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 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 (means +/- 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 X 10(-3) U) and preischemic (10.8 +/- 1.5 and 10.7 +/- 1.4 X 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."

Conjunctive administration of intravenous heparin attenuates cross-linked fibrin degradation in patients treated with streptokinase.

Increases in thrombin activity occur in patients treated with streptokinase, but conjunctive therapy with intravenous heparin does not appear to improve either the rate of early infarct artery patency or survival in patients with acute myocardial infarction. In a recent study we found that concentrations of fibrinopeptide A, a marker of thrombin-mediated fibrin formation, were lower in the first 3 h in patients treated with intravenous heparin (5000 U bolus followed by a fixed-dose 1000 U/h infusion, n = 14) compared with subcutaneous (12,500 U every 12 h, started 4 h after streptokinse, n = 14) administration, but were increased in both groups of patients, consistent with persistent thrombin activity. To determine whether the differential effects of the intensity of heparinization on thrombin formation were reflected in differences in fibrin degradation, we measured cross-linked fibrin degradation products (XL-FDP) before and 1, 2, 3, 8, 12, and 24 h after streptokinase in the same cohort of patients, with a new ELISA with a D-dimer-specific capture antibody (MAb 3B6) and a fibrin-specific tag antibody (MAb 1D2, Agen, Brisbane, Australia). The incidence of early coronary recanalization assessed by creatine-kinase MM isoforms (increase in activity > or = 0.18%/min), was similar in both groups (79 vs 86%). Concentrations of XL-FDP were similar in patients with and without recanalization, but were lower in patients treated with intravenous compared with subcutaneous heparin at 8 h, but the results did not reach statistical significance (627 +/- 151 ng/ml versus 1007 +/- 157 ng/ ml, p = 0.06), and were significantly lower at 12 h (327 +/- 72 versus 781 +/- 162 ng/ml, p = 0.03 at 12 h) (mean +/- SEM). Concentrations of cross-linked fibrin degradation products were also lower in patients in whom the activated partial thromboplastin time was greater than two times the control, compared with those with inadequate anticoagulation (498 +/- 105 versus 1084 +/- 179 ng/ml; p = 0.02) (mean +/- SEM). Thus, more effective inhibition of thrombin with conjunctive intravenous heparin therapy results in less cross-linked fibrin turnover in the first 12 h after thrombolysis with streptokinase. This probably reflects decreased fibrin formation with therapeutic anticoagulation.

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.

Concurrent nitroglycerin therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction.

Nitroglycerin given with tissue-type plasminogen activator (t-PA) has been shown to decrease the thrombolytic effect of t-PA in animal models of coronary artery thrombosis. The present study was conducted to determine whether such an interaction between nitroglycerin and t-PA occurs in patients with acute myocardial infarction undergoing thrombolytic treatment. Patients with acute myocardial infarction were treated with t-PA plus saline solution (group 1; n = 11) or t-PA plus nitroglycerin (group 2; n = 36). Stable coronary artery reperfusion assessed by continuous ST-segment monitoring in 2 electrocardiographic leads, and release of creatine kinase occurred in 91% of group 1 patients and in 44% of group 2 patients (95% confidence interval, 14% to 82%; p < 0.02). Plasma levels of t-PA antigen were consistently (p < 0.005) higher in group 1 than in group 2 patients up to 6 hours after t-PA infusion. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were slightly higher in group 2 than in group 1 patients. These observations indicate that nitroglycerin given with t-PA significantly decreases the plasma t-PA antigen concentrations and impairs the thrombolytic effect of t-PA in patients with acute myocardial infarction.

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.

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.

Clinical relevance of prodromal angina before acute myocardial infarction.

The term preconditioning was applied to the observation made in 1986 by Murry and colleagues that canine myocardium subjected to brief episodes of ischemia and reperfusion would tolerate a more prolonged episode of ischemia better than myocardium not previously exposed to ischemia. Since that seminal observation, protective effect of preconditioning was demonstrated in all animal species tested, resulting in the strongest form of in vivo protection against myocardial injury other than early reperfusion. Angina heralding acute myocardial infarction may represent the clinical correlate of preconditioning phenomenon in humans. Data from small pathophysiological studies demonstrated that prodromal angina (<48 hours prior to index myocardial infarction) causes a reduction of infarct size and consequently a better left ventricular function compared with patients without such clinical feature before myocardial infarction. The protective effect of prodromal angina was also confirmed in larger prospective studies; its presence translates into a significant reduction of a combination of death, cardiogenic shock and pulmonary edema during hospital stay. The exact mechanism of such clinical phenomenon is however not known, but it may include preconditioning. Other mechanisms have been also claimed to play an important role, like a more rapid lysis of the occlusive thrombus within the infarct-related artery, or a rapid opening of intramural collateral not visible at angiography. Whatever the mechanism, it appears that patients with prodromal angina before myocardial infarction exhibit, when rapidly reperfused, a better post-infarction clinical outcome. At the present "optimal preconditioning-mimetic agents" are yet to be found, and "putting preconditioning in a bottle" still remains a pharmacologic challenge.

New markers for early diagnosis of acute myocardial infarction.

The availability of 'new' biochemical markers of myocardial injury such as creatine kinase isoforms and troponins has renewed the interest for rapid confirmation/exclusion of myocardial infarction in patients presented to the hospital for suspected acute myocardial ischemia. Many of these protein markers have the potential to allow the diagnosis of acute myocardial infarction at a time from the onset of symptoms when the activity of creatine kinase MB is still within the reference range. However, the exclusion of classical myocardial infarction as defined by WHO criteria does not allow to conclude that the patient is at low-risk and can be safely sent home since he may have high-risk unstable angina. The sensitivity for the detection of myocardial damage of troponins is such that a substantial proportion of patients with unstable angina develop elevations of troponins in the absence of creatine kinase MB increases. It is now clear that such patients have an increased risk of cardiac events over the short and long-term similar to that of patients with definite myocardial infarction. Such finding may help in developing selective admission policies and deciding which patients deserve aggressive treatment.

Non-invasive assessment of reperfusion of the infarct-related artery during coronary thrombolysis and its relation with left ventricular function.

We monitored ST segment continuously for at least 3 h after the beginning of lytic treatment in 103 patients undergoing early coronary thrombolysis for acute myocardial infarction in order to ascertain whether this technique, which has been shown to be useful to assess recanalization of the infarct-related artery, is also able to identify the improvement in left ventricular function associated with successful reperfusion. Global left ventricular function (assessed in the 30 degrees right anterior oblique projection with the area/length method) and infarct zone wall motion (studied with the centerline method) were evaluated at least 4 weeks after the event. Reperfusion was thought to be achieved when ST segment elevation dropped > 50% relative to the most abnormal peak documented at any time in the study. Eighty patients (78%) met the criterium for successful reperfusion (group 1), and 23 (22%) did not (group 2). Both groups had similar clinical and angiographic characteristics. All indexes of global left ventricular function were significantly better in group 1 than in group 2 patients (end-diastolic volume: 176 +/- 51 vs. 209 +/- 76 ml, end-systolic volume: 66 +/- 40 vs. 97 +/- 55 ml, ejection fraction: 65 +/- 13 vs. 57 +/- 11%, respectively, all P < 0.02). Also the severity (-1.6 +/- 1.3 vs. -2.6 +/- 1.01 S.D./chord, respectively, P < 0.001) and the extension of hypokinesia in the infarct zone (number of chords with > 2 S.D.: 13 +/- 16 vs. 28 +/- 17, respectively, P < 0.0001) were less in group 1 than in group 2 patients. Furthermore, in reperfused patients, both global left ventricular function and regional wall motion were better in those admitted < 60 min from onset of pain. In conclusion, patients with rapid ( > 50%) decrease of ST segment elevation have smaller infarct size and better global left ventricular function than patients without electrocardiographic signs of reperfusion as assessed by continuous ST segment monitoring. This suggests that this non-invasive technique is a powerful tool able to identify patients most benefiting from thrombolytic therapy.

The importance of antibody specificity in measuring cross-linked fibrin degradation products by ELISA.

We and others have previously shown that plasma concentrations of XL-FDPs are accurately characterized with an enzyme-linked immunosorbent assay (ELISA) based on the monoclonal antibody DD-3B6/22, which is specific for D-dimer, and a pan-specific tag antibody (DD-4D2/182) in patients with thrombotic disorders. However, in patients treated with fibrinolytic agents, increases in non-cross-linked fibrin(ogen) degradation products are detected by the pan-specific tag antibody due to formation of complexes between non-cross-linked derivatives and XL-FDPs. Assays based on the use of fibrin degradation product-specific tag antibodies appear to be more specific, but whether they would be clinically more informative is unclear. Accordingly, in the current study we measured concentrations of XL-FDPs with two ELISAs; one based on the pan-specific tag antibody (DD-4D2/182) and another based on a fibrin degradation product-specific tag antibody (DD-1D2/48) in patients treated with three well-characterized thrombolytic regimens: one associated with minimal fibrinogenolysis (100 mg tissue-type plasminogen activator [t-PA]) over 3 h), moderate fibrinogenolysis (100 mg t-PA over 90 min), and one with marked fibrinogenolysis (1.5 MU streptokinase [SK]). In patients treated with t-PA, increases in XL-FDPs were closely correlated with fibrinogenolysis, as characterized by increases in the concentration of the Bbeta1-42 peptide, when measured with the pan-specific tag ELISA (r = 0.7), but not when measured with the fibrin degradation product-specific tag assay (r = 0.2). In patients treated with SK, concentrations of XL-FDPs were significantly higher (> 2000 ng/ml) with the pan-specific tag ELISA compared with the fibrin degradation product-specific tag ELISA (< 1000 ng/ml) 1, 2 and 8 h after start of the infusion (P < 0.01). Concentrations of XL-FDPs were also higher in patients treated with SK compared with t-PA when measured with the pan-specific tag ELISA, but lower with SK with the fibrin-specific ELISA (P < 0.01). The value of measurement of XL-FDPs in patients treated with fibrinolytic agents will need to be reappraised with the use of fibrin degradation product-specific assays, which appear to provide more accurate information on the kinetics of cross-linked fibrin lysis in patients treated with t-PA or SK.

[Low-molecular weight heparin and acute coronary syndrome: theoretical background and its use in clinical practice]. / Eparine a basso peso molecolare e sindromi coronariche acute: razionale teorico ed uso nella pratica clinica.

Thrombosis is responsible for the acute manifestations of coronary artery disease. Intravenous heparin has been shown to be effective in reducing the risk of death or myocardial infarction in patients with acute coronary syndromes. Compared to standard heparin, low-molecular weight heparins (LMWHs) have improved pharmacological and pharmacokinetic properties. A number of LMWHs, such as nadroparin, dalteparin and enoxaparin, have been evaluated in patients with acute coronary syndromes. FRISC (Fragmin during Instability in Coronary Artery Disease) and FRIC (Fragmin in Unstable Coronary Artery Disease), evaluated dalteparin and found the LMWH to be more effective than aspirin alone (FRISC) and as effective as heparin in a direct comparison (FRIC). In a small trial, nadroparin was shown to significantly reduce the risk of ischemic outcomes compared with a combination of aspirin and heparin, but this effect was no longer significant in the large FRAX.I.S. trial (FRAXiparine in Ischaemic Syndrome). Enoxaparin resulted in a statistically significant reduction in the combined outcome of death, myocardial infarction and recurrent angina or of urgent revascularization when compared with heparin in the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) and TIMI 11B trials. Meta-analyzing of the data of these two trials revealed that even the combination of death and myocardial infarction was significantly reduced by the use of enoxaparin. There is accumulating evidence that LMWHs are safe and effective alternatives to standard heparin for the treatment of acute coronary syndromes and that they offer practical and therapeutic advantages.

[The protective effects of glucose in ischaemia, anoxia and reoxygenation (author's transl)]. / Effetti protettivi del glucosio in ischemia, anossia e riossigenazione.

In the present study we used a model of underperfusion or anoxia followed by reperfusion to assess the role of glycolysis by substituting pyruvate or mannitol for glucose as substrate. Hearts were removed from male Sprague-Dawley rats (250-400 g) and perfused by the technique of Langendorff. The perfusate was Krebs-Henseleit bicarbonate buffer gassed with 95% O2, 5% CO2 or with 95% N2, 5% CO2 mixture and containing substrates as can be seen in the figures. The mild ischemia was obtained by reducing the perfusion pressure by 70%, from 60-70 cm H2O to 10-20 cm H2O. The coronary flow was rapidly reduced to 0.8 +/- 0.03 ml/min within the first 5 minutes. After mild ischemia anaerobic glycolysis was accelerated because lactate production in ischemic hearts perfused with glucose (36.2 +/- 15.3 microM/g/min-1) was higher than in the ischemic hearts perfused with mannitol (6.8 +/- 1.9 microM/g/min-1). During mild ischemia or anoxia there was little difference in the rate of release of creatin-kinase for all the substrates tested, but major differences become apparent on reperfusion. In that period the highest values of CK release were found in mannitol perfused hearts, the lowest in glucose perfused hearts. These results suggest that the rate of glycolytic flux during mild ischemia or anoxia may prevent enzyme release. The beneficial effect of glucose has been observed also during reperfusion. In fact enzyme release was higher in hearts reperfused with glucose than with pyruvate. When pyruvate is the only exogenous substrate available for isolated oxigenated hearts, tissue levels of citric acid cycle intermediates are high and oxidation of these substrates can account for 100% of the oxygen consumption. Therefore we suppose that oxidation of noncarbohydrate substrates such as pyruvate in reperfusion is complicated by the high mitochondrial damage. As a consequence anaerobic glycolytic pathway may play a special role in the maintenance of the membrane integrity also in the early phases of reperfusion.

[Angina of effort with a variable threshold: a unique entity due to different mechanisms?]. / Angina da sforzo a soglia variabile: un'unica definizione per meccanismi differenti?

Variable threshold during exertion is a common feature in patients with chronic exertional angina. Changes in coronary vasomotor tone, when occurring at sites of critical narrowings, are a plausible explanation for variability of symptoms in these patients. However, the evidence supporting this hypothesis is still uncertain. Accordingly, we performed four computer assisted, multistage bicycle ergometer tests, without drugs, in 30 patients with chronic exertional angina, exercise induced ST depression, and a history of variable anginal threshold during exertion. Significant coronary artery disease was documented in each case by coronary arteriography. Patients were tested at the same time of day within a two week period. Comparison was made between each single test and the average of the remaining three. Time to 0.1 mV ST depression showed significant (+/- 20%) changes in 27 (90%) patients. Variability was shown in two out of four tests in 25 patients (83%), in three tests in 10 (33%), and in four tests in 2 (7%). Rate pressure product at 0.1 mV ST depression was concurrently changed (+/- 20%) in 20 patients (67%). Variability in two, three and four tests was observed in 7 (22%), 2 (7%) and 2 (7%) patients, respectively. Changes in time to 0.1 mV ST depression paralleled those in rate-pressure product at the onset of ischemia in 6 patients (22%) (dynamic ischemic threshold). Rate pressure product at 0.1 mV ST depression was unchanged despite variations in time to 0.1 mV ST depression in 10 patients (37%) (fixed ischemic threshold). The remaining 11 patients (41%) showed variable exercise tolerance associated with fixed (13 tests) and dynamic (13 tests) ischemic threshold.(ABSTRACT TRUNCATED AT 250 WORDS)

Side effects of prostacyclin in patients with angina pectoris and coronary artery disease.

Although the exposure of human subjects to prostacyclin (PGI2) infusion has been broad, no systematic approaches have been made in order to investigate the dose-related side effects in patients with angina pectoris and coronary artery disease (CAD). We studied 25 patients with typical chest pain and overt CAD. All patients underwent a cycloergometer stress testing (25 W increments at 2-min intervals). PGI2 was infused in scalar doses up to 10 ng/kg/min. During the infusion 25 patients (100%) had facial flushing, 7 (28%) moderate headache and one (4%) had nausea. In addition, 4 patients experienced the typical chest pain and had significant (greater than or equal to 0.1 mV) ST segment depression at 8.10 ng/kg/min infusion rates. These patients had lower tolerance to exercise (6.7 +/- 1.7 vs. 8.8 +/- 1.9 min; p less than 0.05) and coronary artery lesions more severe than those observed in patients without drug-induced angina pectoris. Our data therefore indicate that PGI2 at therapeutic doses may induce myocardial ischemia in patients with angina pectoris, low tolerance to exercise and severe CAD. In patients with mild to moderate degree of CAD, PGI2 was found to be well tolerated. These findings suggest that patients with angina pectoris and low tolerance to exercise should be excluded from clinical studies directed at elucidating the effectiveness of PGI2 in cardiovascular disorders.

[Myocardial ischemia induced by the cold pressor test in patients with exertion angina. Case contribution]. / Ischemia miocardica indotta da Cold Pressor Test in pazienti con angina da sforzo. Contributo casistico.

The aim of the present study was to assess the incidence of myocardial ischemia during cold pressor test in patients with stable exertional angina pectoris. Thirty-seven patients with proven coronary artery disease were submitted to cold pressor and exercise stress testing; computer assisted electrocardiographic recordings were obtained throughout the examinations. Cold stimulation provoked electrocardiographic signs of subendocardial ischemia only in 3 patients. They had suffered of a previous myocardial infarction and showed low exercise tolerance and severe coronary lesions (one with triple vessel and 2 with left main disease). Interestingly, only one of these patients gave an history of angina during cold exposure. Thus these data indicate that chest pain and electrocardiographic signs of ischemia are an uncommon event during cold pressor stimulation which occurs more likely in patients with fairly severe coronary narrowings. More sensitive markers of ischemia and/or different modalities of cold application are required for studies concerning the relationship between cold exposure and angina pectoris.

[Changes in angina threshold induced by administration of ergonovine maleate during pacing in patients with chronic exertional angina]. / Variazioni della soglia d'angina da pacing indotte dalla somministrazione di ergonovina maleato in pazienti con angina cronica da sforzo.

It is widely accepted that the occurrence of chest pain and/or ST segment elevation during ergonovine testing is a hallmark of abnormal coronary constriction. However, the negativity of this test cannot be considered as an incontrovertible proof of the absence of coronary sensitivity to vasoconstriction. Indeed, it could only indicate that the resulting effect is inadequate to critically reduce coronary blood flow. To test this hypothesis we studied 12 patients with proven coronary artery disease and negative ergonovine test who had complained of chronic exertional angina pectoris and referred variable threshold for the occurrence of pain. They were submitted to atrial pacing (starting from 90 bpm, with 10 bpm increments every 2 min) before (control) and after ergonovine administration (total dose = 0.675 mg). Time, heart rate and rate pressure product were evaluated at the onset of angina and significant ischemia (0.1 mV ST segment depression). After ergonovine, angina was achieved earlier (405 +/- 173 vs 526 +/- 180 sec, p less than 0.005) than during control and at a lower heart rate (116 +/- 15 vs 131 +/- 15 bpm, p less than 0.001) and rate pressure product (15.8 +/- 2.0 vs 18.8 +/- 2.3 X 10(3) U, p less than 0.001). Changes in anginal threshold were widely variable among cases being that the time to onset of pain was dramatically reduced in certain patients but unchanged in one. Similar results were obtained when substituting the ischemic to the anginal threshold. Thus, negativity to ergonovine testing does not imply the absence of coronary constriction which may be revealed when increasing myocardial oxygen demand by atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)

[Echocardiographic study of left ventricular function using automated border detection in normal subjects]. / Studio ecocardiografico della funzione ventricolare sinistra mediante automated border detection in soggetti normali.

BACKGROUND: Two-dimensional (2D) echocardiographic automated border detection (ABD) can provide on-line measurement of left ventricular cavity area and fractional area change. However, this new quantitative method has not been extensively validated. METHODS: Values of manually traced areas on 2D-echo images were compared with those obtained from ABD in 34 consecutive normal subjects (age 16-65 years). Only subjects with more than 70% of endocardial border circumferences clearly seen in both selected imaging planes were included in the study. We evaluated left ventricular end-diastolic and end-systolic area, and fractional area change obtained from mid-left ventricular short axis and apical 4-chamber view. Left ventricular volumes (area/length method) and ejection fraction were manually calculated off-line from apical 4-chamber view. RESULTS: From the short axis view, left ventricular cavity area measurements with ABD were obtained in 85% of subjects. The values closely correlated with off-line measurements: end-diastolic area 15.6 +/- 3.1 vs 14.8 +/- 3.3 cm2, r = 0.88 SEE = 1.58; end-systolic area 7.2 +/- 1.7 vs 6.7 +/- 1.7 cm2, r = 0.88 SEE = 0.80. A good correlation was also found for the apical 4-chamber view; end-diastolic area 25.9 +/- 5.9 vs 25.3 +/- 5.5 cm2, r = 0.97 SEE = 1.36; end-systolic area 16.3 +/- 4.1 vs 15.0 +/- 3.8 cm2, r = 0.92 SEE = 1.51. In this view ABD measurements were obtained in 79% of subjects. A significant correlation was also found between the end-diastolic volume and short axis (r = 0.54, SEE = 2.63; p 0.003) and apical 4-chamber (r = 0.66, SEE = 4.51; p = 0.0002) ABD diastolic area. Similarly, the end-systolic volume was significantly correlated with short axis (r = 0.57, SEE = 1.42; p = 0.001) and apical 4-chamber (r = 0.55, SEE = 3.54; p = 0.003) ABD systolic area. However, the on-line fractional area change correlated with off-line ejection fraction better from short axis view: (r = 0.72 SEE = 3.52) than from apical 4-chamber view (r = 0.45 SEE = 6.84). CONCLUSIONS: These data indicate that: 1) left ventricular areas measured by ABD correlate well with manually measured areas and volumes; 2) short axis ABD fractional area change may be a reliable substitute of off-line manually traced ejection fraction in normal subjects.