Inflammation Linked to Peripheral Atherosclerosis


Genetics likely also important, but no genetic marker has been identified

23 sept 2009-- Inflammatory markers are consistently associated with lower extremity peripheral arterial disease (PAD) and particular outcomes, but are not necessarily causally associated; and, although genetics may play an important role, no genetic marker has been associated with the disease, according to a review in the Sept. 29 issue of the Journal of the American College of Cardiology.

Mary M. McDermott, M.D., and Donald M. Lloyd-Jones, M.D., from Northwestern University in Chicago note that patients with lower extremity PAD have higher levels of inflammatory biomarkers, including C-reactive protein, interleukin-6, tumor necrosis factor-alpha and soluble adhesion molecules, and that the biomarkers are associated with adverse outcomes such as adverse calf skeletal muscle characteristics and cardiovascular mortality.

The reviewers observed that statin treatment is beneficial in PAD patients, possibly due to statins' ability to reduce inflammation, although clinical trials examining whether treatments that affect inflammatory biomarkers improve outcomes have not been done. An estimated 20 to 45 percent of PAD risk is attributed to genetics, but the authors note that a consistent genetic marker has not yet been identified.

"Despite the consistent associations of elevated inflammatory biomarkers with adverse outcomes in PAD, there are insufficient data to conclude that inflammatory biomarkers are causally related to adverse outcomes in PAD," the authors conclude. "Similarly, insufficient data exist to support targeting PAD patients who have higher levels of inflammation with more intensive secondary prevention therapies, such as antiplatelet therapies or statins."

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Low-Carb, High-Protein Diet Linked to Atherosclerosis

Study pitted mice on LCHP diet against the typical 'Western' diet and mice 'chow'

30 aug 2009--Mice on a low-carbohydrate, high-protein (LCHP) diet had more aortic atherosclerosis than mice on a typical "Western" diet, despite less weight gain and similar blood lipids, according to a study published online Aug. 24 in the Proceedings of the National Academy of Sciences.

Shi-Yin Foo, M.D., of Beth Israel Deaconess Medical Center in Boston, and colleagues fed mice either standard "chow" diet (65 percent carbohydrate, 15 percent fat, 20 percent protein), Western-style diet (43 percent carbohydrate, 42 percent fat, 15 percent protein, 0.15 percent cholesterol), or LCHP diet (12 percent carbohydrate, 43 percent fat, 45 percent protein, 0.15 percent cholesterol). The researchers examined the mice aortae, performed a serum analysis, and performed vascular or endothelial progenitor cell counts.

The researchers found that the mice on the low-carb diet gained 28 percent less weight than those on the "Western" diet, but had more plaque accumulation (15.3 versus 8.8 percent). The mice on the "chow" diet had minimal evidence of atherosclerosis. Tests for cholesterol, triglycerides, oxidative stress, insulin, glucose, and inflammatory cytokines were similar in the three groups or slightly favored the low-carb group, but endothelial progenitor cell counts dropped 40 percent in the mice on the low-carb diet.

"Although caution is warranted in extrapolating from such animal studies, these data at least raise concern that low-carbohydrate, high-protein diets could have adverse vascular effects not adequately reflected in serum risk markers. Moreover, these observations demonstrate important pathophysiological vascular effects of nonlipid macronutrients that are dissociated from weight gain," the authors conclude.

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Visceral Fat, Social Stress, Atherosclerosis Linked

Study shows social stress may exacerbate atherosclerosis by increasing visceral fat

14 aug 2009-- There is a direct relationship between coronary artery atherosclerosis, a high visceral to subcutaneous abdominal fat ratio, and social stress, supporting the hypothesis that social stress may worsen coronary artery atherosclerosis by increasing the amount of visceral fat in the body, according to research published in the August issue of Obesity.

Carol A. Shively, Ph.D., of the Wake Forest University School of Medicine in Winston-Salem, N.C., and colleagues performed a study in adult female cynomolgus monkeys. These monkeys were chosen from a larger pool because they exhibited a higher plasma ratio of cholesterol to high-density lipoprotein following one month of a moderately atherogenic diet, and were considered to represent the subset of the female population at greatest risk for developing atherosclerosis. These 41 monkeys were then socially housed and continued on this diet for 32 months.

The researchers found that atherosclerosis was more extensive among female monkeys with a higher visceral to subcutaneous abdominal fat ratio. Females with a high ratio of visceral to subcutaneous abdominal fat were found to be relatively subordinate, socially isolated, received less grooming, and were subject to more aggression. Furthermore, the authors note, these monkeys were desensitized to circulating glucocorticoids, had impaired ovarian function, higher heart rates, and increased coronary artery atherosclerosis.

Shively and colleagues conclude that, "an effective strategy to reduce the detrimental effects of stress on coronary artery atherosclerosis may be to directly intervene on the social stressors promoting physiological stress responses including distribution of fat."

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Waist-to-Hip Ratio a Better Marker of Subclinical Atherosclerosis Than BMI and Waist Circumference

August 15, 2007 — The relationship of the waist to hip measurement is independently associated with prevalent atherosclerosis, as measured by coronary artery calcium (CAC) imaging, and is a better discriminator of subclinical disease than other common measures of obesity, such as body mass index (BMI) or waist circumference alone, a new study has shown.[1] Those with the largest waist-to-hip ratio (WHR) were almost twice as likely to have calcium deposits in the coronary arteries compared with those with the least calcification, report investigators.
"These data confirm what others have shown for clinical events, that is when you link this data to some of the large outcome studies, it really does establish a consistent message that these measures of body shape — waist and the waist-to-hip ratio — predict not just clinical events but also atherosclerotic burden," senior investigator Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas, TX) told heartwire. "It also suggests that part of the mechanism in which central adiposity contributes to increased risk is through this increased atherosclerotic burden."
The results of the study are published in the August 14, 2007 issue of the Journal of the American College of Cardiology.
Data from the Dallas Heart Study
Speaking with heartwire, de Lemos said the large INTERHEART study, previously reported by heartwire, showed that the WHR and waist circumference were excellent predictors of cardiovascular events. With this in mind, the group sought to determine the underlying mechanism responsible for this increased cardiovascular risk. Some part of this risk is likely driven by atherosclerosis in the coronaries and the aorta, although high blood pressure, left ventricular hypertrophy, or inflammation and thrombosis have all been proposed as risk factors explaining the increased morbidity and mortality risk associated with obesity, explained de Lemos.
Additionally, de Lemos noted there is a complex relationship between BMI and cardiovascular risk, an almost J-shaped relationship, where those with a very-low BMI having greater atherosclerotic burden than those with a higher BMI. Also, BMI doesn't reflect obesity, but rather mass, and is not a measure of central adiposity and cardiovascular risk. The purpose of this study, he said, was to evaluate the association between different measures of obesity and atherosclerosis in addition to determining if obesity was associated with subclinical cardiovascular disease.
Investigators obtained data from the Dallas Heart Study, a large, multiethnic urban population of patients who successfully completed electron-beam computed tomography (EBCT) to detect coronary artery calcium and magnetic resonance imaging (MRI) to detect aortic plaque. They found that the likelihood of coronary calcification grew in direct proportion to increases in the WHR. In multivariate analysis, after adjusting for standard risk factors, prevalent coronary artery calcium was more frequent in the fifth versus first quintile of WHR. Those with the largest WHR were nearly twice as likely to have calcium deposits in their coronary arteries as those with the smallest WHR. There was no independent positive association observed for BMI or waist circumference.
"The finding that was most striking to me was the linear association with the waist-to-hip ratio," said de Lemos. "We don't have huge statistical power here so this will need to be confirmed in other studies, but it is interesting that this is a linear, step-wise association across the quintiles. From a public health perspective, this is not the sort of thing where we only look at the guy with the biggest beer belly and say this guy is the one to worry about. This thing may have broader implications in the sense that the average person, even though they are average by US standards, still appears to have more atherosclerosis than people with the lowest waist-to-hip ratio."
Among those who underwent MRI, the investigators also showed that the risk of atherosclerotic plaque in the aorta was three times as high in those with the largest WHR compared with those who had the smallest WHR.
The associations between obesity measurements and atherosclerosis in this study, said de Lemos, mirror those observed between obesity and cardiovascular mortality and suggest that obesity contributes to the risk via increased atherosclerotic burden. As to why WHR is a better measure of subclinical disease, de Lemos said it is an indexed value to lower body girth and provides a more precise assessment of relative central adiposity across the body sizes compared with waist circumference. Additionally, there is some evidence that fat accumulated in the hips might be cardioprotective.
"That appears to be the case in this study," said de Lemos. "Large hips seemed to be protective if you had a normal or smaller waist. On the other hand, it didn't appear protective if the waist was greater than the median value. Having big hips doesn't protect you if you let your belly get too big."
See R, Abdullah SM, McGuire DK et al. The association of differing measures of overweight and obesity with prevalent atherosclerosis. J Am Coll Cardiol 2007;50:752-759.

Diesel Fumes Team Up With Cholesterol for Atherosclerosis

LOS ANGELES, July 27 -- Diesel pollution may induce cardiovascular risk, researchers found in a genome-wide study.
Diesel fumes synergistically link up with cholesterol to activate genes that turn up atherosclerosis and vessel inflammation, according to Andre Nel, M.B.Ch.B., Ph.D., of the University of California, Los Angeles, and colleagues.
In vitro and mouse studies revealed that a low dose of diesel exhaust particles combined with oxidized phospholipids generated in LDL cholesterol upregulated 1,555 genes, of which the most upregulated clusters were in pathways related to vascular inflammation and atherosclerosis, they reported in the July 26 issue of Genome Biology.
Of the upregulated genes, 43% exhibited synergy when the diesel particles and oxidized phospholipids were combined.
"Our gene-expression data are of considerable importance in understanding how ambient air pollution might contribute to endothelial injury and to atherosclerosis," they wrote.
Air pollution, particularly ambient particulate matter, has been associated with increased cardiovascular morbidity and mortality in previous studies, although the mechanism has been debated.
But, "it is becoming increasingly clear that particulate matter exerts pro-oxidative and pro-inflammatory effects in the lung that can also spill over to the systemic circulation," they added.
The researchers conducted a series of experiments to clarify how the process occurred. They first looked at heme oxygenase-1, an important oxidative stress sensor in endothelial cells.
They found that human microvascular endothelial cells had a 15-fold higher density of this protein when treated with diesel exhaust particles plus phospholipid oxidation products than when treated with diesel exhaust particles alone and five-fold more than when treated with phospholipid oxidation products alone.
Then, they assessed gene-expression profiles using microarrays and found that at total of 1,555 genes were significantly upregulated by at least 1.5-fold (P<0.05) when the cells were treated with diesel exhaust particles or oxidated phospholipids. Again, the combination showed the largest effect and altered expression of more genes than either alone.
When the genes were grouped using weighted gene coexpression network analysis, 664 of the 1,555 significantly upregulated genes showed synergism when treated with the combination of diesel exhaust and oxidated phospholipids.
Furthermore, 83% of these synergistically expressed genes were concentrated in three groups of densely interconnected genes.
These groups included around 40% of the electrophile-response element-regulated genes, around 58% of the pro-inflammatory response genes, around 84% of the apoptosis pathway genes, and around 79% of the unfolded protein response genes present in entire network.
The synergistic upregulation was confirmed by quantitative polymerase chain reaction (qPCR).
Finally, the researchers showed that these pathways were activated in vivo.
They compared mice fed a high fat diet and exposed to dirty ambient air in a mobile animal laboratory in downtown Los Angeles (concentrated ultrafine particles < 0.18 μm, predominantly diesel exhaust particles) to those exposed to concentrated larger particulate matter (fine particles < 2.5 μm) or to filtered-air or left unexposed.
The mice exposed to the ultrafine, mostly diesel particles, had significantly upregulated genes for heme oxygenase-1, the oxidative stress sensor in endothelial cells, as well as for two key unfolded protein response gene transcription factors compared to the other three groups of mice (P<0.05).
"The systemic effects could result either from the systemic release of inflammatory mediators from the lung or from the possible direct access of particles or chemicals to the systemic circulation," the researchers suggested.
Either way, the interaction of particulate matter vascular endothelium in the lung or systemic circulation "may be relevant in the generation of systemic vascular effects" and, they proposed, may be "magnified by their interaction with oxidized phospholipids generated in LDLs or in the membranes of vascular endothelial cells."
The study was supported by grants from the National Institute of Environmental Health Sciences, the National Institute of Allergy, Immunology and Infectious Diseases, the Robert Wood Johnson Foundation, and the National Heart, Blood and Lung Institute as well as by an award to the Southern California Particle Center. Primary source: Genome BiologySource reference: Gong KW, et al "Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells" Genome Biol 2007.

Middle Age Not Too Late to Lower Cardiac Risk

Adopting a healthy lifestyle after age 45 may confer cardiovascular and mortality benefits even just 4 years later, according to a study in the July edition of the American Journal of Medicine.


To study the origin and progression of atherosclerosis, researchers prospectively followed roughly 16,000 adults aged 45 to 64 at baseline. After 6 years, about 1000 had newly adopted an overall healthy lifestyle, defined as four behaviors: eating at least five fruits and vegetables daily, exercising at least 2.5 hours weekly, maintaining a BMI between 18.5 and 30, and not smoking. Some 11,000 were following three or fewer of these behaviors.


During the next 4 years, those who had newly adopted all four behaviors had a 40% reduction in all-cause mortality and a 35% reduction in cardiovascular events, compared with those who were following three or fewer healthy behaviors.


The authors conclude that adhering to a healthy lifestyle is "extremely worthwhile, and that middle-age is not too late to act."

Statin therapy slows progression of arterial thickening; halts but does not reverse atherosclerosis

Among low-risk middle-aged people with subclinical atherosclerosis, the cholesterol-lowering drug rosuvastatin reduces the rate of progression of arterial thickening and stops but does not reverse atherosclerotic disease, according to a study in the March 28 issue of JAMA. The study is being released early to coincide with its presentation at the American College of Cardiology's annual conference.
Lipid-lowering therapy has been shown to reduce cardiovascular events in a large number of studies. Statin drugs as well as other agents and lifestyle changes have also been shown to slow the progression of and even regress atherosclerosis, according to background information in the article. Atherosclerosis is the progressive thickening and hardening of the walls of medium-sized and large arteries as a result of fat deposits on their inner lining. Atherosclerosis is often advanced before symptoms appear, and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (a measure used to predict the risk of cardiovascular disease) and mild to moderate subclinical atherosclerosis.
John R. Crouse III, M.D., of the Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues conducted a randomized study of 984 individuals. The Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) study was designed to investigate the effect of a 40-mg. dose of rosuvastatin on carotid intima-media thickness (CIMT, a measure of the thickness of the middle layers of the carotid arteries) over two years in middle-aged individuals with low Framingham risk scores, but with evidence of subclinical atherosclerosis.
"Rosuvastatin treatment was associated with a 49 percent reduction in LDL-C ["bad" cholesterol] level, a 34 percent reduction in total cholesterol level, an eight percent increase in HDL-C ["good" cholesterol] level, and a 16 percent reduction in level of triglycerides," the authors write.