By Leah Lawrence

Inflammation burst onto the cardiology scene about 15 years ago when it was first linked with an increased risk for heart disease. True to form, inflammation acts somewhat like a15-year-old adolescent in its relationship with the cardiology community: awkward and still trying to figure itself out. The cardiology community knows a little bit about inflammation, but hears different things from different people. Rumors start. Comments are misconstrued or misinterpreted. Suspicions ensue. And, perhaps as is typical of any budding romance, only time will tell if inflammation is a player.

At its roots, inflammation represents a simple concept: vascular tissue's biological response to harmful stimuli. However, the role of inflammation in atherosclerosis abounds with controversy. And, like any teenage romance, each party can lay claim to confidantes and supporters, debaters and detractors when it comes to their relationship. But the question on everyone's mind: Do inflammation and atherosclerosis have any future together?

New to the Old Boys' Club

So do we really know that sparks fly between inflammation and atherosclerosis or is that up for discussion?

"The fact that inflammation is an important part of what leads to heart disease is well established," said Paul Ridker, MD, Eugene Braunwald Professor of Medicine at the Harvard Medical School and the director of the Center for Cardiovascular Disease Prevention at the Brigham and Women's Hospital, told CardioSource WorldNews. "There are many areas of this field that are controversial, but I do not think that is one of them."

One of several pioneers in the area of inflammation, Dr. Ridker has spent several years—almost 2 decades now—researching inflammation and its connection to atherosclerosis. Specifically, Dr. Ridker has worked on testing the role of C-reactive protein (CRP), a marker for inflammation found in the blood.

His first major research linking levels of CRP with risk for future MI and stroke involved a study of 543 healthy men in the Physicians' Health Study. Published in 1997 in The New England Journal of Medicine, the analysis found that men with higher levels of CRP at baseline had increased risk for MI and stroke.

Thanks to this study, CRP helped inflammation enter the scene as an important factor associated with increased risk for atherosclerosis, adding to the old standards of increased cholesterol, increased BP, smoking, and lack of exercise.

"One of the reasons that the whole concept of inflammation became so controversial is because many people viewed research of inflammation as an attempt to try to supplant the traditional risk factors," said Peter Libby, MD, chief of cardiovascular medicine at the Brigham and Women's Hospital. "Instead, inflammation provides a mechanism that explains how traditional risk factors are altering the biology of the artery in a way that gives rise to the disease and its complications."

Probably the most prominent of these suitors, uh, risk factors: lipoproteins. They can become ensnared in arterial walls, building that most solid of relationships, plaque. Also, according to Ira Tabas, MD, PhD, professor medicine and pathology and cell biology at Columbia University College of Physicians & Surgeons, once these bad boys of serum lipids get into the system, they wreak havoc by "triggering a very long, indolent, and smoldering inflammatory response."

Sounds simple, right? If high LDL cholesterol, then high inflammation, and vice versa. Unfortunately, it's anything but simple.

Mo' Cholesterol, Mo' Inflammation

As more was learned about inflammation and its role in heart disease, the idea that measuring inflammation by way of CRP could help to predict increased risk for CVD became more established. The next question became whether or not lowering inflammation could reduce risk.

In 2005, this hypothesis was tested as a secondary analysis in the PROVE IT-TIMI 22 trial, which compared the outcomes of two statins. The researchers measured LDL cholesterol and CRP levels in a group of 3,745 patients with acute coronary syndrome (ACS) following statin treatment. The results of this secondary prevention study indicated that lower levels of LDL cholesterol resulted in a lower rate of CV events. However, data also indicated that lower levels of CRP, and thus, inflammation, resulted in lower event rates as well, despite the level of LDL cholesterol achieved by the patient. Ultimately, this helped show that the lower CRP level achieved, the better the outcome, said Dr. Libby.

Next, Dr. Ridker and colleagues explored the use of inflammation as a way of identifying people who might be able to benefit from statin therapy, but who did not have LDL levels that would be classified as high or above average. The primary prevention trial JUPITER, the results of which were published in The New England Journal of Medicine in 2008, assigned patients with normal LDL levels to treatment with a statin or placebo. When the trial was stopped, LDL cholesterol had decreased 50% among patients assigned the statin, and CRP had dropped 37%. In addition, the group of patients assigned the statin had significantly decreased rates of major CV events.

Encouraging results to be sure, certainly something to keep the relationship going, but JUPITER does not necessarily tell us that the anti-inflammatory effect led to the clinical benefit. "One could have conducted JUPITER without ever measuring biomarkers of inflammation after enrollment," Dr. Libby added.

Once again, light was shed on the topic of inflammation, but it was more like candlelight than a spotlight. Physicians were still in the dark about whether lowering inflammation directly resulted in decreased risk for heart disease.

Time to Define the Relationship

There always comes a time in a new relationship when a couple wants to establish where they stand. Stop focusing on the past, define the present. Put up or shut up. The same is true with inflammation. Researchers and physicians alike are interested in defining whether inflammation is a viable target for decreasing the risk for atherosclerosis.

"Can we establish that lowering inflammation, per se, lowers cardiovascular risk?" Dr. Ridker said. "That is the truly controversial piece of this puzzle."

According to Dr. Tabas, preclinical models of atherosclerosis seem to indicate that targeting inflammation specifically would decrease risk for cardiovascular disease. But there's the rub. Only correlation studies have been completed in humans, and correlation is far from a slam dunk, he said.

Multiple studies are underway with the goal of targeting markers of inflammation unrelated to cholesterol. The two big boys on the block are the CIRT and CANTOS trials, which are in the enrollment process.

"These trials go under the rubric of CV inflammation reduction trials and are specifically designed to answer the question, 'If we reduce inflammation in high-risk patients, can we reduce CV risk?'" Dr. Ridker said. "The way to do that is to randomize patients to anti-inflammatory drugs versus placebo on top of standard care."

The bigger trick though, according to the experts who spoke with CSWN: Interventions, was to select drugs that target inflammation in the vessel wall but do not change diabetes, cholesterol, or other indices of the disease process. Dr. Ridker is excited to have not one, but two potential drugs undergoing investigation, giving researchers what he called "two swings at the bat to get it done."

Two Shots at One Target

In one corner, researchers have an NHLBI-funded trial, the Cardiovascular Inflammation Reduction Trial (CIRT), which is investigating whether taking low-dose methotrexate will reduce the risk for MI, stroke, or death in patients with type 2 diabetes or metabolic syndrome.

How does methotrexate lower inflammation? The mechanism remains unclear. However, the drug—which is given in a much, much lower dose than its more commonly known high-dose form for cancer treatment—is currently used in patients with rheumatoid arthritis and was found in observational studies to be associated with a reduced risk for CVD. CIRT would be the first trial to provide direct data linking the drug to reduced inflammation.

"The other issue this trial will shed light on is whether or not the adverse effects, which are advertised as being very small, will be cumulatively large enough to be important," Dr. Tabas said. Low-dose methotrexate has been previously associated with a small increase in risk for infection and liver fibrosis. These events do not prohibit its use in patients with rheumatoid arthritis, but Dr. Tabas said, researchers will have to wait and see what happens when "you put tens of thousands of asymptomatic patients at high risk for atherosclerosis" on the drug.

In the second corner, the Novartis-funded Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) will test whether or not the monoclonal antibody canakinumab, which targets interleukin-1 beta, can reduce inflammation and subsequently reduce recurrent CV events in patients with previous MI. Results of a previously published phase II trial examining canakinumab found that the drug reduced several different biomarkers of inflammation, according to Dr. Ridker, including fibrinogen, interleukin-6, and CRP.

"Interleukin-1 beta is one of the many cytokines that is involved in inflammation, and the question with atherosclerosis, where many cytokines are involved, is whether targeting just one will be enough," Dr. Tabas added.

Crashing the Party?

Other agents in the pipeline, such as GlaxoSmithKline's lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor darapladib, may also shed light on the topic.

"Lp-PLA2 is an enzyme that leads to the production of pro-inflammatory mediators within atherosclerotic plaque, and some studies have shown that patients with genetically low levels of Lp-PLA2 are at reduced risk for cardiovascular events," Michelle O'Donoghue, MD, an associate physician in the division of cardiology at Brigham and Women's Hospital told CSWN: Interventions.

In a phase II trial, darapladib halted growth of plaque's necrotic core as compared with statin alone, according to Dr. O'Donoghue. The drug is now being evaluated in STABILITY, which is looking at 16,000 patients with stable coronary heart disease, and SOLID-TIMI 52, a study of 13,000 patients with acute coronary syndrome. Results of these studies are expected next year.

"These are all bold studies with researchers trying to come up with causation data in humans, which we have never had before," Dr. Tabas said. "However, whether or not they will work, nobody knows yet."

What You See Is What You Get

They say love is blind, but when it comes to inflammation, imaging may be able to help show just how deep the relationship goes. There are currently three imaging methods used to evaluate inflammation, according to Ahmed A. Tawakol, MD, co-director of the cardiac MR PET CT Program at Massachusetts General Hospital.

The most frequently discussed and tested is the use of fluorodeoxyglucose positron emission tomography (FDG-PET). This form of imaging evaluates the uptake of FDG in plaque as a measure of inflammation. However, we still need robust evidence in humans that FDG uptake is a true reflection of inflammation. In addition to FDG-PET, magnetic resonance imaging (MRI) to detect inflammation is also being tested in humans.

"One use is to inject iron oxide particles that are easily detected by MRI so that you can see where the iron ends up localizing, providing an index of inflammation," Dr. Tawakol said.

The other, gadolinium-enhanced MRI, involves researchers looking for increased retention and distribution of the agent within atherosclerotic plaques, which Dr. Tawakol believes "is an index of leaky neovessels associated with the plaque and that, in turn, is associated with inflammation."

The imaging of inflammation using optical coherence tomography (OCT), a catheter-based optical technique that can visualize atherosclerotic plaques, offers a more direct method. This technique can provide indices of the architecture of the vessels, especially in the parts of the plaque that are close to the lumen, Dr. Tawakol said. In addition, OCT can provide a visual of macrophage infiltration, or the presence on inflammation cells.

Still No Proof in the Pudding

Molecular imaging for inflammation is hardly picture perfect—there is currently no validated method for humans and information on markers can be had with a relatively inexpensive blood test. So why continue to pursue imaging like a lovesick teen?

Because, Dr. Libby said, with CV drug development in a bit of a "funk," cardiology needs new ways to determine whether a therapy, novel or not, is effective in hitting management targets. Classic methods of identifying biomarkers and see how they change in relation to clinical endpoints require that huge numbers of patients be enrolled in large-scale trials. The breadth and depth of such trials make inflammation imaging less cost ineffective by comparison.

According to Dr. Ridker, both CIRT and CANTOS will have imaging substudies that will test to see if imaging can find inflammation that is seen in study patients and whether or not it can track with whatever benefit might be seen at the end of the trials. Those data will not be available for 5 or 6 years though, he said.

So is the hint of a long-term benefit enough to keep us interested in this relationship between inflammation and cardiology? Hope, like love, springs eternal. And as long as we continue to glean useful information about inflammation, the hot adolescent romance we now enjoy will not cool off in the years to come.

Keywords: Cytokines, Gadolinium, Risk Factors, Hematologic Tests, Methotrexate, Magnetic Resonance Imaging, Primary Prevention, Triazines, Benzaldehydes, Cholesterol, Biomarkers, Thrombosis, Fibrinogen, Liver Cirrhosis, Sulfonamides, Inflammation, Acute Coronary Syndrome, Neoplasms, Stroke, Atherosclerosis, National Heart, Lung, and Blood Institute (U.S.), Macrophages, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Tomography, Optical Coherence, Ferric Compounds, Smoking, Oximes, C-Reactive Protein, Secondary Prevention, Diabetes Mellitus

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