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
Wednesday, November 3, 2010
Sunday, October 3, 2010
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
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
Sunday, September 5, 2010
Does serum lactic acid and lactate dehydrogenase (LDH) levels increase with age?
Loiseleur and Morel were the first to report in 1931 about an increase of serum lactic acid with age (1).
However, in a study by Gottfried, Pelz and Clifford published in 1961 it was observed no difference in serum lactic acid levels between a group of 49 men and women over 70 years of age and a control group under 50 years of age (2).
Also, Davis and colleagues in a study published in 1966 have reported that serum lactic acid does not increase with age. In two groups of ambulatory patients with average age of 67 years, totaling 544 subjects who were free of overt acute diseases, the regression analysis for both serum lactic acid and LDH not revealed any significant change (3).
Contrasting with the reports from Gottfried (2) and Davis (3), a study by Nagamine and Shima published in 1989 indicated from the serum chemical analysis, obtained from 1822 male and 1870 women outpatients, the values for LHD were higher in female over 50 years of age than in their counterpart. When male and female were combined the normal reference ranges for LDH tended to be elevated. The values for total cholesterol and triglyceride reached a peak at a certain age (4).
Taking in view the conflicting results in the above mentioned papers, we think that new investigations are warranted in order to definitively clarify if serum lactic acid and LDH are increased with ageing, if there is correlation with cholesterol levels, and about the potential of causal relations, as preached by the acidity theory of atherosclerosis (5).
Recalling O. J. Pollak, 1952:
“Certainly all tissues change with age. There is anatomic and chemical aging. The acidity of tissues increases with age; this favors the precipitation of cholesterol”
Carlos Monteiro
1. Loiséleur J and R Morel. Influence de l’age et de L’état fonctionnel du foie sur la lacticémie. C. R. Soc. Biol, Paris, 106:35-37, 1931
2. Gottfried S. P., K. S. Pelz and R. C. Clifford. Carbohydrate metabolism in healthy old men over 70 years of age. Amer J. med. Sci, 242: 475-480, 1961
3. Davis R. L., Lawton A. H. et al. Serum lactate and lactic dehydrogenase levels of aging males. J. Gerontology 1966, Oct 21(4):571-4
4. Nagamine Y, Shima K. Changes in normal reference ranges for serum chemical analyses with ageing. Nippon Ronen Igakkai Zasshi. 1989 Jan;26(1):31-6.
5. 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
However, in a study by Gottfried, Pelz and Clifford published in 1961 it was observed no difference in serum lactic acid levels between a group of 49 men and women over 70 years of age and a control group under 50 years of age (2).
Also, Davis and colleagues in a study published in 1966 have reported that serum lactic acid does not increase with age. In two groups of ambulatory patients with average age of 67 years, totaling 544 subjects who were free of overt acute diseases, the regression analysis for both serum lactic acid and LDH not revealed any significant change (3).
Contrasting with the reports from Gottfried (2) and Davis (3), a study by Nagamine and Shima published in 1989 indicated from the serum chemical analysis, obtained from 1822 male and 1870 women outpatients, the values for LHD were higher in female over 50 years of age than in their counterpart. When male and female were combined the normal reference ranges for LDH tended to be elevated. The values for total cholesterol and triglyceride reached a peak at a certain age (4).
Taking in view the conflicting results in the above mentioned papers, we think that new investigations are warranted in order to definitively clarify if serum lactic acid and LDH are increased with ageing, if there is correlation with cholesterol levels, and about the potential of causal relations, as preached by the acidity theory of atherosclerosis (5).
Recalling O. J. Pollak, 1952:
“Certainly all tissues change with age. There is anatomic and chemical aging. The acidity of tissues increases with age; this favors the precipitation of cholesterol”
Carlos Monteiro
1. Loiséleur J and R Morel. Influence de l’age et de L’état fonctionnel du foie sur la lacticémie. C. R. Soc. Biol, Paris, 106:35-37, 1931
2. Gottfried S. P., K. S. Pelz and R. C. Clifford. Carbohydrate metabolism in healthy old men over 70 years of age. Amer J. med. Sci, 242: 475-480, 1961
3. Davis R. L., Lawton A. H. et al. Serum lactate and lactic dehydrogenase levels of aging males. J. Gerontology 1966, Oct 21(4):571-4
4. Nagamine Y, Shima K. Changes in normal reference ranges for serum chemical analyses with ageing. Nippon Ronen Igakkai Zasshi. 1989 Jan;26(1):31-6.
5. 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
Wednesday, August 25, 2010
Migraine, cardiovascular disease and higher lactic acid concentration in plasma
People with migraine, particularly those with aura (temporary visual or sensory disturbances before or during a migraine headache) , are at increased risk of death from coronary heart disease and stroke, according to research published this week on the the British Medical Journal. The study assessed the impact of mid-life migraine episodes in 18,725 men and women born between 1907 and 1935 who took part in the Reykjavik Study (set up in 1967 by the Icelandic Heart Association to study heart disease in Iceland). In total the research team explored over 470,000 person-years of data with a follow-up of 26 years. Their conclusion was that migraine with aura is an independent risk factor for cardiovascular and all cause mortality in men and women(1).
Interesting is that migraine suffers have higher lactic acid concentration in plasma (2), a decisive risk factor for cardiovascular disease, according to the acidity theory of atherosclerosis (3).
Carlos Monteiro
1.Larus S Gudmundsson, Ann I Scher, Thor Aspelund, Jon H Eliasson, Magnus Johannsson,Gudmundur Thorgeirsson, Lenore Launer and Vilmundur Gudnason. Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study. Published 24 August 2010, doi:10.1136/bmj.c3966, BMJ 2010;341:c3966. Full free text at http://www.bmj.com/cgi/content/full/341/aug24_1/c3966
2.Okada H, Araga S, Takeshima T, Nakashima K. Plasma lactic acid and pyruvic acid levels in migraine and tension-type headache. Headache. 1998 Jan;38(1):39-42.
3.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
Interesting is that migraine suffers have higher lactic acid concentration in plasma (2), a decisive risk factor for cardiovascular disease, according to the acidity theory of atherosclerosis (3).
Carlos Monteiro
1.Larus S Gudmundsson, Ann I Scher, Thor Aspelund, Jon H Eliasson, Magnus Johannsson,Gudmundur Thorgeirsson, Lenore Launer and Vilmundur Gudnason. Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study. Published 24 August 2010, doi:10.1136/bmj.c3966, BMJ 2010;341:c3966. Full free text at http://www.bmj.com/cgi/content/full/341/aug24_1/c3966
2.Okada H, Araga S, Takeshima T, Nakashima K. Plasma lactic acid and pyruvic acid levels in migraine and tension-type headache. Headache. 1998 Jan;38(1):39-42.
3.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
Monday, August 9, 2010
Slow breathing increases baroreflex sensitivity and reduces sympathetic activity with beneficial effects on cardiovascular disease
Control breathing have been used as an effective strategy to calm down during stressful situations in daily life during centuries. The usual advice to “take a deep breath” under emotion circumstances such as stress, anxiety and anger is a clear indication of this, yet we do not normally stop to consider the connection between our breathing and emotional states. There is a study realized in Japan where two hundred and forty-one male and female undergraduates completed the questionnaire concerning stressful events in the real life and relaxation strategies they used to overcome these stressful events. The result clearly showed that the most numerous relaxation strategy was deep breathing. About 60% of subjects reported that they control breathing to calm down in their stressful situation. Many subjects have answered this question telling that abdominal breathing technique (diaphragmatic) was an effective strategy to calm down (1).
Relaxation through slower breaths ( fewer than 10 cycles per minute) , used in relaxation techniques like yoga and meditation, have been thought for a long time to have positive effects in the reduction of blood pressure.
Basic studies which support these empirical and clinical observations and looking to clarify the relationship between relaxation and respiratory functions, were started in the 1970s. A paper published in 1996 in Psychosomatic Medicine have referenced many of these basic studies in discussing about the therapeutic usages of the slowed respiration maneuver in attenuating the cardiac autonomic responses in patients with anxiety disorder (2).
However, despite the many clinical observations suggesting this direction, the medical science in general, particularly in cardiology, have overlooked about the influence of breathing and its relationship with the autonomic nervous system and the heart in weighing cardiac risk factors.
Fortunately, recent studies are shedding more light and evidences to the subject giving new grounds for the scientific establishment regarding the link breathing/emotional states. Their findings show that sympathetic activation and parasympathetic withdrawal is implicated in the pathogenesis of hypertension, obstructive sleep apnea, and congestive heart failure and that respiration contributes importantly to the decrease of sympathetic hyperactivity and the improvement of baroreflex sensitivity (3 - 13).
It is interesting to notice what Dr. William Davis, cardiologist and author of “The Heart Scan Blog”, said recently in an invited response to the article by Jimmy Moore “A Reader Asks ‘Does Acidic Blood Lead To Arterial Inflammation?’ Let’s Ask The Low-Carb Experts (14): “One final thought: Interestingly, the easiest and fastest way to increase the alkaline state of the blood is to breathe deeply. Deep breathing results in lower carbon dioxide in the blood, resulting in net alkalinization. Wouldn’t it be neat if we could study and quantify this response over time and its effects on atherosclerotic disease?”
Also interesting is that while some studies have documented greater total muscle sympathetic nerve activity (MSNA) during hypercapnia compared with hypoxia, other studies observed a higher MSNA response to hypoxia compared with hypercapnia in participants with slow and fast spontaneous breathing rates. Whereas the authors were unable to distinguish between chemo reflex, respiratory or cardiovascular induced activation their data suggest that hypercapnia and hypoxia cause distinct patterns of activation within regions normally associated with sympathetic control (15, 16).
Taking in view that continuous positive airway pressure treatment may reverse early signs of atherosclerosis (17) we think the slow breathing practice may also contribute for the prevention or regression of atherosclerosis, by reducing the sympathetic hyperactivity, be it stimulated by hypercapnia, hypoxia or other factors, according to the acidity theory concept (18, 19).
Moreover, hypertension is an important risk factor for the development of atherosclerosis, with these processes sharing some common mechanisms. The endothelium is usually placed as a probable central focus for the effects in both diseases, with evidences leading to the postulation that hypertension predispose and accelerate atherosclerosis (20).
Carlos Monteiro
Remarks:
Transcendental Meditation not only lowers colesterol (21) and blood pressure (22, 23) but also reduce atherosclerosis (18). Most interesting is that a meta-analysis of 31 studies found that TM produces a lowering of plasma lactate (24, 25). Lower plasma lactate indicates profound relaxation, since high concentrations of lactate have been associated with stress situations (for example high anxiety), and high blood pressure (20). More data about lactate, stress, hypertension and reduction of atherosclerosis on patients submitted to Ioga or TM at the acidity theory of atherosclerosis article (18).
1. Yutaka Haruki, I Homma, Akio Umezawa, Y Hasaoka. Facilitation and Emotion of Breathing During Changes in Emotion, Chapter by Akio Umezawa, Book Respiration and Emotion, Springer, 2001
2. Sakakibara M and Hayano J. Effect of Slowed Respiration on Cardiac Parasympathetic Response to Threat. Psychosomatic Medicine 58:32-37 (1996). Full free text at http://www.psychosomaticmedicine.org/cgi/reprint/58/1/32.pdf
3. Clark ME, Hirschman R., Effects of paced respiration on anxiety reduction in a clinical population, Biofeedback Self Regul. 1990 Sep;15(3):273-84.
4. Meles E, Giannattasio C, et al. Nonpharmacologic treatment of hypertension by respiratory exercise in the home setting, Am J Hypertens. 2004 Apr;17(4):370-4
5. Grossman E, Grossman A, et al. Breathing-control lowers blood pressure, Hum Hypertens. 2001 Apr;15(4):263-9.
6. Viskoper R, Shapira I et al. Nonpharmacologic treatment of resistant hypertensives by device-guided slow breathing exercises. Am J Hypertens. 2003 Jun;16(6):484-7.
7. Schein MH, Gavish B, et al. Treating hypertension with a device that slows and regularises breathing: a randomised, double-blind controlled study, J Hum Hypertens. 2001 Apr;15(4):271-8.
8. Elliot WJ, Izzo JL Jr, et al. Graded blood pressure reduction in hypertensive outpatients associated with use of a device to assist with slow breathing. J Clin Hypertens (Greenwich). 2004 Oct;6(10):553-9; quiz 560-1.
9. Oneda B, Ortega KC et al. Sympathetic nerve activity is decreased during device-guided slow breathing, Hypertension Research 33, 708-712 (July 2010) | doi:10.1038/hr.2010.74
10. Anderson DE, McNeely JD, Windham BG. Regular slow-breathing exercise effects on blood pressure and breathing patterns at rest, J Hum Hypertens. 2010 Mar 4. [Epub ahead of print]
11. Joseph CN, Porta C, et al. Slow Breathing Improves Arterial Baroreflex Sensitivity and Decreases Blood Pressure in Essential Hypertension, Hypertension 2005;46;714-718; originally published online Aug 29, 2005
12. Narkiewicz K et al. Sympathetic Neural Outflow and Chemoreflex Sensitivity Are Related to Spontaneous Breathing Rate in Normal Men. Hypertension 2006;47;51-55; originally published online Dec 12, 2005
13. Bernardi L, Porta C, Slow Breathing Increases Arterial Baroreflex Sensitivity in Patients With Chronic Heart Failure, Circulation 2002;105;143-145
14. Jimmy Moore “A Reader Asks ‘Does Acidic Blood Lead To Arterial Inflammation?’ Let’s Ask The Low-Carb Experts!”, published at http://livinlavidalowcarb.com/blog/?p=7270, in February 10, 2010:
15. Bernardi L, Gabutti A et al. Slow breathing reduces chemoreflex response to hypoxia and hypercapnia, and increases baroreflex sensitivity, Journal of Hypertension, V 19;I 12 - pp 2221-2229, 2001
16. Steinback C. et al. Hypercapnic vs. hypoxic control of cardiovascular, cardiovagal and sympathetic function, Am J Physiol Regul Integr Comp Physiol 296: R402-R410, 2009
17. Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176: 706–712.
18. 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
19. 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
20. Hypertension, atherosclerosis, stress and lactic acid, Carlos Monteiro,
Friday, November 27, 2009 at http://aciditytheory.blogspot.com/2009/11/hypertension-atherosclerosis-stress-and.html
21. Cooper M, Aygen M. Transcendental Meditation in the management of hypercholesterolemia, Journal of Human Stress 1979; 5:24-27
22. Schneider RH, Staggers F, Alexander C, et al. A randomized controlled trial of stress reduction for hypertension in older African Americans. Hypertension 1995; 26: 820-827
23. Alexander C, Schneider RH, Staggers F. A trial of stress reduction for hypertension in older African Americans (part II); sex and risk factor subgroup analysis, Hypertension 1996; 28:228-237
24. Michael C. Dillbeck, David W Orme-Johnson. Physiological differences between meditation and rest. American Psychologist, Vol 42(9), Sep 1987, 879-881
25. The Effects of the Transcendental Meditation Technique on Common Risk Factors and Overall Health. Adapted from Chalmers, R. Scientific Research on Maharishi's Vedic Approach to Health: Part I Transcendental Meditation Introduction and Overview of Research, January 1998, at http://www.tm.cme.edu/article.pdf
Relaxation through slower breaths ( fewer than 10 cycles per minute) , used in relaxation techniques like yoga and meditation, have been thought for a long time to have positive effects in the reduction of blood pressure.
Basic studies which support these empirical and clinical observations and looking to clarify the relationship between relaxation and respiratory functions, were started in the 1970s. A paper published in 1996 in Psychosomatic Medicine have referenced many of these basic studies in discussing about the therapeutic usages of the slowed respiration maneuver in attenuating the cardiac autonomic responses in patients with anxiety disorder (2).
However, despite the many clinical observations suggesting this direction, the medical science in general, particularly in cardiology, have overlooked about the influence of breathing and its relationship with the autonomic nervous system and the heart in weighing cardiac risk factors.
Fortunately, recent studies are shedding more light and evidences to the subject giving new grounds for the scientific establishment regarding the link breathing/emotional states. Their findings show that sympathetic activation and parasympathetic withdrawal is implicated in the pathogenesis of hypertension, obstructive sleep apnea, and congestive heart failure and that respiration contributes importantly to the decrease of sympathetic hyperactivity and the improvement of baroreflex sensitivity (3 - 13).
It is interesting to notice what Dr. William Davis, cardiologist and author of “The Heart Scan Blog”, said recently in an invited response to the article by Jimmy Moore “A Reader Asks ‘Does Acidic Blood Lead To Arterial Inflammation?’ Let’s Ask The Low-Carb Experts (14): “One final thought: Interestingly, the easiest and fastest way to increase the alkaline state of the blood is to breathe deeply. Deep breathing results in lower carbon dioxide in the blood, resulting in net alkalinization. Wouldn’t it be neat if we could study and quantify this response over time and its effects on atherosclerotic disease?”
Also interesting is that while some studies have documented greater total muscle sympathetic nerve activity (MSNA) during hypercapnia compared with hypoxia, other studies observed a higher MSNA response to hypoxia compared with hypercapnia in participants with slow and fast spontaneous breathing rates. Whereas the authors were unable to distinguish between chemo reflex, respiratory or cardiovascular induced activation their data suggest that hypercapnia and hypoxia cause distinct patterns of activation within regions normally associated with sympathetic control (15, 16).
Taking in view that continuous positive airway pressure treatment may reverse early signs of atherosclerosis (17) we think the slow breathing practice may also contribute for the prevention or regression of atherosclerosis, by reducing the sympathetic hyperactivity, be it stimulated by hypercapnia, hypoxia or other factors, according to the acidity theory concept (18, 19).
Moreover, hypertension is an important risk factor for the development of atherosclerosis, with these processes sharing some common mechanisms. The endothelium is usually placed as a probable central focus for the effects in both diseases, with evidences leading to the postulation that hypertension predispose and accelerate atherosclerosis (20).
Carlos Monteiro
Remarks:
Transcendental Meditation not only lowers colesterol (21) and blood pressure (22, 23) but also reduce atherosclerosis (18). Most interesting is that a meta-analysis of 31 studies found that TM produces a lowering of plasma lactate (24, 25). Lower plasma lactate indicates profound relaxation, since high concentrations of lactate have been associated with stress situations (for example high anxiety), and high blood pressure (20). More data about lactate, stress, hypertension and reduction of atherosclerosis on patients submitted to Ioga or TM at the acidity theory of atherosclerosis article (18).
1. Yutaka Haruki, I Homma, Akio Umezawa, Y Hasaoka. Facilitation and Emotion of Breathing During Changes in Emotion, Chapter by Akio Umezawa, Book Respiration and Emotion, Springer, 2001
2. Sakakibara M and Hayano J. Effect of Slowed Respiration on Cardiac Parasympathetic Response to Threat. Psychosomatic Medicine 58:32-37 (1996). Full free text at http://www.psychosomaticmedicine.org/cgi/reprint/58/1/32.pdf
3. Clark ME, Hirschman R., Effects of paced respiration on anxiety reduction in a clinical population, Biofeedback Self Regul. 1990 Sep;15(3):273-84.
4. Meles E, Giannattasio C, et al. Nonpharmacologic treatment of hypertension by respiratory exercise in the home setting, Am J Hypertens. 2004 Apr;17(4):370-4
5. Grossman E, Grossman A, et al. Breathing-control lowers blood pressure, Hum Hypertens. 2001 Apr;15(4):263-9.
6. Viskoper R, Shapira I et al. Nonpharmacologic treatment of resistant hypertensives by device-guided slow breathing exercises. Am J Hypertens. 2003 Jun;16(6):484-7.
7. Schein MH, Gavish B, et al. Treating hypertension with a device that slows and regularises breathing: a randomised, double-blind controlled study, J Hum Hypertens. 2001 Apr;15(4):271-8.
8. Elliot WJ, Izzo JL Jr, et al. Graded blood pressure reduction in hypertensive outpatients associated with use of a device to assist with slow breathing. J Clin Hypertens (Greenwich). 2004 Oct;6(10):553-9; quiz 560-1.
9. Oneda B, Ortega KC et al. Sympathetic nerve activity is decreased during device-guided slow breathing, Hypertension Research 33, 708-712 (July 2010) | doi:10.1038/hr.2010.74
10. Anderson DE, McNeely JD, Windham BG. Regular slow-breathing exercise effects on blood pressure and breathing patterns at rest, J Hum Hypertens. 2010 Mar 4. [Epub ahead of print]
11. Joseph CN, Porta C, et al. Slow Breathing Improves Arterial Baroreflex Sensitivity and Decreases Blood Pressure in Essential Hypertension, Hypertension 2005;46;714-718; originally published online Aug 29, 2005
12. Narkiewicz K et al. Sympathetic Neural Outflow and Chemoreflex Sensitivity Are Related to Spontaneous Breathing Rate in Normal Men. Hypertension 2006;47;51-55; originally published online Dec 12, 2005
13. Bernardi L, Porta C, Slow Breathing Increases Arterial Baroreflex Sensitivity in Patients With Chronic Heart Failure, Circulation 2002;105;143-145
14. Jimmy Moore “A Reader Asks ‘Does Acidic Blood Lead To Arterial Inflammation?’ Let’s Ask The Low-Carb Experts!”, published at http://livinlavidalowcarb.com/blog/?p=7270, in February 10, 2010:
15. Bernardi L, Gabutti A et al. Slow breathing reduces chemoreflex response to hypoxia and hypercapnia, and increases baroreflex sensitivity, Journal of Hypertension, V 19;I 12 - pp 2221-2229, 2001
16. Steinback C. et al. Hypercapnic vs. hypoxic control of cardiovascular, cardiovagal and sympathetic function, Am J Physiol Regul Integr Comp Physiol 296: R402-R410, 2009
17. Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176: 706–712.
18. 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
19. 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
20. Hypertension, atherosclerosis, stress and lactic acid, Carlos Monteiro,
Friday, November 27, 2009 at http://aciditytheory.blogspot.com/2009/11/hypertension-atherosclerosis-stress-and.html
21. Cooper M, Aygen M. Transcendental Meditation in the management of hypercholesterolemia, Journal of Human Stress 1979; 5:24-27
22. Schneider RH, Staggers F, Alexander C, et al. A randomized controlled trial of stress reduction for hypertension in older African Americans. Hypertension 1995; 26: 820-827
23. Alexander C, Schneider RH, Staggers F. A trial of stress reduction for hypertension in older African Americans (part II); sex and risk factor subgroup analysis, Hypertension 1996; 28:228-237
24. Michael C. Dillbeck, David W Orme-Johnson. Physiological differences between meditation and rest. American Psychologist, Vol 42(9), Sep 1987, 879-881
25. The Effects of the Transcendental Meditation Technique on Common Risk Factors and Overall Health. Adapted from Chalmers, R. Scientific Research on Maharishi's Vedic Approach to Health: Part I Transcendental Meditation Introduction and Overview of Research, January 1998, at http://www.tm.cme.edu/article.pdf
Monday, July 26, 2010
Obstructive sleep apnea: Intermittent hypoxia leads to sympathetic overactivity and then to atherosclerotic process
Obstructive sleep apnea (OSA) syndrome is caused by upper airway collapse during inspiration, causing intermittent hypoxemia, hypercapnia, acidosis, sympathetic nervous system activation, and arousal from sleep.
Mounting evidence shows that OSA is a risk factor for cardiovascular disease which is supported by epidemiological association studies. Longitudinal cohort studies also provide evidence that patients with untreated severe sleep apnea have an increased rate of cardiovascular events. The prevalence of coronary artery disease (CAD) is 3 to 5 times higher in patients with OSA compared with control populations (1, 2, 3, 4, 5, 6, 7).
Atherosclerosis is recognized as the precursor stage of coronary-myocardial disease.
A very recent paper published in Circulation Journal (8), by far the largest study to date, has showed that moderate to severe obstructive sleep apnea increases the risk of coronary heart disease or death by 68% in men under the age of 70, but does not increase the risk for men over 70 or for women. A total of 1927 men and 2495 women 40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study.
Increased carotid intima-media thickness (IMT) and plaque occurrence was reported in OSA patients without any other significant co-morbidity compared to matched controls (9, 10, 11, 12).
The prevalence of hypertension is very high and the incidence of hypertension increases as the number of apneic and hypopneic events per hour rises. The association of OSA and hypertension has additive effects on the development of atherosclerosis. Daytime hypertension develops secondary to the persistently elevated sympathetic state (13). In a recent study of 94 middle-aged patients, the intima-media thickness of carotid artery was positively related to systolic blood pressure and apnea-hypopnea index (14).
Pathophysiological mechanisms linking OSA to atherosclerosis
OSA patients experience intermittent hypoxaemia and CO2 retention that modify the autonomic and haemodynamic responses to sleep (15). Indeed, chronic intermittent hypoxia may lead to sympathetic overactivity (16, 17). A study has shown that with mild apneic events (duration < 20 seconds), pretreatment with 100% oxygen effectively eliminated most of the increase in sympathetic nerve activity (25).
It is interesting to notice that continuous positive airway pressure treatment may reverse early signs of atherosclerosis (18).
There is increasing evidence that intermittent hypoxia is independently associated with dyslipidemia (19). In addition to clinical data, animal experiments also support a role of intermittent hypoxia in the pathogenesis of dyslipidaemia in sleep-disordered breathing (20, 21, 22).
The studies above mentioned confirm old experiments performed on rabbits where oxygen deficiency was attained by placing the animals daily into a chamber with decreased oxygen content (down to 12%) for 3–6 hours, for 4 months. It was shown that prolonged hypoxia brings about a high hypercholesterolemia and greatly intensifies the development of aortic and coronary atherosclerosis (26).
The demonstration that chronic intermittent hypoxia may lead to sympathetic overactivity and dyslipidemia adds more evidence to the acidity theory concept (23), with intermittent hypoxemia joining to other key factors for atherosclerosis, as discussed recently in this blog (24).
Carlos Monteiro
1. Levy P, Pepin JL, McNicholas WT. Should all sleep apnoea patients be treated? Yes. Sleep Med Rev 2002; 6:17–26.
2. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea–hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365: 1046–1053.
3. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and sub therapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359: 204–210.
4. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365:1046-1053.
5. Unruh ML, Enright PL, Polak JF, et al. The relationship of sleep apnea to carotid wall thickness among a large cohort of older adults. Sleep. 2005;20:A112.
6. Peker Y, Hedner J, Kraiczi H, Loth S. Respiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med. 2000;162:81-86.
7 Mooe T, Franklin KA, Holmstrom K, Rabben T, Wiklund U. Sleep-disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med. 2001;164:1910-1913.
8. Daniel J. Gottlieb et al. Prospective Study of Obstructive Sleep Apnea and Incident Coronary Heart Disease and Heart Failure. The Sleep Heart Health Study. Circulation, Published online before print July 12, 2010
9. Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005; 172: 613–618.
10. Baguet JP, Hammer L, Levy P, et al. The severity of oxygen desaturation is predictive of carotid wall thickening and plaque occurrence. Chest 2005; 128: 3407–3412.
11. Minoguchi K, Yokoe T, Tazaki T, et al. Increased carotid intima–media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med 2005; 172: 625–630.
12. Baguet JP, Hammer L, Levy P, Pierre H, Launois S, Mallion JMv, et al. The severity of oxygen desaturation is predictive of carotid wall thickening and plaque occurrence. Chest 2005; 128: 3407-12.
13. Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand. 2003;177:385-390
14. Drager LF, Bortolotto LA, Krieger EM, Lorenzi-Filho G. Additive effects of obstructive sleep apnea and hypertension on early markers of carotid atherosclerosis. Hypertension 2009; 53 : 64-9.
15. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 1993; 328 : 303-7.
16. Johnson, T. S., J. B. Young, and L. Landsberg. Sympathoadrenal responses to acute and chronic hypoxia in the rat. J. Clin. Invest. 71: 1263-1272, 1983.
17. Greenberg HE, Sica A, Batson D, Scharf SM. Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 1999; 86: 298–305. Full free text at http://jap.physiology.org/cgi/content/full/86/1/298
18. Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176: 706–712.
19. Drager, Luciano F; Jun, Jonathan; Polotsky, Vsevolod Y. Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis. Curr Opin Endocrinol Diabetes Obes. 2010 Apr;17(2):161-5.
20. Li J, Grigoryev DN, Y e SQ, Thorne L, Schwartz AR, Smith PL, et al. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol 2005; 99 :
1643-8.
21. Li J, Thorne LN, Punjabi NM, Sun CK, Schwartz AR, Smith PL, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 2005; 97 : 698-706.
22. Li J, Savransky V, Nanayakkara A, Smith PL. O’Donnell CP, Polotsky VT. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 2007; 102 : 557-63.
23. 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
24. 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
25. Leuenberger U, Jacob E, Sweer L, Waravdekar N, Zwillich C, Sinoway L. Surges of muscle sympathetic activity during obstructive apnea are linked to hypoxemia. J Appl Physiol 1995;79:581– 8.
26. N. N. Kipshidze.The effect of oxygen deficiency on the development experimental atherosclerosis of the coronary arteries Bulletin of Experimental Biology and Medicine, Volume 47, Number 4, 447-453, 1958, DOI: 10.1007/BF00779624
Mounting evidence shows that OSA is a risk factor for cardiovascular disease which is supported by epidemiological association studies. Longitudinal cohort studies also provide evidence that patients with untreated severe sleep apnea have an increased rate of cardiovascular events. The prevalence of coronary artery disease (CAD) is 3 to 5 times higher in patients with OSA compared with control populations (1, 2, 3, 4, 5, 6, 7).
Atherosclerosis is recognized as the precursor stage of coronary-myocardial disease.
A very recent paper published in Circulation Journal (8), by far the largest study to date, has showed that moderate to severe obstructive sleep apnea increases the risk of coronary heart disease or death by 68% in men under the age of 70, but does not increase the risk for men over 70 or for women. A total of 1927 men and 2495 women 40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study.
Increased carotid intima-media thickness (IMT) and plaque occurrence was reported in OSA patients without any other significant co-morbidity compared to matched controls (9, 10, 11, 12).
The prevalence of hypertension is very high and the incidence of hypertension increases as the number of apneic and hypopneic events per hour rises. The association of OSA and hypertension has additive effects on the development of atherosclerosis. Daytime hypertension develops secondary to the persistently elevated sympathetic state (13). In a recent study of 94 middle-aged patients, the intima-media thickness of carotid artery was positively related to systolic blood pressure and apnea-hypopnea index (14).
Pathophysiological mechanisms linking OSA to atherosclerosis
OSA patients experience intermittent hypoxaemia and CO2 retention that modify the autonomic and haemodynamic responses to sleep (15). Indeed, chronic intermittent hypoxia may lead to sympathetic overactivity (16, 17). A study has shown that with mild apneic events (duration < 20 seconds), pretreatment with 100% oxygen effectively eliminated most of the increase in sympathetic nerve activity (25).
It is interesting to notice that continuous positive airway pressure treatment may reverse early signs of atherosclerosis (18).
There is increasing evidence that intermittent hypoxia is independently associated with dyslipidemia (19). In addition to clinical data, animal experiments also support a role of intermittent hypoxia in the pathogenesis of dyslipidaemia in sleep-disordered breathing (20, 21, 22).
The studies above mentioned confirm old experiments performed on rabbits where oxygen deficiency was attained by placing the animals daily into a chamber with decreased oxygen content (down to 12%) for 3–6 hours, for 4 months. It was shown that prolonged hypoxia brings about a high hypercholesterolemia and greatly intensifies the development of aortic and coronary atherosclerosis (26).
The demonstration that chronic intermittent hypoxia may lead to sympathetic overactivity and dyslipidemia adds more evidence to the acidity theory concept (23), with intermittent hypoxemia joining to other key factors for atherosclerosis, as discussed recently in this blog (24).
Carlos Monteiro
1. Levy P, Pepin JL, McNicholas WT. Should all sleep apnoea patients be treated? Yes. Sleep Med Rev 2002; 6:17–26.
2. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea–hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365: 1046–1053.
3. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and sub therapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359: 204–210.
4. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365:1046-1053.
5. Unruh ML, Enright PL, Polak JF, et al. The relationship of sleep apnea to carotid wall thickness among a large cohort of older adults. Sleep. 2005;20:A112.
6. Peker Y, Hedner J, Kraiczi H, Loth S. Respiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med. 2000;162:81-86.
7 Mooe T, Franklin KA, Holmstrom K, Rabben T, Wiklund U. Sleep-disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med. 2001;164:1910-1913.
8. Daniel J. Gottlieb et al. Prospective Study of Obstructive Sleep Apnea and Incident Coronary Heart Disease and Heart Failure. The Sleep Heart Health Study. Circulation, Published online before print July 12, 2010
9. Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005; 172: 613–618.
10. Baguet JP, Hammer L, Levy P, et al. The severity of oxygen desaturation is predictive of carotid wall thickening and plaque occurrence. Chest 2005; 128: 3407–3412.
11. Minoguchi K, Yokoe T, Tazaki T, et al. Increased carotid intima–media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med 2005; 172: 625–630.
12. Baguet JP, Hammer L, Levy P, Pierre H, Launois S, Mallion JMv, et al. The severity of oxygen desaturation is predictive of carotid wall thickening and plaque occurrence. Chest 2005; 128: 3407-12.
13. Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand. 2003;177:385-390
14. Drager LF, Bortolotto LA, Krieger EM, Lorenzi-Filho G. Additive effects of obstructive sleep apnea and hypertension on early markers of carotid atherosclerosis. Hypertension 2009; 53 : 64-9.
15. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 1993; 328 : 303-7.
16. Johnson, T. S., J. B. Young, and L. Landsberg. Sympathoadrenal responses to acute and chronic hypoxia in the rat. J. Clin. Invest. 71: 1263-1272, 1983.
17. Greenberg HE, Sica A, Batson D, Scharf SM. Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 1999; 86: 298–305. Full free text at http://jap.physiology.org/cgi/content/full/86/1/298
18. Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007; 176: 706–712.
19. Drager, Luciano F; Jun, Jonathan; Polotsky, Vsevolod Y. Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis. Curr Opin Endocrinol Diabetes Obes. 2010 Apr;17(2):161-5.
20. Li J, Grigoryev DN, Y e SQ, Thorne L, Schwartz AR, Smith PL, et al. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol 2005; 99 :
1643-8.
21. Li J, Thorne LN, Punjabi NM, Sun CK, Schwartz AR, Smith PL, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 2005; 97 : 698-706.
22. Li J, Savransky V, Nanayakkara A, Smith PL. O’Donnell CP, Polotsky VT. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 2007; 102 : 557-63.
23. 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
24. 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
25. Leuenberger U, Jacob E, Sweer L, Waravdekar N, Zwillich C, Sinoway L. Surges of muscle sympathetic activity during obstructive apnea are linked to hypoxemia. J Appl Physiol 1995;79:581– 8.
26. N. N. Kipshidze.The effect of oxygen deficiency on the development experimental atherosclerosis of the coronary arteries Bulletin of Experimental Biology and Medicine, Volume 47, Number 4, 447-453, 1958, DOI: 10.1007/BF00779624
Tuesday, July 13, 2010
Old experiments with rabbits and dogs provide powerful evidence for the Acidity Theory of Atherosclerosis (1)
Follows a summary about 2 studies from the beginning of the last century showing that acid-fed rabbits and dogs may develop atherosclerotic lesions:
1) Experiments from Oswald Loeb, a well-known professor in pharmacology and scientist from the University of Gottingen - Germany, have demonstrated in study published in 1913, that lactic acid-fed rabbits and dogs have resulted in atherosclerotic lesions in these animals (2). The book “Arteriosclerosis and hypertension, with chapters on blood pressure" (3), by Louis M Warfield, M. D. (Johns Hopkins), showed the following commentary about the experiments from Oswald Loeb:
“Oswald Loeb produced changes in the arteries of rabbits by feeding them sodium lactate (lactic acid). His controls fed on other acids became cachectic, but showed no arterial changes. He further found that in 100 gm. of human blood there was normally from 15 to 30 mg. of lactic acid. After heavy work, he found as much as 150 gm. He considers that after adrenalin or nicotin injections, the function of the liver is so disturbed that lactic acid is not bound. The arteriosclerosis is actually due to the presence of free lactic acid in the circulation. He succeeded, also, in producing lesions of the intima in a dog fed for a long time on protein poor diet, plus lactic acid and sodium lactate.”
2) I. Adler, M.D., from the Laboratories of the New York Board of Health, told in his paper entitled “Studies on Experimental Atherosclerosis” (4), published in 1913, that a casual remark by Dr. P. A. Levene have suggested the simple procedure of adding dilute hydrochloric acid to the dog's food and thus producing a chronic hyperacidity. This led Adler to include acid-fed dogs in his experiments. He told in his paper that though only two dogs have thus far been fed with hydrochloric acid, presenting sclerotic affections, the possibility can not be denied, especially in view of the numerous negative results with other methods, that these positive results are not mere coincidences, but are probably due to the hydrochloric acid. Referring at the end of his paper about the acid-fed dogs presenting atherosclerotic lesions he stated “that the work is being continued, and definite conclusions would at this stage be premature; but perhaps it may be permitted, even now, to venture the statement that in all probability the theory which bases atherosclerosis on a purely mechanical etiology will not prove tenable. Whether mechanical factors come into play at all, and if so, to what extent, remains to be seen. It seems almost certain, at least in our present state of knowledge, influences, subject possibly to more or less nerve control, are dominant factors in the etiology of atherosclerosis. Perhaps it may be discovered also that cholesterin and its various modifications and combinations, while undoubtedly an element of importance in atherosclerosis of the rabbit and human beings, may not be the sole predominant etiological factor.“. He finished telling that “If it should turn out that so simple a procedure as adding a certain proportion of hydrochloric acid to the food of dogs is sufficient to produce lesions of the blood vessels closely analogous, if not wholly identical with human atherosclerosis, a revision of our present theories will become necessary“.
Carlos Monteiro
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
2. Loeb, O., Ueber experimentelle Arterienveraender ungen mit besonderer Beruecksichtigung der Wirkung der Milchsaeure auf Grund eigener Versuche, Deutsch. med. Wchnschr., 1913, xxxix, I819
3. Louis M Warfield, M. D., Third Edition, C. V. Mosby Company, 1920, with full free text at http://www.archive.org/stream/arteriosclerosis00warfuoft/arteriosclerosis00warfuoft_djvu.txt.
4. I. Adler, ‘Studies in Experimental atherosclerosis - A preliminary report’, The Journal of Experimental Medicine, 1913. Free full text at http://jem.rupress.org/content/20/2/93.full.pdf
1) Experiments from Oswald Loeb, a well-known professor in pharmacology and scientist from the University of Gottingen - Germany, have demonstrated in study published in 1913, that lactic acid-fed rabbits and dogs have resulted in atherosclerotic lesions in these animals (2). The book “Arteriosclerosis and hypertension, with chapters on blood pressure" (3), by Louis M Warfield, M. D. (Johns Hopkins), showed the following commentary about the experiments from Oswald Loeb:
“Oswald Loeb produced changes in the arteries of rabbits by feeding them sodium lactate (lactic acid). His controls fed on other acids became cachectic, but showed no arterial changes. He further found that in 100 gm. of human blood there was normally from 15 to 30 mg. of lactic acid. After heavy work, he found as much as 150 gm. He considers that after adrenalin or nicotin injections, the function of the liver is so disturbed that lactic acid is not bound. The arteriosclerosis is actually due to the presence of free lactic acid in the circulation. He succeeded, also, in producing lesions of the intima in a dog fed for a long time on protein poor diet, plus lactic acid and sodium lactate.”
2) I. Adler, M.D., from the Laboratories of the New York Board of Health, told in his paper entitled “Studies on Experimental Atherosclerosis” (4), published in 1913, that a casual remark by Dr. P. A. Levene have suggested the simple procedure of adding dilute hydrochloric acid to the dog's food and thus producing a chronic hyperacidity. This led Adler to include acid-fed dogs in his experiments. He told in his paper that though only two dogs have thus far been fed with hydrochloric acid, presenting sclerotic affections, the possibility can not be denied, especially in view of the numerous negative results with other methods, that these positive results are not mere coincidences, but are probably due to the hydrochloric acid. Referring at the end of his paper about the acid-fed dogs presenting atherosclerotic lesions he stated “that the work is being continued, and definite conclusions would at this stage be premature; but perhaps it may be permitted, even now, to venture the statement that in all probability the theory which bases atherosclerosis on a purely mechanical etiology will not prove tenable. Whether mechanical factors come into play at all, and if so, to what extent, remains to be seen. It seems almost certain, at least in our present state of knowledge, influences, subject possibly to more or less nerve control, are dominant factors in the etiology of atherosclerosis. Perhaps it may be discovered also that cholesterin and its various modifications and combinations, while undoubtedly an element of importance in atherosclerosis of the rabbit and human beings, may not be the sole predominant etiological factor.“. He finished telling that “If it should turn out that so simple a procedure as adding a certain proportion of hydrochloric acid to the food of dogs is sufficient to produce lesions of the blood vessels closely analogous, if not wholly identical with human atherosclerosis, a revision of our present theories will become necessary“.
Carlos Monteiro
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
2. Loeb, O., Ueber experimentelle Arterienveraender ungen mit besonderer Beruecksichtigung der Wirkung der Milchsaeure auf Grund eigener Versuche, Deutsch. med. Wchnschr., 1913, xxxix, I819
3. Louis M Warfield, M. D., Third Edition, C. V. Mosby Company, 1920, with full free text at http://www.archive.org/stream/arteriosclerosis00warfuoft/arteriosclerosis00warfuoft_djvu.txt.
4. I. Adler, ‘Studies in Experimental atherosclerosis - A preliminary report’, The Journal of Experimental Medicine, 1913. Free full text at http://jem.rupress.org/content/20/2/93.full.pdf
Wednesday, May 5, 2010
Cigarette smoking in the development and progression of atherosclerosis: Is sympathetic overactivity the key factor to explain this association?
Sympathetic overactivity seems, in our point of view (1), to be the key factor in cigarette smoking as responsible for the development and progression of atherosclerosis.
Cigarette smoking increases efferent sympathetic nerve traffic acutely, as well norepinephrine and epinephrine release. The adverse effects of cigarette smoking are related to the mixture of chemicals, including nicotine that has been largely accused for many of the adverse effects of smoking on the cardiovascular system, including autonomic imbalance, endothelial dysfunction and coronary blood flow dysregulation. The acute sympathoexcitatory effects of smoking on the cardiovascular system are partially mediated by catecholamine release, muscle sympathetic nerve excitation and peripheral chemoreceptor sensitivity increase, consecutive to nicotinic receptor stimulation in the autonomic nervous system (2).
Both active smoking and exposure to enviromental tobacco smoke are associated with the progression of atherosclerosis as indexed by intimal-medial thickness of the carotid artery assessed by ultrasound (8)
It is interesting to notice about the results from a study published in 2006 revealing that sublingual administration of a 4-mg tablet of Nicotine Replacement Therapy exerts acute deleterious cardiovascular effects and sympathetic activation (3).
Also interesting is the high sugar content (up to 20% - including high fructose corn syrup) of the popular brands of cigarettes (4,5). Sugars and other high-carbohydrate diets, particularly in the form of high-glycemic index carbohydrate, may also contribute for keeping the sympathetic nervous system overactive as discussed recently in this blog (6,7).
Carlos Monteiro
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
2. Adamopoulus D, van de Borne P and Argacha JF, New insights into the sympathetic, endothelial and coronary effects of nicotine. Clin Exp Pharmacol Physiol 2008; 35(4): 458-63
3. Najem B et al. Acute cardiovascular and sympathetic effects of nicotine replacement therapy. Hypertension 2006; 47:1162-67 Full free text at http://hyper.ahajournals.org/cgi/content/full/47/6/1162
4. Elson LA, Betts TE, Passey RD, The sugar content and the pH of the smoke of cigarette, cigar, and pipe tobbacos in relation to lung cancer. International Journal of Cancer, V 9, I 3; 666-675, 1972
5. Stavanja et al. Safety assessment of high fructose corn syrup (HFCS) as an ingredient added to cigarette tobacco. Exp Toxicol Pathol, 57(4): 267-81, 2006
6. Koop W. Chronically increased activity of the sympathetic nervous system: our diet-related “evolutionary” inheritance. The Journal of Nutrition, Health & Aging Volume 13, Number 1, 2009
7. Carlos Monteiro, Fermentable carbohydrates: A link between periodontal disease and cardiovascular disease? Thursday, April 15, 2010 at http://aciditytheory.blogspot.com/2010/04/fermentable-carbohydrates-link-between.html
8. Howard G et al, Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA, 1998 Jan 14;279(2):119-24. Full free text at http://jama.ama-assn.org/cgi/reprint/279/2/119.pdf
Cigarette smoking increases efferent sympathetic nerve traffic acutely, as well norepinephrine and epinephrine release. The adverse effects of cigarette smoking are related to the mixture of chemicals, including nicotine that has been largely accused for many of the adverse effects of smoking on the cardiovascular system, including autonomic imbalance, endothelial dysfunction and coronary blood flow dysregulation. The acute sympathoexcitatory effects of smoking on the cardiovascular system are partially mediated by catecholamine release, muscle sympathetic nerve excitation and peripheral chemoreceptor sensitivity increase, consecutive to nicotinic receptor stimulation in the autonomic nervous system (2).
Both active smoking and exposure to enviromental tobacco smoke are associated with the progression of atherosclerosis as indexed by intimal-medial thickness of the carotid artery assessed by ultrasound (8)
It is interesting to notice about the results from a study published in 2006 revealing that sublingual administration of a 4-mg tablet of Nicotine Replacement Therapy exerts acute deleterious cardiovascular effects and sympathetic activation (3).
Also interesting is the high sugar content (up to 20% - including high fructose corn syrup) of the popular brands of cigarettes (4,5). Sugars and other high-carbohydrate diets, particularly in the form of high-glycemic index carbohydrate, may also contribute for keeping the sympathetic nervous system overactive as discussed recently in this blog (6,7).
Carlos Monteiro
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
2. Adamopoulus D, van de Borne P and Argacha JF, New insights into the sympathetic, endothelial and coronary effects of nicotine. Clin Exp Pharmacol Physiol 2008; 35(4): 458-63
3. Najem B et al. Acute cardiovascular and sympathetic effects of nicotine replacement therapy. Hypertension 2006; 47:1162-67 Full free text at http://hyper.ahajournals.org/cgi/content/full/47/6/1162
4. Elson LA, Betts TE, Passey RD, The sugar content and the pH of the smoke of cigarette, cigar, and pipe tobbacos in relation to lung cancer. International Journal of Cancer, V 9, I 3; 666-675, 1972
5. Stavanja et al. Safety assessment of high fructose corn syrup (HFCS) as an ingredient added to cigarette tobacco. Exp Toxicol Pathol, 57(4): 267-81, 2006
6. Koop W. Chronically increased activity of the sympathetic nervous system: our diet-related “evolutionary” inheritance. The Journal of Nutrition, Health & Aging Volume 13, Number 1, 2009
7. Carlos Monteiro, Fermentable carbohydrates: A link between periodontal disease and cardiovascular disease? Thursday, April 15, 2010 at http://aciditytheory.blogspot.com/2010/04/fermentable-carbohydrates-link-between.html
8. Howard G et al, Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA, 1998 Jan 14;279(2):119-24. Full free text at http://jama.ama-assn.org/cgi/reprint/279/2/119.pdf
Thursday, April 15, 2010
Fermentable carbohydrates: A link between periodontal disease and cardiovascular disease?
The first paper to indicate a link between dental disease and heart disease was wrote by Cleave and Campbell in 1966. In their article these researchers have postulated that excessive fermentable carbohydrates could led to both dental and systemic diseases (1). Yudkin, sharing the same opinion from Cleave, wrote in 1972: “My research on coronary heart disease has convinced me beyond doubt that sugar plays a considerable part in this terrifying epidemic” (2). While both Cleave and Yudkin had distinct hypotheses regarding which dietary carbohydrates caused chronic non-communicable diseases (CNCDs), they were unified regarding the significance of high-glycemic dietary carbohydrates and dental CNCDs. According to Cleave-Yudkin’s hypothesis—both dental and systemic CNCDs were due to an excess intake of fermentable carbohydrates, dental CNCDs were the early marker for systemic CNCDs, and dental CNCDs should be primarily prevented by restriction of fermentable carbohydrates.
Hujoel, in an excellent review paper published in 2009 (3) told that:
“In favor of Cleave-Yudkin’s hypothesis is the ability to predict and explain dental-systemic disease associations that were unknown when the hypothesis was formulated. It is now known, for instance, that markers of abnormal glucose metabolism, such as high levels of advanced glycation end-products or post-load plasma glucose concentration, have been related to diverse systemic outcomes such cardiovascular disease (Jandeleit-Dahm and Cooper, 2008). Similarly, the more a diet drops dental plaque pH, the more it spikes blood glucose levels, providing an elegant biological plausibility model for Cleave-Yudkin’s hypothesis that dental caries is an alarm bell for systemic CNCDs (Lingström et al., 1993)”.
Confirming the Cleave-Yudkin’s hypothesis an Italian study published last week has shown that high dietary glycemic load and carbohydrate intake from high-GI foods increase the overall risk of cardiovascular disease in women, but not in men. In practice the study shows that women who eat more white bread, white rice, pizza, and other carbohydrate-rich foods, that cause blood sugar to spike, are more than twice as likely to develop heart disease than women who eat less of those foods. This study involving 47 749 volunteers (15 171 men and 32 578 women), who completed a dietary questionnaire, had a median duration of 7.9 years of follow-up with 463 CHD cases (158 women and 305 men) identified. The authors said in their paper that a possible reason for the failure to find an association between a high glycemic diet and CHD among men could be that adverse changes in plasma HDL cholesterol and triglyceride levels, as a result of a high glycemic diet, are stronger risk factors for CVD in women than men (4).
It is interesting to notice that high-carbohydrate diets, particularly in the form of high-glycemic index carbohydrate, may keep the sympathetic nervous system overactive (5). Also that high carbohydrate diet may increase significantly the activity of serum lactate dehydrogenase (6).
All the points cited above supply evidences for our acidity theory of atherosclerosis (6).
Treatment of periodontal disease in prevention of atherosclerosis
Some recent studies have shown that treatment of periodontal disease results in benefits for the prevention of atherosclerosis. Tonetti and colleagues have shown that intensive periodontal treatment, 6 months after therapy, the benefits in oral health were associated with improvement in endothelial function (7). Piconi et al have confirmed that treatment of periodontal disease results in improvements of endothelial dysfunction, aside a reduction of the carotid intima-media thickness. The authors of this paper have concluded that these results offer further support to the hypothesis that periodontal disease predisposes to atherosclerosis, shedding some light on the mechanisms possibly associated with this hypothesis, and reinforce the idea that atherosclerosis is an immune-mediated disease (8).
An alternative hypothesis
Taking in view that some risk factors like smoking habits, stress, genetics, increasing age and high-carbohydrates diets contribute to both periodontitis and cardiovascular disease we have an alternative hypothesis through the following mechanisms:
- A street with double directions for driving -
1) From one side the transport from the mouth directly to the blood circulation, through the sublingual route, of sugars related to high-carbohydrate diets leading to an overactive sympathetic nervous system and then to the atherosclerotic process. This idea is based in the regular use of the sublingual route with diffusion directly in the venous circulation for fast effects of remedies including cardiovascular drugs.
2) On the other side the saliva concentrations representing a mix of local chronic inflammatory response plus the acidity of other body conditions derived mostly from chronic stress aside from other factors expressed by markers of blood acidity, lactate dehydrogenase activity, sympathetic nervous system activity and hypothalamic-pituitary-adrenal activity. In our view this second road may also contribute to dental disease.
Carlos Monteiro
1. Cleave TL, Campbell GD (1966). Diabetes, coronary thrombosis, and the saccharine disease Bristol,: Wright
2. Yudkin J (1972b). Sweet and dangerous; the new facts about the sugar you eat as a cause of heart disease, diabetes, and other killers. New York: P.H. Wyden, Inc.
3. Hujoel P, Dietary Carbohydrates and Dental-Systemic Diseases, J Dent Res 2009; 88; 490. Abstract at http://jdr.sagepub.com/cgi/content/abstract/88/6/490
4. Sabina Sieri,Vittorio Krogh, et al . Dietary Glycemic Load and Index and Risk of Coronary Heart Disease in a Large Italian Cohort, EPICOR Study. Arch Intern Med. 2010;170(7):640-647
5. Koop W. Chronically increased activity of the sympathetic nervous system: our diet-related “evolutionary” inheritance. The Journal of Nutrition, Health & Aging Volume 13, Number 1, 2009
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. Tonetti MS et al. Treatment of Periodontitis and Endothelial Function, NEJM - Volume 356:911-920, March 1, 2007
8. Piconi S et al.Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J. 23, 1196–1204 (2009)
Hujoel, in an excellent review paper published in 2009 (3) told that:
“In favor of Cleave-Yudkin’s hypothesis is the ability to predict and explain dental-systemic disease associations that were unknown when the hypothesis was formulated. It is now known, for instance, that markers of abnormal glucose metabolism, such as high levels of advanced glycation end-products or post-load plasma glucose concentration, have been related to diverse systemic outcomes such cardiovascular disease (Jandeleit-Dahm and Cooper, 2008). Similarly, the more a diet drops dental plaque pH, the more it spikes blood glucose levels, providing an elegant biological plausibility model for Cleave-Yudkin’s hypothesis that dental caries is an alarm bell for systemic CNCDs (Lingström et al., 1993)”.
Confirming the Cleave-Yudkin’s hypothesis an Italian study published last week has shown that high dietary glycemic load and carbohydrate intake from high-GI foods increase the overall risk of cardiovascular disease in women, but not in men. In practice the study shows that women who eat more white bread, white rice, pizza, and other carbohydrate-rich foods, that cause blood sugar to spike, are more than twice as likely to develop heart disease than women who eat less of those foods. This study involving 47 749 volunteers (15 171 men and 32 578 women), who completed a dietary questionnaire, had a median duration of 7.9 years of follow-up with 463 CHD cases (158 women and 305 men) identified. The authors said in their paper that a possible reason for the failure to find an association between a high glycemic diet and CHD among men could be that adverse changes in plasma HDL cholesterol and triglyceride levels, as a result of a high glycemic diet, are stronger risk factors for CVD in women than men (4).
It is interesting to notice that high-carbohydrate diets, particularly in the form of high-glycemic index carbohydrate, may keep the sympathetic nervous system overactive (5). Also that high carbohydrate diet may increase significantly the activity of serum lactate dehydrogenase (6).
All the points cited above supply evidences for our acidity theory of atherosclerosis (6).
Treatment of periodontal disease in prevention of atherosclerosis
Some recent studies have shown that treatment of periodontal disease results in benefits for the prevention of atherosclerosis. Tonetti and colleagues have shown that intensive periodontal treatment, 6 months after therapy, the benefits in oral health were associated with improvement in endothelial function (7). Piconi et al have confirmed that treatment of periodontal disease results in improvements of endothelial dysfunction, aside a reduction of the carotid intima-media thickness. The authors of this paper have concluded that these results offer further support to the hypothesis that periodontal disease predisposes to atherosclerosis, shedding some light on the mechanisms possibly associated with this hypothesis, and reinforce the idea that atherosclerosis is an immune-mediated disease (8).
An alternative hypothesis
Taking in view that some risk factors like smoking habits, stress, genetics, increasing age and high-carbohydrates diets contribute to both periodontitis and cardiovascular disease we have an alternative hypothesis through the following mechanisms:
- A street with double directions for driving -
1) From one side the transport from the mouth directly to the blood circulation, through the sublingual route, of sugars related to high-carbohydrate diets leading to an overactive sympathetic nervous system and then to the atherosclerotic process. This idea is based in the regular use of the sublingual route with diffusion directly in the venous circulation for fast effects of remedies including cardiovascular drugs.
2) On the other side the saliva concentrations representing a mix of local chronic inflammatory response plus the acidity of other body conditions derived mostly from chronic stress aside from other factors expressed by markers of blood acidity, lactate dehydrogenase activity, sympathetic nervous system activity and hypothalamic-pituitary-adrenal activity. In our view this second road may also contribute to dental disease.
Carlos Monteiro
1. Cleave TL, Campbell GD (1966). Diabetes, coronary thrombosis, and the saccharine disease Bristol,: Wright
2. Yudkin J (1972b). Sweet and dangerous; the new facts about the sugar you eat as a cause of heart disease, diabetes, and other killers. New York: P.H. Wyden, Inc.
3. Hujoel P, Dietary Carbohydrates and Dental-Systemic Diseases, J Dent Res 2009; 88; 490. Abstract at http://jdr.sagepub.com/cgi/content/abstract/88/6/490
4. Sabina Sieri,Vittorio Krogh, et al . Dietary Glycemic Load and Index and Risk of Coronary Heart Disease in a Large Italian Cohort, EPICOR Study. Arch Intern Med. 2010;170(7):640-647
5. Koop W. Chronically increased activity of the sympathetic nervous system: our diet-related “evolutionary” inheritance. The Journal of Nutrition, Health & Aging Volume 13, Number 1, 2009
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. Tonetti MS et al. Treatment of Periodontitis and Endothelial Function, NEJM - Volume 356:911-920, March 1, 2007
8. Piconi S et al.Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J. 23, 1196–1204 (2009)
Sunday, February 28, 2010
The link between air pollution and atherosclerosis: What is the right biological explanation?
Studies around the world have consistently shown that both short and long term exposures to Particulate Matter (PM) air pollution are associated with a host of cardiovascular diseases, including myocardial ischemia and infarctions, heart failure, arrhythmias, strokes and increased cardiovascular mortality.
Very recently it was published a study in humans confirming the association of the exposure to ambient air pollution and atherosclerosis through the progression of carotid artery intima-media thickness (1).
In an interesting recent paper by Robert Brook (2) he states that there are three putative ‘general’ pathways to explain the biological mechanisms whereby PM exposure may be capable of mediating cardiovascular events: 1) autonomic mechanisms: parasympathetic nervous system withdraw and/or sympathetic nervous system activation; 2) the release of circulating pro-oxidative and/or pro-inflammatory mediators from the lungs (e. g. cytokines and activated immune cells) into the systemic circulation following PM inhalation that, in turn, indirectly mediate CV responses; and; 3) nano-scale particles and/or soluble PM constituents translocating into the systemic circulation after inhalation that then directly interact with the CV system. According to Robert Brook, chronic actions of PM and the enhancement of atherosclerosis, are most likely to be induced by the generation of a chronic pro-inflammatory state (pathway 2).
Taking in view the results of studies in humans showing that particulate air pollutants continuous exposition decreases the heart rate variability (3,4) and may lead to an impaired autonomic control with potential acceleration in the progression of atherosclerosis (5,6,7), with the due respect, I feel obliged to differ from Brook’s opinion regarding the biological mechanism related to chronic PM exposure and atherosclerosis.
In our view the sympathetic over activity may start the whole process of atherosclerosis which ends in the inflammatory state as hypothesized in the acidity theory of atherosclerosis (8) and discussed in our last article in this blog (9)
Carlos Monteiro
1. Nino Kunzli, Michael Jerrett, Raquel Garcia-Esteban, Xavier Basagana, Bernardo Beckermann, Frank Gilliland, Merce Medina, John Peters, Howard N. Hodis, Wendy J. Mack. "Ambient Air Pollution and the Progression of Atherosclerosis in Adults." PloS ONE 5(2): e9096. doi:10.1371/journal.pone.0009096, February 8, 2010. Full free text at http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.00090962. Brook RD, Cardiovascular effects of air pollution. Clinical Science (2008) 115, (175–187) Full free text at http://www.clinsci.org/cs/115/0175/1150175.pdf
3. Duanping Liao, Yinkang Duan, Eric A. Whitsel, Zhi-jie Zheng, Gerardo Heiss, Vernon M. Chinchilli, and Hung-Mo Lin. Association of Higher Levels of Ambient Criteria Pollutants with Impaired Cardiac Autonomic Control: A Population-based Study, Am J Epidemiol 2004;159:768–777
4. C. Arden Pope III, Matthew L. Hansen, Russell W. Long, Karen R. Nielsen, Norman L. Eatough, William E. Wilson, and Delbert J. Eatough. Ambient Particulate Air Pollution, Heart Rate Variability, and Blood Markers of Inflammation in a Panel of Elderly Subjects. Environmental Health Perspectives, V 112; N 3: March 2004
5. Heikki V. Huikuri; Vesa Jokinen; Mikko Syvänne; Markku S. Nieminen; K. E. Juhani et al, Heart Rate Variability and Progression of Coronary Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1979-1985.
6. Anders Gottsäter , Åsa Rydén Ahlgren, Soumia Taimour and Göran Sundkvist, Decreased heart rate variability may predict the progression of carotid atherosclerosis in type 2 diabetes Clinical Autonomic Research Volume 16, Number 3 / June, 2006
7. J. C. Longenecker, M. Zubaid, K.V. Johny, A.I. Attia, J. Ali, W. Rashed, C.G. Suresh, M. Omar. Association of low heart rate variability with atherosclerotic cardiovascular disease in hemodialysis patients. Med Princ Pract 2009;18:85-92
8. 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
9. 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
Very recently it was published a study in humans confirming the association of the exposure to ambient air pollution and atherosclerosis through the progression of carotid artery intima-media thickness (1).
In an interesting recent paper by Robert Brook (2) he states that there are three putative ‘general’ pathways to explain the biological mechanisms whereby PM exposure may be capable of mediating cardiovascular events: 1) autonomic mechanisms: parasympathetic nervous system withdraw and/or sympathetic nervous system activation; 2) the release of circulating pro-oxidative and/or pro-inflammatory mediators from the lungs (e. g. cytokines and activated immune cells) into the systemic circulation following PM inhalation that, in turn, indirectly mediate CV responses; and; 3) nano-scale particles and/or soluble PM constituents translocating into the systemic circulation after inhalation that then directly interact with the CV system. According to Robert Brook, chronic actions of PM and the enhancement of atherosclerosis, are most likely to be induced by the generation of a chronic pro-inflammatory state (pathway 2).
Taking in view the results of studies in humans showing that particulate air pollutants continuous exposition decreases the heart rate variability (3,4) and may lead to an impaired autonomic control with potential acceleration in the progression of atherosclerosis (5,6,7), with the due respect, I feel obliged to differ from Brook’s opinion regarding the biological mechanism related to chronic PM exposure and atherosclerosis.
In our view the sympathetic over activity may start the whole process of atherosclerosis which ends in the inflammatory state as hypothesized in the acidity theory of atherosclerosis (8) and discussed in our last article in this blog (9)
Carlos Monteiro
1. Nino Kunzli, Michael Jerrett, Raquel Garcia-Esteban, Xavier Basagana, Bernardo Beckermann, Frank Gilliland, Merce Medina, John Peters, Howard N. Hodis, Wendy J. Mack. "Ambient Air Pollution and the Progression of Atherosclerosis in Adults." PloS ONE 5(2): e9096. doi:10.1371/journal.pone.0009096, February 8, 2010. Full free text at http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.00090962. Brook RD, Cardiovascular effects of air pollution. Clinical Science (2008) 115, (175–187) Full free text at http://www.clinsci.org/cs/115/0175/1150175.pdf
3. Duanping Liao, Yinkang Duan, Eric A. Whitsel, Zhi-jie Zheng, Gerardo Heiss, Vernon M. Chinchilli, and Hung-Mo Lin. Association of Higher Levels of Ambient Criteria Pollutants with Impaired Cardiac Autonomic Control: A Population-based Study, Am J Epidemiol 2004;159:768–777
4. C. Arden Pope III, Matthew L. Hansen, Russell W. Long, Karen R. Nielsen, Norman L. Eatough, William E. Wilson, and Delbert J. Eatough. Ambient Particulate Air Pollution, Heart Rate Variability, and Blood Markers of Inflammation in a Panel of Elderly Subjects. Environmental Health Perspectives, V 112; N 3: March 2004
5. Heikki V. Huikuri; Vesa Jokinen; Mikko Syvänne; Markku S. Nieminen; K. E. Juhani et al, Heart Rate Variability and Progression of Coronary Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1979-1985.
6. Anders Gottsäter , Åsa Rydén Ahlgren, Soumia Taimour and Göran Sundkvist, Decreased heart rate variability may predict the progression of carotid atherosclerosis in type 2 diabetes Clinical Autonomic Research Volume 16, Number 3 / June, 2006
7. J. C. Longenecker, M. Zubaid, K.V. Johny, A.I. Attia, J. Ali, W. Rashed, C.G. Suresh, M. Omar. Association of low heart rate variability with atherosclerotic cardiovascular disease in hemodialysis patients. Med Princ Pract 2009;18:85-92
8. 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
9. 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
Monday, February 22, 2010
Sympathetic predominance: a primary factor in the cascade of events leading to the atherogenic spiraling.
Sympathetic overactivity has been found to be associated with blood pressure and lipid abnormalities (1,2,3). In this respect a recent study has demonstrated that sympathetic overactivity may favour the development of sustained hypertension and hypercholesterolemia early in life, and lead to increased susceptibility of vascular complications. (4).
In fact accumulating data collected in animals and humans suggest that metabolic syndrome is associated with markers of adrenergic overdrive. Several markers of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals, heart rate and others, have all show an increase in the different conditions clustering in metabolic syndrome like obesity, hypertension and insulin resistance state (5,6). Evidence also has shown that the sympathetic activation participates in the development of hypertension-related target organ damage, such as left ventricular diastolic dysfunction (7).
It is well established that the sympathetic nervous system (SNS) activity is also influenced by food ingestion, and that diet composition plays an important role. What is interesting to note is that, among dietary types, carbohydrates (starch and sugars) ingestion significantly increases SNS activity, especially in high-glycemic load, with deleterious effects to human health (8). On the other side protein or fat ingestion have no significant sympathoexcitatory effect (9,10,11).
The evidences above mentioned strengthen our views regarding to the acidity theory of atherosclerosis where continuous stress is placed as the most important risk factor (12). However, this do not undermine the value of other key factors as expressed in our monography:
“The acidity theory of atherosclerosis does not underestimate the importance of other key factors for atherosclerosis like ageing, improper diet, environmental pollution, lifestyle, physical inactivity, tobacco smoking and genetic predisposition. However, most of these risk factors might result in altered autonomic nervous system, sympathetic bias, increased lactic acid and acidic environment thus propitiating atherogenesis. Our proposal may extend to any respiratory or metabolic disturbances resulting in acidosis.“
Carlos Monteiro
1. Masuo K, Mikami H, Ogihara T, Tuck ML. Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population. Am J Hypertens 1997; 10:77–83.
2. Nakao M, Nomura K, Karita K, Nishikitani M, Yano E. Relationship between brachial-ankle pulse wave velocity and heart rate variability in young Japanese men. Hypertens Res 2004; 27:925–931.
3. Arner P, Wahrenberg H, Lonnqvist F, Angelin B. Adipocyte betaadrenoceptor sensitivity influences plasma lipid levels. Arterioscler Thromb Vasc Biol 1993; 13:967–972.
4. Palatini P, Longo D, Zaetta V, Perkovic D, Garbelotto R and Pessina AC. Evolution of blood pressure and cholesterol in stage 1 hypertension: role of autonomic nervous system activity. Journal of Hypertension 2006, 24:1375-1381
5. Mancia G, Bousquet P et al. The sympathetic nervous system and the metabolic syndrome. Journal of Hypertension 2007, 25 (5):909-920
6.Grassi G, Quarti-Trevano F et al. Cariovascular risk and adrenergic overdrive in metabolic syndrome. Nutr Metab Cardiovasc Dis 2007, 17(6): 473-81
7. Grassi G, Seravalle G et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009;53:205-209. Full free paper at http://hyper.ahajournals.org/cgi/content/full/53/2/205
8. Koop W. Chronically increased activity of the sympathetic nervous system: our diet-related “evolutionary” inheritance. The Journal of Nutrition, Health & Aging Volume 13, Number 1, 2009
9. Welle S, Ulavivat U, Campell G. Thermic effect of feeding in men: Increased plasma
norepinephrine levels following glucose but not protein or fat consumption. Metabolism 1981; 30: 953-958
10. Welle SL, Lilavivathana U,Campell RG. Increased plasma nor epinephrine concentrations and metabolic rates following glucose ingestion in man. Metabolism 1980; 29: 806-09
11. Tentolouris N, Tsigos D, Perea E et al. Differential effect of high-fat and high carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in
lean and obese women. Metabolism 2003; 52: 1426-32
12. 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
In fact accumulating data collected in animals and humans suggest that metabolic syndrome is associated with markers of adrenergic overdrive. Several markers of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals, heart rate and others, have all show an increase in the different conditions clustering in metabolic syndrome like obesity, hypertension and insulin resistance state (5,6). Evidence also has shown that the sympathetic activation participates in the development of hypertension-related target organ damage, such as left ventricular diastolic dysfunction (7).
It is well established that the sympathetic nervous system (SNS) activity is also influenced by food ingestion, and that diet composition plays an important role. What is interesting to note is that, among dietary types, carbohydrates (starch and sugars) ingestion significantly increases SNS activity, especially in high-glycemic load, with deleterious effects to human health (8). On the other side protein or fat ingestion have no significant sympathoexcitatory effect (9,10,11).
The evidences above mentioned strengthen our views regarding to the acidity theory of atherosclerosis where continuous stress is placed as the most important risk factor (12). However, this do not undermine the value of other key factors as expressed in our monography:
“The acidity theory of atherosclerosis does not underestimate the importance of other key factors for atherosclerosis like ageing, improper diet, environmental pollution, lifestyle, physical inactivity, tobacco smoking and genetic predisposition. However, most of these risk factors might result in altered autonomic nervous system, sympathetic bias, increased lactic acid and acidic environment thus propitiating atherogenesis. Our proposal may extend to any respiratory or metabolic disturbances resulting in acidosis.“
Carlos Monteiro
1. Masuo K, Mikami H, Ogihara T, Tuck ML. Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population. Am J Hypertens 1997; 10:77–83.
2. Nakao M, Nomura K, Karita K, Nishikitani M, Yano E. Relationship between brachial-ankle pulse wave velocity and heart rate variability in young Japanese men. Hypertens Res 2004; 27:925–931.
3. Arner P, Wahrenberg H, Lonnqvist F, Angelin B. Adipocyte betaadrenoceptor sensitivity influences plasma lipid levels. Arterioscler Thromb Vasc Biol 1993; 13:967–972.
4. Palatini P, Longo D, Zaetta V, Perkovic D, Garbelotto R and Pessina AC. Evolution of blood pressure and cholesterol in stage 1 hypertension: role of autonomic nervous system activity. Journal of Hypertension 2006, 24:1375-1381
5. Mancia G, Bousquet P et al. The sympathetic nervous system and the metabolic syndrome. Journal of Hypertension 2007, 25 (5):909-920
6.Grassi G, Quarti-Trevano F et al. Cariovascular risk and adrenergic overdrive in metabolic syndrome. Nutr Metab Cardiovasc Dis 2007, 17(6): 473-81
7. Grassi G, Seravalle G et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009;53:205-209. Full free paper at http://hyper.ahajournals.org/cgi/content/full/53/2/205
8. Koop W. Chronically increased activity of the sympathetic nervous system: our diet-related “evolutionary” inheritance. The Journal of Nutrition, Health & Aging Volume 13, Number 1, 2009
9. Welle S, Ulavivat U, Campell G. Thermic effect of feeding in men: Increased plasma
norepinephrine levels following glucose but not protein or fat consumption. Metabolism 1981; 30: 953-958
10. Welle SL, Lilavivathana U,Campell RG. Increased plasma nor epinephrine concentrations and metabolic rates following glucose ingestion in man. Metabolism 1980; 29: 806-09
11. Tentolouris N, Tsigos D, Perea E et al. Differential effect of high-fat and high carbohydrate isoenergetic meals on cardiac autonomic nervous system activity in
lean and obese women. Metabolism 2003; 52: 1426-32
12. 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
Friday, February 5, 2010
What causes the elevation of cholesterol levels in blood?
Follows some suggestions from medical literature about factors, beyond the famous but wronged and simplistic idea that foods based on saturated fats cause the development of atherosclerosis (1, 22, 23), suggesting that stress, high carbohydrate diets and smoke may raise total cholesterol and low density lipoproteins levels:
1. Stress
a) Anxiety and cholesterol elevation (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
b) Hostility and cholesterol elevation (12, 13, 14)
c) Extreme physical exertion and cholesterol elevation (15)
2) High carbohydrate diets and cholesterol elevation (16, 17, 18).
3) Smoke and cholesterol elevation (19, 20).
It is interesting to notice that specially in stress conditions and in high carbohydrate diets there is a significant elevation in blood lactic acid, with paralleling elevation of cholesterol levels in blood which represents in our view, a healing response of the body to the vascular endothelial lesion (21).
As Dr. Malcolm Kendrick, a colleague from the International Network of Cholesterol Skeptics (THINCS), use to say: "Do cigarettes contain fat? No, not at all. So, how can smoking a cigarette, containing no fat or cholesterol, end up depositing fat and cholesterol in the artery walls. What is the mechanism for that?"
By the way, in a recent paper the authors have assessed all dietary interventions using Dietary Cholesterol (DC) or eggs and presented their own conclusions. They point out that short-term effects where there is a rise in plasma cholesterol with DC should be interpreted with caution because they differ from long-term effects where there is no relationship between DC and plasma cholesterol (22).
Carlos Monteiro
Note:
A recent meta-analysis of prospective epidemiologic studies during 5–23 years of follow-up of 347,747 subjects showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD. Consideration of age, sex, and study quality did not changed the results (23)
1. Uffe Ravnskov, Cholesterol Myths at http://www.ravnskov.nu/cholesterol.htm
2) Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response. Wirtz PH, Ehlert U, Bärtschi C, Redwine LS, von Känel R. Metabolism. 2009 Jan;58(1):30-7.
3. Effects of hemoconcentration and sympathetic activation on serum lipid responses to brief mental stress, Elizabeth A. Bachen, Matthew F Muldoon et al, Psychosomatic Medicine 64:587-594 (2002)
4. Serum lipids, neuroendocrine and cardiovascular responses to stress in healthy Type A men, Fredrikson M, Blumenthal JA, Biol Psychol. 1992 Oct;34(1):45-58
5. Factors associated with the development of panic attack and panic disorder: survey in the Japanese population Kaiya H et al. Psychiatry Clin Neurosci. 2005 Apr;59(2):177-82a
6. Changes in mental well-being, blood pressure and total cholesterol levels during workplace reorganization: the impact of uncertainty, Taylor & Francis V15, N1 January 1, 2001: 14-18
7. Examination stress: changes in serum cholesterol, triglycerides and total lipids. Agarwal V, Gupta B, Singhal U, Bajpai SK. Indian J Physiol Pharmacol. 1997 Oct;41(4):404-8.
8. Wives of patients with acute myocardial infarction are at an increased risk of developing coronary artery disease, Papamichael Ch et al, J Cardiovasc Risk. 2002 Feb;9(1):49-52
9. Lipid reactivity to stress: I. Comparison of chronic and acute stress responses in middle-aged pilots, Stoney CM et al, Health Psychol. 1999 May;18(3):241-250
10. Associations between acute lipid stress responses and fasting lipid levels 3 years later, Andrew Steptoe and Lena Brydon, Health Psychology 2005, Vol. 24, No. 6, 601-607
11. Effect of preoperative stress on serum cholesterol level in humans. Sane AS, Kukreti SC, Experientia. 1978 Feb 15; 34(2): 213-4
12. Prevalence of hostility in young coronary artery disease patients and effects of cardiac rehabilitation and exercise training, Lavie CJ, Milani RV, Mayo Clin Proc. 2005 Mar;80(3):335-42
13.Richards JC, Hof A, Alvarenga M. Serum lipids and their relationships with hostility and angry affect and behaviors in men.Health Psychol. 2000 Jul;19(4):393-8.
14. Hostility-related differences in the associations between stress-induced physiological reactivity and lipid concentrations in young healthy women.Suarez EC, Harralson TL. Int J Behav Med. 1999;6(2):190-203.
15. Changes in lipoprotein profiles during intense military training. B. L. Smoak, J. P. Norton, E. W. Ferguson and P. A. Deuster. Journal of the American College of Nutrition, Vol 9, Issue 6 567-572
16. Metabolic effects of dietary fructose in healthy subjects.Swanson JE, Laine DC, Thomas W, Bantle JP. Am J Clin Nutrition 1992;55:851-6
17. Blood lipids, lipoproteins, apoproteins, and uric acid in men fed diets containing fructose or high-amylose cornstarch. Reiser S. Powell AS, Scholfield DI. Panda P. Ellwood KC. Canary II. Am J Clin Nutr 1989:49:832-9.
18. Hallfrisch J, Reiser 5, Prather ES. Blood lipid distribution of hyperinsulinemic men consuming three levels of fructose. Am J Clin Nutr 1983:37:740-8.
19. The Relationship Between Smoking, Cholesterol, and HDL-C Levels in Adult Women
Bert H. Jacobson; Steven G. Aldana; Troy B. Adams; Michael Quirk; Haworth, Women & Health, Volume 23, Issue 4 July 1996 , pages 27 - 38
20. Smoking and smoking cessation -- the relationship between cardiovascular disease and lipoprotein metabolism: a review. Chelland Campbell S, Moffatt RJ, Stamford BA. Atherosclerosis. 2008 Dec;201(2):225-35
21. 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
22. Fernandez ML and Calle M. Revisiting Dietary Cholesterol Recommendations: Does the Evidence Support a Limit of 300 mg/d?, August 4, 2010
23. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease, Patty W Siri-Tarino, Qi Sun, Frank B Hu, and Ronald M Krauss. Am J Clin Nutr doi: 10.3945/ajcn.2009.27725. First published ahead of print January 13, 2010
1. Stress
a) Anxiety and cholesterol elevation (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
b) Hostility and cholesterol elevation (12, 13, 14)
c) Extreme physical exertion and cholesterol elevation (15)
2) High carbohydrate diets and cholesterol elevation (16, 17, 18).
3) Smoke and cholesterol elevation (19, 20).
It is interesting to notice that specially in stress conditions and in high carbohydrate diets there is a significant elevation in blood lactic acid, with paralleling elevation of cholesterol levels in blood which represents in our view, a healing response of the body to the vascular endothelial lesion (21).
As Dr. Malcolm Kendrick, a colleague from the International Network of Cholesterol Skeptics (THINCS), use to say: "Do cigarettes contain fat? No, not at all. So, how can smoking a cigarette, containing no fat or cholesterol, end up depositing fat and cholesterol in the artery walls. What is the mechanism for that?"
By the way, in a recent paper the authors have assessed all dietary interventions using Dietary Cholesterol (DC) or eggs and presented their own conclusions. They point out that short-term effects where there is a rise in plasma cholesterol with DC should be interpreted with caution because they differ from long-term effects where there is no relationship between DC and plasma cholesterol (22).
Carlos Monteiro
Note:
A recent meta-analysis of prospective epidemiologic studies during 5–23 years of follow-up of 347,747 subjects showed that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD. Consideration of age, sex, and study quality did not changed the results (23)
1. Uffe Ravnskov, Cholesterol Myths at http://www.ravnskov.nu/cholesterol.htm
2) Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response. Wirtz PH, Ehlert U, Bärtschi C, Redwine LS, von Känel R. Metabolism. 2009 Jan;58(1):30-7.
3. Effects of hemoconcentration and sympathetic activation on serum lipid responses to brief mental stress, Elizabeth A. Bachen, Matthew F Muldoon et al, Psychosomatic Medicine 64:587-594 (2002)
4. Serum lipids, neuroendocrine and cardiovascular responses to stress in healthy Type A men, Fredrikson M, Blumenthal JA, Biol Psychol. 1992 Oct;34(1):45-58
5. Factors associated with the development of panic attack and panic disorder: survey in the Japanese population Kaiya H et al. Psychiatry Clin Neurosci. 2005 Apr;59(2):177-82a
6. Changes in mental well-being, blood pressure and total cholesterol levels during workplace reorganization: the impact of uncertainty, Taylor & Francis V15, N1 January 1, 2001: 14-18
7. Examination stress: changes in serum cholesterol, triglycerides and total lipids. Agarwal V, Gupta B, Singhal U, Bajpai SK. Indian J Physiol Pharmacol. 1997 Oct;41(4):404-8.
8. Wives of patients with acute myocardial infarction are at an increased risk of developing coronary artery disease, Papamichael Ch et al, J Cardiovasc Risk. 2002 Feb;9(1):49-52
9. Lipid reactivity to stress: I. Comparison of chronic and acute stress responses in middle-aged pilots, Stoney CM et al, Health Psychol. 1999 May;18(3):241-250
10. Associations between acute lipid stress responses and fasting lipid levels 3 years later, Andrew Steptoe and Lena Brydon, Health Psychology 2005, Vol. 24, No. 6, 601-607
11. Effect of preoperative stress on serum cholesterol level in humans. Sane AS, Kukreti SC, Experientia. 1978 Feb 15; 34(2): 213-4
12. Prevalence of hostility in young coronary artery disease patients and effects of cardiac rehabilitation and exercise training, Lavie CJ, Milani RV, Mayo Clin Proc. 2005 Mar;80(3):335-42
13.Richards JC, Hof A, Alvarenga M. Serum lipids and their relationships with hostility and angry affect and behaviors in men.Health Psychol. 2000 Jul;19(4):393-8.
14. Hostility-related differences in the associations between stress-induced physiological reactivity and lipid concentrations in young healthy women.Suarez EC, Harralson TL. Int J Behav Med. 1999;6(2):190-203.
15. Changes in lipoprotein profiles during intense military training. B. L. Smoak, J. P. Norton, E. W. Ferguson and P. A. Deuster. Journal of the American College of Nutrition, Vol 9, Issue 6 567-572
16. Metabolic effects of dietary fructose in healthy subjects.Swanson JE, Laine DC, Thomas W, Bantle JP. Am J Clin Nutrition 1992;55:851-6
17. Blood lipids, lipoproteins, apoproteins, and uric acid in men fed diets containing fructose or high-amylose cornstarch. Reiser S. Powell AS, Scholfield DI. Panda P. Ellwood KC. Canary II. Am J Clin Nutr 1989:49:832-9.
18. Hallfrisch J, Reiser 5, Prather ES. Blood lipid distribution of hyperinsulinemic men consuming three levels of fructose. Am J Clin Nutr 1983:37:740-8.
19. The Relationship Between Smoking, Cholesterol, and HDL-C Levels in Adult Women
Bert H. Jacobson; Steven G. Aldana; Troy B. Adams; Michael Quirk; Haworth, Women & Health, Volume 23, Issue 4 July 1996 , pages 27 - 38
20. Smoking and smoking cessation -- the relationship between cardiovascular disease and lipoprotein metabolism: a review. Chelland Campbell S, Moffatt RJ, Stamford BA. Atherosclerosis. 2008 Dec;201(2):225-35
21. 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
22. Fernandez ML and Calle M. Revisiting Dietary Cholesterol Recommendations: Does the Evidence Support a Limit of 300 mg/d?, August 4, 2010
23. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease, Patty W Siri-Tarino, Qi Sun, Frank B Hu, and Ronald M Krauss. Am J Clin Nutr doi: 10.3945/ajcn.2009.27725. First published ahead of print January 13, 2010
Monday, January 11, 2010
Psoriasis linked to atherosclerosis: An unsolved mystery?
During the last years several studies have reported that patients with psoriasis are more likely to have traditional cardiovascular risk factors, such as hyperlipidemia, hypertension, diabetes, obesity, tobacco use, and a history of previous myocardial infarction (1, 2).
Very recently a new study has suggested that psoriac patients have more propensity for coronary artery, cerebrovascular and peripheral vascular diseases resulting in increased mortality. This study compared rates of heart disease, stroke-related vascular disease and peripheral artery disease (PAD), and death among 3.236 people with psoriasis (mostly men between 50-60 years) and 2.500 people without this condition. Overall people with psoriasis were nearly twice as likely to have been diagnosed with heart disease, stroke related vascular disease or PAD. What’s more, 19.6% of people with psoriasis died during the study, compared with 9.9% of participants who did not have psoriasis (3).
In reality many recent studies are showing the prevalence of subclinical atherosclerosis in patients with psoriasis compared with health patients, through a marked increase in the carotid artery intima-media thickness, measured by ultrasonography (4,5,6 ,7,8).
Also, a study has shown that subclinical atherosclerosis in psoriac patients is significantly associated with increased sugar and triglyceride levels (6)
Other studies have shown that metabolic systems may be disturbed in association with psoriasis, with many compounds formed in excess from glucose, like lactic acid (9). It is interesting to notice that Boyd and Menter found that 13 (62%) of 21 patients with erythroderma, the most severe form of psoriasis, had elevated serum lactic deydrogenase (10). Another study have indicated a shift of enzymatic activity of lactate deydrogenase in erythrocyte in psoriasis towards LDH2 and LDH1, and thus to enhanced energy production by oxidation in psoriatic patients as compared with normal controls (11).
According to some researchers the mechanism by which premature atherosclerosis develops in psoriasis remains an unsolved mystery, becoming a focus of current research to further elucidate the pathophysiology underlying and connecting these two diseases (12).
Taking in view the above findings I think the acidity theory may offer a valid and potential pathophysiological mechanism to explain the link psoriasis/atherosclerosis (13)
1) Matthew Meier and Pranav B. Sheth, Clinical Spectrum and Severity of Psoriasis. Curr Probl Dermatol. Basel, Karger, 2009, vol 38, pp 1–20. Full free paper at http://www.online.karger.com/ProdukteDB/Katalogteile/isbn3_8055/_91/_51/CUPDE38_02.pdf
2) Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J. 2009 Dec 27.
3) Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG.. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009 Jun;145(6):700-3.
4) El-Mongy S, Fathy H, Abdelaziz A, Omran E, George S, Neseem N, El-Nour N. Subclinical atherosclerosis in patients with chronic psoriasis: a potential association. J Eur Acad Dermatol Venereol. 2009 Nov 2
5) Balci DD, Balci A, Karazincir S, Ucar E, Iyigun U, Yalcin F, Seyfeli E, Inandi T, Egilmez E. Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis. J Eur Acad Dermatol Venereol. 2009 Jan;23(1):1-6.
6) Tam LS, Shang Q, Li EK, Tomlinson B, Chu TT, Li M, Leung YY, Kwok LW, Wong KC, Li TK, Yu T, Zhu TY, Kun EW, Yip GW, Yu CM. Subclinical carotid atherosclerosis in patients with psoriatic arthritis. Arthritis Rheum. 2008 Sep 15;59(9):1322-31.
7) Eder L, Zisman D, Barzilai M, Laor A, Rahat M, Rozenbaum M, Bitterman H, Feld J, Rimar D, Rosner I. Subclinical atherosclerosis in psoriatic arthritis: a case-control study. J Rheumatol. 2008 May;35(5):877-82.
8) Gonzalez-Juanatey C, Llorca J, Amigo-Diaz E, Dierssen T, Martin J, Gonzalez-Gay MA. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum. 2007 Aug 15;57(6):1074-80.
9) Meynadier J, Guilhou JJ, The biochemistry of psoriasis. Ann Dermatol Syphiligr (Paris). 1976;103(5-6):525-45.
10) A. Boyd, A. Menter, Erythrodermic psoriasis: Precipitating factors, course, and prognosis in 50 patients.Journal of the American Academy of Dermatology, 1989, Volume 21, Issue 5, Pages 985-991
11) Malina L, Volek V, Bielicky T. The activity of lactate dehydrogenase in the erythrocytes in psoriasis. Z Haut Geschlechtskr. 1969 Oct 1;44(19):877-9.
12) Shelling ML, Federman DG, Prodanovich S, Kirsner RS. Psoriasis and vascular disease: an unsolved mystery. Am J Med. 2008 May;121(5):360-5.
13) 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
Very recently a new study has suggested that psoriac patients have more propensity for coronary artery, cerebrovascular and peripheral vascular diseases resulting in increased mortality. This study compared rates of heart disease, stroke-related vascular disease and peripheral artery disease (PAD), and death among 3.236 people with psoriasis (mostly men between 50-60 years) and 2.500 people without this condition. Overall people with psoriasis were nearly twice as likely to have been diagnosed with heart disease, stroke related vascular disease or PAD. What’s more, 19.6% of people with psoriasis died during the study, compared with 9.9% of participants who did not have psoriasis (3).
In reality many recent studies are showing the prevalence of subclinical atherosclerosis in patients with psoriasis compared with health patients, through a marked increase in the carotid artery intima-media thickness, measured by ultrasonography (4,5,6 ,7,8).
Also, a study has shown that subclinical atherosclerosis in psoriac patients is significantly associated with increased sugar and triglyceride levels (6)
Other studies have shown that metabolic systems may be disturbed in association with psoriasis, with many compounds formed in excess from glucose, like lactic acid (9). It is interesting to notice that Boyd and Menter found that 13 (62%) of 21 patients with erythroderma, the most severe form of psoriasis, had elevated serum lactic deydrogenase (10). Another study have indicated a shift of enzymatic activity of lactate deydrogenase in erythrocyte in psoriasis towards LDH2 and LDH1, and thus to enhanced energy production by oxidation in psoriatic patients as compared with normal controls (11).
According to some researchers the mechanism by which premature atherosclerosis develops in psoriasis remains an unsolved mystery, becoming a focus of current research to further elucidate the pathophysiology underlying and connecting these two diseases (12).
Taking in view the above findings I think the acidity theory may offer a valid and potential pathophysiological mechanism to explain the link psoriasis/atherosclerosis (13)
1) Matthew Meier and Pranav B. Sheth, Clinical Spectrum and Severity of Psoriasis. Curr Probl Dermatol. Basel, Karger, 2009, vol 38, pp 1–20. Full free paper at http://www.online.karger.com/ProdukteDB/Katalogteile/isbn3_8055/_91/_51/CUPDE38_02.pdf
2) Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J. 2009 Dec 27.
3) Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG.. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009 Jun;145(6):700-3.
4) El-Mongy S, Fathy H, Abdelaziz A, Omran E, George S, Neseem N, El-Nour N. Subclinical atherosclerosis in patients with chronic psoriasis: a potential association. J Eur Acad Dermatol Venereol. 2009 Nov 2
5) Balci DD, Balci A, Karazincir S, Ucar E, Iyigun U, Yalcin F, Seyfeli E, Inandi T, Egilmez E. Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis. J Eur Acad Dermatol Venereol. 2009 Jan;23(1):1-6.
6) Tam LS, Shang Q, Li EK, Tomlinson B, Chu TT, Li M, Leung YY, Kwok LW, Wong KC, Li TK, Yu T, Zhu TY, Kun EW, Yip GW, Yu CM. Subclinical carotid atherosclerosis in patients with psoriatic arthritis. Arthritis Rheum. 2008 Sep 15;59(9):1322-31.
7) Eder L, Zisman D, Barzilai M, Laor A, Rahat M, Rozenbaum M, Bitterman H, Feld J, Rimar D, Rosner I. Subclinical atherosclerosis in psoriatic arthritis: a case-control study. J Rheumatol. 2008 May;35(5):877-82.
8) Gonzalez-Juanatey C, Llorca J, Amigo-Diaz E, Dierssen T, Martin J, Gonzalez-Gay MA. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum. 2007 Aug 15;57(6):1074-80.
9) Meynadier J, Guilhou JJ, The biochemistry of psoriasis. Ann Dermatol Syphiligr (Paris). 1976;103(5-6):525-45.
10) A. Boyd, A. Menter, Erythrodermic psoriasis: Precipitating factors, course, and prognosis in 50 patients.Journal of the American Academy of Dermatology, 1989, Volume 21, Issue 5, Pages 985-991
11) Malina L, Volek V, Bielicky T. The activity of lactate dehydrogenase in the erythrocytes in psoriasis. Z Haut Geschlechtskr. 1969 Oct 1;44(19):877-9.
12) Shelling ML, Federman DG, Prodanovich S, Kirsner RS. Psoriasis and vascular disease: an unsolved mystery. Am J Med. 2008 May;121(5):360-5.
13) 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
Tuesday, January 5, 2010
Acidity: The link between Atherosclerosis and Osteoporosis.
Although the prevalence of both atherosclerosis and osteoporosis increase with age, various and accumulating evidence indicate, since the initial studies (1, 2), a more direct relationship between these 2 conditions. Confirming this association, many recent studies have shown an increased carotid intima-media thickness (IMT), a marker for atherosclerosis, among women as they develop osteoporosis (3, 4).
A very recent study have reported that hip fracture is between two and five times more common in people with cardiovascular disease than in those with no history of the disease. The researchers from this study have found that bisphosphonates not only decrease the progression of osteoporosis, but also prevent the development of atherosclerosis and reduce total mortality rate (5).
Regarding this point it is interesting to note that bisphosphonates can reduce the elevated production of lactic acid in the body (6) what allow the acidity theory concept (7) to be a strong explanation for the link atherosclerosis/osteoporosis, taking in view the proposition from A. Wachman and D.S. Bernstein made in 1968 (8), and endorsed by others (9), that the body draws minerals from the bones to neutralize acid or alkaline challenges.
BTW, an editorial published at New England Journal of Medicine (Bone, Acid, and Osteoporosis, New England Journal of Medicine, V 330:1821-1822 , June 23, 1994) brings the following quote and comments:
"Life is a struggle, not against sin, not against the Money Power, not against malicious animal magnetism, but against hydrogen ions"1 Mencken H L. Exeunt omnes. Smart Set. 1919; 60: 138–145). These words, written by H.L. Mencken about the meaning of life and death, may also apply to the struggle of the healthy skeleton against the deleterious effects of retained acid.
Carlos Monteiro
1) Dent CE, Engelbrecht HE, Godfrey RC. Osteoporosis of lumbar vertebrae and calcification of abdominal aorta in women living in Durban. Br Med J. 1968;4:76-79.
2. Fujita T, Okamoto Y, Sakagami Y, Ota K, Ohata M. Bone changes and aortic calcification in aging inhabitants of mountain versus seacoast communities in the Kii Peninsula. J Am Geriatr Soc. 1984;32:124-128
3) J. Tamaki , M. Iki, Y. Hirano, Y. Sato, E. Kajita, S. Kagamimori, Y. Kagawa and H. Yoneshima. Low bone mass is associated with carotid atherosclerosis in postmenopausal women: The Japanese Population-based Osteoporosis (JPOS) Cohort Study , Osteoporosis International, V 20, N 1 / January, 2009
4) Hiroyuki Sumino, Shuichi Ichikawa, Shu Kasama, Takashi Takahashi, Hironosuke Sakamoto, Hisao Kumakura, Yoshiaki Takayama, Tsugiyasu Kanda, Masami Murakami and Masahiko Kurabayashi, Relationship between Carotid Atherosclerosis and Lumbar Spine Bone Mineral Density in Postmenopausal Women, Hypertension Research (2008) 31, 1191–1197;
5) Ulf Sennerby, Håkan Melhus, Rolf Gedeborg, Liisa Byberg, Hans Garmo, Anders Ahlbom, Nancy L. Pedersen, Karl Michaëlsson. Cardiovascular Diseases and Risk of Hip Fracture, JAMA. 2009;302(15):1666-1673.
6 Norman H. Bell and Ralph H. Johnson. Bisphosphonates in the treatment of osteoporosis, Endocrine, Volume 6, Number 2 / April, 1997.
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) Wachman A, Bernstein DS. Diet and osteoporosis. Lancet. 1968;1:958–9.
9) Frances A. Tylavsky, Lisa A. Spence Laura Harkness. The Importance of Calcium, Potassium, and Acid-Base Homeostasis in Bone Health and Osteoporosis Prevention. J. Nutr. 138: 164S–165S, 2008 full free paper at http://jn.nutrition.org/cgi/reprint/138/1/164S
A very recent study have reported that hip fracture is between two and five times more common in people with cardiovascular disease than in those with no history of the disease. The researchers from this study have found that bisphosphonates not only decrease the progression of osteoporosis, but also prevent the development of atherosclerosis and reduce total mortality rate (5).
Regarding this point it is interesting to note that bisphosphonates can reduce the elevated production of lactic acid in the body (6) what allow the acidity theory concept (7) to be a strong explanation for the link atherosclerosis/osteoporosis, taking in view the proposition from A. Wachman and D.S. Bernstein made in 1968 (8), and endorsed by others (9), that the body draws minerals from the bones to neutralize acid or alkaline challenges.
BTW, an editorial published at New England Journal of Medicine (Bone, Acid, and Osteoporosis, New England Journal of Medicine, V 330:1821-1822 , June 23, 1994) brings the following quote and comments:
"Life is a struggle, not against sin, not against the Money Power, not against malicious animal magnetism, but against hydrogen ions"1 Mencken H L. Exeunt omnes. Smart Set. 1919; 60: 138–145). These words, written by H.L. Mencken about the meaning of life and death, may also apply to the struggle of the healthy skeleton against the deleterious effects of retained acid.
Carlos Monteiro
1) Dent CE, Engelbrecht HE, Godfrey RC. Osteoporosis of lumbar vertebrae and calcification of abdominal aorta in women living in Durban. Br Med J. 1968;4:76-79.
2. Fujita T, Okamoto Y, Sakagami Y, Ota K, Ohata M. Bone changes and aortic calcification in aging inhabitants of mountain versus seacoast communities in the Kii Peninsula. J Am Geriatr Soc. 1984;32:124-128
3) J. Tamaki , M. Iki, Y. Hirano, Y. Sato, E. Kajita, S. Kagamimori, Y. Kagawa and H. Yoneshima. Low bone mass is associated with carotid atherosclerosis in postmenopausal women: The Japanese Population-based Osteoporosis (JPOS) Cohort Study , Osteoporosis International, V 20, N 1 / January, 2009
4) Hiroyuki Sumino, Shuichi Ichikawa, Shu Kasama, Takashi Takahashi, Hironosuke Sakamoto, Hisao Kumakura, Yoshiaki Takayama, Tsugiyasu Kanda, Masami Murakami and Masahiko Kurabayashi, Relationship between Carotid Atherosclerosis and Lumbar Spine Bone Mineral Density in Postmenopausal Women, Hypertension Research (2008) 31, 1191–1197;
5) Ulf Sennerby, Håkan Melhus, Rolf Gedeborg, Liisa Byberg, Hans Garmo, Anders Ahlbom, Nancy L. Pedersen, Karl Michaëlsson. Cardiovascular Diseases and Risk of Hip Fracture, JAMA. 2009;302(15):1666-1673.
6 Norman H. Bell and Ralph H. Johnson. Bisphosphonates in the treatment of osteoporosis, Endocrine, Volume 6, Number 2 / April, 1997.
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) Wachman A, Bernstein DS. Diet and osteoporosis. Lancet. 1968;1:958–9.
9) Frances A. Tylavsky, Lisa A. Spence Laura Harkness. The Importance of Calcium, Potassium, and Acid-Base Homeostasis in Bone Health and Osteoporosis Prevention. J. Nutr. 138: 164S–165S, 2008 full free paper at http://jn.nutrition.org/cgi/reprint/138/1/164S
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