Donatella Ferrini

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.

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.

Effects of iloprost, a stable prostacyclin analog, on exercise capacity and platelet aggregation in stable angina pectoris

The effects of iloprost, a chemically stable compound with prostacyclin mimetic activity, on exercise capacity and platelet aggregation were assessed in 24 patients with effort angina and proved critical (at least 70% diameter narrowing) coronary artery disease. Upright bicycle ergometer testing (25-W increments every 2 minutes) was performed during drug and placebo infusions using a crossover, randomized, single-blind protocol. Samples for measurements of adenosine diphosphate-induced platelet aggregation in platelet-rich plasma were obtained in all patients before and during the study. Compared with placebo, intravenous iloprost consistently (p less than 0.001) prolonged exercise duration and time to onset of significant (0.1 mV) ST depression. Angina and ST depression occurred at a greater heart rate and rate-pressure product. Benefits were remarkable in some patients (67%) and not in others. Iloprost administration resulted in reduced platelet aggregation at peak exercise in all patients, whether they had consistent or little response to the drug. Thus, iloprost administration may improve exercise capacity in patients with stable exertional angina pectoris. Improvements are independent of changes in the major determinants of myocardial oxygen demand and associated with markedly reduced platelet aggregation, which may account for increased myocardial perfusion in patients with high sensitivity to coronary constriction.

Myocardial ischemia induced by prostacyclin and iloprost

Vasodilators of resistive vessels may induce ischemia in patients with coronary artery disease. To evaluate this possibility during prostacyclin (PGI2; scalar doses up to 10 ng/kg/min) and prostacyclin analog (iloprost; scalar doses up to 6 ng/kg/min) infusions, we studied 33 patients with angina pectoris and proved coronary artery disease. Patients were also submitted to dipyridamole (0.15 mg/kg/min for 4 minutes) and exercise stress testing (starting at 25 W and increasing 25 W every 2 minutes). In a preliminary study the hemodynamic and side effects of iloprost were studied in seven healthy subjects. At an iloprost dose of 4 to 6 ng/kg/min, these subjects had a significant decrease in mean arterial pressure and total peripheral and pulmonary vascular resistances. Side effects were limited to facial flushing and slight headache and were readily reversible. PGI2 induced typical chest pain and significant ST segment depression in six patients with severe coronary artery disease (three with left main and three with triple vessel disease) and poor exercise tolerance (X̄ ± SD = 362 ± 99 seconds). All six patients had had angina during the dipyridamole infusion. Similar findings were observed after iloprost infusion in four of these. Aminophylline (125 mg iv) completely relieved chest pain. Although the rate‐pressure products occasionally rose during PGI2 and iloprost infusions, there were no significant changes between ischemic (11.3 ± 2.3 and 10.6 ± 1.4 × 10−3 U) and preischemic (10.8 ±1.5 and 10.7 ± 1.4 × 10−3 U) rates of infusion. Our data indicate that PGI2 and iloprost may induce ischemia independently of changes in oxygen demand, and suggest that these drugs dilate small coronary vessels. This may result in decreased subendocardial perfusion pressure and/or “coronary steal.”

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.

Myocardial ischemia during intravenous prostacyclin administration: Hemodynamic findings and precautionary measures

This study reports coronary and systemic hemodynamics, and metabolic responses to atrial pacing, prostacyclin (PGI2), and iloprost, its stable analogue, in 16 patients with severe coronary obstruction as well as predominant narrowing in the left anterior descending artery. PGI2 caused ischemia in six patients with low anginal threshold during pacing. In three of them ischemia was also precipitated by iloprost. Drugs were infused at therapeutic doses and were discontinued when pain occurred. Angina disappeared promptly (less than or equal to 3 minutes) and spontaneously after the infusion of PGI2, whereas after the analogue it was long lasting (greater than or equal to 5 minutes) and was relieved by 125 mg intravenous aminophylline, an antagonist of dipyridamole-induced coronary dilation. Ischemia was associated with a drug-induced decrease in arterial blood pressure and reflex tachycardia, and occurred despite increased great cardiac vein (GCV) blood flow and decreased resistance, which is consistent with either a failure of regional flow to increase proportionally to the metabolic demand or a subendocardial-subepicardial steal. However, the following findings favor the latter hypothesis: heart rate and rate-pressure product at the onset of pain were lower with drugs than with pacing, and GCV blood flow, measured at a comparable heart rate, was less with pacing than with drugs. In conclusion, PGI2 and analogues may induce ischemia in patients with advanced coronary artery disease. The mechanism appears to be related to a dipyridamole-like maldistribution of flow. Counteraction of ischemia can be achieved by aminophylline.

Cardiac markers and risk stratification: an integrated approach.

Risk stratification of patients with acute coronary syndromes (ACS) is pivotal for correct allocation of health resources and for maximizing the benefit of available treatment modalities. However, clinical and electrocardiographic indicators of high risk lack sufficient sensitivity for the detection of major cardiac events. The complementary information provided by the measurement of different biomarkers is believed to be very useful. Specifically, elevations of cardiac troponin I (cTnI) and T (cTnT) are strongly associated with a high-risk profile both at short- and long-term. This has been definitely demonstrated in many studies as well as in cumulative meta-analysis. The role of different biomarkers, such as those reflecting activation of hemostasis and the presence of inflammation, is however less defined. At the moment, no study has prospectively evaluated these biomarkers in the whole spectrum of unselected patients with ACS. It is also unclear whether these biomarkers add independent prognostic value to the clinical and electrocardiographic indicators of adverse outcome and whether they offer additional information when compared to each other. The Early Prognostic Value of Biochemical Markers of Myocardial Damage, Activation of Hemostatic Mechanism and Inflammation in Acute Ischemic Syndromes (EMAI) study has been prospectively designed to solve these issues. In this study, we have evaluated the prognostic value of cTnI and cTnT, D-dimer, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and C-reactive protein (CRP) in patients with ACS at the time of admission. We have enrolled in 31 Italian Coronary Care Units 1971 patients with rest anginal pain within 12 h from admission and electrocardiographic evidence of myocardial ischemia. Of these, 730 patients resulted to have ST-segment elevation myocardial infarction eligible for a reperfusion strategy and 1241, an acute coronary syndrome without persisting ST-segment elevation. Primary outcome measure of the study is the composite of death and non-fatal MI within 30 days from admission, which has occurred in 8.9% of the study population.

Soluble E-Selectin is Not a Marker of Unstable Coronary Plaque in Serum of Patients with Ischemic Heart Disease

Increased level of soluble cell adhesion molecules may be a marker for atherosclerosis and/or reflect complication of the atherosclerotic plaque. To test whether expression of cell adhesion molecules is more pronounced in unstable versus stable coronary plaques, we measured the serum level of soluble E-selectin (sE-selectin) in 99 consecutive patients admitted to the hospital for acute coronary syndromes (ACS) and in 61 patients with chronic coronary artery disease (CAD) using a commercially available ELISA kit. We also measured the sE-selectin concentration in 20 sex- and age-matched subjects without clinical evidence of atherosclerosis, who served as controls. The mean sE-selectin level was higher in both groups of patients compared with controls (ACS, 35.0 ± 23.4 ng/mL; chronic CAD, 32.9 ± 21.0 ng/mL; controls, 14.5 ± 6.6 ng/mL; one-way ANOVA, P = 0.001), but there was no difference between patients with ACS and chronic CAD. Furthermore, there was a trend (P = 0.08) toward a decrease in sE-selectin with an increase in the extent and severity of CAD. In patients with ACS, the in-hospital cardiac event rate was 8%. Although mean sE-selectin concentration tended to be higher in patients with (49.2 ± 42.1 ng/mL) than in those without (33.8 ± 21.3 ng/mL) in-hospital cardiac events, the difference was not significant. In 53 patients with ACS, C-reactive protein was measured and showed no correlation with the sE-selectin concentration. These findings show that although sE-selectin concentration is elevated in the presence of clinically relevant atherosclerosis, it does not further increase during the unstable phase of the disease, indicating that sE-selectin is not a reliable indicator of a complicated atherosclerotic plaque.

Early risk stratification of unstable angina/non-Q myocardial infarction: biochemical markers of coronary thrombosis.

Coronary thrombosis is an important determinant of prognosis in patients with acute coronary syndromes (ACS). However, the identification of patients at high-risk for progression of coronary thrombosis is difficult partly because we currently lack clinically meaningful laboratory methods for its detection. The most promising approaches involve the measurement in plasma of markers of fibrin formation and degradation. Thrombin activity, as reflected by plasma or urine concentrations of fibrinopeptide A, is increased in patients with ACS and is associated with adverse outcome. However, the use of fibrinopeptide A as a marker of fibrin formation is limited by the very short half-life of the compound, by artifact due to sample acquisition, and by extremely long turnaround times. To overcome these limitations, measurement of soluble fibrin has been proposed. We have recently explored the prognostic value of a new fibrin-specific ELISA assay for soluble fibrin in patients with ACS and found that patients with the highest levels had a 2-fold increased risk of early and late cardiac events. Increases in plasma concentrations of cross-linked fibrin degradation products (XL-FDPs), which reflect increased fibrin turn-over, are a marker of risk for complications of myocardial infarction. However, until recently, assays for XL-FDPs lacked specificity, because they did not distinguish between fibrin and fibrinogen degradation products. Recently, fibrin-specific ELISAs have been described and a rapid whole blood assay for D-dimer has been developed. We recently validated the prognostic value of this whole blood agglutination assay in patients with ACS. These results suggest that: (1) The detection of significant activation of the coagulation and/or fibrinolytic system may be important for rapid risk stratification of patients with ACS; (2) patients with biochemical evidence of ongoing coronary thrombosis may particularly benefit from aggressive antithrombotic strategies; (3) sequential measurement of these markers may be useful to guide antithrombotic treatment during the unstable phase of coronary artery disease.