Twenty five years of case finding and audit.
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Humans↗
Biomedical subjects
S Kaul
Publications and source records attributed to S Kaul.
High-performance liquid chromatographic assay of alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802), a potential antipsychotic drug, in monkey and rat plasma.
A high-performance liquid chromatographic-fluorescence method was developed for the quantitative analysis of BMY-14802 (I) in monkey and rat plasma. After the addition of the internal standard (BMY-14853 I.S.), 250 microliters of plasma were made basic by the addition of 2 ml of saturated sodium carbonate buffer. Compound I and the I.S. were then extracted into 5 ml of methyl tert.-butyl ether. The organic phase was evaporated and the resulting residue was reconstituted in mobile phase. Final separation and quantitation of I was achieved on an octadecyl column with a 0.05 M potassium phosphate-acetonitrile-triethylamine-85% phosphoric acid (650:350:0.1:0.05, v/v) mobile phase. Fluorescence detection was used to monitor the eluent at an excitation wavelength of 240 nm and an emission wavelength of 400 nm. The limit of detection was 0.5 ng/ml. The standard curve was linear over the range 5.0-1000 ng/ml. Intra-assay and inter-assay precision values were less than 4.0% relative standard deviation and accuracy was within 12% of nominal values. Compound I was shown to be stable in monkey and rat plasma for at least six months when stored at -20 degrees C.
Animals↗
Contrast echocardiography and myocardial perfusion.
New clinical applications for myocardial contrast echocardiography (MCE) are being developed in both the operating room and the catheterization laboratory. Studies have shown that red blood cell transit time through the myocardium is a measure of myocardial blood flow. Sonicated albumin microbubbles can mimic intramyocardial behavior of red blood cells. Other studies have used MCE to assess collateral flow to determine myocardial viability after acute myocardial infarction. The authors have developed a computer system that allows on-line quantitation of contrast echocardiographic data in the operating room, and this system is able to confirm that bypass grafts are properly placed. The ability to quantitate myocardial flow with MCE may be useful in guiding the sequence of graft placement and for assessing the success of the operation. These measures will help lower the incidence of perioperative infarction. Experiments in our laboratory using the canine model have shown that MCE may be useful in assessing the intramyocardial distribution of retrogradely delivered cardioplegia. This technique may, therefore, assist the surgeon in determining the adequacy of retrograde cardioplegia delivery and may improve myocardial preservation during bypass surgery.
Albumins↗
Tumour-associated antigens of mammary carcinomas recognized by human monoclonal antibody 1G12.
We have reported the production of human monoclonal antibodies (mAb), by the fusion of lymph node lymphocytes from a primary carcinoma patient with murine myeloma cells. Seven heterohybridomas showed reactivity with class III antigens, and five hybridomas (1G12, 2D4, 4H5, 5D10 and 3B10) were reactive with class II antigens. One of these human mAbs (1G12) was intensively studied and results are presented here. 1G12 reacted strongly and specifically with five mammary carcinoma cell lines and showed no cross-reactivity with seven normal fibroblast cells. It continuously produced human mAbs (IgM) at a rate of 4.5-12.5 micrograms/ml over a period of 2 years. Human mAb 1G12 (IgM) was purified by either a combination of anion-exchange chromatography (ABx) and gel filtration (Superose 6) or affinity chromatography (agarose). Immunohistological analysis of frozen tissue sections was performed with biotinylated 1G12. All mammary carcinomas analysed (n = 26) were positive, while the connective tissue of 36 different patients was completely negative with 1G12. In normal breast, endometrium and intestine only a weak or moderate staining of the epithelial cells was observed. Normal oesophagus, small bowel, cervix, uterus, lung and skin were completely negative. Partly purified tumour antigen recognized by 1G12 had a molecular mass of 1-2 MDa and showed strong binding with Ulex europaeus lectin I and Bauhina purpurea agglutinin, indicative for the glucoprotein nature of antigens. These results show that human mAb 1G12 may be useful for the analysis of tumour-associated antigen of mammary carcinoma patients. In further studies the therapeutic and diagnostic application of 1G12 should be analysed in more detail.
Animals↗
Cardiac manifestations of acquired immune deficiency syndrome: a 1991 update.
Cardiac involvement is being identified more often clinically and at autopsy in patients with AIDS. Recent estimates suggest that in the United States as many as 5000 patients per year may have cardiac complications resulting from HIV infection. Patients with AIDS may have pericardial, myocardial, and/or endocardial disease. Pericardial tamponade and/or constriction may be related to neoplasms, infections, or nonspecific effusions. Myocardial dysfunction may result from specific neoplastic infiltration or myocarditis. Particularly intriguing is the role of HIV-1 in the nonspecific myocarditis and dilated cardiomyopathy that occurs in patients with AIDS. As in other debilitating conditions patients with AIDS can have nonbacterial thrombotic endocarditis. Infective endocarditis may be a complication, especially in AIDS associated with intravenous drug abuse. Most patients with AIDS have no overt clinical evidence of cardiac disease. When cardiac dysfunction does develop, the signs and symptoms are often misinterpreted to be the result of noncardiac causes (pulmonary failure or infection) which can mimic heart failure. This review is intended to alert the reader to the cardiac manifestations of AIDS, which present a number of diagnostic and therapeutic challenges.
Acquired Immunodeficiency Syndrome↗
Relation between anterograde blood flow through a coronary artery and the size of the perfusion bed it supplies: experimental and clinical implications.
The relation between anterograde blood flow through a coronary artery and the size of the perfusion bed it supplies is not known. Accordingly, the left circumflex coronary artery was cannulated and perfused with arterial blood in 12 open chest mongrel dogs. In Group I dogs (n = 7), the goal was to correlate the size of the perfusion bed with the magnitude of anterogradely derived myocardial blood flow. The size of the perfusion bed was measured with use of two-dimensional myocardial contrast echocardiography, whereas anterograde myocardial blood flow was determined by injecting radiolabeled microspheres directly into the artery. In Group II dogs (n = 5), the goal was to study the effects of altering coronary blood flow on both anterogradely and collateral vessel-derived myocardial flow within the perfusion bed. In these dogs, microspheres were injected directly into both the coronary artery and the left atrium at each flow rate. In Group I dogs, the left circumflex perfusion bed size, as defined by myocardial contrast echocardiography, decreased at lower anterograde myocardial blood flow rates. The change in perfusion bed size occurred at the lateral zones. There was a linear relation between the normalized perfusion bed size and the normalized anterograde myocardial blood flow: y = 0.45x + 54.2 (p less than 0.001, r2 = 0.77). These results were substantiated in Group II dogs, in which the size of the perfusion bed was approximated with use of radiolabeled microspheres. The size of the perfusion bed was most affected when anterograde myocardial blood flow decreased to less than approximately 33% of normal. At the lowest flow rates, there was a linear relation between anterograde blood flow versus the fraction of the left circumflex flow derived anterogradely: y = 2.41x + 0.22 (p less than 0.001, r2 = 0.90). The lower the level of anterograde flow, the greater was the blood flow derived from remote vessels. It is concluded that the size of the area perfused by a coronary artery is significantly influenced by the magnitude of anterograde blood flow through that artery. These findings may have important implications in experimental and clinical models of myocardial ischemia.
Animal Nutritional Physiological Phenomena↗
Pharmacokinetics of 2',3'-dideoxyinosine (BMY-40900), a new anti-human immunodeficiency virus agent, after administration of single intravenous doses to beagle dogs.
The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were investigated in four adult male beagle dogs that received 15-min infusions of 20-, 50-, and 100-mg/kg doses in a randomized crossover study design. Plasma and urine samples were collected for 10 and 24 h, respectively, and assayed for ddI by high-performance liquid chromatographic methods. The mean maximum concentrations of drug in plasma at the end of 15-min infusions for the 20-, 50-, and 100-mg/kg doses were 33.3, 90.0, and 202 micrograms/ml, respectively. Area under the concentration-time curve data deviated significantly from linearity. The mean total clearance for the low dose (250 ml/min) was significantly greater than that for the high dose (190 ml/min). Renal clearance, which averaged between 98 and 116 ml/min, was dose independent. Renal clearance implied that nonrenal clearance decreased at the high dose (92 ml/min) when compared with that of the low dose (134 ml/min). The average urinary recovery of ddI for the high dose (51.2% of dose) was significantly greater than that for the low dose (45.8%). The volume of distribution at steady state averaged between 7.6 and 10.5 liters and decreased with increasing dose; however, it was not statistically significant. The mean half-life and mean residence time were invariant with respect to dose and averaged between 0.94 and 1.07 h and 0.61 and 0.71 h, respectively. In this dose range, ddI pharmacokinetics are dose dependent.
Animals↗
Prediction of outcome after mitral valve replacement in patients with symptomatic chronic mitral regurgitation. The importance of left atrial size.
BACKGROUND: The ability to predict outcome after mitral valve replacement remains limited in patients with symptomatic chronic mitral regurgitation. The aims of this study were to determine the preoperative predictors of postoperative cardiac-related mortality and to assess the additive prognostic value of tests performed in such patients. METHODS AND RESULTS: Accordingly, 176 patients (mean age, 57 +/- 14 years) who underwent mitral valve replacement were followed up for 3.8 +/- 0.5 years. Four categories of variables were analyzed to predict postoperative cardiac-related mortality: clinical, laboratory, two-dimensional echocardiographic (2DE), and cardiac catheterization. There were 39 cardiac-related deaths (29 due to congestive heart failure and 10 sudden). When the four categories were analyzed separately, two clinical, one laboratory, two 2DE, and one catheterization variable best predicted postoperative death. When these six variables were examined simultaneously, only three (one clinical and two 2DE) remained significant predictors of cardiac-related mortality: presence of pulmonary rales, left atrial size, and the ratio of left ventricular wall thickness to left ventricular cavity dimension in end systole. A model based on these three variables may predict cardiac-related death with considerable accuracy. Laboratory data did not add to clinical information for predicting death. 2DE variables provided significant additional information in this regard (p less than 0.001). Further addition of catheterization variables was not useful. Prognostic value did not change significantly when 50 patients with prior mitral valve surgery or 49 patients undergoing concomitant aortic valve replacement or coronary artery bypass surgery were excluded from analysis. CONCLUSIONS: We conclude that 1) measures of both left ventricular systolic function and left atrial size are equally important in predicting postoperative cardiac-related mortality in patients with symptomatic chronic mitral regurgitation undergoing mitral valve replacement; 2) left atrial size may be important because it reflects the "history" (severity and duration) of mitral regurgitation; 3) 2DE assessment of left atrial size and left ventricular function provides prognostic information that is significantly greater than that obtained from clinical and laboratory parameters alone; the addition of catheterization variables does not increase the prognostic value of the clinical and 2DE data.
Atrial Function, Left↗
Importance of two-dimensional echocardiographic assessment of left ventricular systolic function in patients presenting to the emergency room with cardiac-related symptoms.
BACKGROUND: This prospective study was designed to test the hypothesis that the assessment of left ventricular systolic function at the time of emergency room (ER) presentation provides valuable diagnostic and prognostic information in patients with cardiac-related symptoms. METHODS AND RESULTS: The study is based on a 2-year follow-up of 171 consecutive patients evaluated in the ER for such symptoms. In the course of follow-up, one third of the patients (55 of 171) suffered a major cardiac event. For those with left ventricular systolic dysfunction (LVSD), the age-adjusted rate of early events (occurring within 48 hours of presentation) was more than eight times higher than for those without LVSD (26.9% versus 3.3%, p less than 0.01). For events occurring after 48 hours of ER presentation, LVSD was associated with a nearly fourfold excess of cardiac events (23.9% versus 6.4%, p less than 0.01). Other than advanced age, the most important confounder for early events included an abnormal electrocardiogram diagnostic for acute myocardial infarction. Confounders for late events included advanced age and a history of hypertension. LVSD on two-dimensional echocardiography (2DE) was the only finding associated with early and late events after controlling for other risk factors. In addition, the prediction of these events derived from the combination of historical, clinical, electrocardiographic, and 2DE findings was significantly improved when accounting for the presence or absence of LVSD (p less than 0.01). CONCLUSIONS: We conclude that the 2DE assessment of left ventricular systolic function provides valuable diagnostic and prognostic information in subjects presenting to the ER with cardiac-related symptoms.
Angina Pectoris↗
Mechanism of ischemic mitral regurgitation. An experimental evaluation.
BACKGROUND: Papillary muscle dysfunction (PMD) has been implicated in the pathogenesis of ischemic mitral regurgitation (MR). We hypothesized that ischemic MR is not caused by PMD and/or dysfunction of the myocardial regions from where the papillary muscles arise but is related to reduction in global left ventricular (LV) function. To test this hypothesis, three groups of dogs were studied. METHODS AND RESULTS: In group 1 dogs (n = 8), varying degrees of regional and global LV dysfunction were produced. In group 2 dogs (n = 7), the circulation to the papillary muscles was isolated from that of the rest of the LV. Dysfunction of one or both papillary muscles was produced without producing global LV dysfunction. Global LV dysfunction was also produced while keeping papillary muscle function intact. The degree of MR (assessed using contrast echocardiography) was correlated in both groups of dogs with thickening of the papillary muscles and regional and global LV function. In the group 3 dogs (n = 6), the spatial distribution of blood flow within each papillary muscle was determined during ischemia by using radiolabeled microspheres. Thickening of the papillary muscles was assessed at three different levels along their lengths and was correlated with average blood flow at these levels. In group 1 dogs, MR was noted only when global LV function was affected and its severity correlated inversely with global LV function (r = -0.84 with peak positive LV dP/dt and r = -0.95 with global LV thickening, respectively). In comparison, there was poor correlation between MR and anterior and posterior papillary muscle thickening (r = -0.38 and r = -0.49, respectively). In group 2 dogs, MR did not occur in the presence of either PMD or akinesia of the immediately adjacent LV myocardium. MR occurred only when global LV dysfunction was produced (with the papillary muscle function intact), and its severity correlated inversely with global LV function (r = -0.92 with LV dP/dt and r = -0.86 with global LV thickening, respectively). There was poor correlation between the degree of MR and thickening of the anterior and posterior papillary muscles (r = -0.24 and r = -0.38, respectively). In both groups of dogs, MR was associated with incomplete mitral leaflet closure (IMLC), and the severity of MR correlated linearly with the degree of IMLC (r = 0.98). MR was never associated with mitral valve prolapse. In the group 3 dogs, despite more inhomogeneous flow during ischemia to the anterior compared with the posterior papillary muscle, mean thickening of these muscles was similar (3 +/- 10% and 3 +/- 4%, respectively). Furthermore, there was minimal variability in thickening between different parts of the muscles (3 +/- 2% and 5 +/- 3%, respectively). CONCLUSIONS: It is concluded that PMD and/or dysfunction of the immediately adjacent LV myocardium does not result in MR. MR occurs during ischemia only when global LV function is affected, even when thickening of the papillary muscles and the immediately adjacent LV remains intact. MR in this situation is related to IMLC; the greater the degree of IMLC, the greater the MR. These findings suggest that the mechanism of ischemic MR is not related to PMD. There may also be important therapeutic implications of these findings.
Animals↗
Microcirculatory dysfunction following perfusion with hyperkalemic, hypothermic, cardioplegic solutions and blood reperfusion. Effects of adenosine.
BACKGROUND: Cardioplegic solutions have been used to enhance myocardial preservation during cardiac surgery. The benefits derived from preventing myocardial ischemia with cardioplegic solutions may, however, be countered by tissue damage that occurs when the myocardium is reperfused with oxygenated blood. Furthermore, cardioplegia-induced endothelial dysfunction may contribute to depressed myocardial function postoperatively. The endothelium of coronary arteries and vein grafts is damaged by crystalloid cardioplegic solutions. There is less known about the effects of cardioplegic solutions on the microvasculature. METHODS AND RESULTS: The hypothesis that microvascular damage occurs following perfusion with hyperkalemic, crystalloid, cardioplegic solutions and blood reperfusion, leading to decreased blood flow and increased neutrophil accumulation, was tested in a model system. Intravital microscopic observations were performed during a 20-minute perfusion of the hamster cremaster muscle with cardioplegic solutions (10 degrees C) via the femoral artery with the iliac occluded and during a subsequent 2-hour blood reperfusion period (iliac open). Arteriolar vasoconstriction (27% decrease in diameter, p less than 0.05) and a 25% decrease in the density of perfused capillaries (p less than 0.05) occurred during reperfusion in hamsters receiving crystalloid cardioplegic solution (16 meq K+) compared to control hamsters (no cardioplegic solution given). Neutrophils accumulated on venular endothelium in treated animals (250% increase, p less than 0.05) and extravascularly (myeloperoxidase levels 2.0 +/- 0.4 U/g versus 1.3 +/- 0.3 U/g in control, p less than 0.05). The addition of adenosine (10(-4) M) and albumin (2 g%) to the cardioplegic perfusate, accompanied by the administration of adenosine (10(-4) M) during reperfusion, produced arteriolar vasodilation (34% diameter increase, p less than 0.05) and inhibited extravascular neutrophil accumulation (myeloperoxidase level of 1.5 +/- 0.2 U/g, p greater than 0.05 versus control). Capillary perfusion, however, was still significantly diminished (28% decrease, p less than 0.05.) CONCLUSIONS: We conclude that injury manifest by decreased microvascular blood flow and increased neutrophil accumulation in tissues occurs after perfusion with hypothermic, hyperkalemic, crystalloid cardioplegic solutions and blood reperfusion. Adenosine seems to partially attenuate this injury by dilating arterioles and decreasing extravascular neutrophil accumulation.
Adenosine↗
Quantitation of myocardial perfusion with contrast echocardiography.
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Animals↗
Doppler echocardiography in critically ill cardiac patients.
E-D is a powerful technique that can provide invaluable information in the acutely ill cardiac patient. It can help in the early diagnosis of conditions causing acute chest pain such as AMI and aortic dissection. E-D can help diagnose the causes of underlying hemodynamic instability such as hypotension and pulmonary edema, and it can help determine the initial management strategy. In this regard, E-D can replace Swan-Ganz catheterization in most patients. In patients with AMI who may appear to be hemodynamically stable, it can provide information regarding the following: size of risk area; status of the regions of the myocardium remote from the infarcted zone; effect of reperfusion therapy on regional myocardial function; presence or absence of nonsurgical complications such as ischemic mitral regurgitation, LV thrombus, or aneurysm; and patients at risk for immediate or late cardiac events. It is likely that as the newer generation of cardiologists becomes adequately trained in E-D, this technique will find routine use in every critical care unit.
Acute Disease↗
Value of regional wall motion abnormality in the emergency room diagnosis of acute myocardial infarction. A prospective study using two-dimensional echocardiography.
Because regional wall motion abnormality (RWMA) is usually noted during ischemia, we hypothesized that the presence of this finding with two-dimensional echocardiography would be superior to conventional methods of diagnosing acute myocardial infarction (AMI) in the emergency room. We also hypothesized that because the absence of RWMA would probably not be associated with AMI, the use of two-dimensional echocardiography would significantly limit unnecessary hospital admissions. To test these hypotheses, we undertook a prospective study that used two-dimensional echocardiography in 180 patients presenting to the emergency room with symptoms suggestive of AMI. The emergency room physicians were not informed of the two-dimensional echocardiography findings, and their decision to admit or not admit to the hospital was based on conventional clinical and electrocardiographic criteria. Forty patients were not admitted to the hospital and 140 were admitted. Of the 30 patients with enzyme-confirmed AMI, nine had typical ST elevation on the ECG that was consistent with acute injury, three had normal ECGs, and eight had ECGs in the presence of which AMI could not have been diagnosed (left bundle branch block, paced rhythm, or repolarization changes); the rest had nonspecific ECG findings. Of the 29 AMI patients with technically adequate two-dimensional echocardiography studies, two did not demonstrate RWMA and 27 had RWMA, compared with nine with diagnostic ECG changes (p less than 0.001). Of the 13 patients with in-hospital complications only four had an initial ECG showing ST elevation, and all 13 had RWMA (p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Dipyridamole/thallium-201 imaging: how safe is it? When should it be used?
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Contraindications↗
A model to predict multivessel coronary artery disease from the exercise thallium-201 stress test.
PURPOSE: The aim of this study was to (1) determine whether nonimaging variables add to the diagnostic information available from exercise thallium-201 images for the detection of multivessel coronary artery disease; and (2) to develop a model based on the exercise thallium-201 stress test to predict the presence of multivessel disease. PATIENTS AND METHODS: The study populations included 383 patients referred to the University of Virginia and 325 patients referred to the Massachusetts General Hospital for evaluation of chest pain. All patients underwent both cardiac catheterization and exercise thallium-201 stress testing between 1978 and 1981. RESULTS: In the University of Virginia cohort, at each level of thallium-201 abnormality (no defects, one defect, more than one defect), ST depression and patient age added significantly in the detection of multivessel disease. Logistic regression analysis using data from these patients identified three independent predictors of multivessel disease: initial thallium-201 defects, ST depression, and age. A model was developed to predict multivessel disease based on these variables. As might be expected, the risk of multivessel disease predicted by the model was similar to that actually observed in the University of Virginia population. More importantly, however, the model was accurate in predicting the occurrence of multivessel disease in the unrelated population studied at the Massachusetts General Hospital. CONCLUSION: It is, therefore, concluded that (1) nonimaging variables (age and exercise-induced ST depression) add independent information to thallium-201 imaging data in the detection of multivessel disease; and (2) a model has been developed based on the exercise thallium-201 stress test that can accurately predict the probability of multivessel disease in other populations.
Arrhythmias, Cardiac↗
Prevalence and correlates of increased lung/heart ratio of thallium-201 during dipyridamole stress imaging for suspected coronary artery disease.
There is little information concerning the prevalence and clinical correlates of increased pulmonary thallium-201 uptake during dipyridamole thallium-201 stress imaging. Accordingly, the clinical characteristics and quantitative thallium-201 findings were correlated with quantitative lung/heart thallium-201 ratio in 87 patients undergoing dipyridamole thallium-201 stress testing. Nineteen patients (22%) had an elevated ratio (greater than 0.51). These patients were more likely to have had an infarction, to be taking beta blockers, and have a lower rate-pressure product after dipyridamole administration than those with a normal ratio (p less than 0.03). An elevated ratio was associated with a greater likelihood of initial, redistribution and persistent defects, as well as left ventricular cavity dilatation on thallium-201 imaging (p less than 0.05). In addition, the number of myocardial segments demonstrating initial, redistribution and persistent defects was also greater in patients with increased ratios (p less than 0.03). Multivariate analysis demonstrated that the presence of redistribution and left ventricular cavity dilatation were the most significant correlates of lung/heart thallium-201 ratio. It is concluded that the prevalence of increased lung/heart thallium-201 ratio with dipyridamole thallium-201 stress imaging is similar to that seen with exercise stress imaging. As with exercise thallium-201 imaging, increased pulmonary thallium-201 uptake may be a marker of functionally more significant coronary artery disease.
Adult↗
Clinical relevance of exercise-induced ventricular arrhythmias in suspected coronary artery disease.
Because there is controversy regarding the clinical relevance of exercise-induced ventricular arrhythmias, we analyzed their significance in 383 patients who had undergone both exercise thallium-201 stress-testing and cardiac catheterization. Two-hundred twenty-one patients (58%) had no exercise-induced ventricular arrhythmias while 162 (42%) did. There was no difference between patients with and without exercise-induced ventricular arrhythmias in terms of previous myocardial infarction (p = 0.61), incidence of fixed thallium-201 defects (0.06), number of diseased vessels (p = 0.09) and resting left ventricular ejection fraction (p = 0.06). In contrast, evidence of provocable ischemia (redistribution on thallium-201 and ST-segment depression on the electrocardiogram) were more likely (p less than 0.02) to be seen in patients with exercise-induced ventricular arrhythmias. Discriminant function analysis revealed that these 2 variables best separated patients with and without exercise-induced ventricular arrhythmias. In a 4- to 8-year follow-up, 89 patients had adverse cardiac events. Of these 89, there were 41 deaths, 9 nonfatal myocardial infarctions and 39 coronary revascularization procedures performed later than 3 months after catheterization. Patients with exercise-induced ventricular arrhythmias were more likely (p = 0.01) to have these events than those without these arrhythmias. Moreover, these arrhythmias provided independent prognostic information beyond that provided by the thallium-201 stress test and coronary angiography. We conclude that exercise-induced ventricular arrhythmias are associated with exercise-induced ischemia and provide prognostic information which adds marginally to that provided by other noninvasive and invasive parameters in ambulatory patients being evaluated for chest pain.
Arrhythmias, Cardiac↗