Filippo Ottani

Prodromal Angina Limits Infarct Size A Role for Ischemic Preconditioning

BACKGROUND In the experimental setting, it has been demonstrated that preconditioning myocardium before prolonged occlusion with brief ischemic episodes affords substantial protection to the cells by delaying lethal injury, thereby limiting infarct size. Whether the same occurs in humans remains unknown. METHODS AND RESULTS This study was undertaken to determine whether new-onset prodromal angina, defined as chest pain episodes limited to the 24 hours before myocardial infarction, is the clinical correlate of the ischemic preconditioning phenomenon. Twenty-five patients with their first anterior myocardial infarction treated with thrombolysis (recombinant tissue plasminogen activator [r-TPA], 100 mg/3 hours) were retrospectively included in the study because they met the following criteria: (1) < 120 minutes from onset of symptoms to reperfusion therapy, (2) < 90 minutes from the beginning of thrombolytic therapy to reperfusion (defined as rapid ST elevation reduction > 50%), (3) a patient infarct-related coronary artery with TIMI 3 flow and complete absence of collateral circulation to the infarct related artery (assessed at 24 +/- 5 days), and (4) the presence of new-onset prodromal angina, ie, typical chest pain episodes occurring at rest within 24 hours or, alternatively, a complete absence of symptoms before onset of infarction. Therefore, on the basis of their clinical status before infarction, the patients were divided into two groups: group 1, 13 patients without prodromal angina, and group 2, 12 patients with prodromal angina. Despite no difference in time to treatment (81 +/- 19 versus 75 +/- 21 minutes in group 1 and group 2, respectively; P = NS) and time to reperfusion (58 +/- 34 versus 46 +/- 24 minutes; P = NS), the peak of CKMB release was markedly lower in group 2 (86.3 +/- 66 versus 192.3 +/- 108.3 IU/L; P < .01). In addition, although both groups were comparable in terms of area at risk (amount of myocardium beyond the infarct-related stenosis; 15.1 +/- 4.6 versus 13.7 +/- 4.6 hypokinetic segments in group 1 and group 2, respectively, P = NS), the final infarct size (11 +/- 7.5 versus 5.6 +/- 4 hypokinetic segments, P < .04) was smaller in group 2. Thus, the limitation of the infarct size was significantly greater in group 2 (69% versus 36%; P < .05), and this represents an additional 33% reduction (95% confidence intervals, 7.1% to 58.9%; P = .01) in the group of patients with prodromal angina. Also, the third index, that is, the ECG, showed a favorable trend toward a lesser number of Q waves and a higher sigma R waves, although the values did not reach statistical significance. CONCLUSIONS Despite a similar area at risk, patients with new-onset prodromal angina showed a significantly smaller infarct size compared with patients without prodromal symptoms. Since the two groups had similar times to reperfusion and no evidence of collateral circulation to the infarct related artery, the protection afforded by angina in group 2 patients might be explained by the occurrence of ischemic preconditioning.

N-Terminal Pro-Brain Natriuretic Peptide on Admission Has Prognostic Value Across the Whole Spectrum of Acute Coronary Syndromes

Background—The prognostic value of natriuretic peptide elevations in patients with acute coronary syndromes (ACS) is still incompletely defined. We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) on admission in patients with ACS and ECG evidence of myocardial ischemia. Methods and Results—The NT-proBNP was measured at a median time of 3 hours after symptom onset in 1756 patients. The outcome measure was death at 30 days, which occurred in 113 patients (6.4%). The median NT-proBNP level was 353 ng/L (107 to 1357 ng/L). Compared with the lowest quartile, patients in the second, third, and fourth quartiles had a relative risk of subsequent death of 2.94 (95% CI, 1.15 to 7.52), 5.32 (95% CI, 2.19 to 12.91), and 11.5 (95% CI, 4.90 to 26.87), respectively. The NT-proBNP was independently associated with death in a logistic regression model, which included clinical variables, ECG, and troponin T in patients either with (OR of highest versus lowest quartile, 7.0; 95% CI, 1.9 to 25.6) or without (OR of highest versus lowest quartile, 4.1; 95% CI, 1.1 to 14.6) persistent ST-segment elevation. NT-proBNP was also an independent predictor of severe heart failure. Conclusions—The measurement of NT-proBNP on admission improves the early risk stratification of patients with ACS, suggesting the need for the development of targeted therapeutic strategies.

Angiographic morphology in unstable angina and its relation to transient myocardial ischemia and hospital outcome

Complex stenosis morphology frequently occurs in patients with unstable angina pectoris. However, its relation to transient myocardial ischemia and hospital outcome has not been ascertained. To address this issue, 88 patients with significant (greater than or equal to 50%) coronary artery disease presenting with angina--new onset (n = 38), worsening (n = 20) or at rest (n = 30)-were studied. Patients with left main artery disease, normal coronary arteries or occlusion of the ischemia-related arteries were not included in the study. Continuous electrocardiographic recordings were obtained during the first 24 hours. Angiography was performed within 1 week from admission. Complex morphology was defined as any stenosis with irregular borders, overhanging edges or intracoronary thrombus. Only data referring to the in-hospital outcome were considered in this study. Adverse end points were sudden death, myocardial infarction and emergency revascularization. Analysis of the angiograms revealed a complex morphology in 58 patients (group 1). The remaining 30 patients served as control subjects (group 2). Thirty-two of the 58 group 1 patients had an unfavorable clinical outcome (positive predictive value, 55%). A similar outcome occurred in only 2 of the 30 group 2 patients (negative predictive value, 93%). Of the 32 group 1 patients who had an unfavorable clinical outcome, 29 had a cumulative duration of transient myocardial ischemia of greater than or equal to 60 minutes per 24 hours. A similar duration of ischemia, however, was observed in another 6 group 1 and in 8 group 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Natriuretic peptides for risk stratification of patients with acute coronary syndromes

Natriuretic peptides (BNP and NT‐proBNP) have been shown to be useful tools for risk stratification of patients with acute myocardial ischemia encompassing the whole spectrum of acute coronary syndromes (ACS), particularly for prediction of mortality. Both BNP and NT‐proBNP possess several characteristics of the ideal biomarker, showing independent and incremental prognostic value above traditional clinical, electrocardiographic, and biochemical (particularly troponin) risk indicators. Specifically, in ACS patients, BNP and NT‐proBNP have powerful prognostic value both in patients without a history of previous heart failure or without clinical or instrumental signs of left ventricular dysfunction on admission or during hospital stay. They can also be easily and rapidly measured in an emergency context. We have performed a meta‐analysis of available studies concerning the prognostic value of natriuretic peptides. Our results show that the prognostic value of natriuretic peptides is similar: (1) both at short‐ and long‐term; (2) when natriuretic peptides are measured at first patient contact or during hospital stay; (3) for BNP or NT‐proBNP; and (4) in patients with ST elevation myocardial infarction or no ST elevation ACS. These data suggest that natriuretic peptide measurement should be integrated into routine evaluation of patients with an ACS.

Patency of the infarct-related artery and left ventricular function as the major determinants of survival after Q-wave acute myocardial infarction

One hundred seventy-two patients with 1-vessel disease documented at predischarge angiography who had been followed for 43 +/- 30 months after an initial Q-wave acute myocardial infarction were retrospectively evaluated to investigate the prognostic value of infarct-related artery patency and left ventricular (LV) function. Multiple logistic regression analysis revealed that only infarct artery patency (Thrombolysis in Myocardial Infarction [TIMI] grades 2-3 vs 0-1) (Z = 2.24; p < 0.05) and end-systolic volume index (Z = -2.67; p < 0.01) were independently related to survival. Sixteen cardiac deaths were observed; all 16 patients had LV dysfunction (defined as end-systolic volume index > 40 ml/m2), and 15 had an occluded infarct-related artery. In the subgroup with LV dysfunction, the 10-year percent survival rate was 20% among patients with TIMI grade 0 to 1 versus 96% with grade 2-3 (p < 0.001). Patency of the infarct-related artery was also the only independent predictor of recurrent ischemia (Z = 2.59; p < 0.01). In conclusion, both infarct-related artery patency and LV function are independent predictors of survival after Q-wave acute myocardial infarction. Patients with normal LV function have an excellent long-term prognosis, which is only partially counterbalanced by the tendency toward clinical instability observed in those with an open infarct-related vessel. However, when an occluded infarct-related artery is observed in the setting of LV dysfunction, the long-term outcome appears to be relatively poor.

Increased cardiac troponin I on admission predicts in-hospital mortality in acute pulmonary embolism

Background: To investigate the frequency of cardiac troponin I (cTnI) increases in patients with pulmonary embolism (PE) and to assess the correlation between this finding, the clinical presentation, and outcomes. Methods: Consecutive patients admitted to the coronary care unit with acute PE were prospectively enrolled between January 2000 and December 2001. cTnI was sequentially determined. Various cut off concentrations were analysed, but patients were categorised prospectively as having increased or no increased cTnI based on a cut off concentration of 0.6 ng/ml. The main outcome measure was in-hospital mortality. Results: On admission, 14 of the 48 patients (29%) had cTnI concentrations greater than the receiver operating characteristic curve value used to diagnose acute myocardial infarction (> 0.6 ng/ml). Subsequently, six patients developed increases for an overall prevalence of 42% (20 of 42). The prevalence was higher when lower cut off concentrations were used: 73% (35 of 48) at the 99th centile and 60% (29 of 48) at the 10% coefficient of variability. Increased cTnI > 0.6 ng/ml was associated with a slower oxygen saturation (86 (7)% v 93 (4)%, p < 0.0001) and more frequent involvement of the main pulmonary arteries as assessed by spiral computed tomography (100% v 60%, p  =  0.022). In-hospital mortality was 36% (5 of 14) of patients with increases > 0.6 ng/ml v 3% (1 of 42) of patients with lower concentrations (p  =  0.008). Increased cTnI > 0.6 ng/ml on admission was the most powerful predictor of mortality (p  =  0.046). Conclusions: In high risk patients with acute PE, cTnI was frequently detected on admission. It was the strongest independent predictor of mortality.

Impact of intravascular ultrasound-guided stenting on long-term clinical outcome: a meta-analysis of available studies comparing intravascular ultrasound-guided and angiographically guided stenting

To date, only a few studies have compared the clinical efficacy of intracoronary ultrasound (IVUS)‐guided to angiographically guided stenting. Furthermore, it is not yet known whether the lower restenosis rate shown with the former strategy would translate into a substantial clinical advantage. Therefore, the aim of the present investigation was to improve the level of evidence of these studies by means of a formal meta‐analysis. Nine studies were considered suitable for analysis. Odds ratios (ORs) were calculated for 6‐month clinical follow‐up. Primary endpoint was a composite of death and nonfatal myocardial infarction (MI), as considered in every single study. Secondary endpoints were major adverse cardiac events (MACEs), according to single study definition, the individual cardiac events, as well as several pre‐ and postprocedure and follow‐up angiographic parameters. Overall, 2,972 patients were included. At 6 months, the OR for death and nonfatal MI was 1.13 (95% CI = 0.79–1.61; P = 0.5) for patients with IVUS‐guided stenting. However, patients with IVUS‐guided stenting had less target vessel revascularizations (OR = 0.62; 95% CI = 0.49–0.78; P = 0.00003) and MACEs (OR = 0.79; 95% CI = 0.64–0.98; P = 0.03) compared to angiographically guided stenting. In addition, subjects treated with IVUS‐guided stenting had significantly less binary restenosis (OR = 0.75; 95% CI = 0.60–0.94; P = 0.01). The present meta‐analysis demonstrates that IVUS‐guided stenting implantation has a neutral effect on long‐term death and nonfatal MI compared to an angiographic optimization. However, IVUS‐guided stenting significantly lowers 6‐month angiographic restenosis and target vessel revascularizations. Whether these benefits could be very helpful when dealing with lesions at high risk for restenosis is still an issue. Cathet Cardiovasc Intervent 2003;59:314–321.

Vasotonic angina: A spectrum of ischemic sysdroms involving function abnormalities of the epicardial and microvascular coronary circulation

OBJECTIVES The present study was undertaken to investigate the response of large and small coronary arteries in a subgroup of patients with no or minimal coronary artery disease found to have objective signs of myocardial ischemia. BACKGROUND Many patients apparently have normal coronary arteries despite abnormal electrocardiographic (ECG) changes during spontaneous anginal attacks or exercise stress testing. METHODS Twenty-five patients with no or minimal (< 30% stenosis) coronary artery disease were chosen from a pool initially selected on the basis of spontaneous anginal attacks and ST segment shifts in the anterior leads. Of these, 10 were grouped as having variant angina (at least one episode of ST elevation) and the remaining 15 as having syndrome X (exercise-induced anginal pain, ST depression and reversible thallium abnormalities). Data were compared with those obtained in 10 patients with stable angina and documented coronary artery disease. Eighteen patients with supraventricular arrhythmias and normal coronary arteries served as control patients. Patients showing focal spasm during ergonovine testing were not included in the subsequent angiographic analysis. Great cardiac vein blood flow, aortic pressure and changes in coronary artery diameter were measured at rest and 2 to 4 min after hyperventilation in the remaining study group. The same procedure was repeated after sublingual administration of 0.3 mg of nitroglycerin in eight patients (four with syndrome X and four with variant angina). RESULTS Hyperventilation induced diffuse epicardial coronary diameter reduction, which was marginal in control patients (9 +/- 4%) and those with coronary artery disease (5 +/- 3%) but severe (p < 0.001) in those with variant angina (28 +/- 14%) or syndrome X (25 +/- 13%). Concomitant determination of coronary blood flow showed significant (p < 0.001) decreases in those with variant angina (25 +/- 11%) and syndrome X (28 +/- 10%) but not in control patients (5 +/- 8%) or those with coronary artery disease (4 +/- 5%). Changes in great cardiac vein blood flow during hyperventilation were similar before and after nitroglycerin. CONCLUSIONS These findings indicate that vasoconstrictor stimuli may trigger a diffuse abnormal response of both epicardial and resistance vessels in some patients with chest pain and angiographically normal coronary arteries. Patients showing such diffuse vasoconstrictor abnormalities are suggested to have a single pathogenetic entity with a spectrum of ECG manifestations ranging from ST depression to ST elevation.

The Prognostic Value of Creatine Kinase Elevations Extends Across the Whole Spectrum of Acute Coronary Syndromes

OBJECTIVES The study investigated the relationship among creatine kinase (CK) elevations, clinical characteristics and cardiac events across the whole spectrum of acute coronary syndromes (ACS). BACKGROUND Elevated serum levels of cardiac enzymes have been shown to be a major prognostic determinant in acute myocardial ischemia. Yet prior to this report, the relation between cardiac enzyme levels and other prognostic determinants across the entire spectrum of ACS has not been explored by a large clinical study. METHODS We evaluated the relation between the maximum CK ratio (CK level/upper limit of normal) in the early hours following admission and cardiac events at six months in 11,725 patients enrolled in a large trial of ACS. RESULTS Patients with higher risk characteristics, such as older age, female gender, hypertension, diabetes, prior coronary events or heart failure, more frequently presented without ST-segment elevation on the electrocardiogram and tended to develop lesser enzyme elevations. After adjusting for significant baseline predictors of cardiac events, a continuous correlation was observed between the CK ratio and death (chi-square 63.04, p < 0.0001) and (re)infarction or death (chi-square 55.48, p < 0.0001). This correlation was similar for patients with and without ST-segment elevation. The adjusted incidence of cardiac events at follow-up began to rise even for CK levels within the normal range, the steepest part of the curve residing between one and three times the upper limit of normal. In patients with a CK ratio of >1 to 2 compared with those within the normal range, the adjusted odds ratio for death was 1.26 (95% confidence interval [CI] 0.98 to 1.63), and 1.59 (95% CI 1.38 to 1.90) for (re)infarction and death. For all CK levels, the event rate was higher among patients without ST-segment elevation. CONCLUSIONS Although high-risk patients with ACS often develop lesser CK elevations, this study demonstrated that even minor enzyme elevations appear to have important and independent prognostic implications.

Failure of fixed dose intravenous heparin to suppress increases in thrombin activity after coronary thrombolysis with streptokinase

OBJECTIVES This study was designed to define the extent of inhibition of thrombin activity achieved with conjunctive fixed dose intravenous sodium heparin compared with fixed dose subcutaneous calcium heparin in patients receiving intravenous streptokinase for acute myocardial infarction. BACKGROUND The role of heparin therapy during coronary thrombolysis with streptokinase is controversial, in part because the efficacy of different conjunctive heparin regimens in inhibiting early increases of thrombin activity is not known. METHODS Twenty-eight patients treated with 1.5 million U of streptokinase and 165 mg of aspirin for acute myocardial infarction were randomly assigned to receive fixed dose subcutaneous heparin therapy (12,500 U every 12 h delayed until 4 h after the end of streptokinase therapy [n = 14]) or fixed dose intravenous heparin (5,000-U bolus followed by 1,000-U/h infusion [n = 14]). Anticoagulation was assessed with serial measurements of activated partial thromboplastin time, and thrombin activity by measuring fibrinopeptide A and thrombin-antithrombin III complex levels. Plasma concentrations of creatine kinase (CK) MM isoforms were measured for 3 h to determine recanalization (increase in activity > 0.18%/min). RESULTS Recanalization occurred in 27%, 64% and 79% of patients given subcutaneous heparin versus 43%, 76% and 86% of those given intravenous heparin at 1, 2 and 3 h, respectively (p = 0.6). Concentrations of fibrinopeptide A (mean +/- SEM) at 1 h were higher in patients without (n = 5) than in those with (n = 23) CK-MM isoform criteria for recanalization (76.4 +/- 25.7 vs. 25.2 +/- 5.2 nmol/liter, p = 0.02), and at 1, 2 and 3 h were significantly lower with fixed dose intravenous heparin (18.4 +/- 4.8 vs. 46.7 +/- 10.2 nmol/liter at 1 h, p = 0.004) than without heparin. After fixed dose subcutaneous heparin at 4 h, fibrinopeptide A levels were similar in both groups despite lower activated partial thromboplastin times in patients who received fixed dose subcutaneous heparin. However, fibrinopeptide A was not consistently suppressed in either group (fixed dose subcutaneous heparin 8.7 +/- 1.8 nmol/liter vs. fixed dose intravenous heparin 11.8 +/- 5.2 nmol/liter) at 48 h (p = 0.4). No significant changes in the concentration of thrombin-antithrombin III complexes were found between the two groups. CONCLUSIONS Fixed dose intravenous heparin attenuates increases in fibrinopeptide A early after streptokinase. Subsequent fixed dose intravenous and subcutaneous heparin have similar effects but are relatively ineffective in suppressing thrombin activity, suggesting a role for more potent antithrombin agents during coronary thrombolysis with streptokinase.