By Jeffrey Dach MD
Jim takes Naproxen, an NSAID pain pill, on a regular basis for relief of arthritis pain. In addition, Jim’s Calcium Score is very high, and in fact, Jim had a coronary stent placed about 5 years ago during cardiac catheterization for chest pain. Jim wants to know why he should stop the NSAID arthritis drugs, and switch to a safer and more effective botanical alternative such as Zyflamend by New Chapter.
Vioxx Scandal – 4.85 Billion Settlement
NSAID drugs have been associated with increased heart attacks for many years now.(1-9)
The 2000 Vioxx Scandal was due to increased heart attack rate discovered years later after a introduction of a new NSAID drug called Vioxxx (Rofecoxib). In November 2007, Merck announced a $4.85 billion settlement with 47,000 plaintiffs claiming Vioxx caused their heart attack, the largest drug settlement in drug history.(10)
All NSAIDS Cause Heart Attacks
However, this problem is not restricted to Vioxx. In fact, all NSAID drugs are associated with increased heart attack risk according to a recent publication in the British Medical Journal.(2)
What is the mechanism by which NSAIDS cause heart attacks ? None of the medical publications take the next step of explaining the mechanism by which NSAIDS cause heart attacks.(2-9) In my opinion, the obvious explanation is “LEAKY GUT” with low level endotoxemia.
NSAIDS Cause Leaky Gut
My previous article on NSAIDS and Leaky Gut discusses the overwhelming evidence that NSAIDS cause leaky gut. (1)
Animal studies show NSAID induced damage to the small bowel intestinal brush border, with increased intestinal permeability and “Leaky Gut” in virtually all animals treated with NSAIDS. Left Image: Brush Border of Small Bowel
NSAIDS Cause Leaky Gut Which Causes Heart Disease
My previous article on the Low Level Endotoxemia – LPS theory of heart disease explains the mechanism by which Leaky Gut causes low level endotoxemia, a known risk factor for coronary artery disease and increased risk for heart attacks. Low level endotoxemia is the fancy medical name for leakage of gut bacteria into the blood stream. This has been directly linked to causing atherosclerotic plaque, a form of infected biofilm as discussed in my previous article on this topic.
NSAIDS are Mitochondrial Toxins
Another adverse effect of NSAIDS is they are mitochondrial toxins which target sensitive myocardial muscle cells, causing 20% of hospital admissions for congestive heart failure. (15-16) NSAIDS have been shown to uncouple oxidative phosphorylation in mitochondria. Thus, small bowel damage by NSAID drugs is explained as a “topical effect” of the drug producing mitochodrial damage in cells which line the gut, the enterocytes.(17-19)’
Athletes Sudden Death from Coronary Artery Disease.
“Cardiac arrest is the leading cause of death in young athletes, but the incidence of it is unclear.” (25) (26-29) Strenuous exercise itself can cause leaky gut with endotoxemia as reported in a number of studies of athletes. In addition, serious liver elevation can occur after strenuous exercise probably from the endo toxins released from the gut which travel to the liver. This makes athletes susceptible to coronary artery disease. Risk is increased if the athletes takes NSAIDS for musculoskeletal injuries after exercise. (20-24)
Conclusion: The obvious mechanism by which NSAID drugs cause coronary artery disease and increased heart attack risk is “Leaky Gut”. This allows leakage of LPS and gram negative bacteria into the blood stream, a form of “low level endotoxemia”, directly linked to atherosclerotic disease. Avoiding NSAID drugs is essential for healing the gut and preventing coronary artery disease.
Jeffrey Dach MD
Articles with Related Interest
Links and References:
1) NSAIDS, Small Bowel and Leaky Gut by Jeffrey Dach MD
2) Bally, Michèle, et al. “Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data.” bmj 357 (2017): j1909. Objective To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs).
Results A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations.
Conclusions All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.
Data from nearly half a million patients – a total cohort of 446,763 people – showed that any dose of NSAIDs is associated with an increased risk of heart attack, even within the first week of use. Comparing people who took painkillers to those who didn’t, the team found an increase of heart attack risk of about 20-50 percent, with a similar result for all the different NSAIDs they looked at.
3) Johnsen, Søren P., et al. “Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study.” Archives of internal medicine 165.9 (2005): 978-984.
Conclusions :Current and new users of all classes of non- aspirin NSAIDs had elevated relative risk estimates for
MI. Although the increased risk estimates may partly re-flect unmeasured bias, they indicate the need for fur-ther examination of the cardiovascular safety of all nonaspirin NSAIDs.
4) Olsen, Anne-Marie Schjerning, et al. “Long-term cardiovascular risk of NSAID use according to time passed after first-time myocardial infarction: a nationwide cohort study.” Circulation (2012): CIRCULATIONAHA-112.
Conclusions—The use of NSAIDs is associated with persistently increased coronary risk regardless of time elapsed after first-time MI. We advise long-term caution in using NSAIDs for patients after MI.
6) Kohli, Payal, et al. “NSAID use and association with cardiovascular outcomes in outpatients with stable atherothrombotic disease.” The American journal of medicine 127.1 (2014): 53-60.
Among patients with stable atherothrombosis, NSAID use is associated with a higher risk of myocardial infarction, stroke, and hospitalizations for both ischemia and heart failure.
7) The Guardian – Common painkillers may raise risk of heart attack by 100% – study. Risk of myocardial infarction is greatest in first month of taking NSAIDs such as ibuprofen if dose is high, say researchers
For the paper, published in the BMJ on Tuesday, the researchers analysed results on 446,763 people on healthcare databases in countries including Canada, Finland and the UK, of whom 61,460 had a heart attack.
They said the potential increase in risk was 75% for ibuprofen and naproxen and more than 100% for rofecoxib but that uncertainty about the extent of the increased risk was greatest for ibuprofen and naproxen.
8) The Guardian – Calls for ibuprofen sale restrictions after study finds cardiac arrest risk
Over-the-counter drug linked to 31% increased cardiac arrest risk, with the figure rising to 50% for diclofenac, says research
9) FDA strengthens warning that NSAIDs increase heart attack and stroke risk July 13, 2015 Gregory Curfman, MD, Editor in Chief, Harvard Health Publications
11) NSAIDs Causing Heart Attacks? Guide to the Perplexed
NSAID (non-steroidal anti-inflammatory drugs) are used to reduce pain and inflammation. By Dov Michaeli, MD, PhD -June 30, 2012
12) Opioid Wars: Opioids vs. NSAIDs Cathryn Jakobson Ramin December 08, 2015
13) NSAIDs May Increase Heart Attack Risk Gabe Mirkin MD
14) NSAIDs and Cardiovascular Risk Explained, According to Studies from the Perelman School of Medicine May 02, 2012 PHILADELPHIA — After nearly 13 years of study and intense debate, a pair of new papers from the Perelman School of Medicine, at the University of Pennsylvania have confirmed exactly how a once-popular class of anti-inflammatory drugs leads to cardiovascular risk for people taking it.
NSAIDS are Mitochondrial Toxins
15) Ghosh, Rajeshwary, Azra Alajbegovic, and Aldrin V. Gomes. “NSAIDs and cardiovascular diseases: role of reactive oxygen species.” Oxidative medicine and cellular longevity 2015 (2015).
Mitochondria Are the Main Target Organelles of the NSAIDs. It has been shown that the heart is more susceptible to ROS generation induced by drugs like doxorubicin compared to other tissues of the body although the drugs are evenly distributed throughout the body . This is possibly due to high levels of mitochondria in the heart which are the major producers of ROS in the cardiovascular system. Over 90% of ATP required for the normal functioning of the heart is provided by the mitochondria, which utilizes an efficient oxidative phosphorylation system. ATP production may increase depending upon the requirements of the body, especially at times of excessive physical exertion or other hormonal stimulations . Mitochondria are not only the major producers of the free radicals , but excessive generation of ROS in turn targets the mitochondria itself . NSAIDs have been shown to have adverse effects on the mitochondria resulting in the increased production of ROS.
NSAIDS are Cardiotoxic and Cause Congestive Heart Failure
Responsible for 20% of admissions for CHF
16) Arch Intern Med. 2000 Mar 27;160(6):777-84.
Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem.
Page J1, Henry D. Use of NSAIDs (other than low-dose aspirin) in the previous week was associated with a doubling of the odds of a hospital admission with CHF (adjusted odds ratio, 2.1; 95% confidence interval, 1.2-3.3). Use of NSAIDs by patients with a history of heart disease was associated with an odds ratio of 10.5 (95% confidence interval, 2.5-44.9) for first admission with heart failure, compared with 1.6 (95% confidence interval, 0.7-3.7) in those without such a history. The odds of a first admission to a hospital with CHF was positively related to the dose of NSAID consumed in the previous week, and was increased to a greater extent with long half-life than with short half-life drugs. Assuming these relationships are causal, NSAIDs were responsible for approximately 19% of hospital admissions with CHF.
CONCLUSIONS:The burden of illness resulting from NSAID-related CHF may exceed that resulting from gastrointestinal tract damage. NSAIDs should be used with caution in patients with a history of cardiovascular disease.
17) Somasundaram, S., et al. “Mitochondrial damage: a possible mechanism of the” topical” phase of NSAID induced injury to the rat intestine.” Gut 41.3 (1997): 344. Background—The “topical” effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage.
Aim—To examine the possible mechanism of the “topical” phase of damage in the small intestine.
Methods—Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode.
Results—The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the “topical” phase of NSAID induced damage.
Conclusion—Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the “topical” phase of damage induction.
18)Somasundaram, S., et al. “Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat.” Alimentary pharmacology & therapeutics 14.5 (2000): 639.
The pathogenesis of NSAID-induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation.
AIMS:To assess the role of uncoupling of mitochondrial oxidative phosphorylation in the pathogenesis of small intestinal damage in the rat.
METHODS:We compared key pathophysiologic events in the small bowel following (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhibit cyclooxygenase without causing a ‘topical’ effect and (iii) the two together, using (iv) indomethacin as a positive control.
RESULTS:dinitrophenol altered intestinal mitochondrial morphology, increased intestinal permeability and caused inflammation without affecting gastric permeability or intestinal prostanoid levels. Parenteral aspirin decreased mucosal prostanoids without affecting intestinal mitochondria in vivo, gastric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestinal mitochondrial morphology, permeability, inflammation and prostanoid levels and the macro- and microscopic appearances of intestinal ulcers were similar to indomethacin.
CONCLUSIONS:These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers.
19) Matsui, Hirofumi, et al. “The pathophysiology of non-steroidal anti-inflammatory drug (NSAID)-induced mucosal injuries in stomach and small intestine.” Journal of Clinical Biochemistry and Nutrition 48.2 (2011): 107. “we emphasize the importance of the uncoupling of mitochondrial oxidative phosphorylation as a common first step in NSAID-induced mucosal injury both in stomach and in small intestine.”
20) Free Radic Biol Med. 2003 Aug 1;35(3):284-91.
Exercise-induced endotoxemia: the effect of ascorbic acid supplementation.
Ashton T1, Young IS, Davison GW, Rowlands CC, McEneny J, Van Blerk C, Jones E, Peters JR, Jackson SK.
Strenuous, long-duration aerobic exercise results in endotoxemia due to increased plasma levels of lipopolysaccharide (LPS) leading to cytokine release, oxidative stress, and altered gastrointestinal function. However, the effect of short-term strenuous aerobic exercise either with or without antioxidant supplementation on exercise-induced endotoxemia is unknown. A significant increase in the concentration of bacterial LPS (endotoxin) was noted in the venous circulation of healthy volunteers following maximal acute aerobic exercise (0.14(-1) pre-exercise vs. 0.24(-1) postexercise, p <0.01). Plasma nitrite concentration also increased with exercise (0.09 +/- 0.05 nM x ml(-1) vs. 0.14 +/- 0.01 nM x ml(-1), p <0.05) as did ascorbate free radical levels (0.02 +/- 0.001 vs. 0.03 +/- 0.002 arbitrary units, p <0.05). Oral ascorbic acid supplementation (1000 mg) significantly increased plasma ascorbic acid concentration (29.45 mM x l(-1) to 121.22 mM x l(-1), p <0.05), and was associated with a decrease in plasma LPS and nitrite concentration before and after exercise (LPS: 0.01(-1); nitrite: 0.02 +/- 0.02 nM x ml(-1) vs. 0.02 +/- 0.03 nM x ml(-1)). Ascorbic acid supplementation led to a significant increase in ascorbate free radical levels both before (0.04 +/- 0.01 arbitrary units) and after exercise (0.06 +/- 0.02 arbitrary units, p <0.05). In conclusion, strenuous short-term aerobic exercise results in significant increases in plasma LPS levels (endotoxemia) together with increases in markers of oxidative stress. Supplementation with ascorbic acid, however, abolished the increase in LPS and nitrite but led to a significant increase in the ascorbate radical in plasma. The amelioration of exercise-induced endotoxemia by antioxidant pretreatment implies that it is a free radical-mediated process while the use of the ascorbate radical as a marker of oxidative stress in supplemented systems is limited.
21) J Appl Physiol (1985). 1988 Jul;65(1):106-8.
Strenuous exercise causes systemic endotoxemia.
Bosenberg AT1, Brock-Utne JG, Gaffin SL, Wells MT, Blake GT.
Eighteen triathletes were studied before and immediately after competing in an ultradistance triathlon. Their mean plasma lipopolysaccharide (LPS) concentrations increased from 0.081 to 0.294 ng/ml (P less than 0.001), and their mean plasma anti-LPS immunoglobulin G (IgG) concentrations decreased from 67.63 to 38.99 micrograms/ml (P less than 0.001). Both pretriathlon plasma LPS and anti-LPS IgG levels were directly related to the intensity of training (P less than 0.02 and P less than 0.01, respectively). It is possible that training-induced stress led to some leakage of LPS into the circulation, which, in turn, resulted in self-immunization against LPS. The effects on athletic performance in relation to exercise-induced changes in plasma LPS and anti-LPS IgG levels require further investigation.
Elevated concentrations of total bilirubin appear to be due to changes caused by regular exercise.
22) Biol Sport. 2017 Mar; 34(1): 45–48. Total bilirubin in athletes, determination of reference range K Witek,corresponding author1 J Ścisłowska,2 D Turowski,1 K Lerczak,1 S Lewandowska-Pachecka,2 and A Pokrywka3
Elevated concentrations of total bilirubin appear to be due to changes caused by regular exercise.
23) Why does strenuous exercise cause elevated bilirubin level in blood? Myoglobin which is a heme containing compound is present in the muscles. Strenuous exercise may cause a breakdown of myoglobin leading to a mild rise in bilirubin levels.
24) Br J Clin Pharmacol. 2008 Feb; 65(2): 253–259.
Muscular exercise can cause highly pathological liver function tests in healthy men. Jonas Pettersson, Ulf Hindorf, Paula Persson, Thomas Bengtsson, Ulf Malmqvist,1 Viktoria Werkström,1 and Mats Ekelund2
26) Wasfy, Meagan M., Adolph M. Hutter, and Rory B. Weiner. “Sudden cardiac death in athletes.” Methodist DeBakey cardiovascular journal 12.2 (2016): 76.
27) Hoyt, Walter J., Peter N. Dean, and Robert W. Battle. “The historical perspective of athletic sudden death.” Clinics in sports medicine 34.3 (2015): 571-585.
28) Luong, Michael W., et al. “Sudden cardiac death in young competitive athletes.” BCMJ 58.3 (2016): 138-144.
29) Semsarian, Christopher, Joanna Sweeting, and Michael J. Ackerman. “Sudden cardiac death in athletes.” Br J Sports Med 49.15 (2015): 1017-1023.
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