Increased circulating monocyte activation in patients with unstable coronary syndromes.

OBJECTIVES: The primary objective of this research was to assess the activation level of circulating monocytes in patients with unstable angina. BACKGROUND: Markers of systemic inflammatory responses are increased in patients with unstable coronary syndromes, but the activation state and invasive capacity of circulating monocytes have not been directly assessed. METHODS: Peripheral blood mononuclear cell (MC) activation in blood samples isolated from patients with stable and unstable coronary artery disease was measured in two studies. In study 1, a modified Boyden chamber assay was used to assess spontaneous cellular migration rates. In study 2, optical analysis of MC membrane fluidity was correlated with soluble CD14 (sCD14), a cellular activation marker. RESULTS: Increased rates of spontaneous monocyte migration (p < 0.01) were detected in patients with unstable angina (UA) (Canadian Cardiovascular Society [CCS] angina class IV) on comparison to patients with acute myocardial infarction (MI), stable angina (CCS angina classes I to III) or normal donors. No significant increase in lymphocyte migration was detected in any patient category. Baseline MC membrane fluidity measurements and sCD14 levels in patients with CCS class IV angina were significantly increased on comparison with MCs from normal volunteers (p < 0.001). A concomitant reduction in the MC response to activation was detected (p < 0.05). CONCLUSIONS: Using two complementary assays, activated monocytes with increased invasive capacity were detected in the circulation of patients with unstable angina. This is the first demonstration of increased monocyte invasive potential in unstable patients, raising the issue that systemic inflammation may both reflect and potentially drive plaque instability.

Fluorescence spectroscopic analysis of circulating platelet activation during coronary angioplasty.

BACKGROUND AND OBJECTIVE: Platelet activation during percutaneous transluminal coronary angioplasty (PTCA) initiates thrombus formation and plaque regrowth at sites of arterial injury, limiting procedure efficacy. We have developed a simple assay for circulating platelet activation based on fluorescence analysis of membrane fluidity and intracellular calcium concentration and light scattering analysis of platelet aggregation. STUDY DESIGN/MATERIALS AND METHODS: Platelet activation state was measured in 45 patients undergoing angioplasty, before and after treatment with platelet inhibitors. RESULTS: PTCA alone produced a decrease in pyrene dimer formation (P0.0083) and an increase in light scattering at 650 nm (P0.0128). Treatment with ADP and GPIIb/IIIa receptor antagonists reduced PTCA induced changes in pyrene dimer formation. An unexpected decrease in pyrene dimer formation (P0.05) was detected when the GPIIb/IIIa receptor antagonist was given together with an ADP receptor antagonist. CONCLUSIONS: 1) Analysis of membrane fluidity provides a sensitive marker for platelet activation state. 2) Reduced membrane fluidity after combined platelet inhibitor treatments suggests reduced antiplatelet efficacy.

RAVECAB: improving outcome in off-pump minimal access surgery with robotic assistance and video enhancement.

OBJECTIVE: To determine the efficacy of using the harmonic scalpel and robotic assistance to facilitate thoracoscopic harvest of the internal thoracic artery (ITA). DESIGN: A case series. SETTING: London Health Sciences Centre, University of Western Ontario, London, Ont. PATIENTS AND METHODS: Fifteen consecutive patients requiring harvest of the ITA for coronary artery bypass grafting. INTERVENTION: Robot-assisted, video-enhanced coronary artery bypass (RAVECAB) through limited-access incisions, using the harmonic scalpel and a voice-activated robotic assistant. MAIN OUTCOME MEASURES: Ease and duration of the harvesting technique, complications of the procedure, graft flow and patency, and duration of postoperative hospitalization. RESULTS: RAVECAB facilitated thoracoscopic dissection of the ITA with the harmonic scalpel in all cases. There were no conversions to a standard approach and no reoperations for bleeding. The mean (and standard deviation) ITA harvest time was 64.1 (22.9) minutes (range from 40 to 118 minutes). Robotic voice command capture rate was greater than 95%. Mean (and SD) intraoperative graft flows were 33.1 (26.8) mL/min (range from 14 to 126 mL/min). There was 100% graft patency on postoperative angiography. There were no deaths, perioperaive myocardial infarction or arrhythmias. Mean (and SD) postoperative hospitalization was 3.3 (0.8) days. CONCLUSIONS: RAVECAB is a demanding procedure that addresses many of the disadvantages of the "conventional" minimally invasive coronary artery bypass. It allows complete pedicle dissection with minimal ITA manipulation and assures sufficient conduit length and a tension-free coronary artery anastomosis. All anastomoses were performed under direct vision through a 5- to 8-cm inferior mammary incision.

Robot-assisted computer enhanced closed-chest coronary surgery: preliminary experience using a Harmonic Scalpel and ZEUS.

BACKGROUND: Successful endoscopic harvesting of arterial conduits is critical to the performance of totally endoscopic bypass grafting. Recent success with computer-enhanced robotic systems in the performance of endoscopic single vessel coronary artery bypass (ENDOCAB) has paved the way for developing techniques for multivessel ENDOCAB. The Harmonic Scalpel (Ethicon Endo-Surgery, Cincinnati, OH) has previously demonstrated versatility and efficacy in manual endoscopic internal thoracic artery (ITA) harvesting. This study was undertaken to determine the feasibility of adapting this technology to a robotic telemanipulation system and its safety and efficacy in telerobotic ITA harvesting. METHODS: The Harmonic Scalpel was adapted to the ZEUS robotic surgical system (Computer Motion, Goleta, CA) and used to harvest the ITA in 19 patients undergoing multivessel off-pump coronary artery bypass (OPCAB) surgery. With the left lung collapsed, the ITA was harvested in all patients with CO2 insufflation through three 5 mm ports in the left chest. Postoperative angiography and transthoracic Doppler studies were performed in all patients. RESULTS: There were no ITA injuries and patients tolerated insufflation without hemodynamic compromise. Side branches were controlled easily without bleeding. Average ITA harvest time was 65 +/- 21 minutes. All vessels were patent after harvesting and demonstrated no angiographic evidence of injury. CONCLUSIONS: This paper demonstrates a technique by which the Harmonic Scalpel can be readily adapted to the ZEUS robotic telemanipulation system. Using this system, ITA's can be safely harvested totally endoscopically within a reasonable time frame for patients undergoing ENDOCAB.

Combination (multiple) testing for myocardial infarction using myoglobin, creatine kinase-2 (mass), and troponin T.

We retrospectively determined the mass concentrations of myoglobin, creatine kinase-2 (CK-2), and troponin T in serial samples from 80 patients with confirmed myocardial infarction (MI) and 60 non-MI patients. Results from receiver operating characteristic curve analyses show that all three tests are comparable in their diagnostic utility within the first 12 h of infarction. Decision thresholds were selected at a constant rule-in specificity of 95% and rule-out sensitivities of 95% at, respectively, 3-6, 6-9, and 9-12 h intervals after the onset of symptoms. Test sensitivities and specificities were compared for each, used as: a single test; two-test parallel combination; three-test parallel combination; two-test series combination; and three-test series combination. Our results from combination testing indicate what for the early diagnosis of MI, a single serum myoglobin measurement has diagnostic utility at 3 h after the onset of symptoms, and myoglobin and CK-2 (mass) in combination later than 3 h following the onset of symptoms. Serum troponin T is diagnostically similar to CK-2 (mass), although it has superior cardiac-tissue specificity, but it is not as yet commercially available as a "stat" test. Therefore, we recommend using troponin T as a confirmatory test 9 h after the onset of MI. Based on our findings, we suggest a testing algorithm for the early biochemical diagnosis of MI.

Diagnostic evaluation of creatine kinase-2 mass and creatine kinase-3 and -2 isoform ratios in early diagnosis of acute myocardial infarction.

The diagnostic efficacy of creatine kinase (CK) isoforms (CK-3 and CK-2) was compared with measurement of CK-2 mass concentrations for the early diagnosis of myocardial infarction (MI). Serial serum samples drawn from 76 patients with confirmed MI and 55 non-MI patients were used for determining CK-2 mass concentrations and the MM3/MM1 (CK-3 isoforms) and MB2/MB1 (CK-2 isoforms) ratios. We compared the diagnostic utility of each by receiver-operating-characteristic (ROC) curve and likelihood ratio analyses. Our results indicate that all three tests were ineffective within the first 4 h after the onset of chest pain. All three were most effective at 4-18 h after onset, but both CK-3 and CK-2 isoform ratios were less effective than CK-2 mass concentrations in the next 6-h period (18-24 h). In the critical time between 3 and 6 h, the diagnostic performance of all three was comparable.

Comparison of the diagnostic utility of timed serial (slope) creatine kinase measurements with conventional serum tests in the early diagnosis of myocardial infarction.

We compared the diagnostic utility of recently proposed slope assays for serum creatine kinase and creatine kinase-2 with the optimized decision threshold assays. The former approach has been claimed to be superior to any other single diagnostic technique. We show, by ROC curve and likelihood ratio analyses, that the total creatine kinase slope assay possesses the same diagnostic power, when confidence intervals are used, as the optimized decision threshold assay. Moreover, slope assays of creatine kinase-2 were diagnostically inferior to the optimized decision threshold assays. Indeed, these latter, optimized, assays have the highest likelihood ratios for a positive test result of the available assays, and they should always be used in situations of diagnostic doubt.

Time-related changes in the diagnostic utility of total lactate dehydrogenase, lactate dehydrogenase isoenzyme-1, and two lactate dehydrogenase isoenzyme-1 ratios in serum after myocardial infarction.

Using receiver-operating characteristic (ROC) curve and likelihood ratio analysis, we examined the diagnostic utility of total lactate dehydrogenase (LD; EC 1.1.1.27) activity (I). LD isoenzyme-1 activity (II), and the LD-1 percentage of total LD activity (III), LD-1 LD-2 (IV), and LD-1/LD-4 (V) in 347 persons admitted to the Cardiac Care Unit (of whom 173 were subsequently proven to have had myocardial infarction). Blood was sampled from these subjects at about 6-h intervals for up to 96 h from the onset of chest pain. Defining an "effective" test as one having an area under the ROC curve of greater than or equal to 0.9, we determined the ranked utility (greatest to least) of these tests as V = IV greater than III greater than II greater than I. Tests III, IV, and V had by this criterion, diagnostic effectiveness equivalent to measurements of creatine kinase-2 in serum but in samples obtained at later time intervals. The decision thresholds for both high (constant) test sensitivity and specificity varied with time, to differing extents, over the entire 96-h period, a finding with important diagnostic implications. We document positive and negative likelihood ratio values for each of these tests throughout the entire period of study.

Hemodynamic effects of intravenous procainamide during ventricular tachycardia.

Radionuclide angiography was used to study the hemodynamic effects of intravenous procainamide during stable monomorphic ventricular tachycardia. In four patients studied without procainamide, the ejection fraction was 25% +/- 2.4% during normal sinus rhythm, dropped to 11.3% +/- 2.2% (p less than 0.05) at the onset of ventricular tachycardia, increased to 16.7% +/- 1.7% after remaining in ventricular tachycardia for 10 minutes, and returned to 25.3% +/- 3.7% in sinus rhythm. In the 10 study patients, ejection fraction dropped from 36% +/- 5.8% in sinus rhythm to 25% +/- 5.1% in ventricular tachycardia (p less than 0.2). Ejection fraction decreased further (23% +/- 5.0%) following low doses of procainamide (140 +/- 52 mg) despite cycle length prolongation (354 +/- 18 msec versus 373 +/- 21 msec, p less than 0.5). In 8 of 10 patients, there was a progressive increase in the ejection fraction (28.8% +/- 4.1%). Ventricular tachycardia onset also resulted in a decrease in cardiac output and end-diastolic and end-systolic volumes. Two patients who tolerated procainamide in sinus rhythm showed hemodynamic collapse secondary to procainamide during ventricular tachycardia. We conclude that in some patients hemodynamic intolerance to an antiarrhythmic drug may only become evident during ventricular tachycardia.

Re-evaluation of the diagnostic utility of serum total creatine kinase and creatine kinase-2 in myocardial infarction.

The diagnostic utility of total creatine kinase activity (I), creatine kinase-2 isoenzyme activity (II), and II as a percentage of I, was examined by receiver-operating characteristic curve and likelihood ratio (LR) analyses in 310 persons admitted to the Coronary Care Unit (151 proven cases of myocardial infarction and 159 non-myocardial infarction controls), from whom blood was sampled at 6-h intervals for 48 h after the onset of chest pain. I was ineffective either as a "rule-in" or as a "rule-out" test within the first 6 h of the onset of chest pain; thereafter, it was an effective test. II was the most effective test during the entire 48-h period. III was more effective than I in the first 24-h period, but was less effective than I during the next 24-h period. The decision threshold for high test sensitivities varies with time over the entire 48-h period, but remains constant for high test specificities. It is essential to tabulate the LR(+) and LR(-) values for both test sensitivity and specificity at constant values to determine the utility of each test at each time interval for respectively ruling out or ruling in a diagnosis of myocardial infarction.

Nuclear magnetic resonance and radionuclide angiographic assessment of acute myocardial infarction in a randomized trial of intravenous streptokinase.

Sixty-six patients presenting with their first evolving transmural acute myocardial infarction (AMI) were randomized to receive either streptokinase (n = 41) or placebo therapies (n = 25) within 6 hours of the onset of chest pain. These patients then underwent supine rest, exercise and after-nitroglycerin radionuclide angiography 3 weeks after AMI. Nuclear magnetic resonance (NMR) imaging was performed at 3 weeks as a more direct estimate of AMI size. Although peak creatine kinase values were comparably elevated between groups (2,367 +/- 1,486 IU/liter for streptokinase vs 2,637 +/- 1,305 IU/liter for placebo), there was a significant reduction in NMR-measured AMI size in the streptokinase group (3 +/- 2% of left ventricular volume vs 10 +/- 4% in the placebo group, p less than 0.05). This occurred despite comparable resting (54 +/- 11 vs 47 +/- 10% and exercise (53 +/- 12 vs 49 +/- 11%) global ejection fractions. However, following nitroglycerin, there was an improvement in global ejection fraction in the streptokinase-treated group that was not observed with placebo (61 +/- 13 vs 48 +/- 10%, p less than 0.05). A similar pattern was also observed with regional functional analysis. Thus, streptokinase therapy leads to a significant reduction in NMR-measured AMI size and to a greater degree of reversible left ventricular dysfunction.

Diagnostic efficiency of four lactate dehydrogenase isoenzyme-1 ratios in serum after myocardial infarction.

We compared the diagnostic efficacy of the ratios LD-1/LD-2, LD-1/LD-3, LD-1/LD-4, and LD-1/LD-5 in 69 documented cases of myocardial infarction. We used 149 patients with congestive heart failure and 67 patients with nonmyocardial infarct as controls. We used a computer program to produce receiver-operating characteristic curves, decision threshold plots, and likelihood ratios for these LD ratios at 6-h intervals up to 108 h after the onset of chest pain or hospital admission. All ratios in the myocardial infarction cases peaked around 36 h after the onset of chest pain, while those for the nonmyocardial and congestive cardiac failure cases did not change over the 108-h period. In all patients with infarctions, LD-1/LD-4 and LD-1/LD-5 increased by 1.7 times (when LD-1 was less than 40%) and 3.4 times (when LD-1 was greater than 40%), respectively, over control values. Optimum decision threshold values were obtained at 13-24 h (LD-1/LD-5), 31-36 h (LD-1/LD-4 and LD-1/LD-3), and 55-60 h (LD-1/LD-2) after onset of symptoms. The highest likelihood ratio was obtained with the LD-1/LD-4 ratio; therefore, we suggest that this is a better diagnostic test for myocardial infarction than LD-1/LD-2.

Prophylaxis of post-myocardial infarction dysrhythmias by long-term timolol therapy.

The antiarrhythmic efficacy of timolol maleate was assessed in 94 patients with acute myocardial infarction. No significant differences were noted between early treatment with timolol and placebo in the mean and peak hourly ventricular premature complex rates, ventricular premature complex couplets, or runs. However, compared to the placebo treatment, there was a significant (p less than 0.001) 66% reduction in the relative fraction of early-cycle ventricular premature complexes 7 to 9 days after initiation of timolol therapy and a more prolonged significant (p less than 0.001) 73% reduction in the fraction of early-cycle supraventricular complexes throughout the 28-day timolol and placebo comparison period. The frequency distribution of QRS duration was significantly different between the placebo- and timolol-treated patients, with the mean duration 8 msec longer in the placebo-treated patients (p = 0.008). Adverse effects from early administration of timolol did not differ from those in the placebo-treated patients.

Determination, by radioimmunoassay, of the mass of lactate dehydrogenase isoenzyme 1 in human serum and of its rate of removal from serum after a myocardial infarction.

In this radioimmunoassay of lactate dehydrogenase-1 (LD-1; EC 1.1.1.27) in human serum we use a commercial LD-1-selective assay system and a goat antiserum. We have determined the fractional rate of disappearance from serum and the half-life of LD-1, in terms of both enzyme activity and enzyme mass, in 21 myocardial infarction patients. Our evidence suggests that this isoenzyme is inactivated in serum. Furthermore, our data suggest that the conventionally accepted half-life of about 110 h for serum LD-1 activity may grossly overestimate the actual LD-1 half-life in many post-myocardial infarction patients.

Comparison of bepridil with nadolol for angina pectoris.

Bepridil hydrochloride is a unique calcium channel-blocking drug with anti-ischemic and type 1 antiarrhythmic properties. With a half-life of more than 40 hours, once-daily therapy is possible. Twenty-four patients (22 men, 2 women), mean age 58 years (range 43 to 72), with stable exertional angina were assigned to therapy with bepridil and nadolol in a randomized, double-blind, crossover trial. Antianginal efficacy was assessed by a diary of angina frequency and nitroglycerin consumption as well as by treadmill exercise testing. The effect of therapy on ventricular function was assessed by symptom-limited equilibrium gated exercise radionuclide angiography. During therapy with both nadolol and bepridil, the number of episodes of angina per week was significantly reduced and nitroglycerin consumption decreased compared with baseline evaluation. Exercise duration was prolonged by both therapies (baseline 281 +/- 122 seconds, nadolol 377 +/- 96 seconds, bepridil 400 +/- 109 seconds; p less than 0.005 for nadolol and bepridil vs baseline). Time to the onset of angina was similarly prolonged, 50% by nadolol and 65% by bepridil (p less than 0.005). Bepridil had no effect on PR and QRS durations, although QTc was significantly prolonged (baseline 0.43 +/- 0.03, nadolol 0.42 +/- 0.03, bepridil 0.45 +/- 0.04; p less than 0.005 for bepridil vs baseline and nadolol). By radionuclide angiography, neither nadolol nor bepridil had an adverse effect on left ventricular function at rest or during exercise. Bepridil therefore provides effective therapy for angina without adverse effects on left ventricular function, comparable to the effects of beta blockade with nadolol.

Changes in mass and catalytic activity concentrations of aspartate aminotransferase isoenzymes in serum after a myocardial infarction.

We used an RIA and inhibition of enzyme activity to monitor the changes in mass and catalytic concentrations of the aspartate aminotransferase (EC 2.6.1.1;AST) isoenzymes in serum after myocardial infarction. Cytosolic (c-AST) and mitochondrial (m-AST) forms of AST were present in sera from all 38 of our patients. Although the immunological and catalytic concentrations of both isoenzymes correlated well with the size of the infarct, c-AST gave a better measure than did m-AST. About 20% of the total enzyme activity at peak activity was from the mitochondrial isoenzyme. Both isoenzyme activities peak at very nearly the same time, but m-AST has the longer half-life. Immunological evidence of the mitochondrial isoenzyme can be detected in serum for at least eight days after the infarct. The presence of left ventricular failure produces greater serum isoenzyme activities than in those without failure.

Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial.

We performed a randomized, double-blind, placebo-controlled trial in 555 patients with unstable angina who were hospitalized in coronary care units. Patients received one of four possible treatment regimens: aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily), both, or neither. They were entered into the trial within eight days of hospitalization and were treated and followed for up to two years (mean, 18 months). The incidence of cardiac death and nonfatal myocardial infarction, considered together, was 8.6 per cent in the groups given aspirin and 17.0 per cent in the other groups, representing a risk reduction with aspirin of 51 per cent (P = 0.008). The corresponding figures for either cardiac death alone or death from any cause were 3.0 per cent in the groups given aspirin and 11.7 per cent in the other groups, representing a risk reduction of 71 per cent (P = 0.004). Analysis by intention to treat yielded smaller risk reductions with aspirin of 30 per cent (P = 0.072), 56 per cent (P = 0.009), and 43 per cent (P = 0.035) for the outcomes of cardiac death or nonfatal acute myocardial infarction, cardiac death alone, and all deaths, respectively. There was no observed benefit of sulfinpyrazone for any outcome event, and there was no evidence of an interaction between sulfinpyrazone and aspirin. Considered together with the results of a previous clinical trial, these findings provide strong evidence for a beneficial effect of aspirin in patients with unstable angina.