Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low-Density Lipoprotein Cholesterol.

BACKGROUND: Levels of LDL (low-density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid-related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations. METHODS AND RESULTS: We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low-density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%CI] per SD increment) among placebo-allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non-high-density lipoprotein cholesterol, and triglycerides, but not LDL-c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On-statin levels of the smallest VLDL particle subclass were associated with a 68% per-SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk-this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C-index 0.780 versus 0.712; P<0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN), similar patterns of lipoprotein-related risk were observed. CONCLUSIONS: Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Circulating N-Linked Glycoprotein Side-Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial.

BACKGROUND: GlycA, a novel protein glycan biomarker of N-acetyl side chains of acute-phase proteins, was recently associated with incident cardiovascular disease (CVD) in healthy women. Whether GlycA predicts CVD events in the setting of statin therapy in men and women without CVD but with evidence of chronic inflammation is unknown. METHODS AND RESULTS: In the Justfication for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681), participants with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to rosuvastatin 20 mg/day or placebo. GlycA was quantified by nuclear magnetic resonance spectroscopy in 12 527 before randomization and 10 039 participants at 1 year. A total of 310 first primary CVD events occurred during maximum follow-up of 5.0 years (median, 1.9). GlycA changed minimally after 1 year on study treatment: 6.8% and 4.7% decrease in the rosuvastatin and placebo groups, respectively. Overall, baseline GlycA levels were associated with increased risk of CVD: multivariable-adjusted hazard ratio (HR) per SD increment, 1.20 (95% CI, 1.08-1.34; P=0.0006). After additionally adjusting for hsCRP, this was slightly attenuated (HR, 1.18; 95% CI, 1.04-1.35; P=0.01). On-treatment GlycA levels were also associated with CVD; corresponding multivariable-adjusted HRs per SD before and after additionally adjusting for hsCRP: 1.27 (95% CI, 1.13-1.42; P<0.0001) and 1.24 (95% CI, 1.07-1.44; P=0.004), respectively. Tests for heterogeneity by treatment arm were not significant (P for interaction, >0.20). CONCLUSION: In the JUPITER trial, increased levels of GlycA were associated with an increased risk of CVD events independent of traditional risk factors and hsCRP. CLINICAL TRIALS REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

High-density lipoprotein particle subclass heterogeneity and incident coronary heart disease.

BACKGROUND: Raising the cholesterol of high-density lipoprotein (HDL) particles is targeted as a cardiovascular disease prevention strategy. However, HDL particles are heterogeneous in composition and structure, which may relate to differences in antiatherogenic potential. We prospectively evaluated the association of HDL subclasses, defined by a recently proposed nomenclature, with incident coronary heart disease (CHD). METHODS AND RESULTS: Baseline HDL particle concentrations were measured by nuclear magnetic resonance spectroscopy and categorized into 5 subclasses (very large, large, medium, small, and very small) among 26 332 initially healthy women. During a median follow-up of 17 years, 969 cases of incident CHD (myocardial infarction, revascularization, and CHD death) were ascertained. In Cox models that adjusted for age, race/ethnicity, blood pressure, smoking, postmenopausal status, and hormone therapy, associations with incident CHD were inverse (P trend<0.0001) for concentrations of very large (hazard ratio for top versus bottom quartile, 0.49; 95% confidence interval, 0.41-0.60), large (0.54; 0.45-0.64), and medium (0.69; 0.58-0.83) HDL subclasses. Conversely, hazard ratios (95% confidence intervals) for small and very small HDL were 1.22 (1.01-1.46; P trend=0.08) and 1.67 (1.39-2.02; P trend<0.0001), respectively. However, after additionally adjusting for metabolic and lipoprotein variables, associations for the spectrum of large, medium, and small HDL subclasses were inverse (P trend<0.05 for large and small and 0.07 for medium), whereas subclasses at either end of the spectrum were not associated with CHD (P trend=0.97 for very large and 0.21 for very small HDL). CONCLUSIONS: In this prospective study, associations with incident CHD differed by HDL particle subclass, which may be relevant for developing HDL-modulating therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479.

Changes in mood states and biomarkers during peginterferon and ribavirin treatment of chronic hepatitis C.

OBJECTIVE: Depression is a frequent side effect of interferon therapy in patients with chronic hepatitis C (CHC). The aim of this study was to identify baseline and on-treatment predictors of depression in CHC patients receiving peginterferon and ribavirin. METHODS: In total, 201 prior nonresponders with advanced fibrosis were treated with peginterferon alfa-2a and ribavirin for 24 wk in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial. Of these, 74 continued on antiviral therapy through week 48. Mood states were assessed with the Beck Depression Inventory II and the Composite International Diagnostic Interview. Plasma cortisol and whole blood serotonin levels were measured in 101 subjects at weeks 0, 4, 24, 48, and 72. RESULTS: The incidence of interferon-induced depression was 23% and 42% at weeks 24 and 48, respectively. Although 22% of patients had baseline depression, the absence of a week 20 virological response was the only independent predictor of interferon-induced depression at week 24 (P = 0.0009). Plasma cortisol levels did not change during treatment nor correlate with depression. In contrast, whole blood serotonin/platelet levels significantly decreased during treatment, but did not correlate with interferon-induced depression through week 24 (P = 0.35), nor through week 48 (P = 0.51). CONCLUSION: Depression during peginterferon and ribavirin therapy was associated with a lower antiviral response. The significant reduction in whole blood serotonin levels over time suggest that further studies of the serotonergic pathway are warranted to identify the mediators of interferon-induced depression.

Cognitive function does not worsen during pegylated interferon and ribavirin retreatment of chronic hepatitis C.

UNLABELLED: Treatment of chronic hepatitis C with pegylated interferon (peginterferon) and ribavirin can cause or exacerbate depression but its effects on cognitive function are largely unknown. The aim of this study was to determine whether treatment with peginterferon and ribavirin adversely impacts cognitive function in patients with chronic hepatitis C. Prior nonresponders to interferon were retreated with peginterferon alfa-2a and ribavirin for 24 (n=177) or 48 weeks (n=57) in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial. Cognitive function was prospectively assessed using a battery of 10 standardized neuropsychological tests at weeks 0, 24, 48, and 72. Cognitive impairment was defined based upon a global deficit score. The Beck Depression Inventory and Brief Symptom Inventory were used to assess mood status. The 57 subjects who completed 48 weeks of antiviral therapy reported significant increases in difficulty concentrating, emotional distress, and symptoms of depression, all of which improved after cessation of therapy [P<0.0001, analysis of variance (ANOVA)]. Nonetheless, the frequency of cognitive impairment did not increase during the first 24 weeks of treatment in 177 patients (34% versus 32%, P=0.64) nor in the 57 patients completing 48 weeks of treatment (P=0.48, ANOVA). CONCLUSION: Retreatment of prior non-responders with peginterferon and ribavirin was not associated with objective evidence of cognitive impairment as measured by a comprehensive battery of neuropsychological tests. The lack of cognitive impairment is reassuring and suggests that self-reported symptoms of cognitive dysfunction are more likely related to the systemic and psychiatric side effects of antiviral treatment rather than measurable changes in cognition.

Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial.

BACKGROUND & AIMS: Hepatic steatosis often is observed in patients with chronic hepatitis C and has been reported to be associated with hepatic fibrosis and impaired treatment response in some studies. Our aim was to determine the prevalence of and risk factors for hepatic steatosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, and to determine the relationship between steatosis, fibrosis, and sustained virologic response (SVR) to re-treatment with pegylated interferon and ribavirin. METHODS: Baseline data from 1143 Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, with a mean body mass index of 30, 5% with genotype 3, 38% with cirrhosis, and 24% with diabetes were analyzed. RESULTS: Steatosis scores of 0, 1, 2, 3, and 4 were observed in 19%, 42%, 30%, 8%, and 1% of patients, respectively. High body mass index, triglyceride and alanine aminotransferase levels, and genotype 3 were associated with higher grades of steatosis. Among nondiabetic patients, steatosis scores of 0-2 but not scores of 3-4 were associated significantly with cirrhosis. For diabetic patients, there was no association between steatosis and cirrhosis. Similarly, steatosis scores of 2-4 were associated with a lack of SVR among nondiabetic but not among diabetic patients. CONCLUSIONS: In this cohort with predominantly hepatitis C virus genotype 1 infection, steatosis was associated strongly with metabolic factors that contribute to nonalcoholic fatty liver disease. Steatosis correlated with increasing stages of fibrosis up to but not including cirrhosis. Steatosis had a negative impact on SVR among nondiabetic but not diabetic patients. The discordant findings between nondiabetic and diabetic patients indicate that these 2 groups should be considered separately when analyzing metabolic factors and liver disease outcomes.

Clinical relevance of cognitive scores in hepatitis C patients with advanced fibrosis.

Mild neuropsychological impairment has previously been reported in chronic hepatitis C (CHC) patients. The aim of this study was to assess the presence and severity of cognitive impairment among a cohort of CHC patients with advanced fibrosis using clinician ratings compared to classification based upon statistical methods. In addition, we set out to determine the relationship between cognitive scores and functional status. Two experienced neuropsychologists provided "clinician ratings" on a battery of 10 neuropsychological tests performed in 100 randomly selected patients participating in the HALT-C clinical trial. The overall kappa between the 2 graders on level of impairment was 0.59. Clinician ratings (the gold standard) were similarly sensitive to identifying cognitive impairment as was classification based on standard scores (44% vs. 40%). Global Deficit Scores (GDS), derived from pooling standard scores, also identified 44% of patients as having mild impairment and were highly correlated with clinician ratings (r = .81 p = < 0.0001). Neither clinician ratings nor deficit scores correlated with SF-36 subscale or summary scores but did correlate with depression scores (p < .0007). In summary, clinician ratings and deficit scores identified a similar prevalence of cognitive impairment amongst CHC patients with advanced fibrosis. There was a significant correlation between cognitive impairment and self-reported depression.

Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial.

BACKGROUND/AIMS: Prior studies have demonstrated neuropsychological abnormalities in chronic hepatitis C (CHC) patients even with mild fibrosis. The aim of this study was to determine the frequency, type, and severity of cognitive impairment in a large group of CHC patients with advanced fibrosis. METHODS: Ten validated neuropsychological tests were administered to 201 CHC patients. Standard scores for individual tests were calculated using normative population data that controlled for age, gender, and/or education. Lifetime psychiatric history, alcohol consumption, and mood status were also determined. RESULTS: 33% of patients met criteria for cognitive impairment (i.e. standard score <40 on at least 4 tests). Mild impairment in verbal recall and working memory were noted with other domains remaining intact. Liver disease severity and lifetime psychiatric/substance abuse history did not correlate with group mean cognitive test results or the presence of cognitive impairment. In contrast, IQ and depression scores were significant and independent predictors of cognitive impairment (ROC = 0.84). CONCLUSIONS: 33% of patients entering the HALT-C trial have evidence of a mild, non-focal subcortical processing deficit which was highly correlated with IQ, education, and occupation. Future studies of cognitive function in CHC patients should control for general cognitive ability.

Discontinuation from HIV medical care: squandering treatment opportunities.

The purpose of this study was to assess HIV-infected patients' discontinuation of their primary care. One hundred ninety-eight consecutive outpatients were interviewed on initial HIV primary care presentation, assessed after six months about their discontinuation from primary care, and had characteristics associated with discontinuation determined. Primary care was not continued in 20 percent (40/198) of the cases. Cohort characteristics included 25 percent women; 44 percent black, 28 percent white, 25 percent Hispanic; 69 percent with highest yearly income < or = $16,000; 47 percent injection drug users; and median CD4 count 285/microL. Characteristics significantly associated (p < or = 0.05) with discontinuation were higher CD4 count, less education, no history of victimization, previous jail time, and site of medical care. One-fifth of HIV-infected patients did not remain engaged in primary care after establishing this essential link to treatment.