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1.  Does Abdominal Obesity Accelerate the Effect of Hypertriglyceridemia on Impaired Fasting Glucose? 
Yonsei Medical Journal  2010;51(3):360-366.
This study sought to determine whether abdominal obesity is a risk factor for impaired fasting glucose (IFG) and hypertriglyceridemia and to verify whether moderate effect of abdominal obesity on the relationship between IFG and hypertriglyceridemia in Korea.
Materials and Methods
Data from the Korean National Health and Nutrition Examination Survey was used for the analysis. The study population included 5,938 subjects aged 20 year old drawn from non-diabetic participants in a health examination survey. The subjects were classified according to the presence of abdominal obesity based on waist circumference, IFG based on their fasting blood glucose level, and hypertriglyceridemia on their fasting triglyceride.
The multivariate-adjusted odds ratios for the occurrence of hypertriglyceridemia were 2.91 in the abdominal obesity group as compared with the nonobesity group and 1.31 in subjects with IFG compared with the normoglycemia controls. Abdominal obesity was found to be positively moderated in the interaction between waist circumference and fasting blood sugar.
The moderate effect between abdominal obesity and IFG contributes to the development of hypertriglyceridemia in Korea.
PMCID: PMC2852791  PMID: 20376888
Moderator effect; abdominal obesity; impaired fasting glucose; hypertriglyceridemia
2.  Understanding hypertriglyceridemia in women: clinical impact and management with prescription omega-3-acid ethyl esters 
Elevated triglycerides (TGs) are a common lipid disorder in the US and are associated with comorbidities such as pancreatitis, obesity, type 2 diabetes, and metabolic syndrome. TGs are generally elevated in postmenopausal women compared with premenopausal women. Meta-analysis has shown that elevated TGs are associated with an increased risk of coronary heart disease (CHD).
This article provides a general overview of TG metabolism and reviews data on the epidemiology and risk of elevated TGs in women, as pregnancy and menopause, in particular, have been associated with unfavorable changes in the lipoprotein profile, including elevations in TGs. In addition, this review seeks to explain the recommended TG goals and treatment options for hypertriglyceridemia with an emphasis on severe hypertriglyceridemia (TGs ≥ 500 mg/dL) and its respective treatment with prescription omega-3-acid ethyl esters (P-OM3).
MedLine was searched for articles published through August 2009 using the terms “hypertriglyceridemia” and “dyslipidemia”, with subheadings for “prevalence”, “women”, “treatment”, “guidelines”, “risk”, and “omega-3 fatty acids”. Publications discussing the epidemiology of hypertriglyceridemia, CHD risk, treatment guidelines for lipid management, or clinical trials involving P-OM3 were selected for review. The reference lists of relevant articles were also examined for additional citations.
Hypertriglyceridemia is associated with increased CHD risk. Women, especially those with polycystic ovarian syndrome, type 2 diabetes, or who are postmenopausal, should be monitored regularly for the impact of hypertriglyceridemia on their lipid profile. Cardiovascular risk of TGs can be indirectly assessed by monitoring non-high-density lipoprotein cholesterol (non-HDL-C) levels. There are multiple sets of guidelines providing recommendations for desirable low-density lipoprotein cholesterol, TG, and non-HDL-C levels. Treatment of hypertriglyceridemia includes lifestyle interventions and, if needed, pharmacologic therapy. In patients with severe hypertriglyceridemia, P-OM3 can reduce TGs by up to 45%.
Physicians should regularly monitor the lipid profile of their female patients. Any lipid abnormality should be managed promptly according to established guidelines. P-OM3 provide a well-tolerated option for the treatment of severe hypertriglyceridemia.
PMCID: PMC3061852  PMID: 21445284
triglycerides; Lovaza; P-OM3; women; lipids; omega-3
3.  The Role of Triglycerides in Atherosclerosis 
Current cardiology reports  2011;13(6):544-552.
Hypertriglyceridemia is a prevalent risk factor for cardiovascular disease (CVD) and increasingly important in the setting of current obesity and insulin resistance epidemics. High triglyceride (TG) levels are markers for several types of atherogenic lipoproteins. Patients who have hypertriglyceridemia may be at significant risk for CVD even if low-density lipoprotein cholesterol levels are at goal, and therefore warrant treatment that optimizes diet, reduces overweight, and promotes regular exercise. High-risk patients with hypertriglyceridemia, such as those with diabetes, CVD, or metabolic syndrome, may benefit from additional drug treatment aside from a statin to address other lipid abnormalities. In this discussion, we review the role of hypertriglyceridemia and its associated atherogenic lipoproteins in the pathogenesis of atherosclerosis, the relevance of a high TG level as a predictor of CVD, the cardiovascular outcomes from TG-lowering intervention trials, and the current guidelines for treating hypertriglyceridemia.
PMCID: PMC3234107  PMID: 21968696
Atherogenic dyslipidemia; Atherogenic remnant lipoproteins; Atherosclerosis; Cardiovascular disease; Chylomicron remnants; Lipoprotein lipase; Risk factor; Triglycerides; Triglyceride-rich lipoproteins; Very low density lipoproteins
4.  Dyslipidemia in a Cohort of HIV-infected Latin American Children Receiving Highly Active Antiretroviral Therapy* 
Journal of Tropical Pediatrics  2010;57(5):324-332.
In order to describe the prevalence of hypercholesterolemia and hypertriglyceridemia in a cohort of HIV-infected children and adolescents in Latin America and to determine associations with highly active antiretroviral therapy (HAART), we performed this cross-sectional analysis within the NICHD International Site Development Initiative pediatric cohort study. Eligible children had to be at least 2 years of age and be on HAART. Among the 477 eligible HIV-infected youth, 98 (20.5%) had hypercholesterolemia and 140 (29.4%) had hypertriglyceridemia. In multivariable analyses, children receiving protease inhibitor (PI)-containing HAART were at increased risk for hypercholesterolemia [adjusted odds ratio (AOR) = 2.7, 95% confidence interval (CI) 1.3–5.6] and hypertriglyceridemia (AOR = 3.5, 95% CI 1.9–6.4) compared with children receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing HAART. In conclusion, HIV-infected youth receiving PI-containing HAART in this Latin American cohort were at increased risk for hypercholesterolemia and hypertriglyceridemia compared with those receiving NNRTI-containing HAART.
PMCID: PMC3203396  PMID: 20889625
HIV; cholesterol; triglycerides; pediatric
5.  Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies 
Objective To systematically review interventional studies of the effects of alcohol consumption on 21 biological markers associated with risk of coronary heart disease in adults without known cardiovascular disease.
Design Systematic review and meta-analysis.
Data sources Medline (1950 to October 2009) and Embase (1980 to October 2009) without limits.
Study selection Two reviewers independently selected studies that examined adults without known cardiovascular disease and that compared fasting levels of specific biological markers associated with coronary heart disease after alcohol use with those after a period of no alcohol use (controls). 4690 articles were screened for eligibility, the full texts of 124 studies reviewed, and 63 relevant articles selected.
Results Of 63 eligible studies, 44 on 13 biomarkers were meta-analysed in fixed or random effects models. Quality was assessed by sensitivity analysis of studies grouped by design. Analyses were stratified by type of beverage (wine, beer, spirits). Alcohol significantly increased levels of high density lipoprotein cholesterol (pooled mean difference 0.094 mmol/L, 95% confidence interval 0.064 to 0.123), apolipoprotein A1 (0.101 g/L, 0.073 to 0.129), and adiponectin (0.56 mg/L, 0.39 to 0.72). Alcohol showed a dose-response relation with high density lipoprotein cholesterol (test for trend P=0.013). Alcohol decreased fibrinogen levels (−0.20 g/L, −0.29 to −0.11) but did not affect triglyceride levels. Results were similar for crossover and before and after studies, and across beverage types.
Conclusions Favourable changes in several cardiovascular biomarkers (higher levels of high density lipoprotein cholesterol and adiponectin and lower levels of fibrinogen) provide indirect pathophysiological support for a protective effect of moderate alcohol use on coronary heart disease.
PMCID: PMC3043110  PMID: 21343206
6.  Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis 
Objectives: To examine whether the increased risk of cardiovascular events with rofecoxib represents a class effect of cyclooxygenase-2 (COX-2) specific inhibitors.
Design: Systematic review and meta-analysis of randomized double-blind clinical trials of celecoxib of at least 6 weeks' duration and presented data on serious cardiovascular thromboembolic events. Data sources included six bibliographic databases, the relevant files of the United States Food and Drug Administration, and pharmaceutical company websites.
Main outcome measures: Pooled fixed effects estimates of the odds ratios for risk of cardiovascular events with celecoxib compared with comparator treatment were calculated using the inverse variance weight method. The main outcome measure was myocardial infarction.
Results: Four placebo-controlled trials with 4422 patients were included in the primary meta-analysis comparing celecoxib with placebo. The odds ratio of myocardial infarction with celecoxib compared to placebo was 2.26 (95%confidence interval 1.0 to 5.1). For composite cardiovascular events [odd ratio 1.38 (95% CI 0.91 to 2.10)], cardiovascular deaths [OR 1.06 (95% CI 0.38 to 2.95)] and stroke [OR 1.0(95% CI 0.51 to 1.84)] there was no significant increase in risk with celecoxib. The secondary meta-analysis which included a total of six studies (with placebo, diclofenac, ibuprofen, and paracetamol as comparators) of 12 780 patients, showed similar findings with a significant increased risk with celecoxib for myocardial infarction [OR 1.88 (95% CI 1.15 to 3.08)] but not other outcome measures.
Conclusion: The available data indicate an increased risk of myocardial infarction with celecoxib therapy, consistent with a class effect for COX-2 specific inhibitors.
PMCID: PMC1383759  PMID: 16508052
7.  Severe hypertriglyceridemia-induced pancreatitis during pregnancy. 
Chylomicronemia syndrome is a rare disorder characterized by the presence of chylomicrons in the fasting state. An acute and potentially life-threatening complication of chyiomicronemia syndrome is severe acute pancreatitis. We report a case of a 24-year-old primigravida with severe hypertriglyceridemia-induced pancreatitis. We reviewed the clinical course and treatment of hypertriglyceridemia-induced pancreatitis. She was admitted in the 37th week of gestation with severe abdominal pain, which was radiating to the back, and having uterine contractions. Cesarean delivery was performed under spinal anesthesia, and a healthy male infant was born. Intraoperative findings included milky peritoneal fluid collection. Elevated pancreatic enzymes with significant hypertriglyceridemia (10,092 mg/dL) suggesting acute pancreatitis were also found on chemical analysis. The diagnosis of acute pancreatitis was confirmed by computed tomography scan. Treatment with continuous intravenous insulin--glucose, cessation of oral intake, and nasogastric decompression--dramatically decreased the triglyceride levels to 608 mg/dL within five days. She was discharged as symptom free with strict dietary intervention after 10 days. Intravenous insulin is a low-cost and effective alternative treatment in hypertriglyceridemia-induced pancreatitis during pregnancy. To our knowledge, such a high triglyceride level has not previously been reported in pregnancy.
PMCID: PMC2569241  PMID: 16623082
8.  Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis 
Objective To conduct a comprehensive systematic review and meta-analysis of studies assessing the effect of alcohol consumption on multiple cardiovascular outcomes.
Design Systematic review and meta-analysis.
Data sources A search of Medline (1950 through September 2009) and Embase (1980 through September 2009) supplemented by manual searches of bibliographies and conference proceedings.
Inclusion criteria Prospective cohort studies on the association between alcohol consumption and overall mortality from cardiovascular disease, incidence of and mortality from coronary heart disease, and incidence of and mortality from stroke.
Studies reviewed Of 4235 studies reviewed for eligibility, quality, and data extraction, 84 were included in the final analysis.
Results The pooled adjusted relative risks for alcohol drinkers relative to non-drinkers in random effects models for the outcomes of interest were 0.75 (95% confidence interval 0.70 to 0.80) for cardiovascular disease mortality (21 studies), 0.71 (0.66 to 0.77) for incident coronary heart disease (29 studies), 0.75 (0.68 to 0.81) for coronary heart disease mortality (31 studies), 0.98 (0.91 to 1.06) for incident stroke (17 studies), and 1.06 (0.91 to 1.23) for stroke mortality (10 studies). Dose-response analysis revealed that the lowest risk of coronary heart disease mortality occurred with 1–2 drinks a day, but for stroke mortality it occurred with ≤1 drink per day. Secondary analysis of mortality from all causes showed lower risk for drinkers compared with non-drinkers (relative risk 0.87 (0.83 to 0.92)).
Conclusions Light to moderate alcohol consumption is associated with a reduced risk of multiple cardiovascular outcomes.
PMCID: PMC3043109  PMID: 21343207
9.  Risk of Cardiovascular Disease from Antiretroviral Therapy for HIV: A Systematic Review 
PLoS ONE  2013;8(3):e59551.
Recent studies suggest certain antiretroviral therapy (ART) drugs are associated with increases in cardiovascular disease.
We performed a systematic review and meta-analysis to summarize the available evidence, with the goal of elucidating whether specific ART drugs are associated with an increased risk of myocardial infarction (MI).
Data Sources
We searched Medline, Web of Science, the Cochrane Library, and abstract archives from the Conference on Retroviruses and Opportunistic Infections and International AIDS Society up to June 2011 to identify published articles and abstracts.
Study Selection
Eligible studies were comparative and included MI, strokes, or other cardiovascular events as outcomes.
Data Extraction
Eligibility screening, data extraction, and quality assessment were performed independently by two investigators.
Data Synthesis
Random effects methods and Fisher’s combined probability test were used to summarize evidence.
Twenty-seven studies met inclusion criteria, with 8 contributing to a formal meta-analysis. Findings based on two observational studies indicated an increase in risk of MI for patients recently exposed (usually defined as within last 6 months) to abacavir (RR 1.92, 95% CI 1.51–2.42) and protease inhibitors (PI) (RR 2.13, 95% CI 1.06–4.28). Our analysis also suggested an increased risk associated with each additional year of exposure to indinavir (RR 1.11, 95% CI 1.05–1.17) and lopinavir (RR 1.22, 95% CI 1.01–1.47). Our findings of increased cardiovascular risk from abacavir and PIs were in contrast to four published meta-analyses based on secondary analyses of randomized controlled trials, which found no increased risk from cardiovascular disease.
Although observational studies implicated specific drugs, the evidence is mixed. Further, meta-analyses of randomized trials did not find increased risk from abacavir and PIs. Our findings that implicate specific ARTs in the observational setting provide sufficient evidence to warrant further investigation of this relationship in studies designed for that purpose.
PMCID: PMC3608726  PMID: 23555704
10.  A serum metabolomic investigation on lipoprotein lipase-deficient mice with hyperlipidemic pancreatitis using gas chromatography/mass spectrometry 
Biomedical Reports  2013;1(3):469-473.
Hypertriglyceridemia (HTG) is often associated with acute pancreatitis. The relationship between these diseases and the role that hypertriglyceridemia plays in acute pancreatitis pathogenesis remains to be elucidated. In the present study, in order to investigate the mechanisms of hyper-lipidemic acute pancreatitis (HLP), we established an animal model using lipoprotein lipase (LPL)-deficient heterozygous mice injected with caerulein. Susceptibility to pancreatitis in LPL-deficient heterozygous mice was compared with that of wild-type mice after intraperitoneal (i.p.) injections of caerulein by determining amylase release and pancreatic pathological scores. Furthermore, serum metabolome was detected through chemical derivatization followed by gas chromatography/mass spectrometry (GC/MS). GC/MS data were analyzed by orthogonal-projection to latent structures-discriminant analysis (OPLS-DA). Caerulein induced increased levels of serum amylase and more severe pancreatic inflammation in LPL-deficient mice compared to wild-type mice. HLP was discriminated more accurately from healthy controls by the metabolites, including valine, leucine and citrate. The metabolites included valine, leucine, citrate, malic acid, proline, tetradecanoic acid (14:0), glutamine and oleic acid (18:1). Changes in energy, fat and amino acid metabolism were also evident. In conclusion, LPL-deficient heterozygous mice with hypertriglyceridemia (HTG) exhibited enhanced susceptibility to acute pancreatitis. GC/MS data revealed differences between healthy and HLP mice. Therefore, this technique is novel and a useful tool for the study of the HLP pathogenetic mechanism.
PMCID: PMC3916981  PMID: 24648970
hyperlipidemic acute pancreatitis; metabolism; blood; lipoprotein lipase
11.  Systematic review of long term effects of advice to reduce dietary salt in adults 
BMJ : British Medical Journal  2002;325(7365):628.
To assess the long term effects of advice to restrict dietary sodium in adults with and without hypertension.
Systematic review and meta-analysis of randomised controlled trials.
Data sources
Cochrane library, Medline, Embase, and bibliographies.
Study selection
Unconfounded randomised trials that aimed to reduce sodium intake in healthy adults over at least 6 months. Inclusion decisions, validity and data extraction were duplicated. Random effects meta-analysis, subgrouping, sensitivity analysis, and meta-regression were performed.
Mortality, cardiovascular events, blood pressure, urinary sodium excretion, quality of life, and use of antihypertensive drugs.
Three trials in normotensive people (n=2326), five trials in those with untreated hypertension (n=387), and three trials in people being treated for hypertension (n=801) were included, with follow up from six months to seven years. The large high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported. There were 17 deaths, equally distributed between intervention and control groups. Systolic and diastolic blood pressures were reduced (systolic by 1.1 mm Hg, 95% confidence interval 1.8 to 0.4 mm Hg; diastolic by 0.6 mm Hg, 1.5 to −0.3 mm Hg) at 13 to 60 months, as was urinary 24 hour sodium excretion (by 35.5 mmol/24 hours, 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related.
Intensive interventions, unsuited to primary care or population prevention programmes, provide only small reductions in blood pressure and sodium excretion, and effects on deaths and cardiovascular events are unclear. Advice to reduce sodium intake may help people on antihypertensive drugs to stop their medication while maintaining good blood pressure control.
What is already known on this topicRestricting sodium intake in people with hypertension reduces blood pressureLong term effects (on blood pressure, mortality, and morbidity) of reduced salt intake in people with and without hypertension are unclearWhat this study addsFew deaths and cardiovascular events have been reported in salt reduction trialsMeta-analysis shows that blood pressure was reduced (systolic by 1.1 mm Hg, diastolic by 0.6 mm Hg) at 13 to 60 months, with a reduction in sodium excretion of almost a quarter (35.5 mmol/24 hours)The interventions used were highly intensive and unsuited to primary care or population prevention programmesLower salt intake may help people on antihypertensive drugs to stop their medication while maintaining good control of blood pressure, but there are doubts about effects of sodium reduction on overall health
PMCID: PMC126303  PMID: 12242173
12.  Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a systematic review and meta-analysis 
Aspirin has been recommended for the prevention of major adverse cardiovascular events (MACE, composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in diabetic patients without previous cardiovascular disease. However, recent meta-analyses have prompted re-evaluation of this practice. The study objective was to evaluate the relative and absolute benefits and harms of aspirin for the prevention of incident MACE in patients with diabetes.
We performed a systematic review and meta-analysis on seven studies (N = 11,618) reporting on the use of aspirin for the primary prevention of MACE in patients with diabetes. Two reviewers conducted a systematic search of electronic databases (MEDLINE, EMBASE, the Cochrane Library, and BIOSIS) and hand searched bibliographies and clinical trial registries. Reviewers extracted data in duplicate, evaluated the quality of the trials, and calculated pooled estimates.
A total of 11,618 participants were included in the analysis. The overall risk ratio (RR) for MACE was 0.91 (95% confidence intervals, CI, 0.82-1.00) with little heterogeneity among trials (I2 0.0%). Secondary outcomes of interest included myocardial infarction (RR, 0.85; 95% CI, 0.66-1.10), stroke (RR, 0.84; 95% CI, 0.64-1.11), cardiovascular death (RR, 0.95; 95% CI, 0.71-1.27), and all-cause mortality (RR, 0.95; 95% CI, 0.85-1.06). There were higher rates of hemorrhagic and gastrointestinal events. In absolute terms, these relative risks indicate that for every 10,000 diabetic patients treated with aspirin, 109 MACE may be prevented at the expense of 19 major bleeding events (with the caveat that the relative risk for the latter is not statistically significant).
The studies reviewed suggest that aspirin reduces the risk of MACE in patients with diabetes without cardiovascular disease, while also causing a trend toward higher rates of bleeding and gastrointestinal complications. These findings and our absolute benefit and risk calculations suggest that those with diabetes but without cardiovascular disease lie somewhere between primary and secondary prevention patients on the spectrum of benefit and risk. This underscores the importance of considering individual risk in clinical decision making regarding aspirin in those with diabetes.
PMCID: PMC3098148  PMID: 21453547
13.  Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials 
BMC Medicine  2013;11:108.
Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease.
A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.
Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60).
The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.
PMCID: PMC3648456  PMID: 23597181
Testosterone; Cardiovascular; Men; Trial
14.  Chronic Idiopathic Axonal Polyneuropathy Is Associated With the Metabolic Syndrome 
Diabetes Care  2013;36(4):817-822.
This study aims to investigate the association between chronic idiopathic axonal polyneuropathy (CIAP) and the metabolic syndrome or its individual components.
A total of 249 patients with CIAP and 709 controls underwent fasting laboratory studies, and blood pressure and waist circumference were measured. The metabolic syndrome was diagnosed if three or more of the following Adult Treatment Panel III criteria were present: impaired fasting glucose, hypertension, abdominal obesity, reduced HDL cholesterol, and hypertriglyceridemia. Subgroup analysis was performed for patients with a painful predominantly sensory CIAP, because this phenotype is most similar to diabetic polyneuropathy. Statistical analysis was performed with adjustment for age and gender.
Fifty-five percent of all patients fulfilled the metabolic syndrome criteria compared with 34% of controls (odds ratio 2.2 [95% CI 1.7–3.0]). Multivariate analysis shows hypertension (2.9 [1.7–4.9]) and abdominal obesity (3.3 [2.4–4.6]) to be significantly more prevalent in patients than in controls. Of the patients classified as having a painful predominantly sensory CIAP, 62% fulfilled the metabolic syndrome criteria (3.1 [2.0–4.8]). In this subgroup, hypertension and abdominal obesity also were significantly more prevalent compared with controls.
Abdominal obesity and hypertension seem to be the most consistent contributing components of the metabolic syndrome in patients with CIAP. Evaluation and appropriate treatment of these risk factors in patients with CIAP would be advocated.
PMCID: PMC3609524  PMID: 23204246
15.  Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis 
Objective To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel.
Design Systematic review and meta-analysis with a structured search algorithm and prespecified eligibility criteria for retrieval of relevant studies; dominant genetic model assumptions and quantitative methods for calculating summary effect estimates from study level odds ratios; systematic assessment of bias within and between studies; and grading of the cumulative evidence by consensus criteria.
Data sources Medline, Embase, the Cochrane Library, online databases, contents pages and bibliographies of general medical, cardiovascular, pharmacological, and genetic journals.
Eligibility criteria for selecting studies Original full length reports assessing the cumulative incidence of major adverse cardiovascular events or stent thrombosis over a follow-up period of at least a month in association with carrier status for the loss of function or gain of function CYP2C19 allele in adult patients with coronary artery disease and a clinical presentation of acute coronary syndrome or stable angina pectoris who were taking clopidogrel.
Results 15 studies met the inclusion criteria. The random effects summary odds ratio for stent thrombosis in carriers of at least one CYP2C19 loss of function allele versus non-carriers combining nine studies was 1.77 (95% confidence interval 1.31 to 2.40; P<0.001). This nominally significant odds ratio was subject to considerable bias across the studies (small study effect bias and replication diversity). The adjustment for these quality modifiers tended to abolish the association. The corresponding random effects summary odds ratio of major adverse cardiovascular events for 12 studies combined was 1.11 (0.89 to 1.39; P=0.36). The random effects summary odds ratio of stent thrombosis in carriers versus non-carriers of at least one CYP2C19*17 gain of function allele for three studies combined was 0.99 (0.60 to 1.62; P=0.96), and the corresponding odds ratio of major adverse cardiovascular events in five studies was 0.93 (0.75 to 1.14; P=0.48). The overall quality of epidemiological evidence was graded as low, which excludes reliable clinical assessments.
Conclusions Accumulated information from genetic association studies does not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel. The current evidence does not support the use of individualised antiplatelet regimens guided by CYP2C19 genotype.
PMCID: PMC3191560  PMID: 21816733
16.  Increased amino acids levels and the risk of developing of hypertriglyceridemia in a 7-year follow-up 
Recently, five branched-chain and aromatic amino acids were shown to be associated with the risk of developing type 2 diabetes (T2D).
We set out to examine whether amino acids are also associated with the development of hypertriglyceridemia.
Materials and methods
We determined the serum amino acids concentrations of 1,125 individuals of the KORA S4 baseline study, for which follow-up data were available also at the KORA F4 7 years later. After exclusion for hypertriglyceridemia (defined as having a fasting triglyceride level above 1.70 mmol/L) and diabetes at baseline, 755 subjects remained for analyses.
Increased levels of leucine, arginine, valine, proline, phenylalanine, isoleucine and lysine were significantly associated with an increased risk of hypertriglyceridemia. These associations remained significant when restricting to those individuals who did not develop T2D in the 7-year follow-up. The increase per standard deviation of amino acid level was between 26 and 40 %.
Seven amino acids were associated with an increased risk of developing hypertriglyceridemia after 7 years. Further studies are necessary to elucidate the complex role of these amino acids in the pathogenesis of metabolic disorders.
PMCID: PMC3972444  PMID: 24682914
Amino acids; Hypertriglyceridemia
17.  Smoking in Dialysis Patients: A Systematic Review and Meta-analysis of Mortality and Cardiovascular Morbidity 
Cigarette smoking is associated with increased cardiovascular morbidity and mortality in the general population, but the effect of smoking on these outcomes in the dialysis population is less well studied.
Study Design
Systematic review and meta-analysis of cohort studies.
Setting & Population
Adults treated with long-term hemodialysis or peritoneal dialysis.
Selection Criteria for Included Studies
Cohort studies of unselected dialysis patients reporting the association between smoking status and cardiovascular morbidity and/or mortality.
Smoking status (determined by patient report).
1) All-cause or cardiovascular mortality; 2) Incident cardiovascular events
We identified 34 studies which fulfilled all inclusion criteria. Of these, 26 studies provide data on smoking and mortality and 10 (n = 6538) were included in a meta-analysis. The pooled hazard ratio for all-cause mortality in smokers compared to non-smokers was 1.65 (95% CI , 1.26–2.14; p<0.001) Eleven studies provided data on smoking and incident cardiovascular events, 5 (pooled n = 845) were included in a meta-analysis. The pooled hazard ratio for composite cardiovascular events in smokers compared to non-smokers was 1.01 (95% CI, 0.98–1.05, p 0.4)‥
Data for these meta-analyses were heterogeneous. Few individual studies assessed smoking as the primary variable of interest.
Active smoking is associated with a significant increase in all-cause mortality in dialysis patients, although there was not a corresponding increased risk of cardiovascular events.
PMCID: PMC3247014  PMID: 21664017
18.  Racial/Ethnic Differences in the Association of Triglycerides with Other Metabolic Syndrome Components: The Multi-Ethnic Study of Atherosclerosis 
The aim of this study was to examine whether there are ethnic differences in the association of triglycerides (TG) with waist circumference (WC), blood pressure, high-density lipoprotein cholesterol (HDL-C), fasting glucose, and insulin resistance and to examine the disparities in the prevalence of the metabolic syndrome components between African Americans and non-Hispanic whites who do not have hypertriglyceridemia.
This study used the baseline data from the Multi-Ethnic Study of Atherosclerosis (MESA) study. The analysis included non-Hispanic whites (N = 2,427) and African Americans (N = 1,519) aged 45–84 years free of clinically evident cardiovascular disease and diabetes at baseline. The revised National Cholesterol Education Program (NCEP) criteria were used to define the metabolic syndrome and its components.
African Americans had lower prevalence of elevated TG as compared with non-Hispanic whites. The association of TG with other components of the metabolic syndrome appeared to be similar between African Americans and non-Hispanic whites except for one. There was significant association of TG with WC among white women but not among African American women after adjusting for demographic and other variables (P for interaction of TG with ethnicity <0.001). In participants with TG < 150 mg/dL, African American women had higher prevalence rates than white women of abdominal obesity, elevated blood pressure, low HDL-C, elevated fasting glucose and homeostasis model assessment of insulin resistance (HOMA-IR). In men, the prevalence rates of high blood pressure, elevated fasting glucose, and HOMA-IR were significantly higher in African Americans than in whites.
The study findings suggest that further evaluation is warranted regarding the cutoffs for elevated TG and its clustering effect with other cardiometabolic risk factors on predicting risk for diabetes and cardiovascular disease (CVD) in African Americans.
PMCID: PMC3125569  PMID: 20958206
19.  ABCB1 C3435T Polymorphism and Response to Clopidogrel Treatment in Coronary Artery Disease (CAD) Patients: A Meta-Analysis 
PLoS ONE  2012;7(10):e46366.
A number of investigators have evaluated the association between the ABCB1 polymorphism and clopidogrel responding, but the results have been inconclusive. To examine the risk of high platelet activity and poor clinical outcomes associated with the ABCB1 C3435T polymorphism in CAD patients on clopidogrel, all available studies were included in the present meta-analysis.
We performed a systematic search of PubMed, Scopus and the Cochrane library database for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated by the meta-analysis.
It was demonstrated that the ABCB1 C3435T variation was associated with the risk of early major adverse cardiovascular events (MACE) (T vs. C OR, 1.34; 95% CI, 1.10 to 1.62; P = 0.003; TT vs. CC: OR, 1.77; 95% CI, 1.19 to 2.63; P = 0.005; CT + TT vs.CC: OR, 1.48; 95% CI, 1.06 to 2.06; P = 0.02) and the polymorphism was also associated with the risk of the long-term MACE in patients on clopidogrel LD 300 mg (T vs. C: OR, 1.28; 95% CI, 1.10 to 1.48; P = 0.001; TT vs. CC: OR, 1.59; 95% CI, 1.19 to 2.13; P = 0.002; CT + TT vs.CC: OR, 1.39; 95% CI, 1.08 to 1.79; P = 0.01). The comparison of TT vs. CC was associated with a reduction in the outcome of bleeding (TT vs. CC: OR, 0.51; 95% CI, 0.40 to 0.66; P<0.00001). However, the association between ABCB1 C3435T polymorphism and platelet activity and other risk of poor clinical outcomes was not significant.
The evidence from our meta-analysis indicated that the ABCB1 C3435T polymorphism might be a risk factor for the MACE in patients on clopidogrel LD 300 mg, and that TT homozygotes decreased the outcome of bleeding compared with CC homozygotes.
PMCID: PMC3467260  PMID: 23056288
20.  Cardiovascular risk factor investigation: a pediatric issue 
To correlate cardiovascular risk factors (e.g., hypertension, obesity, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, sedentariness) in childhood and adolescence with the occurrence of cardiovascular disease.
A systematic review of books and selected articles from PubMed, SciELO and Cochrane from 1992 to 2012.
Summary of findings
Risk factors for atherosclerosis are present in childhood, although cardiovascular disease arises during adulthood. This article presents the main studies that describe the importance of investigating the risk factors for cardiovascular diseases in childhood and their associations. Significant rates of hypertension, obesity, dyslipidemia, and sedentariness occur in children and adolescents. Blood pressure needs to be measured in childhood. An increase in arterial blood pressure in young people predicts hypertension in adulthood. The death rate from cardiovascular disease is lowest in children with lower cholesterol levels and in individuals who exercise regularly. In addition, there is a high prevalence of sedentariness in children and adolescents.
Studies involving the analysis of cardiovascular risk factors should always report the prevalence of these factors and their correlations during childhood because these factors are indispensable for identifying an at-risk population. The identification of risk factors in asymptomatic children could contribute to a decrease in cardiovascular disease, preventing such diseases as hypertension, obesity, and dyslipidemia from becoming the epidemics of this century.
PMCID: PMC3598497  PMID: 23515212
Cardiovascular risk; Children; Hypertension; Obesity; Dyslipidemia; Sedentariness; Metabolic syndrome
21.  Association between Hepatitis B Surface Antigen Seropositivity and Metabolic Syndrome 
Infection with hepatitis B virus (HBV) may be a risk factor for cardiovascular disease. We investigated the relationship between HBV infection and metabolic syndrome.
We performed a cross-sectional study of 9,474 Korean men and women who were at least 20 years old and who underwent a routine health check-up at Ulsan University Hospital in Ulsan, South Korea between March 2008 and February 2009. The associations of hepatitis B surface antigen (HBsAg) seropositivity with the presence of metabolic syndrome and its components were investigated by logistic regression analysis. Data were analyzed separately for males and females.
HBsAg seropositivity was significantly negatively associated with hypertriglyceridemia and metabolic syndrome in men (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.29 to 0.50; P < 0.001 and OR, 0.75; 95% CI, 0.57 to 0.98, P = 0.033). In women, HBsAg seropositivity was also significantly negatively associated with hypertriglyceridemia, but not with metabolic syndrome (OR, 0.40; 95% CI, 0.17 to 0.91; P = 0.029 and OR, 0.80; 95% CI, 0.38 to 1.66, P = 0.545).
HBV infection was significantly negatively associated with hypertriglyceridemia and metabolic syndrome in men and hypertriglyceridemia in women.
PMCID: PMC3978189  PMID: 24724003
Hepatitis B; Metabolic Syndrome; Triglycerides
22.  Treatment of Severe Hypertriglyceridemia with Continuous Insulin Infusion 
Case Reports in Critical Care  2011;2011:293917.
Severe hypertriglyceridemia (SH) represents a therapeutic emergency because of the possibility of developing cardiovascular events and hyperlipemic acute pancreatitis (PA). Most patients with SH suffer primary or genetic abnormality in lipid metabolism in combination with a precipitating factor such as uncontrolled diabetes mellitus, alcoholism, and drug intake. The standard treatment of hypertriglyceridemia (HTG) with omega 3 fatty acids and fibrates, along with dietary changes, has no effect on an emergency situation. There are no clinical guidelines to SH, but therapy with insulin, heparin, a combination of both, plasmapheresis, or octreotide have been tested succesfully. We report the case of a 10-year-old girl with clinical acute pancreatitis and diabetic ketoacidosis debut, along with incidental finding of an SH, who had a good outcome after treatment with insulin intravenous infusion.
PMCID: PMC4010023  PMID: 24804116
23.  Near-normal glycemia for critically ill patients receiving nutrition support: Fact or folly 
Purpose of review
In critically ill patients, nutrition support may be a life-saving intervention, but is not without risk. Adverse metabolic changes including hypertriglyceridemia and hyperglycemia are common. Hyperglycemia is associated with adverse outcomes, in particular infection. Four major studies have addressed whether near normal-glycemia (80–110 mg/dl) in this clinical setting improves outcomes compared to blood sugars of ~150mg/dl. The purpose of this review is to determine if tight glycemic control is superior to moderate glycemic control (150mg/dl) in critically ill patients receiving nutrition support.
Initial data conducted in post-surgical patients suggested that near-normal glycemia dramatically improved outcomes compared to moderate glycemic control. However, three recent studies were unable to duplicate these results and suggest that the benefits of tight-glycemic control may be limited to post-surgical patients and that the controlling hyperlipidemia and overfeeding may improve outcomes more than tight control of blood sugars. Furthermore, near-normal glycemic control caused frequent hypoglycemia and in some cases worsened outcomes.
Glycemic control to ~150mg/dl is not inferior to near-normal glycemia in critically ill patients requiring nutrition support, and is clearly safer. Lipid changes caused by insulin infusion may improve outcomes more than glycemic control itself and prevention of hypertriglyceridemia should be a major focus of clinical care.
PMCID: PMC3716007  PMID: 20075724
Glycemic control; nutrition support; diabetes
24.  Association between complementary factor H Y402H polymorphisms and age-related macular degeneration in Chinese: Systematic review and meta-analysis 
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and complement factor H (CFH) polymorphism has been found to associate with the AMD. To investigate whether the Y402H variant in CFH is associated with AMD in Chinese populations, a systematic review and meta-analysis were performed to estimate the magnitude of the gene effect and the possible mode of action.
A meta-analysis was performed using data available from ten case-control studies assessing association between the CFH Y402H polymorphism and AMD in Chinese populations involving 1538 AMD. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) an allele contrast and genotype contrast were estimated using fixed- effects models. The Q-statistic test was used to assess heterogeneity, and Funnel plot was used to evaluate publication bias.
Seven of ten case-control studies were neovascular AMD, and few studies came from west and north of China. There was strong evidence for association between CFH and AMD in Chinese population, with those having risk allele C 2.35 times more likely to have AMD than subjects with T allele. Evidence of publication bias was not observed in our meta-analysis.
This meta-analysis summarizes the strong evidence for an association between CFH and AMD in Chinese and indicates each C allele increasing the odds of AMD by 2.33-fold.But more evidences about the relation between CFH polymorphism and different type of Chinese AMD from various district were needed.
PMCID: PMC3359047  PMID: 22762059
age-related macular degeneration; complement factor H polymorphism; meta-analysis; Chinese population
25.  Effects of Combined Aspirin and Clopidogrel Therapy on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis 
PLoS ONE  2012;7(2):e31642.
Aspirin and clopidogrel monotherapies are effective treatments for preventing vascular disease. However, new evidence has emerged regarding the use of combined aspirin and clopidogrel therapy to prevent cardiovascular events. We therefore performed a comprehensive systematic review and meta-analysis to evaluate the benefits and harms of combined aspirin and clopidogrel therapy on major cardiovascular outcomes.
Methodology/Principal Findings
We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies to fit our analysis. Eligible studies were randomized controlled trials assessing the effect of combined aspirin and clopidogrel therapy compared with aspirin or clopidogrel monotherapy. We identified 7 trials providing data with a total of 48248 patients. These studies reported 5134 major cardiovascular events, 1626 myocardial infarctions, 1927 strokes, and 1147 major bleeding events. Overall, the addition of aspirin to clopidogrel therapy as compared to single drug therapy resulted in a 9% RR reduction (95%CI, 2 to 17) in major cardiovascular events, 14% RR reduction (95%CI, 3 to 24) in myocardial infarction, 16% RR reduction (95%CI, 1 to 28) in stroke, and 62% RR increase (95%CI, 26 to 108) in major bleeding events. We also present the data as ARR to explore net value as the reduction in cardiovascular events. Overall, we observed that combined therapy yielded 1.06% decrease (95%CI, 0.23% to 1.99%) in major cardiovascular events and 1.23% increase (95%CI, 0.52% to 2.14%) in major bleeding events.
Although the addition of aspirin to clopidogrel resulted in small relative reductions in major cardiovascular events, myocardial infarction, and stroke, it also resulted in a relative increase in major bleeding events. In absolute terms the benefits of combined therapy, a 1.06% reduction in major cardiovascular events, does not outweigh the harms, a 1.23% increase in major bleeding events.
PMCID: PMC3278459  PMID: 22348116

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