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1.  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
2.  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
3.  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
4.  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)
5.  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
6.  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)
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  Serum levels of retinol-binding protein-4 are associated with the presence and severity of coronary artery disease 
Cardiovascular Diabetology  2014;13(1):121.
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
16.  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
17.  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
18.  The Effects of Rope Training on Lymphocyte ABCA1 Expression, Plasma ApoA-I and HDL-c in Boy Adolescents 
Background
Early obesity and its transfer to the adulthood, increases likelihood incidence of coronary artery disease (CAD). ATP-binding cassette transporter (ABCA1) as a member of the ABC transporters family plays a crucial role in reverse cholesterol transport and CAD prevention.
Objective
The current study aimed to investigate ABCA1 expression in lymphocytes, plasma apolipoprotein A-I and HDL-C in response to eight-week interval endurance rope training in overweight and obese boy adolescents.
Patients and Methods
Thirty students (17.3 ± 1.1 yr, 85.73 ± 11.68 kg and 28.41 ± 2.36 kg / m²) volunteered and were randomly assigned into training (n= 15) and control (n = 15) groups. Exercise protocol was interval endurance rope training (8 wk, 4 d/wk and 40 min/d). Cell hemolysis and sensitive Elisa method was used for Lymphocyte ABAC1 protein expression.t-test was employed.
Results
The independent-samples T-Test results showed that after 8 weeks IERT, the levels of lymphocyte ABCA1 expression (P = 0/001) and VO2max(P = 0/001) significantly increased and plasma levels of TG (P = 0.017), TC (P = 0.001), LDL-c/HDL-c (P = 0.026),TC/HDL-c (P = 0.002) and measures of BF% (P = 0/015) and BMI (P = 0.042) as anthropometric indicators significantly decreased. Changes of other variables such as increase in ApoA-I, HDL-c and decrease in LDL-c, body weight, were not significant.
Conclusions
The findings of this study proved that eight-week interval endurance rope training can have positive effects on lymphocyte ABCA1 protein expression (as gatekeeper of reverse cholesterol process) and lipid profiles among overweight and obese boy adolescents.
doi:10.5812/ijem.8178
PMCID: PMC3693670  PMID: 23825977
ABCA1; Apolipoprotein A-I; Rope Training; Overweight and Obese Boy Adolescents
19.  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
20.  PPARγ gene C161T substitution alters lipid profile in Chinese patients with coronary artery disease and type 2 diabetes mellitus 
Background
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor, which regulates gene expression of the key proteins involved in lipid metabolism, vascular inflammation, and proliferation. PPARγ may contribute to attenuating atherogenesis and postangioplasty restenosis. PPARγ C161→T substitution is associated with a reduced risk of coronary artery disease (CAD). Whether or not the gene substitution alters the risk of CAD in type 2 diabetes mellitus (T2DM) patients remains unclear.
Methods
A total of 556 unrelated subjects from a Chinese Han population, including 89 healthy subjects, 78 CAD patients, 86 T2DM patients, and 303 CAD combined with T2DM patients, were recruited to enroll in this study. PPARγC161→T gene polymorphism was determined by polymerase chain reaction and restriction fragment length polymorphisms. Plasma levels of lipoproteins, apolipoproteins, glucose, and insulin were measured by ELISA or radioimmunoassay (RIA). The coronary artery lesions were evaluated by coronary angiography.
Results
The frequency of the 161T allele in CAD, T2DM, and CAD combined with T2DM patients was similar to that observed in the healthy control group. However, in CAD combined with T2DM patients, the group with angiographically documented moderate stenoses had a higher frequency of the 161T allele in comparison to the group with severe stenoses (P < 0.05). Moreover, in CAD with T2DM patients, the triglyceride levels and apoB in CC homozygote carriers were significantly higher than those in "T" allele carriers.
Conclusions
PPARγC161→T genotypes weren't significantly associated with the risk of CAD, but were markedly correlated with severity of disease vessels in patients with CAD and T2DM. Furthermore, PPARγC161→T substitution was associated with an altered adipose, but not glucose metabolism. These results indicate that the PPARγ C161→T polymorphism may reduce the risk of severe atherogenesis by modulation of adipose metabolism, especially triglycerides and apoB, in Chinese patients with CAD and T2DM.
doi:10.1186/1475-2840-9-13
PMCID: PMC2859850  PMID: 20334678
21.  Oxidized Low-Density Lipoprotein Cholesterol and the Ratio in the Diagnosis and Evaluation of Therapeutic Effect In Patients with Coronary Artery Disease 
Disease markers  2012;33(6):295-302.
Objective: The purpose of the present study was to investigate the value of ox-LDL and oxidation ratio of LDL (ox-LDL/TC, ox-LDL/HDL-C and ox-LDL/LDL-C) in diagnosis and prognosis evaluation in CAD patients. Also, we aimed to observe the effect of statins on reducing level of ox-LDL and oxidation ratio of LDL, and explore whether statins still have similar effect on ox-LDL in a short period of therapy (within 2 weeks).
Methods: Blood ox-LDL, TC, HDL-C, LDL-C, and TG were measured in cases with acute myocardial infarction (AMI, n = 177), unstable angina pectoris (UAP, n = 195), stable angina pectoris (SAP, n = 228), normal control (n = 120), and high risk control (n = 140).
Results: Mean value of ox-LDL and oxidation ratio of LDL was significantly higher in the CAD group than in the two control groups. The AUC of ROC curve of ox-LDL, ox-LDL/TC, ox-LDL/HDL-C, ox-LDL/LDL-C and apoA1/apoB were more than 0.50 (P < 0.001). Multivariate logistic regression analysis showed that age and ox-LDL/LDL-C related with short-term, while ox-LDL/LDL-C and ox-LDL/TC related with long-term prognosis (P < 0.05). Furthermore, after treatment with statins for 2 weeks, TC, LDL-C, ox-LDL, ox-LDL/TC, ox-LDL/HDL-C and ox-LDL/LDL-C decreased by 22%, 28%, 38%, 29%, 23% and 25% respectively. And the reduction of ox-LDL by statins is independent of lowering of LDL-C and TC.
Conclusions: Ox-LDL and oxidation ratio of LDL are closely related with AS, and they are better biomarkers for discriminating between patients with coronary artery disease and healthy subjects. In addition, statins can decrease level of ox-LDL significantly, which is independent of lowering of LDL-C and TC.
doi:10.3233/DMA-2012-00941
PMCID: PMC3810697  PMID: 23089925
Coronary artery disease; oxidized low density lipoprotein; diagnosis; prognosis
22.  Enhanced External Counterpulsation (EECP) 
Executive Summary
Objective
To assess the effectiveness, and cost effectiveness of EECP in patients with severe anginal symptoms, secondary to chronic coronary disease, who are unresponsive to exhaustive pharmacotherapy and not candidates for surgical/percutaneous revascularization procedures (e.g., angioplasty, coronary bypass surgery).
To assess the effectiveness, and cost effectiveness of EECP in patients with heart failure.
Clinical Need
Angina
Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arm. Angina usually occurs in patients with coronary artery disease (CAD) involving ≥1 large epicardial artery. However it can also occur in people with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension.
Conventional approaches to restoring the balance between oxygen supply and demand focus on the disruption of the underlying disease through: drug therapy (β blockers, calcium channel blockers, nitrates, antiplatelet agents, ACE inhibitors, statins); life-style modifications (smoking cessation, weight loss); or revascularization techniques such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI). (1) Limitations of each of these approaches include: adverse drug effects, procedure-related mortality and morbidity, restenosis after PCI, and time dependent graft attrition after CABG. Furthermore, an increasing number of patients are not appropriate candidates for standard revascularization options, due to co-morbid conditions (HF, peripheral vascular disease), poor distal coronary artery targets, and patient preference. The morbidity and mortality associated with repeat surgical revascularization procedures are significantly higher, and often excludes these patients from consideration for further revascularizations. (2)
Patients with CAD who have chronic ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques have refractory angina pectoris. It has been estimated that greater than 100,000 patients each year in the US may be diagnosed as having this condition. (3) Patients with refractory angina have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III/IV). Also, there must be some objective evidence of ischemia as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies. (1)
Dejongste et al. (4)estimated that the prevalence of chronic refractory angina is about 100,000 patients in the United States. This would correspond to approximately 3,800 (100,000 x 3.8% [Ontario is approximately 3.8% of the population of the United States]) patients in Ontario having chronic refractory angina.
Heart Failure
Heart failure results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump.
A recent study (5) revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.
Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (6) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (7):
Class I: No limitation of physical activity. No symptoms with ordinary exertion.
Class II: Slight limitations of physical activity. Ordinary activity causes symptoms.
Class III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
Class IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.
The National Heart, Lung, and Blood Institute (7) estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. Surveys (8) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.
To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses. (6)
The Technology
Patients are typically treated by a trained technician in a medically supervised environment for 1 hour daily for a total of 35 hours over 7 weeks. The procedure involves sequential inflation and deflation of compressible cuffs wrapped around the patient’s calves, lower thighs and upper thighs. In addition to 3 sets of cuffs, the patient has finger plethysmogram and electrocardiogram (ECG) attachments that are connected to a control and display console.
External counterpulsation was used in the United States to treat cardiogenic shock after acute myocardial infarction. (9;10) More recently, an enhanced version namely “enhanced external counterpulsation” (EECP) was introduced as a noninvasive procedure for outpatient treatment of patients with severe, uncontrollable cardiac ischemia. EECP is said to increase coronary perfusion pressure and reduce the myocardial oxygen demand. Currently, EECP is not applicable for all patients with refractory angina pectoris. For example, many patients are considered ineligible for therapy due to co-morbidities, including those with severe pulmonary vascular disease, deep vein thrombosis, phlebitis and irregular heart rhythms, and heart failure. (1)
Very recently, investigation began into EECP as an adjunctive treatment for patients with HF. Anecdotal reports suggested that EECP may benefit patients with coronary disease and left ventricular dysfunction. The safety and effectiveness of EECP in patients with symptomatic heart failure and coronary disease and its role in patients with nonischemic heart failure secondary to LV dysfunction is unclear. Furthermore, the safety and effectiveness of EECP in the different stages of HF and whether it is only for patients who are refractive to pharmacotherapy is unknown.
2003 Health Technology Assessment by the Medical Advisory Secretariat
The Medical Advisory Secretariat health technology assessment (originally published in February 2003) reported on the effectiveness of EECP for patients with angina and HF. The report concluded that there was insufficient evidence to support the use of EECP in patients with refractory stable CCS III/IV angina as well as insufficient evidence to support the use of EECP in patients with HF.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of EECP for the treatment of refractory stable CCS III/IV angina or HF.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from December 2002 to March 2006.
A modification of the GRADE approach (11) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 – March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 Medical Advisory Secretariat recommendation.
BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. (12) BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well.
On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. (13) Overall, CMS stated that the evidence is not adequate to conclude that external counterpulsation therapy is reasonable and necessary for:
Canadian Cardiovascular Society Classification (CCSC) II angina
Heart failure
NYHA class II/III stable HF symptoms with an EF≤35%
NYHA class II/III stable HF symptoms with an EF≤40%
NYHA class IV HF
Acute HF
Cardiogenic shock
Acute MI
In January 2005, ECRI (14) stated that there was insufficient evidence available to draw conclusions about the long-term effectiveness of EECP, with respect to morbidity, survival, or quality of life, for any coronary indication (refractory angina, congestive heart failure, cardiogenic shock and acute MI).
GRADE Quality of the Studies
According to the GRADE Working Group criteria, the quality of the trials was examined (Table 1). (11)
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and followup.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence. (11)
GRADE Quality of Studies
Economic Analysis - Literature Review
No economic analysis of EECP was identified in the published literature.
Estimated Prevalence of Angina in Ontario
3,800 patients with chronic refractory angina:
The number of patients with chronic refractory angina in the US is estimated to be approximately 100,000 (4), this corresponds to about 3,800 patients in Ontario (3.8% × 100,000) with refractory angina.
3,800 patients × $7,000 Cdn (approximate cost for a full course of therapy) ~ $26.6M Cdn.
Estimated Prevalence of Heart Failure in Ontario
23,700 patients EF ≤ 0.35:
This estimate is from an expert (personal communication) at the Institute for Clinical Evaluative Sciences (ICES), where they examined a sample of echocardiography studies drawn from a diagnostic lab in 2001. They found that the prevalence of EF ≤ 0.35 was 8.3%, and if generalized to all patients undergoing echocardiography, there would be 23,700 patients.
23,700 patients with EF ≤35% × $7,000 Cdn ~ $166 M Cdn.
Conclusions
There is insufficient evidence to support the effectiveness and safety of EECP treatment for patients with refractory stable CCS III-IV angina or HF.
As per the GRADE Working Group, overall recommendations consider 4 main factors. (11)
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
The quality of the evidence.
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
Uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. (11) Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 2 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For angina and heart failure, the overall GRADE and strength of the recommendations is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $26.6 M Cdn or $166 M Cdn respectively while the cost-effectiveness of EECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness.
Overall GRADE and Strength of Recommendation (Including Uncertainty)
PMCID: PMC3379533  PMID: 23074496
23.  Endogenous Estradiol and Testosterone may Predispose toward Atherogenic Lipid Profile, but Higher Blood Level of Testosterone is Associated with Lower Number of Stenoses in the Coronary Arteries of Men with Coronary Disease 
Objectives:
To assess the correlations between blood levels of sex steroid hormones and blood lipid profile or the degree of coronary artery stenosis in men with coronary artery disease (CAD).
Methods:
111 men with stable CAD, aged 36-73 yrs, unselected for the coexisting clinical coronary risk factors were prospectively studied. Degree of coronary stenosis was assessed angiographically using different indices. Total cholesterol (T-Ch), high density lipoproteins cholesterol (HDL-Ch), low density lipoproteins cholesterol (LDL-Ch), triglicerydes (TG), testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone binding globulin (SHBG) were measured in the blood. Free testosterone index (FTI) was calculated.
Results:
A positive, significant correlations were found between blood concentrations of estradiol and T-Ch (r=0.29, p<0.01) or LDL-Ch (r=0.34, p<0.005) as well as between FTI and blood LDL-Ch (r=0.23, p<0.05). Blood level of estradiol negatively correlated with HDL-Ch/T-Ch ratio (r=-0.21, p<0.05). While blood levels of T-Ch correlated positively with 3 out of 5 applied here indices of coronary stenosis, blood LDL-Ch with two of them. In turn, blood level of testosterone negatively correlated with one index of coronary stenosis (r=-0.26, p<0.05).
Conclusion:
In men with CAD, plasma estradiol concentrations are predictive for T-Ch, LDL-Ch and HDL-Ch/TCh ratio, and FTI for LDL-Ch. Regression analyses indicated that while sex steroid hormones may predispose toward atherogenic lipid profile and are predictive for the number and degree of coronary artery stenosis, higher blood level of total testosterone was associated with the lower number of stenosis in the coronary arteries. Hence, endogenous testosterone may have beneficial effect on coronary arteries.
PMCID: PMC3614595  PMID: 23674975
coronary stenosis; estradiol; lipid profile; men; testosterone
24.  Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease 
Background
Visceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT) with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center.
Methods
35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay): apolipoprotein A-I (apoAI), apolipoprotein A-II (apoAII), apolipoprotein B (apoB), apolipoprotein C-II (apoCII), apolipoprotein C-III (apoCIII) and apolipoprotein E (apoE).
Results
MFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI.
Conclusions
Our study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No correlation was observed between mesenteric fat thickness and very low density lipoprotein or chylomicron particles concentration.
doi:10.1186/1476-511X-11-125
PMCID: PMC3477087  PMID: 23025515
Ultrasound; Mesenteric fat thickness; Adipose tissue; Apolipoproteins; Atherosclerosis
25.  Neck circumference and central obesity are independent predictors of coronary artery disease in patients undergoing coronary angiography 
Excess of adiposity is a risk factor for coronary artery disease, but it remains unclear if the distribution of fat is an effect modifier or if the risk is mediate by hypertension, diabetes and dyslipidemia. We investigated the association of central in addition to general obesity with coronary artery disease (CAD). A case-control study was conducted in 376 patients, aged 40 years or more, with chronic coronary disease, undergoing elective coronary angiography. Excess of adiposity was evaluated by the Body Mass Index (BMI), waist circumference, waist-hip ratio, and neck circumference. Cases (n=155) were patients referred for coronary angiography with at least 50% of coronary stenosis in at least one epicardial vessels or their branches, with diameter greater than 2.5 mm. Controls (n=221) were patients referred for coronary angiography without significant coronary disease. Odds ratios and 95%CI for significant coronary stenosis were calculated using multiple logistic regression, controlling for age, sex, years at school, smoking, hypertension, HDL-cholesterol, diabetes mellitus, and an adiposity index. There was a predominance of men and individuals older than 50 years among cases. The waist-hip ratio increased four times the chance of CAD, even after the control for confounding factors, including BMI. Neck circumference above the 90th Percentile doubled the chance of CAD, after adjustment for traditional risk factors. Neck circumference and waist-hip ratio are independent predictors of CAD, even taking into account traditional risk factors for CAD. These findings highlight the need of anthropometric assessment among patients with suspected coronary artery disease.
PMCID: PMC3499931  PMID: 23173107
Obesity; central obesity; abdominal obesity; coronary artery disease; coronary angiography

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