Gyorgy Csako

Effects of Hormone-Replacement Therapy on Fibrinolysis in Postmenopausal Women

Background Plasma levels of plasminogen-activator inhibitor type 1 (PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease. We studied the effects of hormone-replacement therapy on PAI-1 levels. Methods In a randomized, crossover study, we investigated the effects of oral conjugated estrogen (0.625 mg per day) in 30 postmenopausal women and transdermal estradiol (0.1 mg per day) in 20 postmenopausal women, either alone or in combination with medroxyprogesterone acetate (2.5 mg daily) for one month, on plasma PAI-1 antigen levels. Degradation products of cross-linked fibrin (D-dimer) were measured in serum as an index of fibrinolysis. Results PAI-1 levels were inversely associated with D-dimer levels at base line (r = -0.540, P = 0.002). Conjugated estrogen, both alone and in combination with medroxyprogesterone acetate, reduced mean (±SD) plasma levels of PAI-1 from 32±34 ng per milliliter to 14±10 ng per m...

Systematic Review: The Effect of Preventive Lamivudine on Hepatitis B Reactivation during Chemotherapy

Context Does lamivudine prevent hepatitis B virus (HBV) reactivation among patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy? Contribution This systematic review of 14 studies found that, compared with no preventive lamivudine, lamivudine reduced HBV reactivation, HBV-related hepatitis, and HBV-related hepatic failure. Caution Studies were small and heterogeneous. Only 2 were randomized trials, and none compared lamivudine with other, newer anti-HBV agents. Implication Preventive lamivudine may reduce risk for HBV reactivation and associated death in HBsAg-positive patients with cancer who are undergoing chemotherapy. The Editors More than 350 million persons worldwide have hepatitis B virus (HBV) (1). Chronic infection with HBV is a major public health problem and is the leading cause of liver cancer in Asia and Africa (1). In the United States, the prevalence of HBV infection, defined as the presence of hepatitis B surface antigen (HBsAg) in the blood, is less than 1% but may be as high as 5% to 15% in immigrants from Asia, Africa, the Middle East, and Eastern Europe (2, 3). Infection with HBV can lead to chronic liver disease, cirrhosis, and liver cancer (4). However, many persons who continue to harbor HBV in serum and hepatocytes for many years have few (if any) clinical sequelae. These persons are considered to have the inactive HBsAg carrier state and have little evidence of liver disease, despite low levels of HBV replication in hepatocytes (5). In such individuals, immunosuppressive agents can precipitate an increase in HBV replication followed by a flare of hepatitis B that can be severe and even fatal (6). Prompt recognition and institution of anti-HBV therapy are desirable, but therapy may fail if substantial damage has already occurred (7). Because chemotherapy is highly immunosuppressive, it may cause flares of HBV in persons who carry HBsAg in their serum (7). Flares can occur despite normal serum alanine aminotransferase (ALT) levels and low levels of circulating virus before chemotherapy is started (7, 8) and may lead to high HBV-related morbidity and mortality (9). Because cancer is the second leading cause of death in the United States, a large proportion of the population may undergo chemotherapy during their lifetime (10). Therefore, even with a relatively low prevalence of the HBsAg carrier state, prevention of chemotherapy-induced HBV reactivation is an important medical problem and a public health concern. The problem is more critical in areas of the world where HBV infection is endemic (1). Lamivudine, a nucleoside analogue (11), effectively suppresses HBV replication, reduces levels of HBV DNA in serum, and improves liver injury in patients with chronic hepatitis B. Lamivudine also has an excellent long-term safety profile and is generally well tolerated (12). Several studies reported a beneficial effect of lamivudine in preventing HBV reactivation and HBV-related death in patients who tested positive for HBsAg and are undergoing chemotherapy (8, 13, 14). However, the quantitative benefits of preventive therapy with lamivudine have not been carefully defined. The magnitude of response to lamivudine for preventing morbidity and mortality in this clinical setting has direct implications for both clinicians and health policymakers. The research synthesis discussed here explored the following question: Does preventive lamivudine therapy reduce the risk for HBV reactivation, HBV-related hepatitis, acute hepatic failure due to HBV, or HBV-related death in patients who test positive for HBsAg and are undergoing chemotherapy? Methods Data Sources and Searches We searched the following databases in all languages until June 2007: MEDLINE from 1966, Ovid MEDLINE from 1950, TOXNET from 1965, Scopus from 1966, Web of Science from 1955, and the Cochrane Central Register of Controlled Trials from January 1997. Index terms included hepatitis B virus or HBV in combination with reactivation. Figure 1 shows our prespecified protocol. We also did a manual review of the bibliographies for seminal primary and review articles to identify additional relevant studies. Furthermore, we manually searched the 2006 and 2007 American Gastroenterological Association annual meeting abstracts. To maximize data requisition, we contacted authors whose articles contained inadequate information. In addition, we contacted authors of included studies to request information about long-term efficacy and safety outcomes, including cancer-related or all-cause mortality, adverse effects of lamivudine, and any new or unpublished data or relevant meeting abstracts. Figure 1. Study flow diagram. Study Selection The 4 criteria for analyzing studies in this research synthesis were randomized, controlled trials, or retrospective or prospective cohort studies with a control (concurrent or historical) group that allowed assessment of the rate of reactivation of hepatitis B after the start of chemotherapy with or without lamivudine therapy; a report of HBV reactivation, HBV-related hepatitis, acute hepatic failure due to HBV, or HBV-related death; a clear definition of the baseline population in terms of HBsAg positivity; and more than 5 participants per treatment group. Trials were excluded if relevant data could not be extracted. Case reports or series and studies that included posttransplantation patients or those with rheumatologic diseases or HIV were also excluded. The primary outcome measure of this research synthesis was reactivation of hepatitis B, defined as at least a 10-fold increase in serum HBV DNA levels with an accompanying increase in serum ALT compared with baseline. Secondary outcome measures included HBV-related hepatitis, defined as an increase in serum ALT that was 2 or more times greater than baseline levels and a 10-fold increase in serum HBV DNA levels; HBV-related hepatic failure, defined as elevated serum ALT level and prolonged prothrombin time or other evidence of coagulopathy with jaundice with or without encephalopathy after starting chemotherapy in patients who met criteria for HBV-related hepatitis; and HBV-related death, defined as death of a patient who had documented HBV reactivation that was reported by the authors as an HBV-related death and who had no other apparent cause of death. Data Extraction and Study Quality Two investigators independently screened titles and abstracts and extracted data from eligible studies. The independently identified articles that met the initial screening criteria were collectively reviewed in their entirety by these 2 investigators and were verified for the extracted data. Subsequently, 2 additional investigators confirmed whether eligible studies met the inclusion criteria and independently assessed the accuracy of data extraction. When necessary, conflict was resolved by consensus of all 4 investigators. The Appendix Table summarizes the methodological characteristics of the 14 studies eligible for this research synthesis. We considered randomized, controlled trials as high-quality evidence, prospective cohort studies with a concurrent control group as intermediate-quality evidence, and retrospective cohort studies and studies with a historical control group as low-quality evidence. Appendix Table. Methodological Characteristics of Clinical Trials Assessing the Efficacy of Preventive Lamivudine Data Synthesis and Statistical Analysis For each eligible study, relative risk (RR) and the exact 2-sided 95% CI were computed for the primary (HBV reactivation) and secondary (HBV-related hepatitis, HBV-related hepatic failure, and HBV-related death) outcomes by using StatXact PROCs (Cytel, Cambridge, Massachusetts). An RR less than 1.00 indicates risk reduction in the intervention group (lamivudine) over the control group (no or deferred lamivudine use). Graphics were created by using Comprehensive Meta Analysis Software (Biostat, Englewood, New Jersey). Because of the heterogeneity of patient populations, study designs, and other study methods, we considered it inappropriate to compute pooled estimates. Instead, we present study-specific estimates of effect and qualitatively describe the patterns of results overall. Role of the Funding Source This project was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Clinical Center, National Institutes of Health. The funding sources had no role in conducting the study and have no potential conflicts of interest. Results Characteristics and Quality of Studies Fourteen studies met the specified criteria for assessment of HBV reactivation (Figure 1). Of these, 12 studies were conducted in East Asia (8, 13, 1523) and 1 each in Turkey (24) and Israel (25) (Table 1). All studies were in English except for 1 in Chinese (20). There were 2 randomized, controlled trials (8, 21); 8 prospective cohort studies (13, 15, 20, 2226), including 3 with concurrent control groups and 5 with historical control groups (13, 15, 22, 23, 26); and 4 retrospective cohort studies (1619) (Table 1). In addition, we identified 1 study (27) that compared lamivudine versus control in a similar patient population, but it did not report any of the outcomes of interest. The authors were contacted but did not provide further information, and thus we did not include the study. The Appendix Table describes the methodological characteristics and other quality indicators of the studies included in this review. The studies were generally small and did not consistently provide primary and secondary outcomes stratified by age, sex, ethnicity or race, baseline serum ALT levels, serum HBV DNA levels, or HBsAg status. On the other hand, patients included in both the treatment and the control groups were derived from similar patient populations at the same treatment center and received similar chemotherapeutic regimens. Furthermore, few patients

Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels

Infection and inflammation have been suggested to play roles in coronary artery disease (CAD). We hypothesized that: (1) CAD risk is associated with the aggregate number of pathogens (pathogen burden), and (2) increased pathogen burden is associated with elevated levels of C-reactive protein (CRP), a marker of inflammation. We evaluated 233 patients for CAD. Blood samples from each patient were tested for immunoglobulin-G (IgG) antibodies to cytomegalovirus (CMV), Chlamydia pneumoniae, hepatitis A virus (HAV), herpes simplex virus type 1 (HSV-1) and HSV type 2 (HSV-2), and for the CRP levels. Of the 233 study subjects, 68% had evidence of CAD by coronary angiography. Although the prevalence of seropositivity for each pathogen tended to be higher in the patients with CAD than those without, only the association between CAD and seropositivity to HAV was significant in multivariate analysis. Over 75% of study subjects had been exposed to > or =3 of the 5 pathogens tested, and analysis determined that increasing pathogen burden was significantly associated with increasing CAD risk, even after adjustment for traditional CAD risk factors. The prevalence of CAD was 48%, 69%, and 85% in individuals with antibodies to < or =2 pathogens, to 3 or 4 pathogens, and to 5 pathogens, respectively. A similar association between increasing pathogen burden and CRP levels was also found. The pathogen burden remained a significant predictor of CRP levels after multivariate analysis. Our data suggest that infection does play a role in the genesis of atherosclerosis. However, the risk posed by infection is related to the pathogen burden that may contribute to CAD through inflammatory responses.

Vascular Effects of Estrogen and Cholesterol-Lowering Therapies in Hypercholesterolemic Postmenopausal Women

BACKGROUND Lipoproteins affect endothelium-dependent vasomotor responsiveness. Because lipoprotein effects of estrogen and cholesterol-lowering therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic postmenopausal women. METHODS AND RESULTS We randomly assigned 28 women to conjugated equine estrogen (CE) 0.625 mg, simvastatin 10 mg, and their combination daily for 6 weeks. Compared with respective baseline values, simvastatin alone and combined with CE reduced LDL cholesterol to a greater extent than CE alone (both P<0.05). CE alone and combined with simvastatin raised HDL cholesterol and lowered lipoprotein(a) to a greater extent than simvastatin alone (all P<0.05). Flow-mediated dilation of the brachial artery (by ultrasonography) improved (all P<0.001 versus baseline values) on CE (4.0+/-2.6% to 10.2+/-3.9%), simvastatin (4.3+/-2.4% to 10.0+/-3.9%), and CE combined with simvastatin (4.6+/-2.0% to 9.8+/-2.6%), but similarly among therapies (P=0.507 by ANOVA). None of the therapies improved the dilator response to nitroglycerin (all P>/=0.184). Only therapies including CE lowered levels of plasminogen activator inhibitor type 1 and the cell adhesion molecule E-selectin (all P<0. 05 versus simvastatin). CONCLUSIONS Although estrogen and statin therapies have differing effects on lipoprotein levels, specific improvement in endothelium-dependent vasodilator responsiveness is similar. However, only therapies including estrogen improved markers of fibrinolysis and vascular inflammation. Thus, estrogen therapy appears to have unique properties that may benefit the vasculature of hypercholesterolemic postmenopausal women, even if they are already on cholesterol-lowering therapy.

Apolipoprotein B and Cardiovascular Disease Risk: Position Statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices

BACKGROUND Low-density lipoprotein cholesterol (LDL-C) has been the cornerstone measurement for assessing cardiovascular risk for nearly 20 years. CONTENT Recent data demonstrate that apolipoprotein B (apo B) is a better measure of circulating LDL particle number (LDL-P) concentration and is a more reliable indicator of risk than LDL-C, and there is growing support for the idea that addition of apo B measurement to the routine lipid panel for assessing and monitoring patients at risk for cardiovascular disease (CVD) would enhance patient management. In this report, we review the studies of apo B and LDL-P reported to date, discuss potential advantages of their measurement over that of LDL-C, and present information related to standardization. CONCLUSIONS In line with recently adopted Canadian guidelines, the addition of apo B represents a logical next step to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) and other guidelines in the US. Considering that it has taken years to educate physicians and patients regarding the use of LDL-C, changing perceptions and practices will not be easy. Thus, it appears prudent to consider using apo B along with LDL-C to assess LDL-related risk for an interim period until the superiority of apo B is generally recognized.

Divergent Nitric Oxide Bioavailability in Men and Women With Sickle Cell Disease

Background—Although reduced endothelial nitric oxide (NO) bioavailability has been demonstrated in arteriosclerotic vascular disease, the integrity of this system in sickle cell disease remains uncertain. Methods and Results—We measured forearm blood flow in 21 patients with sickle cell disease (hemoglobin SS genotype) and 18 black control subjects before and after intra-arterial infusions of acetylcholine, nitroprusside, and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Endothelium-dependent vasodilation, measured by the percent increase in flow induced by acetylcholine infusion, was significantly greater than in controls (252±37% for patients versus 134±24% for controls;P <0.0001). However, there was a large sex difference in blood flow responses between female and male patients (340±46% versus 173±41%;P =0.035). Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NMMA, was depressed in male compared with female patients (−17±5% versus −34±4%;P =0.01), as was the response to nitroprusside (86±21% versus 171±22%;P =0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 were appreciated, with significant correlations between levels of soluble vascular cell adhesion molecule-1 and blood flow responses to L-NMMA and nitroprusside (r =0.53, P =0.004 and r =−0.66, P <0.001, respectively). Conclusions—NO bioavailability and NO responsiveness are greater in women than in men with sickle cell disease and determines adhesion molecule expression. Endothelium-dependent blood flows are largely non-NO mediated in male patients. These results provide a possible mechanism for reported sex differences in sickle cell disease morbidity and mortality and provide a basis for novel pharmacological interventions.

Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management.

OBJECTIVES The goal of our study was to determine whether hormone therapy alters markers of inflammation in postmenopausal women with chronic stable coronary artery disease (CAD) on appropriate medical management. BACKGROUND Hormone therapy reduces some markers of inflammation associated with atherosclerosis risk (cell adhesion molecules) but increases levels of another marker of inflammation--C-reactive protein-in healthy postmenopausal women. METHODS Ten women (average age 66 years; range 59 to 76 years) with CAD on medical management (including aspirin [9], statin lipid-lowering therapy [7], angiotensin-converting enzyme inhibitors [3]) were randomly assigned to conjugated equine estrogens 0.625 mg (combined with medroxyprogesterone acetate 2.5 mg daily in five women with uterus intact) or placebo(s) daily for one month with crossover to the alternate therapy after one month off of hormone treatment in a double-blind study. At the end of each treatment phase, the following markers of inflammation were measured in serum: interleukin-6, C-reactive protein, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and matrix metalloproteinase-9. RESULTS Hormone therapy significantly lowered serum levels of cell adhesion molecules E-selectin (46.9+/-18.3 vs. 56.3+/-20.6 ng/mL, p = 0.006), intercellular adhesion molecule-1 (282+/-74 vs. 304+/-78 ng/mL, p = 0.013) and vascular cell adhesion molecule-1 (605+/-218 vs. 657+/-214 ng/mL, p = 0.01) but increased levels of matrix metalloproteinase-9 (648+/-349 vs. 501+/-285 ng/mL, p = 0.02). Interleukin-6 (4.33+/-4.78 vs. 3.04+/-1.47 pg/mL, p = 0.283) and C-reactive protein (0.88+/-1.13 vs. 0.61+/-0.50 mg/dL, p = 0.358) were not significantly elevated on hormone therapy compared with placebo values. CONCLUSIONS Hormone therapy has divergent effects on serum markers of inflammation in women with CAD. Reduction in levels of cell adhesion molecules may reduce attachment of white blood cells to the vessel wall, but increases in matrix metalloproteinase-9 within the vessel wall could digest and weaken fibrous caps of vulnerable plaques, thus provoking thrombosis.

Increased Serum Levels of Heat Shock Protein 70 Are Associated With Low Risk of Coronary Artery Disease

Objective—Previous studies suggest that heat shock protein (HSP) 60 has a contributory role in atherosclerosis development. We examined whether circulating HSP70 protein and anti-HSP70 antibodies are associated with coronary artery disease (CAD). Methods and Results—Blood samples from 421 patients (62% men, mean age 57 years) evaluated for CAD by coronary angiography were tested. Serum HSP70 was detectable in 67% of study subjects with levels ranging from 0.2 to 27.1 ng/mL (mean, 1.08; median, 0.5). HSP70 levels were higher in non-CAD patients than CAD patients (median, 0.72 versus 0.34;P =0.0006). Individuals with HSP70 levels above the median (0.5 ng/mL) had half the risk of CAD than individuals with levels below the median (adjusted odds ratio, 0.52; 95% confidence limit, 0.32 to 0.86). The association of high HSP70 levels with low CAD risk was independent of traditional CAD risk factors (P =0.011). Disease severity (number of diseased vessels) was also inversely associated with HSP70 protein levels (P =0.010). The adjusted odds ratio of having multivessel disease for patients with high HSP70 protein levels was 0.54 (95% confidence limit, 0.36 to 0.81). In contrast, no association between anti-HSP70 IgG seropositivity and the prevalence of CAD was found (P =0.916). Conclusions—These data provide the first evidence that high levels of human HSP70 are associated with the low CAD risk, probably through its multiple protective effects on a cell’s response to stress.

Cytomegalovirus in the pathogenesis of atherosclerosis: the role of inflammation as reflected by elevated C-reactive protein levels.

OBJECTIVES We hypothesized that cytomegalovirus (CMV) infection: 1) stimulates an inflammatory response, reflected by elevated C-reactive protein (CRP) levels, and 2) predisposes to coronary artery disease (CAD), in part, through CMV-induced inflammation. BACKGROUND Although some studies show an association between CMV and atherosclerosis, others do not. We believed that CMV exerted an atherogenic effect by inducing inflammation, and the disparate results may derive partly from individual variability in the capacity to control CMV inflammatory activity. METHODS Blood samples were tested for CMV seropositivity and CRP levels from 238 individuals being evaluated for CAD by coronary angiography. RESULTS An elevated CRP level (>0.5 mg/dl) was a significant CAD determinant even after adjustment for traditional CAD risk factors (odds ratio [OR] = 2.4; p = 0.02). Moreover, CMV seropositivity was significantly associated with increased CRP levels (p = 0.04 after adjustment for CAD risk factors), suggesting that CMV could evoke a subclinical inflammatory response. However, considerable host variation existed in this response to CMV. When adjusted for CAD risk factors, the OR for CAD were 1.3 in the subgroup with CMV seropositivity alone (p = 0.7), 2.3 in the subgroup with elevated CRP levels alone (p = 0.2), and 4.3 in the subgroup with combined CMV seropositivity and elevated CRP levels (p = 0.01). CONCLUSIONS Our results suggest that 1) CMV elicits a subclinical inflammatory response, but only in certain individuals, and 2) individuals with an inflammatory response appear susceptible to the atherogenic effects of CMV, whereas those without appear resistant. These results may partly explain the disparate results of studies attempting to relate CMV to atherogenesis.

Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.

Aliment Pharmacol Ther 2012; 35: 66–75