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1.  Is the ratio of apoB/apoA-1 the best predictor for the severity of coronary artery lesions in Chinese diabetics with stable angina pectoris? An assessment based on Gensini scores 
Background
There is a paucity of data about the best lipid ratio predicting the severity of coronary artery disease (CAD) in patients with diabetes mellitus. We determined the relationship between five conventional lipid ratios and the extent of coronary artery lesions in Chinese Type 2 diabetics with stable angina pectoris (SAP).
Methods
A prospective cohort study within 373 type 2 diabetic patients diagnosed with stable CAD by coronary angiography was performed. All patients were classified into three groups according to the tertiles of Gensini scores (GS, low group < 8 points n = 143; intermediate group 8–28 points, n = 109; high group > 28 points, n = 121). Association between the ratios of apolipoprotein (apo) B and apoA-1, total cholesterol and high density lipoprotein cholesterol (TC/HDL-C), triglycerides and HDL-C (TG/HDL-C), low density lipoprotein cholesterol and HDL-C (LDL-C/HDL-C), Non-HDL-C/HDL-C and GS were evaluated using the receivers operating characteristic (ROC) curves and multivariate logistic regression models.
Results
The ratio of apoB/apoA-1, TC/HDL-C, LDL-C/HDL-C, and Non-HDL-C/HDL-C were correlated with Gensini scores. Area under the ROC curves for predicting high Gensini scores in the ratios of apoB/apoA-1, TC/HDL-C, LDL-C/HDL-C and Non-HDL-C/HDL-C were 0.62, 0.60, 0.59 and 0.60, respectively (P < 0.005 for all). According to multivariate logistic regression analysis after adjusted with demographic characteristic and other lipid parameters, the ratio of apoB/apoA-1 is qualified as an independent discriminator for the severity of CAD. However, after further adjusting different baseline variables, such as left ventricular ejective fraction, hemoglobin A1c, leukocytes count and serum creatinine, none of the above lipid ratios remained.
Conclusions
Compared with other lipid parameters, the ratio of apoB/apoA-1 appears to be more significantly correlated with the extent of coronary artery lesions in Chinese diabetics, but it was not an independent predictor in these settings.
doi:10.11909/j.issn.1671-5411.2015.04.012
PMCID: PMC4554779  PMID: 26346771
Coronary artery disease; Diabetic mellitus; Gensini scores; Lipid disorder
2.  Hypertriglyceridemic waist: A useful screening phenotype in preventive cardiology? 
The Canadian Journal of Cardiology  2007;23(Suppl B):23B-31B.
The worldwide increase in the prevalence and incidence of type 2 diabetes represents a tremendous challenge for the Canadian health care system, especially if we consider that this phenomenon may largely be explained by the epidemic of obesity. However, despite the well-recognized increased morbidity and mortality associated with an elevated body weight, there is now more and more evidence highlighting the importance of intra-abdominal adipose tissue (visceral adipose tissue) as the fat depot conveying the greatest risk of metabolic complications. In this regard, body fat distribution, especially visceral adipose tissue accumulation, has been found to be a key correlate of a cluster of diabetogenic, atherogenic, prothrombotic and inflammatory metabolic abnormalities now often referred to as the metabolic syndrome. This dysmetabolic profile is predictive of a substantially increased risk of coronary artery disease (CAD) even in the absence of hyperglycemia, elevated low-density lipoprotein cholesterol or hypertension. For instance, some features of the metabolic syndrome (hyperinsulinemia, elevated apolipoprotein B and small low-density lipoprotein particles – the so-called atherogenic metabolic triad) have been associated with a more than 20-fold increase in the risk of ischemic heart disease in middle-aged men enrolled in the Quebec Cardiovascular Study. This cluster of metabolic complications has also been found to be predictive of a substantially increased risk of CAD beyond the presence of traditional risk factors. These results emphasize the importance of taking into account in daily clinical practice the presence of metabolic complications associated with abdominal obesity together with traditional risk factors to properly evaluate the cardiovascular risk profile of patients. From a risk assessment standpoint, on the basis of additional work conducted by several groups, there is now evidence that the simultaneous presence of an elevated waist circumference and fasting triglyceride levels (a condition that has been described as hypertriglyceridemic waist) may represent a relevant first-step approach to identify a subgroup of individuals at higher risk of being carriers of the features of the metabolic syndrome. Moreover, a moderate weight loss in initially abdominally obese patients is associated with a selective mobilization of visceral adipose tissue, leading to improvements in the metabolic risk profile predictive of a reduced risk of CAD and type 2 diabetes. In conclusion, hypertriglyceridemic waist as a marker of visceral obesity and related metabolic abnormalities is a useful and practical clinical phenotype to screen persons at risk for CAD and type 2 diabetes.
PMCID: PMC2794461  PMID: 17932584
Abdominal obesity; Atherogenic dyslipidemia; Coronary artery disease; Insulin resistance; Metabolic syndrome; Triglycerides
3.  Apolipoprotein gene polymorphisms and plasma levels in healthy Tunisians and patients with coronary artery disease 
Aim
To analyze apolipoprotein gene polymorphisms in the Tunisian population and to check the relation of these polymorphisms and homocysteine, lipid and apolipoprotein levels to the coronary artery disease (CAD).
Methods
In healthy blood donors and in patients with CAD complicated by myocardial infarction (MI) four apolipoprotein gene polymorphisms [APO (a) PNR, APO E, APO CI and APO CII] were determined and plasma levels of total homocysteine, total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HLD-C) and apolipoproteins (apo A-I, Apo B, Apo E) were measured.
Results
Analysis of the four apolipoprotein gene polymorphisms shows a relative genetic homogeneity between Tunisian population and those on the other side of Mediterranean basin. Compared to controls, CAD patients have significantly higher main concentrations of TC, TG, LDL-C, apo B and homocysteine, and significantly lower ones of HDL-C, apo A-I and apo E. The four apolipoprotein gene polymorphisms have not showed any significant differences between patients and controls. However, the APO E4 allele appears to be associated to the severity of CAD and to high levels of atherogenic parameters and low level of apo E, which has very likely an anti-atherogenic role.
Conclusion
Although APO (a) PNR, APO CI and APO CII genes are analyzed in only few populations, they show a frequency distribution, which is not at variance with that of APO E gene and other widely studied genetic markers. In the Tunisian population the APO E 4 appears to be only indirectly involved in the severity of CAD. In the routine practice, in addition of classic parameters, it will be useful to measure the concentration of apo E and that of Homocysteine and if possible to determine the APO E gene polymorphism.
doi:10.1186/1476-511X-7-46
PMCID: PMC2615423  PMID: 19014618
4.  Prevalence and pattern of lipid disorders in Saudi patients with angiographically documented coronary artery disease 
Objective:
The aim of the study was to assess the prevalence and patterns of dyslipidemia in Saudi patients with angiographically documented coronary artery disease (CAD).
Materials and Methods:
This is a cross-sectional, hospital-based study, which was conducted on all Saudi patients who underwent coronary angiography under the author's personal care and were found to have > 50% coronary stenosis. Fasting lipid profile was measured in all patients during the admission for the coronary angiography.
Results:
Two hundred and ninety-five patients were included in the study. The mean age (±Standard deviation) was 55.1 ± 11, ranging from 17 to 86 years. The majority of patients were males: 229 (77.6%). Mean total cholesterol was 175.6 ± 47.6 mg/dl, mean low-density lipoprotein cholesterol (LDL-C) was 111.3 ± 40.3 mg/dl, mean high density lipoprotein cholesterol (HDL-C) was 38.27 ± 9.5 mg/dl and mean triglyceride level was 141.8 ± 74.8 mg/dl. 21 (7.1%) patients had normal coronary arteries, 107 (36.3%) had one vessel disease, 78 (26.4%) had two vessel disease and 89 (30.2%) had three vessel disease. There was a significant correlation between the extent of CAD and age (P = 0.003), sex (P = 0.0002), total cholesterol (P = 0.02) and low HDL-C (P < 0.001. 21 (7.1%) patients were asymptomatic, 110 (37.3%) had stable angina, 127 (43.1%) had none ST elevation acute coronary syndrome, 20 (6.8%) had ST elevation myocardial infarction and 17 (5.7%) had heart failure. There was also a significant correlation between age (P = 0.03), sex (P < 0.001), LDL-C (P = 0.005) and low HDL-C (P < 0.001) and the severity of CAD.
Conclusion:
Dyslipidemia is a very prevalent risk factor in Saudi patients with CAD. Low HDL-C was the most frequent lipid abnormality, which significantly impacts on the extent of the CAD.
doi:10.4103/2230-8229.142970
PMCID: PMC4214005  PMID: 25374467
Acute coronary syndrome; coronary artery disease; dyslipidemia; non ST elevation myocardial infarction; ST elevation myocardial infarction
5.  Identification of the HDL-ApoCIII to VLDL-ApoCIII ratio as a predictor of coronary artery disease in the general population: The Chin-Shan Community Cardiovascular Cohort (CCCC) study in Taiwan 
Background
Apolipoprotein (Apo) levels are considered more reliable than plasma lipoprotein levels for predicting coronary artery disease (CAD). However, a unanimous Apo marker for CAD has not been identified. In the Chin-Shan Community Cardiovascular Cohort (CCCC), we sought to identify a common Apo marker for predicting CAD in the general population.
Methods
We examined the cross-sectional association between Apo markers and CAD in the CCCC from 1990 to 2001. Among 3,602 subjects, 90 had angiographically proven CAD (>50% stenosis in ≥1 vessel), and 200 did not have CAD. These subjects were divided into the following 4 groups for analysis: normolipidemic (total cholesterol [TC] <200 mg/dL, triglyceride [TG] <150 mg/dL), hypertriglyceridemic (TC <200 mg/dL, TG ≥150 mg/dL), hypercholesterolemic (TC ≥200 mg/dL, TG <150 mg/dL), and hyperlipidemic (TC ≥200 mg/dL, TG ≥150 mg/dL).
Results
Compatible with findings in other populations, our results showed that CAD patients in the CCCC had higher ApoB and lower high-density lipoprotein (HDL) cholesterol and ApoAI concentrations than non-CAD subjects, but the differences were not significant in all groups. Plasma concentrations of ApoE and lipoprotein (a) were not consistently correlated with CAD. In contrast, the ratio of HDL-ApoCIII to very-low-density lipoprotein (VLDL)-ApoCIII was the only universal determinant for CAD in the normolipidemic group (P=0.0018), the hypertriglyceridemic group (P=0.0001), the hypercholesterolemic group (P=0.0001), and the hyperlipidemic group (P=0.0001). Overall, a high HDL-ApoCIII/VLDL-ApoCIII ratio was observed in all CAD patients, including those with a normal lipid profile. In multivariate analyses, the HDL-ApoCIII/VLDL-ApoCIII ratio was the strongest predictor for CAD among all lipid factors investigated (odds ratio, 2.04; 95% confidence interval, 1.46–2.84; P<0.0001).
Conclusions
A high HDL-ApoCIII to VLDL-ApoCIII ratio is a better marker for predicting CAD than are the conventional lipid markers or ApoAI and ApoB. High HDL-ApoCIII and low VLDL-ApoCIII values in CAD, irrespective of lipid variations, suggest that ApoCIII is markedly transported from VLDL to HDL in this disease. Measurement of plasma ApoCIII may improve CAD prediction in the general population.
doi:10.1186/1476-511X-11-162
PMCID: PMC3543287  PMID: 23173569
Apolipoproteins; Coronary artery disease; Lipoproteins; Cardiovascular risk factors; Chin-Shan Community Cardiovascular Cohort (CCCC) Study; High-density lipoprotein (HDL); Very-low-density lipoprotein (VLDL); Apolipoprotein CIII (ApoCIII)
6.  Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study 
PLoS Genetics  2009;5(12):e1000754.
Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10−27and−30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research.
Author Summary
The WHO predicts that coronary artery disease (CAD) will become the leading cause of death worldwide in 2010. Currently, major research efforts are focused on understanding the genetics of CAD through multi-center, genome-wide association studies of tens of thousands of patients and controls. Such studies can identify common variants of general importance throughout the entire population, which are likely relatively few. The number of rare genetic variants and variants that act in the context of environmental risk factors for CAD is probably much higher. We performed whole-genome expression analyses in several organs to identify functionally associated genes important for CAD development. We found an atherosclerosis module (A-module) consisting of 128 genes, enriched with genetic risk for CAD, involving transendothelial migration of leukocytes (TEML) and LIM domain binding 2 (LDB2) as its high-hierarchy regulator. Our study design represents a novel way of understanding the molecular underpinnings of CAD, focusing on genome-wide expression sensing both environmental and genetic influences. Investigating the relative enrichment of genetic CAD risk in functional groups (modules and networks) is an alternative approach to extract additional relevant information from genome-wide association studies. The A-module and LDB2 are attractive targets for treatments to modulate TEML and atherosclerosis development.
doi:10.1371/journal.pgen.1000754
PMCID: PMC2780352  PMID: 19997623
7.  Association of elevated apoA-I glycation and reduced HDL-associated paraoxonase1, 3 activity, and their interaction with angiographic severity of coronary artery disease in patients with type 2 diabetes mellitus 
Objective
To investigate whether apolipoprotein A (apoA)-I glycation and paraoxonase (PON) activities are associated with the severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM).
Methods
Relative intensity of apoA-I glycation and activities of high-density lipoprotein (HDL)-associated PON1 and PON3 were determined in 205 consecutive T2DM patients with stable angina with (n = 144) or without (n = 61) significant CAD (luminal diameter stenosis ≥ 70 %). The severity of CAD was expressed by number of diseased coronary arteries, extent index, and cumulative coronary stenosis score (CCSS).
Results
The relative intensity of apoA-I glycation was higher but the activities of HDL-associated PON1 and PON3 were lower in diabetic patients with significant CAD than in those without. The relative intensity of apoA-I glycation increased but the activities of HDL-associated PON1 and PON3 decreased stepwise from 1 - to 3 - vessel disease patients (P for trend < 0.001). After adjusting for possible confounding variables, the relative intensity of apoA-I glycation correlated positively, while the activities of HDL-associated PON1 and PON3 negatively, with extent index and CCSS, respectively. At high level of apoA-I glycation (8.70 ~ 12.50 %), low tertile of HDL-associated PON1 (7.03 ~ 38.97U/mL) and PON3 activities (7.11 ~ 22.30U/mL) was associated with a 1.97− and 2.49− fold increase of extent index and 1.73− and 2.68− fold increase of CCSS compared with high tertile of HDL-associated PON1 (57.85 ~ 154.82U/mL) and PON3 activities (39.63 ~ 124.10U/mL), respectively (all P < 0.01).
Conclusions
Elevated apoA-I glycation and decreased activities of HDL-associated PON1 and PON3, and their interaction are associated with the presence and severity of CAD in patients with T2DM.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0221-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-015-0221-4
PMCID: PMC4432963  PMID: 25964115
Diabetes mellitus; ApoA-I glycation; Paraoxonase; Coronary artery disease
8.  Increased serum level of Lp-PLA2 is independently associated with the severity of coronary artery diseases: a cross-sectional study of Chinese population 
Background
Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays complex and adverse roles on atherosclerosis. Current study was to investigate whether increased plasma Lp-PLA2 level is independently associated with the severity of coronary artery diseases (CAD).
Methods
Totally 781 participants were enrolled and performed coronary angiography (CAG) to figure out the number of coronary artery stenosis. According to clinical presentation, electrocardiography, cardiac biomarker, and CAG result, participants were divided into control (excluded CAD), stable angina (SA), unstable angina (UA) and acute myocardial infarction (AMI) groups. Baseline characteristics were recorded. Statistical analyses were performed to evaluate the relationship between Lp-PLA2 level and CAD severity.
Results
Plasma levels of Lp-PLA2 in control, SA, UA and AMI groups were 7.38(3.33-9.26) μg/L, 5.94(2.89-8.55) μg/L, 8.56(5.34-11.95) μg/L and 8.68(5.56-13.27) μg/L respectively (P < 0.001). After adjusted for age, gender, smoking, diabetes mellitus, hypertension, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), apoprotein A (apoA) and statins, Lp-PLA2 level was still independently associated with CAD severity, with odd ratio (OR) of 1.055 (AMI group versus control group, 95% confidence interval (CI) 1.021-1.090, P < 0.05). Additionally, the relationship between Lp-PLA2 level and the number of stenosis coronary artery was also assessed. Lp-PLA2 levels in control, single-vessel, and multiple-vessels stenosis groups were 7.38(3.33-9.26) μg/L, 7.80 (4.05-10.76) μg/L and 8.29(5.18-11.76) μg/L respectively (P for trend < 0.001). After adjusted for age, gender, smoking, diabetes mellitus, hypertension, LDL-C and HDL-C, apoA and statins, Lp-PLA2 level remained independently associated with the number of coronary artery stenosis, with OR of 1.053 (multiple-vessels stenosis group versus control group, 95% CI 1.025-1.069, P < 0.05).
Conclusion
Increased Lp-PLA2 level is independently associated with CAD severity, and Lp-PLA2 level may be used to discriminate those who are at increased risk of cardiovascular events.
doi:10.1186/s12872-015-0001-9
PMCID: PMC4357056  PMID: 25879827
Coronary artery disease; Lipoprotein-associated phospholipase A2; Atherosclerosis
9.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Background
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Conclusion
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000286.
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
doi:10.1371/journal.pmed.1000286
PMCID: PMC2879408  PMID: 20532236
10.  The Value and Distribution of High-Density Lipoprotein Subclass in Patients with Acute Coronary Syndrome 
PLoS ONE  2014;9(1):e85114.
Background
High-density lipoprotein (HDL) enhances cholesterol efflux from the arterial wall and exhibits potent anti-inflammatory and anti-atherosclerosis (AS) properties. Whether raised HDL levels will clinically benefit patients with acute coronary syndrome (ACS) and the value at which these effects will be apparent, however, is debatable. This study examined the HDL subclass distribution profile in patients with ACS.
Methods
Plasma HDL subclasses were measured in 158 patients with established ACS and quantified by two-dimensional gel electrophoresis and immunoblotting. ACS diagnosis was based on symptoms of cardiac ischemia, electrocardiogram (ECG) abnormalities, speciality cardiac enzyme change along with presence of coronary heart disease (CHD) on coronary angiography.
Results
The small-sized preβ1-HDL, HDL3b, and HDL3a levels were significantly higher, and the large-sized HDL2a and HDL2b levels were significantly lower in patients with ACS than in those with stable angina pectoris (SAP) and in normal control subjects. Meanwhile, with an elevation in the low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), body mass index (BMI), and blood pressure (BP), and the reduction in the high density lipoprotein cholesterol (HDL-C) levels, the HDL2b contents significantly decreased and the preβ1-HDL contents significantly increased in patients with ACS. The correlation analysis revealed that the apolipoprotein (apo)A-I levels were positively and significantly with all HDL subclasses contents; plasma total cholesterol (TC) and fasting plasma glucose (FPG) levels were inversely associated with HDL2a, and HDL2b. Moreover, the FPG levels were positively related to HDL3c, HDL3b, and HDL3a in ACS patients.
Conclusion
The HDL subclass distribution profile remodeling was noted in the patients with ACS. Plasma lipoprotein and FPG levels, BP, and BMI play an important role in the HDL subclass metabolism disorder for patients with ACS. The HDL subclass distribution phenotype might be useful as a novel biomarker to assist in the risk stratification of patients with ACS.
doi:10.1371/journal.pone.0085114
PMCID: PMC3900409  PMID: 24465490
11.  Role of the APOB Gene Polymorphism (c.12669G>A, p. Gln4154Lys) in Coronary Artery Disease in the Indian Punjabi Population 
High concentration of apolipoprotein B (apoB) is a risk factor for coronary artery disease (CAD). The association of the APOB gene polymorphism c.12669G>A, p.Gln4154Lys with the risk of CAD varies considerably in different populations. The present study represents the first investigation regarding the role of this APOB gene polymorphism with CAD in the Indian Punjabi population. We have studied the APOB gene polymorphism c.12669G>A, p.Gln4154Lys and its relationship with lipid, apoB, low-density lipoprotein (LDL) heterogeneity and oxidation in subjects suffering from CAD. The study was conducted on 87 patients with CAD; 75 healthy subjects served as controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the DNA polymorphism in the APOB gene. Frequency of R− (mutant) allele was significantly high (p <0.05) in CAD patients when compared to controls. Variations in serum lipid levels in the R+R+ and R+R− APOB genotypes were insignificant (p >0.05). However, serum apoB levels were significantly raised (p <0.05) in CAD patients with the R+R− genotype as compared to those with the R+R+ APOB genotype. Coronary artery disease patients had raised significantly raised (p <0.01) Log triglyceride/high density lipoprotein-cholesterol (HDL-C) ratio, apoB carbonyl content and increased malondialdehyde-low density lipoprotein (MDA-LDL levels, irrespective of APOB genotype as compared to controls. Carriers of the R− allele are at higher risk of CAD, probably because of elevated serum apoB levels in the Indian Punjabi population. Overall, it may be concluded that the R− allele might be associated with increased susceptibility towards CAD development in the Indian Punjabi population, and one of the linking factor is the elevation in serum apoB levels. However, this association needs further evaluation in a larger population. Secondly, the robust mechanism behind the positive association of the R− allele with raised serum apoB levels needs to be explored, which might be helpful in the strengthening the observed results.
doi:10.2478/v10034-011-0045-9
PMCID: PMC3776703  PMID: 24052710
Apolipoprotein B (apoB); Polymorphism; Coronary artery disease (CAD)
12.  The oxidation ratio of LDL: A Predictor for Coronary Artery Disease 
Disease markers  2008;24(6):341-349.
Objective: Oxidized LDL cholesterol (ox-LDL-C) is considered to be a key factor of initiating and accelerating atherosclerosis (AS). The purpose of this study is to elucidate the sensitivity and specificity of ox-LDL and oxidation ratio of LDL in the diagnosis of coronary artery disease (CAD). For the first time, we investigated the ratio of ox-LDL to ALB(ox-LDL/ALB).
Methods and results: Blood ox-LDL, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and albumin (ALB) were measured in patients with acute myocardial infarction (AMI, n = 80), unstable angina pectoris (UAP, n = 80), stable angina pectoris (SAP, n = 80), normal control (n = 60), and dyslipidemia control (n = 60). Ox-LDL was measured by competitive ELISA. The level of ox-LDL and oxidation ratio of LDL(ox-LDL/TC, ox-LDL/HDL-C, ox-LDL/ LDL-C and ox-LDL/ALB) were significantly higher in each diseased group than controls (P < 0.001). In CAD group, ox-LDL and oxidation ratio of LDL in subjects complicated with hypertension (HT) and/or diabetes mellitus (DM) increased further (P < 0.001). Ox-LDL/ALB in the AMI group was 7 times higher than normal control group (0.068 ± 0.017 vs 0.009 ± 0.007, P < 0.001). The area under the curve (AUC) of receiver operating characteristic curve (ROC curve) is a criterium to evaluate the accuracy of diagnosing a disease. The AUC of ROC curve of ox-LDL/TC, ox-LDL/HDL-C, ox-LDL, ox-LDL/ALB and ox-LDL/ LDL-C for diagnosing CAD were 0.975, 0.975, 0.966, 0.966, 0.957 respectively (P < 0.001). When ox-LDL/TC = 0.175, the sensitivity and specificity of diagnosing CAD were 0.917 and 0.925, which were almost equal to each other, indicating that the rates of missed diagnosis and misdiagnosis for CAD were the lowest.
Conclusions: The level of ox-LDL and the ratio of ox-LDL/TC, ox-LDL/LDL-C, ox-LDL/HDL-C and ox-LDL/ALB are better biomarkers than TC, TG, HDL-C and LDL-C for discriminating between patients with coronary artery disease and healthy subjects. And patients who have a high ratio of ox-LDL /TC may have a higher risk for CAD.
doi:10.1155/2008/371314
PMCID: PMC3850607  PMID: 18688083
Coronary artery disease; atherosclerosis; oxidized low density lipoprotein; cholesterol
13.  Comparative account of serum lipids, lipoproteins and apolipoprotein-B in patients of coronary artery disease 
Serum total lipids (cholesterol and triglyceride), lipoproteins (VLDL, LDL and HDL) and Apolipoprotein-B levels of normal healthy individuals (n=25) and coronary artery disease patients (n=25) were estimated. The objective of the present study was to ascertain the role of apo-B in causation and inheritance of coronary artery disease. It was observed that on an average serum total cholesterol and triglyceride more than 200 mg/dl bring the individuals to a risk of coronary artery disease (CAD) irrespective of the age. CAD patients achieved this value at an early age (35–45 years). Similarly VLDL and LDL levels were found to be significantly raised in CAD patients when compared to that of age matched normal individuals, with patients achieving risk values at an early age. HDL levels were found to be significantly lower in CAD patients as compared to normal individuals. Serum apo-B levels were significantly raised in CAD patients as compared to age matched normal individuals. Patients with positive family history of CAD had raised serum apo-B levels than those having negative family history. A positive coefficient of correlation was observed between serum apo-B and LDL levels suggesting that more the number of Apo-B particles, more will be the synthesis of atherogenic particle (LDL). Patients with negative family history had serum apo-B levels closer to those of normal individuals and in these individuals HDL levels were found to be significantly lowered, suggesting that loss of scavenger role of HDL could be the risk factor responsible for the causation of CAD in these patients, with negative family history of coronary artery disease.
doi:10.1007/BF02872381
PMCID: PMC3453898  PMID: 23105418
Apo-B; age variations; CAD risk; inheritance; lipids; lipoproteins
14.  Effects of a moderate low-carbohydrate diet on preferential abdominal fat loss and cardiovascular risk factors in patients with type 2 diabetes 
Background:
Reports have shown that visceral adipose tissue (VAT) is more closely linked to cardiovascular risk factors (CRFs) than subcutaneous adipose tissue (SAT). We aimed to elucidate preferential abdominal fat loss and the correlations between abdominal fat reductions and changes in CRFs achieved with a moderate low-carbohydrate diet (LCD) in patients with type 2 diabetes (T2DM).
Patients and methods:
Fifty-two outpatients (28 men and 24 women, mean age ± SD: 60.0 ± 10.5 years) with hemoglobin A1c (HbAlc) levels ≥ 6.5% were on an LCD for 6 months. Over a 6-month period, we measured their abdominal fat distribution (using CT) and assessed CRFs, including body mass index (BMI), HbA1c, fasting blood glucose (FBG), serum insulin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels.
Results:
The patients showed good compliance with the LCD (1812 ± 375 kcal/day, % carbohydrate:fat:protein = 35:40:19 for men; 1706 ± 323 kcal/day, % carbohydrate:fat:protein = 41:36:21 for women). Significant decreases (P = 0.05) in BMI and HbA1c levels were observed, along with an increase in HDL-C (P = 0.021) in men and a decrease in LDL-C (P = 0.001) in women. VAT (−21.6 cm2, P < 0.001 in men; −19.6 cm2, P < 0.001 in women) and SAT (−13.5 cm2, P = 0.004 in men; −19.1 cm2, P = 0.003 in women) significantly decreased. The loss of VAT (%ΔVAT) was greater than that of SAT (%ΔSAT) in women (P = 0.022). A similar but not significant predominance of VAT loss was detected in men (P = 0.111). In women, the %ΔSAT significantly correlated with changes in FBG (ΔFBG) (r = 0.417) and HDL-C (ΔHDL) (r = −0.720), as was %ΔVAT with changes in triglyceride (ΔTG) (r = 0.591).
Conclusion:
Six months of a moderate LCD resulted in preferential VAT loss only in women, with significant correlations between %ΔSAT and both ΔHDL and ΔFBG, as well as between %ΔVAT and ΔTG. Our results suggest that an LCD has the potential to reduce abdominal fat in patients with T2DM and deterioration of serum lipid profiles.
doi:10.2147/DMSO.S19635
PMCID: PMC3138148  PMID: 21779148
low-carbohydrate diet; visceral adipose tissue; subcutaneous adipose tissue; cardiovascular risk factors
15.  Several genetic polymorphisms interact with overweight/obesity to influence serum lipid levels 
Background
Information about the interactions of single nucleotide polymorphisms (SNPs) and overweight/obesity on serum lipid profiles is still scarce. The present study was undertaken to detect ten SNPs and their interactions with overweight/obesity on serum lipid levels.
Methods
A total of 978 normal weight and 751 overweight/obese subjects of Bai Ku Yao were randomly selected from our previous stratified randomized cluster samples. Normal weight, overweight and obesity were defined as a body mass index (BMI) < 24, 24–28, and > 28 kg/m2; respectively. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1 and ApoB levels were measured. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) AvaII, hepatic lipase gene (LIPC) -250G>A, endothelial lipase gene (LIPG) 584C>T, methylenetetrahydrofolate reductase (MTHFR) 677C>T, the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP) rs3757354, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator-activated receptor delta (PPARD) +294T>C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The interactions were detected by factorial design covariance analysis.
Results
The genotypic and allelic frequencies of LIPC and PCSK9 were different between normal weight and overweight/obese subjects, the genotypic frequency of LIPG and allelic frequency of MYLIP were also different between normal weight and overweight/obese subjects (P < 0.05-0.001). The levels of TC, ApoA1 (ABCA-1); TC, LDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TG, HDL-C, and ApoA1 (LIPG); TC, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); HDL-C and ApoA1 (MYLIP) in normal weight subjects were different among the genotypes (P < 0.01-0.001). The levels of LDL-C, ApoB and ApoA1/ApoB (ABCA-1); HDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TC, HDL-C, ApoA1 and ApoB (LIPG); TC, TG, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); TC, TG and ApoB (MYLIP); TG (PCSK9); TG, ApoA1 and ApoB (PPARD); and TC, HDL-C, LDL-C, ApoA1 and ApoB (SCARB1) in overweight/obese subjects were different among the genotypes (P < 0.01-0.001). The SNPs of ABCA-1 (LDL-C and ApoA1/ApoB); LIPC (TC, LDL-C, ApoA1 and ApoB); LIPG (ApoB); MTHFR (TC, TG and LDL-C); MYLIP (TC and TG); PCSK9 (TG, HDL-C, ApoB and ApoA1/ApoB); PPARD (TG and ApoA1/ApoB); and SCARB1 (TG, ApoA1 and ApoB) interacted with overweight/obesity to influence serum lipid levels (P < 0.05-0.001).
Conclusions
The differences in serum lipid levels between normal weight and overweight/obese subjects might partly result from different genetic polymorphisms and the interactions between several SNPs and overweight/obesity.
doi:10.1186/1475-2840-11-123
PMCID: PMC3508802  PMID: 23039238
Lipid; Apolipoprotein; Genetic polymorphism; Overweight; Obesity; Interaction
16.  Association of apolipoprotein B, apolipoprotein A, and the its ratio with body fat distribution 
Background:
To evaluate the association of apolipoprotein B (apoB), apolipoprotein A (apoA), and apoB/apoA ratio with the body fat indicators in patients with stable angina pectoris (SA).
Materials and Methods:
One hundred and twenty two participants aged 40-60 years old, with a mean age of 52.1 ± 7.2 years and SA, were recruited for the present study. Body weight, height, and waist circumference (WC) were measured, and waist to height ratio (WHtR) was calculated. After 12 hours of fasting, a blood sample was obtained and serum levels of apoB and apoA were measured and the apoB/apoA ratio was calculated. These patients underwent an abdominal computerized tomography scan (CTS) to assess visceral and subcutaneous adipose tissue (VAT, SAT). Linear regressions were computed to assess the relation of apoB, apoA, and their ratio with various measurements of adiposity (VAT, SAT, WC, and WHtR), with adjustment for age, sex, and BMI ≥ 25, WC ≥ 80 in women and WC ≥ 90 in men and WHtR ≥ 0.59.
Results:
From totally 123 patients with SA with a mean age of 52.1 ± 7.2 years, 44.7% male and 55.3% women were entered. Significant positive associations were found between visceral fat area and the apoB/apoA ratio (P = 0.02, β = 0.2), and significant negative correlations were observed between visceral fat area and apoA concentrations (P = 0.04, β = −0.2).
Conclusion:
As abdominal fat accumulation is associated with other risk factors such as apolipoproteins in ischemic patients, then we most focus on control of these factors.
PMCID: PMC3793379  PMID: 24124431
Apolipoprotein A; apolipoprotein B; apolipoprotein B/apolipoprotein A; cardiovascular disease; intra-abdominal fat
17.  Relationship between epicardial adipose tissue, coronary artery disease and adiponectin in a Mexican population 
Background
The amount of epicardial adipose tissue (EAT) around the heart has been identified as an independent predictor of coronary artery disease (CAD), potentially through local release of inflammatory cytokines. Ethnic differences have been observed, but no studies have investigated this relationship in the Mexican population. The objective of the present study was to evaluate whether a relationship exist between EAT thickness assessed via echocardiography with CAD and adiponectin levels in a Mexican population.
Methods
We studied 153 consecutive patients who underwent coronary angiography and transthoracic echocardiography (TTE). EAT thickness on the free wall of the right ventricle was measured at the end of systole from parasternal long and short axis views of three consecutive cardiac cycles. Coronary angiograms were analyzed for the presence, extent and severity of CAD. Serum adiponectin, lipids, glucose, C-reactive protein and fibrinogen were determined.
Results
EAT thickness was greater in patients with CAD than in those without CAD from both parasternal long (5.39 ± 1.75 mm vs 4.00 ± 1.67 mm p < 0.0001) and short-axis views (5.23 ± 1.67 vs 4.12 ± 1.77, p = 0.001). EAT thickness measured from parasternal long and short-axis showed a statistically significant positive correlation with age (r = 0.354, p < 0.001; r = 0.286, p < 0.001 respectively), and waist circumference (r = 0.189, p = 0.019; r = 0.217, p = 0.007 respectively). A significant negative correlation between EAT thickness from the parasternal long axis with cholesterol-HDL was observed (r = -0.163, p = 0.045). No significant correlation was found between epicardial fat thickness and serum adiponectin or with the severity of CAD.
Conclusions
EAT thickness was greater in patients with CAD. However, no correlation was observed with the severity of the disease or with serum adiponectin levels. EAT thickness measured by echocardiography might provide additional information for risk assessment and prediction of CAD.
doi:10.1186/1476-7120-12-35
PMCID: PMC4163040  PMID: 25200587
Epicardial adipose tissue; Coronary artery disease; Echocardiography; Adiponectin
18.  Conventional and Advanced Lipid Parameters in Premature Coronary Artery Disease Patients in India 
Background
Coronary artery disease (CAD) is the leading cause of death worldwide and has assumed alarming proportions in India with gradual increase in its incidence and prevalence over the last decade. India is in the middle of epidemic of coronary artery disease which is leading cause of hospital admissions, morbidity and mortality. In the Indian population, there is higher tendency to develop CAD at a younger age, which cannot be explained on the basis of conventional lipid parameters.
Aim
The purpose of this study is to find advanced lipid parameters which correlate better with premature CAD, as compared to the conventional lipid parameters.
Materials and Methods
Thirty middle aged individuals suffering from premature CAD and 30 age and gender matched healthy individuals without any history of clinical evidence suggestive of CAD were studied. Fasting venous blood samples of all the subjects under study were collected after an overnight fasting and conventional lipid parameters and advanced lipid parameters (i.e. oxidized LDL, Lp (a), ApoA-1, small dense LDL, ApoB) were estimated. Correlation of conventional and advanced lipid parameters with premature CAD and among each other was calculated using Pearson correlation coefficient.
Results
In our study the values of ox-LDL, sdLDL, Lp (a) and ApoB, total cholesterol, TG, LDL-C were significantly higher while HDL-C and Apo A1 and were significantly lower in cases than in controls. Advanced lipid parameters have higher correlation with premature CAD as compared to conventional lipid parameters. Ox-LDL show the highest correlation coefficient (r=+0.89) among these parameters followed by Lp (a) (r=+0.86) and ApoB (r=+0.79).
Conclusion
Advanced lipid parameters (i.e. oxidized LDL, Lp (a), ApoA-1, small dense LDL, ApoB) are better discriminator of premature CAD as compared to conventional lipid parameters (total cholesterol, triglycerides, low density lipoprotein and high density lipoprotein). Oxidised LDL, small dense LDL and lipoprotein (a) can explain occurrence of CAD in normolipidemic patients and proved to be better markers for explaining high degree of prematurity, morbidity and mortality of CAD in Indian population. They can prove to be better marker for early detection and intervention in premature CAD and site for targeted drug therapy.
doi:10.7860/JCDR/2015/14818.6844
PMCID: PMC4668399  PMID: 26674304
CAD; Oxidized LDL; Small dense LDL; ApoB; ApoA1; Lipoprotein (a)
19.  Serum levels of retinol-binding protein-4 are associated with the presence and severity of coronary artery disease 
Background
The interplay between the novel adipokine retinol-binding protein-4 (RBP4) and coronary artery disease (CAD) is still obscure. We investigated the relationship between RBP4 levels and the presence and severity of angiographically proven CAD and determined its possible role in acute myocardial infarction (AMI).
Methods
305 individuals with angiographically proven CAD (CAD-patients), were classified into 2 subgroups: 1) acute myocardial infarction (AMI, n = 141), and 2) stable angina (SA, n = 164). Ninety-one age- and sex-matched individuals without CAD, but with at least 2 classical cardiovascular risk factors, served as controls (non-CAD group). RBP4 serum levels were measured at hospital admission and were analyzed in relation to the coronary severity stenosis, assessed by the Gensini-score and the number of coronary narrowed vessels. Other clinical parameters, including insulin levels, HOMA-IR, hsCRP, glycaemic and lipid profile, and left-ventricular ejection fraction were also assessed.
Results
Serum RBP4 levels were significantly elevated in patients with CAD compared to non-CAD patients (39.29 ± 11.72 mg/L vs. 24.83 ± 11.27 mg/L, p < 0.001). We did not observe a significant difference in RBP4 levels between AMI and SA subgroups (p = 0.734). Logistic regression analysis revealed an independent association of CAD presence with serum RBP4 (β = 0.163, p = 0.006), and hsCRP (β = 0.122, p = 0.022) levels, in the whole study group. Among variables, hsCRP (β = 0.220), HDL (β = −0.150), and RBP4 (β = 0.297), correlated in both univariate and multivariate analysis with CAD severity (R2 = 0.422, p < 0.001). Similarly, RBP4 concentrations increased with the number of coronary narrowed vessels (p < 0.05).
Conclusion
Patients with CAD, both SA and AMI, showed elevated RBP4 serum levels. Notably, increased RBP4 concentration seemed to independently correlate with CAD severity, but no with AMI.
Trial registration
The ClinicalTrials.gov Identifier is: NCT00636766
doi:10.1186/s12933-014-0121-z
PMCID: PMC4156962  PMID: 25142320
Retinol-Binding Protein-4; Myocardial infarction; Coronary artery disease; Adipokines
20.  Alterations in lipid transfers to HDL associated with the presence of coronary artery disease in patients with type 2 diabetes mellitus 
Background
We previously showed that unesterified-cholesterol transfer to high-density lipoprotein (HDL), a crucial step in cholesterol esterification and role in reverse cholesterol transport, was diminished in non-diabetic patients with coronary artery disease (CAD). The aim was to investigate whether, in patients with type 2 diabetes mellitus (T2DM), the occurrence of CAD was also associated with alterations in lipid transfers and other parameters of plasma lipid metabolism.
Methods
Seventy-nine T2DM with CAD and 76 T2DM without CAD, confirmed by cineangiography, paired for sex, age (40–80 years), BMI and without statin use, were studied. In vitro transfer of four lipids to HDL was performed by incubating plasma of each patient with a donor emulsion containing radioactive lipids during 1 h at 37 °C. Lipids transferred to HDL were measured after chemical precipitation of non-HDL fractions and the emulsion. Results are expressed as % of total radioactivity of each lipid in HDL.
Results
In T2DM + CAD, LDL-cholesterol and apo B were higher than in T2DM. T2DM + CAD also showed diminished transfer to HDL of unesterified cholesterol (T2DM + CAD = 7.6 ± 1.2; T2DM = 8.2 ± 1.5 %, p < 0.01) and of cholesteryl-esters (4.0 ± 0.6 vs 4.3 ± 0.7, p < 0.01). Unesterified cholesterol in the non-HDL serum fraction was higher in T2DM + CAD (0.93 ± 0.20 vs 0.85 ± 0.15, p = 0.02) and CETP concentration was diminished (2.1 ± 1.0 vs 2.5 ± 1.1, p = 0.02). Lecithin-cholesterol acyltransferase activity, HDL size and lipid composition were equal.
Conclusion
Reduction in T2DM + CAD of cholesterol transfer to HDL may impair cholesterol esterification and reverse cholesterol transport and altogether with simultaneous increased plasma unesterified cholesterol may facilitate CAD development in T2DM.
doi:10.1186/s12933-015-0270-8
PMCID: PMC4535391  PMID: 26268997
Coronary artery disease; Type 2 diabetes; Lipid transfers; High-density lipoprotein; HDL; Nanoparticles; Cholesterol
21.  Association of apolipoprotein A5 concentration with serum insulin and triglyceride levels and coronary artery disease in Korean men 
Atherosclerosis  2008;205(2):568-573.
Objective
Whereas the relation between apolipoprotein A5 (APOA5) gene polymorphisms and triglycerides (TG) levels is well established, the associations between apoA5 concentrations, TG and coronary artery disease (CAD) remain controversial. Therefore, we investigated these relations in the setting of a case–control study involving Korean males.
Methods
ApoA5, TG, insulin, free fatty acid (FFA) and lipoprotein profiles were determined using a cross-sectional design in 777 healthy controls and 367 CAD patients.
Results
Plasma apoA5 concentration was lower in CAD patients than controls (192.7 ± 5.2 vs. 237.2 ± 3.7 ng/ml, P < 0.001). Values in the second and top tertiles of apoA5 were associated with a decreased odds ratio (OR) for CAD when compared with values in the bottom tertile; OR for apoA5 top tertile was 0.33 (95% CI, 0.23–0.47) in the age- and BMI-adjusted model and 0.35 (95% CI, 0.23–0.56) following additional adjustments for smoking, drinking status, blood pressure, TG and HDL-cholesterol. After adjustment for age and BMI, plasma apoA5 concentration was negatively correlated with serum TG (r = −0.188, P < 0.001) and insulin (r = −0.185, P < 0.001) in normotriglyceridemic controls (TG < 150 mg/dL, n = 509) whereas apoA5 was positively correlated with serum TG in hypertriglyceridemic controls (TG ≥150 mg/dL, n = 268) (r = 0.246, P < 0.001) and total CAD patients (r = 0.177, P < 0.01). Regardless of TG levels and CAD status, apoA5 concentration was positively correlated with HDL-cholesterol and FFA levels.
Conclusions
Our data supports an inverse association between plasma apoA5 concentrations and CAD risk, probably due to the observed negative correlations of apoA5 with TGs and insulin, although these correlations were affected by TG levels.
doi:10.1016/j.atherosclerosis.2008.12.035
PMCID: PMC4426969  PMID: 19185864
Apolipoprotein A5; Coronary artery disease; Triglycerides; Insulin
22.  Interleukin-15 and Soluble Interleukin-15 Receptor α in Coronary Artery Disease Patients: Association with Epicardial Fat and Indices of Adipose Tissue Distribution 
PLoS ONE  2014;9(3):e90960.
Interleukin-15 (IL-15) is a pro-inflammatory cytokine which signals via a specific alpha receptor subunit (IL-15Rα). Increased IL-15 level has been observed in cardiovascular patients and IL-15 immunoreactivity has been detected at vulnerable atherosclerotic plaques. Due to the association between adipose tissue distribution, inflammation and coronary artery disease (CAD), we quantified IL-15 and IL-15Rα in CAD patients with different adiposity and adipose tissue distribution and we evaluated whether epicardial adipose tissue (EAT), a visceral fat depot surrounding and infiltrating myocardium, may be a source of both molecules. IL-15 and IL-15Rα proteins were quantified by enzyme-linked immunosorbent assays. Gene expression of IL-15 and IL-15Rα in EAT depots was evaluated by one colour microarray platform. EAT thickness was measured by echocardiography. Plasmatic IL-15 and IL-15Rα levels were higher in CAD than non-CAD patients. After classification according to adipose tissue distribution, IL-15 was higher in CAD patients with increased abdominal adiposity. Increased level of IL-15Rα was observed both in CAD and non-CAD patients with increased abdominal fat. EAT was a source of IL-15 and IL-15Rα and their expression was higher in CAD patients with increased EAT thickness. In conclusion, our data suggest that circulating levels of IL-15 and IL-15Rα seem to reflect visceral distribution of adipose tissue and that EAT may be a potential source of both IL-15 and IL-15Rα. Future studies on the relationship between IL-15, visceral fat and characteristics of atherosclerotic plaques could help to better understand the complex biology of this cytokine.
doi:10.1371/journal.pone.0090960
PMCID: PMC3948349  PMID: 24603895
23.  Hsp70-2 gene polymorphism: susceptibility implication in Tunisian patients with coronary artery disease 
Diagnostic Pathology  2012;7:88.
Abstract
Coronary artery disease (CAD) is a multifactorial disease where genetic and environmental factors interact in complex ways to cause the disease. Heat shock protein genes are involved in the progress of CAD. This implies that genetic variants of Hsp70–2 genes might contribute to the development of the CAD.
Aim of study
The aim of this study was to characterize statistical correlation of linkage between lipid profiles, polymorphism PstI site of Hsp70–2 gene and CAD.
Patients and methods
This study was carried out on Tunisian patients with CAD recruited from Hospital of Fattouma Bourguiba of Monastir-Tunisia. Polymerase chain reaction and restriction enzymes were used to determine the genotypic distributions in 252 unrelated patients and 151 healthy control subjects. Further, ApoA-I and ApoB as well as the serum total of cholesterol, HDL, triglyceride, and hs-CRP levels were measured.
Results
We showed a decreased level of ApoA-I, whereas the levels of each of ApoB and hs-CRP were increased in patients with CAD compared with control group. In addition our studies of a polymorphic PstI site of Hsp70-2 gene at position 1267 of the Hsp70–2 gene have revealed that the allelic frequency of P2 was significantly more frequent in CAD patients than controls group (p=0.007, OR=1.495). The genotypic distribution showed a high incidence of P2/P2 genotype in CAD patients (0.190) compared to healthy control (0.009) with reach significant difference (p=0.006). The P2 carriers showed a significantly increased of Total-Cholesterol (CT) and C-reactive protein (hs-CRP) levels in CAD patients (p=0.008 and p=0.018, respectively).
Conclusion
The high incidence of P2-Hsp70-2 genotype in CAD patients and the significantly association of P2/P2 genotype with elevated Total Cholesterol and hs-CRP levels, supported that P2–Hsp70–2 genotype has susceptibility implication in CAD and could increased the risk of CAD in Tunisian population.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1118340895703689
doi:10.1186/1746-1596-7-88
PMCID: PMC3558340  PMID: 22834788
Coronary artery disease; Hsp70-2 genes; Polymorphism; Tunisian patients
24.  Relation between Apolipoprotein E Gene Polymorphism and Severity of Coronary Artery Disease in Acute Myocardial Infarction 
Apolipoprotein E (ApoE) is a plasma protein and associated with cholesterol transport system. In several studies, the relationship between ApoE gene polymorphism and severity of coronary artery disease (CAD) has been shown. However, the relationship between ApoE gene polymorphism and severity of CAD in patients with acute myocardial infarction (MI) has not been well known. The aim of this study is to investigate the relation between ApoE polymorphism and severity of CAD in patients with acute MI by using the Gensini Score. In this study, 138 patients were admitted to cardiology clinic with diagnosis of acute MI, and angiographic assessment was performed using the Gensini Score. Blood samples were obtained from all patients in the first day. The patients with ApoE34 genotype had high Gensini scores. Besides, the patients with E4 allele carriers were associated with high Gensini score compared with the patients without E4 allele carriers (p:0,22). The patients with E4 allele carriers were associated with higher LDL cholesterol and total cholesterol compared with the patients without E4 allele carriers (p:0,001 and p:0,03, resp.). There were no statistically significant differences between ApoE genotypes and severity of CAD by using the Gensini Score. But, the patients with E4 allele carriers were associated with high lipid levels.
doi:10.1155/2015/363458
PMCID: PMC4561336  PMID: 26380146
25.  Comparison of cardiovascular risk factors and biochemical profile in patients with cardiac syndrome X and obstructive coronary artery disease: A propensity score-matched study 
ARYA Atherosclerosis  2013;9(5):269-273.
BACKGROUND
This study was designed to compare the frequency of conventional cardiovascular disease risk factors and clinical biochemistry profile in patients with cardiac syndrome X (CSX) and obstructive coronary artery disease (CAD).
METHODS
A cross-sectional study was conducted on patients with typical angina and positive exercise tolerance test undergoing coronary angiography in our center. 342 consecutive patients with CSX were enrolled into this study and were matched regarding age and sex with 342 patients with acute coronary syndrome (ACS) and also 342 patients with chronic stable angina (SA). Cardiovascular risk factors as well as biochemistry profile of the patients were recorded.
RESULTS
Mean age of the studied patients was 53.0 years and 41.5% were male. There was no significant difference between the CSX patients and CAD patients regarding body mass index (BMI). Frequency of diabetes mellitus, hyperlipidemia, smoking, family history of premature CAD and hypertension was significantly lower in patients with CSX than ACS and SA patients. Patients with CSX had significantly higher levels of high-density lipoprotein cholesterol (HDL-cholesterol) than comparators while the levels of low-density lipoprotein cholesterol (LDL-cholesterol), total cholesterol, triglyceride and fasting blood sugar (FBS) were significantly lower in patients with CSX than CAD patients.
CONCLUSION
The present study demonstrated that CSX patients had substantially lower frequency of all conventional CVD risk factors than patients with obstructive CAD. This might aid in developing novel scoring systems or appropriateness criteria for angiographic evaluation of patients with typical angina and positive exercise test in order to reduce the rate of negative results.
PMCID: PMC3845698  PMID: 24302934
Cardiac Syndrome X; Microvascular Dysfunction; Coronary Artery Disease; Risk Factors

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