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Biomedical subjects

T F Schaible

Publications and source records attributed to T F Schaible.

At least 37 records · Page 2Linked to original sources

Cardiovascular applications: current status of immunoscintigraphy in the detection of myocardial necrosis using antimyosin (R11D10) and deep venous thrombosis using antifibrin (T2G1s).

The remarkable progress in immunologic techniques in the development of monoclonal antibodies offers the potential for powerful new tools for the detection of cardiovascular disorders, such as acute myocardial necrosis and acute deep venous thrombosis, in an accurate, safe, and noninvasive manner. Historically the use of monoclonal antibodies has been viewed as a tool dominated by the field of oncology. However, because of the relative ease of identifying and characterizing well-defined, unique antigens on necrotic cells, blood clots, and cellular components of the circulatory system, the chance for success in developing a clinically useful diagnostic product is significantly enhanced. In addition to being unique, these antigenic sites are also virtually universal in their expression by the targeted tissues or cells in the human population. Also, the epitope for these antibodies is less prone to "shedding" than many of the tumor markers present on the surface of malignant cells. This review describes the clinical experience with two immunoscintigraphic diagnostic agents specifically designed for the assessment of cardiovascular disorders resulting in the death of myocytes and the formation of acute blood clots indium-111 antimyosin-Fab-diethylenetriamine pentaacetic acid for the detection of myocardial necrosis and technetium-99m antifibrin Fab' (T2G1s) for the detection of acute venous thrombosis.

Aged↗

Noninvasive arterial thrombus imaging with 99mTc monoclonal antifibrin antibody.

BACKGROUND: The T2G1s monoclonal antifibrin antibody binds specifically to fibrin but not to fibrinogen. METHODS AND RESULTS: In a canine model of acute arterial thrombosis, we determined the feasibility of imaging thrombi using a 99mTc-labeled Fab' fragment. In 14 dogs, 10 carotid and 13 femoral artery thrombi were produced using 2-hour temporary occlusion, crush injury, and local thrombin injection methods. A sham-operated carotid artery served as control. Antifibrin antibody was injected intravenously at the end of temporary occlusion. Serial planar radionuclide images were obtained immediately and at 1 and 2 hours. Following killing the dogs at 2 hours, we measured antibody uptake ex vivo in 5-mm-long segments of thrombus, the adjacent injured artery, and a control artery. Antibody was cleared from the blood with a mean +/- SD t1/2 of 121 +/- 23 minutes. The thrombi weighed 218 +/- 140 mg. Antibody uptake in the thrombi was patchy, and the thrombi were closely adherent to the injured arterial wall. In the segment with maximal ex vivo antibody uptake, the ratio of control artery to blood counts/g/sec was 0.65 +/- 0.46, the injured artery-to-blood ratio was 2.35 +/- 1.01 (p less than 0.0001 versus control), and the thrombus-to-blood ratio was 4.24 +/- 2.58 (p less than 0.0001 versus control). In three dogs, an isotype-matched ovarian tumor antibody labeled with 111In was injected with T2G1s but was not taken up in the thrombus or the adjacent arterial wall. Visual analysis of the in vivo carotid radionuclide images showed uptake by 2 hours in all 10 carotid thrombi. Quantitative image analysis, measured as the thrombus-to-opposite carotid artery ratio, showed increasing uptake over time with ratios of 1.1 +/- 0.3, 1.6 +/- 2.0, and 2.2 +/- 1.3 on the immediate, 1-hour, and 2-hour images, respectively. All quantitative ratios of 1.3 or greater were visually identified. CONCLUSIONS: 99mTc-labeled Fab' fragments of the T2G1s antibody are taken up specifically by acute arterial thrombi after intravenous injection. Uptake is progressive over a 2-hour period, and all thrombi are detected by radionuclide imaging at 2 hours. These results show that it is feasible to noninvasively detect arterial thrombi within 2 hours of formation.

Animals↗

Antifibrin scintigraphy in the diagnostic evaluation of acute deep venous thrombosis.

Antifibrin scintigraphy is a new and innovative approach to the diagnosis of acute deep venous thrombosis (DVT). Many antifibrin monoclonal antibodies (Mo-Abs) have been described, but only two, 59D8 and T2G1s, have undergone broad preclinical or clinical investigation. Both of these MoAbs recognize an epitope on the amino terminal end of fibrin. The epitope for 59D8 and T2G1s is available for binding only on newly formed, acute thrombi. Preclinical studies have confirmed the specificity of these MoAbs for acute DVT, and have demonstrated their ability to image experimentally induced DVT. Preliminary clinical studies in patients with signs or symptoms of DVT have evaluated indium-111 59D8 Fab and technetium-99m T2G1s Fab'. Fragments of the intact MoAbs are employed to promote faster blood clearance and to reduce immunogenicity. The initial clinical studies indicate that antifibrin scintigraphy has a diagnostic accuracy approaching 90%. Antifibrin scintigraphy has the potential for overcoming many of the deficiencies of both invasive (contrast venography) and noninvasive (Doppler/ultrasound, impedance plethysmography) methods for detecting DVT. With a single procedure, it provides an accurate and rapid evaluation of both lower extremities, both above and below the knee. Because of its unique specificity for acute DVT, it should have excellent potential for use in patients with suspected acute, recurrent DVT, a condition difficult to diagnose by all currently employed tests for DVT.

Animals↗

Radiolabeled antifibrin antibody in the detection of venous thrombosis: preliminary results.

The recent development of monoclonal antibodies against components of coagulated blood may provide new approaches to the diagnosis of venous thrombosis. Scanning with an indium-111-labeled Fab fragment of a murine monoclonal antifibrin antibody (59D8) and ascending contrast venography were performed in 33 patients. Images of the calves, popliteal fossae, thighs, and pelvis were obtained immediately, 4-6 hours, and 24 hours after injection of 2 mCi (74 MBq) of the antibody. All images were read in a blinded manner. Findings in both studies were positive in 28 patients and negative in three. In 19 patients not undergoing heparin therapy, 19 specific anatomic sites were positive on venograms and 29 were positive on antibody images (19 sites matched). In 14 patients undergoing heparin therapy, 34 sites were positive on venograms and 27 were positive on antibody images (22 sites matched). In most patients, positive results were noted within 1 hour of antibody injection. No adverse effects were noted with the antibody preparation. Preliminary data suggest that antifibrin antibody imaging is sensitive in detecting clots, is safe to use, and may have a role in diagnosing and managing venous thrombosis.

Adult↗

Multicenter double-blind placebo-controlled study of gadopentetate dimeglumine as an MR contrast agent: evaluation in patients with cerebral lesions.

A multicenter double-blind randomized study was designed to evaluate and compare the safety and diagnostic efficacy of gadopentetate dimeglumine (Gd-DTPA) (0.1 mmol/kg) against a saline placebo for use as an IV contrast agent for MR. The randomization code provided for a 2:1 ratio of Gd-DTPA and saline patients. Six investigators studied 88 patients with signs and symptoms of a cerebral lesion. Although safety data were complete in all 88 cases, only 83 had valid efficacy data (57 received Gd-DTPA, 26 placebo). Three patients were excluded from efficacy evaluation because of incomplete scans or scans with severe motion artifacts. Two patients were excluded for protocol variations (did not have a mass lesion). The protocol required that spin-echo MR images be acquired both before and after infusion at mode 1, 500/30/2 (TR/TE/excitations), and at a single-echo mode 2 sequence within a selected range, 1500-2000/56-90/2. Additional TEs could also be used at the discretion of each investigator. Efficacy was determined by comparing post- with preinjection images for relative degree of enhancement and improvement of diagnostic ability after injection, and by comparing these results with placebo results. Enhancement was reported in 43 (75%) of 57 Gd-DTPA patients and in none of the 26 placebo patients. Improvement of diagnostic ability was noted in 37 of 57 Gd-DTPA patients and in no placebo patients. Of 17 patients receiving Gd-DTPA for whom no diagnosis could be made before infusion, nine of 17 were diagnosed after infusion. By comparison, none of five patients not diagnosed before infusion of placebo could be diagnosed after infusion. Of 43 patients in whom lesion enhancement was observed after Gd-DTPA infusion, the diagnosis changed after infusion in 16 (37%) and the number of lesions detected after infusion increased in 10 (23%). Safety studies showed no clinically significant abnormal trends. Minor changes in blood pressure, pulse, and serum iron levels were noted in a higher percentage of Gd-DTPA patients. This study confirms that Gd-DTPA is an efficacious contrast agent for use with MR and that it exhibits excellent patient tolerance. Enhancement allows for a decisive diagnosis to be made in selected cases in which such capability had previously been lacking with unenhanced MR.

Adolescent↗

Gd DTPA. Clinical efficacy.

Both the diagnostic accuracy and sensitivity of the MRI diagnosis of central nervous system neoplasms appear to be improved by the administration of a paramagnetic contrast agent, Gd DTPA.

Brain Neoplasms↗

Effects of pregnancy on cardiac function and myosin enzymology in the rat.

Previous studies of cardiac function during pregnancy, while suggesting that this condition is associated with improved myocardial contractility, have been biased by the altered in vivo loading conditions. Therefore, we have investigated intrinsic cardiac function and contractile protein biochemistry during pregnancy in isolated rat hearts under controlled loading conditions. Animals were impregnated and studied after 1 and 3 wk and 2-3 days postpartum (gestation 21 days). The data show that hearts from pregnant animals (at 3 wk) had improved contractile performance as manifested by an 11% increase in fractional shortening, a 20% increase in velocity of circumferential fiber shortening, and an upward-shifted force-velocity relationship. These findings were paralleled by a 16% increase in Ca2+-activated myosin and an 11% increase in actin-activated ATPase activities. Thus pregnancy in the rat is associated with slightly improved cardiac contractility and biochemistry. This may relate directly to the hormonal status of the pregnant animal or to the effects of chronic volume overload.

Actins↗

Effects of gonadectomy and hormonal replacement on rat hearts.

To evaluate the effects of sex hormones on heart function and biochemistry, gonadectomy (GX) was performed in postpubertal male (M) and female (F) rats and compared with sham-operated controls (SH). The groups were MSH; MGX; MGX replaced with testosterone 3 mg/day s.c. (MGX + T), FSH, and FGX replaced with estrogen 2 mg/day (FGX + E), progesterone 0.4 mg/day (FGX + P), estrogen and progesterone (FGX + EP), or testosterone 2 mg/day (FGX + T). Body weight was decreased in MGX and was decreased further in MGX + T. Heart weight was decreased in both MGX and MGX + T. Body weights were increased in FGX and FTX + P and were increased further in FGX + T but were normal in FGX + E and FGX + EP. Heart weights were unchanged in F groups except in FGX + T, where it was increased. Cardiac performance in perfused hearts, as measured by stroke work, ejection fraction, fractional shortening and mean velocity of circumferential fiber shortening, was decreased in MGX but was slightly increased in MGX + T. Papillary muscle studies showed increases in time to peak tension and one-half relaxation in MGX, but these were decreased in MGX + T. Isotonic shortening studies showed decreased velocity of shortening in MGX and increased velocity in MGX + T. Heart function was significantly decreased in FGX and FGX + P compared with FSH but was similar to FSH in FGX + E and FGX + EP. FGX + T had greater stroke work and ejection fraction than FSH and FGX.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗

Combined effects of hypertension and conditioning on coronary vascular reserve in rats.

To evaluate the combined effects of cardiac overload imposed by hypertension and chronic swim training on coronary vascularity, female rats were made hypertensive by unilateral renal artery stenoses and were exercised in an 8- to 10-wk swimming program. Maximal coronary flow was assessed in isolated retrograde buffer-perfused hearts under conditions of minimal coronary resistance (15 microM adenosine or anoxia). Sedentary normotensive animals, sedentary hypertensive animals, and normotensive animals exposed to a swimming program were also studied. Swimming was associated with an 18% increase in heart weight and with increases in both absolute (ml/min) and relative (ml X g-1 X min-1) maximal coronary flow. Hypertension was associated with a 32% increase in heart weight but with a decrease in absolute and relative coronary flow compared with controls. The combined stimuli resulted in a 63% myocardial hypertrophy and a 19% increase in absolute flow. Relative coronary flow (g tissue-1) was similar in hearts from hypertensive sedentary animals and hypertensive swimmers. These data indicate that the coronary vascular deficit that accompanies the cardiac hypertrophy of hypertension is not worsened by the superimposition of an exercise load that exaggerates the hypertrophy.

Animals↗

Chronic swimming reverses cardiac dysfunction and myosin abnormalities in hypertensive rats.

The purpose of this study was to determine whether a chronic swimming program could reverse the decreased cardiac function and altered myosin biochemistry found in hearts of rats with established renal hypertension. Ten wk after the onset of hypertension [midpoint (m)], hearts from normotensive controls (C) and hypertensives (H) were studied in an isolated working heart apparatus, and myosin biochemistry was analyzed. Half of the control and hypertensive animals were then subjected to a 10-wk swimming program (Sw) and their hearts were compared with those from age-matched sedentary rats. Body weight was no different at the midpoint of the study between Cm and Hm or at the end point (e) of the study among Ce, Swe, He, or H-Swe. Swimming had no effect on blood pressure in either normotensive or hypertensive rats. Dry heart weight was increased by 46% in Hm compared with Cm and by 36% in He, 21% in Swe, and 61% in H-Swe when compared with Ce. Hypertension was associated in both the mid- and end-point studies, with decreases in coronary flow, stroke work (both per gram left ventricle), ejection fraction, and midwall fractional shortening. In addition, actin-activated myosin adenosinetriphosphatase (ATPase) activity was decreased in Hm and He associated with an increase in the content of the V3 myosin isoenzyme. Although the coronary deficit was not corrected in H-Swe, stroke work, ejection fraction, and fractional midwall shortening were normalized compared with control hearts. Myosin ATPase activity and the myosin isoenzyme distribution were similarly restored in H-Swe.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗

Abnormal cardiac biochemistry in spontaneously diabetic Bio-Breeding/Worcester rat.

Diabetes produced by injection of alloxan or streptozotocin results in cardiac dysfunction in rats that is associated with lower cardiac contractile protein ATPase activity. The purpose of this investigation was to examine cardiac myosin biochemistry in the Bio-Breeding Worcester (BB/W) rat, a strain in which diabetes occurs spontaneously and closely resembles insulin-dependent diabetes in humans. Hearts from diabetic BB/W rats were studied at 1, 4, and 7 mo after the onset of diabetes and were compared with age-matched BB/W rats that were bred for resistance to diabetes. Calcium-stimulated myosin ATPase activity was significantly decreased after 4 and 7 mo of diabetes, and actin-activated myosin ATPase was significantly depressed at all time points. Differences between hearts from control and diabetic animals increased with the duration of diabetes. Closely associated with reductions in myosin ATPase activity in the diabetes was a shift in the isomyosin content from the normally predominant V1 to the V3 isoenzyme. Thus diabetes that results from genetic causes leads to depressed myosin enzymatic activity in the rat. Furthermore, since previous studies have shown that BB/W diabetic rats do not develop hypothyroidism, the present results support the view that altered thyroid function does not mediate the abnormalities in cardiac contractile proteins in diabetes.

Adenosine Triphosphatases↗

Early increases in coronary vascular reserve in exercised rats are independent of cardiac hypertrophy.

To evaluate the relationship between the physiological cardiac hypertrophy associated with physical training and the increases in vascular capacitance associated with this stimuli, male and female rats trained by a swimming program were studied. Both sexes were used so that the coronary vascular response to exercise could be studied in the presence (females) and absence (males) of cardiac hypertrophy. Coronary vascular reserve was assessed in isolated retrograde buffer-perfused hearts under conditions of minimal coronary resistance (15 microM adenosine or anoxia). Both groups demonstrated an increase in coronary vascular reserve after 8 wk of exercise swim training, male animals increasing flow (per g of myocardium) by 15% and females by 18%. When the time course of this response was compared in female animals with the time course of the development of myocardial hypertrophy, it was evident that the vascular changes occurred early, greater than 80% of the response was seen within the first 10 days of exercise, compared with an approximately 35% increase in cardiac mass. These data suggest that the vascular response to exercise swim training is independent of the hypertrophic response and further that the increase in coronary vascularity is an early event in the cardiac adaptation to a physiological load.

Animals↗

Effects of endurance training on cholinergic and adrenergic receptors of rat heart.

To test the hypothesis that alterations in adrenergic or cholinergic receptors occur in response to physical training, and that changes in receptor properties could be mechanistically important in producting the altered cardiovascular physiology of the trained state, we studied the effects of endurance training by swimming upon beta adrenergic, alpha adrenergic, and muscarinic cholinergic receptors of rat heart. Because of previously reported sex-related differences in the cardiac adaptation to training, male and female rats were studied separately. Despite the occurrence of demonstrable training bradycardia in males, and of cardiac hypertrophy in females, there were no discernible effects of the training program upon the properties of cardiac beta adrenergic receptors. However, hearts from swimmers of both sexes demonstrated fewer numbers of muscarinic cholinergic and alpha adrenergic receptors than sedentary controls, without differences in the receptor affinities for antagonist or agonist compounds. These findings are inconsistent with the hypothesis that altered cardiac sensitivity to neurotransmitters contributes directly to training bradycardia.

Animals↗

Correlation of myosin isoenzyme alterations with myocardial function in physiologic and pathologic hypertrophy.

To explore the interactions of physiologic and pathologic hypertrophy, four groups of hearts were studied in an isolated working rat heart apparatus. Cardiac contractile proteins were also evaluated. The groups were hearts of female control sedentary rats; rats subjected to a 10-week swimming programme; rats with renal hypertension; and hypertensive rats subjected to a 10-week swimming programme. The swimming programme in normotensive female rats caused a 30% cardiac hypertrophy, in hypertensive animals 46% hypertrophy, and in combined hypertension and swimming 70% hypertrophy. Ca2+-myosin ATPase activity and actin-activated myosin ATPase were elevated in hearts of swimmers, depressed in hearts of hypertensive sedentary animals and similar to control values in hearts of hypertensive swimmers. Myosin V1 isoenzyme content was increased in hearts of swimmers, depressed in hearts of hypertensives, but normal in hearts of hypertensive swimmers. Reciprocal relationships were seen with the V3 isoenzyme. Stroke work, mean velocity of circumferential fibre shortening, and per cent fractional shortening at the midwall showed increased values for hearts of swimmers, depressed values for hearts of hypertensives, and normal values or values above the control for hearts of hypertensive swimmers. Myocardial flow measured with microspheres was increased in the left ventricle of swimmers, depressed in hearts of hypertensives and still depressed in hypertensive swimmers, but significantly higher than in the hypertensives alone. The correlation of actin-activated ATPase activity and of fractional shortening was linear among the four groups. These studies demonstrate that physiologic and pathologic hypertrophy in the rat have distinctly opposite effects on contractile proteins and contractile performance. When one type of hypertrophy is superimposed on the other the effects are additive.

Actins↗

Effects of graded insulin therapy on cardiac function in diabetic rats.

To determine the effects of graded insulin therapy on cardiac function and biochemistry, rats were made diabetic by streptozotocin (50 mg/kg) and subsequently treated with either 3 U of insulin per day (D3) or 5 U/day (D5) and compared with untreated diabetic rats (D phi) and a nondiabetic control group (C). Blood glucose, water consumption, and heart and body weights in D3 and D5 showed dose-dependent responses between those of D phi and C. Cardiac function was studied at similar heart rates and similar left atrial and aortic pressures in an isolated working heart apparatus. Hearts from D phi showed significant decreases in end-diastolic pressure, peak left ventricular systolic pressure, and positive dP/dt, whereas these values in D3 and D5 were similar to those in C. The isovolumic relaxation period was significantly longer in the D phi group, intermediate between D phi and C in D3, and the same in D5 and C. Ca2+-ATPase activity of myosin and actin-activated Mg2+-ATPase activity was depressed in D phi, partially corrected in D3, and completely corrected in D5. Myosin isoenzyme distribution displayed a shift from the predominant V1 pattern observed in C to a predominant V3 pattern in D phi. Treatment with 3 U of insulin per day partially corrected the isoenzyme abnormality, and treatment with 5 U/day restored the isoenzyme distribution to normal. These results indicate that gross cardiac contractile function can be normalized with insulin dosages that are not sufficient to correct hyperglycemia, polydipsia, or body and heart weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats.

To examine the influence of the sex hormones on mechanical properties and biochemistry of the adult heart, we studied left ventricular function and cardiac contractile proteins in hearts from 20-week-old male and female rats that had been gonadectomized at 18 days of age, compared with hearts from sham-operated animals. Testosterone and estradiol were not detectable in serum from male and female gonadectomized rats, respectively. The male rats had lower body and heart weights than male sham operated rats, whereas these values were higher in female gonadectomized than in female sham-operated rats. Left ventricular function was studied in a working heart apparatus at similar heart rate and at controlled levels of aortic diastolic pressure and left atrial pressure. At moderate left atrial pressure, end-diastolic pressure and volume per gram dry left ventricle were the same in all groups, but at high left atrial pressure, end-diastolic pressure, and volume per gram dry left ventricle were lower in male and female gonadectomized than in the respective sham-operated rats. Further increases in left atrial pressure were associated with mechanical alternans in male and female gonadectomized rats. Significantly (P less than 0.05) lower values for cardiac output, peak systolic pressure, ejection fraction, and myocardial oxygen consumption occurred in male gonadectomized compared with sham-operated rats at moderate and high left atrial pressure at higher levels of aortic diastolic pressure. Decreases in these values for female gonadectomized compared with sham-operated rats occurred only at high left atrial pressure. A significant downward shift in the mean force-velocity relationship was observed in all gonadectomized rats at both moderate and high left atrial pressure. In a follow-up study, when end-diastolic pressure was kept the same at both moderate and high left atrial pressure in female sham-operated and gonadectomized rats by reducing heart rate, decreases in contractile function in gonadectomized rats were observed at all preloads. Ca++-myosin ATPase activity was significantly reduced by 34% in male and by 19% in female gonadectomized rats when compared to respective sham-operated control hearts. These alterations in myosin ATPase activity were associated with a reduction in the V1 myosin isoenzyme and an increase in the V3 isoenzyme. Thus, left ventricular filling and left ventricular function were impaired in hearts of gonadectomized rats. Alterations in function were associated with depressed cardiac myosin ATPase activity in male and female gonadectomized rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Cardiac conditioning ameliorates cardiac dysfunction associated with renal hypertension in rats.

To explore the effect of physiologic hypertrophy superimposed on pathologic hypertrophy, hearts from female control rats (C), renal hypertensive rats (H), rats conditioned with a 10-12 wk swimming program (Sw), and hypertensive rats trained by the swimming program (H-Sw) were perfused in an isolated working rat-heart apparatus. Systolic blood pressure was approximately 100 mmHg in C and Sw and was 160 mmHg in H and H-Sw. The swimming program had no effect on blood pressure. Compared with C, heart weight was increased by 30% in Sw, 47% in H, and 77% in H-Sw. At high preload and afterload, cardiac output (milliliters per gram dry LV weight) was decreased in H, increased in Sw, and partially restored towards normal in H-Sw. Ejection fraction, percent fractional shortening, and mean velocity of circumferential fiber shortening were enhanced in Sw, depressed in H, and normalized in H-Sw when compared with C. Coronary flow and myocardial oxygen consumption in this series of hearts were depressed in H, with no restoration in H-Sw, but coronary effluent lactate/pyruvate ratios were only elevated in the hearts of H-Sw. Coronary vascular responses were examined in a second series of experiments which used microspheres. In this series, the depressed coronary flow observed in H was partially restored towards normal in H-Sw and the inner/outer myocardial flow ratio was normal when hearts were perfused at 140 cm aortic pressure but was somewhat depressed in both H and H-Sw when the hearts were perfused at 80 cm aortic pressure. These studies demonstrate that hypertrophic hearts from renal hypertensive rats have diminished coronary flow and depressed cardiac function when they are studied in the isolated working heart apparatus, yet there is no evidence of myocardial ischemia. Superimposition of a chronic swimming program results in increased hypertrophy but restoration of cardiac function partially or completely to normal. Thus, pathologic and physiologic hypertrophy are biologically distinct entities. Physiologic hypertrophy may partially ameliorate the defects associated with pathologic hypertrophy.

Animals↗