- Drug treats inflammation associated with genetic heart disease
- ICTR in the News: Mid-Life Chronic Inflammation May be Linked to Frailty Later
- For the Media
- What Is Inflammation?
- Acute inflammation
- Chronic inflammation
- Anti-inflammatory diet
- Anti-inflammatory drugs and supplements
- Fight Inflammation to Help Prevent Heart Disease
- Studies Point to Inflammation
- The Role of Inflammation in Heart Disease
- Anti-Inflammatory Lifestyle Changes
- Fish Oil Drug May Prevent Heart Attack and Strokes in High-Risk Patients
Drug treats inflammation associated with genetic heart disease
When young athletes experiences sudden cardiac death as they run down the playing field, it's usually due to arrhythmogenic cardiomyopathy (ACM), an inherited heart disease.
Now, Johns Hopkins researchers have shed new light on the role of the immune system in the progression of ACM and, in the process, discovered a new drug that might help prevent ACM disease symptoms and progression to heart failure in some patients.
“We realized that heart muscle inflammation in ACM is much more complicated than we thought, but also might provide a therapeutic strategy,” says Stephen Chelko, Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine and senior author of the new paper, in Sept. in Circulation.
In ACM, patients often harbor mutations in any of the five genes that make up the cardiac desmosome — the glue material that holds heart cells together and helps coordinate mechanical and electrical synchronization of heart cells. Because of this, it's often called “a disease of the cardiac desmosome.
” In patients with ACM, heart cells pull apart over time, and these cells are replaced with damaged and inflamed scar tissue. These scars can increase risk of instances of irregular heart rhythms and lead to sudden cardiac death if the scar tissue causes the heart wall to stiffen and renders it unable to pump.
If a person is aware they carry an ACM-causing genetic mutation, doctors help them avoid cardiac death through lifestyle changes, such as exercise restriction, and medications that keep their heart rate low.
However, there are currently no drugs that treat the underlying structural defects of the desmosome.
People who live for many years with ACM still accumulate scar tissue and inflammation in their hearts, leading to chronic heart disease.
“We tended in the past to view ACM as something that kills due to a sudden arrhythmic event,” said Chelko. “But now we're starting to also see it as a chronic inflammatory disease that can progress more slowly over time, leading to heart failure.”
Chelko and his colleagues wanted to determine the molecular cause of inflammation in the hearts of people with ACM. So they studied mice with an ACM-causing mutation, as well as heart muscle cells generated from stem cells isolated from an ACM patient.
They found that the inflammation associated with the disease arose from two separate causes.
First, they noticed high levels of macrophages, a type of immune cell that's normally found at sites of inflammation, such as around cuts or scrapes that are healing.
“Macrophages are usually the good guys who help heal a wound and then leave,” said Chelko. “But in ACM they're permanently setting up shop in the heart, which, over time, reduces its function.”
Chelko's team also found that in ACM, the heart cells themselves are triggered by a protein known as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) to produce chemicals called cytokines, which act as homing beacons for other inflammatory cells and molecules. When the researchers treated mice or isolated cells with a drug blocking NF-κB, heart cells stopped producing many of these cytokines, leading to decreased inflammation and infiltration of inflammatory cells. In mouse models of ACM, animals treated with the NF-κB-blocking drug Bay-11-7082 had a twofold increase in heart function, measured by how much blood their hearts could pump over time compared with untreated ACM animals. They also had a twofold reduction of damaged and inflammatory scar tissue in the heart.
More than one-third of patients with ACM who die of sudden cardiac death have no previous cardiac symptoms, so wouldn't ever know to seek treatment. However, for relatives of these people who discover that they carry a genetic mutation causing ACM — or those who discover the mutation for other reasons — a drug could help stave off long-term heart disease, Chelko said.
While the Bay-11-7082 drug is currently only used in the lab for experimental purposes, the U.S.
Food and Drug Administration has approved canakinumab, a drug that targets the same inflammatory pathway, for use in juvenile arthritis and a collection of rare auto-inflammatory syndromes.
Canakinumab is also being studied for use in coronary artery disease. Chelko's group is now investigating whether this drug would have the same effect as Bay-11-7082 in ACM.
“We're very excited to have found an FDA-approved drug that can reduce heart inflammation in ACM, and we're eager to do more research to ultimately help those who carry these genetic mutations,” said Chelko.
In addition to Stephen Chelko, authors on the Circulation paper are Justin Lowenthal, Djahida Bedja, Nuria Amat-Alarcon, Peter Andersen and Leslie Tung of Johns Hopkins; Angeliki Asimaki and Carlos Bueno-Beti of St. George's University of London; Arianna Scalco of University of Padova; Daniel Judge of Medical University of South Carolina; and Jeffrey Saffitz of Beth Israel Deaconess Medical Center.
Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.
ICTR in the News: Mid-Life Chronic Inflammation May be Linked to Frailty Later
A study of nearly 6,000 Americans followed for 24 years from middle to late adulthood found that having chronic inflammation in middle age may be linked to an increased risk of frailty and overall poorer health decades later.
A report on the study, led by Johns Hopkins Medicine investigators, is published in the March issue of The Journal of Gerontology. Overall for the study sample, each standard deviation of higher inflammation recorded in midlife yielded a 39 percent higher odds of frailty approximately 24 years later.
These associations were stronger among whites than African-Americans. The prevalence of frailty in later life among people who had low levels of inflammation throughout midlife was 4 to 5 percent.
However, the prevalence of later life frailty among adults with high levels of inflammation during midlife was 9 percent — approximately double.
The investigators caution that their study does not establish a cause and effect relationship between their definition of chronic inflammation and frailty, which is generally aligned with overall poorer health, weakness and failure to thrive in older adults.
But the findings, they say, add to evidence that “middle adulthood is a potentially important exposure period,” and the study results “provide support for theories suggesting a role for systemic inflammation in the development of frailty and related poor health in older age,” says lead study author Keenan Walker, Ph.D., a clinical neuropsychology postdoctoral fellow at the Johns Hopkins University School of Medicine. “Our results also support the idea that disease processes leading to frailty may begin decades prior to its onset, in a similar manner to other chronic conditions such as dementia.” While the researchers say the data are too preliminary to suggest biomarker screening for frailty, they encourage maintaining a healthy lifestyle and taking measures to prevent and treat chronic diseases to reduce levels of inflammation, which may help people avoid developing frailty in older adulthood.
Researchers also can’t say for sure this study that treating inflammation can reduce the risk of frailty, says coauthor Jeremy Walston, M.D., the Raymond and Anna Lublin Professor of Geriatric Medicine at Johns Hopkins.
“However, the National Institutes of Health has recently sponsored clinical trials on potential interventions for chronic inflammation,” he says.
These include one at Johns Hopkins that is evaluating whether supplements of lactoferrin, a substance found in mothers’ milk that promotes the growth of beneficial bacteria in the intestines and promotes immune system function, reduce inflammation in older adults.
For the current study, Walker and his colleagues analyzed data from 5,760 adults in their 70s participating in the Atherosclerosis Risk in Communities study, a national, long-term investigation of nearly 16,000 adults living in four U.S.
communities: Washington County, Maryland; Forsyth County, North Carolina; the northwestern suburbs of Minneapolis; and Jackson, Mississippi. The participants’ health has been followed over the course of five medical examinations, starting in 1987–1989, when they were in their 40s and 50s.
The fifth and most recent medical visit and evaluation occurred in 2011–2013.
The investigators specifically examined measures of five markers of inflammation in the bloodstream (white blood cell count, fibrinogen, von Willebrand factor and factor VIII) collected during participants’ initial study visits. Inflammatory biomarker levels were combined to create an inflammation composite score, which was used as a marker of each participant’s overall level of inflammation.
Next, all participants who completed the fifth visit were categorized as frail, pre-frail or robust depending upon how many of the following attributes they had at the time: exhaustion, slowness, low physical activity, weakness and weight loss.
Those deemed frail met three or more of these criteria, while those categorized as pre-frail met one or two of the criteria, and those categorized as robust met none of the criteria.
The researchers used statistical analyses to determine if markers of inflammation at midlife could predict later frailty, and looked at whether race or sex affected this relationship.
Overall, they found, 7 percent of the participants studied were frail at the fifth visit in their 70s, and 48 percent were pre-frail at the fifth visit.
Compared to the robust participants, those who were frail or pre-frail were older (four and three years older, respectively), more ly to be female and African-American, had lower levels of education, and had greater levels of cardiovascular risk factors, such as higher body mass index, blood pressure and total cholesterol, and more chronic health conditions such as high blood pressure, diabetes and coronary heart disease.
Investigators also looked at measures of the blood marker C-reactive protein (CRP)—a protein that rises in response to inflammation from a variety of sources including infections, heart disease and cancer—collected during the study’s second visit (1990–1992) and fourth visit (1996–1999), when most participants were still in their middle-age years. Participants were categorized as having “low” or “elevated” CRP at these visits using a cutoff of 3 mg/L, which is commonly used to define systemic inflammation.
Even after adjusting for demographic characteristics such as age, sex and education, and for co-occurring conditions such as diabetes and high blood pressure, each standard deviation increase in visit 2 CRP was associated with a 32 percent higher chance of frailty features at visit 5, occurring 21 years later. Each standard deviation increase in visit 4 CRP was associated with a 52 percent higher chance of frailty features at visit 5, occurring 15 years later. Among the participants, 2,690 were robust, 2,749 were pre-frail and 391 were frail.
Participants who had elevated CRP at visits 2 and 4 or who transitioned to elevated CRP during the six-year time period were more ly to subsequently meet frailty criteria than those who maintained low CRP.
“Middle adulthood may be an especially important period for poor health in older adults for multiple reasons,” Walker says. “First, it is in middle age when the incidence of common chronic diseases, such as diabetes, begins to accelerate.
Second, compared to individuals who develop systemic disease and inflammation in later life, individuals who develop these conditions in midlife may have a longer exposure and therefore are more susceptible to deleterious physiological effects.
“There are studies underway to see if dropping levels of inflammation, mostly in older age groups, can prevent the progression of declines in mobility and in the muscles that contribute to frailty,” Walston says. “Stay tuned — hopefully we’ll be able to say with more accuracy in the not-too-distant future that treating chronic inflammation will reduce your risk of muscle decline and related frailty.”
Coauthors were Rebecca Gottesman, M.D., Ph.D., of Johns Hopkins; Anna Kucharska-Newton, Ph.D., M.P.H., and Priya Palta, Ph.D., of the University of North Carolina at Chapel Hill; and B. Gwen Windham, M.D., M.H.S., of The University of Mississippi Medical Center.
The work was supported by the National Institute on Aging (grants T32 AG027668, K99-AG052830, K24 AG052573, P30AG021334 and R01AG050560).
For the Media
What Is Inflammation?
Inflammation is a vital part of the immune system's response to injury and infection. It is the body's way of signaling the immune system to heal and repair damaged tissue, as well as defend itself against foreign invaders, such as viruses and bacteria.
Without inflammation as a physiological response, wounds would fester, and infections could become deadly.
However, if the inflammatory process goes on for too long or if the inflammatory response occurs in places where it is not needed, it can become problematic.
Chronic inflammation has been linked to certain diseases such as heart disease or stroke, and may also lead to autoimmune disorders, such as rheumatoid arthritis and lupus.
But a healthy diet and lifestyle can help keep inflammation under control.
Acute inflammation occurs after a cut on the knee, a sprained ankle or a sore throat. It's a short-term response with localized effects, meaning it works at the precise place where a problem exists. The telltale signs of acute inflammation include redness, swelling, heat and sometimes pain and loss of function, according to the National Library of Medicine.
In the case of acute inflammation, blood vessels dilate, blood flow increases and white blood cells swarm the injured area to promote healing, said Dr. Scott Walker, a family practice physician at Gunnison Valley Hospital in Utah. This response is what causes the injured area to turn red and become swollen.
During acute inflammation, chemicals known as cytokines are released by the damaged tissue. The cytokines act as “emergency signals” that bring in your body's immune cells, hormones and nutrients to fix the problem, Walker said.
In addition, hormone- substances known as prostaglandins create blood clots to heal damaged tissue, and they also trigger pain and fever as part of the healing process. As the body heals, the acute inflammation gradually subsides.
Un acute inflammation, chronic inflammation can have long-term and whole-body effects.
Chronic inflammation is also called persistent, low-grade inflammation because it produces a steady, low-level of inflammation throughout the body, as judged by a small rise in immune system markers found in blood or tissue.
This type of systemic inflammation can contribute to the development of disease, according to a summary in the Johns Hopkins Health Review.
Low levels of inflammation can be triggered by a perceived internal threat, even when there isn't a disease to fight or an injury to heal, andsometimes this signals the immune system to respond. As a result, white blood cells swarm but have nothing to do and nowhere to go, and they may eventually start attacking internal organs or other healthy tissues and cells, Walker said.
Researchers are still working to understand the implications of chronic inflammation on the body and the mechanisms involved in the process, but it's known to play a role in the development of many diseases.
For example, chronic inflammation has been linked to heart disease and stroke. One theory suggests that when inflammatory cells stay too long in blood vessels, they promote the buildup of plaque.
The body perceives this plaque as a foreign substance that doesn't belong, so it tries to wall off the plaque from the blood flowing inside the arteries, according to the American Heart Association(AHA).
If the plaque becomes unstable and ruptures, it forms a clot that blocks blood flow to the heart or brain, triggering a heart attack or stroke.
Cancer is another disease linked with chronic inflammation. Over time, chronic inflammation can cause DNA damage and lead to some forms of cancer, according to the National Cancer Institute.
Chronic, low-grade inflammation often does not have symptoms, but doctors can test for C-reactive protein (CRP), a marker for inflammation in the blood. High levels of CRP have been linked with an increased risk of heart disease. CRP levels can also indicate an infection, or a chronic inflammatory disease, such as rheumatoid arthritis or lupus, according to the Mayo Clinic.
Besides looking for clues in the blood, a person's diet, lifestyle habits and environmental exposures can contribute to chronic inflammation. It's important to maintain a healthy lifestyle to keep inflammation in check.
Anti-inflammatory diets have become popular in recent years.
The recommended foods are typical of a Mediterranean diet and include eating more fish, fresh fruits and vegetables, and healthy fats; eating moderate amounts of nuts; eating very little red meat; and drinking red wine in moderation. the Mediterranean diet, the principles of an anti-inflammatory diet are healthful ones and the approach is nutritionally sound, according to the Mayo Clinic.
“Anti-inflammatory food components, such as omega-3 fats, protect the body against the possible damage caused by inflammation,” said Ximena Jimenez, a Miami-based nutritionist and spokesperson for the Academy of Nutrition and Dietetics.
An anti-inflammatory diet also means staying away from foods that can promote inflammation.
It's best to minimize the amount of foods you eat that are high in saturated and trans fats, such as red meats, dairy products and foods containing partially hydrogenated oils, according to the University of Wisconsin.
In addition, limit sugary foods and refined carbohydrates, such as white rice and bread. And cut back on the use of cooking oils and margarines that are high in omega-6 fatty acids, such as corn, safflower and sunflower oils.
Anti-inflammatory drugs and supplements
Currently, there are no prescription drugs that specifically target chronic inflammation, according to an article published in the Johns Hopkins Health Review.
However, there are plenty of over-the-counter and some prescription medications to treat acute, short-term inflammation. The most common ones are the over-the-counter medications known as non-steroidal anti-inflammatory drugs (NSAIDs). They include aspirin, naproxen (Aleve) and ibuprofen (Advil and Motrin).
NSAIDs work by blocking the enzyme cyclooxygenase, which produces prostaglandins, a hormone- substance that promotes inflammation, according to MedicineNet. When over-the-counter medicines aren't effective at relieving short-term pain and inflammation, there are also prescription-strength NSAIDs.
Acetaminophen (Tylenol) is another common pain reliever, but it does not relieve inflammation, according to the National Library of Medicine.
Corticosteroids, such as cortisone and prednisone, may be prescribed for inflammatory conditions, such as asthma and arthritis. They may help suppress inflammation, but these powerful drugs also carry a risk of side effects, such as weight gain and fluid retention, according to the Mayo Clinic.
Several dietary supplements are said to have anti-inflammatory properties, such as devil's claw, turmeric and willow bark.
Although there is some limited evidence that a few natural products may provide modest benefits for acute inflammation, in general, there is insufficient evidence to support the use of many of these products for inflammatory conditions, according to the National Center for Complimentary and Integrative Health.
This article is for informational purposes only and is not meant to offer medical advice. This article was updated on Oct. 19, 2018 by Live Science Contributor, Cari Nierenberg.
Fight Inflammation to Help Prevent Heart Disease
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You probably already know that high cholesterol and blood pressure are major risk factors for heart disease. But do you know about inflammation? Recent research shows it plays a key role, and that working to reduce it can prevent heart attacks and strokes.
“Just we’re targeting blood pressure, cholesterol and blood glucose, we also need to target inflammation,” says Erin Michos, M.D., M.H.S., associate director of preventive cardiology for the Ciccarone Center for the Prevention of Heart Disease. “We all should be making an effort to reduce chronic inflammation in our bodies.”
To protect your heart from the damaging effects of inflammation, here’s what you need to know.
Studies Point to Inflammation
Two decades ago, researchers discovered that high levels of inflammation were associated with an increased chance of having a heart attack or stroke. However, what they didn’t know was whether anti-inflammatory treatments could prevent those events from occurring.
In 2008, the JUPITER study found that for older adults who did not have elevated blood cholesterol but who did have elevated blood levels of inflammatory markers, treatment with cholesterol-lowering statin drugs reduced the number of heart attacks and strokes. But it wasn’t clear whether that was because statins reduced inflammation or because they further lowered bad cholesterol, since they do both.
However, a recent clinical trial called CANTOS studied an injectable antibody type of anti-inflammatory drug in people who had a prior heart attack and who also had elevated inflammatory markers despite statin treatment.
This landmark study finally proved that targeting inflammation without changing cholesterol levels can have a significant impact. People treated with the novel anti-inflammatory treatment reduced their lihood of subsequent heart attacks or strokes by 15 percent.
It also decreased the need for major interventions such as angioplasty and bypass surgery by 30 percent, proving that addressing inflammation to prevent heart disease is essential.
Additional studies are now looking at whether older, cheaper medications taken by mouth (colchine and methotrexate) can have similar heart protection benefits.
The Role of Inflammation in Heart Disease
Inflammation is part of your body’s immune response to an illness or injury. When you have a wound or an infection, inflammation helps fight off germs and facilitates healing. Buildup of cholesterol and other substances in your arteries (called plaques or atherosclerosis) can set off an inflammatory response, too.
“For short-term conditions, inflammation is helpful,” explains Michos. “But sustained low levels of inflammation irritate your blood vessels. Inflammation may promote the growth of plaques, loosen plaque in your arteries and trigger blood clots — the primary cause of heart attacks and strokes.”
When a blood clot blocks an artery to the heart, you have a heart attack. If the blood clot blocks an artery to the brain, the result is a stroke.
Anti-Inflammatory Lifestyle Changes
“The good news is that you can control inflammation by avoiding factors that activate your body’s inflammatory response,” says Michos. “And, these same lifestyle choices decrease bad cholesterol, lower blood pressure and reduce high blood sugar, too.”
Here’s what you can do to reduce inflammation:
- Quit smoking: Smoking damages your blood vessels and promotes atherosclerosis. By quitting, you can cut your heart disease risk in half.
- Maintain a healthy weight: Being overweight increases your risk for multiple diseases. But carrying excess fat around your belly is a red flag for heart disease risk. A type of fat that accumulates in the belly (called visceral fat) secretes a molecule that causes inflammation.
- Increase activity: Exercising for as little as 20 minutes a day can decrease inflammation. You don’t have to do an intense sweat session: Moderate workouts, such as fast walking, are effective.
- Eat a heart-healthy diet: Processed and fast foods produce inflammation. Whole foods, on the other hand, are anti-inflammatory. Eat more fruits, vegetables, whole grains, beans, nuts and fatty fish.
Chronic inflammation doesn’t produce symptoms — the only way to measure it is with a blood test, and most people aren’t regularly screened for inflammation.
Making healthy lifestyle choices is the best way to lower that risk factor, although doctors may also prescribe a statin drug for those with a higher risk of heart disease.
Your doctor can determine your risk level and what next steps are most appropriate for you.
Fish Oil Drug May Prevent Heart Attack and Strokes in High-Risk Patients
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Cardiologists may one day have a new tool to help prevent heart attacks and strokes in some high-risk patients: a prescription drug that contains large doses of EPA, an omega-3 fatty acid contained in fish oil.
A large clinical trial found that the drug, called Vascepa, sharply reduced the rate of cardiovascular events in people with a history of heart disease or Type 2 diabetes, according to early results that were announced on Monday.
The findings were particularly relevant for people with high triglycerides, a type of fat in the blood that has been linked to an increased risk of heart disease.
The new trial, called Reduce-IT, focused on people whose cholesterol levels were well controlled with statins but whose triglyceride levels remained very high.
Many cardiovascular experts were doubtful that adding fish oil on top of statins would produce much if any benefit because a number of smaller and less rigorous studies over the years had failed.
But the new trial showed that statin-treated adults with elevated triglycerides who were prescribed high doses of the purified EPA had a 25 percent reduction in their relative risk of heart attacks, strokes and other cardiac events compared to a control group of patients who received placebo.
“I’m very surprised by the magnitude of the results, which quite frankly are large,” said Dr. Michael J. Blaha, the director of clinical research at the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins Medical School, who was not involved in the study. “My expectations were very low. A lot of people are legitimately surprised by this.”
Fish oil has long been a popular supplement to protect against heart disease. It contains high levels of omega-3 fatty acids, primarily EPA and DHA, which reduce inflammation and lower triglyceride levels. Omega-3 fatty acids also have blood-thinning effects similar to those of aspirin.
But until now most of the clinical trials that have looked at fish oil in heart patients had not found convincing evidence that it helps.
Some argued that the trials were deeply flawed, saying they relied on doses that were too small or that they failed to recruit the patients who were most ly to benefit, those with high triglycerides.
Some of the studies were observational, which are less rigorous than clinical trials, in which different groups of patients receive different treatments. They also used various types of fish oil.
The new trial differed from previous ones in a number of ways. It focused specifically on two groups of high-risk patients: People with a history of cardiovascular events, such as heart attacks, strokes and angina; and those with Type 2 diabetes and other risk factors high blood pressure.
The patients also had to have high triglycerides. The median baseline level of triglycerides among the subjects was 216 milligrams per deciliter — well above the cutoff for what is considered a normal level, which is 150 milligrams per deciliter.
In addition, all of the patients were on statins, which lower cholesterol.
The intervention in this trial, which was sponsored by Amarin, was not the typical fish oil supplement that can be purchased at any supermarket or pharmacy. Vascepa is a prescription drug that contains highly purified EPA.
Fish oil supplements, on the other hand, often contain a mixture of both EPA and DHA and in some cases other oils as well. EPA and DHA are similar but have slightly different effects.
Both can lower triglycerides, for example, but DHA also tends to raise LDL cholesterol, the so-called bad kind associated with heart disease.
The trial enrolled 8,179 adults and followed them on average for about five years. In addition to lowering cardiovascular events, the trial found that Vascepa was safe and well tolerated. Amarin announced the findings on Monday and is expected to present the full results and data at an annual American Heart Association conference in November.
Dr. Ethan Weiss, a cardiologist and associate professor at the University of California, San Francisco, who was not involved in the study, said that the findings confirm the role that high triglycerides play in heart disease but that they nonetheless came as a shock because so many earlier trials of fish oil found little or no benefits.
He pointed to several caveats: He and others need to see all of the data, and the patient population that is ly to benefit from Vascepa is very specific.
Diet and exercise can also lower triglycerides — especially very low carbohydrate diets — and whether the outcome on heart risk might be similar to the effect produced by Vascepa should be studied, he said.
“Lots of questions remain,” he said. “But the takeaway is that this is really big and I was wrong. And I am happy I was wrong and am excited we have a new pathway and set of tools to explore for our patients.”
Some experts cautioned that Vascepa is not for everyone who has heart disease or risk factors for it. The drug is currently approved for certain patients with unusually high triglyceride levels.
“The worried well shouldn’t run out and take fish oil,” said Dr. Michael Shapiro, a site investigator for the Reduce-IT trial and the director of Oregon Health and Science University’s Atherosclerosis Imaging Program. But the group that is ly to benefit includes a large proportion of patients in heart clinics.
“The amount of people around the world who have atherosclerotic disease or diabetes who take a statin and still have elevated triglycerides is enormous,” he said. “This has huge implications.”
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