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Biomedical subjects

J Narula

Publications and source records attributed to J Narula.

At least 19 recordsLinked to original sources
PubMed2003

Cardiac systolic and diastolic dysfunction after a cholesterol-rich diet.

BACKGROUND: Although hypercholesterolemia is a well-established risk factor for coronary artery disease, little is known regarding its direct effects on cardiac function. METHODS AND RESULTS: We examined the effects of cholesterol feeding (0.5%) on cardiac function in rabbits. After 10 weeks, both systolic shortening and diastolic relaxation rates were impaired without any change in aortic pressure or ventricular hypertrophy. However, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA)-2 mRNA levels were reduced within 4 days after initiation of cholesterol feeding. After this effect, SERCA-2 protein and SERCA-mediated Ca uptake into sarcoplasmic reticulum vesicles were impaired, and the ratio of MHC-beta to MHC-alpha mRNA increased 5-fold. Suppression of the SERCA-2 message correlated temporally with enrichment of the cardiac sarcolemma with cholesterol. CONCLUSIONS: These data demonstrate that dietary hypercholesterolemia induces a "cholesterol cardiomyopathy" characterized by systolic and diastolic dysfunction. These alterations were independent of vascular disease and demonstrate a dietary link to cardiac dysfunction.

Animals↗
PubMed2001

Intracytoplasmic gene delivery for in vitro transfection with cytoskeleton-specific immunoliposomes.

A novel and highly efficient method of in vitro gene transfection has been developed. This method employs direct intracytoplasmic gene delivery into embryonic cardiocytes using neutral cytoskeletal-antigen specific immunoliposomes (CSIL). These immunoliposomes target cardiocytes specifically under reversible hypoxic conditions. Two independent reporter genes, pGL2 and pSV-beta-galactosidase, were used to verify CSIL-transfection (CSIL-fection). The efficiency of CSIL-fection with firefly luciferase pGL2 vector was 30+ times greater than controls consisting of hypoxic cardiocytes treated with plain liposomes (PL) or normoxic cardiocytes treated with CSIL, PL or naked DNA. CSIL-fection was also compared to cationic liposome transfection. Net cationic liposome transfection appeared to be more efficient than CSIL-fection for pGL2 vectors. However, a smaller number of viable cells was observed in the cationic liposome treated cultures than in the CSIL treated cultures. Therefore, to determine whether more cells were transfected with cationic liposomes or CSIL, pSV-beta-galactosidase vector was used. CSIL-fection with pSV-beta-galactosidase vector produced at least 40 times more transfected cells than those transfected with cationic liposomes. No transfection with pSV-beta-galactosidase vectors was obtained with IgG-liposome, PL or naked DNA treatments. Targeted enhanced efficiency of transfection by this novel method could have practical therapeutic applications in the genetic modification of cells ex vivo that could then be reimplanted into patients for gene therapy.

Animals↗
PubMed2001

Concordance between rest MIBG and exercise tetrofosmin defects: possible use of rest MIBG imaging as a marker of reversible ischaemia.

Perfusion imaging combined with pharmacological stress is the study of choice in patients with ischaemic heart disease who are incapable of exercising. Some medical conditions, however, can preclude the use of pharmacological stress. In these particular situations, availability of a diagnostic test which allows for the assessment of ischaemic territory at rest would be desirable. With the purpose of providing a marker of reversible ischaemia, we evaluated myocardial iodine-123 metaiodobenzylguanidine (MIBG) uptake in regions with fixed and reversible defects defined by exercise/rest perfusion study. Fifty-four male patients with ischaemic heart disease and previous myocardial infarction were studied by means of exercise/rest tetrofosmin and MIBG single-photon emission tomography (SPET). Regional tracer uptake was quantified and expressed as a percentage of maximum peak activity. Areas with denervated but perfused myocardium and areas with ischaemic myocardium were calculated. Regions with<75% of peak activity in the exercise perfusion study were divided into two groups according to whether the increase in peak activity in the respective rest study was >10% (reversible regional defect) or <10% (fixed regional defect). These percentages were compared with the percentages of the innervation study. The area of the innervation defect was significantly larger when the perfusion defect was reversible than when it was fixed. In regions with reversible perfusion defects, the size of the area of denervated but perfused myocardium was similar to the size of the area of ischaemic myocardium. In regions with reversible defects, the percentage of myocardial MIBG uptake was not significantly different from the percentage of tetrofosmin uptake at exercise, while it was significantly lower than the percentage of tetrofosmin uptake at rest. In regions with fixed defects, the percentage of myocardial MIBG uptake was significantly lower than the percentage of tetrofosmin uptake at exercise and at rest. In patients who developed angina during exercise test, the area of denervated but perfused myocardium was significantly larger than in patients without angina (4.1+/-2.4 vs 3.4+/-2.5, P=0.02). The same trend was observed with regard to the size of the innervation defect (8.6+/-2.4 vs 5.7+/-2.2, P=0.02). It is concluded that when the use of pharmacological stress is not possible in patients incapable of exercising, rest studies with MIBG combined with rest myocardial perfusion studies may be useful as a marker of reversible ischaemia.

3-Iodobenzylguanidine↗
PubMed2001

Management of acute cardiac failure with mechanical assist: experience with the ABIOMED BVS 5000.

BACKGROUND: Mechanical circulatory assist industries have developed ventricular assist devices (VAD) for short-, intermediate-, and long-term use. The purpose of this report is to describe the progress made with the ABIOMED Biventricular System (BVS) 5000 (ABIOMED, Inc, Danvers, MA) short-term VAD. METHODS: From June 1994 through August 2000, all cardiogenic shock patients who required short-term mechanical assist were supported with the ABIOMED BVS 5000. Insertion criteria included any condition that may potentially result in cardiac recovery. A formal algorithm for timing of insertion was established to standardize implantation criteria. RESULTS: A total of 45 patients were supported at Hahnemann University Hospital, Philadelphia, PA. There were 26 male and 19 female patients, with a mean age of 57.9 years (range 33 to 80 years). Devices were inserted for postcardiotomy shock in 36 patients (80%) and precardiotomy shock in 9 patients (20%). The average duration of support was 8.3 days (range 1 to 31 days). Overall, there were 22 (49%) patients weaned from support and 14 (31%) discharged from the hospital. For patients in whom the device was implanted in accordance with an established protocol (group A), the wean and discharge rates were 60% and 43%, respectively. The most common morbidities included bleeding and adverse neurologic events. CONCLUSIONS: The ABIOMED BVS 5000 VAD continues to be a valuable form of short-term mechanical assist for acute cardiogenic shock. The formation of a uniform VAD insertion algorithm has helped to standardize protocols in management.

Acute Disease↗
PubMed2001

Apoptosis and the systolic dysfunction in congestive heart failure. Story of apoptosis interruptus and zombie myocytes.

Although previously it was believed that apoptosis could not occur in the terminally differentiated tissue, such as adult heart muscle cells, recent studies in endomyocardial biopsies from patients with dilated cardiomyopathy and in explanted hearts from patients with end-stage heart failure undergoing cardiac transplantation have demonstrated histologic evidence of apoptosis. Whereas neurohormonal activation during heart failure leads to compensatory hemodynamic alterations, coupled with ventricular dilatation, it induces transcription factors and myocyte hypertrophy. Persistent growth stimulation in terminally differentiated cells may lead paradoxically to apoptotic cell death. The apoptosis in cardiomyopathic hearts is associated with cytochrome c release from mitochondria to cytoplasm and activation of proteolytic caspase-8 and -3. Although the caspases are duly processed, the fragmentation of the nuclear proteins (including DNA) is completed less frequently, and only a variable degree of fragmentation of cytoplasmic proteins (including contractile proteins) is observed. It is hypothesized that release of cytochrome c from mitochondria should interfere with energy production and lead to functional impairment and variable loss of contractile proteins in a living heart muscle cell should contribute to systolic dysfunction. Because a nuclear blueprint is retained, however, the dysfunctional cell may continue to exist and in favorable conditions, such as with LVAD support, the apoptotic process may subside. Potential feasibility of reversal of heart failure should renew efforts to develop more targeted pharmaceutical intervention within the apoptotic cascade and allow newer paradigm for the management of heart failure.

Animals↗
PubMed2001

Apoptosis in atherosclerosis. Does it contribute to plaque instability?

Several reports have demonstrated apoptosis in the advanced human atheroma. Most clinical events however, are precipitated by plaque rupture, to a lesser extent erosion, and the development of occlusive thrombi. Whether the extent of apoptosis can influence lesion stability is not precisely known, however, there is emerging data supporting this role. Obvious difficulties arise when studying apoptosis in atherosclerotic plaques because of the complex nature of the disease and lack of an experimental model of plaque instability. This article applies a systematic approach to discuss the issue of apoptosis in context of early disease to complex symptomatic lesions that may become fatal.

Apoptosis↗
PubMed2001

Apoptosis in cardiac transplant rejection.

Apoptosis occurs in human cardiac allograft rejection and may occur with all degrees of rejection and even in its absence. The prevalence and severity of apoptosis is determined predominantly by the intensity of macrophage infiltration and may be mediated by NO-related mechanisms. Apoptosis of interstitial, endothelial, and inflammatory cells is also present in heart allografts and may influence the degree and extent of vascular injury contributing to allograft rejection. Ongoing apoptosis of inflammatory cells suggests an immunoregulatory role. Studies of the involvement of NO in myocyte damage and Fas-FasL interactions in peripheral tolerance have raised the exciting possibility that these pathways can be exploited in a beneficial way. Further understanding of the role of apoptosis and the cellular and biochemical mechanisms that are involved in cardiac myocyte death and in inflammatory, endothelial, and interstitial cell death may provide insights into therapeutic modalities to suppress allograft rejection and vasculopathy.

Animals↗
PubMed2001

Annexin-V imaging for noninvasive detection of cardiac allograft rejection.

Heart transplant rejection is characterized pathologically by myocyte necrosis and apoptosis associated with interstitial mononuclear cell infiltration. Any one of these components can be targeted for noninvasive detection of transplant rejection. During apoptotic cell death, phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, gets exteriorized. Technetium-99m-labeled annexin-V, an endogenous protein that has high affinity for binding to phosphatidylserine, has been administered intravenously for noninvasive identification of apoptotic cell death. In the present study of 18 cardiac allograft recipients, 13 patients had negative and five had positive myocardial uptake of annexin. These latter five demonstrated at least moderate transplant rejection and caspase-3 staining, suggesting apoptosis in their biopsy specimens. This study reveals the clinical feasibility and safety of annexin-V imaging for noninvasive detection of transplant rejection by targeting cell membrane phospholipid alterations that are commonly associated with the process of apoptosis.

Adult↗
PubMed2001

The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes.

While the concept of plaque 'vulnerability' implies a propensity towards thrombosis, the term vulnerable was originally intended to provide a morphologic description consistent with plaques that are prone to rupture. It is now known that the etiology of coronary thrombi is diverse and can arise from entities of plaque erosion or calcified nodules. These findings have prompted the search for more definitive terminology to describe precursor lesions associated with rupture, now referred to as thin-cap fibroatheromas. This review focuses on the thin-cap fibroatheroma, as a specific cause of acute coronary syndromes. To put these issues into current perspective, we need to revisit some of the older literature describing plaque morphology in stable and unstable angina, acute myocardial infarction, and sudden coronary death. The morphology, frequency, and precise location of these thin-cap fibroatheromas are further discussed in detail. Potential mechanisms of fibrous cap thinning are also addressed, in particular emerging data, which suggests the role of cell death "apoptosis" in cap atrophy.

Acute Disease↗
PubMed2000

Noninvasive characterization of stunned, hibernating, remodeled and nonviable myocardium in ischemic cardiomyopathy.

OBJECTIVES: We evaluated a novel protocol of dual-isotope, gated single-photon emission computed tomographic (SPECT) imaging combined with low and high dose dobutamine as a single test for the characterization of various types of altered myocardial dysfunction. BACKGROUND: Myocardial perfusion tomography and echocardiography have been used separately for the assessment of myocardial viability. However, it is possible to assess perfusion, function and contractile reserve using gated SPECT imaging. METHODS: We studied 54 patients with ischemic cardiomyopathy using rest and 4 h redistribution thallium-201 imaging and dobutamine technetium-99m sestamibi SPECT imaging. The sestamibi images were acquired 1 h after infusion of the maximal tolerated dose of dobutamine and again during infusion of dobutamine at a low dose to estimate contractile reserve. Myocardial segments were defined as hibernating, stunned, remodeled or scarred. RESULTS: Severe regional dysfunction was present in 584 (54%) of 1,080 segments. Based on the combination of function and perfusion characteristics in these 584 segments, 24% (n = 140) were labeled as hibernating; 23% (n = 136) as stunned; 30% (n = 177) as remodeled; and 22% (n = 131) as scarred. Contractile reserve, represented by improvement in wall motion/thickening by low dose dobutamine, was observed in 83% of stunned, 59% of hibernating, 35% of remodeled and 13% of scarred myocardial segments (p<0.05). CONCLUSIONS: It is possible with this new imaging technique to characterize dysfunctional myocardium as stunned, hibernating, remodeled and nonviable. These subtypes often coexist in the same patient.

Aged↗
PubMed2000

Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage.

Activation of the stress-activated protein kinase (SAPK/JNK) by genotoxic agents is necessary for induction of apoptosis. We report here that ionizing radiation ionizing radiation exposure induces translocation of SAPK to mitochondria and association of SAPK with the anti-apoptotic Bcl-x(L) protein. SAPK phosphorylates Bcl-x(L) on threonine 47 (Thr-47) and threonine 115 (Thr-115) in vitro and in vivo. In contrast to wild-type Bcl-x(L), a mutant Bcl-x(L) with the two threonines substituted by alanines (Ala-47, Ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis. These findings indicate that translocation of SAPK to mitochondria is functionally important for interactions with Bcl-x(L) in the apoptotic response to genotoxic stress.

Apoptosis↗
PubMed2000

Somatostatin receptor scintigraphy predicts impending cardiac allograft rejection before endomyocardial biopsy.

The invasive nature of endomyocardial biopsy has led to a search for alternative diagnostic modalities for the detection of cardiac allograft rejection. To date, no non-invasive test meets all the requirements for the detection of acute and chronic rejection. The rejection process usually presents with lymphocyte infiltration with or without myocyte necrosis, which indicates the severity of cardiac allograft rejection and the necessity of treatment. Activated lymphocytes express somatostatin receptors; thus somatostatin receptor imaging could be used to target them. The aim of this study was to assess the feasibility of using somatostatin receptor imaging to target activated lymphocytes in the process of cardiac allograft rejection. Thirteen somatostatin receptor imaging studies were performed on ten cardiac allograft recipients 12-4,745 days after transplantation, simultaneously with endomyocardial biopsy, to assess the imaging of activated lymphocytes in comparison with histological findings. Somatostatin receptor imaging was performed 4 h after the injection of 110 MBq of the somatostatin analogue indium-111 pentetreotide. 111In-pentetreotide uptake was visually scored and semi-quantitatively estimated by the calculation of a heart-to-lung ratio (HLR). The visual score correlated with the HLR. Intense/moderate uptake on visual assessment and an HLR >1.6 was observed in eight studies. In three of these studies there was significant rejection in the simultaneous endomyocardial biopsy [International Society of Heart and Lung Transplantation (ISHLT) rejection grade 3A/4]. Intense/moderate uptake was associated with mild or no rejection in the remaining five patients, and in four of them the next endomyocardial biopsy performed 1 week later demonstrated significant rejection requiring treatment. Two patients with low uptake and an HLR <1.6 had no evidence of rejection either in the simultaneous endomyocardial biopsy or in the endomyocardial biopsy performed the following week. These preliminary results indicate the feasibility of targeting activated lymphocytes with somatostatin receptor imaging in the detection of cardiac allograft rejection. Somatostatin receptor imaging may predict impending rejection at least 1 week before the endomyocardial biopsy becomes positive. The late appearance of diagnostic endomyocardial biopsy probably reflects a lag-time between lymphocytic activation and induction of myocyte damage. Furthermore, somatostatin receptor imaging at 4 h may in any case allow earlier intervention in the event of rejection, given the time required for histological processing of endomyocardial biopsy.

Biopsy↗
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↗