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Subfractionation of Lipoproteins 101 Let's review some subfractionation techniques. On the market 3 main methods exist. They all work. Dr. Davis highly prefers NMR for its subtleties, scope, and particle counts. Superko and Krauss are affiliated with Berkeley HeartLab which uses GGE (BHL). Density gradient ultracentrifugation is very popular among our members (VAP-II and VAP). Recently, Krauss appears to be introducing a new technology based on ion-mobility. Basically, the denser the particle, the faster and more mobile the particle moves through a gel (GGE). The denser the particle, the smaller the diameter (Angstroms or nanometers) as determined via electromagnetic resonance (NMR) or absorbance via density ultracentrifugation (VAP, which are indirectly compared to known sizes).

"Measuring the number of small LDL particles is the best index of carbohydrate intake I know of, better than even blood sugar and triglycerides. In other words, increase carbohydrate intake and small LDL particles increase. Decrease carbohydrates and small LDL particles decrease. Why? Carbohydrates increase small LDL via a multistep process: First step: Increased fatty acid and apoprotein B production in the liver, which leads to increased VLDL production. (Apoprotein B is the principal protein of VLDL and LDL) Second step: Greater VLDL availability causes triglyceride-rich VLDL to interact with other particles, namely LDL and HDL, enriching them in triglycerides (via the action of cholesteryl-ester transfer protein, or CETP). Much VLDL is converted to LDL. Third step: Triglyceride-rich LDL is "remodeled" by enzymes like hepatic lipase, which create small LDL"

Intima-media thickness of the carotid artery and the distribution of lipoprotein subclasses in men aged 40 to 49 years between whites in the United States and the Japanese in Japan for the ERA JUMP study. Sekikawa A, Ueshima H, Sutton-Tyrrell K, Kadowaki T, El-Saed A, Okamura T, Takamiya T, Ueno Y, Evans RW, Nakamura Y, Edmundowicz D, Kashiwagi A, Maegawa H, Kuller LH. Metabolism. 2008 Feb;57(2):177-82. PMID: 18191046 doi: 10.1016/j.metabol.2007.08.022. In men in the post World War II birth cohort, i.e., men aged 40-49, whites in the United States (U.S.) had significantly higher levels of intima-media thickness of the carotid arteries (IMT) than the Japanese in Japan. The whites had significantly higher levels of large very-low-density-lipoprotein particles and significantly lower levels of large high-density-lipoprotein particles than the Japanese, whereas the two populations had similar levels of small low-density-lipoprotein particles. The two populations had similar associations of IMT with NMR lipoproteins. Adjusting for NMR lipoproteins did not attenuate the significant difference in IMT between the two populations (0.671 ± 0.006 for the whites and 0.618 ± 0.006 mm for the Japanese, P=0.01, mean (standard error)). Differences in the distributions of NMR lipoproteins between the two populations did not explain the higher IMT in the whites.

The Diet-Heart Hypothesis: Subdividing Lipoproteins Two posts ago, we made the rounds of the commonly measured blood lipids (total cholesterol, LDL, HDL, triglycerides) and how they associate with cardiac risk. It's important to keep in mind that many things associate with cardiac risk, not just blood lipids. For example, men with low serum vitamin D are at a 2.4-fold greater risk of heart attack than men with higher D levels. That alone is roughly equivalent to the predictive power of the blood lipids you get measured at the doctor's office. Coronary calcium scans (a measure of blood vessel calcification) also associate with cardiac risk better than the most commonly measured blood lipids. Lipoproteins Can be Subdivided into Several Subcategories In the continual search for better measures of cardiac risk, researchers in the 1980s decided to break down lipoprotein particles into sub-categories. One of these researchers is Dr. Ronald M. Krauss. Krauss published extensively on the association between lipoprotein size and cardiac risk, eventually concluding (source): The plasma lipoprotein profile accompanying a preponderance of small, dense LDL particles (specifically LDL-III) is associated with up to a threefold increase in the susceptibility of developing [coronary artery disease]. This has been demonstrated in case-control studies of myocardial infarction and angiographically documented coronary disease. Krauss found that small, dense LDL (sdLDL) doesn't travel alone: it typically comes along with low HDL and high triglycerides*. He called this combination of factors "lipoprotein pattern B"; its opposite is "lipoprotein pattern A": large, buoyant LDL, high HDL and low triglycerides. Incidentally, low HDL and high triglycerides are hallmarks of the metabolic syndrome, the quintessential modern metabolic disorder. Krauss and his colleagues went on to hypothesize that sdLDL promotes atherosclerosis because of its ability to penetrate the artery wall more easily

Fish consumption shifts lipoprotein subfractions to a less atherogenic pattern in humans. Li Z, Lamon-Fava S, Otvos J, Lichtenstein AH, Velez-Carrasco W, McNamara JR, Ordovas JM, Schaefer EJ. J Nutr. 2004 Jul;134(7):1724-8. PMID: 15226460 The effect of fish consumption on plasma lipoprotein subfraction concentrations was studied in 22 men and women (age > 40 y). Subjects were provided an average American diet (AAD, 35% of energy as fat, 14% as saturated fat, and 35 mg cholesterol/MJ) for 6 wk before being assigned to a National Cholesterol Education Program (NCEP) Step 2 high-fish diet (n = 11, 26% of energy as fat, 4.5% as saturated fat, and 15 mg cholesterol/MJ) or a NCEP Step 2 low-fish diet (n = 11, 26% of energy as fat, 4.0% as saturated fat, and 11 mg cholesterol/MJ) for 24 wk. All food and drink were provided to study participants. Consumption of the high-fish NCEP Step 2 diet was associated with a significant reduction in medium and small VLDL, compared with the AAD diet, whereas the low-fish diet did not affect VLDL subfractions. Both diets significantly reduced LDL cholesterol concentrations, without modifying LDL subfractions. Both diets also lowered HDL cholesterol concentrations. However, the high-fish diet significantly lowered only the HDL fraction containing both apolipoprotein (apo) AI and AII (LpAI:AII) and did not change HDL subfractions assessed by NMR, whereas the low-fish diet significantly lowered the HDL fraction containing only apo AI (LpAI) and the large NMR HDL fractions, resulting in a significant reduction in HDL particle size. Neither diet affected VLDL and LDL particle size. Our data indicate that within the context of a diet restricted in fat and cholesterol, a higher fish content favorably affects VLDL and HDL subspecies

The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls. Parish S, Peto R, Palmer A, Clarke R, Lewington S, Offer A, Whitlock G, Clark S, Youngman L, Sleight P, Collins R; International Studies of Infarct Survival Collaborators. Eur Heart J. 2009 Sep;30(17):2137-46. Epub 2009 Jun 11. PMID: 19520708 doi:10.1093/eurheartj/ehp221 Conclusion: Apolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.

If wheat is so bad, what about all the other grains? First of all, I demonize wheat because of its top-of-the-list role in triggering: --Appetite--Wheat increases hunger dramatically --Insulin --Blood sugar--Wheat is worse than table sugar in triggering a rapid, large rise in blood sugar --Triglycerides --Small LDL particles--the number one cause for heart disease in the U.S. --Reduced HDL --Diabetes --Autoimmune diseases--Most notably celiac disease and thyroiditis. Most other "healthy, whole grains" aren't quite as bad. It's a matter of degree.

The results suggest that a short-term ketogenic diet does not have a deleterious effect on CVD risk profile and may improve the lipid disorders characteristic of atherogenic dyslipidemia. A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. Sharman MJ, Kraemer WJ, Love DM, Avery NG, Gómez AL, Scheett TP, Volek JS. J Nutr. 2002 Jul;132(7):1879-85. PMID: 12097663

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T, Beysen C, Hellerstein MK, Berglund L, Havel PJ. J Clin Invest. 2009 May;119(5):1322-34. Epub 2009 Apr 20. PMID: 19381015 doi: 10.1172/JCI37385. Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

"Eating high levels of some soy products - including tofu - may raise the risk of memory loss, research suggests. The study focused on 719 elderly Indonesians living in urban and rural regions of Java. ' The latest study suggests phytoestrogens - in high quantity - may actually heighten the risk of dementia. Lead researcher Professor Eef Hogervorst said previous research had linked oestrogen therapy to a doubling of dementia risk in the over-65s. She said oestrogens - and probably phytoestrogens - tended to promote growth among cells, not necessarily a good thing in the ageing brain. Alternatively, high doses of oestrogens might promote the damage caused to cells by particles known as free radicals. A third theory is that damage is caused not by the tofu, but by formaldehyde, which is sometimes used in Indonesia as a preservative. The researchers admit that more research is required to ascertain whether the same effects are found in other ethnic groups. However, previous research has also linked high tofu consumption to an increased risk of dementia in older Japanese American men. The researchers found high tofu consumption - at least once a day - was associated with worse memory, particularly among the over-68s. "

"[Vitamin K and Bone Update. The biological effects of vitamin K(2) on bone quality.] Amizuka N, Li M, Guo Y, Liu Z, Suzuki R, Yamamoto T. Clin Calcium. 2009 Dec;19(12):1788-96. Japanese. PMID: 19949270 Post-transcriptional maturation with the presence of vitamin K(2) promotesgamma-carboxylation of osteocalcin, enabling further binding to hydroxyapatite, from which one could infer that vitamin K(2) increased the quality of bone matrix. For instance, vitamin K(2) rescued the impaired collagen mineralization caused by Mg insufficiency, by promoting a re-association of the process of collagen mineralization with mineralized nodules. Sodium warfarin, which antagonizes the function of vitamin K(2), reduced the binding of osteocalcin to bone matrices, and consequently resulted in crystalline particles being dispersed throughout the osteoid without forming mineralized nodules. Therefore,gamma-carboxylated Gla proteins mediated by vitamin K(2) appear to play a pivotal role in normal mineralization in bone."

Eggs distinctly modulate plasma carotenoid and lipoprotein subclasses in adult men following a carbohydrate-restricted diet. Mutungi G, Waters D, Ratliff J, Puglisi M, Clark RM, Volek JS, Fernandez ML. J Nutr Biochem. 2009 Apr 13. [Epub ahead of print] PMID: 19369056 We previously reported that carbohydrate restriction (CR) (10-15% en) during a weight loss intervention lowered plasma triglycerides (TG) by 45% in male subjects (P<.05). However, only those subjects from the EGG group presented higher concentrations of these two carotenoids in plasma, which were correlated with the higher concentra

What causes coronary heart disease or coronary atherosclerotic plaque, this thing that we track with heart scans? Well, here are a few little-publicized facts about heart disease that you are unlikely to hear from your When's-the-next-stent? cardiologist or the What is there besides statins? primary care doctor. (Since everybody knows that smoking is a modifiable risk for heart disease that can be readily identified, let's focus on the blood tests that reveal heart disease causes.)

Dietary mono- and polyunsaturated fatty acids similarly affect LDL size in healthy men and women. Kratz M, Gülbahçe E, von Eckardstein A, Cullen P, Cignarella A, Assmann G, Wahrburg U. J Nutr. 2002 Apr;132(4):715-8. PMID: 11925466 In conclusion, our data indicate that dietary unsaturated fat similarly reduces LDL size relative to saturated fat. However, the small magnitude of this reduction also suggests that the composition of dietary fat is not a major factor affecting LDL size.

Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia -- Krauss et al. 83 (5): 1025 -- American Journal of Clinical Nutrition Changes in peak LDL diameter (Table 2) and mass concentrations of LDL subfractions (Table 3) induced by each of the diets were reflected by changes in the proportions of subjects exhibiting LDL subclass pattern B (Figure 2). There were linear reductions in the prevalence of pattern B as a function of reduced carbohydrate intake after both the stable-weight and weight-loss periods. However, the slopes of these relations differed (P = 0.04) such that the magnitude of the reduction in expression of pattern B induced by weight loss increased in association with the percentage of carbohydrate intake. Conclusions: Moderate carbohydrate restriction and weight loss provide equivalent but nonadditive approaches to improving atherogenic dyslipidemia. Moreover, beneficial lipid changes resulting from a reduced carbohydrate intake were not significant after weight loss. Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT. Am J Clin Nutr. 2006 May;83(5):1025-31; quiz 1205. Erratum in: Am J Clin Nutr. 2006 Sep;84(3):668. PMID: 16685042