The effects of recombinant-DNA-derived interferons on the growth of myeloid progenitor cells

Interferons (IFNs) have been shown to have significant effects on hematopoietic cell growth. Previous studies defining these effects have utilized mouse and human alpha-, beta-, and gamma-IFN isolated from supernatants of stimulated cells. Despite purification, the possible presence of other lymphokines and soluble factors remains a concern. In this study, the effects of gene-cloned alpha- and gamma-IFN on colony- forming units of granulocyte/macrophage (CFU-GM) progenitors cultured from the peripheral blood of normal volunteers were examined. In addition, blast cell colonies from one patient with acute myelogenous leukemia (AML) were studied. The growth of normal CFU-GM and AML blast cell colonies was inhibited in a dose-dependent manner by gamma- and alpha-IFN. gamma-IFN was ten to 100 times more potent than alpha-IFN in that this species of IFN reduced colony formation by greater than 50% at concentrations of less than 15 antiviral U/mL. The effects of gamma- IFN were neutralized by a monoclonal antibody specific for gamma-IFN. These in vitro studies indicate that human gamma-IFN may be an important modulator of myelopoiesis. Although these data indicate a possible efficacy of gamma-IFN in the treatment of AML, the in vitro results should be considered for their in vivo significance.     

Using inflammatory biomarkers to guide lipid therapy

Inflammation plays a fundamental role in the pathophysiology of atherothrombotic cardiovascular disease, and lipid-lowering agents appear to have clinically relevant anti-inflammatory properties. In addition to low-ering low-density lipoprotein (LDL) cholesterol, statins improve endothelial function, are clinically effective in a time frame that often precedes LDL reduction, and lower inflammatory markers such as C-reactive protein (CRP) in a largely LDL-independent manner for individual patients. Data from the CARE, AFCAPS/TexCAPS, PROVE IT-TIMI 22, REVERSAL, and A to Z trials suggest that statins provide greater clinical benefit in those who achieve LDL and CRP reductions than in those who achieve LDL reduction alone. We discuss evidence underlying potential anti-inflammatory properties of several lipid-lowering therapies, their impact on measures of endothelial function and vascular inflammation and on subsequent risk reduction, and the use of inflammatory biomarkers as an adjunct to LDL in the monitoring of lipid-lowering therapy.     

Echocardiographic diagnosis of congential absence of the pericardium in a patient with VATER association defects

The VATER association denotes a nonrandom pattern of congential malformations which typically include vertebral defects, anal atresia, tracheo-esophageal fistula, and radial and renal dysplasia. Vascular anomalies including ventricular septal defect and single umbilical artery have also been described, although the frequency of cardiovascular anomalies in this congenital association is unknown. In this report, we describe a 26-year-old patient with several VATER association defects who, in addition, was found to have congenital absence of the left pericardium and an aberrant right subclavian artery.     

Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events : A Meta-Analysis of Statin Trials

Background

Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.

Objectives

The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.

Methods

This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.

Results

Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.

Conclusions

The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.     

D-dimer and inflammatory markers as predictors of functional decline in men and women with and without peripheral arterial disease

OBJECTIVES: To determine whether higher circulating levels of inflammatory and thrombotic markers are associated with greater decline in lower extremity performance. DESIGN: Prospective cohort. SETTING: Academic medical center. PARTICIPANTS: Three hundred thirty-seven men and women with lower extremity peripheral arterial disease (PAD) and 215 without PAD. MEASUREMENTS: Objective measures of leg function, including the 6-minute walk and Short Physical Performance Battery (SPPB), were obtained at baseline and annually for 3 years. D-dimer, high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen levels were measured at baseline. Participants were categorized into one of three groups, ranging from low to high levels of inflammation, depending on the number of individual blood factors in the lowest and highest tertiles for each corresponding blood factor. RESULTS: Adjusting for age, sex, race, ankle brachial index, comorbidities, and other confounders, greater inflammation was associated with greater decline in the SPPB (P=.008). Results were similar when repeated in participants with and without PAD separately (P for trend=.04 for participants with PAD and .07 for participants without PAD). In fully adjusted analyses, there were no significant associations between inflammation group and decline in 6-minute walk performance. CONCLUSION: Higher baseline levels of inflammatory markers and D-dimer were associated with greater decline in the SPPB at 3-year follow-up in persons with and without PAD.     

Elevated C-reactive protein levels are associated with postoperative events in patients undergoing lower extremity vein bypass surgery

OBJECTIVES: Inflammatory markers such as high-sensitivity C-reactive protein (hsCRP) are associated with an increased risk of cardiovascular events and with the severity of peripheral arterial disease. The effects of inflammation on the development of vein graft disease remain speculative. We hypothesized that high levels of inflammatory markers would identify patients at increased risk for adverse events (graft failure, major cardiovascular events) after lower extremity bypass surgery. METHODS: Patients (n = 91) scheduled to undergo lower extremity bypass using autogenous vein were enrolled into a prospective study at two institutions. Exclusion criteria included the presence of major infection. A baseline plasma sample was obtained on the morning of lower extremity bypass. Biomarkers for inflammation included hsCRP, fibrinogen, and serum amyloid A (SAA). Values between patients with and without critical limb ischemia were compared. Proportions of events among dichotomized populations (upper limit of normal of each laboratory assay) were compared by log-rank test. RESULTS: Of the patients undergoing lower extremity bypass, 69% were men, 53% were diabetic, 81% were smokers, and their mean ankle-brachial index was 0.51 +/- 0.19. The indication for lower extremity bypass was critical limb ischemia in 55%. There were no perioperative deaths and two early graft occlusions. During a mean follow-up of 342 days (range, 36-694 days) there were four deaths, 27 graft-related events, and 10 other cardiovascular events. No relationships were found between events and demographics, comorbidities, baseline ankle-brachial index, or statin use. High-sensitivity CRP (P = .005), fibrinogen (P < .001), and SAA (P = .0001) levels were associated with critical limb ischemia at presentation. Among patients with an elevated hsCRP (>5 mg/L) immediately before surgery, major postoperative vascular events occurred in 60% (21/35), compared with a 32% (18/56) rate in those with a baseline CRP <5 mg/L (P = .004, log-rank test). On multivariable analysis, only elevated hsCRP correlated with adverse graft-related or cardiovascular events (P = .018). CONCLUSIONS: The inflammatory biomarkers of hsCRP, fibrinogen, and SAA correlate with peripheral arterial disease severity at presentation in patients undergoing lower extremity bypass. Patients with elevated hsCRP are at increased risk for postoperative vascular events, most of which are related to the vein graft. These findings suggest a potential relationship between inflammation and outcomes after lower extremity vein bypass surgery.