New Generics Soon Available for Best-Selling Drug Lipitor

Newswise — (May 16 2012)- In just days, a number of generic versions of Lipitor will hit pharmacy shelves. Pfizer’s 180-day generic exclusivity agreement for the medication expires at the end of the month. That will bring a host of new generic alternatives, and potential confusion, to more than 3 million Americans looking to control their cholesterol and reduce the cost of their drug therapies.

Clark Kebodeaux, Pharm.D., assistant professor pharmacy practice at St. Louis College of Pharmacy, deals with this issue every day when he’s practicing at Walgreens in St. Louis.

He will answer some common questions including:
• Will the price of Lipitor come down?
• Will the new generic alternatives work as well as Lipitor?
• Does the generic medication affect me differently?
• Do the inactive ingredients in the medication have any effect on patients?
• Are there cases where the brand name works better than the generic?
• Questions patients should ask their pharmacist or doctor about switching to generic.

Lipitor is the best-selling prescription drug of all time, and most prescribed brand-name drug in America. Every day about 3.5 million Americans take Lipitor.

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Study: Raising HDL not a sure route to countering Heart Disease

A new paper published online in The Lancet challenges the assumption that raising a person’s HDL — the so-called “good cholesterol” — will necessarily lower the risk of a heart attack. The new research underscores the value of using genetic approaches to test biological hypotheses about human disease prior to developing specific drugs. A team led by researchers from the Broad Institute and Massachusetts General Hospital (MGH) explored naturally occurring genetic variations in humans to test the connection between HDL levels and heart attack. By studying the genes of roughly 170,000 individuals, the team discovered that, when examined together, the 15 HDL-raising variants they tested do not reduce the risk of heart attack.

“It’s been assumed that if a patient, or group of patients, did something to cause their HDL levels to go up, then you can safely assume that their risk of heart attack will go down,” said senior author Sekar Kathiresan, director of preventive cardiology at MGH, associate professor of medicine at Harvard Medical School, and an associate member of the Broad Institute. “This work fundamentally questions that.”

Each of the variants Kathiresan and his colleagues studied reflects potentially distinct ways the body might raise HDL. The findings raise significant questions about whether developing drugs against the genes explored in this study, which involves an international team of investigators to bring together patient samples, will prove effective in lowering heart attack risk across the population.

“Our study highlights the value of human genetic information in understanding disease biology prior to developing and testing drugs in the clinic,” said co-author David Altshuler, director of the Program in Medical and Population Genetics at the Broad Institute and a Harvard Medical School professor at MGH. “This kind of research is not about personalized prediction — rather, it’s about testing mechanisms and therapeutic hypotheses before drug discovery.”

In the blood, cholesterol is carried by particles called lipoproteins, which come in different sizes and densities. These include HDL, or high-density lipoprotein, and LDL, or low-density lipoprotein. There is a well-studied connection between elevated LDL, often called the “bad cholesterol,” and heart attack. Decades of research, including studies of genetic disorders in humans and the discovery of the LDL receptor and its role in cholesterol regulation, paved the way for the development of life-saving drugs known as statins. This work showed beyond any reasonable doubt that many different methods of reducing a person’s LDL levels lower the risk of heart disease.

Large-scale studies of genetic variation tied to LDL have been revealing, but the data on HDL are not so clear. More than 30 years ago, human epidemiological studies first revealed an association between HDL and risk for heart attack: the higher the levels, the lower the risk. Experiments in cells and mice further support the idea and suggest that HDL is protective because it may remove cholesterol from the sites where it can do damage.

However, it has been difficult for researchers to prove conclusively that raising HDL levels is beneficial, primarily for two reasons. First, studies of human genetic diseases where individuals have very low HDL levels have not yielded definitive answers as to the impact on heart attack. And second, because there are currently no drugs that specifically elevate HDL levels, it has been difficult to prove in humans that such an intervention will lower heart attack risk.

“There are many biomarkers measurable in the blood that track with disease but only a very small number are actually causal and directly participate,” said first author Benjamin Voight, who since completing this work has left the Broad and MGH for a position as an assistant professor at University of Pennsylvania. “The reason you want to distinguish between causal and non-causal biomarkers is because of the implications for therapy.”

To investigate, Kathiresan teamed up with colleagues from MGH, the Broad Institute, and beyond, including Voight and co-first author Gina Peloso. Together, the researchers looked to the human genome for help.

Individuals typically carry two copies of each gene in the genome; which copy a child will inherit from each parent is essentially a random decision, like flipping a coin. This phenomenon, sometimes called “Mendelian randomization,” provides a powerful means of testing connections between genes, biomarkers, and disease — similar to the way that randomized controlled clinical trials can evaluate the effectiveness of new drugs.

Using this technique, researchers study two groups of people — those who carry a particular gene variant, and those who do not. When sufficiently large groups are studied, both groups should be similar in every factor, except for the specific gene variant or biomarker of interest, allowing researchers to home in on whether the biomarker actually causes a particular trait or condition. By harnessing this method, Kathiresan and his team tested whether certain genetic variants that can dial up a person’s HDL levels impact the chances of developing heart attack.

What they found was surprising. Individuals who carried a particular variation in a gene called endothelial lipase had HDL levels that were elevated about 6mg/dl, or 10% — a change expected to decrease heart attack risk by about 13%. However, these individuals showed no difference in their risk of heart disease compared to people without the variant.

Similarly, the researchers identified a panel comprised of not just one but 14 different HDL-raising variants. They devised a scoring system based on the total number of copies of the gene variants a person carries — ranging from 0 to 28 — and then asked whether that score relates to the risk of heart attack. Here also they uncovered no association.

Kathiresan emphasizes that these results do not diminish the value of HDL levels as a predictor — a so-called biomarker — that can help estimate the likelihood of a person going on to develop heart attack. “We know that HDL is a great biomarker ¬— it’s quite useful in identifying individuals at higher risk of having a heart attack in the future,” said Kathiresan. “But we have shown that you cannot assume that raising HDL by any mechanism will help patients. Perhaps other mechanisms exist that can lower risk, but we will need to keep searching for them.”

“It takes a decade or more, and costs up to hundreds of millions of dollars, to discover a drug and carry out clinical trials. And yet, the vast majority of such clinical trials fail due to lack of efficacy or toxicities,” said Altshuler. “Human genetics offers a valuable approach to evaluating the underlying therapeutic hypothesis prior to spending so much time and money on drug discovery, hopefully allowing the industry to focus resources on hypotheses that are most likely to prove safe and effective in patients.”




Other study contributors from the Broad Institute include Christopher Newton-Cheh, Kiran Musunuru, James Pirruccello, Paul de Bakker, Mark Daly, Candace Guiducci, Noel Burtt, Aarti Surti, Elena Gonzalez, Shaun Purcell, and Stacey Gabriel.

This work was funded by the National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation and the German Federal Ministry of Education and Research.

Paper cited: Voight et al. A Mendelian randomization study for plasma high-density lipoprotein cholesterol and risk for myocardial infarction. Published online May 16, 2012 The LancetDOI:10.1016/S0140-6736(12)60312-2

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Johns Hopkins Cardiologists Advocate Statin Use for Primary Prevention of Heart Disease in JAMA’s First Viewpoint Feature

Newswise — Writing the first commentary for a new feature in the Journal of the American Medical Association (JAMA), called Viewpoint, Johns Hopkins cardiologists make the case for why a 55-year-old man with a 10 percent estimated risk of heart attack over the next 10 years should be offered statin medication. They were invited to debate a professor who argues against prescribing statins for “primary” prevention—for those who have not had a cardiovascular event, such as a heart attack—even though they may be considered at “intermediate” risk because of elevated cholesterol or other factors. Readers are then invited to vote on which viewpoint they endorse.

The commentary advocating use of statins for primary prevention was written by Johns Hopkins cardiologists Michael J. Blaha, M.D., M.P.H., Khurram Nasir, M.D., M.P.H., and Roger S. Blumenthal, M.D., a professor of medicine and the director of the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins. The opposing viewpoint is presented by Rita Redberg, M.D., professor of medicine and director of women’s cardiovascular services at the University of California, San Francisco.

In their commentary, the Hopkins cardiologists note the importance of lifestyle changes, such as a healthy diet and exercise, in lowering the risk of cardiovascular disease. “As always, lifestyle change is the first-line therapy.” They add, “However, if this patient’s cholesterol level remains abnormal, despite sustained attempts at lifestyle optimization, statin therapy should be considered, with the goal of reducing CHD (coronary heart disease) risk.”

To support this argument, they cite four major placebo-controlled studies showing that statin therapy used to reduce cholesterol—in particular LDL, the “bad” form of cholesterol—reduced the incidence of heart attack and death significantly among people who had high cholesterol levels but were otherwise at low risk for developing heart disease.

They also suggest that a way to sort out who would be the best candidates for statin therapy is to offer them a coronary artery calcium (CAC) scan, an imaging test that directly shows the amount of calcification in heart arteries that can lead to a heart attack. Large studies published by Johns Hopkins researchers have confirmed the usefulness of CAC in determining risk among their patients, helping doctors decide who needed statin therapy to lower their risk.

The Hopkins cardiologists also dispute the main arguments used by those who are against prescribing statins to prevent cardiovascular disease. Adverse effects, such as muscle pain, they say, are infrequent and reversible when the medication is stopped. They contend that there is no evidence from randomized trials that statins lead to cognitive impairment or memory loss; in fact, they say, there are data showing that statins may improve memory. Also, the risk of type 2 diabetes associated with statins is minimal, especially compared with the benefits in reducing heart attacks. And improvements in diet and weight can negate modest increases in blood sugar associated with statins, they say.

Why not wait until a heart attack or stroke to prescribe statins for those with multiple risk factors? The Hopkins cardiologists argue that would be like shutting the barn door after the horse has escaped: “There’s no apparent logic in waiting for a myocardial infarction (heart attack) or stroke to occur before starting a risk-reducing therapy.”

Another argument against statins for primary prevention is that people may be prone to ignore lifestyle changes if they’re taking drugs. In fact, the Hopkins cardiologists say that there is evidence to the contrary: A recommendation for medication may motivate people to adopt more healthy behaviors.

Finally, they tackle the cost argument—Is taking statins cost-effective? Now that generic statins are on the market at about $4 to $5 a month, Blumenthal and colleagues assert that cost is becoming less of a major factor.

Their commentary concludes, “The cornerstone therapies for patients with elevated cholesterol will always be dietary modification and renewed emphasis on physical activity. Statin therapy is a critical adjunct in those identified to be at increased CHD risk.”

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More Trans Fat Consumption Linked to Greater Aggression

Newswise — Might the “Twinkie defense” have a scientific foundation after all? Researchers at the University of California, San Diego School of Medicine have shown – by each of a range of measures, in men and women of all ages, in Caucasians and minorities – that consumption of dietary trans fatty acids (dTFAs) is associated with irritability and aggression.

The study of nearly 1,000 men and women provides the first evidence linking dTFAs with adverse behaviors that impacted others, ranging from impatience to overt aggression. The research, led by Beatrice Golomb, MD, PhD, associate professor in the UC San Diego Department of Medicine, has been published online by PLoS ONE.

Dietary trans fatty acids are primarily products of hydrogenation, which makes unsaturated oils solid at room temperature. They are present at high levels in margarines, shortenings and prepared foods. Adverse health effects of dTFAs have been identified in lipid levels, metabolic function, insulin resistance, oxidation, inflammation, and cardiac health.

The UC San Diego team used baseline dietary information and behavioral assessments of 945 adult men and women to analyze the relationship between dTFAs and aggression or irritability. The survey measured such factors as a life history of aggression, conflict tactics and self-rated impatience and irritability, as well as an “overt aggression” scale that tallies recent aggressive behaviors. Analyses were adjusted for sex, age, education, and use of alcohol or tobacco products.

“We found that greater trans fatty acids were significantly associated with greater aggression, and were more consistently predictive of aggression and irritability, across the measures tested, than the other known aggression predictors that were assessed,” said Golomb. “If the association between trans fats and aggressive behavior proves to be causal, this adds further rationale to recommendations to avoid eating trans fats, or including them in foods provided at institutions like schools and prisons, since the detrimental effects of trans fats may extend beyond the person who consumes them to affect others.”

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Intracoronary vs Intravenous Abciximab in STEMI undergoing PCI : Dr. Shimada

Meta-Analysis of Prospective Randomized Controlled Trials Comparing Intracoronary Versus Intravenous Abciximab in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Author Interview: Yuichi J. Shimada, MD

Beth Israel Medical Center
University Hospital and Manhattan Campus
for the Albert Einstein College of Medicine

What are the main findings of the study?

Heart attacks are caused by blood clot in the coronary artery (blood vessel surrounding the heart to supply oxygen and nutrition). Abciximab helps to decrease the amount of clot when added to placing a stent (a metal mesh placed in the coronary artery to keep the blood vessel open).

Our study demonstrated that injecting Abciximab directly into the coronary artery (intracoronary injection) reduces risk of death compared to injecting into the veins in the arm or leg (intravenous injection).

Furthermore, among patients with higher risk profiles, the intracoronary injection reduced risk of developing major adverse cardiac events such as heart failure and necessity for repeated procedures or surgery.

Were any of the findings unexpected?

Among patients that received a special procedure to remove blood clot, the intracoronary injection of Abciximab did not recude the risk of major adverse cardaic events compared to the regular intravenous injection.

This was not expected before the analysis of the study, however, it made clinical sense because Abciximab cannot remove any more blood clot if there is no clot to remove.

What should clinicians and patients take away from this study?

Clinicians should consider the intracoronary injection of Abciximab when the patient presents with heart attack and higher risk profile (delay in seeking medical attention, larger amount of blood clot in the blood vessel, etc).

What further research do you recommend as a result of your study?

Our analysis was performed by summarizing the currently available data, but it is not enough to reach a definite conclusion by itself.

Further research is warranted to figure out exactly what kind of risk profiles of heart attacks is associated with most benefit from the intracoronary injection of Abciximab.


Meta-Analysis of Prospective Randomized Controlled Trials Comparing Intracoronary Versus Intravenous Abciximab in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Yuichi J. Shimada, Navin C. Nakra, John T. Fox, Yumiko Kanei

American Journal of Cardiology – 1 March 2012 (Vol. 109, Issue 5, Pages 624-628, DOI: 10.1016/j.amjcard.2011.10.016)

Posted in Coronary Artery Disease, coronary plaques, Stent - PCI for CAD | Leave a comment

Electrocardiographic Abnormalities Associated with the Metabolic Syndrome and Its Components: The Multi-Ethnic Study of Atherosclerosis: Dr. Ebong


Electrocardiographic Abnormalities Associated with the Metabolic Syndrome and Its Components: The Multi-Ethnic Study of Atherosclerosis.

Author interview: Dr Imo A. Ebong

Department of Epidemiology and Prevention
Wake Forest University School of Medicine
Winston Salem, NC 27157

What are the main findings of the study?

The main findings of this study are that the metabolic syndrome and its components are associated with electrocardiographic abnormalities.

The metabolic syndrome has been associated with heart disease morbidity and mortality in previous studies. Electrocardiographic abnormalities have also been associated with heart disease morbidity and mortality in previous studies. Therefore, electrocardiographic abnormalities may be an indicator of people with the metabolic syndrome who are at especially high risk of heart disease.

Were any of the findings unexpected?

Our findings were in agreement with our study hypothesis, and although not explored in this study, we considered that the metabolic syndrome and its components may result in changes in the electrical status and structure of the heart that manifest as electrocardiographic abnormalities.

What should clinicians and patients take away from this study?

The increasing prevalence of metabolic syndrome in the US and worldwide makes it necessary for clinicians to identify patients with the metabolic syndrome who are at higher risk of heart disease.

Irrespective of the fact that our findings do not imply causation, and although not currently recommended by practice guidelines, it is important for clinicians to know that a screening electrocardiogram may be useful to identify people with metabolic syndrome who are at a higher risk of heart disease.

People with metabolic syndrome and concurrent electrocardiographic abnormalities can then be specifically targeted to reduce their risk of heart disease.

What recommendations do you have for future research as a result of your study?

Clinical trials should be done to determine if care guided by the results of routine electrocardiographic screening will improve outcomes in people with the metabolic syndrome.


Electrocardiographic Abnormalities Associated with the Metabolic Syndrome and Its Components: The Multi-Ethnic Study of Atherosclerosis.

Ebong IA, Bertoni AG, Soliman EZ, Guo M, Sibley CT, Chen YD, Rotter JI, Chen YC, Goff DC.
Metab Syndr Relat Disord. 2011 Nov 4. [Epub ahead of print]


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Study: Learning How Cholesterol Gets Moved from HDLs to LDLS

Researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) have found new evidence to explain how cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol from “good” high density lipoproteins (HDLs) to “bad” low density lipoproteins (LDLs). These findings point the way to the design of safer, more effective next generation CETP inhibitors that could help prevent the development of heart disease.

Gang Ren, a materials physicist and electron microscopy expert with Berkeley Lab’s Molecular Foundry, a DOE nanoscience research center, led a study in which the first structural images of CETP interacting with HDLs and LDLs were recorded. The images and structural analyses support the hypothesis that cholesterol is transferred from HDLs to LDLs via a tunnel running through the center of the CETP molecule.

“Our images show that CETP is a small (53 kilodaltons) banana-shaped asymmetric molecule with a tapered N-terminal domain and a globular C-terminal domain,” Ren says. “We discovered that the CETP’s N-terminal penetrates HDL and its C-terminal interacts with LDL forming a ternary complex. Structure analyses lead us to hypothesize that the interaction may generate molecular forces that twist the terminals, creating pores at both ends of the CETP. These pores connect with central cavities in the CETP to form a tunnel that serves as a conduit for the movement of cholesterol from the HDL.”

Ren reports the results of this study in a paper in the journal Nature Chemical Biology titled “Structure basis of transfer between lipoproteins by cholesteryl ester transfer protein.” Co-authoring this paper were Lei Zhang, Feng Yan, Shengli Zhang, Dongsheng Lei, M. Arthur Charles, Giorgio Cavigiolio, Michael Oda, Ronald Krauss, Karl Weisgraber, Kerry-Anne Rye, Henry Powna and Xiayang Qiu.

Cardiovascular or heart disease, mainly atherosclerosis, remains the leading cause of death in the United States and throughout the world. Elevated levels of LDL cholesterol and/or reduced levels of HDL cholesterol in human plasma are major risk factors for heart disease. Since CETP activity can reduce HDL-cholesterol concentrations and CETP deficiency is associated with elevated HDL-cholesterol levels, CETP inhibitors have become a highly sought-after pharmacological target for the treatment of heart disease. However, despite this intense clinical interest in CETP, little is known concerning the molecular mechanisms of CETP-mediated cholesterol transfers among lipoproteins, or even how CETP interacts with and binds to lipoproteins.

“It has been very difficult to investigate CETP mechanisms using conventional structural imaging methods because interaction with CETP can alter the size, shape and composition of lipoproteins, especially HDL,” Ren says. “We were successful because we used our optimized negative-staining electron microscopy protocol that allows us to flash-fix the structure and efficiently screen more than 300 samples prepared under different conditions.”

CETP Moving Cholesterol from HDL to LDL

Image by Gang Ren, Lawrence Berkeley National Laboratory

Ren and his colleagues used their optimized negative-staining electron microscopy protocol to image CETP as it interacted with spherical HDL and LDL particles. Image processing techniques yielded three-dimensional reconstructions of CETP and CETP-bound HDL. Molecular dynamic simulations were used to assess CETP molecular mobility and predict the changes that would be associated with cholesterol transfer. CETP antibodies were used to identify the CEPT interaction domains and validate the cholesterol transfer model by inhibiting CETP. This model presents inviting new targets for future CETP inhibitors.

“Our model identifies new interfaces of CETP that interact with HDL and LDL and delineates the mechanism by which the transfer of cholesterol takes place,” Ren says. “This is an important step toward the rational design of next generation CETP inhibitors for treating cardiovascular disease.”

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CDC study finds levels of trans-fatty acids in blood of U.S. white adults has decreased

Blood levels of trans–fatty acids (TFAs) in white adults in the U.S. population decreased by 58 percent from 2000 to 2009 according to a Centers for Disease Control and Prevention study published in the Feb. 8 edition of the Journal of the American Medical Association. This is the first time CDC researchers have been able to measure trans fats in human blood.

CDC researchers selected participants from the National Health and Nutrition Examination Survey (NHANES) years 2000 and 2009 to examine trans–fatty acid blood levels before and after the Food and Drug Administration′s 2003 regulation, which took effect in 2006, requiring manufacturers of food and some dietary supplements to list the amount of TFAs on the Nutrition Facts panel of the product label. During this period, some local and state health departments took steps to help consumers reduce their daily consumption by requiring restaurants to limit their use of TFAs in food and increase public awareness campaigns about the health risks associated with TFAs.

“The 58 percent decline shows substantial progress that should help lower the risk of cardiovascular disease in adults,” said Christopher Portier, Ph.D., director of CDC′s National Center for Environmental Health. “Findings from the CDC study demonstrate the effectiveness of these efforts in reducing blood TFAs and highlight that further reductions in the levels of trans fats must remain an important public health goal.”

The current study provides information for white adults only, and additional CDC studies are under way to examine blood TFAs in other adult race/ethnic groups, children, and adolescents, Dr. Portier added.

This research is a part of CDC′s larger National Biomonitoring program, which currently measures more than 450 environmental chemicals and nutritional indicators in people.

Unlike other dietary fats, trans fats are not essential to human health and do not promote good health. Research has indicated that high consumption of trans–fatty acids is linked to cardiovascular disease in part because TFAs increase LDL cholesterol (“bad” cholesterol). Changing to a diet low in TFAs may lower LDL cholesterol levels, thus decreasing the risk for cardiovascular disease.

Background on study
CDC studied four major TFAs to provide a reasonable representation of TFAs in blood: elaidic acid, linoelaidic acid, palmitelaidic acid, and vaccenic acid. The study measured TFAs in 229 fasting adults from the 2000 NHANES and 292 from 2009 NHANES.

The study found the overall decrease in trans–fatty acids was 58 percent. For specific trans–fatty acids, decreases were: elaidic acid – 63 percent, linoelaidic acid – 49 percent, palmitelaidic acid – 49 percent, and vaccenic acid – 56 percent.


About Trans Fats

  • The USDA/HHS Dietary Guidelines for Americans 2010 recommend keeping TFA consumption as low as possible, especially by limiting foods that contain synthetic sources of trans fats, such as partially hydrogenated oils, and by limiting other solid fats.
  • TFAs in blood come from synthetic sources in foods, such as partially hydrogenated vegetable oils, and natural sources in foods, such as milk.
  • Hydrogenation is used by food manufacturers to make products containing unsaturated fatty acids solid at room temperature and therefore more resistant to becoming spoiled or rancid.
  • Trans–fatty acids are produced by grazing animals, and small quantities are therefore found in meat and milk products.
  • Since 2006, FDA has required nutrition facts labels to list the amount of trans fats in food products. At restaurants, customers can ask before they order, to know which fats are being used to prepare the food. Many restaurants display nutritional content or can provide it upon request.

CDC recommends

  • Look for the trans fat listing on the Nutrition Facts label. Compare brands and choose the one lowest in trans fat, preferably with no trans fat.
  • Replace margarine containing trans fat with unsaturated vegetable oil.
  • If you use margarine, choose a soft margarine spread instead of stick margarine. Check your labels to be sure the soft margarine does contain less trans fat. If possible, find one that says zero grams of tran fat.


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Statins Promote the Regression of Atherosclerosis via Activation of the CCR7-Dependent Emigration Pathway in Macrophages : Author Interview Dr. Garabedian

Author Interview:  Dr. Michael Garabedian
Professor of Microbiology & Urology
NYU School of Medicine
550 First Avenue New York, NY 10016

Statins Promote the Regression of Atherosclerosis via Activation of the CCR7-Dependent Emigration Pathway in Macrophages

What are the main findings of the study?

Our findings lend a plausible mechanism to the recent clinical observations from the SATURN trial published in the NEJM that high dose statins promote atherosclerosis regression.

This is an important clinical observation, but there was no mechanism associated with this clinical study.

Our study using mouse models indicates that statins, known to activate the transcription factor SREBP, induce the expression of the cell surface chemokine receptor CCR7 through the action of SREBP.  We have previously shown that CCR7 induction promotes macrophage emigration and regression of atherosclerosis in mouse models.

Were any of the findings unexpected?

Yes, we did not know whether statins would promote regression.
Since we found they did, we deciphered the mechanism and found that  the transcription factor SREBP inducted changes in histone modifications and activated CCR7 gene expression, which promoted macrophage emigration from the plaque and regression of atherosclerosis.

What should clinicians and patients take away from this study? 

It is important that clinicians understand that atherosclerosis (plaque formation) is a dynamic process and a balance between macrophages entering the plaque( progression ) and macrophages exiting the plaque

High dose statins might act at both steps by slowing progression through lower bad cholesterol as well as  accelerating regression, perhaps through induction of the CCR7-dependent macrophage emigration pathway.

Thus, the molecular mechanisms underlying atherosclerosis progression and regression are is distinct.

Patients should be happy that high dose statins can not only stop plaques from increasing in size, but also reduce the plaques once they are formed.  This should help reduce heart attacks and strokes.

What recommendations do you have for future research as a result of your study?

Our future directions include further elucidating the molecular mechanism of atherosclerosis regression and to translate these findings to the clinic.

For example, we are exploring additional ways to induce CCR7 expression and promote atherosclerosis regression.

We are also examining whether statin induction of CCR7 is affected under conditions of diabetes and hyperglycemia, since diabetes is a established risk factor for atherosclerosis.

In fact, the Fisher lab has recently shown in mouse models that regression is indeed impaired in mice with diabetes compared to their non-diabetic counterparts.

The role of statins remains to be explored.


Statins Promote the Regression of Atherosclerosis via Activation of the CCR7-Dependent Emigration Pathway in Macrophages

Feig JE , Shang Y , Rotllan N , Vengrenyuk Y , Wu C , et al.
PLoS ONE 2011 6(12): e28534. doi:10.1371/journal.pone.0028534

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Researchers identify agent responsible for protection against early stages of atherosclerosis

(Boston) – Researchers from Boston University School of Medicine (BUSM) have identified for the first time the A2b adenosine receptor (A2bAR) as a possible new therapeutic target against atherosclerosis resulting from a diet high in fat and cholesterol. The findings, which appear on-line in Circulation, may have significant public health implications.

Adenosine is a metabolite produced naturally by cells at low levels, and at higher levels during exercise or stress. Adenosine binds to and activates cell surface receptors, one of which is the A2bAR. Previous studies have described the A2bAR as anti-inflammatory and protective against kidney ischemia, cardiac reperfusion injury and restenosis, typically via bone marrow cell signals.

In mouse models, BUSM researchers found atherosclerosis induced by a high-fat diet was more pronounced in the absence of the A2bAR. They also found bone marrow transplantation experiments indicated that A2bAR bone marrow cell signals alone were not sufficient to elicit this effect. “A2bAR genetic ablation led to elevated levels of liver and plasma cholesterol and triglycerides, and to fatty-liver pathology typical of steatosis, assessed by enzymatic assays and analysis of liver sections,” explained senior author Katya Ravid, MD, a professor of medicine and biochemistry at BUSM.

The researchers also identified the mechanism underlying this effect in the liver, involving the control of the transcription factor SREBP-1 and its downstream targets-regulators of lipid synthesis. They found restoration of the A2bAR in the liver of A2bAR null mice reduced the lipid profile and atherosclerosis. “Most importantly, in vivo administration of a pharmacological activator of the A2bAR in control mice on a high fat diet reduced lipid profile and atherosclerosis. Thus, this study provides the first evidence that the A2bAR regulates liver hyperlipidemia and atherosclerosis, suggesting that this receptor may be an effective therapeutic target against earlier stages of atherosclerosis,” Ravid added.


Funding for this study was provided by the National Heart, Lung and Blood Institute.

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