Heart disease and inflammation.
A few people have sent me links to a recent paper called ‘Inflammation and Atherosclerosis.’ This was published in Circulation, and the authors were: Peter Libby, MD; Paul M. Ridker, MD; Attilio Maseri, MD. Remember two of the names.
Here is a relatively long section of the abstract:
‘Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis.
Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors.
Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.’ http://circ.ahajournals.org/content/105/9/1135.full
This paper interested me for a number of reasons. I focused down for a few moments on the phrase ‘Atherosclerosis, formerly consider a bland lipid storage disease…’ Does this mean that the world is moving on… Atherosclerosis has nothing to do with lipids e.g. LDL a.k.a. ‘bad cholesterol’? Now that would be something. Especially as it was published in the mainstream CV journal ‘Circulation.’
It seems that these authors are trying to shift the thinking away from cholesterol to inflammation. However, before discussing anything else I wanted to point out something that most people may have missed – by looking at a bit of background on the authors. First, Paul Ridker, who ran the JUPITER study, and who is a hugely influential cardiologist.
It should be noted that Paul Ridker has a major interest in moving thinking about atherosclerosis from a lipid storage disorder to an inflammatory condition. Because he has patent on the high sensitivity CRP test (C-reactive protein).
‘Dr Ridker is named as a coinventor on patents filed by the Brigham and Women’s Hospital that relate to the use of inflammatory markers in cardiovascular disease.’ http://circ.ahajournals.org/content/108/12/e81.long
What this means is that every time someone uses a high sensitivity CRP test, Paul Ridker becomes a little bit richer. However, in this paper, this massive financial conflict of interest is not mentioned. Instead, we get Acknowledgements:
This work was supported in part by grants from the National Heart, Lung, and Blood Institute to Drs Libby (HL-34636, HL-48743, and HL-56985) and Ridker (HL-58755 and HL-63293), and by the Leducq Foundation (to Drs Libby and Ridker). Dr Ridker is also supported by a Distinguished Scientist Award from the Doris Duke Foundation. Dr Maseri is supported by a grant from Fondazione Internazionale di Ricerca Per il Cuore onlus
No conflicts Dr Ridker? Mind you, Paul Ridker does have considerable form in not disclosing his financial conflicts. Some years ago, the Journal of the American Medical Association JAMA, was forced to publish a statement on ‘Unreported Financial Disclosures’ that were spotted in paper ‘Associations of LDL, Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B levels With Risk of Cardiovascular Events Among Patients Treated with Statins: A meta-analysis.’
This statement mentioned many, many conflicts that the authors had failed to mention at the time. The section on Dr Ridker reads thus:
‘…Dr Ridker reports board membership of Merck Sharp and Dohme and receipt of a grant or pending grant to his institution from Amgen.’ [Amgen, as you may know are pushing PCSK-9 inhibitors]. This is covered in my book Doctoring Data.
Just to spell this out in a little more detail, Paul Ridker was an author on a meta-analysis of statins, yet failed to report that he was a board member of a pharmaceutical company (Merck) that marketed statins.
In truth, the moment I saw a paper promoting the ‘new idea’ that atherosclerosis is all due to inflammation, my antennae started to twitch. Especially when I knew that Paul Ridker was involved. A man who holds patents on a test for the inflammatory marker that we should be using.
I then immediately wondered, Is Paul Ridker now running a clinical trial on behalf of a pharmaceutical company, looking at the use of an anti-inflammatory agent to treat CVD. So, I had a little look round the internet. And guess what. Paul Ridker is, indeed, running a trial on an ant inflammatory for the treatment of CVD. The CANTOS study http://www.thecantos.org/steering-committee.html If you look down the list those on the committee running this study, you will find that Peter Libby is also on the steering committee. A conflict that remained unmentioned in the Circulation paper either.
What is the drug, it is Canakinumab. Here, from Wiki:
Canakinumab (INN, trade name Ilaris, previously ACZ885) is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.
Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the U.S. Food and Drug Administration (FDA) on June 2009[4] and by the European Medicines Agency in October 2009.CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.
Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial was completed in October 2009. Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease, gout and coronary artery disease. It is also in trials for Schizophrenia. In gout it may result in better outcomes than a low dose of a steroid but costs five thousand times more. https://en.wikipedia.org/wiki/Canakinumab
I thought I would highlight the final sentence, just to give you some idea of the potential cost of this drug, should it ever be marketed for the treatment of CVD.
I know that this may seem a diversion. However, I have been around the world of cardiovascular research for long enough to take nothing at face value. Here is a paper suggesting that atherosclerosis has little or nothing to do with lipids. It is primarily due to inflammation. Which is a reasonable hypothesis. But guess what, one of the authors has a patent for an inflammatory marker. He and another author are running a clinical study, funded by Novartis, on the use of an anti-inflammatory agent in CVD.
However, just because there is money in the background, it does not necessarily mean that everything written is wrong. Perhaps inflammation truly is the underlying cause of atherosclerosis. Many other people have been saying this for years. Some of them, I know, certainly believe it from a purely objective scientific perspective. For example, Duane Graveline – who writes a great deal about CVD on his blog www.spacedoc.com, and is also a friend. He fully believes that atherosclerosis is an inflammatory condition, and he has no horse in the race.
My own take on this matter is slightly different. Yes, if you have a high C-reactive protein (CRP) level, this means that there is inflammation going on within the artery, and this is a sign of increased CVD risk. This is true, but what does it mean? Is the inflammation causing the CVD?
Whenever I see anyone stating that inflammation is a cause of anything I simply change the word inflammation to the word ‘healing,’ to see how sensible it then sounds. Inflammation is, in most cases, the way the body heals itself after injury. If you twist your ankle, it will become swollen and inflamed. The injury comes first, then you get the inflammation/healing. You would be hard pressed to state that inflammation causes twisted ankles.
Of course, there are some conditions where the inflammation itself can become greater than the original problem. Just to name three: Asthma, Crohn’s disease and Rheumatoid arthritis. In these diseases the body’s inflammatory/healing system becomes revved up, and starts attacking itself. This out of control inflammation can then lead to further problems downstream e.g. joint destruction. Such conditions are often ‘treated’ or controlled by anti-inflammatory agents e.g. steroids.
Equally, if you have Systemic Lupus Erythematosus (SLE), this is an ‘inflammatory’ disease, and you also have a severe vasculitis (inflammation of vasculature). As mentioned before SLE can raise the risk of CVD, in young women, by up to five thousand per cent. Case proven? Inflammation causes atherosclerosis?
No, I don’t think so. The sequence in SLE is that the vasculature is damaged (the endothelium is damaged). This stimulates the body to try and heal the damage. The healing is what we call inflammation and the C-reactive protein level goes up.
Get rid of the inflammation, and you will not be treating anything. You will simply be interfering with the healing process, and the CVD will, most likely, accelerate. Even if C-reactive protein levels go down, along with any observable inflammatory action.
If I may return for a moment or two to twisted ankles. To quote Dr Mirkin:
‘When I wrote my best-selling Sports medicine Book in 1978, I coined the term RICE (Rest, Ice, Compression, Elevation) for the treatment of athletic injuries. Ice has been a standard treatment for injuries and sore muscles because it helps to relieve pain caused by injured tissue. Coaches have used my “RICE” guideline for decades, but now it appears that both Ice and complete Rest may delay healing, instead of helping.’
As he goes on to say:
‘Anything That Reduces Inflammation Also Delays Healing [I cannot resist stating that, this is because inflammation is healing]
Anything that reduces your immune response will also delay muscle healing. Thus, healing is delayed by:
cortisone-type drugs,
almost all pain-relieving medicines, such as non-steroidal anti-inflammatory drugs like ibuprofen
immune suppressants that are often used to treat arthritis, cancer or psoriasis,
applying cold packs or ice, and
anything else that blocks the immune response to injury.’ http://www.drmirkin.com/fitness/why-ice-delays-recovery.html
At least Dr Mirkin has had the grace to admit that he was wrong. RICE reduces inflammation, but interferes with healing.
I am pretty certain that exactly the same thing will happen with ‘inflammation’ in CVD. I can state this with relative confidence, because the most powerful anti-inflammatory agent known to man are steroids/corticosteroids. Corticosteroids e.g. prednisolone, or hydrocortisone are potent anti-inflammatory agents, they are all based on the natural stress hormone cortisol – produced in the adrenal glands. Steroids = corticosteroids = cortisol (just about).
Cushing’s disease is a disease whereby too much cortisol is produce in the adrenal glands, usually due to a small tumour that overproduces the hormone. So, if you have Cushing’s disease, you have a powerful anti-inflammatory agent coursing through your blood vessels – at all times. And what is the effect of this on CVD?
‘In patients with Cushing’s syndrome (CS) cardiovascular complications determine a mortality rate four times higher than in an age- and gender-matched population.’ http://www.ncbi.nlm.nih.gov/pubmed/15579193
The same thing happens when you prescribe steroids, for various conditions:
‘Individuals who use glucocorticoids and exhibit iatrogenic (caused by the medicine) Cushing’s syndrome should be “aggressively” targeted for early screening of cardiovascular (CV) risk factors, say researchers.
Laurence Fardet (University College London, UK) and colleagues found that individuals with iatrogenic Cushing’s syndrome who were prescribed glucocorticoids had a significantly higher incidence of CV events (including coronary heart disease, heart failure, or ischemic cerebrovascular events) than individuals prescribed glucocorticoids without iatrogenic Cushing’s syndrome, or those not prescribed glucocorticoids.
Indeed, Cushing’s syndrome patients prescribed glucocorticoids had a CV incidence rate per 100 person-years at risk of 15.1 compared with 6.4 and 4.1 in those without Cushing’s but who were prescribed glucocorticoids and those not prescribed glucocorticoids, respectively.
Multivariate analysis revealed that iatrogenic Cushing’s patients had a 2.27-fold increased risk for coronary heart disease, a 3.77-fold increased risk for heart failure, and a 2.23-fold increased risk for ischemic cerebrovascular events.’ http://www.news-medical.net/news/20120807/Cushinge28099s-patients-must-be-screened-for-heart-disease.aspx
Proving a medical hypothesis is never that simple. However, if you believe that CVD is due to inflammation, then the world’s most potent anti-inflammatory agents ought to decrease CVD risk. Instead, it increases it by at least 400%. [Far more in some studies]
Other anti-inflammatory agents, known as Non-steroidal anti-inflammatories (NSAIDs) also greatly increase the risk of CVD. Vioxx (a potent NSAID), launched then pulled off the market, was estimated to have killed over one hundred thousand people in the US alone, from increasing CV risk.
In short, if CVD is primarily a disease of inflammation, then potent anti-inflammatory agents ought to reduce the risk. Instead they increase it massively. There is no doubt that inflammation is associated with CVD. Equally, if you measure C-reactive protein (a marker of inflammation), a high level is associated with a higher risk of CVD. However, it is not a cause, and if you try to reduce inflammation you will almost certainly increase the risk of CVD, not decrease it.
Ergo. Inflammation is sign of active CVD. That is all.
