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Conversely, lifestyle, diabetes, dyslipidemia, cigarette smoking and hypertension contribute to most of the population-attributable risk in the large, international INTERHEART study of acute myocardial infarction (heart attacks). The identification of single gene disorders may pave the way to a better understanding of complex metabolic pathways. Understanding the genes that regulate high density lipoprotein (HDL) metabolism may lead to novel therapeutic approaches. This has been emphasized by two therapeutic approaches for the treatment of CAD:

 

• The infusion of apo AI containing proteoliposomes, using wild-type or a mutant form of apo AI, apo AIMilano, in patients with acute coronary syndromes;

   

   

• The long-term treatment of subjects with low HDL-C with the cholesteryl ester transfer protein (CETP) inhibitor Torcertapib. While Torcetrapib proved to have off-target toxic effects, two other CETP inhibitors (Anacetrapib and Delcetrapib) are being tested clinically. Experimentally, however, CETP inhibitors may not reduce atherosclerosis

   

Novel therapeutic approaches using agonists of the LxR/RxR pathway to up-regulate the ABCA1 transporter, or the transcriptional regulation of apo AI, are being explored.

Plasma (or serum) level of HDL-C is a continuous and graded negative cardiovascular risk factor. Most international CAD prevention guidelines define HDL-C as a categorical risk factor and the absolute level of HDL-C is used in a multivariate model to predict cardiovascular risk and determine the need and intensity of preventive therapies. A low HDL-C is considered a diagnostic criterion for the metabolic syndrome.

To underlie the importance of plasma lipoproteins in the pathogenesis of CAD and acute myocardial infarction, the largest case-control study of myocardial infarction (INTERHEART) has shown that the apo B/apo AI ratio (respectively an index of atherogenic lipoproteins and protective lipoproteins) accounts for approximately half (49%) of the population-attributable risk of acute myocardial infarction. The prevalence of a low HDL-C in patients with CAD has been examined in several case-control and prospective studies. It is estimated that approximately 40% of patients with premature CAD have a low HDL-C and this represents the most common lipoprotein disorder in patients with CAD. Most patients with a low HDL-C have multiple cardiovascular risk factors and features of the metabolic syndrome, with obesity (predominantly abdominal), elevated plasma triglyceride levels, high blood pressure and hyperglycemia, insulin resistance or diabetes. Despite the strong association between metabolic disorders and HDL-C, plasma levels of HDL-C are strongly genetically determined. Experimental evidence shows that the atheroprotective effects of HDL are pleiotropic and extend beyond removing cholesterol from lipid-laden macrophages in the atherosclerotic plaque. HDL are known to have anti-inflammatory effects, to prevent oxidation of low-density lipoproteins (LDL), possess anti-thrombotic properties, modulate vasomotor tone and may improve endothelial cell survival (by preventing apoptosis), migration and proliferation. Nonetheless, the major cardio-protective effect of HDL has been attributed to its key role in reverse cholesterol transport, a process in which cholesterol from peripheral tissues such as foam cells is selectively returned to the liver for excretion in the bile. Mutations in any of the proteins regulating this complex metabolic pathway may potentially decrease HDL-C levels and accelerate CAD.

Mutations or polymorphisms in several genes have been associated with altered plasma HDL-C levels. Mutations in the cholesteryl ester transfer protein (CETP) gene are associated with increases in HDL-C whereas mutations in the apolipoprotein (apo) AI gene (the major apolipoprotein of HDL particles), or the lecithin:cholesterol acyl transferase (LCAT) gene cause a low HDL-C. Of the approximately 46 mutations affecting the structure of apo AI, not all are associated with CAD. Mutations in the lipoprotein lipase (LPL) and hepatic lipase (HL) genes also affect HDL-C levels. The identification of the ATP binding cassette A1 gene (ABCA1) as the cause of Tangier disease and familial HDL deficiency has led to a better understanding of the role of cellular cholesterol and phospholipid transport in the metabolism of nascent HDL particles. Based upon the analysis of a selected group of subjects, we estimate that approximately 10-20% of subjects with severe HDL deficiency have mutations of the ABCA1 gene. Other genes have been found in animal models to have a profound impact on HDL-C levels, although no human counterpart disorders have yet been identified.

To examine the genetic contribution to the determination of HDL-C levels, there have been at least nine published studies in twins and 14 family studies. Estimates for the heritability of plasma HDL-C levels varies between 0.24 to 0.83 and is most often quoted as approximately 0.5.

The inverse epidemiological association between serum levels of HDL-C and risk of CAD is graded and has been validated in multiple studies. However, there is remaining controversy whether a low HDL-C should not predominantly be considered a marker of poor lifestyle (obesity, lack of exercise, hypertriglyceridemia, diet, etc.), rather than a primary causal agent for atherosclerosis in the majority of the population. Specific mutations in genes affecting HDL-C levels have had considerable discordant effects on CAD risk. For instance, mutations in the apo AI gene affecting HDL-C levels can be strongly associated with premature CAD, but apo AIMilano and apo AIParis are notable exceptions. Mutations in the LCAT gene cause a marked decreased level of HDL-C but are not considered to be associated with CAD. While loss-of-function mutations in the CETP gene cause an elevated HDL-C, cardiovascular risk does not seem decreased and may in fact be increased. Mutations in ABCA1 are associated with very low HDL-C and increase cardiovascular risk 3.5 fold in one study, but more recent data from the Copenhagen Heart Study suggests that ABCA1 mutations are not associated with increase cardiovascular risk, despite being associated with a low HDL-C. Important questions therefore remain which genetic forms of HDL deficiency confer cardiovascular risk. This has implications for the identification and treatment of patients with HDL deficiency. It remains to be determined whether a genetic form of HDL deficiency confers cardiovascular risk.

Source: European Society of Cardiology

Genetics of HDL and risk of cardiovascular disease

Heritability of HDL-C

Genes that affect HDL-C levels

Epidemiology of HDL and risk of coronary artery disease CAD risk

Elevated cholesterol levels return to normal or near normal levels over time in four out of 10 children with uncontrollable epilepsy treated with the high-fat ketogenic diet, according to results of a Johns Hopkins Children’s Center study reported in the Journal of Child Neurology. The study appears online ahead of print at http://jcn.sagepub.com/cgi/reprint/23/7/758.

In the four-year study, the Hopkins Children’s team followed 121 epileptic children with intractable seizures on the high-fat, low-carbohydrate ketogenic diet designed to control such seizures. While most children developed high cholesterol after starting the diet, cholesterol gradually improved in nearly half of them, returning to normal or near-normal levels, with or without modifications to their diet to reduce fat intake.

In fact, researchers point out, diet modifications-including reducing total fat content or certain types of fats called saturated fats and adding nutritional supplements-reduced high cholesterol just as much as doing nothing. High cholesterol is defined as total cholesterol greater than 200 mg per deciliter of blood, bad or LDL (low-density lipoprotein) cholesterol greater than 130, triglycerides greater than 130, and good or HDL (high-density lipoprotein) lower than 35.

Researchers prescribed dietary modifications to increase “good,” polyunsaturated fats in the diets of 15 children with elevated cholesterol. Dietary modifications decreased cholesterol by 20 percent in 9 out of the 15 (60 percent) children whose diets were modified. Surprisingly, cholesterol also dropped by at least 20 percent in 41 percent of the 37 children whose diets remained unchanged. The findings, while encouraging overall, also mean that relying on diet changes alone may not do much for those children in whom cholesterol remains persistently elevated, and that new approaches for these patients are needed, researchers say.

The findings should come as comforting news to pediatric neurologists, general pediatricians and parents of children treated with the ketogenic diet, and reassure them that, in most patients, increases in cholesterol may be short-lived, researchers say. Previous long-term studies by the Hopkins group of children who were on the diet between six and 12 years echoed these findings. The ketogenic diet, believed to work by triggering biochemical changes that eliminate seizure-provoking short-circuits in the brain’s signaling system, is used in many children with hard-to-control epilepsy and in those whose seizures do not respond to traditional anticonvulsant medications.

“We are greatly encouraged by our findings because the nearly half of the children on the diet were either able to maintain healthy cholesterol or gradually metabolized the extra fat and returned to somewhat normal cholesterol levels,” says senior investigator Eric Kossoff, M.D., a pediatric neurologist at Hopkins Children’s. “This means the benefits of the diet-a diet that is lifesaving in many children and therapeutic in most of them-continue to outweigh the risks.”

Noting that 40 percent of children maintained normal cholesterol even after starting the diet, researchers found that children fed a formula-based, liquid-only ketogenic diet were nearly three times less likely to develop high cholesterol. Researches attribute this finding to the nearly zero fat content in commonly used ketogenic diet formulas.

In the group with normal cholesterol, 78 percent of children (31 out of 40) were fed formula-based ketogenic diet. This finding, while requiring further study, points to another possible treatment for high cholesterol, Kossoff says, by switching children with persistently elevated cholesterol to formula-based ketogenic diets at least some of the time. The formula-based ketogenic diet contains only one-third the amount of saturated fats-the worst kind in terms of cholesterol-of the solid food version of the ketogenic diet. Because doctors can tweak the ratio of fat vs. carbohydrates depending on each child’s severity of seizures, the investigators examined whether higher-fat versions of the ketogenic diet raised cholesterol additionally, but found that higher-fat ratio did not make cholesterol worse than a lower-fat ratio.

Some of the other findings:

• One-fourth of 121 children had elevated total cholesterol before starting the diet, which increased to 60 percent (59 out of 99 children at follow-up) after the initiation of the diet.
• 18 percent (22 out of 119) had triglycerides over 130 before the diet, which increased to 51 percent (49 out of 96) after starting the diet.
• 19 percent (21 out 110) had bad cholesterol over 130 before the diet, which increased to 53 percent (48 out of 93) after starting the diet.

Source: Johns Hopkins Medical Institutions

Beware of mini-packs and mini-foods, especially if you’re a dieter.

Chronic dieters tend to consume more calories when foods and packages are smaller, according to a new study in the Journal of Consumer Research. Authors Maura L. Scott, Stephen M. Nowlis, Naomi Mandel, and Andrea C. Morales (all Arizona State University) examined consumer behavior regarding “mini-packs,” 100-calorie food packages that are marketed to help people control calorie intake.

“Interestingly, one group that over-consumes the mini-packs is chronic dieters—individuals constantly trying to manage their weight and food intake,” write the authors.

The researchers believe their research shows that the ubiquitous small packages may actually undermine dieters’ attempts to limit calories. “On the one hand, consumers perceive the mini-packs to be a generous portion of food (numerous small food morsels in each pack and multiple mini-packs in each box); on the other hand, consumers perceive the mini-packs to be diet food. For chronic dieters, this perceptual dilemma causes a tendency to overeat, due to their emotion-laden relationship with food.”

In a series of studies, the researchers assessed peoples’ perceptions of M&Ms in mini-packs versus regular-sized packages. They found that participants tended to have conflicting thoughts about the mini-packs: They thought of them as “diet food,” yet they overestimated how many calories the packages contained. In subsequent studies, the researchers assessed participants’ relationship with food, dividing them into “restrained” and “unrestrained” eaters. The “restrained” eaters tended to consume more calories from mini-packs than “unrestrained” participants.

The authors conclude that dieters should keep an eye on small packages: “While restrained eaters may be attracted to smaller foods in smaller packages initially, presumably because these products are thought to help consumers with their diets, our research shows that restrained eaters actually tend to consume more of these foods than they would of regular foods.”

Source: University of Chicago Press Journals

“We know that parents have tremendous influence over how many fruits and vegetables their children eat,” says Debra Haire-Joshu, Ph.D., a professor at the George Warren Brown School of Social Work. “When parents eat more fruits and vegetables, so do their children. When parents eat and give their children high fat snacks or soft drinks, children learn these eating patterns instead.”

Haire-Joshu and researchers at Saint Louis University School of Public Health tested a program that taught parents in their homes how to provide preschool children easy access to more fruits and vegetables and examined whether changes in what the parents ate affected what their children consumed. The study was published in the July issue of the journal Preventive Medicine.

“This research shows that it’s important to communicate with parents in real world settings,” Haire-Joshu says. “They control the food environment for their young child. This environment is key to not only what children eat today but how they will eat in the future.”

Past research has shown that diets high in fruits and vegetables are associated with a lower risk of obesity. Previous studies also have established that children learn to like and eat vegetables at a young age — before they turn five years old.

In this five-year study in rural, southeast Missouri, 1,306 parents and children between the ages of two and five participating in Parents As Teachers, a national parent education program, were randomly assigned to two groups. One group enrolled in the High 5 for Kids program, and the other group received standard visits from Parents as Teachers. In the High 5 for Kids group, parents first completed a pretest interview about fruit and vegetable consumption.

Parent educators then visited the home four times, providing examples of parent-child activities designed around nutrition, such as teaching the child the names and colors of various fruits and vegetables and having the child select a variety of fruits and vegetables for breakfast. At each visit, parents also received materials and informational handouts with suggestions for improving feeding practices and the food environment in the home. Many of these materials were tailored to the individual patterns of that parent, with suggestions for how to improve his or her specific intake and that of their child.

Additionally, children were given four High 5 for Kids sing-along-stories with audiocassettes and coloring books.

The same parent interviewed before the intervention completed a telephone survey to determine changes in the number of fruits and vegetables eaten and behaviors of both the preschool children and parent. The average time between the before and after intervention survey was seven months.

Parents in the High 5 for Kids group ate significantly more fruits and vegetables, and a change in the parent’s servings of fruits and vegetables predicted a change in the child’s diet, too. An increase of one fruit or vegetable serving per day in a parent was associated with an increase of half a fruit or vegetable serving per day in his or her child. These parents also reported an increase in fruit and vegetable knowledge and availability of fruits and vegetables in the home.

Although the High 5 for Kids program was effective in improving fruit and vegetable intake in children of normal weight, overweight children in this group did not eat more of these foods. “Overweight children have already been exposed to salty, sweet foods and learned to like them,” says Haire-Joshu, who also holds an appointment at the School of Medicine as a professor. “To keep a child from becoming overweight, parents need to expose them early to a variety of healthy foods and offer the foods many times.”

Haire-Joshu says many children today are taught patterns that lead to obesity. “We want families to provide their child with an environment in which they not only learn how to eat healthy but have the opportunity to practice what they learn,” she says. “And by partnering with Parents As Teachers, we now can disseminate this program to their sites nationwide. This further impacts healthy eating patterns in parents and their preschool children.”

Source: Washington University in St. Louis