The JUPITER Trial: thoughts on C-Reactive Protein, how to lower it and a comparison with vitamin D

Jacob Schor, ND, FABNO

November 13, 2008

All it seems my patients want to ask about these days is, “… the new drug study, the one that says I need to take statins even though my cholesterol is normal.” 

They are referring to a recent and widely publicized paper in the November 9 issue of the New England Journal of Medicine (NEJM) nicknamed the JUPITER Trial. The catchy name JUPITER stands for “Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin.” Drug company AstraZeneca funded this study and in it refers to their product Crestor by its technical name, Rosuvastatin.  I confess to wondering if this acronym ‘just happened’ or whether some brilliant PR wonk got paid for making it up.

After reading the local newspapers or hearing a quick summary on the evening news, my patients believe exactly what the people at AstraZeneca want them to, “Everyone should be taking this drug.”  I want to separate what parts of this study are clinically relevant apart from all the sales hype designed to sell the drug.

 The JUPITER study looked at people with what, up to now, was considered acceptable levels of low density lipoprotein  (LDL) but who had high levels of C-reactive protein (CRP).  Remember LDL is what everyone calls ‘bad cholesterol.’  CRP is a marker for inflammation, and high levels increase risk for cardiovascular disease. You don’t hear much about CRP in the popular press yet.  Yet it’s well established that high CRP is a marker for high risk of heart attack or stroke. It’s also already been proven that statin drugs lower CRP.  No wonder AstraZeneca had the foresight to pay big bucks for this experiment that showed statins could, by lowering CRP, prevent heart attacks.  We are not talking about just any statin, Rosuvastatin (aka Crestor) is the Cadillac of statin drugs costing about $3.45 per day. 

Speaking of Cadillacs, JUPITER was one fancy trial.  Test subjects numbered nearly 18,000 and were followed at 1315 different locations in 26 countries. To find these ideal test subjects, AstraZeneca screened nearly 90,000 people. The study was randomized, placebo-controlled, and double blinded.  It clearly demonstrated that Crestor worked, lowering CRP, lowering the risk of having a heart attack, lowering the risk of stroke and in act lowering the risk of dying from anything.

Test subjects were either men over 50 or women over 60 with no history of cardiovascular disease.  To be enrolled in the study, initial LDL cholesterol levels had to be below 130 and CRP over 2.0 mg.

The results were striking enough that after only two years, the researchers dramatically shut down the study, broke the code and announced that Crestor worked better than placebo.  The study was supposed to go for five years.  Critics have suggested the early shutdown was because the longer it lasted the more likely to see harmful side effects build up.

Still the reported numbers are impressive.  Compared to placebo, daily doses of Crestor:

  • Lowered LDL cholesterol 50% .
  • Lowered CRP 37%
  • Reduced first major cardiovascular event from 1.36 per 100 person-years to 0.77.
  • Reduced  MI from 0.37 to 0.17.
  • Reduced stroke from 0.34 to 0.1.
  • Reduction of revascularization for unstable angina from 0.77 to 0.41
  • Reduced all-cause death rate from 1.25 to 1.0

The important thing here is that Crestor worked people with reasonable cholesterol levels who are at low risk.  Thus this information opens the doors to sell these drugs to more people. 

During the two years of the study no huge danger was seen in those using Crestor. Older fears that statins cause cancer had already been silenced by a paper published in September.   The same was seen in the JUPITER data; fewer cancer diagnoses and fewer cancer deaths in the Crestor group. There was an increase in people who developed diabetes during the study in those taking Crestor, 3 % versus 2.4 %.

This study is clearly brilliant if you want to sell an expensive drug to people who didn’t think they need it.  Though the statistics look dramatic at first glance, recall they are dealing with people at low risk for having cardiovascular problems. The researchers drafted a lot of people for the study in order to tease out these results.   If you do the math, 95 people need to take Crestor for over 2 years or 25 people have to take it for more than 5 years to prevent one cardiovascular event.  Actually that 95 statistic comes from the study authors.  When the editors at the NEJM did the math they came up with a different number, writing that “treating 120 people for about two years would help one person.”

At a cost of $3.45 a day for those 120 people, the cost of helping that one person would be about $302, 220.

LDL cholesterol levels in the people taking Crestor, dropped way down, to about 55 mg/deciliter.  We don’t know what this might do to people who take the drug longer than the two years this trial lasted.  Past research has shown a link between low cholesterol and increased risk of death by suicide. There are other things we don’t know.  We don’t know if other cheaper statin drugs will work.  We have no idea if Crestor will help people who start with normal CRP levels.  We do know that this study is a goldmine for AstraZeneca.

 Probably the most important gem of information that JUPITER reveals is that lowering CRP is a good thing.  This should encourage us to test for CRP.  It only costs about $25 to run the test and seems like money well invested.

Here’s the other detail that both AstraZeneca and NEJM forgot to mention. Paul Ridker, the lead investigator of the study, apparently owns the patent on the test used to measure CRP.  If true, every time the test is run, he makes money. 

So what about all this hype is useful.  JUPITER does seem to confirm the idea that lowering CRP is good for people.  It tells us that people can do this with drugs, expensive drugs.  It doesn’t tell us that drugs are the only or the most effective way to lower CRP.

Natural Ways to Lower CRP:

There are more ways to lower CRP than by swallowing expensive pills.  The best strategies to lower CRP focus on lifestyle not drugs.  Fat tissue secretes inflammatory chemicals that trigger the liver to make CRP.  Reduce fat tissue and you reduce CRP.  Weight loss lowers CRP. Exercise lowers CRP.  Regular consumption of a little alcohol interestingly lowers CRP.  High CRP also increases risk of type 2 diabetes, colorectal and other cancers. Lowering it makes good sense for numerous reasons.

What one eats makes a difference.  High intakes of carotenoids and vitamin C decrease CRP.  High consumption of vegetables and fruit are also lowers CRP, perhaps by exerting anti-inflammatory effects. 

The anti-inflammatory effects of the Mediterranean Diet are well documented. A Greek study found cardiac risk varied with how closely people followed a ‘traditional  Mediterranean diet.”   The more you eat like you are from Greece, the lower your CRP will be. Probably the most important chemicals to lower CRP are the flavonoids. An article in last April’s Journal of Nutrition found CRP had a direct inverse relationship to dietary flavonoid intake in the American population.  The more flavonoids in the diet, the lower the CRP. Not just flavonoids but also anthocyanidins, and isoflavones made a difference.  These are the chemicals found in fruits and vegetables.

In the modern American diet the most common sources of flavonoids are, “tea (157 mg), citrus fruit juices (8 mg), wine (4 mg), and citrus fruits (3 mg).”

Remember CRP is a marker of inflammation so it’s no surprise that foods that have an anti- inflammatory effect lower CRP. For example fruit juice lowers CRP.  Not surprisingly, sugar sweetened water raises CRP.   Both orange juice and tomato juice in particular lower CRP. Two weeks of drinking tomato juice lowers CRP by almost 20%.   Replacing sugar sweetened carbonated drinks with fruit juices may have as much impact as putting the same people on drugs.

Our regular readers understand that I am fixated with curcumin.  As you’ve heard me explain too many times already, curcumin is the active chemical extract from the Asian spice turmeric.  Recall that it has a pronounced anti-inflammatory action, protects against cancer, heals nerve damage, and in some studies lowers cholesterol.  It is not surprising to read that it also lowers CRP.   In contrast to these new drugs, turmeric and curcumin have a long, long history of use and no worries about safety.   The mechanics of how curcumin works and how it triggers anti-inflammatory action are well understood.  

The omega-3 fats are often promoted as anti-inflammatories that are protective against heard disease.  So far the results have been mixed on whether they lower CRP. Concentrated fish oils are a current best seller in the supplement world, mostly for their anti-inflammatory effect.  At this point it isn’t clear what they do to CRP.  Some studies show that fish oils reduces CRP.   Other studies, for unknown reasons, do not  demonstrate these positive effects. 

Similar data exists for another omega-3 fat source, nuts.  Some studies show that nuts lower CRP.   Other studies show no change in CRP with high nut consumption.

Plant sterols, the stuff plants make instead of cholesterol,  that are promoted to lower cholesterol, clearly lower CRP.  Drinking an orange juice and sterol mix for two months lowered CRP by 12 %.     Drinking tomato juice prevents oxidation of LDL cholesterol, the thing that most scientists view as the crucial step in triggering atherosclerosis, and tomato juice lowers CRP.   Grape juice and wine probably do the same as they contain resveratrol, a chemical that lowers CRP.   Grape juice has an additional advantage as it also lowers the monocyte attractant protein, making blood cells less sticky and more likely to clump together and clot triggering strokes.   Flax seed lignins also lower CRP.   

Are you getting the idea? 

Lots of things lower CRP.  Exactly how much lifestyle and diet will lower CRP is not clear.  Neither AstraZeneca nor other major drug manufacturers are investing money to find this out.

CRP versus Vitamin D:

To put these JUPITER results in some perspective contrast both the press coverage and the results of the JUPITER trial to the lack of attention given the German vitamin D and cardiovascular risk paper published last June in the Archives of Internal Medicine.  In that study, researchers reported that of 3,258 consecutive patients followed for almost 8 years.  Those patients with low levels of vitamin D were almost twice as likely to die from any cause and also from heart disease compared to those who had the highest levels of vitamin D in their blood.  Here’s the part that gets me.  Those patients who had the most vitamin D, the ones half as likely to die, had a median 25(OH)D level of 28.4 ng/mL.   This is a low;  all experts and most labs classify as ‘insufficient.’

An American study published in January’s issue of Circulation had reported similar findings.  Their results showed that the lower a person’s vitamin D, the higher their risk of having heart problems.  Following patients for five and a half years (not the two in JUPITER), people with levels below 15 ng/mL were 60% more likely to have a ‘cardiac event’ as those who had vitamin D levels above 15 ng/mL.  Again both these levels are considered deficient.

Those Germans from June had a second paper published just this past October, providing even more information, most importantly giving us information on patients with decent vitamin D status, not just comparing the deficient with the more deficient.  Just to make life complicate, the authors switched units of measurement for reporting vitamin D, using nanomoles per liter instead of nanograms/ml.   For those of you who will ask if I don’t tell: one ng/ml equals about 2.496 nanomoles per liter.  Patients with vitamin D levels below  25 nmol/liter (10 ng/mL) compared to those over  75 nmol/liter (30 ng.mL) were 2.84 times as likely to die due to heart failure and 5.05 times as likely to die of sudden cardiac death. 

Keep these various tidbits of information in perspective.  Vitamin D deficiency is at least as common if not more common than elevated CRP.  The significant difference in comparing the vitamin D studies to JUPITER is who the people they followed were.  JUPITER looked at low risk populations.  Though they cut heart attack risk by 50%, what this means is from 0.37 to 0.17 per hundred people per year.  Hardly something you would notice clinically. The German vitamin D studies in contrast looked at consecutive patients waiting to have a coronary angiograph, in other words people at ten times the risk as the JUPITER participants of dying from a heart attack. Lowering CRP makes sense but identifying and treating low vitamin D may save more lives.

Even if there are underlying and undisclosed profit motives behind the JUPITER Trial, the benefit of screening for and treating elevated c-reactive protein levels now appears valid. Whether lifestyle, diet and nutritional interventions will prove to be as effective as Crestor at lowering CRP is not known.  Testing for and treating for vitamin D deficiency continues to appear more important especially in a high risk population.

 

 

 

 

Note: testing for c-reactive protein  (CRP) cost about $25.  Testing for vitamin D, the 25(OH)D level, about $75.  We can order both tests for out clinic patients.

Full text of the JUPITER Trial:  http://content.nejm.org/cgi/content/full/NEJMoa0807646v1

Abstract: http://content.nejm.org/cgi/content/abstract/NEJMoa0807646v1

References:

New York Times. A Call for Caution in the Rush to Statins. November 18, 2008  Tara Parker-Pope.

J Am Coll Cardiol. 2008 Sep 30;52(14):1141-7.  

    Statins, low-density lipoprotein cholesterol, and risk of cancer.

    Alsheikh-Ali AA, Trikalinos TA, Kent DM, Karas RH

Editorial NEJM Nov 9, 2008

Asian Pac J Cancer Prev. 2007 Apr-Jun;8(2):167-77.

    Impact of C-reactive protein on disease risk and its relation to dietary factors.

    Nanri A, Moore MA, Kono S.

    Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. nnrakiko@phealth.med.kyushu-u.ac.jp

    C-reactive protein (CRP) is one of the acute-phase proteins in inflammation and CRP serum concentrations are therefore of interest. Data for high-sensitivity CRP (hs-CRP) with a low detection limit of approximately 0.04 mg/L have become available over the past decade and research has shown a link between high concentrations of hs-CRP and obesity as well as smoking. Expanded adipose tissue is in fact known to secrete proinflammatory cytokines which enhance hepatic synthesis of CRP. Moderate alcohol consumption and high physical activity have been associated with low levels of hs-CRP, but the evidence in these cases is not conclusive. It has been suggested that hs-CRP is an independent marker of the risk of cardiovascular disease, but the predictive capacity remains controversial. However, many prospective studies have observed increased risk of type 2 diabetes mellitus associated with high concentrations of hs-CRP, independent of obesity and other cardiovascular risk factors. On the other hand, no measurable increase in the risk associated with high levels of hs-CRP was observed with multivariate adjustment in several studies. A number of authors have reported that high concentrations of hs-CRP are associated with increased risks of colorectal and other cancers, but the findings again are inconsistent. Diet and hs-CRP are also of increasing research interest. High intakes of carotenoids and vitamin C, but not of vitamin E, seem to decrease the level of circulating hs-CRP. In addition, high consumption of vegetables and fruit are associated with lower levels of circulating hs-CRP, perhaps by exerting anti-inflammatory effects. Both mechanistic and epidemiologic studies regarding dietary factors and low-grade inflammation are necessary to add to our knowledge of dietary influence on chronic disease development.

Vasc Med. 2008;13(2):113-21.   

    Five-year incidence of cardiovascular disease and its predictors in Greece: the ATTICA study.

    Panagiotakos DB, Pitsavos C, Chrysohoou C, Skoumas I, Stefanadis C; ATTICA Study.

    Collaborators (14)

    Skoumas Y, Katinioti N, Papadimitriou L, Masoura D, Vellas S, Lentzas Y, Tsetsekou E, Vassiliadou C, Kambaxis M, Palliou K, Toutouza-Giotsa M, Tselika C, Poulopoulou S, Toutouza M.

    Department of Dietetics-Nutrition, Harokopio University, Athens, Greece. d.b.panagiotakos@usa.net

    The 5-year incidence of cardiovascular disease (CVD) and its determinants, in a sample of men and women from Greece, was evaluated. From May 2001 to December 2002, 1514 men and 1528 women (>18 years old) without any clinical evidence of CVD, living in the Attica area, Greece, were enrolled in the ATTICA study. In 2006, a group of experts performed the 5-year follow-up (941 of the 3042 (31%) participants were lost to follow-up). Development of CVD (coronary heart disease, acute coronary syndromes, stroke, or other CVD) during the follow-up period was defined according to WHO-ICD-10 criteria. The 5-year incidence of CVD was 11.0% in men and 6.1% in women (p<0.001); the case fatality rate was 1.6%. Multi-adjusted logistic regression analysis revealed that increased age (odds ratio per year=1.09, p=0.04), waist-to-hip ratio (odds ratio=5.07, p=0.02), hypertension (odds ratio=4.53, p=0.001), diabetes (odds ratio=4.53, p=0.001) and C-reactive protein levels (odds ratio per 1 mg/dl=1.31, p=0.02) were the most significant baseline bio-clinical predictors of CVD. Furthermore, an increased education level and greater adherence to the Mediterranean diet (among 35-65-year-old individuals) were associated with a lower CVD incidence (odds ratio per 3 years of school difference=0.83, p<0.001 and odds ratio per 1/55 units in diet score=0.94, p<0.001), irrespective of various potential confounders. In conclusion, aging, central fat, hypertension and diabetes, inflammation process, low social status and abstinence from a Mediterranean diet seem to predict CVD events within a 5-year period.

 

J Nutr. 2008 Apr;138(4):753-60.   

    Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults.

    Chun OK, Chung SJ, Claycombe KJ, Song WO.

    Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.

    Serum C-reactive protein (CRP) is a biomarker for chronic inflammation and a sensitive risk factor for cardiovascular diseases. Though CRP has been reported to be related to food intake, there is no documentation of a direct association with flavonoid intake. We aimed to test the associations between dietary flavonoid intake and serum CRP concentrations among U.S. adults after adjusting for dietary, sociodemographic, and lifestyle factors. Data from the NHANES 1999-2002 were used for this cross-sectional study. Subjects were > or = 19-y-old adults (n = 8335), and did not include pregnant and/or lactating women. Flavonoid intake of U.S. adults was estimated by the USDA flavonoid databases matched with a 24-h dietary recall in NHANES 1999-2002. The serum CRP concentration was higher in women, older adults, blacks, and smokers, and in those with high BMI or low exercise level, and in those taking NSAID, than in their counterparts (P < 0.01). Intakes of apples and vegetables were inversely associated with serum CRP concentrations after adjusting for covariates (P < 0.05). Total flavonoid and also individual flavonol, anthocyanidin, and isoflavone intakes were inversely associated with serum CRP concentration after adjusting for the covariates (P < 0.05). Among the flavonoid compounds investigated, quercetin, kaempferol, malvidin, peonidin, daidzein, and genistein had inverse associations with serum CRP concentration (P < 0.05). These associations did not change even after the additional adjustment for fruit and vegetable consumption. Our findings demonstrate that intake of dietary flavonoids is inversely associated with serum CRP concentrations in U.S. adults. Intake of flavonoid-rich foods may thus reduce inflammation-mediated chronic diseases.

J Nutr. 2007 May;137(5):1244-52.   

    Estimated dietary flavonoid intake and major food sources of U.S. adults.

    Chun OK, Chung SJ, Song WO.

    Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.

    Estimating flavonoid intake is a first step toward documenting the protective effects of flavonoids against risk of chronic diseases. Although flavonoids are important dietary sources of antioxidants, insufficient data on the comprehensive food composition of flavonoids have delayed the assessment of dietary intake in a population. We aimed to estimate the dietary flavonoid intake in U.S. adults and its sociodemographic subgroups and to document major dietary sources of flavonoids. We expanded the recently released USDA Flavonoid Database to increase its correspondence with the 24-h dietary recall (DR) of the NHANES 1999-2002. We systematically assigned a particular food code to all foods that were prepared or processed similarly. This expanded database included 87% of fruits and fruit juices, 86% of vegetables, 75% of legumes, and, overall, 45% of all foods reported by the 24-h DR of the NHANES 1999-2002. Estimated mean daily total flavonoid intake, 189.7 mg/d, was mainly from flavan-3-ols (83.5%), followed by flavanones (7.6%), flavonols (6.8%), anthocyanidins (1.6%), flavones (0.8%), and isoflavones (0.6%). The flavonoid density of diets increased with age (P < 0.001) and income (P < 0.05). It was higher in women (P < 0.001), Caucasians (P < 0.001), and vitamin supplement users (P < 0.001) and lower in adults with high levels of nonleisure time physical activity (P < 0.01) compared with their counterparts. The greatest daily mean intake of flavonoids was from the following foods: tea (157 mg), citrus fruit juices (8 mg), wine (4 mg), and citrus fruits (3 mg). The proposed relation between flavonoid intake and the prevention of chronic diseases needs further investigation using the estimates introduced in this study.

Br J Nutr. 2008 May 28:1-7. [Epub ahead of print]   

    Supplementation with orange and blackcurrant juice, but not vitamin E, improves inflammatory markers in patients with peripheral arterial disease.

    Dalgård C, Nielsen F, Morrow JD, Enghusen-Poulsen H, Jonung T, Hørder M, de Maat MP.

    Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

    Inflammation and endothelial activation are associated with an increased risk of CVD and epidemiological evidence suggests an association between levels of markers of inflammation or endothelial activation and the intake of fruit. Also, vitamin E, a fat-soluble antioxidant, has anti-inflammatory properties. We performed a randomised 2 x 2 factorial, crossover trial to determine the effect of orange and blackcurrant juice (500 ml/d) and vitamin E (15 mg RRR-alpha-tocopherol/d) supplementation on markers of inflammation and endothelial activation in forty-eight patients with peripheral arterial disease. Patients were randomly allocated to two dietary supplements from the four possible combinations of juice and vitamin E: juice+vitamin E; juice+placebo; reference beverage (sugar drink)+vitamin E; and reference beverage+placebo. The supplementations were given for 28 d, separated by a 4-week wash-out period. Analysis of main effects showed that juice decreased C-reactive protein (CRP) by 11 % and fibrinogen by 3 % while the reference drink increased CRP by 13 % and fibrinogen by 2 % (P < 0.008 and P < 0.002, respectively). No significant differences were measured for IL-6 and the endothelial activation markers von Willebrand factor, tissue-plasminogen activator and plasmin activator inhibitor-1. Vitamin E supplementation had no significant effects on the various markers. We observed no significant interaction between juice and vitamin E. In this study, orange and blackcurrant juice reduced markers of inflammation, but not markers of endothelial activation, in patients with peripheral arterial disease, relative to sugar drinks.

 

Br J Nutr. 2008 Jan;99(1):137-46. Epub 2007 Jul 19.   

    Influence of lycopene and vitamin C from tomato juice on biomarkers of oxidative stress and inflammation.

    Jacob K, Periago MJ, Böhm V, Berruezo GR.

    Department of Food Technology, Food Science and Human Nutrition, Faculty of Veterinary Sciences, University of Murcia, 30071, Murcia, Spain.

    A human study was carried out to investigate whether tomato juice, rich in natural lycopene and fortified with vitamin C, is able to reduce several biomarkers of oxidative stress and inflammation and whether the effect can be attributed to lycopene, vitamin C or any other micronutrient. Following a 2-week depletion phase, volunteers were assigned randomly to ingest either tomato juice with (LC) or without (L) vitamin C fortification for 2 weeks (daily dose 20.6 mg lycopene and 45.5/435 mg vitamin C). Plasma and urine were analysed for carotenoids and vitamin C, lipid status, antioxidant capacity, thiobarbituric acid reactive substances (TBARS) and 8-epi-PGF2alpha, protein carbonyls, cytokines IL-1beta and TNFalpha and C-reactive protein (CRP). The consumption of tomato juice led to a reduction in total cholesterol levels (L: 157.6 v. 153.2 mg/dl, P = 0.008; LC: 153.4 v. 147.4 mg/dl, P = 0.002) and that of CRP (L: 315.6 v. 262.3 microg/l, P = 0.017; LC: 319.2 v. 247.1 microg/l, P = 0.001) in both groups. The vitamin C-fortified juice slightly raised the antioxidant capacity in urine and decreased TBARS in plasma and urine. All other markers were affected to a lesser extent or remained unchanged. Cholesterol reduction was correlated with lycopene uptake (P = 0.003), whereas the other effects could not be related with particular micronutrients. Any beneficial effects of tomato consumption for human health cannot be attributed only to lycopene and, as the additional supplementation with ascorbic acid indicates, a variety of antioxidants might be needed to optimize protection against chronic diseases.

J Nutr. 2003 Jul;133(7):2204-9.   

    High-pressurized orange juice consumption affects plasma vitamin C, antioxidative status and inflammatory markers in healthy humans.

    Sánchez-Moreno C, Cano MP, de Ancos B, Plaza L, Olmedilla B, Granado F, Martín A.

    Nutrition and Neurocognitive Laboratory, Jean Mayer U.S. Department of Agriculture-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.

    We examined the bioavailability of vitamin C in orange juice processed using high pressure (HP) and its effects on plasma levels of vitamin C, uric acid (UA), F2-isoprostanes (8-epiPGF(2alpha)), C-reactive protein (CRP) and prostaglandin E(2) (PGE(2)) in a healthy human population. Subjects (6 men, 6 women) enrolled in the study consumed 500 mL/d of HP orange juice for 14 d, corresponding to an intake of 250 mg of vitamin C. On d 1 of the study, subjects drank the juice in one dose; on d 2 until the end of the study, d 14, they drank 250 mL in the morning and 250 mL in the afternoon. Blood was collected every h for 6 h, on d 1, and then on d 7 and 14 of the study. Baseline plasma vitamin C concentration was higher (P = 0.014) in women (55.8 +/- 3.8 micro mol/L) than in men (42.8 +/- 2.1 micro mol/L). The maximum plasma vitamin C increase occurred 3 h after drinking the juice, and it remained elevated on d 7 and 14. Plasma 8-epiPGF(2alpha) concentration did not differ between men and women at baseline. However, it was lower at the end of the study in both men (P = 0.044) and women (P = 0.034). Plasma levels of vitamin C and 8-epiPGF(2alpha) were inversely correlated (r = -0.615, P = 0.001). Plasma CRP concentrations tended to be lower on d 14 than at baseline in men (P = 0.317) and women (P = 0.235). Plasma PGE(2) was lower at the end of the study in both men and women (P <or= 0.037). Drinking orange juice increases plasma vitamin C, and decreases 8-epiPGF(2alpha) and PGE(2) levels in humans, which may help reduce the risk of chronic diseases.

Immunopharmacol Immunotoxicol. 2003 May;25(2):213-24.Links

    Modulation of inflammatory mediators by ibuprofen and curcumin treatment during chronic inflammation in rat.

    Banerjee M, Tripathi LM, Srivastava VM, Puri A, Shukla R.

    Division of Pharmacology, Central Drug Research Institute, Lucknow, India.

    Inflammation is a protective tissue response occurring in three distinct phases, acute, subacute and a chronic proliferative phase. We undertook the present study to understand the overall immune response of the body during adjuvant induced chronic inflammation in rat and the effect of ibuprofen and curcumin on this response. Inflammatory mediators were estimated on day 21 and day 35 after adjuvant injection. The level of C-reactive protein increased to 200% on day 21 and then reduced to 50% on day 35 compared to control. Curcumin and ibuprofen further reduced the increased levels at both the time intervals. Haptoglobin level decreased to 42% on day 21 but increased to 5 times of control on day 35. Curcumin and ibuprofen reduced the increased levels at day 35. No significant change was observed in Prostaglandin-E2 and Leukotriene-B4 levels and in Lymphocyte proliferation. The level of Tumor Necrosis Factor-alpha increased by three folds on day 21, but came down to 88% on day 35. Ibuprofen treatment decreased the raised level on day 21 and increased the reduced level on day 35. Interleukin-1beta increased to 2 folds on day 21 and 10 folds on day 35 which were significantly brought down by curcumin and ibuprofen. Nitric oxide level was reduced at both the time intervals, which were increased by drug treatment.

J Altern Complement Med. 2003 Feb;9(1):161-8.   

    Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa).

    Chainani-Wu N.

    Department of Stomatology, University of California, San Francisco, CA 94143-0658, USA. nitacwu@itsa.ucsf.edu

    INTRODUCTION: Tumeric is a spice that comes from the root Curcuma longa, a member of the ginger family, Zingaberaceae. In Ayurveda (Indian traditional medicine), tumeric has been used for its medicinal properties for various indications and through different routes of administration, including topically, orally, and by inhalation. Curcuminoids are components of tumeric, which include mainly curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcmin. OBJECTIVES: The goal of this systematic review of the literature was to summarize the literature on the safety and anti-inflammatory activity of curcumin. METHODS: A search of the computerized database MEDLINE (1966 to January 2002), a manual search of bibliographies of papers identified through MEDLINE, and an Internet search using multiple search engines for references on this topic was conducted. The PDR for Herbal Medicines, and four textbooks on herbal medicine and their bibliographies were also searched. RESULTS: A large number of studies on curcumin were identified. These included studies on the antioxidant, anti-inflammatory, antiviral, and antifungal properties of curcuminoids. Studies on the toxicity and anti-inflammatory properties of curcumin have included in vitro, animal, and human studies. A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be safe. These human studies have found some evidence of anti-inflammatory activity of curcumin. The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12). CONCLUSIONS: Curcumin has been demonstrated to be safe in six human trials and has demonstrated anti-inflammatory activity. It may exert its anti-inflammatory activity by inhibition of a number of different molecules that play a role in inflammation.

Adv Exp Med Biol. 2007;595:105-25.Links

    Antioxidant and anti-inflammatory properties of curcumin.

    Menon VP, Sudheer AR.

    Department of Biochemistry & Center for Micronutrient Research, Annamalai University, Tamilnadu, India. biocmr@sify.com

    Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food-coloring agent. It is also used as a cosmetic and in some medical preparations. The desirable preventive or putative therapeutic properties of curcumin have also been considered to be associated with its antioxidant and anti-inflammatory properties. Because free-radical-mediated peroxidation of membrane lipids and oxidative damage of DNA and proteins are believed to be associated with a variety of chronic pathological complications such as cancer, atherosclerosis, and neurodegenerative diseases, curcumin is thought to play a vital role against these pathological conditions. The anti-inflammatory effect of curcumin is most likely mediated through its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). COX-2, LOX, and iNOS are important enzymes that mediate inflammatory processes. Improper upregulation of COX-2 and/or iNOS has been associated with the pathophysiology of certain types of human cancer as well as inflammatory disorders. Because inflammation is closely linked to tumor promotion, curcumin with its potent anti-inflammatory property is anticipated to exert chemopreventive effects on carcinogenesis. Hence, the past few decades have witnessed intense research devoted to the antioxidant and anti-inflammatory properties of curcumin. In this review, we describe both antioxidant and anti-inflammatory properties of curcumin, the mode of action of curcumin, and its therapeutic usage against different pathological conditions.

Adv Exp Med Biol. 2007;595:213-26.Links

    Regulation of COX and LOX by curcumin.

    Rao CV.

    Hematology-Oncology Section, University of Oklahoma Cancer Institute, Oklahoma City 73104, USA. cv-rao@ouhsc.edu

    Turmeric (Curcuma longa) is extensively used as a household remedy for various diseases. For the last few decades, work has been done to establish the biological activities and pharmacological actions of curcumin, the principle constituent of turmeric. Curcumin has proven to be beneficial in the prevention and treatment of a number of inflammatory diseases due to its anti-inflammatory activity. Arachidonic acid-derived lipid mediators that are intimately involved in inflammation are biosynthesized by pathways dependent on cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. The role of LOX and COX isoforms, particularly COX-2, in the inflammation has been well established. At cellular and molecular levels, curcumin has been shown to regulate a number of signaling pathways, including the eicosanoid pathway involving COX and LOX. A number of studies have been conducted that support curcumin-mediated regulation of COX and LOX pathways, which is an important mechanism by which curcumin prevents a number of disease processes, including the cancer. The specific regulation of 5-LOX and COX-2 by curcumin is not fully established; however, existing evidence indicates that curcumin regulates LOX and COX-2 predominately at the transcriptional level and, to a certain extent, the posttranslational level. Thus, the curcumin-selective transcriptional regulatory action of COX-2, and dual COX/LOX inhibitory potential of this naturally occurring agent provides distinctive advantages over synthetic COX/LOX inhibitors, such as nonsteroidal anti-inflammatory drugs. In this review, we discuss evidence that supports the regulation of COX and LOX enzymes by curcumin as the key mechanism for its beneficial effects in preventing various inflammatory diseases.

Horm Metab Res. 2008 Mar;40(3):199-205.Links

    High omega-3 fat intake improves insulin sensitivity and reduces CRP and IL6, but does not affect other endocrine axes in healthy older adults.

    Tsitouras PD, Gucciardo F, Salbe AD, Heward C, Harman SM.

    Kronos Longevity Research Institute, Phoenix, AZ 85016, USA. tsitouras@kronosinstitute.org

    Aging diminishes hormone secretion and target cell responsiveness, possibly due to loss of cell membrane fluidity or alteration of membrane phospholipids affecting signal transduction. We investigated whether a high omega-3 polyunsaturated fatty acid diet would improve endocrine function in 6 men and 6 women aged over 60 years. Subjects first ate an isocaloric control diet for 6 weeks, followed by an 8-week experimental diet, which included 720 g of fatty fish weekly plus 15 ml of sardine oil daily. In the last week, we measured RBC membrane fatty acids on each diet, performed pituitary, adrenal, hepatic, and Leydig cell endocrine provocative testing, and assayed selected cytokines. We also assessed insulin sensitivity utilizing octreotide insulin suppression testing and assessed free fatty acid (FFA) responses to isoproteronol. Insulin sensitivity increased significantly after 8 weeks on the omega-3 diet and FFA responses trended lower. Serum C-reactive protein was significantly reduced and a trend towards lower IL-6 was noted. No differences were found in other metabolic parameters, adiponectin levels, or hormone responses. We conclude that, in older people, high omega-3 consumption increases insulin sensitivity, may reduce FFA mobilization by catecholamines, and reduces inflammatory markers, but did not alter endocrine responsiveness after 8 weeks.

Diabetes Obes Metab. 2007 Jan;9(1):70-80.   

    The impact of long chain n-3 polyunsaturated fatty acid supplementation on inflammation, insulin sensitivity and CVD risk in a group of overweight women with an inflammatory phenotype.

    Browning LM, Krebs JD, Moore CS, Mishra GD, O'Connell MA, Jebb SA.

    MRC Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge, UK. lucy.browning@mrc-hnr.cam.ac.uk

    BACKGROUND: Inflammation is strongly related to obesity and the risk of cardiovascular disease (CVD). The metabolic benefits of long chain (LC) n-3 polyunsaturated fatty acid (PUFA) may be attributable to its anti-inflammatory properties. OBJECTIVE: To investigate whether an individual's habitual inflammatory status influences the impact of a LC n-3 PUFA intervention on CVD risk. DESIGN: The study was a randomized crossover design. Subjects received LC n-3 PUFA capsules or a placebo for 12 weeks, with 4-week washout between phases. Thirty women, in the top and bottom tertiles of baseline sialic acid concentration, formed raised inflammatory status (top, n = 12) and reference (bottom, n = 18) groups. Baseline data were analysed using one-way anova, differences between treatment phases were calculated at each timepoint and analysed using a random effects model. RESULTS: At baseline, the raised inflammatory status group had significantly higher body mass index and area under the curve (AUC) insulin than the reference group. With LC n-3 PUFA supplementation, both groups showed significantly higher plasma eicosapentaenoic acid and docosahexaenoic acid at 4 and 12 weeks (p < 0.001), and lower triacylglycerols (4 weeks p < 0.01 and 12 weeks p < 0.05). The difference in AUC insulin between the two treatment phases at 12 weeks was significantly greater in the raised inflammatory status group compared to the reference group (p < 0.05). Inflammatory markers were significantly lower after 12 weeks LC n-3 PUFA supplementation compared to baseline (C-reactive protein p < 0.05 and interleukin-6 p < 0.01), but there was no significant group effect. CONCLUSIONS: Habitual inflammatory status influences the impact of LC n-3 PUFA supplementation, but it is not clear whether the effect of LC n-3 PUFA on AUC insulin is mediated through inflammatory mechanisms.

J Nutr. 2008 Jun;138(6):1061-6.   

    Fish oil in combination with high or low intakes of linoleic acid lowers plasma triacylglycerols but does not affect other cardiovascular risk markers in healthy men.

    Damsgaard CT, Frøkiaer H, Andersen AD, Lauritzen L.

    Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, DK-1958 Frederiksberg C, Denmark. ctd@life.ku.dk

    Both (n-3) long-chain PUFA (LCPUFA) and linoleic acid [LA, 18:2(n-6)] improve cardiovascular disease (CVD) risk factors, but a high-LA intake may weaken the effect of (n-3) LCPUFA. In a controlled, double-blind, 2 x 2-factorial 8-wk intervention, we investigated whether fish oil combined with a high- or low-LA intake affects overall CVD risk profile. Healthy men (n = 64) were randomized to 5 mL/d fish oil capsules (FO) [mean intake 3.1 g/d (n-3) LCPUFA] or olive oil capsules (control) and to oils and spreads with either a high (S/B) or a low (R/K) LA content, resulting in a 7.3 g/d higher LA intake in the S/B groups than in the R/K groups. Diet, (n-3) LCPUFA in peripheral blood mononuclear cells, blood pressure (BP), heart rate (HR), and plasma CVD risk markers were measured before and after the intervention. FO lowered fasting plasma triacylglycerol (TAG) (P < 0.001) by 51% and 19% in the FO+R/K-group and FO+S/B-group, respectively, which was also reflected in postprandial TAG measured after the intervention (P < 0.01). Although a fat x FO interaction was found for monocyte chemoattractant protein-1, neither the FO nor fat intervention affected fasting plasma cholesterol, glucose, insulin, fibrinogen, C-reactive protein, interleukin-6, vascular cell adhesion molecule-1, P-selectin, oxidized LDL, cluster of differentiation antigen 40 ligand (CD40L), adiponectin, or fasting or postprandial BP or HR after adjustment for body weight changes. In conclusion, neither fish oil supplementation nor the LA intake had immediate pronounced effects on the overall CVD risk profile in healthy men, but fish oil lowered plasma TAG in healthy subjects with initially low concentrations.

Clin Nutr. 2008 Apr;27(2):241-7. Epub 2008 Jan 31.   

    Omega-3 polyunsaturated fatty acid in peripheral arterial disease: effect on lipid pattern, disease severity, inflammation profile, and endothelial function.

    Schiano V, Laurenzano E, Brevetti G, De Maio JI, Lanero S, Scopacasa F, Chiariello M.

    Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples Federico II, Naples, Italy.

    BACKGROUND & AIMS: Peripheral arterial disease (PAD) is strongly associated with endothelial dysfunction and inflammation, which portend a high cardiovascular risk. Accordingly, we investigated the effects of omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on endothelial function and inflammatory status in affected individuals. METHODS: PAD patients were randomly divided into two groups. In Group I (n=16) pre-enrollment therapy was not modified, while in Group II (n=16) n-3 PUFAs 1 g b.i.d. for 3 months were added to the previous treatment. Endothelial function was assessed by measuring plasma soluble thrombomodulin (sTM) and brachial artery flow-mediated dilation (FMD), and the inflammatory status by measuring high-sensitivity C-reactive protein and myeloperoxidase. RESULTS: In Group II, n-3 PUFAs reduced sTM levels from the median value of 33.0 ng/mL (interquartile range 16.7, 37.2) to 17.0 ng/mL (11.2, 33.7) (p=0.04), and improved FMD from 6.7% (3.7, 8.7) to 10.0% (6.2, 14.2) (p=0.02). Conversely, these markers did not change in Group I. After 3 months, the levels of inflammatory markers remained unmodified in both groups. CONCLUSIONS: In PAD, n-3 PUFAs induced a marked improvement in endothelial function. Conversely, they did not affect the inflammatory status. In future, large, prospective studies are needed to investigate whether n-3 PUFAs, by improving endothelial function, would reduce the incidence of ischemic events in a population at high risk.

Asia Pac J Clin Nutr. 2008;17 Suppl 1:333-6.Links

    The effect of nuts on inflammation.

    Salas-Salvadó J, Casas-Agustench P, Murphy MM, López-Uriarte P, Bulló M.

    Human Nutrition Unit, Department of Biochemistry and Biotech-nology, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C/Sant Llorenc, 21, 43201 Reus, Spain. jordi.salas@urv.cat

    Inflammation is one of the recognised mechanisms involved in the development of atherosclerotic plaque and insulin resistance. Inflammatory or endothelial markers such as C-Reactive Protein (CRP), Interleukin-6 (IL-6), fibrinogen, Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) have been identified as independent predictors of cardiovascular disease (CVD) or diabetes in human prospective studies. Epidemiological and clinical studies suggest that some dietary factors, such as n-3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.

Am J Epidemiol. 2006 Feb 1;163(3):222-31. Epub 2005 Dec 15.   

    Nut and seed consumption and inflammatory markers in the multi-ethnic study of atherosclerosis.

    Jiang R, Jacobs DR Jr, Mayer-Davis E, Szklo M, Herrington D, Jenny NS, Kronmal R, Barr RG.

    Division of General Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

    Nuts and seeds are rich in unsaturated fat and other nutrients that may reduce inflammation. Frequent nut consumption is associated with lower risk of cardiovascular disease and type 2 diabetes. The authors examined associations between nut and seed consumption and C-reactive protein, interleukin-6, and fibrinogen in the Multi-Ethnic Study of Atherosclerosis. This 2000 cross-sectional analysis included 6,080 US participants aged 45-84 years with adequate information on diet and biomarkers. Nut and seed consumption was categorized as never/rare, less than once/week, 1-4 times/week, and five or more times/week. After adjustment for age, gender, race/ethnicity, site, education, income, smoking, physical activity, use of fish oil supplements, and other dietary factors, mean biomarker levels in categories of increasing consumption were as follows: C-reactive protein-1.98, 1.97, 1.80, and 1.72 mg/liter; interleukin-6-1.25, 1.24, 1.21, and 1.15 pg/ml; and fibrinogen-343, 338, 338, and 331 mg/dl (all p's for trend < 0.01). Further adjustment for hypertension, diabetes, medication use, and lipid levels yielded similar results. Additional adjustment for body mass index moderately attenuated the magnitude of the associations, yielding borderline statistical significance. Associations of nut and seed consumption with these biomarkers were not modified by body mass index, waist:hip ratio, or race/ethnicity. Frequent nut and seed consumption was associated with lower levels of inflammatory markers, which may partially explain the inverse association of nut consumption with cardiovascular disease and diabetes risk.

Asia Pac J Clin Nutr. 2008;17 Suppl 1:333-6.Links

    The effect of nuts on inflammation.

    Salas-Salvadó J, Casas-Agustench P, Murphy MM, López-Uriarte P, Bulló M.

    Human Nutrition Unit, Department of Biochemistry and Biotech-nology, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, C/Sant Llorenc, 21, 43201 Reus, Spain. jordi.salas@urv.cat

    Inflammation is one of the recognised mechanisms involved in the development of atherosclerotic plaque and insulin resistance. Inflammatory or endothelial markers such as C-Reactive Protein (CRP), Interleukin-6 (IL-6), fibrinogen, Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) have been identified as independent predictors of cardiovascular disease (CVD) or diabetes in human prospective studies. Epidemiological and clinical studies suggest that some dietary factors, such as n-3 polyunsaturated fatty acids, antioxidant vitamins, dietary fiber, L-arginine and magnesium may play an important role in modulating inflammation. The relationship observed between frequent nut consumption and the reduced risk of cardiovascular mortality and type 2 diabetes in some prospective studies could be explained by the fact that nuts are rich in all of these modulator nutrients. In fact, frequent nut consumption has been associated with lower concentrations of some peripheral inflammation markers in cross-sectional studies. Nut consumption has also been shown to decrease the plasma concentration of CRP, IL-6 and some endothelial markers in recent clinical trials.

Br J Nutr. 2007 Jun;97(6):1144-53. Epub 2007 Mar 7.   

    Effects of a high walnut and high cashew nut diet on selected markers of the metabolic syndrome: a controlled feeding trial.

    Mukuddem-Petersen J, Stonehouse Oosthuizen W, Jerling JC, Hanekom SM, White Z.

    School of Computer, Mathematical and Statistical Sciences, North-West University (Potchefstroom Campus), Potchefstroom, South Africa. Janine.MukuddemPetersen@NWU.ac.za

    We investigated the effects of a high walnut diet and a high unsalted cashew nut diet on selected markers of the metabolic syndrome. In a randomized, parallel, controlled study design, sixty-four subjects having the metabolic syndrome (twenty-nine men, thirty-five women) with a mean age of 45 (sd 10) years and who met the selection criteria were all fed a 3-week run-in control diet. Hereafter, participants were grouped according to gender and age and then randomized into three groups receiving a controlled feeding diet including walnuts, or unsalted cashew nuts or no nuts for 8 weeks. Subjects were required to have lunch at the metabolic ward of the Nutrition Department of the North-West University (Potchefstroom Campus). Both the walnut and the unsalted cashew nut intervention diets had no significant effect on the HDL-cholesterol, TAG, total cholesterol, LDL-cholesterol, serum fructosamine, serum high-sensitivity C-reactive protein, blood pressure and serum uric acid concentrations when compared to the control diet. Low baseline LDL-cholesterol concentrations in the cashew nut group may have masked a possible nut-related benefit. Plasma glucose concentrations increased significantly (P = 0.04) in the cashew nut group compared to the control group. By contrast, serum fructosamine was unchanged in the cashew nut group while the control group had significantly increased (P = 0.04) concentrations of this short-term marker of glycaemic control. Subjects displayed no improvement in the markers of the metabolic syndrome after following a walnut diet or a cashew nut diet compared to a control diet while maintaining body weight.

Am J Clin Nutr. 2006 Oct;84(4):756-61.    

    Reduced-calorie orange juice beverage with plant sterols lowers C-reactive protein concentrations and improves the lipid profile in human volunteers.

    Devaraj S, Autret BC, Jialal I.

    Laboratory for Atherosclerosis and Metabolic Research and General Clinical Research Center, University of California Davis Medical Center, Sacramento, CA 95817, USA. sridevi.devaraj@ucdmc.ucdavis.edu

    BACKGROUND: Dietary plant sterols effectively reduce LDL cholesterol when incorporated into fat matrices. We showed previously that supplementation with orange juice containing plant sterols (2 g/d) significantly reduced LDL cholesterol. Inflammation is pivotal in atherosclerosis. High-sensitivity C-reactive protein (hs-CRP), the prototypic marker of inflammation, is a cardiovascular disease risk marker; however, there is a paucity of data on the effect of plant sterols on CRP concentrations. OBJECTIVE: The aim of this study was to examine whether plant sterols affect CRP concentrations and the lipoprotein profile when incorporated into a reduced-calorie (50 calories/240 mL) orange juice beverage. DESIGN: Seventy-two healthy subjects were randomly assigned to receive a reduced-calorie orange juice beverage either without (Placebo Bev) or with (1 g/240 mL; Sterol Bev) plant sterols twice a day with meals for 8 wk. Fasting blood was obtained at baseline and after 8 wk of Placebo Bev or Sterol Bev supplementation. RESULTS: Sterol Bev supplementation significantly reduced total cholesterol (5%; P < 0.01) and LDL cholesterol (9.4%; P < 0.001) compared with both baseline and Placebo Bev (P < 0.05). HDL cholesterol increased significantly with Sterol Bev (P < 0.02). No significant changes in triacylglycerol, glucose, or liver function tests were observed with Sterol Bev. Sterol Bev supplementation resulted in no significant change in vitamin E and carotenoid concentrations. Sterol Bev supplementation resulted in a significant reduction of CRP concentrations compared with baseline and Placebo Bev (median reduction: 12%; P < 0.005). CONCLUSION: Supplementation with a reduced-calorie orange juice beverage containing plant sterols is effective in reducing CRP and LDL cholesterol and could be incorporated into the dietary portion of therapeutic lifestyle changes.

Diabetes Care. 2000 Jun;23(6):733-8.   

    Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.

    Upritchard JE, Sutherland WH, Mann JI.

    Department of Human Nutrition, University of Otago, Dunedin, New Zealand.

    OBJECTIVE: To compare the effects of short-term dietary supplementation with tomato juice, vitamin E, and vitamin C on susceptibility of LDL to oxidation and circulating levels of C-reactive protein (C-RP) and cell adhesion molecules in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 57 patients with well-controlled type 2 diabetes aged <75 years treated with placebo for 4 weeks and then randomized to receive tomato juice (500 ml/day), vitamin E (800 U/day), vitamin C (500 mg/day), or continued placebo treatment for 4 weeks. Susceptibility of LDL to oxidation (lag time) and plasma concentrations of lycopene, vitamin E, vitamin C, C-RP, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 were measured at the beginning of the study, after the placebo phase, and at the end of the study. RESULTS: Plasma lycopene levels increased nearly 3-fold (P = 0.001), and the lag time in isolated LDL oxidation by copper ions increased by 42% (P = 0.001) in patients during supplementation with tomato juice. The magnitude of this increase in lag time was comparable with the corresponding increase during supplementation with vitamin E (54%). Plasma C-RP levels decreased significantly (-49%, P = 0.004) in patients who received vitamin E. Circulating levels of cell adhesion molecules and plasma glucose did not change significantly during the study. CONCLUSIONS: This study indicates that consumption of commercial tomato juice increases plasma lycopene levels and the intrinsic resistance of LDL to oxidation almost as effectively as supplementation with a high dose of vitamin E, which also decreases plasma levels of C-RP, a risk factor for myocardial infarction, in patients with diabetes. These findings may be relevant to strategies aimed at reducing risk of myocardial infarction in patients with diabetes.

 

J Thromb Haemost. 2007 Jun;5(6):1309-17.   

    Effect of wine phenolics on cytokine-induced C-reactive protein expression.

    Kaur G, Rao LV, Agrawal A, Pendurthi UR.

    Center for Biomedical Research, The University of Texas Health Center at Tyler, Tyler, TX 75703, USA.

    BACKGROUND: Elevation of C-reactive protein (CRP) levels in blood was recognized as one of the cardiac disease risk factors. Consumption of wine is shown to reduce the risk from heart disease and improve longevity. OBJECTIVES: In the present study, we evaluated the effect of various wine polyphenolic compounds and several active synthetic derivatives of resveratrol on the inflammatory cytokines (IL-1beta + IL-6)-induced CRP expression in Hep3B cells. RESULTS: Among the wine phenolics tested, quercetin and resveratrol, in a dose-dependent manner, suppressed cytokine-induced CRP expression. Two of the synthetic derivatives of resveratrol, R3 and 7b, elicited a fiftyfold higher suppressive effect compared with resveratrol. The inhibitory effects of resveratrol and its derivatives on CRP expression were at the level of mRNA production. Investigation of signaling pathways showed that the cytokines induced the phosphorylation of p38 and p44/42 MAP kinases. Inhibitors of p38 and p44/42 mitogen-activated protein kinase (MAPK) activation inhibited CRP expression, implicating the involvement of both pathways in cytokine-induced CRP expression. These data revealed a previously unrecognized role of the p44/42 MAPK signaling pathway in CRP expression. Wine polyphenolics or the synthetic compounds of resveratrol did not affect cytokine-activated phosphorylation of these MAPKs. CONCLUSIONS: Wine phenolics inhibit CRP expression; however, to do so, they do not utilize the MAPK pathways.

Am J Clin Nutr. 2006 Jul;84(1):252-62.   

    Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects.

    Castilla P, Echarri R, Dávalos A, Cerrato F, Ortega H, Teruel JL, Lucas MF, Gómez-Coronado D, Ortuño J, Lasunción MA.

    Servicio de Bioquímica-Investigación, Hospital Ramon y Cajal, Madrid, Spain.

    BACKGROUND: Patients treated with hemodialysis frequently experience cardiovascular complications attributed, among other causes, to dyslipidemia, increased oxidative stress, and inflammation. OBJECTIVE: The aim of the study was to study the effects of dietary supplementation with concentrated red grape juice (RGJ), a source of polyphenols, on lipoprotein profile, antioxidant capacity, LDL oxidation, and inflammatory biomarkers. DESIGN: Twenty-six patients receiving hemodialysis and 15 healthy subjects were instructed to drink 100 mL RGJ/d for 14 d. Blood was drawn at baseline, twice during RGJ supplementation, and twice during the 6-mo follow-up period. As a control, 12 other randomly recruited hemodialysis patients not receiving RGJ were studied. Lipids, apolipoproteins, oxidized LDL, and antioxidant vitamins were measured in plasma. The bioavailability of RGJ polyphenols was assessed in healthy subjects. RESULTS: The maximum plasma concentration of quercetin was achieved 3 h after RGJ ingestion, which indicates that supplement-derived polyphenols are rapidly absorbed. In both healthy subjects and hemodialysis patients, RGJ consumption increased the antioxidant capacity of plasma without affecting concentrations of uric acid or ascorbic acid; reduced the concentration of oxidized LDL; and increased the concentration of cholesterol-standardized alpha-tocopherol. RGJ supplementation also caused a significant decrease in LDL-cholesterol and apolipoprotein B-100 concentrations, while increasing the concentrations of HDL cholesterol and apolipoprotein A-I. In a further study in hemodialysis patients, RGJ supplementation for 3 wk significantly reduced plasma monocyte chemoattractant protein 1, an inflammatory biomarker associated with cardiovascular disease risk. CONCLUSION: Dietary supplementation with concentrated RGJ improves the lipoprotein profile, reduces plasma concentrations of inflammatory biomarkers and oxidized LDL, and may favor a reduction in cardiovascular disease risk.

    PMID: 16825703 [PubMed - indexed for MEDLINE]

 

Nutr Metab Cardiovasc Dis. 2008 Sep;18(7):497-502. Epub 2008 May 23.   

    The effect of a lignan complex isolated from flaxseed on inflammation markers in healthy postmenopausal women.

    Hallund J, Tetens I, Bügel S, Tholstrup T, Bruun JM.

    Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 30, 1958 Frederiksberg C, Denmark. jeha@life.ku.dk

    BACKGROUND AND AIM: Plant lignans are metabolised by the colonic micro-flora to the mammalian lignans enterodiol and enterolactone, which are hypothesized to be cardioprotective. The aim of this study was to investigate the effects of a plant lignan complex isolated from flaxseed, providing 500 mg/d of secoisolariciresinol diglucoside, on inflammatory markers. METHODS AND RESULTS: Healthy postmenopausal women (n=22) completed a randomised double-blind, placebo-controlled crossover study. Women consumed daily a low-fat muffin, with or without a lignan complex, for 6 weeks, separated by a 6-week washout period. A significant difference of approximately 15% (P=0.028) was observed for C-reactive protein (CRP) concentration between the lignan complex intervention period and placebo period. CRP concentrations (median; 25th, 75th percentiles) were 0.88 (0.63, 2.05) mg/L at baseline and 0.92 (0.59, 1.49) mg/L after the lignan complex intervention period compared with 0.80 (0.62, 1.62) mg/L at baseline and 1.10 (0.72, 1.62) mg/L after placebo. No significant differences in interleukin-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 were found between the lignan complex intervention period and placebo period. CONCLUSION: Daily consumption for 6 week of a low-fat muffin enriched with a lignan complex may reduce CRP concentrations compared to a low-fat muffin with no lignans added.

 

 

Arch Intern Med. 2008 Jun 23;168(12):1340-9.   

    Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality.

    Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W.

    Division of Endocrinology and Nuclear Medicine, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. harald.dobnig@meduni-graz.at

    BACKGROUND: In cross-sectional studies, low serum levels of 25-hydroxyvitamin D are associated with higher prevalence of cardiovascular risk factors and disease. This study aimed to determine whether endogenous 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are related to all-cause and cardiovascular mortality. METHODS: Prospective cohort study of 3258 consecutive male and female patients (mean [SD] age, 62 [10] years) scheduled for coronary angiography at a single tertiary center. We formed quartiles according to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels within each month of blood drawings. The main outcome measures were all-cause and cardiovascular deaths. RESULTS: During a median follow-up period of 7.7 years, 737 patients (22.6%) died, including 463 deaths from cardiovascular causes. Multivariate-adjusted hazard ratios (HRs) for patients in the lower two 25-hydroxyvitamin D quartiles (median, 7.6 and 13.3 ng/mL [to convert 25-hydroxyvitamin D levels to nanomoles per liter, multiply by 2.496]) were higher for all-cause mortality (HR, 2.08; 95% confidence interval [CI], 1.60-2.70; and HR, 1.53; 95% CI, 1.17-2.01; respectively) and for cardiovascular mortality (HR, 2.22; 95% CI, 1.57-3.13; and HR, 1.82; 95% CI, 1.29-2.58; respectively) compared with patients in the highest 25-hydroxyvitamin D quartile (median, 28.4 ng/mL). Similar results were obtained for patients in the lowest 1,25-dihydroxyvitamin D quartile. These effects were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism, and New York Heart Association functional class. Low 25-hydroxyvitamin D levels were significantly correlated with variables of inflammation (C-reactive protein and interleukin 6 levels), oxidative burden (serum phospholipid and glutathione levels), and cell adhesion (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 levels). CONCLUSIONS: Low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are independently associated with all-cause and cardiovascular mortality. A causal relationship has yet to be proved by intervention trials using vitamin D.

 

Circulation. 2008 Jan 29;117(4):503-11. Epub 2008 Jan 7.   

    Vitamin D deficiency and risk of cardiovascular disease.

    Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M, Vasan RS.

    Framingham Heart Study, Framingham, Mass, USA. tjwang@partners.org

    BACKGROUND: Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. METHODS AND RESULTS: We studied 1739 Framingham Offspring Study participants (mean age 59 years; 55% women; all white) without prior cardiovascular disease. Vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Prespecified thresholds were used to characterize varying degrees of 25-OH D deficiency (< 15 ng/mL, < 10 ng/mL). Multivariable Cox regression models were adjusted for conventional risk factors. Overall, 28% of individuals had levels < 15 ng/mL, and 9% had levels < 10 ng/mL. During a mean follow-up of 5.4 years, 120 individuals developed a first cardiovascular event. Individuals with 25-OH D < 15 ng/mL had a multivariable-adjusted hazard ratio of 1.62 (95% confidence interval 1.11 to 2.36, P=0.01) for incident cardiovascular events compared with those with 25-OH D > or = 15 ng/mL. This effect was evident in participants with hypertension (hazard ratio 2.13, 95% confidence interval 1.30 to 3.48) but not in those without hypertension (hazard ratio 1.04, 95% confidence interval 0.55 to 1.96). There was a graded increase in cardiovascular risk across categories of 25-OH D, with multivariable-adjusted hazard ratios of 1.53 (95% confidence interval 1.00 to 2.36) for levels 10 to < 15 ng/mL and 1.80 (95% confidence interval 1.05 to 3.08) for levels < 10 ng/mL (P for linear trend=0.01). Further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings. CONCLUSIONS: Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

 

J Clin Endocrinol Metab. 2008 Oct;93(10):3927-35. Epub 2008 Aug 5.   

    Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.

    Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H.

    Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. stefan.pilz@chello.at

    CONTEXT: Vitamin D has been shown to influence cardiac contractility and myocardial calcium homeostasis. OBJECTIVES: We aimed to elucidate whether insufficient vitamin D status is associated with heart failure and sudden cardiac death (SCD). DESIGN, SETTING, AND PARTICIPANTS: We measured 25-hydroxyvitamin D [25(OH)D] levels in 3299 Caucasian patients who were routinely referred to coronary angiography at baseline (1997-2000). MAIN OUTCOME MEASURES: The main outcome was cross-sectional associations of 25(OH)D levels with measures of heart failure and Cox proportional hazard ratios for deaths due to heart failure and for SCD according to vitamin D status. RESULTS: 25(OH)D was negatively correlated with N-terminal pro-B-type natriuretic peptide and was inversely associated with higher New York Heart Association classes and impaired left ventricular function. During a median follow-up time of 7.7 yr, 116 patients died due to heart failure and 188 due to SCD. After adjustment for cardiovascular risk factors, the hazard ratios (with 95% confidence intervals) for death due to heart failure and for SCD were 2.84 (1.20-6.74) and 5.05 (2.13-11.97), respectively, when comparing patients with severe vitamin D deficiency [25(OH)D <25 nmol/liter)] with persons in the optimal range [25(OH)D > or =75 nmol/liter]. In all statistical analyses, we obtained similar results with 25(OH)D and with 1,25-dihydroxyvitamin D. CONCLUSIONS: Low levels of 25(OH)D and 1,25-dihydroxyvitamin D are associated with prevalent myocardial dysfunction, deaths due to heart failure, and SCD. Interventional trials are warranted to elucidate whether vitamin D supplementation is useful for treatment and/or prevention of myocardial diseases.

 


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