Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIGMS study.

OBJECTIVE: PARADIGMS demonstrated superior efficacy and comparable safety of fingolimod versus interferon ß-1a (IFN ß-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study. METHODS: Patients with multiple sclerosis (MS) (aged 10-<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN ß-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA). RESULTS: Of the randomised patients, 107 each were treated with fingolimod and IFN ß-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN ß-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (-72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (-0.48% vs -0.80%, p=0.014) were lower with fingolimod versus IFN ß-1a, the latter partially due to accelerated atrophy in the IFN ß-1a group. CONCLUSION: Fingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN ß-1a in PoMS.

Lipid effects of peroxisome proliferator-activated receptor-δ agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome.

OBJECTIVE: Peroxisome proliferator-activated receptor-δ-induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins. METHODS AND RESULTS: GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (-7.3%), triglycerides (-16.9%), apoB (-14.9%), and free fatty acids (-19.4%). The exploratory study showed significant reductions in the concentration of very LDL (-19%), intermediate-density lipoprotein (-52%), and LDL (-14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL). CONCLUSIONS: GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-δ being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients.

Evaluation of topically administered diclofenac liposomal cream for treatment of horses with experimentally induced osteoarthritis.

OBJECTIVE: To assess the clinical, biochemical, and histologic effects of topically administered diclofenac liposomal cream (DLC) in the treatment of horses with experimentally induced osteoarthritis. ANIMALS: 24 horses. PROCEDURES: Osteoarthritis was induced arthroscopically in 1 middle carpal joint of all horses. Eight horses treated with DLC were given 7.3 g twice daily via topical application. Eight horses treated with phenylbutazone were given 2 g orally once daily. Eight control horses received no treatment. Evaluations included clinical, radiographic, magnetic resonance imaging, synovial fluid, gross, and histologic examinations as well as histochemical and biochemical analyses. RESULTS: No adverse treatment-related events were detected. Horses that were treated with DLC or phenylbutazone had significant clinical improvement of lameness, unlike the control horses. Treatment with DLC induced significant improvement in staining and total articular glycosaminoglycan content, compared with no treatment. Treatment with phenylbutazone induced significant reduction in synovial fluid prostaglandin E2 concentration, compared with DLC and no treatment. Treatment with DLC induced significantly less radial carpal bone sclerosis and overall gross cartilage erosion, compared with phenylbutazone. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that DLC had both clinical sign-modifying and disease-modifying effects. Only clinical sign-modifying effects were detected in association with phenylbutazone administration. Treatment with DLC had significant beneficial effects, compared with phenylbutazone, and no detrimental effects. Results suggested that DLC is a viable therapeutic option for horses with osteoarthritis.

Usefulness of increased skin cholesterol to identify individuals at increased cardiovascular risk (from the Predictor of Advanced Subclinical Atherosclerosis study).

In patients with symptomatic coronary heart disease, skin cholesterol (SC) content is associated with the presence and extent of coronary artery disease; however, its relation to subclinical arterial disease in asymptomatic patients is unknown. The purpose of this study was to determine the relations between SC and carotid intima-media thickness (CIMT) in asymptomatic subjects across a wide range of cardiovascular risk. SC was measured using a noninvasive assay. CIMT and carotid plaque presence were determined by high-resolution B-mode ultrasound. Associations among SC, CIMT, carotid plaque presence, and cardiovascular risk factors were evaluated by multivariable logistic regression analyses. SC and CIMT were measured in 565 asymptomatic subjects (57 +/- 10 years of age, 38% women) from 6 sites in North America. The mean Framingham 10-year cardiovascular risk was 8.4 +/- 7.2%. A 10-U increase in SC was associated with a 12% increase in the odds of having increased CIMT (p = 0.006) and a 15% increase in carotid plaque presence (p = 0.002). Odds ratios (95% confidence intervals) associated with SC >110 U were 2.19 (1.25 to 3.85, p = 0.006) for increased CIMT and 2.89 (1.61 to 5.19, p <0.001) for carotid plaque presence. In conclusion, SC identified the presence of advanced subclinical atherosclerosis. The relations among increasing SC, increasing CIMT, and carotid plaque presence were consistent across all levels of cardiovascular risk and were independent of cardiovascular risk factors. SC may be a useful test for cardiovascular risk prediction.

Skin cholesterol adds to Framingham risk assessment.

INTRODUCTION: It has been demonstrated that skin tissue cholesterol (SkinTc) is associated with angiographic disease. Now, we further delineate the relative risk of multivessel disease (>50% stenosis in at least two vessels) in the conjoint presence of high SkinTc and high traditional risk burden. METHODS: Patients scheduled for angiography (N = 649) had SkinTc measured immediately prior to the procedure. Patients were classified according to the presence of high (>110) SkinTc and high (>10) Framingham global risk scores. Multivariable logistic regression models were used to estimate relative risk of multivessel disease for patients with isolated high skin tissue cholesterol, isolated high Framingham risk or conjoint high skin tissue cholesterol and high Framingham risk (each compared to neither factor elevated). RESULTS: The mean age was 63 +/- 12 years and 33% (n = 214) were women. Thirty seven percent (n = 237) had angiographically determined multivessel disease. Patients with isolated high SkinTc showed a relative risk of multivessel disease of 1.6 (95% CI = 1.0-2.4), while patients with isolated high Framingham risk had an odds ratio of 1.8 (CI = 1.0-3.4). However, when both scores were elevated, risk of multivessel disease was increased 4.3 times (CI = 2.6-7.2) compared to neither elevated. CONCLUSIONS: We see an independent, additive risk of concurrent multivessel disease when Framingham risk and skin cholesterol are both elevated. Skin tissue cholesterol may have value in further stratifying subjects with Framingham scores >10.

Association between apolipoprotein E alleles and calcific valvular heart disease.

BACKGROUND: Studies on apolipoprotein E (apoE) alleles have reported an increased risk of coronary heart disease in patients with the apoE4 allele. Given the risk factor and histological similarities between coronary and calcific valvular heart disease (aortic stenosis [AS] and mitral annular calcification [MAC]), we postulated that apoE alleles might be associated with the development of these valvular lesions. METHODS AND RESULTS: We evaluated the association between apoE alleles and calcific valvular lesions in 802 patients undergoing transthoracic echocardiography using logistic regression analyses. No difference was noted in genotype distribution (P=0.59) or prevalence of apoE4 between those with or without MAC (30% versus 27%, respectively; P=0.57). Compared with patients without AS, the genotype distribution of patients with AS differed significantly (P=0.03), with increasing prevalences of the apoE 4 allele (27% in those without versus 40% in those with AS; P=0.01). In multivariate analyses adjusting for age, gender, low-density lipoprotein cholesterol levels, and coronary artery disease, increasing age and the apoE4 allele were significant independent predictors of AS (odds ratio, 1.94; 95% confidence interval, 1.01 to 3.71; P=0.046), whereas the apoE4 allele was not predictive of MAC. CONCLUSIONS: These findings support extension of the importance of the apoE4 allele beyond atherosclerosis and Alzheimer's disease to calcific AS.

Elevated skin tissue cholesterol levels and myocardial infarction.

BACKGROUND: Skin cholesterol has been associated with coronary artery disease, extent of angiographic disease and inflammatory markers such as hs-CRP. Based on these findings we sought to determine whether skin cholesterol was associated with myocardial infarction (MI). METHODS: Patients (N = 649) underwent diagnostic catheterization and concurrent skin cholesterol measurement. History of MI was determined at the time of hospitalization. RESULTS: Patients with a history of MI (n = 225, 35%) had significantly higher skin cholesterol than those without MI (127+/-29 versus 120+/-20, p = 0.002). The odds ratio for high skin cholesterol (for MI) was 1.6 (95% CI = 1.1, 2.6; p = 0.01) after adjustment for traditional risk and extent of angiographic disease. CONCLUSION: Skin cholesterol may indicate increased risk of coronary-related events rather than simply the presence of angiographic narrowing.

Elevated fibrinogen and homocysteine levels enhance the risk of mortality in patients from a high-risk preventive cardiology clinic.

Fibrinogen (Fib) plays an important role in platelet aggregation and thrombus formation, and homocysteine (tHcy) causes endothelial dysfunction and injury. Therefore, an interaction toward an enhanced risk of thrombotic events and consequent mortality might be expected in patients with both factors elevated. To determine whether patients exposed jointly to high Fib and high tHcy were at increased risk of mortality, we compared them with those with only one or neither risk factors elevated. Prevalence of coronary artery disease (cross-section) and short-term mortality (30+/-14 months) were assessed in 2084 patients with available baseline tHcy and Fib. Upper quartiles were used to define high tHcy (>14.2 micromol/L) and high Fib (>382 mg/dL). Cox models adjusting for Framingham risk score, creatinine, and coronary artery disease status were used to estimate the risk of high tHcy and high Fib and their combinations. Mean age of the patients was 56+/-12 years (35% women) with 71 (3.4%) recorded deaths. Risk-adjusted longitudinal models showed a hazard ratio of 2.14 (P=0.03) for isolated high tHcy, 2.28 (P=0.02) for isolated high Fib, and 3.29 (P<0.001) for both high tHcy and high Fib in comparison with neither risk factor high. Independence of each parameter and lack of synergism was found on longitudinal as well as cross-sectional analyses. Conjoint elevation of Fib and tHcy increased the risk of death by approximately 3-fold in three years. Although no significant interaction between Fib and tHcy was demonstrated, both provided independent information after adjustment for traditional risk factors.

Skin tissue cholesterol (SkinTc) is related to angiographically-defined cardiovascular disease.

UNLABELLED: Parallel changes associated with aging found in the vasculature and skin at necropsy, have prompted small preliminary studies to assess the relation between skin tissue cholesterol (SkinTc) and cardiovascular disease. While these studies have been suggestive, no formal investigation is available to test this association. It would, therefore, be valuable to determine whether a relation between SkinTc and angiographic narrowing actually exists, the latter representing one accepted measurement of coronary atherosclerosis. METHODS: Patients at three hospitals undergoing coronary angiography and not on lipid altering agents (n = 649) were examined for skinTc using a non-invasive method. Vessels were evaluated manually (number with stenosis > or = 50%). Clinical characteristics, current medication use, and Framingham global risk score were recorded. RESULTS: SkinTc was significantly higher in patients with angiographic disease (124 +/- 30 vs. 118 +/- 30, P = 0.02). After adjustment for traditional coronary artery disease risk factors, SkinTc provided 7% additional risk (per 10 SkinTc units) for angiographic disease. CONCLUSION: SkinTc, measured with a non-invasive method, is associated with the presence of coronary artery disease as determined by catheterization. Such an assay may eventually help stratify patient risk and target prevention efforts.

Pilot study of coronary atherosclerotic risk and plaque burden in HIV patients: 'a call for cardiovascular prevention'.

BACKGROUND: Highly active antiretroviral therapy (HAART) has dramatically improved the life expectancy of patients with human immunodeficiency virus (HIV) prompting increasing concerns related to chronic management. Suggestions of greater cardiovascular risk, partially related to recently proposed HAART-induced dyslipidemia and glucose intolerance, amplify these concerns. At this time, further corroboration of the emerging evidence for increased coronary risk, as well as complimentary estimates of coronary artery atherosclerotic burden, would be valuable to practicing physicians. METHODS: Seventeen HIV patients on HAART (all from the same HIV clinic population) without coronary artery disease (CAD) were referred to Preventive Cardiology for treatment of dyslipidemia ('referred group'). Upon entry, they underwent computed tomography (CT) of the coronary arteries. Subsequently, the referred group was matched (1:4) for age, gender and traditional risk to non-HIV non-CAD subjects (matched group, n=68) from the University of Illinois CT database. A serial review of 90 subjects from the original HIV population was sampled to determine general cardiovascular risk. RESULTS: Thirteen (76%) of the 17 referred patients revealed the presence of coronary calcium compared with 63% in the matched HIV seronegative controls (P=0.18). Log-transformed median calcium score was 2.93+/-2.3 in the referred group versus 1.97+/-2.5 in the matched group (P=0.09). Fifty one percent of the overall population smoked cigarettes, 11% were diabetic (30% diagnosed pre-HAART and 70% post-HAART) and 30% were hypertensive (33% diagnosed pre-HAART and 67% post-HAART). CONCLUSIONS: In a particularly dyslipidemic subgroup of HIV subjects without known CAD we found evidence for atherosclerosis in three-quarters based on coronary calcium. Further, in this population of HIV patients on HAART, we found an enhanced prevalence of traditional cardiovascular risk. This pilot study encourages the development of preventive strategies in this population.

Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.

BACKGROUND: Statins have become a mainstay in the treatment of hyperlipidemia, based on their potency and favorable side-effect profile. Drug choice is presumed to be guided by the estimated degree of low-density lipoprotein (LDL) cholesterol lowering required in a particular patient and the projected efficacy of any drug-dose combination, as contained in the package inserts for each medication. We investigated whether these expectations were met in a clinical practice. METHODS: Data were analyzed for 367 hyperlipidemic patients in a preventive cardiology practice who were not taking statins at entry, who were given a standard statin dose at their first visit, and who had at least one follow-up visit on the same drug/dose. Expected LDL cholesterol reductions were calculated for each patient based on guidelines in the package inserts for each drug. RESULTS: The mean (+/-SD) observed LDL cholesterol reduction of 26% +/- 20% was significantly less than expected (34% +/- 7%, P < 0.001). The ratio of observed to expected reduction was not different for the three statins used (atorvastatin, 0.79 +/- 0.48; simvastatin, 0.88 +/- 0.61; pravastatin, 0.75 +/- 0.69; P = 0.39). CONCLUSIONS: The use of statins in a clinical practice led to observed reductions in LDL cholesterol level that were significantly less than those projected by package insert guidelines. We believe this gap reflects the reduced patient compliance frequently observed in clinical practice settings, rather than any inherent difference in statin responsiveness of a practice versus a trial population. Physicians should be aware of this disparity when using statins in the clinical setting.

Fibrinogen: associations with cardiovascular events in an outpatient clinic.

BACKGROUND: Fibrinogen, known to influence the coagulation process, is an independent risk factor for coronary artery disease (CAD). However, its association with myocardial infarction (MI) and its predictive potential for short-term mortality, in an ongoing clinical practice, has not been characterized. OBJECTIVES: In a high-risk outpatient practice we sought to demonstrate whether baseline fibrinogen levels related to MI rather than CAD alone, and whether baseline serum fibrinogen levels predicted mortality over a short-term follow-up. METHODS AND RESULTS: From a total of 2126 patients with baseline fibrinogen measurements (mean age, 56 +/- 12 years, 35% female), 1187 patients with CAD (n = 606 with MI) and 939 patients without CAD were evaluated in an active preventive cardiology unit of a large city hospital. Logistic regression models were used to determine the association of fibrinogen with differing CAD presentations. Fibrinogen quartile showed a significant correlation with CAD both univariately and after adjustment for Framingham risk score (odds ratio [OR] = 1.22, P <.001). Fibrinogen levels were significantly associated with the presence of CAD and history of MI (adjusted OR = 1.25, P =.001). Fibrinogen did not show a significant association to CAD when MI was not considered in the analysis (OR = 1.01, P =.82). In this same clinical cohort, after a mean follow-up of 24 +/- 13 months, 41 patients had died. Consistent with the observed association with MI, fibrinogen quartile showed a graded independent relation to mortality in a cohort of both men and women (hazard ratio = 1.81, P <.001). CONCLUSIONS: In the clinical setting of an outpatient clinic, fibrinogen was directly associated with the presence of MI and was revealed to be an independent short-term predictor of mortality.

Impact of nonprescriptive factors on low-density lipoprotein cholesterol reduction with statins.

Nonprescriptive factors, including patient adherence, can affect the fluctuations in low-density lipoprotein (LDL) cholesterol observed in the clinical setting. In 241 statin-treated patients, although drugs and doses remained fixed, 57% of patients initially successful in reaching LDL cholesterol targets showed subsequent increases in LDL cholesterol. Conversely, 60% of patients who initially failed to reach targets had subsequent reductions in LDL cholesterol, with nearly 1/3 eventually attaining their LDL cholesterol goals.

Relation of albumin/creatinine ratio to C-reactive protein and to the metabolic syndrome.

We hypothesized that the association of high sensitivity C-reactive protein (CRP) with urinary albumin excretion (UAE) is predominately mediated through its correlation with the metabolic syndrome. Serum CRP and urine albumin:creatinine ratios (ACR) from 720 preventive cardiology patients were analyzed to estimate age- and gender-adjusted relative risk of high CRP and metabolic syndrome for high ACR. These data demonstrate that CRP independently predicts the presence of UAE, a marker of endothelial dysfunction.

Relation of homocysteine and C-reactive protein to urinary albumin loss.

This study shows that elevated high-sensitivity C-reactive protein and plasma total homocysteine contribute independently to the likelihood of an increased urinary albumin:creatinine ratio. This result suggests that total homocysteine and C-reactive protein may be acting by separate mechanistic pathways.

Fiber-multivitamin combination therapy: a beneficial influence on low-density lipoprotein and homocysteine.

Proven effective alternative and adjunctive therapies for lipid lowering could be beneficial for patients with hyperlipidemia. We evaluated a 90% soluble fiber for its ability to alter lipid, lipoprotein, and homocysteine levels in the setting of coadministered folate and B vitamins. Patients (n = 119) were randomized to either the fiber and vitamin combination, or placebo. Fasting lipid, glucose, and homocysteine concentrations, and body mass index (BMI) were obtained at baseline and weeks 4 and 8. Both between-group (Wilcoxon rank-sum test) and within-group (paired t test) comparisons were used to evaluate treatment effects. After 6 weeks of a diet therapy (National Cholesterol Education Program [NECP] Step I) run-in period, subjects in both groups had similar low-density lipoprotein cholesterol (LDL-C) levels (159 mg/dL v 158 mg/dL). The treated group showed a 7.1% +/- 11.6% reduction by 4 weeks, which was maintained at 8 weeks (7.9% +/- 11.0%). Placebo patients had a slight increase in LDL-C values over the same period (+2.4% +/- 11.7%), for a 10.3% difference between groups. The treatment effect was statistically significant both between groups (P <.001) and within the active-treatment group (P <.001) after the 8-week intervention. Apolipoprotein B (ApoB) levels in a representative subset of the treated group (n = 53) decreased by 20% (P =.004). The fiber blend neither raised triacylglycerol (TG) (P =.95) nor lowered high-density lipoprotein cholesterol (HDL-C) levels (P =.54), and lowered homocysteine (active, 9.8 to 8.7/micromol/L, P =.02; placebo, 9.4 to 9.2 /micromol/L, P =.98). Thus, a significant LDL-C lowering effect, with parallel Apo B reduction, was demonstrated for this fiber/vitamin combination. No adverse changes on TG or HDL-C levels were noted, and folate/B vitamin benefits attributed to homocysteine reduction were preserved. Concurrent administration of fiber and vitamins represents a preventive approach that may reduce the need for concomitant lipid-lowering therapies or serve as an adjunct therapy.