[The Clinical use of Stress Echocardiography in Ischemic Heart Disease Cardiovascular Ultrasound (2017)15:7. Translation authors: Arystan A.Zh., Fettser D.V.]

Stress echocardiography is an established technique for the assessment of extent and severity of coronary artery disease. The combination of echocardiography with a physical, pharmacological or electrical stress allows detecting myocardial ischemia with an excellent accuracy. A transient worsening of regional function during stress is the hallmark of inducible ischemia. Stress echocardiography provides similar diagnostic and prognostic accuracy as radionuclide stress perfusion imaging or magnetic resonance, but at a substantially lower cost, without environmental impact, and with no biohazards for the patient and the physician. The evidence on its clinical impact has been collected over 35 years, based on solid experimental, pathophysiological, technological and clinical foundations. There is the need to implement the combination of wall motion and coronary flow reserve, assessed in the left anterior descending artery, into a single test. The improvement of technology and in imaging quality will make this approach more and more feasible. The future issues in stress echo will be the possibility of obtaining quantitative information translating the current qualitative assessment of regional wall motion into a number. The next challenge for stress echocardiography is to overcome its main weaknesses: dependence on operator expertise, the lack of outcome data (a widespread problem in clinical imaging) to document the improvement of patient outcomes. This paper summarizes the main indications for the clinical applications of stress echocardiography to ischemic heart disease.

Sulfido-peptide leukotrienes in coronary heart disease - relationship with disease instability and myocardial ischaemia.

BACKGROUND: Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate. METHODS AND RESULTS: Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9). CONCLUSIONS: In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

Combined low dose dipyridamole-dobutamine stress echocardiography to identify myocardial viability.

OBJECTIVES: We sought to evaluate the effects of combined administration of infra-low dose dipyridamole and low dose dobutamine on assessment of myocardial viability. BACKGROUND: Low dose pharmacologic stress echocardiography with either dobutamine or dipyridamole infusion has been proposed for the recognition of myocardial viability. METHODS: Thirty-four patients with rest wall motion dyssynergy by two-dimensional echocardiography and with angiographically proved coronary artery disease underwent in combination with two-dimensional echocardiographic monitoring: 1) low dose (5 to 10 microgram/kg per min over 3 min) dobutamine infusion; 2) infra-low dose (0.28 mg/kg over 4 min) dipyridamole infusion; 3) combination of infra-low dose dipyridamole infusion immediately followed by low dose dobutamine infusion (combined dipyridamole-dobutamine). RESULTS: Follow-up rest echocardiography was available in 30 patients. After revascularization, 82 segments showed a contractile improvement of > or = 1 grade, whereas 63 segments remained unchanged. The sensitivity of dobutamine, dipyridamole and combined dipyridamole-dobutamine for predicting recovery was 72% (95% confidence interval [CI] 60.9% to 81.3%), 67% (CI 55.8% to 77%) and 94% (CI 86.3% to 97.9%), respectively. The specificity of dipyridamole, dobutamine and combined dipyridamole-dobutamine was 95% (CI 86.7% to 99%), 92% (CI 82.4% to 97.3%) and 89% (CI 78.4% to 95.4%), respectively. The accuracy of the dobutamine, dipyridamole and combined dipyridamole-dobutamine test was 80%, 79% and 92%, respectively (combined dipyridamole-dobutamine vs. dobutamine, p < 0.05; combined dipyridamole-dobutamine vs. dipyridamole, p < 0.01). CONCLUSIONS: Infra-low dose dipyridamole added to low dose dobutamine recruits an inotropic reserve in asynergic segments that were nonresponders after either dobutamine or dipyridamole alone and destined to recover after revascularization.

Flow-function relation in patients with chronic coronary artery disease and reduced regional function. A positron emission tomographic and two-dimensional echocardiographic study with coronary vasodilator stress.

OBJECTIVES: We sought to elucidate the flow-function relation in chronic postischemic dysfunction during vasodilator stress. BACKGROUND: In patients with ischemia and regional dysfunction, stress echocardiography can elicit three responses in the dysfunctioning segments: no change, improvement or worsening. The physiology underlying these responses is unclear. METHODS: Seventeen patients with ischemia and left ventricular dysfunction underwent evaluation of regional function by two-dimensional echocardiography and myocardial blood flow by positron emission tomography and 13N-ammonia. Flow (ml/min per g) and function (regional wall motion score [RWMS] from 1 = normal to 4 = dyskinetic) were evaluated both at rest and after dipyridamole (0.56 mg/kg body weight over 4 min). RESULTS: In 45 normal segments, rest to dipyridamole flow increased from 0.83 +/- 0.22 (mean +/- 1 SD) to 1.87 +/- 0.90 (p < 0.01) with a hyperkinetic contraction pattern. Among dysfunctioning segments, responders (n = 11) showed an upsloping flow-function curve during stress (i.e., increased function [RWMS rest 2.5 +/- 0.5 vs. dipyridamole 1.2 +/- 0.4] and increased flow [rest 0.69 +/- 0.30 vs. dipyridamole 1.89 +/- 1.43, p < 0.01]); nonresponders (n = 20) had a flat flow-function curve during dipyridamole (i.e., fixed function [RWMS rest and dipyridamole 2.6 +/- 0.5] and no flow increase [rest 0.64 +/- 0.24 vs. dipyridamole 0.87 +/- 0.51, p = NS): Ischemic segments (n = 9) exhibited a downsloping flow-function curve during dipyridamole (i.e., worsened function [RWMS rest 2 +/- 0.5, dipyridamole 3.1 +/- 0.6] and no significant flow change [rest 0.67 +/- 0.29 vs. dipyridamole 0.79 +/- 0.23, p = NS]). CONCLUSIONS: Myocardial segments with rest dysfunction and a contractile reserve elicitable by a vasodilator stress more often exhibit residual flow reserve, whereas segments with a fixed or worsening mechanical response during stress show a flat flow response.

Stress echocardiographic results predict risk of reinfarction early after uncomplicated acute myocardial infarction: large-scale multicenter study. Echo Persantine International Cooperative (EPIC) Study Group.

OBJECTIVES: This study sought to assess the value of dipyridamole echocardiography in predicting reinfarction in patients evaluated early after uncomplicated acute myocardial infarction. BACKGROUND: The identification of future nonfatal reinfarction seems an elusive target for physiologic testing. However, a large sample population is needed to detect minor differences in phenomena with a low event rate. METHODS: We assessed the value of dipyridamole echocardiography in predicting reinfarction in 1,080 patients (mean [+/- SD] age 56 +/- 9 years; 926 men, 154 women) evaluated early (10 +/- 5 days) after uncomplicated acute myocardial infarction and followed up for 14 +/- 10 months. RESULTS: Submaximal studies due to limiting side effects occurred in 14 patients (1.3%); these test results were included in the analysis. Results of dipyridamole echocardiography were positive in 475 patients (44%). During follow-up, there were 50 reinfarctions: 45 nonfatal, 5 fatal (followed by cardiac death < or = 4 days after reinfarction). Reinfarction (either nonfatal or fatal) occurred in 30 patients with positive and 20 with negative results (6.3% vs. 3.3%, p < 0.01). Nonfatal reinfarction occurred in 25 patients with positive and 20 with negative results (5% vs. 3.3%, p < 0.05). Reinfarction was fatal in 5 of 30 patients with positive and in none of 20 with negative results (16.6% vs. 0%, p = 0.07). The relative risk of reinfarction was 1.9. CONCLUSIONS: Dipyridamole echocardiographic positivity identifies patients evaluated early after uncomplicated acute myocardial infarction at higher risk of reinfarction, especially fatal reinfarction.

Prognostic value of dobutamine-atropine stress echocardiography early after acute myocardial infarction. Echo Dobutamine International Cooperative (EDIC) Study.

OBJECTIVES: The aim of this multicenter, multinational, prospective, observational study was to assess the relative value of myocardial viability and induced ischemia early after uncomplicated myocardial infarction. BACKGROUND: Dobutamine-atropine stress echocardiography allows evaluation of rest function (at baseline), myocardial viability (at low dose) and residual ischemia (peak dose, up to 40 micrograms with atropine up to 1 mg) in one test. METHODS: Dobutamine-atropine stress echocardiography was performed 12 +/- 5 days (mean +/- SD) after a first uncomplicated acute myocardial infarction in 778 patients (677 men; mean age 58 +/- 10 years) with technically satisfactory rest echocardiographic study results. Patients were followed-up for 9 +/- 7 months. RESULTS: Dobutamine-atropine stress echocardiographic findings were positive for myocardial ischemia in 436 of patients (56%) and negative in 342 (44%). During follow-up, there were 14 cardiac-related deaths (1.8% of the total cohort), 24 (2.9%) nonfatal myocardial infarctions and 63 (8%) hospital readmissions for unstable angina. One hundred seventy-four patients (22%) underwent coronary revascularization (bypass surgery or coronary angioplasty). Spontaneous events occurred in 61 of 436 patients with positive and 40 of 342 patients with negative findings on dobutamine-atropine stress echocardiography (14% vs. 12%, p = 0.3). When only spontaneously occurring events were considered, the most important predictor was myocardial viability (chi-square 9.7). Using the Cox proportional hazards model, only the presence of myocardial viability (hazard ratio [HR] 2.0, p < 0.002) and age (HR 1.03, p < 0.001) were predictive of spontaneously occurring events. When only hard cardiac events were considered, age was the strongest predictor (chi-square 3.6, p = 0.056), followed by wall motion score index (WMSI) at peak dose (chi-square 3.3, p = 0.06) and remote ischemia (chi-square 2.25, p = 0.1). When cardiac death was considered, WMSI at peak dose was the best predictor (HR 9.2, p < 0.0001). CONCLUSIONS: During dobutamine stress, echocardiographic recognition of myocardial viability is more prognostically important than echocardiographic recognition of myocardial ischemia for predicting unstable angina, whereas WMSI at peak stress was the best predictor of cardiac-related death. Different events can be recognized with different efficiency by various stress echocardiographic variables.

Does stress echocardiography predict the site of future myocardial infarction? A large-scale multicenter study. EPIC (Echo Persantine International Cooperative) and EDIC (Echo Dobutamine International Cooperative) study groups.

OBJECTIVES: We sought to assess whether the site of future myocardial infarction can be predicted on the basis of induced dyssynergy ("area at risk") recognized by stress echocardiography. BACKGROUND: The severity and extent of stress-induced dyssynergy are strong predictors of subsequent major cardiac events. However, high grade stenotic lesions are not strictly associated with the site of future coronary occlusions. METHODS: From the stress echocardiography multicenter trials data bank, we selected 70 patients (56 men; mean age +/- SD 58 +/- 11 years) meeting the following inclusion criteria: 1) dipyridamole (n = 53) or dobutamine (n = 17) stress echocardiography; 2) a spontaneously occurring infarction, with no intercurrent revascularization procedure between the initial study and the infarction; and 3) a follow-up rest echocardiogram obtained 41 +/- 90 days after the infarction. RESULTS: A complete ischemia-infarction mismatch (infarct-related dysfunction in a patient with negative stress test results) occurred in 29 patients (41%). A partial mismatch (ischemic dysfunction in a territory different from the infarct area) occurred in nine patients (13%). A match (ischemia-related and infarction-related dyssynergy involving the same region) occurred in 32 patients (46%). The average time interval between the stress examination and the occurrence of infarction or reinfarction was 144 +/- 160 days in patients with a match and 439 +/- 622 days in patients with a mismatch (p < 0.05). CONCLUSIONS: Induced ischemia (imaged as transient dyssynergy by pharmacologic stress echocardiography) inconsistently identifies the site of future infarction. The majority of spontaneous coronary occlusions leading to infarction are unheralded by induced ischemia. However, most infarctions occurring within 1 year of stress testing are in the area identified as ischemic during testing.

The atropine factor in pharmacologic stress echocardiography. Echo Persantine (EPIC) and Echo Dobutamine International Cooperative (EDIC) Study Groups.

OBJECTIVES: This study sought to compare, head to head, the two most popular pharmacologic stress echocardiographic tests--dipyridamole and dobutamine--with state of the art protocols in a large multicenter prospective study. BACKGROUND: In the continuing quest for ideal diagnostic accuracy, pharmacologic stress echocardiography has quickly moved over the years from low to high dose regimens and is currently performed with atropine coadministration. METHODS: Dobutamine (up to 40 microgram/kg body weight per min) plus atropine (up to 1 mg over 4 h) and dipyridamole (up to 0.84 mg/kg per min over 10 h) plus atropine (up to 1 mg over 4 h) stress echocardiography was performed on different days, in random order and within 1 week in 360 patients with chest pain syndrome. Thirteen different echocardiographic laboratories, all fulfilling quality control criteria for stress echocardiographic reading, contributed to the study. RESULTS: No major complications occurred during either test. The test was interrupted before achievement of predetermined end points for limiting side effects in 37 dobutamine-atropine and 7 dipyridamole-atropine stress echocardiographic studies (feasibility 90% vs. 98%, p < 0.01). Diagnostic accuracy was assessed in a subset of 110 patients with no obvious rest dyssynergy (akinesia or dyskinesia) who underwent coronary angiography independently of test results and within 1 week of testing. Significant coronary artery disease (> or = 50% diameter reduction in at least one major coronary vessel by quantitative coronary angiography) was found in 92 patients. Sensitivity for detection of coronary artery disease was 84% (77 of 92) for dobutamine-atropine and 82% (75 of 92) for dipyridamole-atropine stress echocardiography (p = NS), with a specificity of 89% (16 of 18) for dobutamine-atropine and 94% (17 of 18) for dipyridamole-atropine stress echocardiography (p = NS). A significant correlation was present between peak wall motion score index during dipyridamole-atropine and dobutamine-atropine stress echocardiography (r = 0.83, p < 0.0001). CONCLUSIONS: Dobutamine-atropine and dipyridamole-atropine stress echocardiography are safe and feasible, although submaximal studies are more frequent with dobutamine. The two stresses have comparable accuracy in the detection of angiographically assessed coronary artery disease, although dobutamine is marginally more sensitive and dipyridamole marginally more specific. Stratification of the ischemic response in the space domain is also comparable with the two stresses.

Stress echocardiography.

Stress echocardiography is the combination of 2D echocardiography with a physical, pharmacological or electrical stress. The diagnostic end point for the detection of myocardial ischemia is the induction of a transient worsening in regional function during stress. Stress echocardiography provides similar diagnostic and prognostic accuracy as radionuclide stress perfusion imaging, but at a substantially lower cost, without environmental impact, and with no biohazards for the patient and the physician. Among different stresses of comparable diagnostic and prognostic accuracy, semisupine exercise is the most used, dobutamine the best test for viability, and dipyridamole the safest and simplest pharmacological stress and the most suitable for combined wall motion--coronary flow reserve assessment. The additional clinical benefit of myocardial contrast echocardiography, tissue Doppler imaging and real time 3-D echocardiography has been inconsistent and disappointing, whereas the potential of adding coronary flow reserve evaluation of left anterior descending coronary artery by transthoracic Doppler echocardiography adds another potentially important dimension to stress echocardiography. In spite of its dependence upon operator's training, stress echocardiography is today the best possible imaging choice to achieve the still elusive target of sustainable cardiac imaging in the field of noninvasive diagnosis of coronary artery disease.

Benefit/risk profile of combined antiplatelet therapy with ticlopidine and aspirin.

Ticlopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 microM; adrenaline 0.75-2.5 microM; collagen 1.5-150 micrograms/ml; arachidonic acid 1 mM; PAF 1 microM; adrenaline 0.17 microM + ADP 0.62 microM; serum thromboxane [( TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p less than 0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean +/- SEM: T: 95 +/- 3; ASA: 96 +/- 5; T + ASA: 89 +/- 4).(ABSTRACT TRUNCATED AT 250 WORDS)

The d-enantiomer form of indobufen totally accounts for the anti-cyclooxygenase and antiplatelet activity ex vivo and for the increase in bleeding time by indobufen in man.

Indobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean +/- S.D., 58.7 +/- 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 +/- 3% for both treatments). At 12 h inhibition was 87 +/- 6% for d-indobufen and 88 +/- 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiographically assessed coronary collateral circulation increases vulnerability to myocardial ischemia during vasodilator stress testing.

In patients with a major coronary vessel occluded, the presence of good coronary collateral circulation increases vulnerability to myocardial ischemia induced by pharmacologic coronary vasodilation. The presence of good collaterals results in a greater frequency, severity, and extent of dipyridamole-induced regional left ventricular dysfunction, consistent with the hypothesis of angiographically assessed collaterals facilitating "steal phenomena" during dipyridamole-induced coronary vasodilation.

Comparison of combination of dipyridamole and dobutamine during echocardiography with thallium scintigraphy with thallium scintigraphy to improve viability detection.

The aim of this study was to investigate the relation between radioisotopic and echocardiographic markers of myocardial viability and their correlation with functional recovery after coronary revascularization. Myocardial viability can be detected by techniques exploring various aspects of cell physiology: thallium-201 scintigraphy and dobutamine and dipyridamole echocardiography focus on cell membrane integrity, beta-1 and adrenoceptor, and A2-adenosine receptor-mediated inotropic response, respectively. Fifty-seven patients (mean age 60+/-8 years) with previous myocardial infarction (>3 months), angiographically assessed coronary artery disease, and resting regional dysfunction underwent rest-redistribution 201-thallium scintigraphy and low-dose pharmacologic stress echo with dobutamine (up to 10 microg/kg/min), very low dose regimen of dipyridamole (0.28 mg/kg over 4 minutes), and combined dipyridamole-dobutamine. Criteria for viability in a 13-segment model for both techniques were percent peak activity in redistribution images >55% for thallium-201 and a decrease in wall motion score >1 grade (1 [normal] to 4 [dyskinetic]) for stress echo. Thirty patients underwent coronary revascularization (bypass surgery in 8, angioplasty in 22) and were followed up at 4 weeks from intervention with a resting echocardiogram. The rate of agreement between thallium-201 and stress echo was 63% for dipyridamole, 66% for dobutamine, and 74% for combined dipyridamole-dobutamine (p <0.05 vs dipyridamole and dobutamine). In the 30 patients who underwent revascularization, a regional resting dyssynergy was observed in 225 segments, assuming that postrevascularization functional recovery (which occurred in 126 segments) was the gold standard; combined dipyridamole-dobutamine showed a higher sensitivity (90% confidence interval [CI] 85% to 95%) than thallium-201, dobutamine, or dipyridamole (87%, CI 81% to 92%; 82%, CI 76% to 89%; and 82%, CI 76% to 89%, respectively). Specificity was lower for viability recognition with thallium-201 (61%, CI 51% to 71%) than with dobutamine (93%, CI 88% to 98%), dipyridamole (95%, CI 91% to 99%), and combined dipyridamole-dobutamine (92%; CI 87% to 97%). Combined adrenergic and adenosinergic stimulation recruits an inotropic reserve in a significant proportion of segments with preserved thallium uptake that were nonresponders after either dipyridamole or dobutamine. When functional recovery after successful revascularization is considered as the postoperative gold standard, thallium has a higher sensitivity than dipyridamole or dobutamine; this sensitivity gap is filled with combined dipyridamole-dobutamine. The specificity of all forms of pharmacologic stress echo is better than thallium-201.

Relative role of coronary stenosis severity and morphology in determining pharmacologic stress echo positivity.

Angiographically assessed plaque morphology, not only plaque severity, may affect myocardial vulnerability to ischemia during stress testing. The aim of this study was to evaluate directly, in a head-to-head comparison, the relation between coronary stenosis severity and morphology and pharmacologic stress echo response. From our inpatients echo databank, we selected 68 patients (62 men, mean age 57 +/- 9 years) who had undergone high-dose dipyridamole and high-dose dobutamine-atropine echocardiography, performed within 1 week and in random order, before coronary angiography that showed significant coronary artery disease by selection. There were altogether 121 vessels with visually assessed stenosis >50% in 68 patients. Thirty-three had complex-type and 56 simple-type lesions (according to the Ambrose classification), whereas 32 vessels were occluded. During dobutamine echocardiography there were 51 dyssynergic regions of the left ventricle fed by different coronary arteries in 50 patients and dipyridamole stress was able to induce ischemia in 45 separate regions in 44 patients. The overall agreement between the 2 tests in recognizing ischemia was 76%. Induced ischemia was associated with greater quantitatively assessed stenosis severity for both dipyridamole (positive, 70 +/- 12% vs negative, 63 +/- 12% area reduction; p <0.05) and dobutamine (positive, 68 +/- 12% vs negative, 63 +/- 12% area reduction; p <0.05). The simple-type stenosis was more frequently identified with dobutamine (46%) versus dipyridamole (21%, [p <0.01]), whereas the complex-type stenosis was associated with a trend toward more frequent positivity of dipyridamole (55%) versus dobutamine (36%), p = 0.13. Adenosinergic stress positivity is affected not only by plaque severity, but also by plaque morphology, whereas adrenergic stress positivity is affected by plaque severity, not by plaque morphology.

Macrophage-specific eicosanoid synthesis inhibition and lipocortin-1 induction by glucocorticoids.

It has been suggested that the induction of lipocortin-1, a phospholipase A2-inhibitory protein, may mediate the anti-inflammatory action of glucocorticoids. We assessed the production of prostaglandin E2, thromboxane B2, and leukotriene B4 and the expression of lipocortin-1 in different populations of blood leukocytes and in alveolar macrophages (obtained by bronchoalveolar lavage) from patients with inflammatory lung diseases (bronchial asthma, n = 21; interstitial lung disease, n = 6) undergoing glucocorticoid treatment at clinically effective doses. No inhibition of eicosanoid production was observed in either whole blood or single populations of blood leukocytes (granulocytes and monocytes) stimulated with ionophore A-23187, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, or zymosan. Conversely, eicosanoid production from alveolar macrophages (assessed in 9 cases) was significantly inhibited by glucocorticoids. After ionophore stimulation, eicosanoid production was as follows (in ng/ml): prostaglandin E2, 0.19 +/- 0.06 and 0.06 +/- 0.01; thromboxane B2, 2.9 +/- 0.9 and 0.5 +/- 0.1; leukotriene B4, 6.6 +/- 1.1 and 3.6 +/- 1.0, before and after treatment, respectively (P < 0.05 for all differences). Lipocortin-1 expression, determined by Western blot and enzyme immunoassay, was significantly (P < 0.05) stimulated in alveolar macrophages, but not in blood leukocytes, by glucocorticoid treatment. These results indicate that alveolar macrophages, at variance from blood leukocytes, are the most likely cell target for glucocorticoid-induced eicosanoid inhibition and lipocortin expression. We suggest that cell responsiveness to glucocorticoids is acquired during differentiation from monocyte to tissue macrophage.

High dose dipyridamole myocardial imaging: simultaneous sestamibi scintigraphy and two-dimensional echocardiography in the detection and evaluation of coronary artery disease. Italian Group of Nuclear Cardiology.

BACKGROUND: Dipyridamole stress combined with echocardiography or perfusion scintigraphy can be used to detect coronary artery disease, but head-to-head comparative data are lacking. The aim of this study was to compare the relative accuracy of high-dose dipyridamole stress imaging (up to 0.84 mg/kg over 10 min) with two-dimensional echocardiography and sestamibi perfusion scintigraphy in detecting coronary artery disease. METHODS: One-hundred and one patients with a history of chest pain and no previous myocardial infarction, were studied simultaneously using planar perfusion scintigraphy and echocardiography during a high-dose dipyridamole stress, at seven different institutions. RESULTS: During coronary angiography, 21 patients had non-significant lesions, and 80 had significant lesions (> or = 50% diameter reduction): 37 had single-, 19 double- and 24 triple-vessel disease. Sensitivity for disease detection was 78% [95% confidence interval (CI) 67-86%] for echocardiography and 79% (CI 68-87%) for scintigraphy. The specificity was 76% (CI 67-84%) for echocardiography and 90% (CI 83-95%) for scintigraphy. The inter-center variation in accuracy ranged from 50 to 100% for echocardiography (coefficient of variation 19.7%) and from 71 to 100% for scintigraphy (coefficient of variation 15%). The angiographically assessed extent and severity of coronary artery disease, evaluated using the Duke score, was correlated to the extent and severity of perfusion defects with scintigraphy (r = 0.65, P < 0.0001) and regional wall motion abnormalities by echocardiography (r = 0.57, P < 0.0001). CONCLUSIONS: Perfusion scintigraphy and echocardiography have similar accuracies for the non-invasive identification of angiographically assessed coronary artery disease during high-dose dipyridamole stress. Inter-center variability in diagnostic accuracy is higher for echocardiography than scintigraphy. Both methods allow a reasonably accurate estimation of extent and severity of disease, via a semiquantitative assessment of extent and severity of perfusion of functional defects.

Dipyridamole stress echocardiography.

Dipyridamole stress is the forerunner and prototype of pharmacological stress echo tests in the diagnosis of coronary artery disease. The safety of this test has been conclusively demonstrated as a result of extensive experience in large-scale multicenter projects. The diagnostic accuracy of dipyridamole stress echo is comparable to dobutamine and largely a function of the employed dose. Higher dosages (up to 0.84 mg/kg) are being required to achieve good sensitivity. The prognostic value has been shown to be independent and additive to clinical, exercise echocardiogram, and angiographic data. The test positive response should be titrated on the basis of severity, extent, and timing of induced dyssynergy with low positivity being associated to more anatomically and functionally severe forms of disease. Multicenter, randomized, prospective, international studies on cost-effectiveness directly comparing a noninvasive strategy centered on stress echo versus an invasive strategy centered on coronary angiography are currently ongoing.

Quantitative assessment of coronary atherosclerotic plaque profile by morphometric analysis of angiographic images.

Coronary plaque morphology (simple or complex) has a recognized clinical, pathophysiologic, and prognostic importance, but its routine use is hampered by the subjective and qualitative nature of the assessment. The aim of this study was to assess the feasibility and accuracy of mathematical, objective, operator-independent assessment of plaque morphology, by means of algorithms based on vector and fractal analysis, previously developed for describing continuous curves. Twenty coronary angiograms were analyzed: 10 with "simple-type" stenosis (defined according to Ambrose type I pattern, Group I) and 10 with "complex-type" stenosis (Ambrose type II pattern, Group II). Five morphometric parameters effectively separated simple and complex-type stenosis: peaks/cm (Group I = 0.24 +/- 0.31 vs Group II = 2.46 +/- 1.83, P < .01); summed maximum error/cm (I = 0.94 +/- 1.19 vs II = 4.53 +/- 0.56, P < .01); integrated error/cm (I = 0.22 +/- 0.27 vs II = 2.25 +/- 1.68, P < .01); number of features/cm (I = 0.02 +/- 0.05 vs II = 1.19 +/- 0.65, P < .01); standard deviation curvature (I = 0.07 +/- 0.01 vs II = 0.22 +/- 0.21, P = 0.06). The scaled edge-length ratio-the only parameter based on fractal analysis-was not different between the two groups (I = 1.03 +/- 0.01 vs II = 1.13 +/- 0.10, P = ns). Hence, a quantitative description of plaque morphology is feasible and allows an effective discrimination of simple and complex plaque profiles with morphometric parameters based on vector analysis.

Studies on the induction of lipocortin-1 by glucocorticoids.

Part of the anti-inflammatory efficacy of glucocorticoids has been ascribed to the inhibition of eicosanoid formation which is brought about by lipocortins (LC, phospholipase A2 inhibitory proteins) whose synthesis is induced by corticosteroids. We have investigated the effect of glucocorticoids on eicosanoid formation and lipocortin-1 induction in a human cell line in vitro and in patients with inflammatory lung disease in vivo. Human promyelocitic U-937 cell line was differentiated by 24 h incubation with phorbol myristate acetate (PMA, 6 ng/ml), then dexamethasone (1 microM) was added for further 16 h. In these conditions the steroid treatment caused both the release of lipocortin-1 in the cellular supernatant and the inhibition of eicosanoid release. These results suggest that the responsiveness of these cells to steroids is dependent on the phase of cell activation-differentiation. The selective release of the lipocortin-1 may explain the inhibition of eicosanoid formation. Patients with inflammatory lung disease underwent glucocorticoid treatment at clinically effective doses. LC-1 expression was significantly stimulated in alveolar macrophages, but not in blood-derived lympho-monocytes. These results suggest that also in vivo cell responsiveness to glucocorticoids is acquired during cell differentiation from blood monocyte to tissue macrophage.

Cardiovascular function in healthy Himalayan high-altitude dwellers.

BACKGROUND: Residents of the Himalayan valleys uniquely adapted to their hypoxic environment in terms of pulmonary vasculature, but their systemic vascular function is still largely unexplored. The aim of the study was to investigate vascular function and structure in rural Sherpa population, permanently living at high altitude in Nepal (HA), in comparison with control Caucasian subjects (C) living at sea level. METHODS AND RESULTS: 95 HA and 64 C were enrolled. Cardiac ultrasound, flow-mediated dilation (FMD) of the brachial artery, carotid geometry and stiffness, and aortic pulse wave velocity (PWV) were performed. The same protocol was repeated in 11 HA with reduced FMD, after 1-h 100% O2 administration. HA presented lower FMD (5.18 ± 3.10 vs. 6.44  ±  2.91%, p = 0.02) and hyperemic velocity than C (0.61 ± 0.24 vs. 0.75 ± 0.28 m/s, p = 0.008), while systolic pulmonary pressure was higher (29.4 ± 5.5 vs. 23.6 ± 4.8 mmHg, p < 0.0001). In multiple regression analysis performed in HA, hyperemic velocity remained an independent predictor of FMD, after adjustment for baseline brachial artery diameter, room temperature and pulse pressure, explaining 8.7% of its variance. On the contrary, in C brachial artery diameter remained the only independent predictor of FMD, after adjustment for confounders. HA presented also lower carotid IMT than C (0.509 ± 0.121 vs. 0.576 ± 0.122 mm, p < 0.0001), higher diameter (6.98 ± 1.07 vs. 6.81 ± 0.85 mm, p = 0.004 adjusted for body surface area) and circumferential wall stress (67.6 ± 13.1 vs. 56.4 ± 16.0 kPa, p < 0.0001), while PWV was similar. O2 administration did not modify vascular variables. CONCLUSIONS: HA exhibit reduced NO-mediated dilation in the brachial artery, which is associated to reduced hyperemic response, indicating microcirculatory dysfunction. A peculiar carotid phenotype, characterized by reduced IMT and enlarged diameter, was also found.