Replication in restenotic atherectomy tissue.

Previously, we demonstrated that replication in restenotic coronary atherectomy specimens was an infrequent and modest event. In general, this data was interpreted with caution, as immunocytochemistry for the proliferating cell nuclear antigen (PCNA) was used to subjectively assess proliferation and most of the tissue specimens were resected more than 3 months after the initial interventional procedure. The purpose of the present study was to use a more sensitive method of detecting replication, in situ hybridization for histone 3 (H3) mRNA, to determine the replication profile of human directional atherectomy specimens. Restenotic directional coronary atherectomy specimens from lesions that had undergone an interventional procedure within the preceding 3 months were studied. In addition, larger atherectomy specimens from peripheral arterial lesions were assessed to ensure that pockets of replication were not being overlooked in the smaller coronary specimens. We found evidence for replication in tissue resected from 2/17 coronary and 9/12 peripheral artery restenotic lesions. In contrast, 3/11 specimens resected from primary lesions of peripheral arteries also expressed H3 mRNA. We estimated that the maximum percentage of cells that were replicating in restenotic coronary, restenotic peripheral and primary peripheral artery tissue slides to be <0.5, < or =1.2 and <0.01%, respectively. Replication was found in tissue specimens resected both early and late after a previous interventional procedure. For specimens with >15 replicating cells per slide we found high levels of focal replication. Therefore, cell replication, as assessed by the expression of H3 mRNA, was infrequent in restenotic coronary artery specimens, whereas peripheral restenotic lesions had more frequent and higher levels of replication regardless of the interval from the previous interventional procedure. For all specimens the percentage of cells that were replicating was low, however focal areas with relatively high replication indices were presented. Although replication was more abundant in restenotic lesions it does not appear to be a dominant event in the pathophysiology of restenosis.

Safety and effect on anti-Chlamydia pneumoniae antibody titres of a 1 month course of daily azithromycin in adults with coronary artery disease.

A pilot study of azithromycin treatment following percutaneous coronary revascularization procedures was performed to assess safety and the effect of azithromycin treatment on anti-Chlamydia pneumoniae antibody titres. Patients were randomized to a 1 month course of azithromycin (total dose of 8.0 g) or placebo. Safety and compliance were assessed at 2 and 4 weeks and serological testing was performed on samples obtained at enrolment and at 6 months post-enrolment. Azithromycin was well tolerated at this dose. No effect of treatment on antibody titres was demonstrated. These results support further clinical trials to assess the effect of azithromycin treatment on cardiovascular disease outcomes.

Effectiveness of revascularization in the Emory angioplasty versus surgery trial. A randomized comparison of coronary angioplasty with bypass surgery.

BACKGROUND: The Emory Angioplasty Versus Surgery Trial (EAST) was designed to determine whether percutaneous transluminal coronary angioplasty (PTCA) is as effective as coronary artery bypass graft surgery (CABG) in restoring arterial perfusion capacity in eligible patients with multivessel disease. METHODS AND RESULTS: Of 392 patients in EAST, 198 were randomized to PTCA and 194 to CABG. Index lesions (2.7 +/- 1.0 per patient) were those with > or = 50% stenosis judged treatable by both angioplasty and surgery. Coronary segments jeopardized by these index lesions were designated as index segments (4.4 +/- 1.4 per patient). Percent stenosis was measured by quantitative angiography at the point of greatest obstruction in the main perfusion path of each index segment. The EAST primary arteriographic end point was the percent of a patient's index segments with < 50% stenosis in the main perfusion pathways at 1 and 3 years. At baseline, the percent of index segments for which revascularization was attempted was 85% for PTCA and 98% for CABG (P < .0001). At 1 year, PTCA patients had a smaller percentage of successfully revascularized index segments than CABG patients (59% versus 88%, P < .001). At 3 years, the findings were similar but less striking (70% versus 87%, P < .001). When only "high-priority" index segments (2.1 +/- 1.6 per patient) were considered, baseline attempts were comparable (96% versus 99%, P = NS); despite this, CABG remained more successful at 1 (64% versus 93%, P < .001) and 3 (76% versus 89%, P < .01) years. However, the mean percent of index segments free of severe stenosis (> or = 70%) did not differ between PTCA and CABG patients at 3 years (93% versus 95%, P = NS). Furthermore, the frequency of patients with all index segments free of severe stenosis did not differ between the two groups at 1 (76% versus 83%, P = NS) or 3 (82% for both PTCA and CABG) years. CONCLUSIONS: In patients with multivessel disease, index segment revascularization was more complete with CABG than PTCA at both 1 and 3 years. However, when the physiological priority of the target lesion and the measured severity of the residual stenosis are taken into account, the advantage of CABG becomes less significant or nonsignificant. This may, in part, explain why these two strategies did not differ in terms of the EAST primary clinical end points over 3 years.

A pilot study of intravenous ondansetron for hyperemesis gravidarum.

OBJECTIVE: We attempted to determine whether the antiemetic ondansetron would be more effective than promethazine in treating hyperemesis gravidarum. STUDY DESIGN: Patients with hyperemesis gravidarum who required hospital admission were randomized to receive either intravenous ondansetron (n = 15) or intravenous promethazine (n = 15) in a double-blind manner. Severity of disease was determined by electrolyte status, weight loss, ketonuria, and prior use of outpatient antiemetics. Outcome variables included degree of nausea, weight gain during treatment, days of hospitalization, and number of medication doses. RESULTS: In this preliminary investigation ondansetron offered no advantage when compared with promethazine in the relief of nausea, weight gain, days of hospitalization (4.5 +/- 2.3 vs 4.5 +/- 1.5), and total doses of medication per hospitalization (2.1 +/- 1.2 vs 1.9 +/- 1.3). CONCLUSION: This preliminary trial of ondansetron demonstrated no benefit over promethazine in patients hospitalized for hyperemesis gravidarum.

Reduced peak aerobic capacity in asymptomatic left ventricular systolic dysfunction. A substudy of the studies of left ventricular dysfunction (SOLVD). SOLVD Investigator. Studies of Left Ventricular Dysfunction.

BACKGROUND: Peak oxygen consumption is reduced in patients with symptomatic congestive heart failure, but functional capacity of patients with asymptomatic left ventricular systolic dysfunction has not been assessed by measurement of peak oxygen consumption attained during graded exercise testing. METHODS AND RESULTS: Peak oxygen consumption, that is, aerobic capacity (VO2, mL/kg per minute), was determined during graded treadmill exercise using the modified Naughton protocol in 40 patients with left ventricular systolic dysfunction (mean ejection fraction ranging from 14% to 35%; mean, 29%) who, while not receiving any cardiac medications, were totally asymptomatic, and in 41 age-matched normal subjects. Peak exercise duration and VO2 were significantly lower in patients with asymptomatic left ventricular systolic dysfunction than in normal subjects (948 +/- 273 versus 1239 +/- 372 seconds, P < .001, and 22.1 +/- 5.9 versus 29.8 +/- 7.7 mL/kg per minute, respectively, P < .001), while asymptomatic patients and normal subjects reached similar respiratory equivalents (1.14 +/- 0.11 versus 1.11 +/- 0.11 [NS]) and level of perceived exertion, using the modified Borg scale (7.4 +/- 2.6 versus 8.1 +/- 1.5 [NS]). Heart rate, systemic blood pressure, and oxygen pulse response to peak exercise were significantly lower in asymptomatic patients than in normal subjects. CONCLUSIONS: Although patients with left ventricular systolic dysfunction can be totally asymptomatic in their daily activities, they have experienced a substantial reduction in peak aerobic capacity when compared with normal subjects of similar age.

Angiogenesis in human coronary atherosclerotic plaques.

Neovascularization in the walls of coronary arteries is associated with the presence of atherosclerotic plaque. The mechanisms responsible for the formation of these intraplaque microvessels are not understood. The purpose of this study is to examine the prevalence of endothelial cell replication in plaque microvessels. Two hundred and one primary and restenotic coronary atherectomy specimens were analyzed for the presence of microvessels and proliferation as reflected by positive immunolabeling for Ulex agglutinin and the proliferating cell nuclear antigen, respectively. In primary but not restenotic specimens, proliferation of any cell type was associated with the detection of microvessels on the same slide. However, intraplaque microvessels were more commonly found in restenotic compared to primary specimens (P = 0.004). Twelve highly vascularized specimens with evidence of replication were subjected to detailed histomorphological and quantitative image analyses. At 200 x, the most vascular optical field of each slide was identified and consistently included plaque macrophages. Total slide endothelial cell replication indices for these specimens varied, but in some instances were remarkably elevated (eg, 43.5%). The role of intraplaque angiogenesis may be analogous to that of tumor or wound angiogenesis and be important in development and progression of coronary artery lesions and restenosis.

Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques.

How an atherosclerotic plaque evolves from minimal diffuse intimal hyperplasia to a critical lesion is not well understood. Cellular proliferation is a relatively infrequent and modest event in both primary and restenotic coronary atherectomy specimens, leading us to believe that other processes, such as the formation of extracellular matrix, cell migration, neovascularization, and calcification might be more important for lesion formation. The investigation of proteins that are overexpressed in plaque compared with the normal vessel wall may provide clues that will help determine which of these processes are key to lesion pathogenesis. One such molecule, osteopontin (OPN), is an arginine-glycine-aspartate-containing acidic phosphoprotein recently shown to be a novel component of human atherosclerotic plaques and selectively expressed in the rat neointima following balloon angioplasty. Using in situ hybridization and immunohistochemical methods, we demonstrate that in addition to macrophages, smooth muscle and endothelial cells synthesize OPN mRNA and protein in human coronary atherosclerotic plaque specimens obtained by directional atherectomy. In contrast, OPN mRNA and protein were not detected in nondiseased vessel walls. Furthermore, extracellular OPN protein collocalized with sites of early calcification in the plaque that were identified with a sensitive modification of the von Kossa staining technique. These findings, combined with studies showing that OPN has adhesive, chemotactic, and calcium-binding properties, suggest that OPN may contribute to cellular accumulations and dystrophic calcification in atherosclerotic plaques.

Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy.

On the basis of animal models of arterial injury, smooth muscle cell proliferation has been posited as a dominant event in restenosis. Unfortunately, little is known about this proliferation in the human restenotic lesion. The purpose of this study was to determine the extent and time course of proliferation in primary and restenotic coronary atherectomy-derived tissue. Primary (n = 118) and restenotic (n = 100) coronary atherectomy specimens were obtained from 211 nonconsecutive patients. Immunocytochemistry for the proliferating cell nuclear antigen (PCNA) was used to gauge proliferation in the atherectomy specimens. The identity of PCNA-positive cells was then determined using immunohistochemical cell-specific markers. Eighty-two percent of primary specimens and 74% of restenotic specimens had no evidence of PCNA labeling. The majority of the remaining specimens had only a modest number of PCNA-positive cells per slide (typically < 50 cells per slide). In the restenotic specimens, PCNA labeling was detected over a wide time interval after the initial procedure (eg, 1 to 390 days), with no obvious proliferative peak. Cell-specific immunohistochemical markers identified primary and restenotic PCNA-positive cells as smooth muscle cells, macrophages, and endothelial cells. In conclusion, the findings were as follows: (1) Proliferation in primary and restenotic coronary atherectomy specimens, as indicated by PCNA labeling, occurs infrequently and at low levels. (2) The response to injury in existing animal models of angioplasty may follow a very different course of events from the clinical reality in human atherosclerotic coronary arteries and may help explain why current approaches to restenosis therapy have been ineffective.

Characteristics of peak aerobic capacity in symptomatic and asymptomatic subjects with left ventricular dysfunction. The Studies of Left Ventricular Dysfunction (SOLVD) Investigators.

Expired gas analysis was used to determine the aerobic exercise performance of subjects with depressed left ventricular (LV) systolic function and congestive heart failure (CHF). To determine whether subjects with no or minimal CHF have better aerobic exercise performance than do those with overt CHF, oxygen consumption (VO2) at anaerobic threshold (AT) and peak exercise was measured in 184 subjects with LV ejection fraction less than or equal to 0.35 who participated in the Studies of Left Ventricular Dysfunction. Subjects were divided into those with overt CHF needing treatment (treatment trial; n = 20) and those who had neither overt CHF nor treatment for CHF (prevention trial; n = 164). Treatment trial subjects had a lower LV ejection fraction (0.25 +/- 0.07) than did prevention trial ones (0.29 +/- 0.05; p = 0.001), but there were no differences in age, gender, body weight, resting heart rate and blood pressure. Treadmill exercise testing was performed after 2 to 3 weeks of placebo (no angiotensin-converting enzyme inhibitor) treatment. Treatment trial subjects exercised for a shorter time (493 +/- 160 seconds) and attained a lower peak VO2 (13 +/- 4 ml/kg/min) and VO2 at AT (11 +/- 4 ml/kg/min) than did prevention trial ones (842 +/- 277 seconds, and 20 +/- 6 and 16 +/- 5 ml/kg/min, respectively). Analysis of covariance showed that the differences in peak VO2 and VO2 at AT were statistically significant between the 2 trials after adjusting for age, gender, LV ejection fraction and New York Heart Association functional class.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlamydia pneumoniae strain TWAR antibody and angiographically demonstrated coronary artery disease.

A recent case-control study from Finland reported a strong association between high antibody titers to Chlamydia pneumoniae, strain TWAR, and both chronic coronary heart disease and acute myocardial infarction. The current case-control study investigated the relation between C. pneumoniae immunoglobulin G antibody titers and angiographically diagnosed coronary artery disease. Cases (n = 461) were angiography patients with at least one coronary artery lesion occupying at least 50% of the luminal diameter. Controls (n = 95) were angiography patients with no demonstrable coronary artery disease. After standardization for age and gender, the geometric mean antibody titer was higher for cases than for controls (30.0 versus 24.0, p = 0.04). The estimated risk of coronary artery disease, adjusted for age and gender, was greater among subjects with high (greater than or equal to 1:64) antibody titers than among subjects with low (less than or equal to 1:8) antibody titers (relative risk, 2.0; 95% confidence interval, 1.0-4.0). The risk associated with a high antibody titer was particularly great for coronary artery disease with five or more lesions (relative risk, 2.8; 95% confidence interval, 1.2-7.0). The results of this cross-sectional study support an association between infection with C. pneumoniae and coronary artery disease.

Intraoperative autotransfusion: a community program.

The Southern Arizona Regional Blood Program of the American Red Cross in cooperation with Tucson hospitals conducted a pilot program of the provision of intraoperative autologous transfusion services. The service provided instruments, staff, and disposables to salvage and wash red cells shed during scheduled and emergency surgical procedures. The lower cost and other efficiencies of providing this service through a regional blood center suggest that it may be more appropriate to offer this service on a regional basis than exclusively within a hospital. Hospitals and regional blood centers should consider offering this advanced form of hemotherapy to their communities.

Coronary artery bypass graft surgery early after acute myocardial infarction.

Seven hundred ninety-three patients had coronary artery bypass graft (CABG) surgery within 30 days after acute myocardial infarction (AMI) between August 1982 and July 1987. Hospital mortality was 5.7%. Age, surgical priority, prior CABG surgery, congestive heart failure (CHF), and type of AMI were associated with increased hospital mortality by logistic regression analysis of nine independent variables. When the analysis was carried out separately for men and women, the same predictive variables were identified for men, but only surgical priority and age were predictive of operative mortality for women. Elective CABG surgery can be carried out at low risk following AMI in stable patients regardless of the interval between AMI and surgery. Patients who undergo urgent or emergency surgery and those who have CHF, Q wave infarction, or a history of prior AMI are at increased risk.

Oral nifedipine for the treatment of patients with severe hypertension.

Ten mg of nifedipine was administered to 19 patients with severe hypertension (mean blood pressure 187 +/- 17/122 +/- 12 mm Hg) without intensive care monitoring. Patients were instructed to bite and swallow the contents of the capsule. Blood pressure declined significantly to a mean of 149 +/- 17/92 +/- 10 mm Hg. No adverse side effects or hypotension occurred. Ten patients required an additional dose 30 to 60 minutes after the initial dose. Mean heart rate increased from 79 to 95 beats per minute without symptomatic consequences. Laboratory parameters measured before and after the four-hour study did not change significantly, although peripheral renin activity rose transiently. Urinary sodium excretion increased 43 percent over four hours after therapy in three patients in whom it was measured. Cardiac output, which was measured noninvasively in seven patients, rose nonsignificantly whereas systemic vascular resistance declined from 2,070 dynes/second/cm-5 to 1,271 dynes/second/cm-5 (statistically significant difference) in 20 minutes. These results indicate that oral nifedipine, when bitten and swallowed, effectively lowers blood pressure in patients with severe hypertension without the occurrence of adverse side effects or hypotension. Oral nifedipine may be used safely in an outpatient setting when urgent intervention is required.

Diltiazem-induced blockade of sympathetically mediated constriction of normal and diseased coronary arteries: lack of epicardial coronary dilatory effect in humans.

To determine mechanisms of benefit from diltiazem, 13 patients with coronary disease performed sustained isometric handgrip exercise and repeated the procedure during intravenous infusion of diltiazem (0.25 mg/kg bolus followed by 0.003 mg/kg/min). Cardiovascular responses to handgrip, diltiazem, their combination, and nitroglycerin were assessed by hemodynamic and electrocardiographic measurements and by computer-assisted measurements of normal and diseased segments of epicardial coronary arteries. Handgrip produced increases in heart rate (12%; p less than .001), pulmonary arterial pressure (19%; p less than .005), and pulmonary wedge pressure (33%; p less than .005). Diltiazem produced significant reductions in heart rate (7%; p less than .05) and aortic pressure (14%; p less than .001). Pulmonary arterial pressure and pulmonary wedge pressure were unchanged by diltiazem. Diltiazem did not prevent the increase in heart rate or in aortic or wedge pressure associated with handgrip. Diltiazem prolonged atrioventricular conduction from 0.18 +/- 0.03 to 0.20 +/- 0.03 sec (p less than .001). Compared with control values, nitroglycerin reduced aortic pressure (14%; p less than .005), pulmonary arterial pressure (38%; p less than .001), and pulmonary wedge pressure (42%; p less than .005). Heart rate was unchanged. The constriction (20%) in lumen area of normal coronary arterial segments during handgrip was effectively prevented by infusion of diltiazem (1%; p less than .001). Nitroglycerin produced a significantly greater increase (20%) in diameter of normal coronary arterial segments than diltiazem (3%; p less than .001) and tended to have a more favorable effect than diltiazem on stenosis minimum area and flow resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Interventional coronary arteriography.

During the past five years percutaneous transluminal coronary angioplasty (PTCA) and intracoronary infusion of streptokinase have been introduced and rapidly accepted as new methods for the treatment of patients with ischemic heart disease. Both of these methods hold great promise for the future. PTCA is established as useful in some selected patients while intracoronary streptokinase is still investigational.

Value of partial ejection fraction, volume increment, and regional wall motion in identifying patients with clinically significant coronary artery disease.

Recent studies suggest that the partial ejection fraction (EF) in early systole is a more sensitive index of left ventricular (LV) dysfunction than the holosystolic EF. We examined LV volume, partial EF, and volume increment at each of 12 time points in systole to determine which parameter best distinguishes normal subjects from patients with coronary artery disease (CAD). Contrast ventriculograms, obtained either in the right anterior oblique projection (60 frames/sec) or in the biplane projection (30 frames/sec), of 58 normal subjects and 68 patients with CAD were studied. The endocardial contour in each frame of a sinus beat was traced to derive a volume curve. At each twelfth of systole, LV volume was extrapolated from the curve and the partial EF was calculated. The increment in volume between successive time points was also calculated. Both partial EF and LV volume in patients with CAD became progressively more abnormal with time; peak abnormality occurred at end-systole. In a subgroup of patients with CAD who had normal holosystolic EF, both partial EF and volume were normal throughout systole. The increment in volume with each twelfth of systole in patients with CAD deviated less than 1 SD from normal throughout systole. Thus, maximum abnormality in partial EF and volume occurs at end-systole. Of the parameters of global LV function tested, holosystolic EF best distinguishes patients with CAD from normal subjects. However, regional wall motion measured in the area of interest is more sensitive to localized abnormality, the severity of which may be overestimated or underestimated by the EF due to hyperkinesis or hypokinesis in other regions of the left ventricle.

Variability in the measurement of regional left ventricular wall motion from contrast angiograms.

Four types of variability affecting quantification of regional wall motion from contrast left ventriculograms (LVgrams) were studied. These included beat-to-beat variability in 24 LVgrams, intraobserver and interobserver variability in 20 LVgrams, and study-to-study variability in serial LVgrams of 21 patients with stable coronary artery disease. Motion was measured at 100 equidistant chords perpendicular to a center line drawn midway between the end-diastolic and end-systolic contours and normalized for heart size. Variability was computed as the absolute difference between observations. Beat-to-beat, intraobserver, and interobserver variability at the 100 chords were similar, averaging 14%, 14%, and 17%, respectively, of the mean motion in 64 patients with normal ventriculograms. Study-to-study variability was significantly higher, averaging 30% of mean normal motion, but was reduced when regional motion was calculated as the mean motion of chords within a region of interest. Variability peaked at the apex. Realignment to correct for cardiac rotation significantly increased variability. Investigators whose methods of wall motion analysis rely on identification of the apex as a landmark should be aware of this source of potential variability and error.

Angina in thyrotoxicosis. Thyroid-related coronary artery spasm.

Ischemic heart disease is a common complication of thyrotoxicosis, although the exact mechanism has not been defined. A case is reported of angina and thyrotoxicosis in which the angina was reproduced by coronary artery spasm induced by ergonovine maleate, relieved by thyroid ablation, and reactivated by postablative thyroid replacement. Coronary arteriography did not show significant stenoses prior to ergonovine injection. Possible mechanisms of coronary artery spasm in thyrotoxicosis are briefly discussed. Hyperthyroidism should be considered as a cause of angina in any patient with rest pain and normal coronary arteries.

Noninvasive Doppler determination of cardiac output in man. Clinical validation.

A noninvasive technique for assessing cardiac output (CO) was evaluated by comparing it with thermodilution determinations in patients in the intensive care unit. The new method uses pulsed ultrasound to measure aortic diameter and continuous-wave Doppler ultrasound to obtain aortic blood velocity. An initial study evaluating just the velocity measurement showed that changes of the Doppler index of output (DI) correlated well with those of thermodilution cardiac output (TDCO). Linear regression analysis yielded delta DI = 0.87 delta TDCO + 0.14 (r = 0.83, n = 95). Using a university research instrument these measurements were possible in 54 of 60 patients (90%). A second study using a prototype commercial device incorporated the diameter measurement. Ultrasonic cardiac output (UCO), calculated as the time integral of velocity multiplied by the aortic area, was compared to TDCO. The data, obtained from 45 of 53 patients (85%), are described by the linear regression UCO = 0.95TDCO + 0.38 (r = 0.94, n = 110) over a range of 2-11 l/min. Patients with aortic stenosis, aortic insufficiency or a prosthetic valve have been excluded from the second study due to conditions likely to violate the assumptions upon which the calculation of absolute cardiac output is based. These results indicate that accurate CO can be measured by noninvasive ultrasound in most patients. The technique may be useful for extended CO monitoring in acute care patients and for CO assessment in many other types of patients undergoing diagnostic studies and therapeutic interventions.