Is it LDL cholesterol unquestionably and unequivocally a causal risk factor for myocardial infarction?

It is my pleasure to share the following point of view of Dr. David Diamond, researcher, scientist and professor from the University of South Florida – and our colleague from THINCs – about low density lipoprotein and its relationship with the incidence of myocardial infarction:

“If only it were that simple, then reducing LDL by any means would reduce and even eliminate MI from occurring, and enable people to live longer. However, serum cholesterol levels had been reduced with treatments long before statins were developed, first with corn oil, and then GI surgery and cholestyramine and then there were the statins, including Baycol and Torcetrapib, which reduced LDL and even raised HDL. Baycol and Torcetrapib were very effective as LDL reducing agents, but they were also very effective at killing people, which is why they are no longer on the market. So lowering LDL levels, alone, is not sufficient to reduce the incidence of MI and to enable someone to survive the treatment.

The question should be, why are elevated levels of LDL associated with MI? The answer is that LDL is not "bad cholesterol" which is destined to harm blood vessel walls and "clog arteries" as drug company ads incorrectly state. Part of the problem is that LDL gets glycated by glucose, which distorts the lipoprotein sufficiently that it can't bind to the LDL receptor. The glycated LDL molecule then accumulates in the blood and becomes oxidized. It is the oxidized LDL that contributes to the deterioration of the blood vessel wall, not the native (normal) LDL. How do you stop sugar from glycating LDL? Keep blood sugar low through exercise and a low carb diet - 2 rather simple strategies which have never been compared head-to-head to statins in a clinical trial for reducing CHD, perhaps because the outcome would be unappealing to the drug companies that sponsor this research.

The other way of looking at LDL and MI is that when LDL becomes oxidized and glycated it becomes ineffective at doing what it's supposed to do, which is to kill bacteria (yes, LDL is a part of the immune system) and to build new cells. In response to the increasing concentration of oxidized (ineffective) LDL, the liver makes more LDL, thereby raising the concentration of total serum LDL. This is actually why total LDL levels can correlate with MI incidence, but it's actually the synergy between high sugar diets and oxidized LDL (and high blood pressure) which causes to damage to artery walls.

So, it's not that LDL is inherently atherogenic. The LDL molecule is an essential part of optimal health, serving to work with white blood cells to kill pathogens and to rebuild damaged tissue. It is the oxidization of LDL, which is precipitated by stress, smoking, lack of exercise and a high sugar diet, that is atherogenic. The literature on this work is vast, but I cite at the end of this little article some papers showing that ox-LDL levels are a much better indicator of CHD than native LDL (1, 2, 3).

I have reviewed only a small part of the thousands of medical papers and dozens of books I've read on this subject. Based on my reading, and the findings of experts in the field, there is good reason to be skeptical about the claims that statins have enhanced cardiac health in the absence of substantial side effects. In my recent talk** I reviewed well-documented evidence published in highly respected medical journals of more extensive adverse side effects of statins than is typically reported in the drug company sponsored research papers. For a relatively small reduction of cardiac events in the treated population, the cost of statins financially and in terms of insufficient improvement in overall health and survival is unjustified.”
* David Diamond, Ph.D, is Professor from the Depts of Psychology and Molecular Pharmacology and Physiology, Center for Preclinical and Clinical Research on PTSD. Director, USF Neuroscience Collaborative, 4202 E. Fowler Ave (PCD 4118G), Tampa, FL 33620. His homepage is http://psychology.usf.edu/faculty/diamond/
** The web article that summarizes his talk and includes the on-line video is at http://www.cas.usf.edu/news/s/176/
References:
1. Margareta Kristenson, Bo Ziedén, et al. Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: concomitant cross sectional study of men aged 50. BMJ 1997;314:629–33
2. Christa Meisinger, Jens Baumert, et al. Plasma Oxidized Low-Density Lipoprotein, a Strong Predictor for Acute Coronary Heart Disease Events in Apparently Healthy, Middle-Aged Men From the General Population. Circulation 2005;112;651-657
3. Huiling Huang, Weiyi Mai, Dan Liu, et al. The oxidation ratio of LDL: A predictor for coronary artery disease. Disease Markers 24 (2008) 341–349

Note:
In the acidity theory of atherosclerosis we support a link between LDL oxidation and acidic pH presenting different studies showing this relationship (1).
1. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at
http://www.infarctcombat.org/AcidityTheory.pdf

Hemodynamic shear stress, calcification and atherosclerosis

Atherosclerosis calcification occurs at sites of atherosclerotic plaques, where there is a combination of cellular necrosis, inflammation and cholesterol deposition.
Ectopic vascular calcification was viewed until recently as a passive consequence of aging. Although it is recognized that ectopic vascular calcification is a consequence of a dysregulated process, the specific molecular etiology remains unclear. There are conflicting ideas regarding the mechanisms underlying cardiovascular calcification, and the pathological and prognostic importance of vascular calcification still a matter of debate (1).
Osteoporosis, that is associated with calcium deficiency, has been also associated with atherosclerosis in many studies, with findings that bone mineral density declined while atherosclerotic plaque increased. We have discussed about this subject during the last year advocating acidosis as the link between these two diseases (2).
Coronary artery calcification measured by computed tomography (CT scans) is considered a radiographic confirmation of atherosclerosis, predicting cardiovascular events, and has been evaluated as a surrogate measure in randomized trials. However, in a study published in 2009 the annual rate of CAC increase was measured in 10 trials having observed a rate of 17% which was seen as moderately higher for patients with chronic kidney disease and those receiving dialysis. The study observed no consistent or reproducible treatment effect of any therapy on this outcome. These data have suggested to the authors that CAC may not be a suitable surrogate target for treatment trials in patients with cardiovascular or renal disease when measured after 12 months or reported on an annualized basis (3)
Nevertheless a very recently study from MESA (Multi Ethnic Study of Atherosclerosis) has shown that even healthy patients with low-density lipoprotein cholesterol (LDL-C) are associated with adverse coronary heart disease events if their CT scans demonstrate calcium buildup in their coronary arteries. Of 5,627 participants who were not receiving any baseline lipid-lowering therapies 3,714 (66%) had LDL-C 130mg/dl. Among the persons with low LDC-C, older age, male sex, hypertension, diabetes and low HDL-C were associated with adverse events (4).
It is interesting to notice that increased calcium content in diets supplemented with cholesterol has been show to decrease atherosclerosis in rabbits. Also, some epidemiological studies suggested that high levels of calcium in drinking water may decrease atherosclerosis (5).
Hemodynamic shear stress and calcification
A recent study developed in Switzerland, aimed to investigate regional plaque morphology and using intravascular ultrasound and virtual histology in coronary artery bifurcations, found that segments on the contralateral wall of the bifurcation which have previously identified as regions with low shear stress not only exhibited a higher plaque burden but also a higher degree of calcification (6). An analogous relationship was suggested by previous studies indicating that mechanical forces play a role in aortic valve calcification. Since calcium deposits occur almost exclusively on the aortic surfaces of AV leaflets it has been hypothesized that adverse pattern of fluid shear stress on the aortic surface of AV leaflets promotes calcification (7,8,9)
In the acidity theory of atherosclerosis the hemodynamic shear stress is an important step in the process leading to atherogenesis (10).
Carlos Monteiro
1. Johnson RC, Leopold JA and Loscalzo J. Vascular calcification: Pathological mechanisms and clinical implications. Circulation Research 2006; 99: 1044 -1059. Full free text at http://circres.ahajournals.org/content/99/10/1044.full
2. Acidity: The link between atherosclerosis and osteoporosis, January 5, 2010 at http://aciditytheory.blogspot.com/2010/01/acidity-link-between-atherosclerosis.html
3. McCullow PA and Chinnayan KM. Annual progression of coronary calcification in trials of preventive therapies: A systematic review. Arch Intern Med 2009, 169 (22):2064-70. Full free text at http://archinte.ama-assn.org/cgi/reprint/169/22/2064
4. Blankstein R, Budoff MJ, Shaw LJ et al. Predictors of coronary heart disease events among asymptomatic persons with low low-density lipoprotein cholesterol. J Am Coll Cardiol, 2011;58:364-374
5. HSU HH and Culley NC. Effects of dietary calcium on atherosclerosis, aortic calcification, and icterus in rabbits fed a supplemental cholesterol diet. Lipids in Health and Disease 2006, 5.16. Full free text http://www.lipidworld.com/content/5/1/16
6. Toggweiler S, Urbanek N, Schoenenberger AW, Erne P. Atherosclerosis, 2010 Oct;212(2):524-7
7. Hoehn D, Sun L and Sucosky P. Role of pathologic shear stress alterations in aortic valve endothelial activation. Cardiovascular Engineering and Technology 2010, V1;N2: 165-178. Full free text at http://www.springerlink.com/content/f777qk521lr48237/
8. Ge L, Sotiropoulos F. Direction and magnitude of blood flow shear stresses on the leaflets of aortic valves: is there a link with valve calcification? J Biomech Eng 2010 Jan;132(1): 014505
9. Yap CH, Saikrishnan N, Tamilselvan G and Yoganathan AP. Experimental measurement of dynamic fluid shear stress on the aortic surface of the aortic valve of the aortic valve leaflet. Biomech Model Mechanobiol, 2011 Mar 18
10. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf

The final evidence: Milk and dairy products prevent heart attacks!

Dr. J. E. Crewe, in 1929, along with the Mayo Foundation, reported uniformly excellent results using whole milk in the treatment of tuberculosis, diseases of the nervous system, cardiovascular and renal conditions, hypertension, and in patients who are underweight, run-down, etc. Striking results were seen in diseases of the heart and kidneys and high blood pressure. The milk used was, in all cases, the only kind of milk available in those days—raw milk from pasture-fed cows, rich in butterfat. Dr. Crewe asserted that the only problem of using raw milk to treat these diseases, was that it was too simple. So, the therapeutic use of milk didn’t attracted the interest from his colleagues in their patients (1).
In 1991, the New Scientist magazine reported that Dr. Peter Elwood, director of the Epidemiology Unit of Landough Hospital in Penarth, South Glamorgan, in his study of lifestyle involving 5,000 men between the ages of 45 and 59, with a duration of 10 years, found that men who drank the most full-fat milk and ate butter (rather than margarine) had a lower risk of suffering from heart attacks! (New Scientist 1991; 129(1759):17). According to Dr. David Williams article published the same year, discussing the findings of Peter Elwood, among those who drank at least a pint of milk per day, only 1% suffered heart attacks (2, 3).
Dr. Peter Elwood, in a paper published in 2004, reported the data about the Caerphilly Study dietary data, including consumption of milk, were they have collected by a semiquantative food frequency questionnaire, during a period of 1979-1983. The group was followed by 20-24 years in a population sample of 2,512 men aged 45-49, with incident ischemic heart disease and stroke events identified. The study reached the conclusion that their data provide no convincing evidence that milk consumption is associated with an increased risk of vascular disease (4). At the same time and in the same issue of the European Journal of Clinical Nutrition he had published another study saying that no group studies have provided convincing evidence to date on the milk to be harmful (5).
In 2007, Peter Elwood and his group published another study concluding that the consumption of milk and other dairy products is associated with a markedly reduced prevalence of metabolic syndrome, and these items, therefore, would fit well within a healthy eating pattern (6).
More recently, in 2009, a survey conducted by the Universities of Reading, Cardiff and Bristol found by reviewing the evidence from 324 published studies that milk intake may reduce the chances of dying from diseases such as coronary heart disease and stroke, in 15-20% (7).
Contrary to what is usually advocated by conventional medicine, that saturated fats can lead to myocardial infarction, a very recent study found that nutrients in milk and its derivatives (cheese, butter) actually neutralize the effects of cholesterol that the researchers (still) consider harmful. Their findings, taken from 3630 middle-aged men and women from Costa Rica, have shown that the intake of dairy products in those that had myocardial infarction was not different from those who had not. Assessing about the amount of dairy food that was ingested by the participants in the Epidemiologic study between 1994 and 2004, there was no link between consumption and risk of myocardial infarction, even among those who consumed as much as 593 grams per day. This research (8), confirm the results of several other studies showing the benefits of milk and dairy products in cardiovascular disease.
Interestingly to note is that endogenous digitalis like compounds (DLCs), similar to the cardiotonics used to treat heart failure, were found in tissues and fluids of animals and humans with increased concentration in amniotic fluid, umbilical cord, serum and urine of pregnant women and neonates, the saliva of pregnant women, and in the milk collected from women during breastfeeding at different days after birth. According to an article published in 1992 DLCs could be secreted or concentrated in human milk providing to children with a exogenous contribution of DLCs to replace the endogenous production which tends to decrease after the first few weeks of life out of the womb. The authors have place in the article that additional studies were needed before the physiological actions in children be assigned to DLCs in human milk (9).
Certainly there are other mechanisms that could explain the benefits of the whole milk in the prevention of diseases. However, we believe that the increased concentration of DLCs in milk fits perfectly with our postulation that an insufficient production of endogenous DLCs, to attend the demand in some medical conditions such as coronary artery disease, can be resolved through the use of cardiac glycosides in low doses as a supplement. This is confirmed by clinical studies using cardiac glycosides in prevention of acute coronary syndromes (10).
Some other benefits of milk fat in atherosclerosis:
Milk fat, included among animal ones, does not impend over sclerosis, on the contrary, it prevent diseases of cardiovascular system, because it contains various bioactive constituents (11), that:
a) limit synthesis of liver cholesterol and triglycerides (short chain saturated fatty acids, Omega-3 polyunsaturated fatty acids, oleic acid);
b) intensify estrification and metabolism of cholesterol (phospholipids, oleic acid, Omega-6 and Omega-3 polyunsaturated fatty acids in optimal proportions);
c) prevent cholesterol oxidation (conjugated linoleic acid--CLA, alpha-tokoferol, coenzyme Q10, vitamins A and D3, phospholipids),
d) reduce level of LDL-cholesterol in blood plasma (linolenic acids Omega-3, linoleic acid W-6, also oleic acid).
e) Unique components of milk fat i.e. short chain saturated fatty, conjugated linoleic acid, vaccenic acid (natural trans isomer), and other milk components possess additionally anticancerogenic activity.
Moreover, the fatty acid series n-3 (or omega-3), through its ability to reduce blood lactic acid production (12), and butyric acid (GABA), which has an inhibitory effect on the sympathetic nervous system (13) may possibly reduce the progression of coronary atherosclerosis, according to the concepts of the theory of acidity in atherosclerosis (10).
As Peter Elwood and colleagues said recently, “An evaluation based upon a single risk factor for a disease can, however, be misleading. At the same time as affecting lipid markers of heart disease, the consumption of milk and dairy produce is associated with an increase in the level of high-density lipoprotein cholesterol and with a reduction in blood pressure and furthermore, milk and dairy food items are likely to have effects upon many other biological mechanisms and disease processes” (14)
Carlos Monteiro
Referências:
1) Real Milk Cures Many Diseases, Dr. J. R. Crewe, Certified Milk Magazine, January 1929, em http://www.realmilk.com/milkcure.html
2) Milk Decreases Heart Attacks? Dr. David Williams, Alternatives Newsletter, 1991 em http://www.realmilk.com/heart_disease.html
3) Fuss over fat leads to rethink on publicity, issue 1759 of News Scientist magazine, 09 March 1991, page 17. Texto integral em http://www.newscientist.com/article/mg12917592.800-fuss-over-fat-leads-to-rethink-on-publicity-.html
4) Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort. Elwood PC, Pickering JE, Hughes J, Fehily AM, Ness AR, Eur J Clin Nutr. 2004 May;58(5):711-7.
5) Milk drinking, ischaemic heart disease and ischaemic stroke II. Evidence from cohort studies. Elwood PC, Pickering JE, Hughes J, Fehily AM, Ness AR. Eur J Clin Nutr. 2004 May;58(5):718-24.
6) Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study, Elwood PC, Pickering JE, Hughes J, Fehily AM, J Epidemiol Community Health. 2007 Aug;61(8):695-8. Texto integral gratuito em http://jech.bmj.com/cgi/reprint/61/8/695.pdf
7) The survival advantage of milk and dairy consumption: an overview of evidence from cohort studies of vascular diseases, diabetes and cancer. Elwood et al . Journal of the American College of Nutrition. 2009 V27, N6, &23S-734S em http://www.jacn.org/cgi/content/abstract/27/6/723S
8) Aslibekyan S, Campos H, Baylin A. Biomarkers of Dairy intake and the risk of heart disease. Nutr Metab Cardiovasc Dis. May 4, 2011
9) Endogenous Digitalis-Like Factors in Human Milk, Aldo Clerico, Anna Pad, Maria Grazia Del Chicca, Pascal Biver,’ and Ottavio Giampietro, Clin Chem 38/4, 504-506 (1992). Texto integral gratuito em http://www.clinchem.org/cgi/reprint/38/4/504.pdf
10) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
11) Atherogenic properties of milk fat: facts or myths?, Cichosz G. Przegl Lek 2007; 64 Suppl 4:32-4
12) Ogilve GK, Fettman MJ et al. Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: A double-blind, randomized placebo-controlled study, Cancer; 2000, 88: 1016-28.
13) Hayakawa K et al. Effect of a gamma-aminobutyric acid enriched dairy product on the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats. Br. J. Nutr 2004; 92:411-417
14. Peter Elwood et al. The consumption of milk and dairy foods and the incidence of vascular disease and diabetes: An overview of the evidence. Lipids. 2010 Oct;45(10):925-39. Full free paper at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950929/?tool=pubmed

Lactic acid elevation: the link between rheumatoid arthritis and atherosclerosis?

Rheumatoid arthritis (RA) is considered a systemic autoimmune disease. However, what triggers the onset of rheumatoid arthritis still unknown.
Patients with RA have a high prevalence of preclinical atherosclerosis independent of traditional risk factors, suggesting that chronic inflammation, and, possibly, disease severity are atherogenic in this population (1).
Regarding this matter an editorial published at Circulation Journal in 1999 have discussed about the many similarities shared by RA and atherosclerosis (2).
Recent investigations found that the atherosclerotic process begins very early in the course of rheumatoid arthritis with the study revealing a significant increase in intima-media thickness, an indicator of atherosclerosis, in just 18 months (3).
Other investigators found a rapid increase in myocardial infarction risk following diagnosis of RA amongst patients diagnosed between 1995 and 2006 (4)
Studying about the matter we have looked for studies investigating cardiovascular autonomic dysfunction in rheumatic diseases. Although there are few studies in this direction, we have noticed that the sympathetic nervous system activity may be elevated in RA compared with health patients (5, 6). According our view the sympathetic predominance is the primary factor in the cascade of events leading to increased lactic acid and acidic environment generating atherogenesis (7, 8).
Also, we have discovered a study from the eighties showing high values of lactate in seropositive RA and crystal-induced arthritis, with the author suggesting that synovial lactate measurement could be a reliable indicator for differentiating inflammatory arthritides (9). In parallel, the amount of lactate released by the myocardium has been shown to be related to the severity of coronary artery disease (10, 11).
Going deeper on our research I got very surprised with the following information from a paper published in 1924 (12), entitled “The alleged role of lactic acid in arthritis and rheumatoid conditions”, that says:
“In 1858 Richardson published the results of extensive experiments on dogs in which the injection of large quantities of lactic acid, intraperitoneally, was followed by severe joint involvement. The condition of the joints was similar to that seen in acute arthritis, and Richardson suggested that the arthritic syndrome was due to an accumulation of lactic acid in the body. This theory found further support in 1877, when Foster reported that the administration of lactic acid by mouth to two diabetic patients resulted in painful and swollen joints. The pain and swelling persisted as long as the lactic acid administration was continued and disappeared promptly after the acid was discontinued. These early experiments were apparently never repeated or extended but they have exerted some influence in the formation of hypotheses regarding the disease”.
This paper from 1924 strengthen our thoughts placed in the article “Old experiments with rabbits and dogs provide powerful evidence for the Acidity Theory of Atherosclerosis” where was shown that acid-fed rabbits and dogs may develop atherosclerotic lesions (13).
Carlos Monteiro
1. Roman M. J, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 2006; 144: 249-256. Full free text at http://www.annals.org/content/144/4/249.full.pdf+html
2. Vincenzo Pasceri and Edward Yeh. Editorial, “A tale of two diseases - Atherosclerosis and Rheumatoid Arthritis“, Circulation, 1999; 100:2124-2126. Full free text at http://circ.ahajournals.org/cgi/content/full/circulationaha;100/21/2124
3. Sodergren et al. Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness. Arthritis Research & Therapy 2010, 12:R158. Full free text at http://arthritis-research.com/content/12/4/R158
4. Holmqvist M. E. et al. Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006”, J Intern Med 2010; 268:578-585.
5. Aydemir , V. Yazisiz et al. Cardiac autonomic profile in rheumatoid arthritis and systemic lupus erythematosus. Lupus (2010) 19, 255—261.
6. Dekkers JC et al. Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. Clin Exp Rheumatol. 2004 Jan-Feb;22(1):63-70.
7. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
8. Sympathetic predominance: a primary factor in the cascade of events leading to the atherogenic spiraling, Carlos Monteiro, Monday, February 22, 2010 at http://aciditytheory.blogspot.com/2010/02/sympathetic-predominance-primary-factor.html
9. Gobelet C and Gerster J. C. Synovial fluid lactate levels in septic and non-septic arthritides. Annals of the Rheumatic diseases, 1984, 43, 742-745.
10. G. Jackson, Lynne Atkinson, M. Clark, B. Crook, P. Armstrong, and S. Oram, Diagnosis of coronary artery disease by estimation of coronary sinus lactate. British Heart Journal, 1978, 40, 979-983 Full free text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC483520/
11 Gertz EW, Wisneski JA, Neese R, Bristow JD, Searle GL, Hanlon JT: Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man. Circulation 1981, 63: 1273-1279. Full free text at http://circ.ahajournals.org/cgi/reprint/63/6/1273
12. F . A Cajori et al. The alleged role of lactic acid in arthritis and rheumatoid conditions. Arch Intern Med. 1924;34(4):566-572.
13. Old experiments with rabbits and dogs provide powerful evidence for the Acidity Theory of Atherosclerosis, Carlos Monteiro, July 13, 2010 at http://aciditytheory.blogspot.com.br/2010/07/old-experiments-with-rabbits-and-dogs.html 

The potential positive effect of improvement in baroreflex function on prevention and treatment of atherosclerosis

The baroreflex or baroreceptor reflex is one of the body’s homeostatic mechanisms for regulating blood pressure by controlling heart rate, strength of heart contractions, and diameter of blood vessels. The most important arterial baroreceptors are located in the carotid sinus and in the aortic arch. These baroreceptors respond to stretching of the arterial wall so that if arterial pressure suddenly rises, the walls of these vessels passively expand, which stimulates the activation of these receptors. If arterial blood pressure suddenly falls, decreased stretch of the arterial walls lead to a decrease in receptor activation. The loss of the stabilizing influence of vagal control raise the susceptibility to sympathetic influences. On the other hand the result of the baroreceptor improvement is the inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system.
It is interesting to notice the impairment or decrease of baroreflex sensitivity in front of some key factors for atherosclerosis, cardiovascular disease and stroke, like in ageing, ingestion of sugars, in special high-fructose diets and smoking.
Related to atherosclerosis there are some studies showing that in bilateral carotid atherosclerosis (1) and in greater intima-media thickness (2) the baroreflex sensitivity is reduced or impaired.
In this direction a study published in 2005 have indicated that arterial baroreflex dysfunction promotes the development of atherosclerosis in rats, and that inflammation may be involved in this process (3). The same authors have demonstrated in a very recent publication that low dose ketanserin, an anti-hypertensive, prevented the development of atherosclerosis in spontaneous hypertensive rats and rabbits at least in part via enhancement of arterial baroreflex function (4). Other anti-hypertensive drugs like Beta blockers may also enhance baroreflex sensitivity (5) with positive effects on atherosclerosis (6). Digitalis glycosides, another class of drugs, also augments cardiopulmonary baroreflex control of sympathetic activity (7), that probably is responsible for potential benefic effects of digitalis on atherosclerosis (6,8,9).
Aside of the above mentioned drugs there are some recent studies suggesting that polyunsaturated fatty acids - PUFA (19), cacao (10), vitamins like vitamin C (11,12), vitamin E (13) and folic acid (14,15), apart of aerobic exercise (16,17) and slow breathing (18), improve baroreflex sensitivity with possible positive effects on the treatment or prevention of atherosclerosis according to the acidity theory of atherosclerosis point of view (6) where sympathetic predominance is the primary factor in the cascade of events leading to the atherogenic spiraling.
Carlos Monteiro

1. Nasr N et al. Baroreflex sensitivity is impaired in bilateral carotid atherosclerosis. Stroke, 2005;36:1891-1895
2. Gianoros PJ et al. Greater intima-media thickness in the carotid bulb is associated with reduced baroreflex sensitivity. Am J Hypertens. 2002; 15(6): 486-491
3. Cai GJ et al. Arterial baroreflex dysfunction promotes atherosclerosis in rats. Atherosclerosis, 2005 Nov; 183(1):41-7
4. Yu YS et al. Effects of low-dose ketanserin on atherosclerosis in rats and rabbits. Can J Pysiol Pharmacol 2010 Nov;88(11):1054-60
5. Truijen J et al. Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under B-adrenergic blockade. Clin Sci (Lond), Feb 2011; 120(4):161-167
6. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
7. Schobel HP et al. 1991.Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans, Circulation V84, 1118-1129. Full free paper at http://circ.ahajournals.org/cgi/reprint/84/3/1118
8. Jagielska J. et al. Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis?, doi:10.1016/j.atherosclerosis.2009.03.019
9. Kolkhof P et al. Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes. Biochem Biophys Res Commun. 2010 Mar 26;394(1):233-9. Epub 2010 Mar 3.
10. Akita M et al., Effects of cacao liquor polyphenols on cardiovascular and autonomic nervous functions in hypercholesterolaemic rabbits. Basic Clin Pharmacol Toxicol. 2008 Dec;103(6):581-7.
11. Kevin D. Monahan et al, Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men. Am J Physiol Heart Circ Physiol 286: H2113–H2117, 2004.
12. Gianfranco Piccirillo et al., Influence of Vitamin C on Baroreflex Sensitivity in
Chronic Heart Failure. Hypertension. 2003; 41:1240-1245.
13. Peter Studinger et al., Effect of vitamin E on carotid artery elasticity and baroreflex gain in young, health adults. Autonomic Neuroscience, V 113, I1, Pages 63-70; 2004
14. Béchir M et al., Folic Acid Improves Baroreceptor Sensitivity in Hypertension. J Cardiovasc Pharmacol;45:44–48), 2005
15. Xiu-juan MA et al, Clonidine, moxonidine, folic acid, and mecobalamin improve baroreflex function in stroke-prone, spontaneously hypertensive rats. Acta Pharmacol Sin 2007 Oct; 28 (10): 1550–1558
16. Deley G et al., Arterial baroreflex control of cardiac vagal outflow in older individuals can be enhanced by aerobic exercise training. Hypertension, 2009;53:826-832
17. Effects of long-term exercise training on cardiac baroreflex sensitivity in patients with coronary artery disease: a randomized controlled trial. Clin Rehabil. 2011 Mar;25(3):217-27
18. Carlos Monteiro, Slow breathing increases baroreflex sensitivity and reduces sympathetic activity with benefic effects to cardiovascular disease, August 9, 2010 at http://www.aciditytheory.blogspot.com/
19. Radaelli A, Cazzaniga M, Viola A, et al. Enhanced baroreceptor control of the cardiovascular system by polyunsaturated fatty acids in heart failure patients J Am Coll Cardiol 2006;48:1600-1606. Free full text at http://content.onlinejacc.org/cgi/reprint/48/8/1600.pdf 

Infection through bacteremia leads to sympathetic overactivity and then to the atherosclerotic process

Research long suggested infection to be a cause or to promote atherosclerosis. This idea is supported by many reports and epidemiological studies (1).
However, main trials using antibiotics have failed to prove their protective effects in secondary prevention of coronary artery disease (2).
Periodontal disease, one of the most common chronic bacterial infection, may represent a favorable scenario to verify the connection of infection and atherosclerosis/cardiovascular disease.
The first researchers to indicate a relationship between oral infections and atherosclerosis were Mattila and colleagues. In their study published in 1989 they have identified periodontal disease as an independent predictor of elevated risk of myocardial infarction (3).
Several studies are suggesting an oral source for atherosclerotic plaque - associated bacteria with demonstration about the presence of viable periodontal pathogens in atherosclerotic plaques (4, 5, 6, 7). In this regard an interesting hypothesis was proposed in 2004 that periodontal infection may lead to brief episodes of bacteremia with inoculation of atherosclerotic plaque by periodontal pathogens such as Porphyromonas gingivalis, Actinobacillus actinomycetemcomitants and Tannerela forsythensis (8).
Related to the subject a recent review says that clinical procedures by dentists on the teeth and periodontal, along with the daily brush made by patients, produce a transient bacteremia, which may cause a secondary infection in a distant tissue or organ, including arteries. For the authors of this review it is evident that both endodontic surgical procedures and non-surgical instrumentation of root channels during endodontia can produce a transient bacteremia. Also, they have stressed that a tooth extraction causes bacteremia in 100% of times (9).
Coincidently to the present matter a study published last month revealed data from Medicaid patients showing that the risk of adverse vascular events sharply increases in the month following invasive dental treatment and then gradually returns to normal over six months (10).
However, an important information is generally left aside by investigators studying the connection between oral infection and atherosclerosis/cardiovascular disease. These investigators don’t take in consideration that the sympathetic nervous system is intensely activated during bacteremia. This was demonstrated by studies showing that the sympathetic tone rapidly increases after the experimental injection or infusion of bacteria and similarly during bacteremia in humans (11, 12, 13, 14).
Moreover, in a systematic review published in 2007 about 57 per cent of studies reviewed showed a positive relationship between stress/psychological factors and periodontal disease (15). These results are reinforced by a very recent study indicating that the sympathetic nervous system is involved in the development of periodontitis and that blockade of beta-receptors in periodontal tissue by a sympatholitic (propranolol) inhibited osteoclast differentiation and prevented alveolar bone loss induced by Porphyromonas gingivalis (16)
In the acidity theory of atherosclerosis point of view the sympathetic predominance is the primary factor in the cascade of events leading to the atherogenic spiraling.
Therefore, we think infection through bacteremia can be added to the long list of risk factors for atherosclerosis/cardiovascular disease, as mentioned in the acidity theory paper and in other previous articles published in this blog (17).
Carlos Monteiro
1. Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis. Emerging mechanistic
paradigms. Circulation 1999;100:20–8.
2. Anderson JL. Infection, antibiotics and atherothrombosis: end of the road or new beginnings?, N Eng J Med 2005;352:1706-1709
3. Mattila K, Nieminen MS, Valtonen VV, et al. Association between dental health and acute myocardial infarction. Br Med J 1989;298:779–82.
4. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. Identification of
periodontal pathogens in atheromatous plaques. J Periodontol 71:1554–1560, 2000
5. Stelzel M, et al. Detection of Porphyromonas gingivalis DNA in aortic tissue by PCR. J Periodontol 73:868–870, 2002
6. Kozarov EV, Dorn BR, Shelburne CE, Dunn WA, Jr, Progulske-Fox A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol 25:e17–e18, 2005
7. Gaetti-Jardim E, Jr, Marcelino SL, Feitosa AC, Romito GA, Avila-Campos MJ. Quantitative detection of periodontopathic bacteria in atherosclerotic plaques from coronary arteries. J Med Microbiol 58:1568–1575, 2009
8. Giacona MB, Papapanou PN, Lamster IB, Rong IL, D’Agati VD, Schmidt AM, and Lalla E. Porphyromonas gingivalis induces its uptake by human monocytes/macrophages and promotes foam cell formation in vitro. FEMS Microbiol Letter. 241, 95-101, 2004
9. Cotti E, Dessi C, Piras A, Mercuro G. Can a chronic dental infection be considered a cause of cardiovascular disease? A review of the literature. International Journal of Cardiology, 2010, doi 10.1016/j.ijcard.2010.08.011
10. Minassian C, D’Aiuto F, Hingoriani AD, Smeeth L. Invasive dental treatment and risk for vascular events. A self-controlled case series. Ann Intern Med 2010; 153:499-506
11. Palsson J, Ricksten SE, Delle M, Lundin S. Changes in renal sympathetic nerve activity during experimental septic and endotoxin shock in conscious rats. Circ Shock 1988; 24:13341.
12. Jones SB, Kovarik MF, Romano FD. Cardiac and splenic norepinephrine turnover during septic peritonitis. Am J Physiol 1986; 250:R8927.
13. Leinhardt DJ, Arnold J, Shipley KA, Mughal MM, Little RA, Irving MH. Plasma NE concentrations do not accurately reflect sympathetic nervous system activity in human sepsis. Am J Physiol 1993; 265:E2848.
14. Straub RH, Pongratz G, Weidler C, Linde HJ, Kirschning CJ, Glück T, Schölmerich J, Falk W. Ablation of the sympathetic nervous system decreases gram-negative and increases gram-positive bacterial dissemination: key roles for tumor necrosis factor/phagocytes and interleukin-4/lymphocytes. Infect Dis. 2005 Aug 15;192(4):560-72.
15. Daiane C. Peruzzo, Bruno B. Benatti, Glaucia M.B. Ambrosano, Getúlio R. Nogueira-Filho, Enilson A. Sallum, Márcio Z. Casati, and Francisco H. Nociti Jr. A Systematic Review of Stress and Psychological Factors as Possible Risk Factors for Periodontal Disease. Journal of Periodontology, August 2007, Vol. 78, No. 8, Pages 1491-1504
16. Okada Y, Hamada N, Kim Y, Takahashi Y, Sasaguri K, Ozono S, Sato S. Blockade of sympathetic b-receptors inhibits Porphyromonas gingivalis-induced alveolar bone loss in an experimental rat periodontitis model. Arch Oral Biol. 2010 Jul;55(7):502-8.
17. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf

Association of lipid abnormalities with lactate and coronary artery disease progression

Lactate as a screening test for coronary artery disease
The association of increased lipid levels with abnormal lactate metabolism may provide a useful screening test for the detection of coronary artery disease (1). In fact it was demonstrated that plasma lipid abnormalities and myocardial lactate production at the time of the initial study were significantly associated with subsequent arteriographic progression (2).
In our opinion the raise in plasma lipids presented in these studies might be a response to injury of the arterial endothelium due to an increased release of lactate. The response to injury concept is supported by the acidity theory of atherosclerosis (4)
Lactate and severity of coronary artery disease
The amount of lactate released by the myocardium has been shown to be related to the severity of coronary artery disease (1,2,3). One of these studies (3) have shown heterogeneity of myocardial lactate metabolism at rest in patients with coronary-myocardial disease. Lactate was released or produced by the myocardium when there was no clinical evidence of ischemia and the chemical arterial-coronary sinus lactate difference showing net global lactate extraction (3).
Carlos Monteiro
1. G. Jackson, Lynne Atkinson, M. Clark, B. Crook, P. Armstrong, and S. Oram, Diagnosis of coronary artery disease by estimation of coronary sinus lactate. British Heart Journal, 1978, 40, 979-983 Full free text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC483520/
2. Bemis CE, Gorlin R, et al. Progression of coronary artery disease: A clinical arteriographic study. Circulation, Vol XLVII, March 1973. Full free text at http://circ.ahajournals.org/content/47/3/455.full.pdf
3. Gertz EW, Wisneski JA, Neese R, Bristow JD, Searle GL, Hanlon JT: Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man. Circulation 1981, 63: 1273-1279. Full free text at http://circ.ahajournals.org/cgi/reprint/63/6/1273
4. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf