHA functional class and quality of life. Conclusion: The ‘‘Off-Label’’ use of ivabradine significantly improves the exercise capacity, gas exchange, functional heart failure class, quality of life, and neurohormonal modulation in pts with ischemic CHF.

Cardiopulmonary Exercise Testing in Patients with Chronic Heart Failure: Prognostic Comparison from Peak VO2 and VE/VCO2 Slope.

Background: Cardiopulmonary exercise testing with ventilatory expired gas analysis (CPET) has proven to be a valuable tool for assessing patients with chronic heart failure (CHF). The maximal oxygen uptake (peak V02) is used in risk stratification of patients with CHF. The minute ventilation-carbon dioxide production relationship (VE/VCO2 slope) has recently demonstrated prognostic significance in patients with CHF. Methods: Between January 2006 and December 2007 we performed CPET in 184 pts (146 M, 38 F, mean age 59.8 ± 12.9 years), with stable CHF (96 coronary artery disease, 88 dilated cardiomyopathy), in NYHA functional class II (n.107) - III (n.77), with left ventricular ejection fraction (LVEF) ≤ 45%,. The ability of peak VO2 and VE/VCO2 slope to predict cardiac related mortality and cardiac related hospitalization within 12 months after evaluation was examined. Results: Peak VO2 and VE/VCO2 slope were demonstrated with univariate Cox regression analysis both to be significant predictor of cardiac-related mortality and hospitalization (p < 0.0001, respectively). Non survivors had a lower peak VO2 (10.49 ± 1.70 ml/kg/min vs. 14.41 ± 3.02 ml/kg/min, p < 0.0001), and steeper Ve/VCO2 slope (41.80 ± 8.07 vs. 29.84 ± 6.47, p < 0.0001) than survivors. Multivariate survival analysis revealed that VE/VCO2 slope added additional value to VO2 peak as an independent prognostic factor (χ2: 56.48, relative risk: 1.08, 95% CI: 1.03 – 1.13, p = 0.001). The results from Kaplan-Meier analysis revealed a 1-year cardiac-related mortality of 75% in patients with VE/VCO2 slope ≥ 35.6 and 25% in those with VE/VCO2 slope < 35.6 (log rank χ2: 67.03, p < 0.0001) and 66% in patients with peak VO2 ≤ 12.2 ml/kg/min and 34% in those with peak VO2 > 12.2 ml/kg/min (log rank χ2: 50.98, p < 0.0001). One-year cardiac-related hospitalization was 77% in patients with VE/VCO2 slope ≥ 32.5 and 23% in those with VE/VCO2 slope < 32.5 (log rank χ2: 133.80, p < 0.0001) and 63% in patients with peak VO2 ≤ 12.3 ml/kg/min and 37% in those with peak VO2 > 12.3 ml/kg/min (log rank χ2: 72.86, p < 0.0001). The VE/VCO2 slope was demonstrated with receiver operating characteristic curve analysis to be equivalent to peak VO2 in predicting cardiac-related mortality (0.89 vs. 0.89). Although area under the receiver operating characteristic curve for the VE/VCO2 slope was greater than peak VO2 in predicting cardiac-related hospitalization (0.88 vs 0.82), the difference was no statistically significant (p = 0.13). Conclusion: These results add to the present body of knowledge supporting the use of CPET in CHF patients. The VE/VCO2 slope, as an index of ventilatory response to exercise, is an excellent prognostic parameter and improves the risk stratification of CHF patients. It is easier to obtain than parameters of maximal exercise capacity and is of equivalent prognostic importance than peak VO2.

Comparison of Ivabradine Versus Metoprolol in Early Phases of Reperfused Anterior Myocardial Infarction With Impaired Left Ventricular Function: Preliminary Findings

BACKGROUND beta-blockers in ST-segment elevation myocardial infarction (STEMI) are indicated for patients without a contraindication, particularly in patients with high heart rates (HR) or blood pressures. Epidemiological studies have shown that elevated HR represents a risk factor for cardiovascular morbidity. The study investigates the feasibility, tolerability, and the effects after 30 days of follow-up of ivabradine (IVA) versus metoprolol (METO) in early phases of anterior STEMI reperfused by percutaneous coronary intervention (PCI). METHODS AND RESULTS Patients with a first anterior STEMI, Killip class I-II, an acceptable echocardiographic window, and admitted within 4hours of the onset of symptoms, with an ejection fraction <50%. METO or IVA, 12hours after PCI (double blind), were administered twice per day. Blood pressure (BP), heart rate (HR), electrocardiogram (ECG), and laboratory parameters were monitored during the study. At entry, day 10, day 30, and day 60, by echocardiography, the ESV, EDV, E/A ratio, E wave deceleration time, isovolumetric relaxation time were measured. A total of 155 (50 females, 105 males) patients were randomized in 2 groups: a group received METO (76 patients) 12hours after PCI and a group received IVA (79 patients) 12hours after PCI. The 2 groups were similar for clinical characteristics. No difference was evidenced in HR, systolic blood pressure, diastolic blood pressure, age (range, 39-73 years), sex, ejection fraction (EF), creatine kinase peak, between the 2 groups at entry. Both groups were similar for time to angiography and interventional procedures and number of vessels diseased. IVA group: the 79 patients showed 2 side effects and 5 readmissions: 4 for ischemic events and 1 for heart failure, and 1 sudden death; METO group: the 76 patients had 4 ischemic events, 2 side effects, and 1 patient died during re-acute MI (intrastent thrombosis) and 8 readmissions for heart failure signs. The systolic blood pressure and diastolic blood pressure showed a significant reduction in both groups, P < .0001, respectively), and significant lower values were observed in METO group, P=.0001). The HR was significantly reduced in both groups, P < .0001). IVA group showed a significant increase in EF, P=.0001, with concomitant reduction in ESV and EDV (P=.0001, and .048, respectively). The diastolic parameters were similar in both groups during study period. CONCLUSIONS Our results suggest that ivabradine may be administered early (12hours after PCI) to patients with successful PCI for anterior STEMI with an impaired left ventricular function and high HR and sinus rhythm. A larger sample of patients and further studies are required to evaluate the effects of ivabradine on clinical end points.