Circulation. 2009;119:2471-2479
Insights From the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) Study
Background— Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction.
Methods and Results— In a substudy of the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), which evaluated the effects of the selective aldosterone receptor antagonist eplerenone versus placebo, serum levels of collagen biomarkers were measured in 476 patients with congestive heart failure after acute myocardial infarction complicated with left ventricular systolic dysfunction. The combination of the type I collagen telopeptide and brain natriuretic peptide levels above median at baseline was associated with all-cause mortality and the composite end point of cardiovascular death or heart failure hospitalization, with hazard ratios of 2.49 (P=0.039) and 3.03 (P=0.002), respectively. During follow-up, levels of aminoterminal propeptide of type I and type III procollagen were found to be consistently lower in the eplerenone group and significantly lower beginning at 6 months.
Conclusions— Changes in biomarkers of collagen synthesis and degradation suggest that extracellular matrix remodeling is an active process in patients with congestive heart failure and left ventricular systolic dysfunction after acute myocardial infarction. High type I collagen telopeptide and high brain natriuretic peptide serum levels are associated with the highest event rate. Eplerenone suppresses post–acute myocardial infarction collagen turnover changes.
Wafae Iraqi, PharmD; Patrick Rossignol, MD, PhD; Michael Angioi, MD; Renaud Fay, PharmD; Josette Nuée, PhD; Jean Marie Ketelslegers, MD, PhD; John Vincent, MD; Bertram Pitt, MD; Faiez Zannad, MD, PhD
Tuesday
RENIN AND HEART FAILURE
THE RENIN SYSTEM AND ATRIAL NATRIURETIC HORMONE IN CONGESTIVE HEART FAILURE
Abstract. The renin angiotensin system is activated in the majority of patients with chronic congestive heart failure of moderate to severe symptomology. Renin release may result from one of several different stimuli: renal tubular sodium delivery and sensing by the macula densa, sympathetic nervous system activity, and baroreceptor to changes in renal blood flow. Difficulties arise with an analysis of renin angiotensin system activity due to the necessity for diuretic therapy in the majority of these patients. Despite the presence of diuretic therapy, however, there is a wide range of renin angiotensin system activity. In evaluating this activity the administration of a converting enzyme inhibitor will block the contribution of angiotensin mediated vasoconstriction, thereby confirming the importance of the renin angiotensin system activity as a mediator of the long-term consequences of heart failure In situations of low plasma renin activity, vasoconstriction is mediated by an alternate mechanism. The mechanisms of this non-renin mediated vasoconstriction are less apparent, but may include calcium mediated vasoconstriction, and the effects of increased cytosolic content.
This low renin group of patients appear to be very sensitive to reversal of vasoconstriction by calcium channel antagonists, especially when converting enzyme inhibitors are ineffective. In an analysis of the factors that may result in renin release, tubular delivery of sodium to the macula densa may emerge as the most important regulator of renin release.
In milder forms of heart failure, or in the absence of diuretic therapy, the renin angiotensin system does not show the degree of activation that occurs in the more severe form of heart failure when diuretics are given. From a theroretical standpoint, endogenous atrial natriuretic factor may emerge as an important regular of sodium and water excretion, acting either independently, or as a regulator of the renin angiotensin system, It will therefore be necessary to evaluate the impact of atrial natriuretic factor in patients with congestive heart failure particularly in relation to the renin angiotensin system.
John H. Laragh M.D., Robert J. Cody M.D., Andrew B. Covit M.D. and Steven A. Atlas M.D.Cardiovascular Center, The New York Hospital-Cornell University Medical Center, New York, N.Y.
Abstract. The renin angiotensin system is activated in the majority of patients with chronic congestive heart failure of moderate to severe symptomology. Renin release may result from one of several different stimuli: renal tubular sodium delivery and sensing by the macula densa, sympathetic nervous system activity, and baroreceptor to changes in renal blood flow. Difficulties arise with an analysis of renin angiotensin system activity due to the necessity for diuretic therapy in the majority of these patients. Despite the presence of diuretic therapy, however, there is a wide range of renin angiotensin system activity. In evaluating this activity the administration of a converting enzyme inhibitor will block the contribution of angiotensin mediated vasoconstriction, thereby confirming the importance of the renin angiotensin system activity as a mediator of the long-term consequences of heart failure In situations of low plasma renin activity, vasoconstriction is mediated by an alternate mechanism. The mechanisms of this non-renin mediated vasoconstriction are less apparent, but may include calcium mediated vasoconstriction, and the effects of increased cytosolic content.
This low renin group of patients appear to be very sensitive to reversal of vasoconstriction by calcium channel antagonists, especially when converting enzyme inhibitors are ineffective. In an analysis of the factors that may result in renin release, tubular delivery of sodium to the macula densa may emerge as the most important regulator of renin release.
In milder forms of heart failure, or in the absence of diuretic therapy, the renin angiotensin system does not show the degree of activation that occurs in the more severe form of heart failure when diuretics are given. From a theroretical standpoint, endogenous atrial natriuretic factor may emerge as an important regular of sodium and water excretion, acting either independently, or as a regulator of the renin angiotensin system, It will therefore be necessary to evaluate the impact of atrial natriuretic factor in patients with congestive heart failure particularly in relation to the renin angiotensin system.
John H. Laragh M.D., Robert J. Cody M.D., Andrew B. Covit M.D. and Steven A. Atlas M.D.Cardiovascular Center, The New York Hospital-Cornell University Medical Center, New York, N.Y.
Thursday
Preoperative serum placenta growth factor level is a prognostic biomarker in colorectal cancer
PURPOSE: Increased angiogenesis at the site of the primary tumor in colorectal cancer has been associated with poor prognosis and relapse of disease. We previously demonstrated that the tissue level of placenta growth factor expression was upregulated in colorectal cancer and correlated with disease progression and patient survival. The aims of this study are to examine the prognostic value of serum placenta growth factor, vascular endothelial growth factor, and sFlt-1 and to compare them with the carcinoembryonic antigen levels in patients with colorectal cancer.
METHODS: Preoperative serum from 86 patients and serum from 30 healthy controls was included. The levels of sFlt-1, placenta growth factor, vascular endothelial growth factor in the serum were assayed and correlated with the clinical stage results.
RESULTS: Serum placenta growth factor, but not vascular endothelial growth factor, increased; sFlt-1 decreased in patients with preoperative colorectal cancer, compared with healthy controls. Higher preoperation serum placenta growth factor levels were associated with higher risk of recurrence. Preoperation serum placenta growth factor, but not carcinoembryonic antigen, was a prognostic indicator in patients with Stage III colorectal cancer. When we use the median level (20.6 pg/ml) of preoperative serum placenta growth factor as a cutoff point, the sensitivity, specificity, and positive predictive value for tumor recurrence and survival was 80, 54, 80% and 70, 56, 70%, respectively.
CONCLUSIONS: Preoperative serum placenta growth factor levels were higher in patients with colorectal cancer, were negatively correlated with the serum sFlt-1, and could be used as a prognostic indicator for recurrence and survival for colorectal cancer.
Wei SC, Liang JT, Tsao PN, Hsieh FJ, Yu SC, Wong JM.
Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
METHODS: Preoperative serum from 86 patients and serum from 30 healthy controls was included. The levels of sFlt-1, placenta growth factor, vascular endothelial growth factor in the serum were assayed and correlated with the clinical stage results.
RESULTS: Serum placenta growth factor, but not vascular endothelial growth factor, increased; sFlt-1 decreased in patients with preoperative colorectal cancer, compared with healthy controls. Higher preoperation serum placenta growth factor levels were associated with higher risk of recurrence. Preoperation serum placenta growth factor, but not carcinoembryonic antigen, was a prognostic indicator in patients with Stage III colorectal cancer. When we use the median level (20.6 pg/ml) of preoperative serum placenta growth factor as a cutoff point, the sensitivity, specificity, and positive predictive value for tumor recurrence and survival was 80, 54, 80% and 70, 56, 70%, respectively.
CONCLUSIONS: Preoperative serum placenta growth factor levels were higher in patients with colorectal cancer, were negatively correlated with the serum sFlt-1, and could be used as a prognostic indicator for recurrence and survival for colorectal cancer.
Wei SC, Liang JT, Tsao PN, Hsieh FJ, Yu SC, Wong JM.
Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
Sunday
Depletion of one, six, twelve or twenty major blood proteins before proteomic analysis:
Depletion of major blood proteins is one of the most promising approaches to access low abundant biomarkers using proteomics. Immunocapture columns often used for this purpose exist in different formats depending on the number of major proteins removed. In this article, we compared the relative interest of depleting either one (albumin), six (albumin, IgG, IgA, transferrin, alpha1-antitrypsin, and haptoglobin), twelve (the previous six and apo A-I and -II, orosomucoid, alpha2-macroglobulin, fibrinogen, IgM) or twenty blood proteins (the previous twelve and IgD, ceruloplasmin, apo B, complement C1q, C3, C4, plasminogen, and prealbumin). Such study raises interesting issues related to the reproducibility, practicability, specificity of the immunocapture, and to the impact of removing not only the selected molecules, but also associated peptides and proteins. Depleted sera were here analysed using different proteomic approaches, including two dimensional electrophoresis and SELDI-TOF. Altogether, our results clearly confirmed the interest of depleting major blood proteins for the proteomic detection of low abundant components. However, we observed that increasing the number of depleted proteins from twelve to twenty had a limited beneficial impact and might increase drawbacks in removing associated peptides and proteins. This conclusion is however related to the technologies that we have used, and we believe that it is necessary to adapt the immunocapture to the analytical method employed, and to the ratio between wanted and unwanted proteins removed.
Roche S, Tiers L, Provansal M, Seveno M, Piva MT, Jouin P, Lehmann S.
CHU Montpellier, Biochimie Saint Eloi, Plateforme de Protéomique Clinique 80 av A. Fliche, 34295 Montpellier Cedex 5, France; Institut de Génétique Humaine du CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
Roche S, Tiers L, Provansal M, Seveno M, Piva MT, Jouin P, Lehmann S.
CHU Montpellier, Biochimie Saint Eloi, Plateforme de Protéomique Clinique 80 av A. Fliche, 34295 Montpellier Cedex 5, France; Institut de Génétique Humaine du CNRS, 141 rue de la Cardonille, 34396 Montpellier, France.
Wednesday
Cystatin C in cerebrospinal fluid as a biomarker of ALS.
Department of Neurology, Graduate School of Medicine, Hokkaido University, Sapporo City, Hokkaido, Japan. tujitti@jb3.so-net.ne.jp
Amyotrophic lateral sclerosis (ALS) is diagnosed on the basis of progressive symptoms in both the upper and lower motor neurons. Because there are no specific biomarkers for ALS, it is difficult to diagnose this disease in its early stages. Cerebrospinal fluid (CSF) samples were obtained from 14 patients in the early stages of ALS, from 13 with polyneuropathy, and from 16 with other neurological disorders. The concentration of cystatin C in the CSF was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) kit. The concentration of cystatin C in the CSF was significantly lower in ALS patients than in the control subjects who were patients with polyneuropathy or other neurological diseases (patients with ALS, polyneuropathy, and other diseases exhibited 5.5 +/- 0.3, 6.7 +/- 0.4, and 6.9 +/- 0.3 mg/L cystatin C, respectively; ALS patients vs. control subjects: p = 0.014 and ALS patients vs. polyneuropathy patients: p = 0.024). Cystatin C may be a useful biomarker of ALS and can be used to distinguish between ALS and polyneuropathy.
Amyotrophic lateral sclerosis (ALS) is diagnosed on the basis of progressive symptoms in both the upper and lower motor neurons. Because there are no specific biomarkers for ALS, it is difficult to diagnose this disease in its early stages. Cerebrospinal fluid (CSF) samples were obtained from 14 patients in the early stages of ALS, from 13 with polyneuropathy, and from 16 with other neurological disorders. The concentration of cystatin C in the CSF was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) kit. The concentration of cystatin C in the CSF was significantly lower in ALS patients than in the control subjects who were patients with polyneuropathy or other neurological diseases (patients with ALS, polyneuropathy, and other diseases exhibited 5.5 +/- 0.3, 6.7 +/- 0.4, and 6.9 +/- 0.3 mg/L cystatin C, respectively; ALS patients vs. control subjects: p = 0.014 and ALS patients vs. polyneuropathy patients: p = 0.024). Cystatin C may be a useful biomarker of ALS and can be used to distinguish between ALS and polyneuropathy.
Evaluation of the DNA Damaging Potential of Cannabis Cigarette Smoke
United Kingdom, Department of Biosciences and Nutrition, Unit of Molecular Epidemiology, Karolinska Institute, S-141 57 Huddinge, Sweden, and Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Fifth Floor RKCSB, Leicester Royal Infirmary, Leicester, LE2 7LX United Kingdom.
Acetaldehyde is an ubiquitous genotoxic compound that has been classified as a possible carcinogen to humans. It can react with DNA to form primarily a Schiff base N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) adduct. An online column-switching valve liquid chromatography tandem mass spectrometry (LC-MS/MS) selected reaction monitoring (SRM) method was developed for the determination of N(2)-ethylidene-dG adducts in DNA following reduction with sodium cyanoborohydride (NaBH(3)CN) to the chemically stable N(2)-ethyl-2'-deoxyguanosine (N(2)-ethyl-dG) adduct. Accurate quantitation of the adduct was obtained by the addition of the [(15)N(5)]N(2)-ethyl-dG stable isotope-labeled internal standard prior to enzymatic hydrolysis of the DNA samples to 2'-deoxynucleosides with the incorporation of NaBH(3)CN in the DNA hydrolysis buffer.
The method required 50 mug of hydrolyzed DNA on column for the analysis, and the limit of detection for N(2)-ethyl-dG was 2.0 fmol. The analysis of calf thymus DNA treated in vitro with acetaldehyde (ranging from 0.5 to 100 mM) or with the smoke generated from 1, 5, and 10 cannabis cigarettes showed linear dose-dependent increases in the level of N(2)-ethyl-dG adducts (r = 0.954 and r = 0.999, respectively). Similar levels (332.8 +/- 21.9 vs 348.4 +/- 19.1 adducts per 10(8) 2'-deoxynucleosides) of N(2)-ethyl-dG adducts were detected following the exposure of calf thymus DNA to 10 tobacco or 10 cannabis cigarettes.
No significant difference was found in the levels of N(2)-ethyl-dG adducts in human lung DNA obtained from nonsmokers (n = 4) and smokers (n = 4) with the average level observed as 13.3 +/- 0.7 adducts per 10(8) 2'-deoxynucleosides. No N(2)-ethyl-dG adducts were detected in any of the DNA samples following analysis with the omission of NaBH(3)CN from the DNA hydrolysis buffer. In conclusion, these results provide evidence for the DNA damaging potential of cannabis smoke, implying that the consumption of cannabis cigarettes may be detrimental to human health with the possibility to initiate cancer development.
Acetaldehyde is an ubiquitous genotoxic compound that has been classified as a possible carcinogen to humans. It can react with DNA to form primarily a Schiff base N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) adduct. An online column-switching valve liquid chromatography tandem mass spectrometry (LC-MS/MS) selected reaction monitoring (SRM) method was developed for the determination of N(2)-ethylidene-dG adducts in DNA following reduction with sodium cyanoborohydride (NaBH(3)CN) to the chemically stable N(2)-ethyl-2'-deoxyguanosine (N(2)-ethyl-dG) adduct. Accurate quantitation of the adduct was obtained by the addition of the [(15)N(5)]N(2)-ethyl-dG stable isotope-labeled internal standard prior to enzymatic hydrolysis of the DNA samples to 2'-deoxynucleosides with the incorporation of NaBH(3)CN in the DNA hydrolysis buffer.
The method required 50 mug of hydrolyzed DNA on column for the analysis, and the limit of detection for N(2)-ethyl-dG was 2.0 fmol. The analysis of calf thymus DNA treated in vitro with acetaldehyde (ranging from 0.5 to 100 mM) or with the smoke generated from 1, 5, and 10 cannabis cigarettes showed linear dose-dependent increases in the level of N(2)-ethyl-dG adducts (r = 0.954 and r = 0.999, respectively). Similar levels (332.8 +/- 21.9 vs 348.4 +/- 19.1 adducts per 10(8) 2'-deoxynucleosides) of N(2)-ethyl-dG adducts were detected following the exposure of calf thymus DNA to 10 tobacco or 10 cannabis cigarettes.
No significant difference was found in the levels of N(2)-ethyl-dG adducts in human lung DNA obtained from nonsmokers (n = 4) and smokers (n = 4) with the average level observed as 13.3 +/- 0.7 adducts per 10(8) 2'-deoxynucleosides. No N(2)-ethyl-dG adducts were detected in any of the DNA samples following analysis with the omission of NaBH(3)CN from the DNA hydrolysis buffer. In conclusion, these results provide evidence for the DNA damaging potential of cannabis smoke, implying that the consumption of cannabis cigarettes may be detrimental to human health with the possibility to initiate cancer development.
Saturday
Prediction of bone metastases by combination of tartrate-resistant acid phosphatase, alkaline phosphatase and prostate specific antigen in patients wi
Choichiro Ozu, Jun Nakashima, Yutaka Horiguchi, Mototsugu Oya, Takashi Ohigashi and Masaru Murai, Keio University School of Medicine , Department of Urology, Tokyo, Japan
ABSTRACT
Objective: The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated.
Methods: TRACP, PACP, ALP, and PSA serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis .
Results: Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers.
Conclusions: Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.
International Journal of Urology
Volume 15 Issue 5, Pages 419 - 422
Published Online: 28 Mar 2008
ABSTRACT
Objective: The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated.
Methods: TRACP, PACP, ALP, and PSA serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis .
Results: Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers.
Conclusions: Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.
International Journal of Urology
Volume 15 Issue 5, Pages 419 - 422
Published Online: 28 Mar 2008
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