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Biomedical subjects

J Narula

Publications and source records attributed to J Narula.

At least 127 records · Page 7Linked to original sources
PubMedDate not supplied

Noninvasive localization of human atherosclerotic lesions with indium 111-labeled monoclonal Z2D3 antibody specific for proliferating smooth muscle cells.

BACKGROUND: Targeting exclusive antigens in atherosclerotic plaques with antibodies may provide a noninvasive means to detect rapidly proliferative atherosclerotic lesions. 111In-labeled negative charge-modified Z2D3 F(ab')2 (Z2D3) specific for an antigen expressed exclusively by proliferating smooth muscle cells has been shown to accumulate in rabbit atherosclerotic plaques. METHODS: The safety, biodistribution, accumulation, and elimination of Z2D3 were assessed in 11 patients who were candidates for carotid endarterectomy. The presence of atheromas in these patients was confirmed by angiography and Doppler ultrasound. Z2D3 (250 microg) labeled with 5 mCi of 111In was administered by slow intravenous injection. Planar and single photon emission computed tomography (SPECT) images were obtained 4, 24, 48, and 72 hours later. Carotid endarterectomy was performed and the surgical specimens were imaged, weighed, gamma-counted, and analyzed by immunostaining. RESULTS: Uptake of Z2D3 at the site of the carotid plaques was observed in the planar and SPECT views at 4 hours in all subjects. In addition, antibody uptake was noted in the contralateral vessel in 5 subjects. SPECT images identified the atherosclerotic plaques with focal uptake. The antibody uptake corresponded with the angiographic location of the disease. Immunohistochemical studies of the endarterectomy specimens confirmed the localization of Z2D3 into the plaque areas containing smooth muscle cells. Adverse drug reactions were not observed. CONCLUSION: This study demonstrates the feasibility of targeting atherosclerotic lesions with negative charge-modified antibody. It also proposes the possibility of selective identification of various components of atherosclerotic plaque, which may contribute to determining strategies of intervention in future.

Aged↗
PubMedDate not supplied

In vivo detection of apoptotic cell death: a necessary measurement for evaluating therapy for myocarditis, ischemia, and heart failure.

If life is to continue, cells that have completed their useful function(s) must die in a timely manner. Apoptosis, programmed cell death, is a natural, orderly, energy-dependent process that causes cells to die without inducing an inflammatory response. In the heart, apoptosis plays pivotal roles in the development of myocarditis, cardiomyopathies, transplant rejection, the periinfarct zone in myocardial infarction, and reperfusion injury. Apoptosis is triggered either by a decrease in factors required to maintain the cell in good health or by an increase in factors which cause damage to the cell. When these factors tilt in the direction of death and the cell has sufficient time to respond, a common proteolytic cascade involving cysteine aspartic acid-specific proteases (caspases) is activated to initiate apoptosis. Cells that die by apoptosis autodigest their DNA and nuclear proteins, change the phospholipid composition on the outer surface of their cell membrane, and form lipid enclosed vesicles, which contain noxious intracellular contents, organelles, autodigested cytoplasm, and DNA. The compositional cell membrane phospholipid change that occurs with the onset of apoptosis is marked by the sudden expression of phosphatidylserine (PS), a phospholipid that ordinarily appears on the inner leaflet of the membrane, on the external leaflet of the membrane. The constant exposure of PS during apoptosis makes it an attractive target for radiopharmaceutical imaging. An endogenous human protein, annexin V, has a high affinity (kd = 7 nmol/L) for PS bound to the cell membrane. Fluorescence-labeled annexin V is used for histologic and cell-sorting studies to identify apoptotic cells. Annexin has been radiolabeled and binds to cells undergoing apoptosis in vivo. This review outlines some of the key features of apoptosis as contrasted to necrosis (unregulated cell death) and describes how these processes can be imaged with radionuclide techniques.

Apoptosis↗
PubMedDate not supplied

Complementary roles of antibody affinity and specificity for in vivo diagnostic cardiovascular targeting: how specific is antimyosin for irreversible myocardial damage?

BACKGROUND: Identification of irreversible myocyte injury with antimyosin antibody imaging depends on both antibody specificity and affinity. To characterize the role of antibody affinity, we performed studies in dogs with acute coronary occlusion followed by reperfusion using 3 monoclonal antimyosin antibodies with different affinities. METHODS AND RESULTS: Dogs with experimental reperfused acute myocardial infarction were injected with 2 high-affinity radiolabeled monoclonal antimyosin Fab fragments (R11D10 and 2G42D7), 1 low-affinity antimyosin Fab (3H31E6), and a nonspecific Fab. The left lateral gamma images at 5 H were used to assess the infarct (I) to blood (B) region of interest (ROI) count density ratios by computer planimetry. All infarcts were confirmed by in vivo imaging with 201Tl for perfusion defects as well as by postmortem histochemical staining. The mean I/B ROI (+/-standard deviation [SD]) for R11D10 (1.701+/-0.376) was not significantly different from that of 2G42D7 (1.501+/-0.267, P = NS), but both were significantly greater than that of 3H31E6 Fab (0.85+/-0.12, P = .0001 and .0012, respectively). The I/B ROI of 3H31E6 Fab was similar to that of nonspecific Fab (0.75 to 0.77 range). Radiolabeled R11D10 and 2G42D7 were unequivocally positive by gamma imaging in all infarcts by 5 H. No infarcts were visualized with 3H31E6 or nonspecific Fab. CONCLUSIONS: The low-affinity antibody, despite its specificity for cardiac myosin, cannot be used to image the infarct zone. Therefore immunoscintigraphic diagnosis of irreversible myocardial injury with radiolabeled antimyosin Fab is doubly specific because in vivo visualization required both specificity and high enough affinity of the antibody.

Animals↗
PubMedDate not supplied

Use of left ventricular pacing in heart failure: evaluation by gated blood pool imaging.

BACKGROUND: Left ventricular (LV) pacing has been suggested to complement other forms of therapy in patients with heart failure. METHODS AND RESULTS: We investigated 17 patients (15 men, 2 women, aged 68 +/- 6 years, 10 ischemic and 7 primary dilated cardiomyopathy) with heart failure (13 were in New York Heart Association class IV and 4 in class III). One month after LV pacer implantation, 12 patients reported clinical improvement (mean class 3.7 before pacing vs 2.6 with LV pacing; P = .001). We report the results of 3 equilibrium-gated blood pool studies performed in each patient, 1 before pacing and 2 after pacer implantation (1 with pacing on, and 1 after turning off the pacer). LV pacing did not modify LV ejection fraction. Phase analysis demonstrated a significant decrease of the interventricular phase shift (delta(pi)) with LV pacing (no pacing, delta(pi) = 8.99 degrees +/- 19.05 degrees; delta7n= -0.97 degrees +/- 27.85 degrees with LV pacing). Clinical improvement was observed in patients with an initial positive delta(pi) that decreased with pacing and/or an initial LV phase standard deviation >50 degrees that decreased with pacing. CONCLUSION: LV pacing induces interventricular and intraventricular synchronization. A decrease of the interventricular phase shift seems to be the most important predictor of functional recovery for paced patients with heart failure.

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PubMedDate not supplied

Chemically optimized antimyosin Fab conjugates with chelating polymers: importance of the nature of the protein-polymer single site covalent bond for biodistribution and infarction localization.

Murine antimyosin Fab fragment was conjugated with 111In-labeled N-terminal-modified DTPA-polylysine using three bifunctional reagents: N-hydroxysuccinimide esters of 3-(2-pyridyldithio)propionic acid (SPDP conjugate), 4-(maleimidomethyl)cyclohexanecarboxylic acid (SMCC conjugate) and bromoacetic acid (BrAc conjugate) for potential localization of experimental myocardial infarction. Using various antibody preparations and a rabbit acute myocardial infarction model the following parameters were observed: (1) an in vitro antigen binding activity of SPDP conjugate = SMCC conjugate > BrAc conjugate, (2) a blood clearance rate of SPDP conjugate > BrAc conjugate > SMCC conjugate, (3) a liver and splenic accumulation of SPDP conjugate > BrAc conjugate > SMCC conjugate, and (4) the infarcted tissue activity showed an accumulation of SMCC conjugate > SPDP conjugate > BrAc conjugate. This study exemplifies the importance of rational chemical design of antimyosin Fab-chelating polymer conjugate for improved target tissue localization in vivo.

Animals↗
PubMedDate not supplied

Myocardial sympathetic innervation in the athlete's sinus bradycardia: is there selective inferior myocardial wall denervation?

BACKGROUND: Sinus bradycardia in trained athletes is predominantly a manifestation of increased vagal tone, but it is not known whether an alteration in the cardiac sympathetic system can contribute to blunted chronotropic response. This study assessed the integrity of the sympathetic system in trained athletes with sinus bradycardia by means of the iodine-123-metaiodobenzylguanidine (123I-MIBG) procedure. METHODS AND RESULTS: Fourteen athletes with sinus bradycardia and 8 athletes with a normal heart rate were explored by means of planar and single photon emission computed tomography MIBG studies. The heart/mediastinum ratio, regional myocardial distribution, and percent of regional myocardial MIBG uptake were evaluated. The heart/mediastinum ratio in athletes with sinus bradycardia was 1.87+/-0.10, and in athletes with a normal heart rate, the heart/mediastinum ratio was 1.86+/-0.16 (P = not significant). In athletes with sinus bradycardia, the regional distribution of MIBG showed an inferior and apical uptake defect in 8 athletes, an inferior, apical, and septal defect in 3 athletes, an inferior defect in 1 athlete, and normal distribution in 2 athletes (14%). In athletes with a normal heart rate, the regional distribution of MIBG showed an apical uptake defect in 3 athletes and normal distribution in 5 athletes (63%). The percent of regional MIBG uptake in the inferior region was significantly reduced in athletes with sinus bradycardia (44%+/-13% vs. 72%+/-11%, P<.01). CONCLUSION: These results show severely reduced myocardial MIBG distribution in the inferior region in athletes with sinus bradycardia, suggesting selective inferior myocardial wall sympathetic denervation, which may be related to increased vagal tone.

3-Iodobenzylguanidine↗
PubMedDate not supplied

Functional, structural, and genetic mitochondrial abnormalities in myocardial diseases.

Myocardial tissue is highly dependent on energy supplied by normal mitochondrial function. Therefore defects of energy production or utilization affect the heart in both syndromic and isolated disorders. Knowledge of the peculiar structural, functional, and genetic characteristics of mitochondria provides the basis for identification and classification of mitochondrial defects as well as for establishment of a diagnostic workup useful for related cardiac disorders. This review is therefore dedicated to the characteristics of normal mitochondria and the pathologic alterations of these organelles in various cardiovascular diseases.

Cardiomyopathies↗