Both initial red cell distribution width (RDW) and change in RDW during heart failure hospitalization are associated with length of hospital stay and 30-day outcomes.

INTRODUCTION: We examined the predictive ability of red cell distribution width (RDW) and the change in RDW during hospitalization (ΔRDW) for length of stay (LOS) and 30-day outcomes after heart failure (HF) inpatient stay. METHODS: Electronic query of Intermountain Healthcare medical records identified patients (N = 6414) with a primary diagnosis of HF who were discharged between 2004 and 2013, had RDW measured within 24 h after admission, and had RDW tested at least once more during the same hospitalization. ΔRDW was defined as the last RDW within 24 h prior to discharge minus the first RDW. RESULTS: Median LOS by initial RDW quartiles was Q1: 3.0, Q2: 3.1, Q3: 3.7, and Q4: 4.0 days (P-trend<0.001), and by ΔRDW quartiles was Q1: 4.1, Q2: 3.4, Q3: 3.6, and Q4: 4.7 days (P-trend<0.001). Both initial RDW (16.8 ± 2.8% vs. 16.3 ± 2.7%, P < 0.001) and ΔRDW (0.21 ± 1.09% vs. 0.14 ± 1.04%, P = 0.039) predicted 30-day readmission vs. no readmit. For 30-day decedents vs. survivors, initial RDW was 17.3 ± 3.0% vs. 16.3 ± 2.6% (P < 0.001), while ΔRDW was +0.20 ± 1.14% vs. +0.14 ± 1.04% (P = 0.15). CONCLUSIONS: Greater initial RDW and ΔRDW during HF hospitalization were associated with 30-day mortality, longer LOS, and 30-day all-cause readmission, suggesting both ΔRDW and initial RDW may aid in personalizing prognosis and treatment.

A risk stratification model to predict adverse neonatal outcome in labor.

OBJECTIVE: The development and evaluation of a labor risk model consisting of a combination of antepartum risk factors and intrapartum fetal heart rate (FHR) characteristics that can reliably identify those infants at risk for adverse neonatal outcome in labor. STUDY DESIGN: A nested case-control study of term singleton deliveries at the nine hospitals between March 2007 and December 2009. Eligibility criteria included: gestational age ≥ 37.0 weeks; singleton pregnancy; documented continuous FHR monitoring for ≥ 2 h before delivery; assessment of FHR tracing at least every 20 min; and, available maternal and neonatal outcomes. Adverse neonatal outcome was defined as nonanomalous infants admitted to the newborn intensive care unit with either a 5 minute Apgar score <7 or an umbilical artery pH<7.1. Initial risk score was determined using data available at 1 h after admission. Patients with an initial risk score between 7 and 15 were considered high risk. Intrapartum risk scores were then created for these patients using FHR tracing data and labor characteristics. RESULT: A total of 51 244 patients were identified meeting study criteria. Of the antepartum variables evaluated (n=31), 10 were associated with an adverse outcome. The high-risk group made up 28% of the population and accounted for 59.8% of the adverse outcomes. Intrapartum characteristics were then evaluated in this high-risk group. Intrapartum evaluation identified the highest risk group with a C/S rate of 40% and adverse outcome rate of 11.3%. CONCLUSION: Incorporation of maternal and antepartum risk factors with FHR analysis can improve the ability to identify the fetus at risk in labor.

Randomized cross-over trial of short-term water-only fasting: metabolic and cardiovascular consequences.

BACKGROUND AND AIMS: Routine, periodic fasting is associated with a lower prevalence of coronary artery disease (CAD). Animal studies show that fasting may increase longevity and alter biological parameters related to longevity. We evaluated whether fasting initiates acute changes in biomarker expression in humans that may impact short- and long-term health. METHODS AND RESULTS: Apparently-healthy volunteers (N = 30) without a recent history of fasting were enrolled in a randomized cross-over trial. A one-day water-only fast was the intervention and changes in biomarkers were the study endpoints. Bonferroni correction required p ≤ 0.00167 for significance (p < 0.05 was a trend that was only suggestively significant). The one-day fasting intervention acutely increased human growth hormone (p = 1.1 × 10⁻4), hemoglobin (p = 4.8 × 10⁻7), red blood cell count (p = 2.5 × 10⁻6), hematocrit (p = 3.0 × 10⁻6), total cholesterol (p = 5.8 × 10⁻5), and high-density lipoprotein cholesterol (p = 0.0015), and decreased triglycerides (p = 1.3 × 10⁻4), bicarbonate (p = 3.9 × 10⁻4), and weight (p = 1.0 × 10⁻7), compared to a day of usual eating. For those randomized to fast the first day (n = 16), most factors including human growth hormone and cholesterol returned to baseline after the full 48 h, with the exception of weight (p = 2.5 × 10⁻4) and (suggestively significant) triglycerides (p = 0.028). CONCLUSION: Fasting induced acute changes in biomarkers of metabolic, cardiovascular, and general health. The long-term consequences of these short-term changes are unknown but repeated episodes of periodic short-term fasting should be evaluated as a preventive treatment with the potential to reduce metabolic disease risk. Clinical trial registration (ClinicalTrials.gov): NCT01059760 (Expression of Longevity Genes in Response to Extended Fasting [The Fasting and Expression of Longevity Genes during Food abstinence {FEELGOOD} Trial]).

Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis.

A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I(2) = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

Effect of blood product transfusion-induced tolerance on incidence of cardiac allograft rejection.

BACKGROUND: Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial. OBJECTIVE: To investigate the effect of cellular blood product transfusion within 2 weeks posttransplantation on the incidence of cellular and antibody-mediated rejection. PATIENTS AND METHODS: Patients were grouped on the basis of number of blood transfusions; group 1 received no transfusions, and groups 2, 3, and 4 each received an incremental number of transfusion units. All endomyocardial biopsy samples were routinely studied using immunofluorescence in the first 12 weeks posttransplantation. RESULTS: Baseline characteristics including age, sex, body mass index, history of diabetes, donor characteristics, and pretransplantation laboratory values were similar except that group 4 had a higher rate of previous sternotomy and longer ischemic time during transplantation. Approximately 9200 endomyocardial biopsy samples composed the data. Short- and long-term freedom from the International Society for Heart & Lung Transplantation grade 3A or higher cellular rejection and from antibody-mediated rejection were comparable between groups. CONCLUSIONS: Blood transfusions within the first 2 weeks post-transplantation do not seem to confer any protective effect against posttransplantation cellular rejection or antibody- mediated rejection. Whether other unmeasured confounding factors mask their effect requires further prospective studies.

Integration of genetic, clinical, and INR data to refine warfarin dosing.

Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

Generating genetic risk scores from intermediate phenotypes for use in association studies of clinically significant endpoints.

While previous results of genetic association studies for common, complex diseases (eg., coronary artery disease, CAD) have been disappointing, examination of multiple related genes within a physiologic pathway may provide improved resolution. This paper describes a method of calculating a genetic risk score (GRS) for a clinical endpoint by integrating data from many candidate genes and multiple intermediate phenotypes (IPs). First, the association of all single nucleotide polymorphisms (SNPs) to an IP is determined and regression beta-coefficients are used to calculate an IP-specific GRS for each individual, repeating this analysis for every IP. Next, the IPs are assessed by a second regression as predictors of the clinical endpoint. Each IP's individual GRS is then weighted by the regression beta-coefficients from the second step, creating a single, composite GRS. As an example, 3,172 patients undergoing coronary angiography were evaluated for 3 SNPs from the cholesterol metabolism pathway. Although these data provide only a preliminary example, the GRS method detected significant differences in CAD by GRS group, whereas separate genotypes did not. These results illustrate the potential of the GRS methodology for multigenic risk evaluation and suggest that such approaches deserve further examination in common, complex diseases such as CAD.

Femoral arterial puncture management after percutaneous coronary procedures: a comparison of clinical outcomes and patient satisfaction between manual compression and two different vascular closure devices.

BACKGROUND: Vascular access site management is crucial to safe, efficient and comfortable diagnostic or interventional transfemoral percutaneous coronary procedures. Two new femoral access site closure devices, Perclose and Angio-Seal , have been proposed as alternative methods to manual compression (MC). We compared these two devices and tested them in reference to standard MC for safety, effectiveness and patient preference. METHODS: Prospective demographic, peri-procedural, and late follow-up data for 1,500 patients undergoing percutaneous coronary procedures were collected from patients receiving femoral artery closure by MC (n = 469), Perclose (n = 492), or Angio-Seal (n = 539). Peri-procedural, post-procedural, and post-hospitalization endpoints were: 1) safety of closure method; 2) efficacy of closure method; and 3) patient satisfaction. RESULTS: Patients treated with Angio-Seal experienced shorter times to hemostasis (p < 0.0001, diagnostic and interventional) and ambulation (diagnostic, p = 0.05; interventional, p < 0.0001) than those treated with Perclose. Those treated with Perclose experienced greater access site complications (Perclose vs. Angio-Seal, p = 0.008; Perclose vs. MC, p = 0.06). Patients treated with Angio-Seal reported greater overall satisfaction, better wound healing and lower discomfort (each vs. Perclose or vs. MC, all p < or = 0.0001). For diagnostic cath only, median post-procedural length of stay was reduced by Angio-Seal (Angio-Seal vs. MC, p < 0.0001; Angio-Seal vs. Perclose, p = 0.009). No difference was seen in length of stay for interventional cases. CONCLUSIONS: Overall, Angio-Seal performed better than Perclose or MC in reducing time to ambulation and length of stay among patients undergoing diagnostic procedures. There was a higher rate of successful deployment and shorter time to hemostasis for Angio-Seal, and this was accomplished with no increase in bleeding complications throughout the follow-up. Additionally, Angio-Seal performed better than Perclose in exhibiting a superior 30-day patient satisfaction and patient assessment of wound healing with less discomfort.

Usefulness of in-hospital prescription of statin agents after angiographic diagnosis of coronary artery disease in improving continued compliance and reduced mortality.

Despite well-documented clinical benefit of the use of statins in patients with coronary artery disease (CAD) and even mild lipid elevations, studies have documented the presence of a significant "treatment gap" between those patients in whom treatment is indicated and those patients who actually receive it. It has been proposed that a prescription for statin therapy given to indicated patients at the time of initial angiographic diagnosis of CAD has the potential to improve long-term medication compliance, but this requires further evaluation. We prospectively followed 600 patients with angiographically demonstrated CAD (diameter stenosis > or = 70%) who met the National Cholesterol Education Project (NCEP) guidelines for statin therapy for an average of 3.0 years (range 2.0 to 4.6). Patients were an average of 65 years of age, 78% were men, 77% presented initially with acute ischemic syndrome, and 64 (10.7%) died during follow-up. Overall, 105 patients (18%) were discharged from the initial hospitalization with a statin prescription. At long-term follow-up, the number of patients taking statins had increased to 47%. However, long-term statin compliance was significantly higher among patients initially discharged with a statin prescription than those who were not (77% vs 40%; p < 0.0001). Additionally, those patients discharged with a statin prescription had significantly reduced mortality rate at long-term follow-up (5.7% vs 11.7%; p = 0.05). Cox hazard regression analysis, controlling for all known clinical baseline variables, confirmed the absence of a prehospital discharge statin prescription to be an independent predictor of increased mortality (hazard ratio 2.4) with a statistical trend (p = 0.06). Thus, this study demonstrates that after angiographic diagnosis of CAD, prescription of appropriate statin therapy at the time of hospital discharge improves long-term statin compliance and may significantly enhance survival.

Prospective study of pathogen burden and risk of myocardial infarction or death.

BACKGROUND: We previously demonstrated that the risk of coronary artery disease (CAD) increased in relation to the number of pathogens (the "pathogen burden") in a cross-sectional study. In the present prospective study with a different patient cohort, we evaluated the effect of pathogen burden on the risk of myocardial infarction (MI) or death among CAD patients. METHODS AND RESULTS: IgG antibodies to cytomegalovirus (CMV), hepatitis A virus (HAV), herpes simplex virus type 1 (HSV1), HSV type 2 (HSV2), Chlamydia pneumoniae and Helicobacter pylori, and C-reactive protein (CRP) levels were tested in baseline blood samples from 890 patients who had significant CAD on angiography. The mean follow-up period was 3 years. The baseline prevalence of antibodies directed against CMV, HAV, HSV1, or HSV2, but not C pneumoniae and H pylori, was significantly higher among patients who subsequently developed MI or death than among control subjects. After adjustment for traditional risk factors, number of diseased vessels, and clinical presentation, relative hazards (95% confidence limits) for MI or death were 2.0 (1. 4 to 3.2) for CMV, 1.6 (1.1 to 2.3) for HAV, and 1.5 (1.0 to 2.2) for HSV2. Increasing pathogen burden was significantly associated with increasing risk of MI or death in a dose-response fashion. Adjusted relative hazards of MI or death associated with pathogen burden were significant among individuals with low or high CRP levels. CONCLUSIONS: The results suggest that infection plays an important role in incident MI or death and that the risk posed by infection is independently related to the pathogen burden.

Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease.

OBJECTIVES: The joint predictive value of lipid and C-reactive protein (CRP) levels, as well as a possible interaction between statin therapy and CRP, were evaluated for survival after angiographic diagnosis of coronary artery disease (CAD). BACKGROUND: Hyperlipidemia increases risk of CAD and myocardial infarction. For first myocardial infarction, the combination of lipid and CRP levels may be prognostically more powerful. Although lipid levels are often measured at angiography to guide therapy, their prognostic value is unclear. METHODS: Blood samples were collected from a prospective cohort of 985 patients diagnosed angiographically with severe CAD (stenosis > or =70%) and tested for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and CRP levels. Key risk factors, including initiation of statin therapy, were recorded, and subjects were followed for an average of 3.0 years (range: 1.8 to 4.3 years) to assess survival. RESULTS: Mortality was confirmed for 109 subjects (11%). In multiple variable Cox regression, levels of TC, LDL, HDL and the TC:HDL ratio did not predict survival, but statin therapy was protective (adjusted hazard ratio [HR] = 0.49, p = 0.04). C-reactive protein levels, age, left ventricular ejection fraction and diabetes were also independently predictive. Statins primarily benefited subjects with elevated CRP by eliminating the increased mortality across increasing CRP tertiles (statins: HR = 0.97 per tertile, p-trend = 0.94; no statins: HR = 1.8 per tertile, p-trend < 0.0001). CONCLUSIONS: Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP.

Randomized secondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study.

BACKGROUND: Chlamydia pneumoniae is associated with coronary artery disease (CAD), although its causal role is uncertain. A small preliminary study reported a >50% reduction in ischemic events by azithromycin, an antibiotic effective against C pneumoniae, in seropositive CAD patients. We tested this prospectively in a larger, randomized, double-blind study. METHODS AND RESULTS: CAD patients (n=302) seropositive to C pneumoniae (IgG titers >/=1:16) were randomized to placebo or azithromycin 500 mg/d for 3 days and then 500 mg/wk for 3 months. The primary clinical end point included cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction (MI), stroke, unstable angina, and unplanned coronary revascularization at 2 years. Treatment groups were balanced, and azithromycin was generally well tolerated. During the trial, 47 first primary events occurred (cardiovascular death, 9; resuscitated cardiac arrest, 1; MI, 11; stroke, 3; unstable angina, 4; and unplanned coronary revascularization, 19), with 22 events in the azithromycin group and 25 in the placebo group. There was no significant difference in the 1 primary end point between the 2 groups (hazard ratio for azithromycin, 0.89; 95% CI, 0.51 to 1.61; P:=0.74). Events included 9 versus 7 occurring within 6 months and 13 versus 18 between 6 and 24 months in the azithromycin and placebo groups, respectively. CONCLUSIONS: This study suggests that antibiotic therapy with azithromycin is not associated with marked early reductions (>/=50%) in ischemic events as suggested by an initial published report. However, a clinically worthwhile benefit (ie, 20% to 30%) is still possible, although it may be delayed. Larger (several thousand patient), longer-term (>/=3 to 5 years) antibiotic studies are therefore indicated.

Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease.

BACKGROUND: The role of inflammation in coronary artery disease (CAD) is being increasingly recognized. Markers of inflammation (eg, C-reactive protein [CRP]) and infection (eg, seropositivity to Chlamydia pneumoniae, cytomegalovirus [CMV], and Helicobacter pylori) have been proposed as risk factors for CAD, but these associations require further evaluation. METHODS AND RESULTS: We prospectively tested whether CRP levels and IgG seropositivity to C pneumoniae, CMV, and H pylori are predictors of subsequent mortality in 985 consecutive patients with angiographically demonstrated CAD (stenosis >/=70%). Patients were followed for an average of 2.7 years (range 1.5 to 4.0 years). Patients averaged 65 years of age; 77% were men; and 110 (11.2%) died during follow-up. CRP levels were significantly elevated in nonsurvivors compared with survivors (mean CRP 3.1 mg/dL versus 1.5 mg/dL, P:=0.003). After controlling for all known baseline variables, the 2nd and 3rd tertiles of CRP compared with the 1st produced a Cox hazard ratio (HR) for mortality of 2.4 (P:=0.001). Of the 3 infectious markers tested, only seropositivity to CMV (HR=1.9, P:<0.05) was predictive of mortality. The majority of mortality risk associated with elevated CRP or CMV seropositivity occurred when both risk factors were present (P: for trend <0.0001). Other independent predictors of increased risk of mortality were age (HR=1.07 per year, P:<0.0001), left ventricular ejection fraction (HR=0.97 per percent, P:<0.0001), and diabetes mellitus (HR=1.7, P:=0.02). CONCLUSIONS: CMV seropositivity and elevated CRP, especially when in combination, are strong, independent predictors of mortality in patients with CAD. This suggests an interesting hypothesis that a chronic, smoldering infection (CMV) might have the capacity to accelerate the atherothrombotic process.

The effect of chronic azithromycin therapy on soluble endothelium-derived adhesion molecules in patients with coronary artery disease.

In patients with coronary artery disease (CAD), azithromycin therapy is associated with decreased cytokine levels and overall reduction of inflammation. Chlamydia pneumoniae (C.Pn) is a common pathogen that may be an important factor in the development and progression of atherosclerosis. Cell-adhesion molecules have an important role in recruitment of inflammatory cells during plaque development and are expressed by endothelial cells on activation. We sought to define the effect of treatment with azithromycin on circulating levels of soluble vascular cell-adhesion molecule (VCAM-I), intercellular adhesion molecule (ICAM-1), and E-selectin in patients with CAD. Plasma concentrations of VCAM-1, ICAM-1, and E-selectin were measured in 40 patients with documented CAD and a positive (> or = 1:16) immunoglobulin G (IgG) titer against C.Pn, 20 subjects with normal coronary arteries, and 14 healthy volunteers. Patients were assigned randomly to receive either 500 mg/wk of azithromycin or placebo for 3 months. Serum samples were obtained at baseline, at 3 months, and during the follow-up visit at 6 months. Patients with documented CAD exhibited elevation of VCAM-1 (535 +/- 227 ng/ ml; p = 0.0001) and E-selectin (69 +/- 29 ng/ml; p = 0.006), but not ICAM-1 (321 +/- 65 ng/ml) concentrations as compared with the patients with angiographically proven normal coronary arteries (252 +/- 80; 50 +/- 22; and 311 +/- 40 ng/ml) and healthy controls (110 +/- 18; 29 +/- 2; and 238 +/- 47 ng/ml, respectively). Prolonged treatment with azithromycin did not significantly affect the plasma levels of soluble VCAM-1, ICAM-1, and E-selectin. Soluble markers of endothelial activation are markedly increased in patients with documented CAD as compared with those with normal coronary arteries and healthy controls. Despite substantial heterogeneity in plasma E-selectin, ICAM-1, and VCAM-1 levels, long-term azithromycin treatment did not affect plasma levels of these adhesion molecules, indicative of endothelial activation, over a period of 6 months.

A common variant of the AMPD1 gene predicts improved cardiovascular survival in patients with coronary artery disease.

OBJECTIVE: We tested whether a common AMPD1 gene variant is associated with improved cardiovascular (CV) survival in patients with coronary artery disease (CAD). BACKGROUND: Reduced activity of adenosine monophosphate deaminase (AMPD) may increase production of adenosine, a cardioprotective agent. A common, nonsense, point variant of the AMPD1 gene (C34T) results in enzymatic inactivity and has been associated with prolonged survival in heart failure. METHODS: Blood was collected from 367 patients undergoing coronary angiography. Genotyping was done by polymerase chain reaction amplification and restriction enzyme digestion, resulting in allele-specific fragments. Coronary artery disease was defined as > or =70% stenosis of > or =1 coronary artery. Patients were followed prospectively for up to 4.8 years. Survival statistics compared hetero- (+/-) or homozygotic (-/-) carriers with noncarriers. RESULTS: Patients were 66 +/- 10 years old; 79% were men; 22.6% were heterozygous and 1.9% homozygous for the variant AMPD1(-) allele. During a mean of 3.5 +/- 1.0 years, 52 patients (14.2%) died, 37 (10.1%) of CV causes. Cardiovascular mortality was 4.4% (4/90) in AMPD1(-) allele carriers compared with 11.9% (33/277) in noncarriers (p = 0.046). In multiple variable regression analysis, only age (hazard ratio, 1.11/year, p < 0.001) and AMPD1(-) carriage (hazard ratio, 0.36, p = 0.053) were independent predictors of CV mortality. CONCLUSIONS: Carriage of a common variant of the AMPD1 gene was associated with improved CV survival in patients with angiographically documented CAD. The dysfunctional AMPD1(-) allele may lead to increased cardiac adenosine and increased cardioprotection during ischemic events. Adenosine monophosphate deaminase-1 genotyping should be further explored in CAD for prognostic, mechanistic and therapeutic insights.

Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease.

BACKGROUND: Plasma homocysteine (tHCY) has been associated with coronary artery disease (CAD). We tested whether tHCY also increases secondary risk, after initial CAD diagnosis, and whether it is independent of traditional risk factors, C-reactive protein (CRP), and methylenetetrahydrofolate reductase (MTHFR) genotype. METHODS AND RESULTS: Blood samples were collected from 1412 patients with severe angiographically defined CAD (stenosis >/=70%). Plasma tHCY was measured by fluorescence polarization immunoassay. The study cohort was evaluated for survival after a mean of 3.0+/-1.0 years of follow-up (minimum 1.5 years, maximum 5.0 years). The average age of the patients was 65+/-11 years, 77% were males, and 166 died during follow-up. Mortality was greater in patients with tHCY in tertile 3 than in tertiles 1 and 2 (mortality 15.7% versus 9.6%, P:=0.001 [log-rank test], hazard ratio [HR] 1.63). The relative hazard increased 16% for each 5-micromol/L increase in tHCY (P:<0.001). In multivariate Cox regression analysis, controlling for univariate clinical and laboratory predictors, elevated tHCY remained predictive of mortality (HR 1.64, P:=0.009), together with age (HR 1. 72 per 10-year increment, P:<0.0001), ejection fraction (HR 0.84 per 10% increment, P:=0.0001), diabetes (HR 1.98, P:=0.001), CRP (HR 1. 42 per tertile, P:=0.004), and hyperlipidemia. Homozygosity for the MTHFR variant was weakly predictive of tHCY levels but not mortality. CONCLUSIONS: In patients with angiographically defined CAD, tHCY is a significant predictor of mortality, independent of traditional risk factors, CRP, and MTHFR genotype. These findings increase interest in tHCY as a secondary risk marker and in secondary prevention trials (ie, with folate/B vitamins) to determine whether reduction in tHCY will reduce risk.

Soluble VCAM-1 and E-selectin, but not ICAM-1 discriminate endothelial injury in patients with documented coronary artery disease.

It has been shown that endothelial cell adhesion molecules play an important role in the development of coronary atherosclerosis and inflammatory disease. We sought to test whether soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin are increased in patients with documented coronary artery disease (CAD). Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured in 40 patients with documented CAD, 20 subjects with angiographically documented normal coronary arteries, and 14 healthy volunteers. Patients with documented CAD exhibited significant elevation of VCAM-1 (535 +/- 227.1 ng/ml, p = 0.0001), E-selectin (69.4 +/- 29.4 ng/ml, p = 0.006), but not ICAM-1 (320.5 +/- 65.1 ng/ml, p = 0.9) concentrations as compared to subjects with normal coronary arteries (252.3 +/- 79.8, 49.7 +/- 22.0 and 311.4 +/- 40.2 ng/ml), and healthy controls (110.0 +/- 17.7, 29.0 +/- 2.0 and 237.5 +/- 46.5 ng/ml), respectively. Soluble markers of endothelial injury are not uniformly increased in patients with documented CAD as compared to those with normal coronary arteries and healthy controls. However, VCAM-1 and E-selectin, but not ICAM-1 could identify endothelial injury in such patients.

Seasonal variation in reproductive steroids of male and female yellow-blotched map turtles, Graptemys flavimaculata.

From April to October of 1996 and 1997, we measured seasonal changes in plasma testosterone (T) in male and plasma T and estradiol-17beta (E(2)) in female yellow-blotched map turtles, Graptemys flavimaculata, from the Pascagoula River, Mississippi. In 1996, plasma from females was analyzed for progesterone. In 1997, ovaries of adult females were ultrasound imaged to determine stages of follicular development. Males exhibited peak T levels in September and October of both years, indicating fall gonadal activity. Males also exhibited a low level spring peak in T during April. Female E(2) levels increased significantly in May and June, the primary period of ovarian development. Females with preovulatory follicles did not have significantly higher E(2) levels than females with medium- or small-sized follicles. When compared to other freshwater turtle species, peak levels of E(2) were low. Testosterone levels did not follow a distinct yearly pattern in females. Progesterone levels were elevated in June when peak nesting was observed. Ultrasound and hormone data indicate that females lack ovarian development in the fall and produce on average only one clutch per year.

Evaluation of C-reactive protein, an inflammatory marker, and infectious serology as risk factors for coronary artery disease and myocardial infarction.

OBJECTIVES: We sought to test whether C-reactive protein (CRP) and seropositivity to any of three infectious agents are associated with angiographic coronary artery disease (CAD) and clinical myocardial infarction (MI). BACKGROUND: CRP, an inflammatory marker, is reported to predict risk of MI. The stimulus for CRP is unknown but might include infection. Chlamydia pneumoniae, cytomegalovirus and Helicobacter pylori have been linked to risk of MI or CAD. METHODS: Blood samples were collected from 363 patients undergoing coronary arteriography and tested for CRP and IgG titers to the infectious agents. RESULTS: CRP was higher in patients with CAD (1.32 mg/dl [SE 0.22, n = 80] vs. 0.58 mg/dl [SE 0.11 mg/dl, n = 109], p = 0.004) and in those with MI (2.05 mg/dl [SE 0.36, n = 47] vs. 0.54 mg/dl [SE 0.08, n = 133], p = 0.0002) than in respective control subjects. Seropositivity for each agent was present in a high proportion of patients with CAD (58% to 77%) or MI (54% to 75%) as well as in control subjects (no CAD: 46% to 74%; no MI: 50% to 77%). However, subjects seropositive to both C. pneumoniae and H. pylori had an increased prevalence of CAD (odds ratio [OR] 2.6, p = 0.02) and MI (OR 2.0, p = 0.15) and tended to have higher CRP levels (1.07 mg/dl [SE 0.16]) than those seronegative to both infectious agents (0.53 mg/dl [SE 0.10], p = 0.06). CONCLUSIONS: CRP is elevated in patients with CAD (more than twofold) and in those with MI (fourfold). Infectious serology is highly prevalent in both patients and control subjects. Seropositivity to both C. pneumoniae and H. pylori (but not one agent alone) may predict increased risk and may be associated with higher CRP levels. Infectious serology may be less predictive than previously suggested, but the cause of inflammation in CAD and MI deserves further study.

Leaking Glenn anastomosis demonstrated by first pass radionuclide angiography.

First pass radionuclide angiography was used to demonstrate a leaking Glenn anastomosis at the superior vena cava--right atrial junction as well as tricuspid atresia and a ligated persistent left superior vena cava. First pass radionuclide angiography may demonstrate anatomic configurations not obvious at cardiac catheterization and can be useful for adults with complicated congenital heart disease, particularly when biplane or multiple view angiography is not possible. Lung perfusion imaging can lead to an incorrect diagnosis of pulmonary embolism if the presence of a Glenn anastomosis in not known.