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Biomedical subjects

B Chandrasekar

Publications and source records attributed to B Chandrasekar.

At least 37 records · Page 2Linked to original sources
PubMed1999

Percutaneous transvenous mitral commissurotomy for significant calcific mitral stenosis: utility of the stepwise balloon dilatation technique and follow-up results.

The present study examined the utility of the stepwise balloon dilatation technique in 41 patients with significant calcific mitral stenosis undergoing percutaneous transvenous mitral commissurotomy (PTMC). Thirty-five patients (85.4%) had a successful procedure; one patient developed cardiac tamponade and underwent mitral valve replacement. The mitral valve area increased from 0.9 +/- 0.2 cm2 to 1.7 +/- 0.3 cm2 following PTMC. Increase in mitral regurgitation (MR) was seen in 11 patients (26.8%). All patients showed improvement in functional class of > or =1 level following PTMC, which was sustained in 34 patients at follow-up. At a mean follow-up period of 20 +/- 12 months (range 3-51 months) in 35 patients, 26 patients (74.3%) were in New York Heart Association (NYHA) functional Class I, 8 patients (22.9%) were in NYHA Class II, and 1 patient (2.8%) was in NYHA Class III. The cumulative 4-year cardiac event-free survival rate was 81.8%. However, patients with grade 4+ calcification had only 50% event-free survival rate. At follow-up, an increased incidence of cardiac events was seen in female patients as compared with male patients (83.3% versus 16.7%). Restenosis was seen in 3 patients (8.6%). One patient underwent repeat PTMC 37 months after the initial procedure. There was no incidence of death or mitral valve replacement at follow-up. We conclude that the stepwise balloon dilatation technique can be safely and effectively applied for patients with significant calcific mitral stenosis to achieve an optimal mitral valve area with low incidence of significant increase in MR. Favorable long-term benefits also accrue in the form of improved functional status and low incidence of repeat procedures (repeat PTMC or mitral valve replacement). The majority of patients (74.3%) were in NYHA functional class I without medication. Patients with grade 4+ calcification show less benefit from PTMC and may be considered for mitral valve replacement. Cardiac events occur more frequently in female patients than in male patients during follow-up.

Adult↗
PubMed1999

Angioplasty and stenting of solitary supra-aortic artery and aortoplasty by kissing balloon technique.

A child presented with symptoms of compromise to cerebral blood flow and cardiac failure. On diagnostic angiography, he was found to have a discrete coarctation and related ostial stenosis of the left subclavian artery, which acted as the sole source of cerebral blood flow. The subclavian lesion was initially dilated with a 6 mm x 50 mm balloon. The discrete coarctation was then dilated with an 8 mm x 50 mm balloon. Since significant residual stenosis was present at the subclavian origin, it was stented with a 20 mm Palmaz-Schatz stent (Cordis Corporation, Miami Lakes, Florida). Since the coarcted segment required further dilatations, the kissing balloon technique was used, wherein the 6 mm balloon was placed extending from the left subclavian lesion distally to the related aortic lesion proximally, along with another 10 mm balloon in the aorta. The end result was acceptable and the patient's symptoms improved significantly after the procedure.

Angioplasty, Balloon↗
PubMed1998

Inhibition of nuclear factor kappa B attenuates proinflammatory cytokine and inducible nitric-oxide synthase expression in postischemic myocardium.

We have previously reported that induction of nuclear factor-kappa B (NF-kappa B) occurs in a biphasic manner in postischemic myocardium. Because interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric-oxide synthase (iNOS) contain kappa B-response elements, and since transforming growth factor-beta 1 (TGF-beta 1) down-modulates both cytokine and iNOS expression, we studied their temporal expression during myocardial ischemia/reperfusion (I/R). Northern and Western analyses showed low levels of IL-6 and no signal for IL-1 beta, TNF-alpha and iNOS under basal conditions. Their expression rose significantly over sham-operated controls by 1 h reperfusion, and persisted high for various periods. Under basal conditions, low levels of TGF-beta 1 were detected, which rose significantly at 3 h reperfusion, and remained high until 24 h reperfusion. Administration of diethyldithiocarbamate (DDC) inhibited induction of NF-kappa B and concomitantly the expression of IL-1 beta, IL-6, TNF-alpha as well as iNOS. However, expression of TGF-beta was not altered. Our results indicate that ischemia/reperfusion induces NF-kappa B, and upregulates kappa B-response genes. Administration of DDC inhibits NF-kappa B levels, and attenuates expression of inflammatory cytokines and iNOS.

Animals↗
PubMed1998

Expression of apoptosis-related proteins in experimental coxsackievirus myocarditis.

OBJECTIVE: The extent to which apoptosis contributes to myocyte cell loss during acute carditic viral infection is unknown. To assess whether apoptosis occurs in acute viral myocarditis, and how it is modulated, we studied mice inoculated with coxsackievirus B3 (CVB3). METHODS: Five CD1 and C3H.HeJ (C3H) mice/group were sacrificed as saline vehicle-injected controls, and at 1, 2, and 3 weeks post-inoculation (p.i.) with 5 x 10(6) pfu CVB3. Histopathological status and terminal transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assays quantified inflammation, necrosis and apoptosis in myocardium. Apoptosis-related protein immunoreactivity defined presence and location of Bax, Fas, Fas Ligand (FasL), Bcl-2, interleukin-1 beta converting enzyme (ICE), inducible nitric oxide synthase (iNOS) and the proto-oncogene p53. RESULTS: Both strains exhibited significant histopathology at all time points. Saline-injected control animals showed no signs of inflammation and no significant difference in apoptosis-related protein immunoreactivity was observed between strains. Myocardial TUNEL-positive cells were exceedingly rare though apoptosis was present in thymic medulla and spleen follicles. Pro-apoptotic proteins Bax, Fas, and FasL were present in all groups though no clear correlation with histopathology was apparent. By contrast, the anti-apoptotic protein Bcl-2 showed mild immunoreactivity in controls, which increased following infection and correlated well with histopathological scores in both strains. Myocardial iNOS immunoreactivity displayed a similar though weaker staining pattern to Bcl-2 over the 3 week study period in both strains. Neither ICE nor p53 immunoreactivity could be demonstrated in myocardium. CONCLUSION: Thus, despite marked inflammatory activity, myocyte apoptosis is rare in acute CVB3 myocarditis in CD1 and C3H.HeJ mice.

Animals↗
PubMed1998

Overexpression of cardiotrophin-1 and gp130 during experimental acute Chagasic cardiomyopathy.

Cardiotrophin-1 (CT-1), a cytokine with structural similarities to interleukin-6, has been shown to signal through gp130-dependent pathways. In vitro, CT-1 promotes the survival and induces hypertrophy of neonatal cardiomyocytes. Since acute Chagas' disease involves an inflammatory response followed by chamber dilation, with subsequent compensatory hypertrophy, we hypothesized CT-1 and gp130 may participate in this disease process. Thus, we investigated expression and localization of these moieties during acute Chagasic cardiomyopathy. Lewis rats (n = 6/group) were either inoculated with cell culture-derived T. cruzi trypomastigotes or saline, and sacrificed 15 days later. Hearts were collected for histology, immunohistochemistry (IHC), mRNA, and protein analyses. Histology showed dense myocardial infection with amastigotes and diffuse mononuclear cell infiltrate. Northern blot analysis showed low level expression of CT-1 mRNA in controls, which was markedly elevated in infected animals (2.5-fold; P < 0.001). Similarly, Western blotting showed a twofold elevation of CT-1 protein in infected animals (P < 0.025). Likewise, levels of both gp130 mRNA and protein were low in controls, but were approximately threefold higher in infected animals. IHC showed weak and diffuse staining for CT-1 in control myocardium, while intense staining especially localized to the cytoplasmic region of cardiomyocytes, was found in infected animals. Although gp130 immunoreactivity was observed in both normal and infected myocardium, more intense staining was found in infected animals. Unlike CT-1, gp130 staining was granular, and was present in both the cytoplasm as well as in the perinuclear region. These data suggest that there is substantial overexpression of both CT-1 and gp130 in the heart during acute Chagasic carditis. Their overexpression may provide a mechanism for myocyte protection, and for development of compensatory cardiac hypertrophy following myocardial damage in this form of cardiomyopathy.

Acute Disease↗
PubMed1998

Cloning of Syrian hamster (Mesocricetus auratus) cytokine cDNAs and analysis of cytokine mRNA expression in experimental visceral leishmaniasis.

The Syrian golden hamster (Mesocricetus auratus) is uniquely susceptible to a variety of intracellular pathogens and is an excellent model for a number of human infectious diseases. The molecular basis for this high level of susceptibility is unknown, and immunological studies related to this model have been limited by the lack of available reagents. In this report we describe the cloning and sequence analysis of portions of the Syrian hamster interleukin 2 (IL-2), IL-4, gamma interferon (IFN-gamma), tumor necrosis factor alpha, IL-10, IL-12p40, and transforming growth factor beta cDNAs. In addition, we examined the cytokine response to infection with the intracellular protozoan Leishmania donovani in this animal model. Sequence analysis of the hamster cytokines revealed 69 to 93% homology with the corresponding mouse, rat, and human nucleotide sequences and 48 to 100% homology with the deduced amino acid sequences. The hamster IFN-gamma, compared with the mouse and rat homologs, had an additional 17 amino acids at the C terminus that could decrease the biological activity of this molecule and thus contribute to the extreme susceptibility of this animal to intracellular pathogens. The splenic expression of these genes in response to infection with L. donovani, the cause of visceral leishmaniasis (VL), was determined by Northern blotting. VL in the hamster is a progressive, lethal disease which very closely mimics active human disease. In this model there was pronounced expression of the Th1 cytokine mRNAs, with transcripts being detected as early as 1 week postinfection. Basal expression of IL-4 in uninfected hamsters was prominent but did not increase in response to infection with L. donovani. IL-12 transcript expression was detected at low levels in infected animals and paralleled the expression of IFN-gamma. Expression of IL-10, a potent macrophage deactivator, increased throughout the course of infection and could contribute to the progressive nature of this infection. These initial studies are the first to examine the molecular immunopathogenesis of a hamster model of VL infection and indicate that progressive disease in this model of VL is not associated with early polarization of the splenic cellular immune response toward a Th2 phenotype and away from a Th1 phenotype.

Amino Acid Sequence↗
PubMed1998

Contractile depression and expression of proinflammatory cytokines and iNOS in viral myocarditis.

We assessed two strains of mice [CD-1 and C3H.HeJ (C3H)] with different responses to coxsackievirus B3 (CVB3) infection at 7, 14, and 21 days after inoculation with 10(5) pfu of CVB3. CD-1 mice developed inflammatory lesions at 7 days that nearly recovered by 21 days; C3H mice demonstrated persistence of infiltrates. Although there were differences in the baseline fractional shortening, it was further reduced at 7 and 14 days in both strains. It recovered in CD-1 mice but remained depressed at 21 days in C3H mice. Interleukin-6 and tumor necrosis factor-alpha transcripts were increased in both strains at 7 days. Levels dropped to near control in CD-1 mice at 21 days but remained elevated in C3H mice. Interleukin-1 beta was minimally elevated in CD-1 mice but increased progressively in C3H mice. mRNA for the inducible form of NO synthase (iNOS) was increased at 7 days in the CD-1 mice, returning to baseline by 14 days; it rose progressively in C3H mice, with a fivefold increase at 21 days. We conclude that mice infected with CVB3 show increased expression of proinflammatory cytokines as well as iNOS associated with reduced contractile performance. In more susceptible mice, contractile depression and cytokine and iNOS expression are more pronounced.

Animals↗
PubMed1998

Percutaneous Transvenous Mitral Commissurotomy for Post-Surgical Mitral Restenosis: Acute Outcome and Analysis of Factors Influencing Results.

The present study examined the utility of percutaneous transvenous mitral commissurotomy (PTMC) for post-surgical mitral restenosis (Group I, n = 71 patients), and the factors influencing the outcome of the procedure. The results of PTMC were also compared with a group of patients (Group II, n = 70 patients), who underwent PTMC for de novo mitral stenosis. Both the groups were matched for age, pre-procedure mitral valve area and echocardiographic score. PTMC was successful in 60 patients (85%) in group I and in 68 patients (97%) in group II (p < 0.05). However, the final mitral valve area achieved was similar between the two groups (1.8 +/- 0.3 vs. 1.9 +/- 0.2 sq.cm, p = NS). Patients in group I had significantly greater mitral valve calcification (0.6 +/- 0.8 vs. 0.3 +/- 0.6, p < 0.05). Multiple regression analysis of results in patients with post-surgical restenosis revealed that only basal mean pulmonary artery pressure and basal cardiac index correlated significantly with increase in valve area. Mitral valve leaflet mobility, thickness and subvalvular deformity did not correlate significantly with the increase in mitral valve area. CONCLUSION: PTMC is a safe procedure for post-surgical mitral restenosis with negligible complication, with a higher success and significantly lower complication rate than that reported for repeat surgical commissurotomy. Although patients with surgical restenosis had a greater degree of calcification of mitral valve leaflets; only basal mean pulmonary artery pressure and cardiac index significantly influenced the increase in mitral valve area. Increased fibrosis of mitral leaflet following surgery probably adversely influences the results of PTMC for post-surgical mitral restenosis.

Journal Article↗
PubMed1998

Temporal expression of pro-inflammatory cytokines and inducible nitric oxide synthase in experimental acute Chagasic cardiomyopathy.

To characterize the kinetics of myocardial cytokine and inducible nitric oxide synthase (iNOS) expression in acute Chagasic cardiomyopathy, we studied a rat model of acute Trypanosoma cruzi infection. Rats were euthanized 36 hours and 5, 10, and 15 days after infection, and hearts were collected for histology, mRNA, and protein analyses. Histological analysis of myocardium showed a progressive increase in the number of amastigotes and mononuclear inflammatory cells. Organisms were first detected 5 days after intraperitoneal inoculation as isolated nests and became numerous by day 15. Northern blot analysis of total RNA revealed no signal for interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha and a weak signal for IL-6 in control hearts. High levels of expression for the three genes were detected in the infected animals at 36 hours after infection. Although IL-1beta and IL-6 levels increased steadily up to 10 days, TNF-alpha levels were the highest at 5 days, remained high at 10 days, and declined thereafter. Western blot analysis showed similar results to that of mRNA expression. No signal was detected for iNOS in the controls, but both its mRNA and protein were found in the infected animals, with levels being highest at 15 days after infection. Immunohistochemistry revealed no iNOS immunoreactivity in uninfected animals, but intense iNOS staining was detected in blood vessels of infected animals, which decreased progressively with period of infection. Positive staining for iNOS in cardiomyocytes was first detected at 36 hours after infection (at a time when there was no histological inflammatory reaction), which steadily increased, being the highest at 15 days after infection. These results indicate that, in addition to mechanical damage by T. cruzi, substantial pro-inflammatory cytokine production within the myocardium is likely to participate in the pathophysiology of acute Chagasic cardiomyopathy.

Animals↗
PubMed1997

Induction of nuclear factor kappaB and activation protein 1 in postischemic myocardium.

Ischemia/reperfusion induces nuclear factor kappaB (NF-kappaB) and AP-1 in rat hearts after 15 min of ischemia followed by reperfusion (R) for various periods of time (15 and 30 min, 1, 2, 3, 6, 12, and 24 h). Low levels of NF-kappaB and no signal for AP-1 were detected in shams and in non-ischemic tissue distant from the ischemic zone. In postischemic tissue, NF-kappaB levels increased biphasically with peak levels at 15 min and again at 3 h R. Immunoblotting showed minimal NF-kappaB p50 subunit at all times, with changes in p65 similar to EMSA results. Northern blots showed low p50 and increased p65 expression levels at both 2 and 3 h R. By contrast, AP-1 increased monophasically, with peak levels at 15 min R, which dropped steadily thereafter. These results indicate that NF-kappaB and AP-1 are differentially regulated during reperfusion, which may be a control mechanism for gene expression in reperfused myocardium.

Animals↗
PubMed1997

Induction of proinflammatory cytokine and antioxidant enzyme gene expression following brief myocardial ischaemia.

The purpose of this study was to determine if proinflammatory cytokines are up-regulated during reperfusion following sublethal ischaemia, and whether concurrent up-regulation of antioxidant enzymes occurs. Open-chest rats were subjected to 15 min of ischaemia followed by 1 or 3 h reperfusion (R). Myocardium from the ischaemic zone showed a significantly higher (P<0.01) generation of thiobarbituric acid-reactive substances at 1 h and 3 h R. Northern blots showed a weak signal in controls for IL-6 mRNA (0.13 +/- 0.01); this was elevated to 0.68 +/- 0.12 at 1 h and 0.69 +/- 0.10 at 3 h R. Neither IL-1beta nor tumour necrosis factor-alpha (TNF-alpha) were detectable in controls. IL-1beta rose to 0.78 +/- 0.07 at 1 h and 0.51 +/- 0.08 at 3 h R, and TNF-alpha rose to 0.69 +/- 0.10 at 1 h and 0.38 +/- 0.15 at 3 h R. Western blotting showed no signals in the control, but readily detectable signals at 1 h R; these remained high (IL-6) or decreased (IL-1beta and TNF-alpha at 3h R. mRNA analysis for antioxidant enzymes revealed a weak signal in controls for catalase (CAT; 0.16 +/- 0.08), glutathione peroxidase (GSH-Px; 0.15 +/- 0.06) and superoxide dismutase (SOD; 0.21 +/- 0.05). After 1 h R, levels increased significantly for CAT (0.46 +/- 0.10; P < 0.025) and GSH-Px (0.51 +/- 0.13; P < 0.01), but remained similar to controls for SOD (0.26 +/- 0.15). At 3 h R the mRNA levels were significantly elevated for the three enzymes (CAT 0.48 +/- 0.13; GSH-Px 0.47 +/- 0.10; SOD 0.54 +/- 0.08). We conclude that mRNA for proinflammatory cytokines is expressed early in reperfusion, and that the proteins are present in heart tissue. Also, reperfusion is associated with rapid expression of genes for antioxidant enzymes, which may enhance reactive oxygen intermediate (ROI) scavenging.

Animals↗
PubMed1997

Calorie restriction decreases platelet-derived growth factor (PDGF)-A and thrombin receptor mRNA expression in autoimmune murine lupus nephritis.

Calorie restriction (CR) and supplementation with fish oil (FO) are known to increase the life span and diminish histological evidence of glomerulonephritis in lupus prone (NZB x NZW)F1 (B/W) mice. Cellular proliferation is an important pathological element in the development of lupus nephritis, and we have examined the expression of thrombin receptor (TR) and the mitogenic agents PDGF-A and -B. Weanling B/W mice were fed either ad libitum or a calorie restricted (CR; 40% less calories than ad libitum) diet supplemented with either 5% (w/w) corn oil (CO) or FO. CR animals consumed 2.7-3.0 g of wet food per day versus 4.5-5.0 g for the ad libitum animals. Renal RNA was extracted from young (3.5-4.0 months of age) and old (8-10 months of age) mice. Densitometric analysis (reference gene GAPDH) of blots from Northern (PDGF-A and -B) and ribonuclease protection assays (TR) produced the following data: (i) in young mice no signal was detected for PDGF-A, -B and TR in all four groups, while the signals were readily detectable in old mice; (ii) in old mice low and similar levels of PDGF-B were detected, and neither CR nor the source of lipid altered its expression; (iii) CR significantly inhibited PDGF-A and TR expression in both CO (ad libitum versus CR; PDGF-A, 3.25-fold, P < 0.025; TR, 3.7-fold, P < 0.01) and FO (ad libitum versus CR; PDGF-A, 4.56-fold, P < 0.01; TR, 3.6-fold, P < 0.025) groups; (iv) although FO (versus CO) produced a trend towards decreased expression, results were not statistically significant. We conclude that suppression of renal disease in lupus-prone mice by CR is accompanied by decreased expression of PDGF-A and the thrombin receptor.

Animals↗
PubMed1997

Percutaneous Transvenous Mitral Commissurotomy Without Heparin.

Six-hundred twenty-nine patients with rheumatic mitral stenosis in normal sinus rhythm underwent percutaneous transvenous mitral commissurotomy (PTMC) by the standard Inoue balloon technique. All patients underwent transthoracic echocardiography, when necessary, transesophageal echocardiogram was done before PTMC to exclude left atrial clot. In all cases, the PTMC procedure was completed without administration of heparin. There was no incidence of embolism either in the immediate post-procedure period or at a median follow-up of 3 months. There were no femoral artery or venous complications in any of the cases. We conclude that the conventional use of heparin during PTMC may not be required in patients with sinus rhythm and no left atrial clot.

Journal Article↗
PubMed1996

Induction of proinflammatory cytokine expression in experimental acute Chagasic cardiomyopathy.

One of the hallmarks of Chagas' disease (caused by Trypanosoma cruzi) is progressive cardiomyopathy. The disease is associated with increased serum TNF-alpha levels, and TNF-alpha is known to depress cardiac function. It is, however, not known whether the cytokines are produced within the infected myocardium. One-month-old male Lewis rats were injected with cell culture-derived T. cruzi trypomastigotes and killed 15 days post-infection. As compared to normal animals, histologic analysis of infected animals revealed dense infection with amastigotes within myocytes and a minimal inflammatory infiltrate in the myocardium. Northern blot analysis of total RNA revealed no signal for IL-1beta or TNF-alpha, and a weak signal for IL-6 in the control rat hearts, and high levels of expression for the three genes in the infected rats. Western blots revealed results similar to that of mRNA levels, suggesting that, in addition to mechanical damage, infection by T. cruzi induces proinflammatory cytokine production in the myocardium itself, which may further exacerbate the pathology, and affect adversely myocardial function.

Animals↗
PubMed1996

Modulation of antioxidant enzymes and programmed cell death by n-3 fatty acids.

Studies from our laboratory indicate that n-3 (fish oil, FO) lipids at 10% (w/w) in a nutritionally adequate, semipurified diet, and supplemented with equal levels of antioxidants, extended the life span of lupus-prone (NZB/NZW)F1 (B/W) female mice as compared to n-6 (corn oil, CO) lipids. The early rise of autoimmune disease in CO-fed mice was closely linked to the loss of T-cell function. Both IL-2 production and IL-2 receptor expression were reduced due to the loss of naive T-cells and a rise in memory T-cells. Proliferative response to both mitogens and superantigens (staphylococcal enterotoxins A and B) was higher in FO-fed 6.5-mon-old mice. These changes paralleled decreased PGE2 production by splenic cells from FO-fed mice. Analysis of mRNA expression in different organs revealed differential effects of dietary lipids. In FO-fed mice, transforming growth factor beta 1 (TGF beta 1) expression was decreased in kidneys, but splenic tissues had higher expression of TGF beta mRNA. As TGF beta promotes programmed cell death (PCD), we studied the effects of CO and FO on PCD rates in lymphocytes. Both propidium iodide staining and DNA fragmentation were elevated in lymphocytes of FO-fed mice when compared to CO-fed mice of similar age. Also, increased PCD correlated closely with increased Fas gene expression. Thus, in addition to various other antiinflammatory effects, dietary FO appears to increase PCD and prevent accumulation of self-reactive immune cells in lymphoid organs. Further studies are required to dissect the pro- and antiinflammatory mechanisms associated with dietary n-3 and n-6 lipids in modulating autoimmune disorders or malignancy during aging.

Animals↗