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Biomedical subjects

Umesh C Sharma

Publications and source records attributed to Umesh C Sharma.

10 recordsLinked to original sources
PubMed2006

Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure.

OBJECTIVES: This study sought to explore the role of new biomarkers in heart failure (HF). BACKGROUND: We investigated the utility of novel serum markers alone or together with natriuretic peptide testing for diagnosis and short-term prognosis estimation in subjects with acute HF. METHODS: Plasma levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP), apelin, and galectin-3 were measured in 599 patients presenting with dyspnea at the emergency department, of which 209 (35%) had acute HF. RESULTS: The NT-proBNP was superior to either apelin or galectin-3 for diagnosis of acute HF, although galectin-3 levels were significantly higher in subjects with HF compared with those without. Receiver operating characteristic analysis for mortality prediction showed that, for 60-day prognosis, galectin-3 had the greatest area under the curve (AUC) at 0.74 (p = 0.0001), whereas NT-proBNP and apelin had an AUC of 0.67 (p = 0.009) and 0.54 (p = 0.33). In a multivariate logistic regression analysis, an elevated level of galectin-3 was the best independent predictor of 60-day mortality (odds ratio 10.3, p < 0.01) or the combination of death/recurrent HF within 60 days (odds ratio 14.3, p < 0.001). The Kaplan-Meier analyses showed that the combination of an elevated galectin-3 with NT-proBNP was a better predictor of mortality than either of the 2 markers alone. CONCLUSIONS: Our data show potential utility of galectin-3 as a useful marker for evaluation of patients with suspected or proven acute HF, whereas apelin measurement was not useful for these indications. Moreover, the combination of galectin-3 with NT-proBNP was the best predictor for prognosis in subjects with acute HF.

Acute Disease↗
PubMed2005

Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic.

The serological hallmark of primary biliary cirrhosis (PBC) is the presence of pyruvate dehydrogenase complex E2 subunit (PDC-E2) antimitochondrial antibodies (AMAs). Anti-PDC-E2 antibodies cross-react specifically with mycobacterial hsp65, and we have demonstrated that the motif SxGDL[ILV]AE shared by PDC-E2(212-226) and hsp's is a cross-reactive target. Having found that this same motif is present only in beta-galactosidase of Lactobacillus delbrueckii (BGAL LACDE), we hypothesized that this homology would also lead to cross-reactivity. The mimics were tested via ELISA for reactivity and competitive cross-reactivity using sera from 100 AMA-positive and 23 AMA-negative PBC patients and 190 controls. An Escherichia coli (ECOLI) PDC-E2 mimic that has been pathogenetically linked to PBC but lacks this motif has been also tested. Anti-BGAL(266-280) LACDE antibodies were restricted to AMA-positive patients (54 of 95, 57%) and belonged to immunoglobulin (Ig) G3. Of the 190 controls, 22 (12%; P < .001) had anti-BGAL(266-280) antibodies, mainly of the IgG4 subclass. ECOLI PDC-E2 reactivity was virtually absent. BGAL(266-280)/PDC-E2(212-226) reactivity of the IgG3 isotype was found in 52 (52%) AMA-positive PBC patients but in only 1 of the controls (P < .001). LACDE BGAL(266-280)/PDC-E2(212-226) reactivity was due to cross-reactivity as confirmed via competition ELISA. Antibody affinity for BGAL(266-280) was greater than for PDC-E2 mimics. Preincubation of a multireactive serum with BGAL(266-280) reduced the inhibition of enzymatic activity by 40%, while marginal effect (12%) or no effect (2%) was observed in human or ECOLI PDC-E2 mimics. In conclusion, IgG3 antibodies to BGAL LACDE cross-react with the major mitochondrial autoepitope and are characteristic of PBC.

Adult↗
PubMed2005

A systematic review of large scale and heterogeneous gene array data in heart failure.

Microarray analysis has become a widely available tool for the generation of gene expression data on a genomic scale. Since the studies with similar protocols are growing, it has become necessary to systematically revise the large body of literature to decipher the gene expression data. In this review, we analyzed and critically discussed the database presented from 14 published studies that showed the gene expression profile in heart failure (HF) using microarray as a primary tool. After comparing the diverse database from these studies, we explain the protein translational, matri-cellular, immunological and fibrosis-related mechanisms in HF. In addition to previously annotated genes, we analyzed two differentially expressed expressed sequence tags (ESTs) (KIAA0152 and Suppressor of G(Two) allele of the suppressor of kinetochore protein-1, SGT1) in HF and showed how bio-informatic analysis of ESTs can lead to the identification of novel pathways active in HF. We have also discussed the new publicly accessible tools that link the gene expression data to gene ontogeny (GO) and functionality. Finally, we have systematically revised the chromosomal localization of the genes that are specifically up-regulated in HF. We have thus spotted chromosome 1, 2, 11 and 12 as the chromosomal hotspots of HF. This methodical approach will simplify the existing concepts on the evolution and progression of HF and lead us toward the development of newer diagnostic and therapeutic tools. Although modeled to HF, this approach should be of broader scientific interest to elaborate multiple genes and complex pathways.

Cell Cycle Proteins↗
PubMed2004

Increased myocardial collagen content in transgenic rats overexpressing cardiac angiotensin-converting enzyme is related to enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased phosphorylation of Smad2/3.

BACKGROUND: Although increased activity of angiotensin-converting enzyme (ACE) has been associated with increased cardiac collagen, no studies to date have established a direct cause-and-effect relation between the two. METHODS AND RESULTS: We used transgenic rats that overexpress human ACE selectively in the myocardium. Two independent heterozygous transgenic rat lines were studied, one expressing 2 to 3 copies (L1172) and the other expressing 5 to 10 copies (L1173) of the ACE transgene. These rats were normotensive but developed a proportionate increase in myocardial collagen depending on the ACE gene dose (up to 2.5-fold, P<0.01), but cardiac angiotensin II levels remained normal, whereas collagen content reversed to control levels on ACE inhibition. To explain these changes, we investigated N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), an alternative substrate that is catabolized exclusively by ACE. Increased cardiac expression of ACE was paralleled by a reciprocal decrease in cardiac AcSDKP and a proportionate increase in phosphorylated Smad2 and Smad3, all of which normalized after both ACE inhibition and AcSDKP infusion. Furthermore, a functional link of this signaling cascade was demonstrated, because AcSDKP inhibited Smad3 phosphorylation in a dose-dependent manner in cultured cardiac fibroblasts and in vivo. CONCLUSIONS: Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP, an inhibitor of the phosphorylation of transforming growth factor-beta signaling molecules Smad2 and Smad3. This implies that the antifibrotic effects of ACE inhibitors are mediated in part by increasing cardiac AcSDKP, with subsequent inhibition of Smad 2/3 phosphorylation.

Activin Receptors, Type I↗
PubMed2004

Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction.

BACKGROUND: Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF. METHODS AND RESULTS: In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction. CONCLUSIONS: This study shows that an early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.

Animals↗
PubMed2004

Systematic review of the outcome of aortic valve replacement in patients with aortic stenosis.

BACKGROUND: After the establishment of aortic valve replacement procedure for aortic stenosis, there are heterogeneous studies and varying reports on outcome. An analysis that compares individual studies to summarize the overall effect is still lacking. This study systematically analyzes the change in left ventricular (LV) mass index and ejection fraction after aortic valve replacement in adult patients. METHODS: We performed MEDLINE and bibliographic searches and included 27 articles published between 1980 and 2003 about the outcome of valve replacement in 1546 aortic stenosis patients. To allow comparisons, we stratified the patients into early (0-6 months), intermediate (7-24 months), and late (25-120 months) follow-up groups for the analysis of both LV mass regression and ejection fraction. We separately analyzed five articles that reported groups of patients with low preoperative ejection fraction. RESULTS: Increase in ejection fraction after surgery is more pronounced in the patients that have low preoperative ejection fraction (28% +/- 4.3%(preop) vs 40% +/- 9.4%(6-41 months) follow-up). Patients with normal or high preoperative ejection fraction have variable outcomes. However, regression of LV mass is uniformly achieved regardless of age, sex, time of operation, or types of valve substitute. Furthermore, LV mass regresses predominantly within the first 6 months after surgery (g/m2, 181 +/- 25.8(preop) vs 124 +/- 27(6 months), 117 +/- 15(24 months), and 113 +/- 14(120 months) follow-up). CONCLUSIONS: This systematic review supports the concept that aortic stenosis patients with LV dysfunction show a clear functional improvement after aortic valve replacement. Ventricles regress rapidly and reach their approximate final size within the first 6 months of surgery.

Adult↗
PubMed2003

Left ventricular hypertrophy: virtuous intentions, malign consequences.

Left ventricular hypertrophy (LVH) is currently the focus of intense cardiovascular research, with the resultant rapid evolution of novel concepts relating to its exceedingly complex pathophysiology. In addition to the alterations in signal transduction and disturbances in Ca(2+) homeostasis, there are structural changes in myofilaments, disorganization of the cytoskeletal framework and increased collagen synthesis. LVH is associated with progressive left ventricular remodeling that culminates to heart failure. The modern treatment of left ventricular hypertrophy is now largely based on the hypothesis that neuroendocrine activation is important in the progression of the disease and inhibition of neurohormones is likely to have long-term benefit with regard to morbidity and mortality. Drugs specifically designed to unload the left ventricle, such as diuretics and vasodilators, appears to be less effective in reducing LV mass and improving prognosis. Thus, the evolution of treatment for LVH itself has provided much enlightenment for our understanding of the fundamental biology of the disorder.

Activin Receptors, Type I↗
PubMed2002

Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis.

BACKGROUND/AIMS: Antibodies to caseinolytic protease P(177-194) (ClpP(177-194)) of the proteolytic subunit of the Clp complex of Escherichia coli (E. coli) are uniquely present in primary biliary cirrhosis (PBC). Molecular mimicry between the regulatory subunit ClpX and the principal T-cell epitope of pyruvate dehydrogenase complex (PDC-E2) in PBC, has been proposed to account for this. Since ClpP is highly conserved among bacteria we investigated whether the micro-organisms triggering these antibodies may be other than E. coli. METHODS/RESULTS: E. coli ClpP(177-194) is homologous with ClpP peptides of Yersinia enterocolitica (YEREN) and Haemophilus influenzae (HAEIN). Enzyme linked immunosorbent assay (ELISA) reactivity to these peptides was tested in 45 patients with PBC, 44 pathological and 32 healthy controls. Reactivity to at least one of the ClpP peptides was observed in 21 (47%) PBC patients, 5.8% pathological and 3.1% healthy controls (P<0.01 for all). Among these 21 seropositive PBC patients, 15 (71%) reacted to ECOLI ClpP(177-194), alone or in association with YEREN and/or HAEIN peptides, compared to three (14.2%) reactive with YEREN, two (9.5%) with YEREN/HAEIN and one (4.7%) with HAEIN peptide. Simultaneous reactivity to homologous sequences was due to cross-reactivity as confirmed by competition ELISAs. CONCLUSIONS: The PBC-specificity of anti-microbial ClpP reactivity is confirmed: the questions as to primary trigger(s) and relevance to PBC pathogenesis remain open.

Adenosine Triphosphatases↗