Alessandro Salvioni

Isolated ultrafiltration in moderate congestive heart failure.

OBJECTIVES The aim of this study was to evaluate whether ultrafiltration is beneficial in patients with moderate congestive heart failure. BACKGROUND Ultrafiltration is beneficial in patients with severe congestive heart failure. METHODS We studied 36 patients in New York Heart Association functional classes II and III in stable clinical condition. Eighteen patients (group A) were randomly selected and underwent a single session of ultrafiltration (venovenous bypass, mean [+/- SEM] ultrafiltrate 1,880 +/- 174 ml, approximately 600 ml/h) and 18 (group B) served as control subjects. RESULTS Two patients in group A and three in group B did not complete the 6-month follow-up study. In group A, soon after ultrafiltration there were significant reductions in right atrial pressure (from 8 +/- 1 to 3.4 +/- 0.7 mm Hg, pulmonary wedge pressure (from 18 +/- 2.5 to 10 +/- 1.9 mm Hg) and cardiac index (from 2.8 +/- 0.2 to 2.3 +/- 0.2 liters/min). During the follow-up period, lung function improved, extravascular lung water (X-ray score) decreased and peak oxygen consumption (ml/min per kg) increased significantly from 15.5 +/- 1 (day -1) to 17.6 +/- 0.9 (day 4), to 17.8 +/- 0.9 (day 30), to 18.9 +/- 1 (day 90) and to 19.1 +/- 1 (day 180). Oxygen consumption at anaerobic threshold (ml/min per kg) also increased significantly from 11.6 +/- 0.8 (day -1) to 13 +/- 0.7 (day 4), to 13.7 +/- 0.5 (day 30), to 15.5 +/- 0.8 (day 90) and to 15.2 +/- 0.8 (day 180). These changes were associated with increased ventilation, tidal volume and dead space/tidal volume ratio at peak exercise. The improvement in exercise performance was associated with a decrease in norepinephrine at rest, a downward shift of norepinephrine kinetics at submaximal exercise and an increase in norepinephrine during orthostatic tilt. None of these changes were recorded in group B. CONCLUSIONS In patients with moderate congestive heart failure, ultrafiltration reduces the severity of the syndrome.

Interrelation of humoral factors, hemodynamics, and fluid and salt metabolism in congestive heart failure: Effects of extracorporeal ultrafiltration

PURPOSE We investigated the mechanisms involved in the regulation of salt and water metabolism in patients with congestive heart failure (CHF). Extracorporeal ultrafiltration was utilized as a nonpharmacologic method for withdrawal of body fluid. PATIENTS, METHODS, AND RESULTS In 32 consecutive patients with CHF (New York Heart Association functional class II to IV) and different degrees of water retention, 24-hour diuresis and natriuresis were inversely best correlated with the combination of circulating renin, aldosterone, norepinephrine, and renal perfusion pressure (RPP, mean aortic pressure minus mean right atrial pressure). Fluid withdrawal (600 to 5,000 mL) at a rate of 500 mL/h, until right atrial pressure decreased to 50% of baseline, caused variable humoral, circulatory, and diuretic effects that were mainly related to the extent of fluid retention. In fact, in 10 patients (Group 1) with overhydration refractory to drug therapy and with urinary output less than 1,000 mL/24 h (mean, 370 mL), soon after the procedure, plasma renin (-39%), aldosterone (-50%), and norepinephrine (-47%) were reduced and RPP was increased (+16%), and in the subsequent 24 hours, diuresis was increased by 493%; in 9 patients (Group 2) whose baseline urinary output exceeded 1,000 mL/24 h (mean, 1,785 mL), renin increased by 40%, norepinephrine, aldosterone, and RPP each decreased by 12%, and diuresis remained unchanged; in 13 patients (Group 3) with a daily urinary excretion as in Group 2 and without overhydration, RPP decreased (-7%), renin (+196%), aldosterone (+170%), and norepinephrine (+52%) increased, and diuresis decreased by 45%. There was an overall correlation (p < 0.0001) between the combination of changes in these circulatory and hormonal variables and changes in diuresis and natriuresis with ultrafiltration. CONCLUSIONS It appears that in CHF, (1) retention of sodium and water results from an interaction of hormonal and hemodynamic (primarily RPP) alterations that may exert a reciprocal positive feedback; (2) depending on the presence and severity of fluid retention, the response to withdrawal of body fluid may vary from neurohumoral activation and restriction of diuresis to neurohumoral depression and extreme potentiation of salt and water excretion; (3) refractory CHF requires the interruption of the humoral-hemodynamic vicious circle, and ultrafiltration is able to accomplish that.

Calcium-channel blockade with nifedipine and angiotensin converting-enzyme inhibition with captopril in the therapy of patients with severe primary hypertension.

Nifedipine (10 mg qid) and captopril (25 mg qid) were tested alone and in combination in 14 patients suffering from severe primary hypertension. Each study period was of 1 weeks duration. Circulatory response was evaluated through hourly pressure and pulse rate readings. The fall in pressure after oral nifedipine was maximal within 1 hr or less and was generally accompanied by palpitation and increase in pulse rate; with a six hourly dosing regimen the tendency of blood pressure to recover after each dose was interrupted by the next dose, so that values remained significantly reduced throughout the 24 hr, although pressure fluctuations were evident. Promptness of the antihypertensive action of captopril was similar, but the magnitude and the duration of the fall in pressure were less pronounced. When the converting-enzyme inhibitor was combined with the calcium-channel blocker, pressure fluctuations were not abolished, but the antihypertensive response was definitely enhanced, so that normal blood pressure was maintained for several hours during the day. Additional positive effects of captopril were mitigation of the heart rate reaction and prevention of the ankle pitting or edema elicited by nifedipine. A balance in arteriolar and venular dilatation promoted by captopril is the suggested mechanism for these effects. With the two-drug combination the function of the left ventricle was not reduced and possibly improved; blood urea nitrogen and serum electrolyte and creatinine concentration were not affected. Plasma renin activity increased with captopril and reverted toward baseline with the addition of nifedipine, suggesting an interference of the calcium-channel blocker with the release of renin.

Effect of Tamoxifen on Venous Thromboembolic Events in a Breast Cancer Prevention Trial

Background—Tamoxifen, a selective estrogen-receptor modulator, increases venous thromboembolic events (VTE), but the factors explaining this risk are unclear. Atherosclerosis may induce VTE, or the 2 conditions may share common risk factors. We assessed the effect of tamoxifen on VTE in a breast cancer prevention trial and studied its association with risk factors for VTE. Methods and Results—The incidence of VTE was studied in 5408 hysterectomized women randomly assigned to tamoxifen 20 mg/d or placebo for 5 years. There were 28 VTEs on placebo and 44 on tamoxifen therapy (hazard ratio [HR]=1.63; 95% confidence interval [CI], 1.02 to 2.63), 80% of which were superficial phlebitis, accounting for all of the excess due to tamoxifen within 18 months from randomization. Compared with placebo, the risk of VTE on tamoxifen was higher in women aged 55 years or older, women with a body mass index ≥25 kg/m2, elevated blood pressure, total cholesterol ≥250 mg/dL, current smoking, and a family history of coronary heart disease (CHD). Of the 685 women with a CHD risk score ≥5 who entered the trial, 1 in the placebo arm and 13 in the tamoxifen arm developed VTE (log-rank P=0.0013). In multivariate regression analysis, age ≥60 years, height ≥165 cm, and diastolic blood pressure ≥90 mm Hg had independent detrimental effects on VTE risk during tamoxifen therapy, whereas transdermal estrogen therapy concomitant with tamoxifen was not associated with any excess of VTE (HR=0.64; 95% CI, 0.23 to 1.82). Conclusions—Women with conventional risk factors for atherosclerosis have a higher risk of VTE during tamoxifen therapy. This information should be incorporated into counseling women on its risk-benefit ratio, particularly in the prevention setting.

Activation of complement and kinin systems after thrombolytic therapy in patients with acute myocardial infarction. A comparison between streptokinase and recombinant tissue-type plasminogen activator

BackgroundWe have previously shown that treatment with streptokinase induces abrupt complement activation and transient neutropenia in patients with acute myocardial infarction (AMI). The purpose of this study was to compare the effects of two different thrombolytic agents—streptokinase (SK) and recombinant tissue-type plasminogen activator (rTPA)—on activation of the complement and kinin systems in plasma of patients with AMI. Methods and ResultsForty-one patients with AMI who were eligible for thrombolytic therapy were studied. Twenty-three patients were treated with streptokinase (1.5 million IU IV over 60 minutes) and 18 were treated with rTPA (8 with bolus of 10 mg IV, followed by 50 mg infused over 60 minutes and then 40 mg infused over 120 minutes; 10 patients were administered rTPA and heparin according to the accelerated infusion protocol indicated by the GUSTO study). C4a and C3a were measured by radioimmunoassay, soluble terminal complement components (SC5b-9) and anti-SK IgG antibodies were measured by ELISA. Cleaved high molecular weight kininogen (HK) was quantitated in plasma by SDS-PAGE and immunoblotting analysis. C4a levels were significantly and similarly increased in both groups, whereas the levels of C3a and SC5b-9 after rTPA infusion were only slightly elevated and were significantly lower than after SK. No differences were observed between patients treated with slow or accelerated rTPA regimens. The titer of antibodies to SK was highly correlated with the levels of C3a and SC5b- 9, whereas a lesser correlation was observed with C4a. Treatment with rTPA did not induce the transient neutropenia observed after SK infusion. The cleavage products of HK were significantly greater after SK than after rTPA infusion. ConclusionsOur results show that both thrombolytic agents activate the classic complement pathway and that plasmin could be the common trigger for this phenomenon. A significant activation of the complement common pathway (from C3 to terminal components) was observed only with SK infusion and is attributable to the rapid formation of immunocomplexes between SK and anti-SK antibodies present in plasma as a consequence of previous streptococcal infections. The minimal activation of C5 component of the common pathway explains the absence of leukopenia in patients treated with rTPA. Cleavage of HK, larger after SK than after rTPA infusion, represents a condition enhancing the generation of bradykinin by kallikrein. The recent experimental data that indicate a damaging effect of complement activation on the infarcted zone and the contrasting favorable effect consequent to bradykinin formation raise some questions about the clinical importance of the different biological consequences of SK versus rTPA.

Facilitating influence of disopyramide on atrial flutter termination by overdrive pacing

Long-lasting (mean 30 days) type I atrial flutter was treated with overdrive pacing in 30 patients (mean age 69 years) with organic heart disease. To evaluate the effect of pretreatment with disopyramide, the study population was divided in 3 groups of 10 patients each: group A, no disopyramide therapy; group B, intravenous disopyramide (maximum dose 250 mg in 1 hour); and group C, oral disopyramide (400 mg daily for 4 days). There were no differences in baseline cycle length of atrial flutter among the 3 groups before drugs were given. The stimulation protocol included overdrive atrial pacing up to the shortest paced cycle of 150 ms performed at a maximum of 3 atrial sites. Reversion to sinus rhythm occurred in 2 patients in group A, 7 in group B (p less than 0.01) and 5 in group C. Pacing was performed from a mean number of 2.1 sites/patient in group A, 1.2 in group B and 2.0 in group C. Atrial fibrillation occurred in 7, 3 and 4 patients, respectively. Acceleration to a faster form of atrial flutter occurred in 3, 3 and 4 patients, respectively, and reversion to sinus rhythm occurred in all patients who had intravenous disopyramide and in 1 who took the drug orally. The administration of disopyramide before overdrive pacing improved the rate of conversion to sinus rhythm and allowed an easier stimulation protocol with a lower incidence of pacing-induced atrial fibrillation. Disopyramide is beneficial when overdrive atrial pacing is performed for the treatment of long-standing atrial flutter in patients with organic heart disease.

Thrombin activation and late restenosis after percutaneous transluminal coronary angioplasty

BACKGROUND Mechanisms of restenosis after percutaneous transluminal coronary angioplasty (PTCA) have not been defined yet. Experimental studies have shown that thrombin, by stimulating platelet growth factor secretion and smooth muscle cell proliferation, can play a major role. METHODS AND RESULTS In 34 patients with single-vessel coronary disease undergoing PTCA, thrombin activity was evaluated through serial fibrinopeptide A (FPA) plasma determinations. Samples were performed before PTCA, immediately after and 24 hours, 72 hours, and 6 months later. Patients were grouped according to the development (group 1, n = 13) or nondevelopment (group 2, n = 21 ) of restenosis at a 6-month angiographic control. No difference in the two groups was found concerning baseline FPA values. In patients in group 1, soon after PTCA higher FPA levels (27.3 +/- 13.7 ng/ml) than those in group 2 (9.2 +/- 5.6 ng/ml; p < 0.05 vs pre-PTCA, and p < 0.01 between the two groups) were observed. No differences in FPA levels were detected at the other steps between the two groups. CONCLUSION Our data suggest that thrombin plays a role in the process of restenosis after PTCA; acute FPA response to the procedure seems to have a predictive value.

Nitrendipine vs. long-acting nifedipine in mild, moderate and severe hypertension.

Long-acting nifedipine and nitrendipine, a nifedipine analogue, have been proposed for single-drug therapy of hypertension. In this study we compared the two preparations in three groups (10 subjects in each group) of mild (group 1), moderate (group 2), and severe (group 3) hypertensives. Drugs were admin istered for seven days (20 mg every 8 hr), according to a randomized, double- blind, crossover design. Blood pressure and heart rate readings were taken hourly, from 8 A.M. to 7 P.M., for the duration of the trial. In group 1, pressure was lowered to normal levels by both compounds and did not recover in the interval between one dose and the other, so that it re mained normal throughout the day. In group 2, from an average of 170/109, values were reduced by the two preparations to 140/90 mm Hg within two hours, and then they tended to recover. This tendency was interrupted by the next dose. Because of this pattern, compared with the placebo period, pressure was substantially reduced during the twelve hours of the day; however, for a certain span it remained higher than normal. In group 3, the immediate re sponses to the two drugs were similar (from an average of 208/130, pressure was lowered to an average of 170/95 mm Hg), and then it tended to rise again and recovery was faster with nifedipine. Although pressure was significantly re duced throughout the day by both preparations, normotension was never achieved in this group. Neither drug induced a tachycardia reaction, altered renal or cardiac func tion, or affected body weight or plasma renin activity. The tendency to produce dependent edema was less pronounced with nitrendipine. In conclusion, these calcium channel antagonists were equally effective in mild and moderate hypertension, while in the severe form the action of nitrendi pine was more persistent. Within the limits of the drug regimens used in this study, it seems that both preparations as monotherapy may be satisfactory in mild, questionable in moderate, and inadequate for severe hypertension, al though the action of nitrendipine is more lasting.

β-Thromboglobulin plasma levels in the first week after myocardial infarction: Influence of thrombolytic therapy

In vitro and in vivo studies have shown both an inhibition and an activation of platelets after thrombolysis in acute myocardial infarction. Plasma beta-thromboglobulin, a marker of platelet activity, was evaluated daily during the first week after myocardial infarction in 24 patients who received intravenous streptokinase (group 1) and 26 who did not (group 2). On admission, levels of beta-thromboglobulin, as compared to those in healthy subjects (35 +/- 9 IU/ml), were similarly augmented in group 1 (105 +/- 27 IU/ml) and in group 2 (115 +/- 30 IU/ml); 3 hours later, values averaged 191 +/- 58 IU/ml in group 1 (p < 0.001 vs baseline) and 95 +/- 28 IU/ml in group 2 (not significant vs baseline; p < 0.001 between the two groups). From the second to the seventh day, beta-thromboglobulin augmented in those patients in both groups with postinfarction angina. From day 5 to day 7, patients of group 1 without angina had lower beta-thromboglobulin levels than patients of group 2 who had no symptoms. The lowest levels of platelet activity were observed in group 1 reperfused patients. These data indicate that in myocardial infarction an early platelet activation takes place that is enhanced by thrombolytic treatment; recurrence of angina is associated with persistent activation; in the absence of recurrent angina, thrombolysis can limit late platelet activation.

Platelet Activity in the Early Stage of Acute Myocardial Infarction: Relation to Time of Presentation, Treatment with Either Tissue Plasminogen Activator or Streptokinase and Cyclooxygenase Inhibition

Background. Platelet activation after myocardial infarction and thrombolytic treatment has been documented; but its relationship with the onset of symptoms and with thrombolysis, and the influence of aspirin in this setting is not well defined. In this study we measured platelet activity in the early phase of myocardial infarction treated with either streptokinase or rt-PA and evaluated influence of aspirin in this framework.Methods. 41 patients (age 57 ± 6 years) were treated with thrombolytic therapy during myocardial infarction; 21 patients with 1,5 million units of streptokinase (Group 1) and 20 patients with 100 mg of rt-PA (Group 2); 10 randomly selected patients in each group were given 500 mg aspirin i.v. prior to infusion of thrombolytic drug and, subsequently, 325 mg aspirin a day orally. Consecutive samples of beta-thromboglobulin (BTG), a marker of platelet activity, were collected at admission and after thrombolysis for the following 48 hours. Results. At admission, BTG plasma levels averaged 125 ± 31 IU/ml in Group 1 and 134 ± 35 IU/ml in Group 2 (p = 0.81). Thrombolysis was followed by a similar increase of platelet activity with maximal values reached at the 3rd hour in both groups (196 ± 43 IU/ml in Group 1 and 192 ± 39 in Group 2: p < 001 versus baseline and p NS between the groups). Higher levels of BTG were observed in streptokinase-treated group starting from the 24th hour (p < 0.05). Patients treated with aspirin showed lower levels of BTG only from the 48th hour after thrombolysis in both groups. An inverse correlation was found between time elapsed from onset of symptoms to admission and BTG value on admission (r = −0.86 p < 0.001); in patients admitted within two hours from the beginning of symptoms, with higher levels of BTG, thrombolysis not induced a significant increase of platelet activity; who was observed in patients admitted later. Conclusions. A marked platelet activation is more evident in the first hours of myocardial infarction and is differently influenced by thrombolytic treatment in relation with the delay of patient presentation. Both streptokinase and rt-PA induce a similar increase of platelet activity which is more persistent after streptokinase; cyclooxygenase inhibition seems to influence the platelet activity only from the second day.Condensed abstract. Influence of aspirin on platelet activity during myocardial infarction treated with thrombolytic therapy is not well defined. Twenty-one patients treated with streptokinase (Group 1) and 20 patients treated with rt-PA (Group 2) were randomly selected to give 500 mg of aspirin i.v. prior thrombolysis and subsequently 325 mg a day orally. Platelet activity was evaluated through determination of beta-thromboglobulin plasma levels. Thrombolysis was followed by a similar increase of platelet activity in both groups with maximal values reached at the 3rd hour; higher levels of beta-thromboglobulin were observed in streptokinase-treated group starting from 24th hour. Treatment with aspirin reduced beta-thromboglobulin plasma levels only at 48th hour in both groups.