Journal of Clinical Lipidology

Editorial Board

2012-01-01

From the Editor: Five Years of Growth for the Journal

W. Virgil Brown — 2011-12-12

This issue marks the end of our fifth year as a professional publication focusing on clinical lipidology. The Journal began with the first issue in March of 2007 as an initiative of the National Lipid Association (NLA) and is the property of this Association. Having our own journal was stated as a long-term goal by the leadership of the Association at the time of its birth in 2002. Most of us did not believe that it would be possible within 5 years of the founding of the NLA, but with the very positive attitude of the Board and an excellent administrative staff, this task was undertaken successfully. I have been honored by being appointed Editor and by the tremendous support given with enthusiasm by the Associate Editors, the Editorial Board, the NLA, and our contracted publisher, Elsevier. I owe a particular debt of gratitude to Angelica Kerr, my Managing Editor in the New York office of Elsevier and Megan Seery at the NLA, who have made my job possible through continuing electronic communications. With their help, we have reviewed the progress of the Journal in terms of the editorial activity since its inception and I wish to summarize some of that in this short report.

News from the NLA

2012-01-06

The Nominating Committees of the NLA Board of Directors and the regional Boards of Directors are seeking nominations. Each year, the term of approximately one-third of each Board expires. New Board members are elected each May at the NLA Annual Scientific Sessions. Please go to http://www.lipid.org/about/committees to nominate a colleague.

Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: A review

Terry A. Jacobson, Sara B. Glickstein, Jonathan D. Rowe, Paresh N. Soni — 2011-11-04

Abstract: In this exploratory, hypothesis-generating literature review, we evaluated potentially differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and non-HDL-C in published studies of ω-3 fatty acid supplementation or prescription ω-3 fatty acid ethyl esters. Placebo-adjusted changes in mean lipid parameters were compared in randomized, controlled trials in subjects treated for ≥4 weeks with DHA or EPA. Of 22 studies identified, 6 compared DHA with EPA directly, 12 studied DHA alone (including 14 DHA–treated groups), and 4 examined EPA alone. In studies directly comparing EPA with DHA, a net increase in LDL-C of 3.3% was observed with DHA (DHA: +2.6%; EPA: −0.7%). In such head-to-head comparative studies, DHA treatment was associated with a net decrease in TG by 6.8% (DHA: −22.4%; EPA: −15.6%); a net increase in non-HDL-C by 1.7% (DHA: −1.2%; EPA −2.9%); and a net increase in HDL-C by 5.9% (DHA: +7.3%; EPA: +1.4%). Increases in LDL-C were also observed in 71% of DHA-alone groups [with demonstrated statistical significance (P < .05) in 67% (8 of 12) DHA-alone studies] but not in any EPA-alone studies. Changes in LDL-C significantly correlated with baseline TG for DHA-treated groups. The range of HDL-C increases documented in DHA-alone vs EPA-alone studies further supports the fact that HDL-C is increased more substantially by DHA than EPA. In total, these findings suggest that DHA-containing supplements or therapies were associated with more significant increases in LDL-C and HDL-C than were EPA-containing supplements or therapies. Future prospective, randomized trials are warranted to confirm these preliminary findings, determine the potential effects of these fatty acids on other clinical outcomes, and evaluate the generalizability of the data to larger and more heterogeneous patient populations.

Evaluation of the incidence and risk factors for development of fenofibrate-associated nephrotoxicity

2011-09-14

Background: Fenofibrate-associated nephrotoxicity has been described in two randomized controlled trials and several observational studies. However, little is known regarding its incidence and the population(s) at risk.Objective: This study aims to quantify the incidence and identify potential risk factors for development of nephrotoxicity in patients receiving fenofibrate.Methods: A retrospective, observational study was conducted in the South Texas Veterans Health Care System. Data were collected regarding baseline demographics, concurrent medical conditions, medications, laboratory results, and fenofibrate use.Results: Within 6 months after initiation of fenofibrate in 428 patients, 115 (27%) experienced an increase in serum creatinine of ≥0.3 mg/dL. Any renal disease (P = .001), chronic kidney disease (P = .01), and diabetes (P = .02) were significantly more prevalent in patients with fenofibrate-associated nephrotoxicity. Patients with nephrotoxicity had significantly greater serum creatinine (1.2 [SD 0.3] vs. 1.1 mg/dL [SD 0.3], P = .0002) and lower estimated glomerular filtration rate (72 [SD 20] vs 81 mL/min/1.73m2 [SD 20], P < .0001) at baseline. These patients also had greater use of calcium channel blockers (P = .0003), furosemide (P = .02), and angiotensin-converting enzyme inhibitors (P = .02). The incidence of nephrotoxicity was significantly greater in patients initiated on high-dose versus those on low-dose fenofibrate (P = .002). In a multivariable regression model, renal disease (P = .02), high-dose fenofibrate (P = .001), and dihydropyridine calcium channel blocker use (P = .02) were determined to be independent predictors of development of increased serum creatinine on fenofibrate.Conclusion: This observational study suggests fenofibrate-associated nephrotoxicity occurs more frequently than previously reported, particularly in patients with renal disease and in those receiving high-dose fenofibrate or concomitant calcium channel blockers.

Evidence of dependence of lipoprotein(a) on triglyceride and high-density lipoprotein metabolism

Matthew Konerman, Krishnaji Kulkarni, Peter P. Toth, Steven R. Jones — 2011-09-14

Abstract: Lipoprotein(a) [Lp(a)] is a complex lipoprotein consisting of a low-density lipoprotein (LDL)-like ApoB100-containing core particle covalently bound to apo(a), a large functionally complex glycoprotein. The mechanisms of Lp(a) metabolism and its interactions with cell-surface lipoprotein receptors are incompletely understood. In this study, we investigated the relationship of Lp(a) to other lipoproteins at high and normal levels of serum triglycerides (TGs). We measured serum lipid and Lp(a) particle concentrations in 148 unselected primary- and secondary-prevention patients. Subjects with TG > 200 mg/dL were classified as having high TG in accordance with National Cholesterol Education Program Adult Treatment Panel III guidelines. Our analysis revealed mean TG levels of 100 and 270 mg/dL in the normal and high TG groups, respectively. Lp(a)-C, Lp(a)-P, and Lp(a) cholesterol content per particle [Lp(a)-C/Lp(a)-P] did not differ between groups. At normal TG levels, stepwise multiple linear regression revealed that Lp(a)-P correlated with Lp(a)-C (P < 10−6), ApoAI (P = .0001), the high-density lipoprotein cholesterol subfraction ratio (HDL2-C/HDL3-C; P = .002), and dense very-low-density lipoprotein cholesterol (VLDL3-C; P = .04), overall model R = 0.74. At high TG levels, Lp(a)-P very strongly correlated primarily with HDL2-C/HDL3-C and TG-related variables with minimal dependence on Lp(a)-C (P = .09), overall model R = 0.96. These findings provide evidence of shared metabolic mechanisms for Lp(a), HDL, TG, and very low-density lipoprotein at high serum TG. Future studies are needed to elucidate common mechanisms, enzymes, and receptors involved in Lp(a) and HDL/TG metabolism with a focus on how these mechanisms are modified in the setting of hypertriglyceridemia.

Measurement of cholesterol and triglycerides from a dried blood spot in an Indian Council of Medical Research–World Health Organization multicentric survey on risk factors for noncommunicable diseases in India

2011-11-14

Background: Dried blood may be a convenient method of sample collection in epidemiological studies; however, the method needs evaluation in a field settings. In the present study, feasibility of using dried blood for measurement of cholesterol and triglycerides was evaluated in multicenter surveillance study for noncommunicable disease (NCD).Methods: Samples were collected in a cross-sectional study for NCD risk factor surveillance conducted in six centers in India. For every tenth subject recruited, a blood sample was also collected on filter paper. These 10% serum samples and dried blood spots were analyzed for cholesterol and triglycerides.Results: The mean coefficient of variation (CV) for cholesterol was less than 10% between dried blood and serum in five of the six participating centers. Only one center showed a high CV of 14%. Similarly, the mean bias was less than 10% in five centers. The intraclass correlation between cholesterol values in dried blood and serum were greater than 0.638 in all centers, which suggests a good homogeneity of results. The mean CV for triglycerides ranged from 0.36% to 17.97%. The intraclass correlation between triglyceride values in dried blood and serum ranged from 0.756 to 0.880 in the six centers.Conclusion: In conclusion, dried blood would be a good method for collection of blood for measurement of cholesterol and triglycerides for population health surveys. However, the benefits of blood spot analysis should be weighed against potential sources of errors attributable to sampling and other factors, such as temperature and humidity, in a country like India.

The differential effect of statins on oxidative stress and endothelial function: Atorvastatin versus pravastatin

2011-09-14

Background: Atherogenic risk in subjects with metabolic syndrome is partly mediated by increased oxidative stress and subsequent endothelial dysfunction. Clinical trials have demonstrated differences in outcomes between subjects receiving lipophilic statins (atorvastatin) compared with hydrophilic statins (pravastatin). However, whether these findings are attributable to differences in the doses administered or to nonlipid-lowering pleiotropic effects of statins on oxidative stress and vascular function remains unknown. We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function.Methods: Thirty-six subjects with hyperlipidemia and metabolic syndrome and/or diabetes were randomized in a double-blind manner to either pravastatin 80 mg or atorvastatin 10 mg daily. Oxidative stress (dROMs assay that measures lipid hydroperoxides, plasma thiobarbituric acid reactive substances [TBARS], and aminothiol levels) and brachial artery flow-mediated dilation (FMD) were measured at baseline and after 12 weeks of statin therapy.Results: Statin therapy reduced serum low-density lipoprotein cholesterol levels equally in both groups. Atorvastatin therapy was associated with a significant reduction in TBARS (P = .006) and dROMs levels (P = .02), which was not observed in subjects treated with pravastatin. Endothelial function improved with statin therapy (P = .02), but there was no difference between the statin groups.Conclusion: In hyperlipidemic subjects with metabolic syndrome, atorvastatin is associated with a greater reduction in lipid markers of oxidation compared with pravastatin. Whether these effects are responsible for the outcome differences in trials comparing these agents needs further investigation.

Non–high-density lipoprotein cholesterol calculation and goal awareness among physicians-in-training

2011-11-09

Background: Non-high density lipoprotein cholesterol (non-HDL-C) goal attainment per Adult Treatment Panel III (ATP III) guidelines remains low.Objective: To understand gaps in knowledge and practices of physicians-in-training (internal medicine, family medicine, cardiology, endocrinology) towards non-HDL-C.Methods: A survey based on a conceptual model to assess the trainee’s knowledge, attitudes, and practice regarding non-HDL-C was developed and administered to physicians-in-training (n = 655) at 26 training programs in the United States. Responses of those in internal medicine and family medicine (residents-in-training; n = 418) were compared with those in cardiology and endocrinology (fellows-in-training; n = 124).Results: Response rate was 83.7%. Fifty-three percent of residents and 31% of fellows-in-training had not read the ATP III guidelines (P < .001). Thirty-three percent of the residents and 35% fellows-in-training could not calculate non-HDL-C from a standard lipid panel (P = .7). Sixty-seven percent of the residents and 52% of fellows were not aware of treatment goals for non-HDL-C (P = .004 for comparison between residents and fellows). Both residents and fellows reported infrequent calculation of non-HDL-C levels in patients with elevated triglycerides (≥200 mg/dL; 32.5% vs 35.4%, respectively, P = .6). Lack of familiarity with ATP III guidelines, lack of knowledge regarding importance of non-HDL-C, lack of institutional mandate to calculate non-HDL-C, and lack of emphasis on non-HDL-C by teaching staff were reported as barriers to non-HDL-C use in routine clinical practice.Conclusions: At least one-third of physicians-in-training could not calculate non-HDL-C from a standard lipid panel, and a large number were not aware of ATP III treatment goals pertaining to non-HDL-C. This area represents one for improvement if non-HDL-C is to be retained as a treatment target in the forthcoming ATP-IV guidelines.

Benefits associated with achieving optimal risk factor levels for the primary prevention of cardiovascular disease in older men

2011-11-09

Background: Most incident cardiovascular disease (CVD) occurs after patients reach the age of 65. The additive benefits of aggressive risk factor management with advancing age are not well established.Objective: To evaluate the relationship between control of four modifiable risk factors (smoking, non-high density lipoprotein cholesterol, blood pressure, and aspirin use) and risk of CVD in a primary prevention population of older men.Materials and Methods: U.S. male physicians from the Physicians’ Health Study (n = 4182; an epidemiologic follow-up of a randomized trial of aspirin and beta-carotene) who in 1997 were ≥65 years, free of CVD and diabetes, and had a blood sample on file were studied. Cox proportional hazard models were adjusted for age and competing causes of death. The first of any CVD event, defined as cardiovascular death, nonfatal myocardial infarction, angina, coronary revascularization, nonfatal stroke, transient ischemic attack, carotid artery surgery, and other peripheral vascular disease surgery, was measured.Results: Mean follow-up was 9.3 years, mean age was 73 years, and 96% were nonsmokers. Compared with when 4 of 4 risk factors were controlled (6.0% of participants), control of 0 of 4 risk factors almost quadrupled the risk of CVD (0.4% of participants; event rate 41.2%; hazard ratio [HR] 3.83, 95% confidence interval [95% CI] 1.72–8.55); control of 1 of 4 risk factors more than doubled the risk (14.2% of participants; HR 2.53, 95% CI 1.80–3.57); control of 2 of 4 risk factors almost doubled the risk (43.8% of participants; HR 1.94, 95% CI 1.41–2.69), and those with control of 3 of 4 risk factors also were at increased risk (35.6% of participants; HR 1.80, 95% CI 1.30–2.50). Control of each additional risk factor was associated with greater cardiovascular protection (P for trend P = .002). Depending on the number of risk factors controlled, the number-needed to control to prevent one CVD event ranged from 5 to 22.Conclusion: Control of 4 treatable risk factors (nonsmoking, control of non-high density lipoprotein cholesterol and blood pressure, and aspirin use) was associated with substantial protection against incident cardiovascular events in older men even after adjustment for competing causes of mortality.

Lipoprotein (a): Perspectives from a lipid-referral program

2011-06-23

Background: Lipoprotein (a) [Lp(a)] has a strong association with coronary disease (CHD). We evaluated the implications of implementing a niacin strategy in persons above low risk by the Framingham risk score (FRS).Methods: Patients referred to a university lipid management program from January 2004 to June 2010 had an Lp(a) level measured at initial evaluation. Factors associated with an increase in Lp(a) and predictors of a high risk Lp(a) (≥50 mg/dL) were assessed. FRS and Lp(a) levels were used to assess eligibility for niacin with an Lp(a) ≥50 mg/dL.Results: A total of 692 patients (57% male, mean age 52 ± 14 years) had a mean Lp(a) of 32 ± 40 mg/dL. In a multiple logistic regression model, African-American race, female gender, presence of CHD, and lower triglyceride levels were significant predictors of high risk Lp(a). Ten percent were determined to be intermediate and 44% high risk by FRS. A total of 9% of intermediate- and 26% of high-risk patients had an Lp(a) ≥50 mg/dL, and 84% were not taking niacin. A total of 19% of moderate- and high-risk patients were eligible for initiation of niacin based upon values ≥50 mg/dL. If niacin were also used for an high-density lipoprotein cholesterol levels ≤40 mg/dL, only 5.1% additional patients would require niacin.Conclusion: High-risk levels of Lp(a) are associated with female gender, African- American race, and CHD. 19% of moderate and high risk patients would be candidates for treatment with niacin if the indication is a cutpoint Lp(a) ≥50mg/dL.

Reduced cellular cholesterol efflux and low plasma high-density lipoprotein cholesterol in a patient with type B Niemann-Pick disease because of a novel SMPD-1 mutation

2011-09-15

Background: Type A or B Niemann-Pick disease (NPD) is characterized by the accumulation of sphingomyelin in the lysosomes and cell membranes. This accumulation results because of a mutation in the sphingomyelin phosphodiesterase-1 (SMPD-1) gene that causes a deficit in the acid sphingomyelinase (ASM).Objective: Herein, we report on a new point mutation in the SMPD-1 gene that was discovered in a patient with type B NPD.Methods and Results: A culture of the patient’s fibroblasts demonstrated that the observed clinical symptoms and reduced plasma high-density lipoprotein cholesterol (HDL-C) were associated with a reduced efflux of cholesterol. Examination of the skin fibroblasts demonstrated that ASM activity was reduced to approximately 60% of that observed in control cells, and a newly identified point mutation was found in codon 494 [Gly (GGT) → Cys (TGT)] in the SMPD-1 gene. Furthermore, repeated measurements of the plasma HDL-C levels remained low (17.5-20.5 mg/dL), and the Apo A-I− or HDL−mediated cholesterol efflux from the patient’s fibroblasts was significantly reduced as compared with control fibroblasts.Conclusion: In summary, we identified a unique point mutation in a patient with type B NPD that was associated with various clinical findings, including a low plasma HDL-C level. This reduced cellular cholesterol efflux may be implicated, at least in part, in low plasma HDL levels.

The association of apolipoprotein E polymorphism and lipid levels in children with a family history of premature coronary artery disease

Dilek Yılmaz Çiftdoğan, Senol Coskun, Cevval Ulman, Hakan Tıkız — 2011-08-01

Background: Polymorphisms in the apolipoprotein E (apoE) gene may modulate lipoprotein metabolism and influence plasma lipid levels. Thus, they have been associated with relative risk of coronary artery disease (CAD).Objective: To evaluate the association of apolipoprotein E polymorphism and lipid levels in children with family history of premature coronary artery disease.Methods: The apoE genotypes, allele frequencie,s and plasma lipid levels were analyzed in 137 children. Among these children, 70 (study group) had and 67 (control group) did not have a parental history of premature CADResults: Total cholesterol (Tc) levels were greater in the study group (P = .04). The frequencies of ɛ3ɛ4 genotype and ɛ4 allele were significantly greater in the study group (P = 005 for both), Thɛ ɛ2 allele correlated negatively with Tc and low-density lipoprotein cholesterol levels, and ɛ4 had a positive correlation with Tc and low-density lipoprotein cholesterol levels.Conclusions: Tc levels are influenced by apoE genotypes in childhood. Also, the frequency of the ɛ4 allele is greater in children with family history of premature CAD. The ɛ4 allele may be associated with an increased risk for development of atherosclerosis by elevated levels of Tc in children with family history of CAD. The evaluation of apoE gene polymorhisms may contribute to the assessment of cardiovascular risk in children with a family history of CAD.

Management of familial hypercholesterolemia during pregnancy: Case series and discussion

Danny J. Eapen, Kiran Valiani, Shilpa Reddy, Laurence Sperling — 2011-09-22

Abstract: With an occurrence of approximately 1 in 500 individuals worldwide, the heterozygous form of familial hypercholesterolemia is not uncommon. With statins being contraindicated in pregnancy (Category X), the management of pregnant women who carry this diagnosis has not been clearly defined. This case series describes five pregnant women seen at the Emory Center for Heart Disease Prevention between 2004 and 2010 who carried this diagnosis, their treatment, and subsequent outcomes. The article concludes with treatment options for clinicians in dealing with such individuals.

High HDL and ATD

W.E. Feeman — 2011-11-21

The article by Costacou et al on the link between very high levels of high-density lipoprotein (HDL) cholesterol (80 mg/dL and greater) and atherothrombotic disease (ATD) in patients with type I diabetes prompted me to review my database of ATD patients, focusing on those with similar HDL levels. The subject matter is important because of the continuing controversy regarding “dysfunctional” HDL.

Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance

Niki Katsiki, Vasilios G. Athyros, Asterios Karagiannis, Dimitri P. Mikhailidis — 2011-09-22

We congratulate Kennedy et al on publishing the first randomized controlled trial that investigated the use of once-weekly rosuvastatin in patients with previous myalgia on statins. Some additional comments may be of interest. It would be useful to document factors that may increase the risk of statin myopathy (eg, impaired renal function, hypothyroidism or ethnicity). More specifically, did the patients who did not tolerate rosuvastatin once a week have any of these characteristics? An additional factor to consider is vitamin D deficiency. There is evidence suggesting that vitamin D replacement in deficient patients decreases their risk of developing statin-related myalgia.