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Biomedical subjects

J Narula

Publications and source records attributed to J Narula.

At least 37 records · Page 2Linked to original sources
PubMed2000

Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death.

Although apoptosis is a well-recognized phenomenon in chronic atherosclerotic disease, its role in sudden coronary death, in particular, acute plaque rupture is unknown. Culprit lesions from 40 cases of sudden coronary death were evaluated. Cases were divided into two mechanisms of death: ruptured plaques with acute thrombosis (n = 25) and stable plaques with and without healed myocardial infarction (n = 15). Apoptotic cells were identified by staining of fragmented DNA and confirmed in select cases by gold conjugate labeling combined with ultrastructural analysis. Additional studies were performed to examine the expression and activation of two inducers of apoptosis, caspases-1 and -3. Ruptured plaques showed extensive macrophage infiltration of the fibrous cap, in particular at rupture sites contrary to stable lesions, which contained fewer inflammatory cells. Among the culprit lesions, the overall incidence of apoptosis in fibrous caps was significantly greater in ruptured plaques (P < 0.001) and was predominantly localized to the CD68-positive macrophages. Furthermore, apoptosis at plaque rupture sites was more frequent than in areas of intact fibrous cap (P = 0. 028). Plaque rupture sites demonstrated a strong immunoreactivity to caspase-1 within the apoptotic macrophages; staining for caspase-3 was weak. Immunoblot analysis of ruptured plaques demonstrated caspase-1 up-regulation and the presence of its active p20 subunit whereas stable lesions showed only the precursor; nonatherosclerotic control segments were negative for both precursor and active enzyme. These findings demonstrate extensive apoptosis of macrophages limited to the site of plaque rupture. The proteolytic cleavage of caspase-1 in ruptured plaques suggests activation of this apoptotic precursor. Whether macrophage apoptosis is essential to acute plaque rupture or is a response to the rupture itself remains to be determined.

Apoptosis↗
PubMed2000

Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy.

OBJECTIVES: To assess the prevalence of dystrophin defects in dilated cardiomyopathy (DCM) in male patients and to formulate investigation strategies for their identification. BACKGROUND: Dystrophin defects presenting with predominant or exclusive cardiac involvement may be clinically indistinguishable from "idiopathic" DCM. Diagnosis may be missed, unless specifically investigated. METHODS: Clinical and biochemical evaluation, right ventricular endomyocardial biopsy (EMB), light and electron microscopic and immunohistochemical studies of biopsy samples, six multiplex and two single polymerase chain reactions for 38 exons and automated sequencing of exon 9 and muscle promoter-exon 1 were undertaken in 201 consecutive male patients presenting with DCM, with (n = 14) and without (n = 187) increased serum creatine phosphokinase (sCPK). RESULTS: Dystrophin defects were identified in 13 of the 201 patients (6.5%, age 16-50). Family history was positive in four patients. Serum CPK levels were increased in 11 of 13 patients. Light microscopy examination of EMB was uninformative; ultrastructural study showed multiple membrane defects. Dystrophin immunostain was abnormal. Eight patients, all older than 20, had deletions affecting midrod domain, normal or mildly increased CPK and better outcome than the five remaining cases all younger than 20, with more than five-fold increase of sCPK. Two of these latter had proximal and rod-domain deletions. Sisters of two patients were diagnosed as noncarriers with microsatellite analysis. CONCLUSIONS: Although the overall prevalence of dystrophin defects in our consecutive DCM male series is low (6.5%), immunohistochemical and molecular studies are essential to identify protein and gene defects; screening studies are justified to define prevalence, clinical profile and genotype-phenotype correlation.

Adolescent↗
PubMed2000

Myocardial cell damage in human hypertension.

OBJECTIVES: The goal of this study was to investigate the presence of myocardial cell damage in patients with systemic hypertension and its relationship with left ventricular hypertrophy (LVH). BACKGROUND: Although initially compensatory, LVH adversely affects myocellular integrity and contributes to congestive heart failure in hypertensive patients. Noninvasive detection of myocardial damage can be of value. METHODS: We performed imaging studies with 111In-labeled monoclonal antimyosin antibodies to identify myocardial damage in 39 patients with systemic hypertension and variable degrees of LVH. Three groups were considered: 16 asymptomatic patients with normal echocardiographic left ventricular mass (LVM) (group I); 14 asymptomatic patients with LVH (group II) and 9 patients with symptomatic hypertensive heart disease and advanced LVH (group III). The severity of myocardial damage was represented as heart-to-lung (target-to-background) antibody uptake ratio (normal: <1.55). RESULTS: Mean LVM index was 105+/-14 g/m2 in group I, 124+/-24 in group II and 174+/-29 in group III. Heart-to-lung ratios of antimyosin uptake were: 1.45+/-0.14 in group I, 4 of the 16 (25%) patients showing an abnormal scan; 1.50+/-0.07 in group II with abnormal scans in 2 of the 14 (16%) patients and 1.77+/-0.16 (p < 0.001) in group III, all 9 patients presenting with abnormal antimyosin scans. On multivariate regression analysis LVM index was the main variable that independently correlated with the degree of myocardial uptake of antimyosin (r = 0.815; p = 0.001). CONCLUSIONS: This study provides the first in vivo evidence of myocyte damage in patients with hypertension. The severity of myocardial damage can be related to the magnitude of LVH.

Aged↗
PubMed2000

Radionuclide imaging for the assessment of myocardial viability in chronic LV dysfunction.

Clinical decision making for the selection of patients with coronary artery disease and depressed left ventricular (LV) function for coronary revascularization is very critical but at times difficult. There is strong evidence of an increased event rate (myocardial infarction, death, unstable angina) in one fourth of patients with viable myocardium who are treated medically compared with only one sixteenth after revascularization. Documentation of the presence of viable myocardium best allows identification of patients who are most likely to benefit from coronary revascularization as evident by postoperative improvement in LV systolic function, exercise capacity, quality of life, or survival. On the other hand, identifying patients who would not demonstrate significant improvement is equally important in view of the high morbidity and mortality rates associated with surgery in such patients. Noninvasive imaging to determine the presence and extent of viable myocardium has become an important component of the assessment of patients with coronary artery disease and depressed LV function. About 40% of such patients have the potential for significant improvement after successful surgical revascularization. This review summarizes the role of radionuclide myocardial perfusion imaging for the assessment of viable myocardium.

Adult↗
PubMed2000

Apoptosis and cardiomyopathy.

Apoptosis is a form of cell death that has been described as distinct from necrotic cell death. It is believed to be genetically programmed and occurs as a physiologic process in various organ systems of body. Although it has been tacitly believed that apoptosis does not occur in the terminally differentiated adult heart muscle cells, studies in endomyocardial biopsies from patients with dilated and ischemic cardiomyopathy and in explanted hearts from patients with end-stage heart failure undergoing cardiac transplantation have demonstrated histochemical evidence of apoptosis. It has been proposed that ventricular dilatation and neurohormonal activation during heart failure lead to upregulation of transcription factors, induce myocyte hypertrophy, and prepare the cell for entry into the cell cycle. However, terminally differentiated myocytes cannot divide, and failing to divide they undergo apoptosis. Initiation of apoptosis is associated with activation of upstream cascade, including the release of cytochrome c from mitochondria to cytoplasm and the processing of proteolytic caspases. The activation of caspases leads to fragmentation of various cytoplasmic proteins, including contractile proteins. However, the nuclear fragmentation and condensation is completed only rarely. It is hypothesized that the release of cytochrome c from mitochondria and cytoplasmic protein loss in a living heart muscle cell should lead to systolic dysfunction.

Apoptosis↗
PubMed1999

Comparison of dobutamine echocardiography, dobutamine sestamibi, and rest-redistribution thallium-201 single-photon emission computed tomography for determining contractile reserve and myocardial ischemia in ischemic cardiomyopathy.

Both dobutamine stress echocardiography (DSE) and myocardial perfusion scintigraphy are used to assess myocardial viability. Few studies have compared the data on myocardial viability and ischemia by low and peak dose DSE and myocardial perfusion imaging in the same patients. Fifty-four patients (45 men and 9 women aged 65 +/- 9 years) with ischemic cardiomyopathy (mean ejection fraction 24 +/- 9%) underwent rest 4-hour redistribution thallium-201 single-photon emission computed tomography (SPECT), low and peak dose DSE, and dobutamine sestamibi SPECT. A total of 864 segments were analyzed (16 segments/patient). Wall motion abnormality was present in 796 segments (92%), and contractile reserve during dobutamine infusion was seen in 400 of these segments (50%). Contractile reserve was seen in 331 of 509 hypokinetic segments (65%) and 69 of 287 akinetic/dyskinetic segments (24%) (p <0.001). Contractile reserve was more frequent in segments with normal thallium uptake (64%), reversible thallium defects (42%), or mild to moderate fixed thallium defects (48%) than severely fixed defects (22%) (p <0.05 each). Concordant information about viability by thallium imaging and DSE was obtained in 62% of segments. Dobutamine sestamibi ischemia was seen in 518 of 796 segments (65%) compared with 265 segments (33%) by DSE (p <0.001). Scintigraphic ischemia was noted in 126 of 195 segments (65%) demonstrating biphasic response, 129 of 205 segments (63%) showing sustained improvement, 42 of 70 segments (60%) deteriorating during dobutamine infusion, and 221 of 326 (68%) demonstrating no change (p = NS). Thus, in patients with ischemic cardiomyopathy, contractile reserve is more frequent in hypokinetic segments than akinetic/dyskinetic segments. The number of segments with normal or near-normal thallium uptake or with scintigraphic ischemia is significantly greater than the number of those capable of increasing contractile function or demonstrating an ischemic response during dobutamine echocardiography.

Adult↗
PubMed1999

Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy.

Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3. The hearts explanted from five victims of motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage cardiomyopathy. There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C delta but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.

Animals↗
PubMed1999

Radionuclide imaging of cardiac pathology: a mechanistic perspective.

Cardiac imaging is performed for a variety of indications using different radiotracers and ligands. The most common is the use of thallium-201 and Tc-labeled tracers for myocardial perfusion imaging. Its uses are manifold, and range from the diagnosis of coronary artery disease to the risk stratification of patients and prognostication. Ischemia is being imaged with nitroimidazole compounds, myocardial necrosis with antimyosin and myocardial infiltration with gallium-labeled leukocytes and somatostatin receptor analogs. The status of myocardial innervation has been evaluated with radiolabeled MIBG. Metabolism in the heart in the normal and ischemic state can be studied with PET and SPECT using fatty acid and glucose analogs. The expression of accessory molecules on the surface of cardiac myocytes in patients with cardiac allograft rejection is now possible. Clearly, much has been accomplished for imaging the heart and pathology related to it. The past has been satisfying, the present interesting and the future promises to be even more exciting!

Journal Article↗
PubMed1999

Comparison of the prognostic value of qualitative versus quantitative stress tomographic perfusion imaging.

This study compared qualitative assessment of exercise thallium imaging to quantitative assessment in predicting outcome in 713 patients with 78% prevalence of coronary artery disease by coronary angiography; during a mean follow-up of 52 months, there were 106 hard cardiac events (death or nonfatal myocardial infarction). The qualitative method provided important prognostic information; however, unlike the quantitative technique, less patients were assigned to either the low- or high-risk group and proportionally more patients into the intermediate-risk group, which may limit the clinical usefulness of the technique.

Coronary Angiography↗
PubMed1999

Predictors of outcome of medically treated patients with left main/three-vessel coronary artery disease by coronary angiography.

This study examined the prognostic value of single-photon emission computed tomography in angiographically high-risk patients with left main and/or 3-vessel coronary artery disease who were treated medically. Multivariable Cox survival analysis revealed the single-photon emission computed tomography score (based on size of perfusion abnormality, multivessel abnormality, left ventricular dilation, and lung uptake) as the only independent predictor of outcome.

Adenosine↗
PubMed1999

Apoptosis in human atherosclerotic plaques.

Intimal cell death has been a recognized feature of advanced atherosclerotic disease. With the advent of DNA in situ end labelling and/or ultrastructural techniques, recent findings suggest that cells of an atheroma undergo programmed cell death or apoptosis. The pathophysiologic relevance of apoptosis in atherosclerotic disease is debatable. Apoptotic cell death may influence lesion progression and thus reduce overall plaque burden. Alternatively, apoptosis may prove a means of quenching the inflammation, converting cellular-rich lesions to so-called 'stable' fibrous hypocellular plaques or conversely weaken the fibrous cap causing plaque rupture, a major cause of acute coronary syndromes. Apoptotic cells within plaques are typically macrophages, smooth muscle cells and T-cells and the frequency of death varies in the different regions of the lesion. The precise signalling pathways of apoptosis in plaques are unknown. There is however, some evidence that production of immune cytokines may promote apoptosis through activation of the Fas ligand-mediated death pathway. Genetic signals that regulate apoptosis in the atheroma, at least in smooth muscle cells, may involve the tumour suppressor genes p105RB and p53. Further studies as to the relevance of apoptosis in acute coronary syndromes and potential mechanisms are emerging.

Journal Article↗
PubMed1999

Sympathetic reinnervation of cardiac allografts evaluated by 123I-MIBG imaging.

UNLABELLED: Some heart-transplant patients present with improved heart rate response to exercise and anginal pain suggesting reinnervation of allografts. Studies performed up to 5 y post-transplantation have suggested that reinnervation is a slow process that occurs only after 1 y post-transplantation. The purpose of this study was to evaluate the extent of sympathetic reinnervation in heart-transplant patients and its relation to cardiac function. METHODS: We performed 123I-metaiodobenzylguanidine (MIBG) studies and rest/exercise radionuclide ventriculography in 31 heart-transplant patients 6 mo to 12 y post-transplantation. Intensity of myocardial MIBG uptake was quantified by a heart-to-mediastinum ratio (HMR), and the regional distribution of MIBG was determined by tomographic studies. RESULTS: HMR correlated positively with time after transplantation (r = 0.607, P < 0.001). Patients studied from 2 to 12 y post-transplantation had an HMR significantly higher than patients studied before 2 y post-transplantation (1.62 +/- 0.2 versus 1.34 +/- 0.2, P < 0.05). Myocardial MIBG uptake was anterolateral in 16 patients, anterior in 3 and anterolateral and septal in 3. Myocardial MIBG uptake was absent in 9 patients. Vasculopathy developed in 8 patients, and 5 of them (63%) had decreased myocardial MIBG uptake. Peak filling rate was higher in patients studied from 2 to 12 y post-transplantation (2.7 +/- 0.8 end-diastolic volume (EDV)/s versus 2.16 +/- 0.5 EDV/s, P = 0.02). CONCLUSION: Sympathetic reinnervation increases with time after heart transplantation and is seen more frequently after 2 y post-transplantation. Complete reinnervation of the transplanted heart does not occur even up to 12 y post-transplantation. Early vasculopathy may delay the process of sympathetic reinnervation.

3-Iodobenzylguanidine↗
PubMed1998

Pattern of changes over time in myocardial blood flow and microvascular dilator capacity in patients with normally functioning cardiac allografts.

This study tests the hypothesis that myocardial blood flow and coronary microvascular dilator capacity vary as a function of time after orthotopic heart transplantation in humans. Positron emission tomography measurements of myocardial blood flow were obtained at rest and during adenosine in 24 patients between 1 and 86 months after heart transplantation. At the time of the study all patients were clinically well and had angiographically normal epicardial coronary artery vessels. Patients were divided into 3 groups based on time from transplant to positron emission tomography measurement of myocardial blood flow: group 1 to 12 months (n = 9); group 13 to 34 months (n = 8); and group > or = 37 months (n = 7). Basal myocardial blood flow in group 1 to 12 months (1.86+/-1.01 ml/min/g) exceeded (p <0.05) that of group 13 to 34 months (1.17+/-0.73) and group > or = 37 months (0.98+/-0.34). In group 13 to 34 months, basal myocardial blood flow and maximal dilator capacity (minimal coronary vascular resistance with adenosine 36+/-12 mm Hg/ml/min/g) were comparable to that of normal volunteers (1.01+/-0.20 and 37+/-, respectively). In group > or = 37 months, maximal flow response to adenosine was reduced (2.54+/-1.25 vs 3.16+/-0.52, respectively, p = 0.06). Maximal dilator capacity in group > or = 37 months (60+/-34) was impaired versus group 1 to 12 months (36+/-10) and group 13 to 34 months (36+/-12; both p <0.05) as well as normals (37+/-9, p <0.05). During the first year after cardiac transplantation basal myocardial blood flow is elevated out of proportion to external determinants of myocardial oxygen demand, but maximal dilator capacity of the coronary microcirculation is normal. Between 1 and 3 years both basal myocardial blood flow and microvascular function tend to normalize. After 3 years, although basal myocardial blood flow is normal, microvascular dilator capacity is impaired.

Adult↗