Cynthia O. Siu

A Randomized Trial of Intravenous Tissue Plasminogen Activator for Acute Myocardial Infarction with Subsequent Randomization to Elective Coronary Angioplasty

Patients presenting within four hours of the onset of acute myocardial infarction were randomly assigned to receive 80 to 100 mg of recombinant human-tissue plasminogen activator (t-PA) intravenously over a period of three hours (n = 72) or placebo (n = 66). Administration of the study drug was followed by coronary arteriography, and candidates for percutaneous transluminal coronary angioplasty were randomly assigned either to undergo angioplasty on the third hospital day (n = 42) or not to undergo angioplasty during the 10-day study period (n = 43). The patency rates of the infarct-related arteries were 66 percent in the t-PA group and 24 percent in the placebo group. No fatal or intracerebral hemorrhages occurred, and episodes of bleeding requiring transfusion were observed in 7.6 percent of the placebo group and 9.8 percent of the t-PA group. As compared with the use of placebo, administration of t-PA was associated with a higher mean (+/- SEM) ejection fraction on the 10th hospital day (53.2 +/- 2.0 vs. 46.4 +/- 2.0 percent, P less than 0.02), an improved ejection fraction during the study period (+3.6 +/- 1.3 vs. -4.7 +/- 1.3 percentage points, P less than 0.0001), and a reduction in the prevalence of congestive heart failure from 33 to 14 percent (P less than 0.01). Angioplasty improved the response of the ejection fraction to exercise (+8.1 +/- 1.4 vs. +1.2 +/- 2.2 percentage points, P less than 0.02) and reduced the incidence of postinfarction angina from 19 to 5 percent (P less than 0.05), but did not influence the ejection fraction at rest. These data support an approach to the treatment of acute myocardial infarction that includes early intravenous administration of t-PA and deferred cardiac catheterization and coronary angioplasty.

A Preliminary Study of Cardiopulmonary Resuscitation by Circumferential Compression of the Chest with Use of a Pneumatic Vest

BACKGROUND More than 300,000 people die each year of cardiac arrest. Studies have shown that raising vascular pressures during cardiopulmonary resuscitation (CPR) can improve survival and that vascular pressures can be raised by increasing intrathoracic pressure. METHODS To produce periodic increases in intrathoracic pressure, we developed a pneumatically cycled circumferential thoracic vest system and compared the results of the use of this system in CPR (vest CPR) with those of manual CPR. In phase 1 of the study, aortic and right-atrial pressures were measured during both vest CPR (60 inflations per minute) and manual CPR in 15 patients in whom a mean (+/- SD) of 42 +/- 16 minutes of initial manual CPR had been unsuccessful. Vest CPR was also carried out on 14 other patients in whom pressure measurements were not made. In phase 2 of the study, short-term survival was assessed in 34 additional patients randomly assigned to undergo vest CPR (17 patients) or continued manual CPR (17 patients) after initial manual CPR (duration, 11 +/- 4 minutes) had been unsuccessful. RESULTS In phase 1 of the study, vest CPR increased the peak aortic pressure from 78 +/- 26 mm Hg to 138 +/- 28 mm Hg (P < 0.001) and the coronary perfusion pressure from 15 +/- 8 mm Hg to 23 +/- 11 mm Hg (P < 0.003). Despite prolonged unsuccessful manual CPR, spontaneous circulation returned with vest CPR in 4 of the 29 patients. In phase 2 of the study, spontaneous circulation returned in 8 of the 17 patients who underwent vest CPR as compared with only 3 of the 17 patients who received continued manual CPR (P = 0.14). More patients in the vest-CPR group than in the manual-CPR group were alive 6 hours after attempted resuscitation (6 of 17 vs. 1 of 17) and 24 hours after attempted resuscitation (3 of 17 vs. 1 of 17), but none survived to leave the hospital. CONCLUSIONS In this preliminary study, vest CPR, despite its late application, successfully increased aortic pressure and coronary perfusion pressure, and there was an insignificant trend toward a greater likelihood of the return of spontaneous circulation with vest CPR than with continued manual CPR. The effect of vest CPR on survival, however, is currently unknown and will require further study.

Different Effects of Fosinopril and Atenolol on Wave Reflections in Hypertensive Patients

We conducted this study to compare the effects of fosinopril versus atenolol on peripheral blood pressure, central arterial wave reflection, and left ventricular mass in a group of patients with essential hypertension. We conducted a double-blind, randomized trial of fosinopril and atenolol in 79 hypertensive patients (52 men, 27 women; mean age, 45.8 +/- 8.5 years; range, 30 to 68 years). Carotid pressure waveforms were recorded noninvasively by applanation tonometry with a Millar micromanometer-tipped probe. The extent of wave reflection was estimated by the augmentation index defined as the ratio of the amplitude of pressure wave above its systolic shoulder to the pulse pressure. The augmentation index, left ventricular mass index by two-dimensional echocardiography, and 24-hour ambulatory blood pressures were determined before and after 8 weeks of daily treatment with fosinopril (10 to 20 mg) or atenolol (50 to 100 mg) with or without diuretics and compared with those values in 79 normotensive control subjects. After 8 weeks of treatment, both drugs lowered 24-hour ambulatory peripheral systolic and diastolic pressures into the normal range to a similar extent (fosinopril, -18/-13 mm Hg; atenolol, -23/-17 mm Hg, both P = NS). On the other hand, whereas the elevated augmentation index in hypertensive patients compared with normotensive subjects (16 +/- 11% versus 10 +/- 8%) was completely normalized by fosinopril (-9.3 +/- 9.8%, P < or = .002), it was lowered by atenolol (-4.8 +/- 8.9%, P < .002) but to a significantly smaller extent (fosinopril versus atenolol effect, P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Transient atrial dysfunction after conversion of chronic atrial fibrillation to sinus rhythm.

Although conversion of atrial fibrillation (AF) to sinus rhythm can usually be accomplished by electrical or drug therapy, effective atrial systole may not be restored. To investigate the return of atrial transport function and its relation to the duration of the arrhythmia, Doppler echocardiography was performed after conversion in 18 patients with acute AF (less than or equal to 1 week duration), 14 patients with chronic AF (greater than 1 week duration) and 15 control patients. Flow velocities during rapid filling (E wave) and atrial systole (A wave) were measured in both left and right ventricles. Patients in the acute AF group had left ventricular A waves (49 +/- 4 cm/s) and A/E ratios (0.97 +/- 0.1) similar to those of the control patients (55 +/- 7 cm/s, 0.87 +/- 0.08, respectively). In contrast, patients in the chronic AF group had much smaller A waves (19 +/- 5 cm/s) and A/E ratios (0.30 +/- 0.08) than those in the other 2 groups (p less than 0.001). Five patients with chronic AF (36%) had complete left atrial paralysis (A/E = 0) despite normal sinus P waves. Measurements in the right ventricle showed similar differences among the groups. Patients with chronic AF who maintained sinus rhythm showed an increase in A/E ratio to control levels, from 0.45 +/- 0.1 to 0.93 +/- 0.1 (p = 0.003) at 48 days (average) after conversion. Thus, atrial transport function is normal after brief periods of AF, but reduced or absent when conversion is achieved after the arrhythmia has been sustained greater than 1 week.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of afterload on regional left ventricular torsion

OBJECTIVE To determine if left ventricular torsion, as measured by magnetic resonance tissue tagging, is afterload dependent in a canine isolated heart model in which neurohumoral responses are absent, and preload is constant. METHODS In ten isolated, blood perfused, ejecting, canine hearts, three afterloads were studied, while keeping preload constant: low afterload, high afterload (stroke volume reduced by approx. 50% of low afterload), and isovolumic loading (infinite afterload). RESULTS There were significant effects of afterload on both torsion (P < 0.05) and circumferential shortening (P < 0.0005). Between low and high afterloads, at the anterior region of the endocardium only, where torsion was maximal, there was a significant reduction in torsion (15.1 +/- 2.2 degrees to 7.8 +/- 1.8 degrees, P < 0.05). Between high afterload and isovolumic loading there was no significant change in torsion (7.8 +/- 1.8 degrees to 6.2 +/- 1.5 degrees, P = NS). Circumferential shortening at the anterior endocardium was significantly reduced both between low and high afterload (-0.19 +/- 0.02 to -0.11 +/- 0.02, P < 0.0005), and also between high afterload and isovolumic loading (-0.11 +/- 0.02 to 0.00 +/- 0.02, P < 0.05). Plots of strains with respect to end-systolic volume demonstrated a reduction in both torsion and shortening with afterload-induced increases in end-systolic volume. Torsion, but not circumferential shortening, persisted at isovolumic loading. CONCLUSIONS Maximal regional torsion of the left ventricle is afterload dependent. The afterload response of torsion appears related to the effects of afterload on end-systolic volume.

Variability in measures of coronary lumen dimensions using quantitative coronary angiography

OBJECTIVES The purpose of this study was to determine the true total variability of quantitative coronary angiographic measures and their components in the clinical setting. BACKGROUND Many studies describe quantitative coronary angiographic variability on the basis of repeated quantitative coronary angiographic measures from the same cineangiogram. Although these studies characterize well the performance of quantitative coronary angiographic analysis methods, they do not include other potentially important sources of variability in results of this procedure, such as day to day variations in patients and equipment or variability in selection of frames for analysis. METHODS Coronary angiograms from 20 patients who underwent diagnostic angiography followed by percutaneous transluminal coronary angioplasty an average of 2.9 days later were reviewed. A total of 30 lesions well visualized in both films were analyzed multiple times using an automated first-derivative edge-detection quantitative coronary angiographic technique. RESULTS The coefficient of variation for quantitative coronary angiographic measures of the same lesions from separate angiograms ranged from 8.11% to 14.01%. Average diameter was the least variable and percent diameter stenosis the most variable. Day to day variations in the patient, procedure and equipment accounted for an average of 30% of the total variability. Of the remaining variability, only 13.26% was due to variability in frame selection. CONCLUSIONS These results provide useful information for planning clinical studies using quantitative coronary angiography, identify areas where additional improvements in this technology are needed and define more clearly the applicability of quantitative coronary angiography in the setting of routine clinical practice.

Clinical predictors of myocardial damage after high voltage electrical injury

Myocardial damage after high voltage electrical body injury is a serious and often life-threatening situation. The purpose of this pilot study was to identify early clinical predictors of myocardial damage in patients with high voltage electrical injury. Twenty-four patients with high voltage electrical injuries and no evidence of arc burns were evaluated. In 13/24 patients the diagnosis of myocardial damage was confirmed by total creatine kinase (CK) and creatine kinase MB (CK-MB) isoenzyme elevation (group A). In these patients the total CK range was 1373 to 52,544 mU/ml. In 11/24 patients CK-MB was negative (group B) indicating absence of myocardial damage. ECG changes occurred in 10/13 group A and 4/11 group B patients (p less than .095). No patient in either group gave a history suggestive of myocardial ischemia after the electrical injury. The pathways of electricity through the body, as mapped by a line drawn between the wound(s) of entrance and exit, were vertical in all group A patients, i.e., from upper to lower body segment, vs. 5/11 group B patients with evidence of a vertical pathway (p less than .003). Group A patients also had greater body surface burns (16.0 +/- 2.7%) vs. group B patients (4.0 +/- 1.6%, p less than .001). The presence of a vertical pathway and the magnitude of percent surface burns were found to be the most significant clinical predictors of myocardial damage in multiple logistic regression analysis (p less than .0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency of Hypoxanthine Guanine Phosphoribosyltransferase (HPRT−) T Cells in the Peripheral Blood of Cardiac Transplant Recipients A Noninvasive Technique for the Diagnosis of Allograft Rejection

BACKGROUND Histological evaluation of serial endomyocardial biopsies performed at fixed time intervals after cardiac transplantation is the universal method used for the detection of cardiac rejection and assessment of the adequacy of antirejection therapy. No noninvasive methodology thus far investigated has achieved a high enough sensitivity and predictive accuracy to be considered as a potential replacement for endomyocardial biopsy in the detection of rejection in adults. The present study exploited the finding that the rate of spontaneous mutation in the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene is higher in proliferating human T cells than in resting cells. Thus, it was reasoned that in the posttransplantation setting, the frequency of HPRT- cells in peripheral blood may provide an indirect measure of alloactivated T lymphocytes. METHODS AND RESULTS This study consisted of determining the clonal frequency of HPRT- mutant cells (FMC/10(6) peripheral blood mononuclear cells [PBMCs]) within a total of 293 peripheral blood samples representing various numbers of sequential samples from each of 27 transplant recipients. These sequential samples represented time periods when endomyocardial biopsy specimens showed either (1) no evidence of rejection (n = 5 patients), (2) a single initial episode after transplantation of early (< 1 year) or late (> 1 year) rejection (n = 12 patients), or (3) multiple rejection episodes (n = 10 patients). Statistical analyses were used to quantify the time profiles of FMC/10(6) PBMCs in serial samples among transplant recipients and to determine the association of these profiles with both the onset of first rejection episodes and, in appropriate patients, the recurrence of rejection episodes. Data showed that PBMCs from patients with no evidence of rejection uniformly gave low values of < 6 FMC/10(6) cells, a frequency similar to that seen in healthy nontransplanted volunteers. In contrast, 19 of the 22 PBMC samples that were obtained from patients whose corresponding biopsy sample was diagnosed with a histological rejection grade of > or = 3 gave values of > 6 FMC/10(6) cells, 11 of which gave values > 50/10(6) cells (range, 146 to 46,982 FMC/10(6) cells). A significant association between the onset of first rejection and an increased rate of FMC/10(6) values was noted (P = .0001). The ability of a rising trend in FMC/10(6) values to correctly identify the onset of rejection was 81.8% and to correctly identify no rejection, 100%. In addition, a significant association between recurrent rejection episodes and persistence of high FMC/10(6) values in the weeks after treated rejection episodes was noted (P = .0003). The ability of a persistently elevated trend in values of FMC/10(6) cells to correctly identify recurrent rejection was 90% and to correctly identify no rejection, 100%. CONCLUSIONS Increasing frequencies of HPRT- mutant cells in peripheral blood correlated with the onset of first rejection, and persistently elevated HPRT- mutant cells in the weeks after a treated rejection episode correlated with recurrent rejection. This quantitative noninvasive assay may thus serve as a useful adjunct to endomyocardial biopsy for monitoring post-cardiac transplantation patients, and its use as a prospective diagnostic tool merits further study.

Augmentation of pressure in a vessel indenting the surface of the lung

The lungs and intrathoracic cardiovascular structures compete for space within the thorax, interacting through their adjacent surfaces via the pleural space. Theoretical analysis and in vitro model studies (detailed here) established that when a vessel indents the lung surface, the increase in intravascular pressure with positive pressure lung inflation can be greater than the change in the pleural surface pressure measured outside of the interaction area. We define this phenomenon asintravessel pressure augmentation. We determined theaverage intravessel pressure gain as the slope of the linear regression of the pressure in a vascular structure of balloon indenting the lung on the pleural surface pressure measured by a flat disk-shaped device (disk). The analysis showed that the disk pressure overestimates the pleural pressure. Therefore, the derived pressure gain underestimated the pressure augmentation. In five dogs, the disk and a 2-ml balloon were placed in the lateral pleural space, and a segment of IVC was ligated at both ends and filled with saline. The dogs were ventilated with fixed tidal volumes, while the positive end-expiratory pressure was changed. The pressures were compared at the end of expiration. For the IVC segment, the pressure gains under four different tidal volumes were significantly greater than one [95% confidence interval of mean value (CIM)=1.57±0.16, P<10−4], and for the small balloon, this was the case for three of four tidal volumes (95% CIM for all four volumes 1.13±0.04, P<10−4). We conclude that the surface interaction of the lungs with adjacent cardiovascular structures causes appreciable pressure augmentation in those structures during ventilation with the positive end-expiratory pressure.

P-selectin inhibition prevents early neutrophil activation but provides only modest protection against myocardial injury in dogs with ischemia and forty-eight hours reperfusion

OBJECTIVES This study was designed to determine whether antibody neutralization of the adhesion protein P-selectin would prevent neutrophil activation and reduce myocardial reperfusion injury. BACKGROUND Although inhibition of P-selectin markedly reduces short-term myocardial injury after ischemia and reperfusion, it is unknown whether it can provide meaningful long-term protection and preserve left ventricular function. METHODS Closed-chest dogs underwent 90 min left anterior descending coronary artery occlusion and 48 h reperfusion, and were randomized to 1) a treatment group (n = 11) receiving 1 mg/kg of the blocking anti-P-selectin antibody PB1.3, or 2) a control group receiving 1 mg/kg PNB1.6 (nonblocking antibody against P-selectin, n = 7) or an equivalent volume of saline (n = 2) 10 min before reperfusion. Infarct size was assessed postmortem by triphenyl tetrazolium chloride staining. Contrast left ventriculography was used to measure left ventricular function. Activation of circulating polymorphonuclear neutrophils (PMNs) was assessed by an increase in surface CD18 expression. RESULTS Neutrophil activation was observed at 30 min after reperfusion in the control group, but was abolished in the treatment group. Infarct size was reduced about 25% in the treatment group after controlling for variations in ischemic blood flow (p = 0.003, by analysis of covariance). However, this protective effect was not associated with preservation of blood flow to the ischemic-reperfused myocardium, nor with any improvement in global or regional left ventricular function. CONCLUSIONS The anti-P-selectin antibody PB1.3 prevented early PMN activation, but had only a modest long-term infarct-limiting effect over 48 h reperfusion. Adhesion molecules other than P-selectin may mediate delayed PMN activation and accumulation in reperfused myocardium.