A Summary and Critical Assessment of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Filling the Gaps

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines has recently released the new cholesterol treatment guideline. This update was based on a systematic review of the evidence and replaces the previous guidelines from 2002 that were widely accepted and implemented in clinical practice. The new cholesterol treatment guideline emphasizes matching the intensity of statin treatment to the level of atherosclerotic cardiovascular disease (ASCVD) risk and replaces the old paradigm of pursuing low-density lipoprotein cholesterol targets. The new guideline also emphasizes the primacy of the evidence base for statin therapy for ASCVD risk reduction and lists several patient groups that will not benefit from statin treatment despite their high cardiovascular risk, such as those with heart failure (New York Heart Association class II-IV) and patients undergoing hemodialysis. The guideline has been received with mixed reviews and significant controversy. Because of the evidence-based nature of the guideline, there is room for several questions and uncertainties on when and how to use lipid-lowering therapy in clinical practice. The goal of the Mayo Clinic Task Force in the assessment, interpretation, and expansion of the ACC/AHA cholesterol treatment guideline is to address gaps in information and some of the controversial aspects of the newly released cholesterol management guideline using additional sources of evidence and expert opinion as needed to guide clinicians on key aspects of ASCVD risk reduction.     

Beyond fasting plasma glucose: The association between coronary heart disease risk and postprandial glucose,postprandial insulin and insulin resistance in healthy,nondiabetic adults

Objective

Prediabetes is defined by elevations of plasma glucose concentration, and is aimed at identifying individuals at increased risk of type 2 diabetes and coronary heart disease (CHD). However, since these individuals are also insulin resistant and hyperinsulinemic, we evaluated the association between several facets of carbohydrate metabolism and CHD risk profile in apparently healthy, nondiabetic individuals.

Methods

Plasma glucose and insulin concentrations were measured before and at hourly intervals for eight hours after two test meals in 281 nondiabetic individuals. Insulin action was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. CHD risk was assessed by measurements of blood pressure and fasting lipoprotein profile.

Results

For purposes of analysis, the population was divided into tertiles, and the results demonstrated that the greater the 1) fasting plasma glucose (FPG) concentration, 2) incremental plasma insulin response to meals, and 3) SSPG concentration, the more adverse the CHD risk profile (p < 0.05). In contrast, the CHD risk profile did not significantly worsen with increases in the incremental plasma glucose response to meals.

Conclusions

In nondiabetic individuals, higher FPG concentrations, accentuated daylong incremental insulin responses to meals, and greater degrees of insulin resistance are each associated with worse CHD risk profile (higher blood pressures, higher triglycerides, and lower high density lipoprotein cholesterol concentrations). Interventional efforts aimed at decreasing CHD in such individuals should take these abnormalities into consideration.     

Transfer of lipids to high-density lipoprotein (HDL) is altered in patients with familial hypercholesterolemia

Objective

In familial hypercholesterolemia (FH), the metabolism and anti-atherogenic functions of HDL can be affected by the continuous interactions with excess LDL amounts. Here, lipid transfers to HDL, an important step for HDL intravascular metabolism and for HDL role in reverse cholesterol transport (RCT) were investigated in FH patients.

Methods

Seventy-one FH patients (39 ± 15 years, LDL-cholesterol = 274 ± 101; HDL-cholesterol = 50 ± 14 mg/dl) and 66 normolipidemic subjects (NL) (38 ± 11 years, LDL-cholesterol = 105 ± 27; HDL-cholesterol = 52 ± 12 mg/dl) were studied. In vitro, lipid transfers were evaluated by incubation of plasma samples (37 °C, 1 h) with a donor lipid nanoemulsion labeled with 3H-triglycerides (TG) and 14C-unesterified cholesterol (UC) or with 3H-cholesteryl ester (EC) and 14C-phospholipids (PL). Radioactivity was counted at the HDL fraction after chemical precipitation of apolipoprotein (apo) B-containing lipoproteins and the nanoemulsion. Data are % of total radioactivity measured in the HDL fraction.

Results

Transfer of UC to HDL was lower in FH than in NL (5.6 ± 2.1 vs 6.7 ± 2.0%, p = 0.0005) whereas TG (5.5 ± 3.1 vs 3.7 ± 0.9%, p = 0.018) and PL (20.9 ± 4.6 vs 18.2 ± 3.7 %, p = 0.023) transfers were higher in FH. EC transfer was equal. By multivariate analysis, transfers of all four lipids correlated with HDL-cholesterol and with apo A-I.

Conclusion

FH elicited marked changes in three of the four tested lipid transfers to HDL. The entry of UC into HDL for subsequent esterification is an important driving force for RCT and reduction of UC transfer to HDL was previously associated to precocious coronary heart disease. Therefore, in FH, HDL functions can be lessened, which can also contribute to atherogenesis.     

Elevated plasma fractalkine levels are associated with higher levels of IL-6, Apo-B,LDL-C and insulin,but not with body composition in a large female twin sample

Objective

Plasma fractalkine (FRACT) is involved in the development of numerous inflammatory conditions including atherosclerosis. It is associated with type 2 diabetes mellitus and adipose inflammation. However, whether FRACT is associated with major risk factors for cardiovascular disease, in particular obesity, metabolic syndrome and blood lipids, is virtually unknown.

Methods

The study included a large community-based sample of 3306 middle-aged women drawn from the general UK population. Blood samples were analyzed for circulating levels of FRACT, leptin, insulin, glucose, LDL-C, HDL-C, Apo-A, ApoB and IL-6. Obesity was assessed by fat body mass (FBM) using dual-energy x-ray absorptiometry and by body mass index (BMI).

Results

We found no association between FRACT and body composition, in particular adiposity. Obese and non obese subjects with metabolic syndrome tended to have higher levels of FRACT compared with non-obese subjects without metabolic syndrome but this did not reach statistical significance. Most importantly we report significant correlations between FRACT and circulating IL-6, Apo-B, LDL-C and insulin. The associations with IL-6 and Apo-B were particularly significant (P-value < 0.001), and survived correction for multiple testing and adjustment for age and other covariates.

Conclusion

Higher FRACT levels correlated with elevated levels of IL-6, Apo-B, LDL-C and insulin, all known risk factors for several clinical related diseases suggesting a potential role of FRACT in inflammation and tissue injury. Variations of FRACT levels are not influenced by body composition and are not correlated with leptin indicating that fat mass alone is not responsible for elevation of FRACT seen in obese individuals.     

Stereology of the myocardium and blood biochemistry in aged rats fed with a cholesterol-rich and canola oil diet (n-3 fatty acid rich)

The myocardial changes brought about by canola oil (n-3 fatty acid rich) and hyperlipidic diets were studied in 45 rats. Three groups each consisting of 15 animals was separated into (A) which receiving a normal balanced diet; and in groups (CHO) and (O) the animals receiving hyperlipidic and canola oil diet, respectively. These diets were fed to the animals from 21 days until 15 months old, then a blood analysis was performed, after which they were sacrificed and the hearts taken for light microscopic studies. The total lipids serum was extracted and the low density lipoproteins (LDL-C and VLDL-C) and chylomicron fractions were determined as well as the cholesterol concentration in the high density lipoprotein fraction (HDL-C). The myocardium was composed of myocytes and cardiac interstitium, which is made up of connective tissue and blood vessels. The following stereological parameters were determined: a) from myocyte: volume density of myocyte, total volume of myocytes surface density of myocyte, total surface of myocyte and cross sectional area of myocyte; b) from blood vessels: volume density of blood vessels, total volume of blood vessels, length density of blood vessels, surface density of blood vessels, total surface of blood vessels and cross sectional area of vessels; c) from connective tissue: volume density of connective tissue and total volume of connective tissue. The differences were tested by the analysis of variance and Tukey test. The Mantel-Haenezel test analyzed the survival curve test comparing the different groups. Many stereological parameters had significant differences: cardiac weight, thickness of the right and left ventricular wall, aorta and pulmonary artery inner diameters, HDL-C, LDL-C, volume density of myocyte, total surface of myocyte, surface density of myocyte, total surface of myocyte, total volume of blood vessel, length density of blood vessels, surface density of blood vessels, total surface of blood vessels, volume density of connective tissue, total volume of connective tissue. Differences in survival curves were significant between groups CHO×A and CHO×O (p<0.05) but not between groups A×O (p=0.48). For the cardiac weight, the smallest values were found in group O. The aorta and artery pulmonary internal diameters were smaller in group CHO. The HDL-C serum was about 40% greater in group O. The LDL-C serum was more than 80% less in the same group. The average of volume density of myocyte was less in group CHO, while the average of volume density of connective tissue was greater in group CHO in comparison to groups A and O. The length density of blood vessels was greater in group O than in groups A and CHO. The surface density of myocyte and surface density of blood vessels were smaller in group CHO and greater in group A. The total surface of myocyte and total surface of blood vessels were greater in group CHO and smaller in group O. Differences were significant between groups A×CHO. The total volume of myocytes was greater in group A, while the total volume of connective tissue was greater in group CHO. The cross sectional area of myocyte and cross sectional area of vessels were greater in group CHO and smaller in group O suggesting that the canola oil diet (n-3 fatty acid rich) preserves the myocardium more than the standard and cholesterol-rich diets. Received: 7 April 1997, Returned for 1. Revision: 6 May 1997, 1. Revision received: 15 July 1997, Returned for 2. Revision: 29 August 1997, 2. Revision received: 15 October 1997, Accepted: 28 October 1997     

高密度脂蛋白胆固醇直接测定方法学评价

作者通过一系列实验,从稳定性、特异性、线性和回归分析,干扰物分析及方法学比较等方面对高密度脂蛋白胆固醇的无标本预处理的直接测定法进行了讨论。HDL—C重复测定的最大CV为5.7％,直接法与磷酸钨镁沉淀法有很好的相关性,Y=0.00256±XO.045mmol/1,r=0.970。当TG=2.2时,HDL—C的浓度仅增加2％,Hb对结果有明显的正干扰作用,而胆红素却使HDL—C的结果偏低。实验表明,HDL—C的直接测定法具有操作简单,一定条件下结果稳定,准确,能够应用于全自动分析的特点,该方法对于人群血脂代谢的筛查工作,及时发现和预防心血管疾患的危险致病因素提供了相当便利的条件。     

Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes

The niacin receptor GPR109A is a G_i-protein-coupled receptor which mediates the effects of niacin on inhibiting intracellular triglyceride lipolysis in adipocytes. However, the role of GPR109A in mediating the effects of niacin on high density lipoprotein (HDL) metabolism is unclear. We found niacin has no effect on HDL-C in GPR109A knockout mice. Furthermore, niacin lowered intracellular cAMP in primary hepatocytes mediated by GPR109A. We used an adeno-associated viral (AAV) serotype 8 vector encoding GPR109A under the control of the hepatic-specific thyroxine-binding globulin promoter to specifically overexpress GPR109A in mouse liver. Plasma HDL-C, hepatic ABCA1 and the HDL cholesterol production rate were significantly reduced in mice overexpressing GPR109A. Overexpression of GPR109A reduced primary hepatocyte free cholesterol efflux to apoA-I; conversely, GPR109A deficient hepatocytes had increased ABCA1-mediated cholesterol efflux. These data support the concept that the HDL-C lowering effect of niacin in wild-type mice is mediated through stimulation of GPR109A in hepatocytes; such an effect then leads to reduced hepatocyte ABCA1 expression and activity, decreased cholesterol efflux to nascent apoA-I, and reduced HDL-C levels. These results indicate that niacin-mediated activation of GP109A in liver lowers ABCA1 expression leading to reduced hepatic cholesterol efflux to HDL.     

Association between apolipoprotein E polymorphism and serum lipid and apolipoprotein levels with Alzheimer's disease

We have recently demonstrated that apolipoprotein E (APOE)-varepsilon4 allele is a risk factor for Alzheimer disease (AD) in Tehran, Iran. The current study specifically aimed to examine whether APOE polymorphism in association with serum lipids-apolipoprotein level is a risk factor for AD in a population from Tehran, Iran. APOE polymorphism and plasma lipids, apoA1, apoB and lipoprotein (a) (Lp(a)) levels were determined in 94 AD patients and 111matched controls. Our study demonstrated a significant association between APOE polymorphism and the level of plasma lipids and apolipoprotein with AD in this population. The AD subjects had significantly lower apoA1 (p<0.001) and HDL-C (p<0.01) and higher apoB (p=0.01) and LDL-C (p=0.02) levels than that of the control group. The AD subjects carrying APOE-varepsilon4 allele had lower plasma apoA1 (t=5.2, p<0.002) and HDL-C level (t=2.7, p=0.01) but had higher plasma apoB (t=-5.4, p<0.002), LDL-C (t=-4.6, p=0.005) and total cholesterol (TC) (t=-2.7, p=0.01) than that of the non APOE-varepsilon4 carriers. These results indicated that AD patients with APOE-varepsilon4 allele has a distinct plasma lipid profile and carrier of this allele with low levels of apoA1 and HDL-C may be more susceptible to AD.     

Serum HDL-C levels, log (TG/HDL-C) values and serum total cholesterol/HDL-C ratios significantly correlate with radiological extent of disease in patients with community-acquired pneumonia

BACKGROUND: In several studies, it was shown that there was a marked decrease in serum levels of HDL-C during infection and inflammation in general. In particular, a decrease in the level of serum HDL-C was also shown in pneumonia. Correlations between inflammatory markers such as acute phase proteins, cytokines and serum HDL-C levels were shown. However, there are no studies indicating a correlation between serum HDL-C levels and the radiological extent of the disease (RED) in community-acquired pneumonia (CAP). AIM: We hypothesized that there could be a relationship between serum HDL-C levels and RED in CAP. MATERIALS AND METHODS: A case-controlled study, including 97 patients with CAP and 45 healthy subjects, was performed. Chest X-rays of CAP patients were scored for RED, and correlations were investigated between RED scores, serum lipid parameters, the erythrocyte sedimentation rate (ESR) and serum albumin levels. RESULTS: The mean serum HDL-C level was lower in CAP patients than in controls. A significant and negative correlation between RED scores (REDS) and serum HDL-C levels was detected (r = -0.64, P = 0.0001). There were also significant correlations between REDS and other lipid parameters. Significant correlations between ESR and serum HDL-C levels and between ESR and other serum lipid parameters were also found. CONCLUSION: It appears that serum HDL-C levels are generally lower in CAP cases than in healthy controls. Serum HDL-C levels and serum albumin levels might decrease and serum total cholesterol/HDL-C ratios and log (TG/HDL-C) values might increase proportionally with RED in CAP patients. These results might have some significance for individuals having long-standing and/or recurrent pneumonia and other cardiovascular risk factors.     

Influence of chrysin on hepatic marker enzymes and lipid profile against d-galactosamine-induced hepatotoxicity rats

Chrysin is a flavonoid that exists in nature and is the major component of some traditional medicinal herbs. We investigated the hepatoprotective and antihyperlipidaemic potential of chrysin against d-galactosamine (a single intraperitoneal injection 400 mg/kg BW) induced hepatotoxicity in male albino Wistar rats. d-GalN rats exhibited an increased hepato and nephro toxicity marker activities aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase and total bilirubin level while urea, uric acid and creatinine and lipid profile. It also negatively affected the serum total protein, albumin and A/G ratio. Rats treated with chrysin at different concentrations (25, 50 and 100 mg/kg BW) caused a significant improvement in serum protein level, decreased hepato and nephro toxicity markers. It also decreased the levels of very low density lipoprotein cholesterol and low density lipoprotein cholesterol while high density lipoprotein cholesterol significantly increased. It also decreased the levels of total cholesterol, phospholipids, triglycerides, free fatty acids in the plasma and tissues of liver and kidney. The effect of chrysin (25 mg/kg) is comparable with silymarin, a known hepatoprotective drug. Chrysin thus exhibits hepatoprotective and antihyperlipidaemic activity.