Safety of granulocyte-colony-stimulating factor in acute myocardial infarction (the Rigenera study).
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Adjuvants, Immunologic↗
Biomedical subjects
A G Rebuzzi
Publications and source records attributed to A G Rebuzzi.
Prognostic value of ventricular arrhythmias and heart rate variability in patients with unstable angina.
OBJECTIVES: To assess the prognostic value of ventricular arrhythmias (VA) and heart rate variability (HRV) in patients with unstable angina. DESIGN: Multicentre prospective study. SETTING: 17 cardiological centres in Italy. PATIENTS: 543 consecutive patients with unstable angina and preserved left ventricular function (ejection fraction >or=40%) enrolled in the SPAI (Stratificazione Prognostica dell'Angina Instabile) study. METHODS: Patients underwent 24 h ECG Holter monitoring within 24 h of hospital admission. Tested variables were frequent ventricular extrasystoles (>or=10/h), complex (that is, frequent or repetitive) VA, and bottom quartile values of time-domain and frequency-domain HRV variables. Primary end points were in-hospital and six-month total and cardiac deaths. RESULTS: Eight patients died in hospital (1.5%) and 32 (5.9%, 29 cardiac) during follow up. Both complex VA and frequent extrasystoles were strongly predictive of death in hospital and at follow up, even after adjustment for clinical (age, sex, cardiac risk factors and history of myocardial infarction) and laboratory (troponin I, C reactive protein and transient myocardial ischaemia on Holter monitoring) variables. At univariate analysis bottom quartile values of three HRV variables (standard deviation of RR intervals index, low-frequency amplitude and low to high frequency ratio) were associated with in-hospital death, and bottom quartile values of most HRV variables predicted six-month fatal events. At multivariate Cox survival analysis reduced low-frequency amplitude was consistently found to be independently associated with fatal end points. CONCLUSION: In patients with unstable angina with preserved myocardial function, both VA and HRV are independent predictors of in-hospital and medium-term mortality, suggesting that these factors should be taken into account in the risk stratification of these patients.
Aged↗
Myocardial infarction in isolated ventricular non-compaction: contrast echo and MRI.
We describe the case of an occasional discovery of isolated ventricular non-compaction in an adult recovered for an acute myocardial infarction, in which only the echocardiogram revealed an isolated ventricular non-compaction, confirmed by MRI: an unusual association between coronary artery disease and isolated ventricular non-compaction.
Electrocardiography↗
Temporal evolution and functional outcome of no reflow: sustained and spontaneously reversible patterns following successful coronary recanalisation.
OBJECTIVE: To identify in humans the temporal patterns of no reflow and their functional implications. METHODS: 24 patients with first acute myocardial infarction and successful coronary recanalisation by recombinant tissue-type plasminogen activator (n = 15) or primary percutaneous transluminal coronary angioplasty (n = 9) were studied by myocardial contrast echocardiography within 24 hours of recanalisation and at one month's follow up. Myocardial contrast echocardiography was performed by intermittent harmonic power Doppler and intravenous Levovist. The regional contrast score index (CSI) was calculated within dysfunctioning myocardium. Videointensity was measured (dB) within risk and control areas and their ratio was calculated. RESULTS: In 8 patients reflow was observed at 24 hours and persisted at one month. Conversely in 16 patients areas of no reflow were detectable at 24 hours. At one month, no reflow was spontaneously reversible in 9 patients (mean (SD) CSI and videointensity ratio improved from 2.5 (0.5) to 1.4 (0.6) and from 0.6 (0.1) to 0.7 (0.1), respectively; p < 0.05) and was sustained in the remaining 7 patients (CSI and videointensity ratio remained unchanged from 2.6 (0.6) to 2.6 (0.5) and from 0.5 (0.2) to 0.5 (0.2), respectively; NS). Left ventricular function improved significantly in patients with reflow and reversible no reflow. Volumes were enlarged only in patients with sustained no reflow. CONCLUSIONS: No reflow detected at 24 hours may be sustained or spontaneously reversible at one month. Such reversibility of the phenomenon is associated with preserved left ventricular volumes and function. Clarification of the mechanisms of delayed reversibility may lead to tailored treatment of no reflow even in the subacute phase of myocardial infarction.
Angioplasty, Balloon, Coronary↗
Reversible left anterior descending artery spasm, prolonged cardiac arrest and left main thrombosis during a PTCA attempt of the circumflex artery.
The authors report a case of percutaneous transluminal coronary angioplasty of the circumflex artery complicated by occlusion of the non-diseased left anterior descending artery by spasm. During advanced cardiac life support, required for the subsequent cardiac arrest, intra-coronary nitrates and calcium antagonists were administered. After 45 minutes, the spasm resolved, but N probably as a result of prolonged blood stasis N a thrombus appeared in the left main artery. While attempting to stent the left main, the thrombus was mechanically dislodged, leaving the epicardial coronary tree free, with a good flow.
Angioplasty, Balloon, Coronary↗
Enhanced inflammatory response in patients with preinfarction unstable angina.
OBJECTIVES: We assessed the extent and the time course of the acute phase response following myocardial cell necrosis and its relationship with the presence of preinfarction unstable angina (UA). BACKGROUND: Elevated levels of acute phase proteins have been reported in patients with UA and in patients with acute myocardial infarction (MI). METHODS: C-Reactive Protein (CRP), serum amyloid A protein (SAA) and interleukin-6 (IL-6) were measured in 36 patients with MI admitted within 3 h from symptoms onset. All patients had normal levels of creatine kinase and of troponin T on admission, rising above diagnostic levels within 6 to 12 h. Blood samples for CRP, SAA and IL-6 measurements were taken on admission, at 6, 24, 48, 72 h and at discharge. RESULTS: Twenty of the 36 patients studied presented an unheralded MI (Group 1); the remaining 16 patients had symptoms of unstable angina in the preceding 7 days (Group 2). Group 2 patients have much higher levels of CRP and SAA on admission (median values 8.8 vs. 3 mg/L and 28 vs. 3.4 mg/L, respectively, all p<0.001). Following the necrotic insult, despite similar infarct size and clinical signs of reperfusion, Group 2 patients had strikingly higher peaks of IL-6 (median values 85.2 vs. 19 pg/ml, p<0.05), CRP (50 vs. 31.4 mg/L, p<0.05) and SAA (228 vs. 45 mg/L, p<0.001). CONCLUSIONS: Our data demonstrated that the acute phase response is greatly enhanced in patients with preinfarction UA compared with those presenting with an unheralded MI. The significant differences in acute phase response observed in these two clinical presentations of MI indicate a major difference in their underlying pathogenetic components.
Acute-Phase Reaction↗
Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty.
OBJECTIVES: We sought to investigate whether early and late outcome after percutaneous transluminal coronary angioplasty (PTCA) could be predicted by baseline levels of acute-phase reactants. BACKGROUND: Although some risk factors for acute complications and restenosis have been identified, an accurate preprocedural risk stratification of patients undergoing PTCA is still lacking. METHODS: Levels of C-reactive protein (CRP), serum amyloid A protein (SAA) and fibrinogen were measured in 52 stable angina and 69 unstable angina patients undergoing single vessel PTCA. RESULTS: Tertiles of CRP levels (relative risk [RR] = 12.2, p < 0.001), systemic hypertension (RR = 4.3, p = 0.046) and female gender (RR = 4.1, p = 0.033) were the only independent predictors of early adverse events. Intraprocedural and in-hospital complications were observed in 22% of 69 patients with high serum levels (>0.3 mg/dl) of CRP and in none of 52 patients with normal CRP levels (p < 0.001). Tertiles of CRP levels (RR = 6.2, p = 0.001), SAA levels (RR = 6.0, p = 0.011), residual stenosis (RR = 3.2, p = 0.007) and acute gain (RR = 0.3, p = 0.01) were the only independent predictors of clinical restenosis. At one-year follow-up, clinical restenosis developed in 63% of patients with high CRP levels and in 27% of those with normal CRP levels (p < 0.001). CONCLUSIONS: Preprocedural CRP level, an easily measurable marker of acute phase response, is a powerful predictor of both early and late outcome in patients undergoing single vessel PTCA, suggesting that early complications and clinical restenosis are markedly influenced by the preprocedural degree of inflammatory cell activation.
Aged↗
Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events.
BACKGROUND: A growing body of evidence suggests a role for inflammation in acute coronary syndromes. The aim of this study was to assess the role of proinflammatory cytokines, their time course, and their association with prognosis in unstable angina. METHODS AND RESULTS: We studied 43 patients aged 62+/-8 years admitted to our coronary care unit for Braunwald class IIIB unstable angina. In each patient, serum levels of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6) (which represent sensitive markers of biologically active IL-1beta and tumor necrosis factor-alpha levels, respectively), and troponin T were measured at entry and 48 hours after admission. Troponin T-positive patients were excluded. Patients were divided a posteriori into 2 groups according to their in-hospital outcome: group 1 comprised 17 patients with an uneventful course, and group 2 comprised 26 patients with a complicated in-hospital course. In group 1, mean IL-1Ra decreased at 48 hours by 12%, and IL-6 diminished at 48 hours by 13%. In group 2, IL-1Ra and IL-6 entry levels were higher than in group 1 and increased respectively by 37% and 57% at 48 hours (P<0.01). CONCLUSIONS: These findings indicate that although they receive the same medical therapy as patients who do not experience an in-hospital event, patients with unstable angina and with complicated in-hospital courses have higher cytokine levels on admission. A fall in IL-1Ra and IL-6 48 hours after admission was associated with an uneventful course and their increase with a complicated hospital course. These findings may suggest novel therapeutic approaches to patients with unstable angina.
Angina, Unstable↗
Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability.
BACKGROUND: In a group of patients admitted for unstable angina, we investigated whether C-reactive protein (CRP) plasma levels remain elevated at discharge and whether persistent elevation is associated with recurrence of instability. METHODS AND RESULTS: We measured plasma levels of CRP, serum amyloid A protein (SAA), fibrinogen, total cholesterol, and Helicobacter pylori and Chlamydia pneumoniae antibody titers in 53 patients admitted to our coronary care unit for Braunwald class IIIB unstable angina. Blood samples were taken on admission, at discharge, and after 3 months. Patients were followed for 1 year. At discharge, CRP was elevated (>3 mg/L) in 49% of patients; of these, 42% had elevated levels on admission and at 3 months. Only 15% of patients with discharge levels of CRP <3 mg/L but 69% of those with elevated CRP (P<0.001) were readmitted because of recurrence of instability or new myocardial infarction. New phases of instability occurred in 13% of patients in the lower tertile of CRP (</=2.5 mg/L), in 42% of those in the intermediate tertile (2.6 to 8.6 mg/L), and in 67% of those in the upper tertile (>/=8.7 mg/L, P<0.001). The prognostic value of SAA was similar to that of CRP; that of fibrinogen was not significant. Chlamydia pneumoniae but not Helicobacter pylori antibody titers significantly correlated with CRP plasma levels. CONCLUSIONS: In unstable angina, CRP may remain elevated for at >/=3 months after the waning of symptoms and is associated with recurrent instability. Elevation of acute-phase reactants in unstable angina could represent a hallmark of subclinical persistent instability or of susceptibility to recurrent instability and, at least in some patients, could be related to chronic Chlamydia pneumoniae infection.
Aged↗
[Stratification of risk in clinical practice].
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Biomarkers↗
Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina.
BACKGROUND: Systemic markers of inflammation have been found in unstable angina. Disruption of culprit coronary stenoses may cause a greater inflammatory response in patients with unstable than those with stable angina. We assessed the time course of C-reactive protein (CRP), serum amyloid A protein (SAA), and interleukin-6 (IL-6) after single-vessel PTCA in 30 patients with stable and 56 patients with unstable angina (protocol A). We also studied 12 patients with stable and 15 with unstable angina after diagnostic coronary angiography (protocol B). METHODS AND RESULTS: Peripheral blood samples were taken before and 6, 24, 48, and 72 hours after PTCA or angiography. In protocol A, baseline CRP, SAA, and IL-6 levels were normal in 87% of stable and 29% of unstable patients. After PTCA, CRP, SAA, and IL-6 did not change in stable patients and unstable patients with normal baseline levels but increased in unstable patients with raised baseline levels (all P<0.001). In protocol B, CRP, SAA, and IL-6 did not change in stable angina patients after angiography but increased in unstable angina patients (all P<0.05). Baseline CRP and SAA levels correlated with their peak values after PTCA and angiography (all P<0.001). CONCLUSIONS: Our data suggest that plaque rupture per se is not the main cause of the acute-phase protein increase in unstable angina and that increased baseline levels of acute-phase proteins are a marker of the hyperresponsiveness of the inflammatory system even to small stimuli. Thus, an enhanced inflammatory response to nonspecific stimuli may be involved in the pathogenesis of unstable angina.
Acute-Phase Proteins↗
Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris.
Management of unstable angina is largely determined by symptoms, yet some symptomatic patients stabilize, whereas others develop myocardial infarction after waning of symptoms. Therefore, markers of short-term risk, available on admission, are needed. The value of 4 prognostic indicators available on admission (pain in the last 24 hours, electrocardiogram [ECG], troponin T, and C-reactive protein [CRP]), and of Holter monitoring available during the subsequent 24 hours was analyzed in 102 patients with Braunwald class IIIB unstable angina hospitalized in 4 centers. The patients were divided into 3 groups: group 1, 27 with pain during the last 24 hours and ischemic electrocardiographic changes; group 2, 45 with pain or electrocardiographic changes; group 3, 30 with neither pain nor electrocardiographic changes. Troponin T, CRP, ECG on admission, and Holter monitoring were analyzed blindly in the core laboratory. Fifteen patients developed myocardial infarction: 22% in group 1, 13% in group 2, and 10% in group 3. Twenty-eight patients underwent revascularization: 37% in group 1, 35% in group 2, and 7% in group 2 (p <0.01 between groups 1 or 2 vs group 3). Myocardial infarction was more frequent in patients with elevated troponin T (50% vs 9%, p=0.001) and elevated CRP (24% vs 4%, p= 0.01). Positive troponin T or CRP identified all myocardial infarctions in group 3. Only 1 of 46 patients with negative troponin T and CRP developed myocardial infarction. Among the indicators available on admission, multivariate analysis showed that troponin T (p=0.02) and CRP (p=0.04) were independently associated with myocardial infarction. Troponin T had the highest specificity (92%), and CRP the highest sensitivity (87%). Positive results on Holter monitoring were also associated with myocardial infarction (p=0.003), but when added to troponin T and CRP, increased specificity and positive predictive value by only 3%. Thus, in patients with class IIIB unstable angina, among data potentially available on admission, serum levels of troponin T and CRP have a significantly greater prognostic accuracy than symptoms and ECGs. Holter monitoring, available 24 hours later, adds no significant information.
Adult↗
[The absence of a procoagulant effect after TNK-t-PA: a comparison with streptokinase and rt-PA].
A limitation of current fibrinolytic drugs is the procoagulant activity induced by their administration. TNK is a mutant of tissue plasminogen activator (t-PA) with high fibrin specificity, resistance to plasminogen activator inhibitor-1 and slow plasma clearance, which is administered in a single intravenous bolus. In this study we investigated the procoagulant effect of TNK-t-PA compared to streptokinase, rt-PA or no thrombolysis. Twenty-nine patients with acute myocardial infarction, treated within 6 hours of symptom onset with 1.5 MU streptokinase over 1 hour (n = 12), 100 mg rt-PA in 1.5 hours (n = 12) or 30-40 mg TNK-t-PA in 15 s (n = 5), were studied and compared to 7 patients with contraindications to thrombolysis (control group). All patients received a similar i.v. heparin regimen for at least 24 hours. Blood samples were drawn before the start of treatment (time 0) and after 2 hours. Thrombin formation was assessed as plasma concentrations of thrombin-antithrombin complex (TAT). The four patient groups did not differ significantly in age, sex, time to treatment, infarct location, and TAT values at time 0 (mean value +/- standard error of the mean 9 +/- 2 micrograms/l). Mean TAT levels at 2 hours were 26 +/- 6 micrograms/l in streptokinase treated patients (p = 0.005 vs time 0), 21 +/- 4 micrograms/l in rt-PA treated patients (p < 0.05 vs time 0), 5 +/- 0.6 micrograms/l in TNK treated patients, and 4 +/- 0.4 micrograms/l in controls (NS vs time 0 for TNK and controls). In conclusion, our data suggest that, in patients with acute myocardial infarction, bolus TNK-t-PA, unlike streptokinase or rt-PA infusions, is devoid of procoagulant effects, evaluated 2 hours after its administration.
Aged↗
Need for a composite risk stratification of patients with unstable coronary syndromes tailored to clinical practice.
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Angina, Unstable↗
Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina.
BACKGROUND: We have previously reported aspirin failure in suppressing enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation during the acute phase of unstable angina. The recent discovery of a second prostaglandin H synthase (PGHS-2), inducible in response to inflammatory or mitogenic stimuli, prompted us to reexamine TXA2 biosynthesis in unstable angina as modified by two cyclooxygenase inhibitors differentially affecting PGHS-2 despite a comparable impact on platelet PGHS-1. METHODS AND RESULTS: We randomized 20 patients (15 men and 5 women aged 59+/-10 years) with unstable angina to short-term treatment with aspirin (320 mg/d) or indobufen (200 mg BID) and collected 6 to 18 consecutive urine samples. Urinary 11-dehydro-TXB2 was extracted and measured by a previously validated radioimmunoassay as a reflection of in vivo TXA2 biosynthesis. Metabolite excretion averaged 102 pg/mg creatinine (median value; n=76) in the aspirin group and 55 pg/mg creatinine (median value; n=99) in the indobufen group (P<.001). There were 16 samples (21%) with 11-dehydro-TXB2 excretion >200 pg/mg creatinine among patients treated with aspirin versus 6 such samples (6%) among those treated with indobufen (P<.001). In vitro and ex vivo studies in healthy subjects demonstrated the capacity of indobufen to largely suppress monocyte PGHS-2 activity at therapeutic plasma concentrations. In contrast, aspirin could only inhibit monocyte PGHS-2 transiently at very high concentrations. CONCLUSIONS: We conclude that in unstable angina, episodes of aspirin-insensitive TXA2 biosynthesis may reflect extraplatelet sources, possibly expressing the inducible PGHS in response to a local inflammatory milieu, and a selective PGHS-2 inhibitor would be an ideal tool to test the clinical relevance of this novel pathway of arachidonic acid metabolism in this setting.
Aged↗
Usefulness of the addition of heart rate variability to Holter monitoring in predicting in-hospital cardiac events in patients with unstable angina pectoris.
Transient ischemia on Holter monitoring is a major determinant of outcome in unstable angina. In this study we investigated whether analysis of heart rate variability (HRV) may further improve the prognostic yield of Holter monitoring in this clinical setting. We performed 24-hour Holter monitoring in 75 patients with unstable angina (59 men, aged 62 +/- 9 years) within 12 hours of hospital admission. Number and duration of myocardial ischemic episodes, and both time domain and frequency domain HRV measures were obtained from Holter recordings. In-hospital major cardiac events (death or myocardial infarction) occurred in 7 patients (9%). Episodes of ST-segment depression on Holter monitoring were found in 6 of 7 patients (86%) with and in 26 of 68 patients (38%) without events (p <0.05). There were no differences between patients with or without events in both time domain (standard deviation [SD] of all normal RR intervals in the entire 24-hour electrocardiographic recording (SDNN), SD of the mean RR intervals for all 5-minute segments (SDANN-i), mean of SD of all RR intervals for all 5-minute segments (SDNN-i), percentage of differences between adjacent RR intervals >50 ms (pNN50), and square root of the mean squared differences of successive RR intervals) (RMSSD), and frequency domain (ultra low, very low, low, and high frequency) HRV indexes. However, the low-frequency/high-frequency (LF/HF) ratio was significantly higher in patients with cardiac events (2.12 +/- 1.4 vs 1.48 +/- 0.5, p = 0.01). Moreover, when considering only the 32 patients with myocardial ischemic episodes on Holter monitoring, the LF/HF ratio was again higher in the 6 patients with than the 26 patients without major cardiac events (2.45 +/- 1.5 vs 1.31 +/- 0.3, p <0.01). Multivariate logistic regression, including clinical and angiographic variables, showed that transient ischemia on Holter monitoring was the only independent determinant of outcome (odds ratio = 12.2, p = 0.03), with the LF/HF ratio being only slightly over statistical significance (odds ratio for 0.1 increments = 2.8, p = 0.08). Our data confirm that transient ischemia on Holter monitoring is a powerful predictor of cardiac events in unstable angina and indicates that an imbalance in cardiac autonomic tone toward a prevalence of sympathetic activity increases the risk of events in this group of patients.
Aged↗
Plasma protein acute-phase response in unstable angina is not induced by ischemic injury.
BACKGROUND: Elevated levels of C-reactive protein (CRP) are associated with an unfavorable clinical outcome in patients with unstable angina. To determine whether ischemia-reperfusion injury causes this acute-phase response, we studied the temporal relation between plasma levels of CRP and ischemic episodes in 48 patients with unstable angina and 20 control patients with active variant angina, in which severe myocardial ischemia is caused by occlusive coronary artery spasm. METHODS AND RESULTS: Blood samples were taken on admission and subsequently at 24, 48, 72, and 96 hours. All patients underwent Holter monitoring for the first 24 hours and remained in the coronary care unit under ECG monitoring until completion of the study. On admission, CRP was significantly higher in unstable angina than in variant angina patients (P < .001). In unstable angina, 70 ischemic episodes (1.5 +/- 2 per patient) and in variant angina 192 ischemic episodes (9.6 +/- 10.7 per patient) were observed during Holter monitoring (P < .001), for a total ischemic burden of 14.8 +/- 30.2 and 44.4 +/- 57.2 minutes per patient, respectively (P < .001). The plasma concentration of CRP did not increase in either group during the 96 hours of study, even in patients who had episodes of ischemia lasting > 10 minutes. CONCLUSIONS: The normal levels of CRP in variant angina, despite a significantly larger number of ischemic episodes and greater total ischemic burden, and the failure of CRP values to increase in unstable angina indicate that transient myocardial ischemia, within the range of duration observed, does not itself stimulate an appreciable acute-phase response.
Acute-Phase Reaction↗
Elevated levels of interleukin-6 in unstable angina.
BACKGROUND: Elevated plasma levels of C-reactive protein have been found in the majority of patients with unstable angina. The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence that suggests that inflammation plays a role in this syndrome and is an indirect sign of increased production of interleukin-6, which is the major determinant of acute-phase-protein production by the liver. However, in unstable angina, there is no direct proof of the role played by interleukin-6. METHODS AND RESULTS: We measured levels of interleukin-6 in 38 patients with unstable angina at the time of their admission to the coronary care unit and in 29 patients with stable angina. In the same groups of patients, we also measured C-reactive protein. Interleukin-6 (undetectable, ie, < 3 pg/mL, in healthy volunteers) was detectable in 23 (61%) of 38 patients with unstable angina but in only 6 (21%) of 29 with stable angina (P < .01). Median interleukin-6 levels were 5.25 pg/mL (range, 0 to 90 pg/mL) in patients with unstable angina but were below the detection limit of the assay in patients with stable angina (range, 0 to 7 pg/mL). A significant correlation was observed between interleukin-6 and C-reactive protein levels (r = .4, P = .013). CONCLUSIONS: Our study demonstrates that raised levels of interleukin-6 are common in unstable angina, correlate with C-reactive protein, and are associated with prognosis, thus confirming the importance of the cytokine pathway for the production by the liver of acute-phase proteins and strengthening the importance of inflammation in this syndrome. Further studies are required to elucidate better the role of interleukins in unstable angina.
Aged↗