Evaluation of the patient with angina pectoris

All patients with chronic stable angina presumed to be due to coronary artery disease should undergo exercise stress testing early in evaluation for evidence of high-risk coronary disease. If the exercise stress test shows early positive findings, patients should undergo cardiac catheterization to exclude left main coronary vessel disease and three-vessel disease with concomitant left ventricular dysfunction. Patients with unstable angina who are subsequently stabilized on medical therapy should undergo a limited exercise stress test before discharge from the hospital to identify those at high risk. An ambulatory ECG is also helpful in evaluating for evidence of silent ischemia in these patients.     

急性非ST段抬高心肌梗死患者临床特点分析

目的 分析急性非ST段抬高心肌梗死(NSTEMI)患者的临床特点.方法 对211例NSTEMI和急性ST段抬高心肌梗死(STEMI)116例患者行冠状动脉造影、超声心动图检查,采集病史和症状特征进行分析.结果 与STEMI患者相比,NSTEMI患者危险因素较多,梗死后心绞痛常见,重度冠状动脉病变和三支病变多见,对心功能影响相对较小.结论 NSTEMI患者冠状动脉病变严重,梗死后心肌缺血常见,应重视对其治疗.     

Current medical management of chronic stable angina

Severe atherosclerotic narrowing of one or more coronary arteries is responsible for myocardial ischemia and angina pectoris in most patients with stable angina. The coronary arteries of patients with stable angina also contain many more non-obstructive plaques, which are prone to rupture resulting in acute coronary syndrome (unstable angina, myocardial infarction, sudden ischemic death). Therefore, the medical management must use strategies which not only relieve symptoms and prolong angina free walking but also reduce the incidence of adverse clinical outcomes. Whether any of the approved antianginal drugs, nitrates, beta-blockers, and calcium channel blockers reduce the incidence of adverse clinical outcomes in patients with stable angina has not been studied to date. Published data shows that percutaneous coronary revascularization procedures and coronary bypass surgery are effective in relieving angina but these procedures do not reduce mortality or the incidence of myocardial infarction compared to anti-anginal drug therapy. From the available data, an initial trial of medical treatment with anti-anginal drugs and strategies to reduce adverse clinical outcomes (smoking cessation, daily aspirin, treatment of dyslipidemias and hypertension) is indicated in most patients with stable angina pectoris. The initial choice of drug will depend on the presence or absence of comorbid conditions. Patients who do not respond to medical therapy or do not wish to take anti-anginal drugs and whose life style is limited because of anginal symptoms should be offered percutaneous revascularization procedures with or without stent placement or coronary bypass surgery. New drug-coated stents hold promise but long-term data and large-scale trials assessing the continued long-term improvement in symptoms and reduction of adverse outcomes is needed before offering such devices to all patients with stable angina. Newer medical therapies such as metabolic modulators and sinus rate lowering drugs also hold promise but need further evaluation. Patients who have refractory angina despite optimal medical therapy and are not candidates for revascularization procedures may be candidates for some new techniques of enhanced external Counterpulsation, Spinal Cord Stimulation, sympathectomy or direct transmyocardial revascularization. The usefulness of these techniques, however, needs to be confirmed in large randomized trials.     

Chronic stable angina pectoris. Risk stratification and treatment.

Workup of stable angina patients begins with careful history taking and evaluation of various risk factors, physical examination, and a resting electrocardiogram (ECG). A noninvasive exercise stress test is valuable for risk stratification. Abnormalities on a resting ECG or equivocal results on a stress test warrant an exercise test combined with thallium scintigraphy, which is more sensitive and specific. Cardiac catheterization is advisable for patients with chest discomfort and multiple risk factors, even if results of thallium testing are negative. Patients with severe or progressive angina or congestive heart failure should also have cardiac catheterization. Nitrates, beta-adrenergic blockers, and calcium channel blockers are cornerstones of medical therapy. Revascularization with coronary artery bypass graft is recommended for patients with left main coronary artery disease, left ventricular dysfunction, or severe proximal three-vessel coronary artery disease. Percutaneous transluminal coronary angioplasty (PTCA) is a good alternative for one- or two-vessel disease. Three-vessel PTCA can be accomplished, but its real role still remains to be established.     

血管内超声评价冠心病患者的冠状动脉

目的报告应用血管内超声(IVUS)评估冠心病患者冠状动脉重构及斑块稳定性诊疗的体会。方法使用血管内超声观察236例冠心病患者(经冠状动脉造影确诊),其中不稳定型心绞痛(UA)78例,稳定型心绞痛(SA)61例,急性心肌梗死(AMI)97例。结果SA组以稳定的纤维斑块为主,UA和AMI组以不稳定的软斑为主;UA和AMI组的偏心指数明显高于SA组(P<0.05)。UA组和AMI组以正性重构为主。结论IVUS能更准确观察冠状动脉内粥样斑块的特点,观察冠状动脉管腔的形态及狭窄的严重程度,对冠心病诊断具有独特的临床价值。     

Percutaneous transluminal coronary angioplasty in patients over 75 years old with acute myocardial infarct or unstable angina pectoris

Both increasing frequency and technical improvements of percutaneous transluminal coronary angioplasty (PTCA) have focussed attention on possible applications of PTCA in elderly patients with coronary artery disease. From January 1986 to June 1989, among 1872 patients treated with PTCA in our hospital, 42 patients (2.3%) were 75 or more years old. Of these patients, 14 presented with unstable angina, 28 patients suffered from acute myocardial infarction. PTCA was performed on stenoses of left anterior descending artery (43%), circumflex coronary artery (18%), and right coronary artery (39%), respectively. In patients with unstable angina, PTCA in 81% could reduce diameter stenoses of culprit lesions to 50% or less. 43% of patients with acute myocardial infarction had received previous thrombolytic therapy with streptokinase or urokinase applied either systemically or intracoronarily. On cardiac catheterization, 39% of patients presenting with acute myocardial infarction showed total occlusion of the infarct-related vessel. In 75% of patients with acute myocardial infarction, after PTCA, patency of the infarct-related artery (diameter stenoses 50% or less) was observed. In-hospital mortality of patients with acute myocardial infarction subjected to PTCA was 10%, two patients dying in prolonged cardiogenic shock, one in septic shock. In 20% of cases, coronary dissection was observed after PTCA. Non-Q-wave infarction developed in one patient. Three patients had a peripheral vascular complication, and in one patient a transient ischemic attack was observed. No severe catheter-related complications occurred after thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical predictors of 30-day cardiac events in patients with acute coronary syndrome at a community hospital

OBJECTIVE: We sought to determine predictors of coronary events (cardiac death, acute myocardial infarction, and urgent revascularization) within 30 days after admission. METHODS: We prospectively collected data on 400 patients admitted through our emergency room for unstable angina and acute coronary syndromes. Patients with ST-segment elevation myocardial infarction and those who required thrombolysis were excluded. RESULTS: Of 383 patients who were eligible, 120 patients had coronary events within 30 days. Statistically significant variables associated with coronary events were advanced age, male sex, family history of premature coronary artery disease (CAD), diabetes mellitus, tobacco abuse, prior congestive heart failure, prior myocardial infarction, and history of CAD. Symptoms at presentation associated with cardiac events were typical angina and shortness of breath. Objective measures of ischemia associated with cardiac events were elevated troponin T, elevated creatine kinase MB, and ischemic electrocardiographic changes. Using forward stepwise regression analysis, we generated a model to predict 30-day major adverse cardiac events. The strongest predicting variable was serum troponin T (accounting for 33% of predicting r2, P < 0.001) followed by typical angina (r2 increasing to 37%), ischemic electrocardiographic changes (40%), prior CAD (42%), family history of premature CAD (44%), shortness of breath (46%), and positive creatine kinase MB (48%). The positive predictive power of the complete model was r2 = 48%, P < 0.001. CONCLUSION: Our model incorporating elements from the patient's demographic, medical history, presentation, and ischemic assessment identified 48% of patients presenting with unstable angina and acute coronary syndromes who will suffer a major adverse cardiac event within 30 days of admission. Although the strongest predictor was identified as serum troponin T, other clinical criteria offered improvement in our predictive abilities. Therefore, good initial clinical evaluation in addition to simple tests such as serum cardiac markers and electrocardiography are valuable in risk stratification of patients presenting with acute coronary syndromes and cardiac chest pain. Additional testing may be necessary to improve the positive predictive value of the model. Cardiac enzymes and electrocardiographic changes have the highest negative predictive value for occurrence of major adverse cardiac events. Identification of high-risk patients is essential to direct resources toward these patients and to avoid unnecessary costs and risk to the low-risk population.     

Update on exercise stress testing

Exercise stress testing is an important diagnostic tool for the evaluation of suspected or known cardiac disease. In 2002, the American College of Cardiology (ACC) and the American Heart Association (AHA) revised their guidelines for exercise testing. Ten categories from the ACC/ AHA 1997 guidelines were modified: ST heart rate adjustment, unstable angina, older patients, acute coronary syndromes, chest pain centers, acute myocardial infarction, asymptomatic patients, valvular heart disease, rhythm disturbances, and hypertension. Adjustment of the ST heart rate can identify myocardial ischemia in asymptomatic patients with elevated cardiac risk. Intermediate- and low-risk patients with unstable angina, acute coronary syndromes, or chest pain should undergo exercise stress testing when clinically stable. Provided they are stable, patients who have had acute myocardial infarction can undergo a submaximal exercise test before discharge or a symptom-limited exercise stress test any time after two to three weeks have elapsed. In asymptomatic patients with cardiac risk factors, the exercise stress test may provide valuable prognostic information. Aortic regurgitation is the only valvular heart disorder in which there is significant evidence that exercise stress testing is useful in management decisions. The stress test also can be used in older patients to identify the presence of coronary artery disease. However, because of other comorbidities, a pharmacologic stress test may be necessary. Exercise stress testing can help physicians successfully evaluate arrhythmia in patients with syncope. The exercise stress test also can help identify patients at risk of developing hypertension if they show an abnormal hypertensive response to exercise.     

Management of coronary heart disease: stable angina, acute coronary syndrome, myocardial infarction

Stable angina should first be treated medically, particularly with aspirin and beta-blockers. Diagnostic stress tests are used in patients who have intermediate probability of CHD to further assess the likelihood of disease,with catheterization reserved for patients who have symptoms despite optimal medical therapy or are at risk for multivessel CHD. The work-up for low-risk unstable angina can involve medical management followed by stress testing. Moderate-to-high risk unstable angina and NSTEMI should be treated with an integrated approach, using medical therapy, cardiac catheterization, and revascularization. Patients who have STEMI require urgent reperfusion either with thrombolytic agents or primary angioplasty. Follow-ing a diagnosis of CHD, patients should undergo intense coronary risk-fac-tor modification to reduce the risk of future events.     

超声评价冠心病患者血管内皮舒张功能

目的 通过超声检测肱动脉内径评价冠心病患者肱动脉血管内皮舒张功能变化.方法 采用高分辨率超声检测稳定型心绞痛、不稳定型心绞痛、急性心肌梗死患者及正常对照组血流介导的肱动脉血管舒张功能和硝酸甘油介导的肱动脉血管舒张功能.结果 冠心病各组血流介导的血管舒张反应均较正常对照组降低（P〈0.05）.稳定型心绞痛组与正常对照组,硝酸甘油介导的血管舒张反应无显著性差异（P〉0.05）,而不稳定型心绞痛组和急性心肌梗死组硝酸甘油介导的血管舒张反应均低于正常对照组与稳定型心绞痛组（P〈0.05）.结论 冠心病患者存在内皮舒张功能损害,这种损害呈渐进性发展.     

Serum neopterin, nitric oxide, inducible nitric oxide synthase and tumor necrosis factor-alpha levels in patients with ischemic heart disease

BACKGROUND: Atherosclerosis, a chronic inflammatory disease, underlies the pathogenesis of coronary artery disease. The present study assessed the diagnostic possibilities of inflammatory biomarkers, serum neopterin, nitrite/nitrate (NO2(-)/NO3(-)), inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha), and their correlation with risk factors in patients with acute coronary syndromes and stable angina pectoris. METHODS: We studied 44 patients with chronic stable angina pectoris, 46 with unstable angina, 55 with acute ST-elevation myocardial infarction and 39 age-matched healthy volunteers (control group). Serum neopterin, iNOS and TNF-alpha were determined with commercially available enzyme linked immunosorbent assay methods and NO2(-)/NO3(-) by the modified cadmium-reduction method. RESULTS: Mean serum neopterin levels were significantly higher in patients with unstable and stable angina pectoris in comparison to control subjects (p<0.01 and p<0.05, respectively). Serum NO2(-)/NO3(-) values were significantly elevated (p<0.01) only in patients with unstable angina. ST-elevation myocardial infarction patients with cardiac death during follow-up showed significantly lower baseline neopterin values (p<0.001), and higher NO2(-)/NO3(-) levels (p<0.05) in comparison to those without adverse events. Significantly higher NO2(-)/NO3(-) values (p<0.05) were also found in patients who had myocardial reinfarction. Serum iNOS and TNF-alpha in all patient groups were within control ranges. A strong correlation was found between neopterin and both smoking (p<0.01) and triglycerides (p<0.05) in unstable angina patients. In stable angina patients, neopterin, iNOS and TNF-alpha significantly correlated with hypertension (p<0.01) and triglycerides (p<0.05). A significant difference in neopterin concentration was found between smokers and non-smokers (p<0.05). CONCLUSIONS: The results of this study suggest that in stable angina patients, if studied over time, serum neopterin or NO2(-)/NO3(-) levels may indicate future plaque instability. In ST-elevation myocardial infarction patients, neopterin and/or NO2(-)/NO3(-) levels may identify patients at long-term risk of death or recurrent acute coronary events after myocardial infarction.     

New approaches to the treatment of angina pectoris

Patients with coronary artery disease represent a highly heterogeneous group and require individualized treatment based on severity of symptoms, extent and distribution of coronary artery lesions, and left ventricular function. Patients with left main coronary artery disease or triple-vessel disease and left ventricular dysfunction should be referred for surgery, as should patients satisfying the Veterans Administration high-risk group criteria, as well as those patients with intractable symptoms unsuitable for PTCA. Patients in whom discrete proximal lesions in a single coronary artery have caused recent onset of medically refractory angina should be considered for PTCA. In these patients, PTCA has been proven to be both a safe and effective technique. The procedure will relieve the signs and symptoms of myocardial ischemia in half of these patients. One third of this group will have a recurrence of their symptoms but will return to an asymptomatic state for a prolonged period following a second PTCA procedure. The rate of infarction and death compares favorably with that seen with CABG surgery. What are the relative merits of PTCA vs. CABG surgery or drug regimens in the treatment of ischemic heart disease? To answer this critical question, a well-defined prospective randomized clinical trial is needed. The results of such a trial may usher in a new era in the treatment of ischemic heart disease.     

不同类型冠心病患者的胰岛素抵抗

目的　探讨不同类型冠心病患者与胰岛素抵抗之间的关系。方法　急性心肌梗死组 2 3例 ,不稳定型心绞痛组 2 9例 ,稳定型心绞痛组 2 6例 ,对照组 5 5例。测定空腹血糖、空腹胰岛素水平、总胆固醇、甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、肌酐、尿酸水平。评价胰岛素敏感性采用稳态模式评估法 (HOMA)及改良的胰岛素敏感性指数 (ISI)公式计算。结果　急性心肌梗死组、不稳定型心绞痛组与对照组比较 ,存在高胰岛素血症 (P <0 .0 1)和胰岛素敏感性的降低 (P <0 .0 1)。而稳定型心绞痛组与对照组比较 ,胰岛素水平及胰岛素敏感性的差异均无统计学意义 (P >0 .0 5 )。结论　急性心肌梗死及不稳定型心绞痛患者存在高胰岛素血症和胰岛素抵抗 ,胰岛素抵抗在两者的发病中可能发挥一定作用。     

State of percutaneous transluminal coronary artery angioplasty and effectiveness of low-density lipoprotein apheresis.

We have recognized percutaneous transluminal coronary artery angioplasty (PTCA) as an important procedure for achieving myocardial revascularization. PTCA has been performed for stable and unstable angina, acute myocardial infarction, and silent myocardial ischemia. Among many new devices, the coronary stent is the most important advancement in PTCA. Frequent stent use is due to the introduction of antiplatelet therapy to prevent stent thrombosis. One serious problem is that PTCA, even with stent use, often causes chronic restenosis. This problem has not been solved, however, despite various strategies. Aggressive lipid-lowering therapy is one of the most important therapies for coronary heart disease. The findings in aggressive lipid-lowering therapy show us its importance. We report that low-density lipoprotein (LDL) apheresis, when performed immediately before and after PTCA, can prevent restenosis of coronary artery lesions. Lipid-lowering therapy should be applied more aggressively with medicine and/or with LDL apheresis for patients who have undergone PTCA.     

Platelet glycoprotein IIB-IIIA receptor inhibitors in patients with ischemic heart disease

Glycoprotein IIb-IIIa receptor inhibitors are the newest anti-platelets drugs currently used in patients with coronary artery disease. We examined mechanisms of their action and different pharmacokinetic and pharmacodynamic characteristics of the four glycoprotein IIb-IIIa antagonists evaluated in randomized, controlled and multicenter trials. We reviewed results of these trials in the settings of percutaneous revascularizations procedures or unstable coronary syndromes. Platelet glycoprotein IIb-IIIa receptor inhibitors reduced incidence of cardiac death and myocardial infarction during the short- and midterm, and benefit was greater in: a) patients undergoing coronary angioplasty with or without stent implantation, particularly in the presence of unstable angina, diabetes or complex and diffuse coronary artery disease; b) as a direct therapy of unstable coronary syndromes, particularly in patients with refractory angina, diabetes and elevated Troponin; more recently they have been used as adjuvant therapy in acute myocardial infarction. Infusion of these drugs was not associated with higher rates of major bleedings.     

Angiographic correlates of a positive troponin T test in patients with unstable angina

OBJECTIVE: To study the angiographic correlates of cardiac troponin T (cTnT)-positive and -negative patients with unstable angina pectoris. BACKGROUND: A positive cTnT test identifies a high-risk subgroup of unstable angina pectoris patients. Only the high-risk cTnT-positive patients seem to benefit from a more aggressive antithrombotic treatment regimen. The underlying coronary pathology in cTnT-positive and -negative patients that explains the predictive power of cTnT on prognosis and response to antithrombotic therapy is largely unknown. METHODS: A total of 197 subsequently admitted patients with unstable angina pectoris underwent cTnT testing by a rapid bedside assay and early qualitative and quantitative angiography. Long-term follow-up was 12 months. RESULTS: Patients with cTnT-positive tests revealed more critical stenoses of culprit lesions (p =.041), more severe reductions of thrombolysis in myocardial infarction flow grades (p <.037), a higher prevalence of intracoronary thrombus (p =.079), and a poorer left ventricular function (p =.047). The odds ratio of cTnT was 5.8 (p <.0001) for presence of thrombus, reduced thrombolysis in myocardial infarction flow, and/or critical stenosis (>90%), and was 3.1 (p =.005) for presence of three-vessel disease, left main disease, and/or reduced left ventricular ejection fraction. Coronary bypass grafting was more frequently performed in the cTnT-positive group. However, event-free survival was not different in our cohort characterized by a high rate of percutaneous coronary interventions. CONCLUSIONS: A positive cTnT test in patients with unstable angina pectoris indicates presence of more severe coronary artery disease and poorer left ventricular function. This finding could explain the differences in short- and long-term outcome and treatment responses to antithrombotic regimens.     

Percutaneous transluminal coronary angioplasty and the changing indications for coronary artery bypass grafting for single-vessel coronary artery disease.

Patients with single-vessel coronary artery disease have a good long-term prognosis with either medical or surgical therapy. Because percutaneous transluminal coronary angioplasty has become widely available for treating patients with symptomatic single-vessel coronary artery disease, those who currently undergo coronary artery bypass grafting may be a select group. In this study, we examined the effects of the increasing use of percutaneous transluminal coronary angioplasty on the indications for coronary artery bypass grafting in patients with symptomatic single-vessel coronary artery disease and reviewed the type of procedures performed in such patients at our institution between 1983 and 1988. During this period, 115 patients underwent coronary artery bypass grafting for single-vessel coronary artery disease. The indication for revascularization was angina in 111 patients (88% were in class III or IV, Canadian Cardiovascular Society classification), acute myocardial infarction in 3, and a strongly positive result of an exercise test in 1. The number of surgical revascularization procedures annually for single-vessel coronary artery disease remained consistent throughout the study period. In a comparison of the first 3 years of the study with the last 3 years, the number of patients who underwent coronary artery bypass grafting for restenosis after coronary angioplasty increased, but the number who had surgical revascularization because of failure of coronary angioplasty decreased. In addition, more patients received internal mammary grafts during the second half of the study (42 or 72%) than during the first half (24 or 42%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary revascularization on balance: Robert L. Frye lecture.

The first generation of multicenter randomized controlled trials of coronary artery bypass surgery vs medical treatment in the 1970s found survival advantage only in patients with left main coronary artery disease or with multiple risk factors. Over time, these results have remained reproducible and biologically plausible and continue to be the basis for contemporary guidelines for bypass surgery. Percutaneous coronary intervention (PCI), which became available some 10 years after surgery, was compared with medical treatment in various clinical settings. Patients with stable angina receiving aggressive medical therapy had survival rates comparable to those undergoing PCI in several trials. In the presence of unstable angina, evidence suggests benefit from intervention after stabilization. In the setting of acute myocardial infarction or cardiogenic shock, PCI showed results superior to lytic therapy in centers with large PCI volume. A comparison of the 2 revascularization methods in the 1990s resulted in no overall 7-year survival difference except in patients with treated diabetes in whom bypass surgery prolonged life compared with angioplasty. None of the revascularizations had an effect on the incidence of myocardial infarctions, but importantly, the presence of bypass grafts reduced their fatal impact compared with both medical treatment and PCI. All revascularization trials reported improvement in quality of life, including symptoms, compared with less aggressive therapy. In the pursuit to explain 3 decades of steady decline of cardiovascular mortality in the United States, health economists attempted to model the decline due to availability of intervention by estimates obtained from contemporary randomized prevention and intervention trials. They concluded that, thus far, treatments have made a greater contribution to the decline than has primary prevention. Randomized trials not only contribute to evidence-based clinical practice, but also can reveal underlying biological mechanisms and provide quantitative data to model population trends. Thus, they should be regarded as the basic science of medical therapeutics and population health.     

冠心病患者纤溶系统的异常变化

目的探讨冠状动脉病变中血清纤维蛋白原（Fg）、组织型纤溶酶原激活物（t-PA）、血浆D-二聚体（D-Dimer）与血栓形成关系，并就其作用机理进行研究，为临床治疗提供科学依据。方法急性心肌梗死（AMI）组28例、不稳定心绞痛（UAP）组24例、稳定心绞痛（SAP）组30例和正常对照组20例。分别检测血清Fg、血浆D-Dimer、t-PA及其抑制物（PAI）活性，并对照比较其含量与冠状动脉粥样硬化血栓形成的关系。结果血浆t-PA活性：AMI和UAP明显低于SAP与健康对照组（P〈0．01）；AMI组和UAP组之间，SAP组与健康对照组之间差异无统计学意义（P〉0．05）。血浆PAI活性、D-Dimer和Fg含量：AMI和UAP组明显高于SAP和健康对照组（P〈0．01）；AMI组和UAP组之间，SAP组与健康对照组之间差异无统计学意义（P〉0．05）。结论监测冠状动脉粥样硬化患者血清中血清Fg含量、t-PA、D-Dimer含量，可以及时判断凝血和纤溶功能失衡状况，预防和干扰血栓形成，提高患者良性预后。     

Management of the post-myocardial infarction patient. Essential considerations

Management of patients who survive acute myocardial infarction (MI) demands the physician's awareness of certain essential considerations. Risk stratification, a useful prognostic indicator of mortality, should be done early in convalescence. If present, postinfarction angina or postinfarction syndrome warrants appropriate therapy. Low-level exercise testing should be under-taken within three weeks of acute MI, and left ventricular function should be assessed and arrhythmias delineated before the patient's discharge from the hospital. Findings may indicate the need for coronary bypass surgery or angioplasty, antiarrhythmic drug therapy, or permanent pacing. Digitalis should be used for treating congestive heart failure only if deemed absolutely necessary. If there are no contraindications, all postinfarction patients should receive beta blockers for at least two years after MI. Control of coronary risk factors is essential. Aspirin can be used prophylactically in patients at risk for recurrent MI; routine use of anticoagulants is not indicated.