Inflammation And Heart Disease

“With 60 staring me in the face, I have developed inflammation of the sentence structure and definite hardening of the paragraphs.” James Thurber

Many doctors and researchers agree that inflammation is intimately involved in coronary artery heart disease in one way or another: “….inflammation is common for heart disease and stroke patients and is thought to be a sign or atherogenic[forming plaques inside arteries] response” according to past American Heart Association president Donna Arnett, Ph.D. 1“The original observation nearly 18 years ago that we made about inflammatory markers and risk was very positive for stroke as well as myocardial infarction (MI),” said Paul M. Ridker, M.D., MPH.

Most of us take coronary artery function for granted. Under normal circumstances, coronary arteries and the myocardium, or heart muscle, interact in a straightforward supply and demand format. When you exercise or undergo stress, your heart speeds up and pumps more forcefully, requiring more blood to meet its metabolic demands. The coronary arteries oblige by dilating and supplying the muscle with more blood and everything is fine. However, if for any reason, blood flow through coronary arteries is diminished, things are no longer fine. Evidence suggests that “atherosclerosis (the arterial disease characterized by deposition plaques of fatty material on their inner walls) is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate and activate lesions in the arterial tree.”

How does a coronary artery become diseased such that it ultimately cannot supply blood at all, and a heart attack ensues? The answer begins with something all doctors agree on: the coronary artery initially becomes narrowed by what is called an “atheroma.” Think of an atheroma as a glob of fat, cells, debris and connective tissue lodged under the lining of the artery. Much of the problem fat is the LDL type (the “bad cholesterol”) which becomes oxidized making it toxic. Much like high speed turns in a race car track, there are certain high flow areas of hemodynamic strain in the arterial system, and oxidized LDL gets deposited at these locations, under the lining of the artery. The coronary artery registers this damage and launches a programmed repair sequence, which can ultimately result in blockage of the artery, a myocardial infarction (MI), and death.

Deposition of oxidized LDL at high flow strain areas sets up an inflammatory reaction in the lining of the artery. The inflamed lining cells start making chemicals called “chemokines” which attract inflammation blood cells to the site of the injury. These cells include platelets (help you clot offcuts), macrophages (cells which kill bacteria and clean up all kinds of cellular debris), lymphocytes (usually help fight bacterial and viral infections). Fibroblasts are called in and produce connective tissue elements (collagen) in an attempt to “cap off” the damaged area.

The entire process is a complex, elegant, fascinating, cascading symphony of activity by which the body is determined to rid itself of the inflamed plaque of cholesterol droplets under the artery lining. All the immune cells that arrive secrete their own chemokines calling yet more cells to the site of damage. Inflammatory blood cells arriving on the scene try to kill the “offending” lesion by secreting destructive substances: proteases (usually dissolve invading organism proteins), cytotoxic oxygen (oxygen radicals which can kill bacteria), nitrogen radical molecules (antimicrobial molecules), etc.

Some very fascinating activity occurs at the site of the atheroma: like policemen walking a beat, immune T cells and others actively “patrol” tissue in search of foreign substances (called “antigens”) that need destruction and removal, including oxidized LDL cholesterol lodged under the arterial lining. Even more fascinating are different T cells, CD8+, programmed to recognize viral antigens and destroy them – and these cells are found in many coronary atheromata. Why are there virus-fighting cells in some plaques? There is research suggesting that influenza infection may be linked to the development of coronary artery disease in some people.

If all this weren’t enough, activated T cells secrete their own chemokines among which is interferon−γ. Interferon-γ helps other immune cells kill more efficiently, and amplifies more inflammatory chemokines, namely TNF (tumor necrosis factor) and Interleukin-1. So, cells call other cells, which call other cells to the atheroma. Inside the atheroma, they secrete various killing chemicals, augmenting each others’ actions in a frenzy of destruction, even eroding the connective tissue fibrous “cap” that keeps the whole thing confined to the arterial wall.

Well, you can see where this is going if the cap comes off this whole mess inside your coronary artery……..two things can happen: 1) the fibrous cap erodes, spilling the atheroma’s contents into the inside of the coronary artery, or 2) the contents of the atheroma literally erupt into the inside of the coronary artery. Either way, the result is the same: blocked artery, downstream heart muscle abruptly gets no blood and dies = acute myocardial infarction.

But, wait. There’s more bad news. Remember those collagen eating enzymes called “proteases” and very toxic oxygen and nitrogen molecules? While they’re great for killing invading bacteria and removing useless debris, the fact is they will efficiently dissolve ALL local structural proteins including the collagen and elastin holding your own coronary artery blood vessels together. The weakened vascular wall can then bulge under pressure of blood flow to produce an aneurysm. What’s wrong with an aneurysm? The ballooned out the wall is thin and weak, and will basically pop, spilling whatever blood it contains out into surrounding areas where it doesn’t belong.

But, wait. It’s not ALL bad news. There are safety mechanisms built into this elegant system which are protective factors in atherosclerosis. There are two anti-inflammatory cytokines, interleukin-10, and transforming growth factor-β (TGF-β)which continually inhibit or tone down T-cell immune reactions, thereby limiting inflammatory activity. And, guess what? The spleen plays an active role in limiting atherogenic inflammation by supplying B cells which recognize and eliminate oxidized LDL. One might ask, then, does a person without a spleen have the greater risk of coronary artery disease (CAD)? And the answer would be “yes.”

Ultimately, the goal will be to eliminate the inflammation which is so thoroughly involved in coronary plaque formation, inflammation of the plaque, and eruption of the contents causing myocardial infarctions. Meanwhile, other strategies based on the knowledge of inflammation in CAD are used to detect inflammation before a heart attack. Some inflammatory markers generated in an atheroma are detectable in the blood downstream, and can be measured in a lab. These include C-reactive protein (“CRP”), fibrinogen, VCAM-1, among others.

One might reason that since inflammation is such a big part of coronary artery disease, might not anti-inflammatory medications help to prevent CAD? The answer is: “yes, they can.” Consider the fascinating situation with rheumatoid arthritis. Everyone knows rheumatoid arthritis (RA) is the sine qua non of inflammatory diseases. Accordingly, RA victims have an increased prevalence of coronary artery disease. One main treatment for RA is the chemotherapy agent “methotrexate.” It is anti-inflammatory in this context, and guess what? Yes, it reduces coronary artery disease in people with RA who are treated with methotrexate. However, methotrexate is NOT a recognized treatment for coronary artery disease, but this relationship and these data serve to emphasize the extreme role inflammation plays in CAD. Another question might arise as to whether the widely prescribed baby aspirin is anti-inflammatory in the context of heart attacks and other acute coronary syndromes. The recommended dose is too small to be anti-inflammatory, but it is just enough to knock out platelet function to prevent platelets from completing coronary obstruction when plaque has ruptured into the artery.

One more fun fact for your next cocktail party: a very large Dutch study has confirmed that periodontal disease is strongly linked to the development of atherosclerotic coronary artery disease. It appears that chronic gum infection, inflammation, and continual release of bacteria and bacterial debris into the bloodstream may provoke inflammatory responses elsewhere in the body, including in the coronary arteries.

References

  • Inflammation and Heart Disease, American Heart Association, July 2015 http://www.heart.org/HEARTORG/Conditions/Inflammation-and-Heart-Disease_UCM_432150_Article.jsp#.V-gB2fkrJWs
  • Inflammation and Vascular Disease: Exciting Times, Feb 2, 2015, theheart.org on Medscape > Clot Blog with Dr. Sam Goldhaber, http://www.medscape.com/viewarticle/838660#vp_2
  • Hansson, G.K., “Inflammation, Atherosclerosis, and Coronary Artery Disease,” New England Journal of Medicine 2005;352:16, https://www.researchgate.net/publication/7695778_Hansson_GKInflammation_atherosclerosis_and_coronary_artery_disease_N_Engl_J_Med_3521685-1695
  • Siriwardena, “Increasing Evidence that Influenza is a Trigger for Cardiovascular Disease,”Journal of Infectious Diseases2012http://jid.oxfordjournals.org/content/early/2012/10/09/infdis.jis598.full
  • Westlake, et al., “The Effect of Methotrexate on Cardiovascular Disease in Patients With Rheumatoid Arthritis: A Systematic Literature Review,”Rheumatology2010;49(2):295-307 http://www.medscape.com/viewarticle/716450
  • Tuttolomondo, et al., “Atherosclerosis as an Inflammatory Disease,” Curr Pharm Des. 2012;18(28):4266-88.http://www.ncbi.nlm.nih.gov/pubmed/22390643
  • Beukers, et al.,”Periodontitis is an Independent Risk Factor for Atherosclerotic Cardiovascular Disease…” J Epidemiol Community Health2015http://jech.bmj.com/content/early/2016/08/08/jech-2015-206745