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Stress: the triggering factor of Cardiovascular disease

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1 Stress: the triggering factor of Cardiovascular disease
The Acidity Theory of Atherosclerosis Fourth International Conference on Advanced Cardiac Sciences King of Organs, 2012 Kingdom of Saudi Arabia Carlos Monteiro Infarct Combat Project

2 In Recognition In July 29, 2006, during a discussion in the internal forum at internet of the International Network of Cholesterol Skeptics (THINCS) , about the role of mechanical forces in atherosclerosis, Melchior Meijer, a journalist specialized in medical area, noticed about the demonstration by scientists from California that normal stretching/relaxing of an artery does not produce atherosclerosis, while stretching/relaxing in different directions simultaneously on every heart beat does. Dr. Paul Rosch, participating in the discussion about these findings, told that in relation of the contribution of psychological stress his friend Meyer Texon, the developer of the hemodynamic theory of atherosclerosis, conceded to him in a conversation that stress might accelerate the development of atherosclerotic lesions by aggravating the basic mechanism of shear stress, that he felt was responsible. Few days after, inspired by the findings from the researchers in California and by the information brought by Dr. Paul Rosch, I came to the draft about the acidity theory of atherosclerosis.

3 In Recognition Gaskett demonstrated in 1880 that acid solutions have effects on the contractility of heart tissues and vascular smooth muscle, reasoning that this was one important mechanism for the local regulation of blood flow during increased metabolic activity. (Gaskell WH. On the tonicity of the heart and blood vessels. J Physiol 1880;3:48-75) Zsoter et al have shown in 1961 that reduction of blood pH increases blood flow. (Zsoter, Bandeman L, Chappel CL. The effect of local pH changes on blood flow in the dog. Am Heart J. 1961;61: )

4 In Recognition In 1977 James P. Henry and Patricia M. Stephens were the first to postulate that chronic stress or the constantly heightened sympathetic-adrenomedullary activity may lead to atherosclerosis and cardiovascular disease*. *J.P. Henry , P.M. Stephens. Stress, Health, and the Social Environment: A Sociobiologic Approach to Medicine. Springer; First edition, Dec

5 The Acidity Theory of Atherosclerosis
Sequence of events* I. Sympathetic dominance by continuous stress plus II. Deficiency in production of endogenous digitalis-like compounds with alterations of sodium-potassium pump activity results in III. Lowered pH (acidity) that increases perfusion pressure and provokes effects on contractility of coronary arteries, leading to changes in hemodynamic shear stress and atherosclerosis as consequence. *Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at

6 The Acidity Theory of Atherosclerosis: Introduction and Fundamentals
The heart is an organ of high metabolic activity – that cannot rest as other body muscles, being susceptible to drops in pH during ischemia and hypoxia. The chronic or acute elevated catecholamine release, mainly from sympathetic nerve terminals in cardiac tissue, may accelerate the myocardial glycolysis leading to significant increase in lactate production. The association of increased lipid levels with abnormal lactate metabolism may provide a useful screening test for the detection of coronary artery disease, according a study. Other study has demonstrated that plasma lipid abnormalities and myocardial lactate production were significantly associated with subsequent arteriographic progression. The amount of lactate released by the myocardium has been shown to be related to the severity of coronary artery disease. 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 and the resulting changes in hemodynamic shear stress. The response to injury concept is supported by the acidity theory of atherosclerosis. (G. Jackson, et al. Diagnosis of coronary artery disease by estimation of coronary sinus lactate. British Heart Journal, 1978, 40, ; Bemis CE, Gorlin R, et al. Progression of coronary artery disease: A clinical arteriographic study. Circulation, Vol XLVII, March 1973)

7 The sympathetic activation with elevation of circulating catecholamine (adrenaline, etc..), cause coronary vasoconstriction and consequent reduction in blood flow. On the other hand the increased lactate (or decreased blood pH) may evoke vascular smooth muscle relaxation and increase of blood flow. These opposite forces working in sequence - with the sympathetic overdrive leading to metabolic acidosis, in our view, may be reconciled to partially explain the occurrence of the resulting abnormal stretching/relaxing of coronary arteries, in different directions, simultaneously, producing changes in hemodynamic shear stress leading to atherosclerosis. Book “Acidity Theory of Atherosclerosis – New Evidences”, 2012

8 What causes the elevation of cholesterol levels in blood?
Studies suggest that some risk factors for coronary artery disease, like stress (anxiety, hostility, extreme physical exertion , etc..), high carbohydrate diets and smoke may raise total cholesterol and low density lipoproteins levels. Also, it is interesting to notice that in stress conditions, high carbohydrate diets and cigarette smoking there is a significant elevation in blood lactate levels. As Dr. Malcolm Kendrick 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?“ References at the book: Acidity Theory of atherosclerosis – New Evidences, 2012

9 Risk factors for atherosclerosis/ coronary artery disease In the acidity theory point of view
In the next slides we will discuss about the dysregulation of the autonomic nervous system, as the underlying mechanism in psychosocial and other risk factors for atherosclerosis/coronary artery disease that are related with sympathetic dominance, through sympathetic over-activity or parasympathetic withdrawal.

10 Psychosocial factors The 5 specific psychosocial domains that contribute significantly to the pathogenesis and expression of coronary artery disease are: Depression; Anxiety; Personality factors and character traits; Social isolation; Chronic life stress. (Alan Rozanski, James A. Blumenthal and Jay Kaplan. Impact of Psychological Factors on the Pathogenesis of Cardiovascular Disease and Implications for Therapy. Circulation. 1999;99: ; Veith RC et al. Sympathetic nervous system activity in major depression. Basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry May;51(5):411-22)

11 Age Atherosclerosis and age are intimately linked, being the best example of an age-related disease. It is generally accepted that sympathetic nervous activity increases progressively with age. Also that plasma noradrenaline levels increase may be mediated by the age related impairment of baroreflex sensitivity. (Ziegler MG, Lake CR and Kopin IJ. Plasma noradrenaline increases with age. Nature 261, (27 May 1976); Shimada and all. Age-related changes of baroreflex function, plasma norepinephrine , and blood pressure. Hypertension 7: , 1985; Narkiewicz et al. Gender-selective interaction between aging, blood pressure and sympathetic nerve activity. Hypertension 2005;45: )

12 Dyslipidemia A recent study have demonstrated that sympathetic predominance may favor the development of sustained hypertension and hypercholesterolemia early in life, and lead to increased susceptibility to vascular complications. (Palatini P, et al. Evolution of blood pressure and cholesterol in stage 1 hypertension: role of autonomic nervous system activity. Journal of Hypertension 2006, 24: )

13 Hypertension Hypertension is considered as an important risk factor for the development of atherosclerosis, with these processes sharing some common mechanisms. The endothelium is usually placed as the probable central focus for the effects in both diseases, with evidences leading to the postulation that hypertension predispose and accelerate atherosclerosis. The sympathetic activation plays an important role in the regulation of the blood pressure. (Grassi G, Seravalle G et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009;53: ; Grassi G, Bertoli S, Seravalle G. Sympathetic nervous system: role in hypertension and in chronic kidney disease. Curr Opin Nephrol Hypertens, 2010, Nov 10; Joyner MJ, Charkoudian N and Wallin BG. Sympathetic nervous system and blood pressure in humans. Individualized patterns of regulation and their implications. Hypertension 2010; 56:10-16)

14 Chronic kidney disease
Patients with chronic kidney disease are at increased risk of atherosclerotic cardiovascular disease. A marked increase in sympathetic neural discharge, as assessed via the microneurographic technique, has been shown to occur in the predialytic stage of chronic renal failure. Recent evidence, however, indicates that also in the earlier clinical phases of kidney disease, sympathetic activation is detectable. Further data show that sympathetic neural mechanisms participate in renal and/or hypertensive disease progression, favoring the development of target organ damage. (Grassi G, Bertolli S, Seravalle G. Sympathetic nervous system: role in hypertension and in chronic kidney disease. Curr Opin Nephrol Hypertens 2012 Jan;21(1):46-51.)

15 Diabetes Patients with diabetes are at increased risk for atherosclerosis. It has long been recognized that cardiac autonomic neuropathy increases morbidity and mortality in diabetes and may have greater predictive power than traditional risk factors for cardiovascular events. Significant morbidity and mortality in diabetes can now be attributable to autonomic imbalance between the sympathetic and parasympathetic nervous system regulation of cardiovascular function. (Beckman JA,Creager MA, Libby P. Diabetes and Atherosclerosis. JAMA. 2002; 287(19): ; Vinik AI, Zieglert D. Autonomic imbalance: prophet of doom or scope for hope? Diabet. Med. 28, (2011)

16 Cigarette Smoking Cigarette smoking increases efferent sympathetic nerve traffic acutely, as well norepinephrine and epinephrine release. 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. Both active smoking and exposure to environmental tobacco smoke are associated with the progression of atherosclerosis as indexed by intimal-medial thickness of the carotid artery assessed by ultrasound. Carotid intima-media thickness is a valid surrogate measure for coronary atherosclerosis. Blood lactate levels are increased after passive smoking. (Niedermaier ON, Smith ML. Influence of cigarette smoking on human autonomic function. Circulation 1993, 88: ; 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): ; Howard G et al, Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA, 1998 Jan 14;279(2): Yarlioglues M. Kaya MG et al. Dose-dependent acute effects of passive smoking on left ventricular cardiac function in health volunteers. J Investig Med 2012 , Feb; 60 (2): )

17 Air Pollution A recent study in humans have confirmed the association of the exposure to ambient air pollution and atherosclerosis, through the progression of carotid artery intima-media thickness . Also, some investigators have demonstrated that particulate air pollutants continuous exposition decreases the heart rate variability and may lead to an impaired autonomic control with potential acceleration in the progression of atherosclerosis. (Nino Kunzli et al. "Ambient Air Pollution and the Progression of Atherosclerosis in Adults." PloS ONE 5(2): e9096, February 8, 2010; Duanping Liao et al. Association of Higher Levels of Ambient Criteria Pollutants with Impaired Cardiac Autonomic Control: A Population-based Study, Am J Epidemiol 2004;159:768–777; C. Arden Pope III et al. 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; Heikki V et al. Heart Rate Variability and Progression of Coronary Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19: )

18 Noise Road traffic and aircraft noise near airports causes stress reactions similar to other stressors in the occupational and ambient environment. In these situations of sympathetic and endocrine arousal, concentrations of stress hormones in the blood are increased. Laboratory and epidemiological studies have demonstrated a link between noise and cardiovascular disease. (Babisch W. Stress hormones in the research on cardiovascular effects of noise. Noise Health 2003;5:1-11; Babisch W. Transportation noise and cardiovascular risk: updated review and synthesis of epidemiological studies indicate that the evidence has increased. Noise Health 2006;8:1–29; Eriksson C, Rosenlund M, Pershagen G, Hilding A, Ostenson C, Bluhm G. Aircraft noise and incidence of hypertension. Epidemiology 2007;18:716–721; Jarup L, Babisch W, Houthuijs D, Pershagen G, Katsouyanni K, Cadum E, Dudley M, Savigny P, Seiffert I, Swart W, et al. Hypertension and exposure to noise near airports: the HYENA Study. Environ Health Perspect 2008;116:329–333)

19 High Carbohydrate Diets
It is well established that the sympathetic nervous system activity is also influenced by food ingestion, and that diet composition plays an important role. High carbohydrate diets, particularly in the form of high-glycemic carbohydrate, have the ability to directly induce endothelial dysfunction, vascular inflammation and subsequent development of atherosclerosis. A study from 2009 defends that the widespread use of starchy food and sugars has brought about a new metabolic problem: a chronically increased sympathetic nervous system activity, where the high-glycemic index nutrition has been suggested to play a key role in the pathogenesis of hypertension and atherosclerosis. On the other side protein or fat ingestion have no significant sympathoexcitatory effect. (Koop W. The atherogenic potential of dietary carbohydrate. Preventive Medicine 42 (2006): ; 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; Welle S, et al Thermic effect of feeding in men: Increased plasma norepinephrine levels following glucose but not protein or fat consumption. Metabolism 1981; 30: ; Tentolouris 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: )

20 Obstructive sleep apnea
The prevalence of coronary artery disease is 3 to 5 times higher in patients with obstructive seep apnea (OSA) compared with control populations. Increased carotid intima-media thickness and plaque occurrence was reported in OSA patients without any other significant co-morbidity compared to matched controls. OSA patients experience intermittent hypoxaemia and CO2 retention that modify the autonomic and haemodynamic responses to sleep. Chronic intermittent hypoxia may lead to sympathetic overactivity. (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; Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 1993; 328 : 303-7; Johnson, T. S. and all. Greenberg HE, and all. Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 1999; 86: 298–305)

21 Erectile dysfunction Some recent studies have demonstrated that coronary atherosclerosis is more severe in patients with vascular erectile dysfunction (ED), with indications that ED may be an additional, early warning sign of coronary atherosclerosis. One of these has shown that men with idiopathic ED have evidence of endothelial dysfunction in forearm resistance vessels, increased pulse pressure and impaired heart rate variability. The authors say this support the concept that erectile dysfunction is a predictor of cardiovascular dysfunction and a precursor of clinical cardiovascular disease. A very recent study has demonstrated that patients with ED exhibited different heart rate variability compared with normal controls, confirming the results of other studies showing that patients with ED may have excessive sympathetic activity. (Chiurlia E et al. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol, 2005; 46: ; Stuckey BG, Walsh JP et al. Erectile dysfunction predicts generalised cardiovascular disease. Evidence from a case control study. Atherosclerosis 2007, 194(2):458-64; Lee JY et al. Heart rate variability in men with erectile dysfunction. Int Neurourol J 2011;15:87-91)

22 Metabolic Syndrome The metabolic syndrome is associated with increased risk for development of both cardiovascular disease and type-2 diabetes in humans. Central obesity and insulin resistance are thought to represent common underlying factors of the syndrome, which features a chronic low-grade inflammatory state . Several markers of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals, heart rate and others, with sympathetic activation, have all shown an increase in the different conditions clustering in metabolic syndrome like obesity, hypertension and insulin resistance state. (Paoletti R, Bolego C, Poli A, and Cignarella A. Metabolic Syndrome, Inflammation and Atherosclerosis. Vasc Health Risk Manag June; 2(2): 145–152; Mancia G, Bousquet P et al. The sympathetic nervous system and the metabolic syndrome. Journal of Hypertension 2007, 25 (5): ; Grassi G, Quarti-Trevano F et al. Cardiovascular risk and adrenergic overdrive in metabolic syndrome. Nutr Metab Cardiovasc Dis 2007, 17(6): )

23 Infection through bacteremia
Periodontal disease, one the most common chronic bacterial infection, may represent a favorable scenario to verify the connection of infection and atherosclerosis/cardiovascular disease. Several studies are suggesting an oral source for atherosclerotic plaque - associated bacteria with demonstration about the presence of viable periodontal pathogens in atherosclerotic plaques. 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. However, important information is left aside by most investigators studying the connection between oral infection and atherosclerosis/coronary myocardial disease. These investigators don’t take in consideration that the sympathetic nervous system is intensely activated during bacteremia. (Gaetti-Jardim E et al. Quantitative detection of periodontopathic bacteria in atherosclerotic plaques from coronary arteries. J Med Microbiol 58:1568–1575, 2009; Leinhardt DJ et al. Plasma NE concentrations do not accurately reflect sympathetic nervous system activity in human sepsis. Am J Physiol 1993; 265:E2848; Straub RH et al. 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 Aug 15;192(4):560-72)

24 Salt There is an intense discussion on the benefits and potential harm of reducing salt intake in the general population. In our view, both restriction and high salt intake may result in coronary artery disease*. The reason is that in both cases exists an increased sympathetic nerve activity. (*Book “Acidity theory of atherosclerosis – New Evidences”, by Carlos Monteiro. Chapter: ‘Both restriction and high salt intake may result in cardiovascular disease’, 2012,; Stolarz-Skrypek K, et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA 2011; 305: ; Guido Grassi, et al. Short- and Long-Term Neuroadrenergic Effects of Moderate Dietary Sodium restriction in Essential Hypertension. Circulation. 2002;106: ; 'Volume-expanded' hypertension: the effect of fluid overload and the role of the sympathetic nervous system in salt-dependent hypertension, Journal of Hypertension, V30; N1: January 2012)

25 Insomnia Insomnia is characterized by a constant sympathetic hyper-activation. In 1999 was hypothesized that insomnia may be related to continual stressors, reduced slow-wave sleep, and autonomic dysfunction, which increase the risk of heart problems. (de Zambotti M, Covassin N, Sarlo M, De Min Tona G, Trinder J, Stegagno L. Nighttime cardiac sympathetic hyper-activation in young primary insomniacs. Clin Auton Res Feb;23(1):49-56; Schwartz S, McDowell Anderson W, Cole SR, Cornoni-Huntley J, Hays JC, Blazer D. Insomnia and heart disease: a review of epidemiologic studies. J Psychosom Res Oct;47(4):313-33;)

26 Extreme Physical Exertion
Studies have shown that long-term marathon runners may have increased coronary calcium and calcified plaque volume. Other studies support an increased awareness of atherosclerosis prevalence and cardiovascular risk factors in marathon runners. In our view the sympathetic activation and the resulted increase in blood lactate levels may represent the biological mechanism leading to atherosclerosis in marathon runners. (Schwartz JG, Merkel-Kraus S, Duval S, et al. Does elite athleticism enhance or inhibit coronary artery plaque formation. American College of Cardiology 2010 Scientific Sessions; March 16, 2010; Atlanta, GA; Kroger K et al. Carotid and peripheral atherosclerosis in male marathon runners. Med Sci Sports Exerc Jul;43(7):1142-7; Beth A Taylor et al. Influence of chronic exercise on carotid atherosclerosis in marathon runners, BMJ Open 2014;4:e004498)

27 Preeclampsia A history of preeclampsia have a higher risk of cardiovascular disease and mortality in later life. Studies have shown that women with preeclampsia had significantly more atherosclerostic plaques than parous controls. The carotid intima-media thickness in these women with pre-eclampsia also tended to be higher than in other groups. The autonomic nervous system appears to play an important role in the etiology of preeclampsia where there is increased sympathetic and decreased parasympathetic control of heart rate. The lactate dehydrogenase levels are also significantly elevated in women with preeclampsia. (Haukkamaa L, Moilanen L, Kattainen A, Luoto R et al Pre-eclampsia is a risk factor of carotid artery atherosclerosis. Cerebrovasc Dis 27(6): ; Blaauw J, van Pampus MG, Doormal JV, et al Increased intima-media-thickness after early onset of preeclampsia. Obstet Gynecol 107(6): N. Sharashkina et al. Preeclampsia and pregnancy induced hypertension and carotid artery atherosclerosis. Pregnancy Hypertension 2012,V2; I3: ; Yang, Cheryl C. H., Te-Chang Chao et al. Preeclamptic pregnancy is associated with increased sympathetic and decreased parasympathetic control of HR. Am J Physiol Heart Circ Physiol 2000, 278: 1269–1273; He S, Bremme K, Kallner A, et al. Increased concentrations of lactate dehydrogenase in pregnancy with preeclampsia; a predictor for birth of small for gestational age infants. Gynecol Obstet Invest. 1995;39:234–8; Catanzerite VA, Steinberg SM, Mosley CA, et al. Severe preeclampsia with fulminant and extreme elevation of aspartate aminotransferase and lactate dehydrogenase levels. Am J Perinatol. 1995;12:310–3)

28 Other Risk factors for atherosclerosis/ coronary artery disease In the acidity theory point of view

29 Homocysteine Hyperhomocysteinemia has been reported to be associated with both vascular structure alteration and increased cardiovascular risk. Some studies have shown a relationship between homocysteine and psychological risk factors for cardiovascular diseases, like hostility and anger. However, a subsequent study revealed that there is no evidence for an association between homocysteine levels and cardiovascular autonomic function in either diabetic or nondiabetic subjects. So, according this later study the cardiovascular autonomic dysfunction does not help to explain why hyperhomocysteinaemia is related to cardiovascular mortality. My take on the biological mechanism is that homocysteine and its acidic derivatives might contribute to the acidic coronary blood flow that lead to increased perfusion pressure and effects on contractility of coronary arteries, resulting in changes in hemodynamic shear stress that ends in atherosclerosis/coronary myocardial disease. (Stoney CM, Engebretson TO. Plasma homocysteine concentrations are positively associated with hostility and anger. Life Sci. 2000;66(23): ; Spoelstra-De Man AM, Smulders YM et al. Homocysteine levels are not associated with cardiovascular autonomic function in elderly Caucasian subjects without or with type 2 diabetes mellitus: the Hoorn Study. J Intern Med Dec;258(6): )

30 Chemical and Organic Pollutants
The studies associating cardiovascular disease with the exposition to certain chemicals like perfluorooctanoic acid , arsenic, lead and cadmium besides some persistent organic pollutants, reminds me the experiments from the beginning of the last century showing that acid-fed rabbits and dogs develop atherosclerotic lesions. In our opinion the effects generating atherosclerotic lesions in these experiments were caused not only by chronic hyperacidity in rabbits and dogs but also related to an intense activation of the sympathetic system provoked by acid ingestion. (Shankar A, Xiao J, Ducatman A. Perfluorooctanoic Acid and Cardiovascular Disease in US Adults. Archives of Internal Medicine, 2012; Hsieh YC, Lien LM et al. Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes. Environ Res Aug;111(6):804-10; Revis NW, Zinsmeister AR, Bull R. Atherosclerosis and hypertension induction by lead and cadmium ions: an effect prevented by calcium ion. Proc Natl Acad Sci USA 1981; 78 : ; Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B, et al. Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. Arterioscler Thromb Vasc Biol 2009; 29: 1392 – 1398; P. Monica Lind, Bert van Bavel, Samira Salihovic and Lars Lind. Circulating Levels of Persistent Organic Pollutants (POPs) and Carotid Atherosclerosis in the Elderly. Environ Health Perspect 120:38–43 (2012); Loeb, O., Ueber experimentelle Arterienveraender ungen mit besonderer Beruecksichtigung der Wirkung der Milchsaeure auf Grund eigener Versuche, Deutsch. med. Wchnschr., I913, xxxix, I819; I. Adler, ‘Studies in Experimental atherosclerosis - A preliminary report”, The Journal of Experimental Medicine, 1913)

31 Chemotherapy Studies also suggest that chemotherapy may be a risk factor for the development of atherosclerosis. (Sajima T, Tanabe A et al. Impact of platinum-based chemotherapy on the progression of atherosclerosis. Climateric 2011 Feb;14 (1): 31-40; Kalabova H, Melichar B et al. Intima-media thickness, myocardial perfusion and laboratory risk factors of atherosclerosis in patients with breast cancer treated with anthracycline-based chemotherapy. Med Oncol 2011 Dec; 28 (4): )

32 Ionizing Radiation Radiation may also induce atherosclerosis. Recent epidemiological studies provided evidence that an excess risk of cardiovascular disease can be associated with moderate and low dose radiation. It is reconized for more than 50 years the effects of radiation over the nervous system. In this relationship W. O Caster from US said in a Symposium on the Effects of Ionizing Radiation on the Nervous System held by the International Atomic Energy Agency (IAEA), in 1961: “it may turn out that a central nervous system response is an important underlying factor in the causation of many of the common manifestations of radiation damage” (Andrea Borghini et al. Ionizing radiation and atherosclerosis: Current knowledge and future challenges. Atherosclerosis 2013, V 230; I 1: 40 – 47)

33 Myocardial Infarction A paradoxical risk factor?
Recent studies show that acute myocardial infarction leads to acceleration of atherosclerosis. In our view this happens because the acute sympathetic activity in AMI results in lactic acidosis and lactate accumulation leading to increased perfusion pressure and effects on contractility of coronary arteries ,with changes in hemodynamic shear stress ending in atherosclerosis as consequence. Mechanism supported by the acidity theory of atherosclerosis. (Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, et al. Myocardial infarction accelerates atherosclerosis. Nature Jul 19;487(7407):325-9; Hui Wang, Daniel T. Eitzman. Acute myocardial infarction leads to acceleration of atherosclerosis. Atherosclerosis, Volume 229, Issue 1 , Pages 18-22, July 2013)

34 Associated Diseases: Elevated Lactic Acid or Lactate
In addition of diabetes and hypertension there are various diseases associated with atherosclerosis/coronary artery disease where the common denominator is the elevation of lactic acid or lactate, for example: psoriasis, rheumatoid arthritis, osteoporosis and migraine. Certainly the raise in lactic acid/lactate levels might also be related to an altered autonomic nervous system with sympathetic predominance. (Stephen O Crawford et al, Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study. International Journal of Epidemiology 2010;1–9; F. E. Demartini, P. J. Cannon, W. B. Stason, and J. H. Laragh. Lactic Acid Metabolism in Hypertensive Patients. Science 11 June 1965, Vol no. 3676; Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database. Eur Heart J Dec 27.; Malina L, Volek V, Bielicky T. The activity of lactate dehydrogenase in the erythrocytes in psoriasis. Z Haut Geschlechtskr Oct 1;44(19):877-9; Roman M. J, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 2006; 144: ; Gobelet C and Gerster J. C. Synovial fluid lactate levels in septic and non-septic arthritides. Annals of the Rheumatic diseases, 1984, 43, ; Dekkers JC et al. Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. Clin Exp Rheumatol Jan-Feb;22(1): Larus S Gudmundsson, Ann I Scher, Thor Aspelund, et al. Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study, BMJ 2010;341:c3966; Okada H, Araga S, Takeshima T, Nakashima K. Plasma lactic acid and pyruvic acid levels in migraine and tension-type headache. Headache Jan;38(1):39-42)

35 Individuals with lower degree or absence of atherosclerosis

36 Why atherosclerosis is milder or non-existent in individuals with Down syndrome?
Different necropsy studies have shown that the occurrence of atherosclerosis is milder or non-existent in subjects with Down syndrome. A reasonable explanation for the reduced incidence of atherosclerosis is the altered autonomic regulation in individuals with DS, with effects of smaller changes in baroreflex sensitivity and in sympatho-excitation response. The reduced sympathetic response to stress in DS is supported by the low circulating catecholamines levels in response to incremental cycle ergometer exercise in individuals with DS. (Ylä-Herttuala S, Luoma J, Nikkari T, Kivimäki T. Down's syndrome and atherosclerosis. Atherosclerosis, 1989 Apr;76(2-3):269-72; Murdoch JC, Rodger JC, Rao SS, Fletcher CD, Dunnigan MG. Down's syndrome: an atheroma-free model? Br Med J Jul 23;2(6081):226-8; Iellamo F, Galante A, et al. Altered autonomic cardiac regulation in individuals with Down syndrome. Am J Physiol Heart Circ Physiol Dec;289(6):H ; Bo Fernhall and Mari Otterstetter. Attenuated responses to sympatho-excitation in individuals with Down syndrome. J Appl Physiol 94: 2158–2165, 2003); Eberhard Y, Etarradossi J and Terminarias A. Biochemical changes and catecholamine response in Down’s syndrome adolescents in relation to incremental maximal exercise. J Ment Defic Res 35: , 1991)

37 Why atherosclerosis has a lower degree in individuals suffering from alcoholism?
Necropsy studies have shown that individuals suffering from alcoholism have a significantly lower degree of atherosclerosis in the coronary arteries. A paper published in 2002 may have the answer to this question. William Lovallo, one of the authors of this paper, told in interview to EurekAlert that:“:“Before testing alcoholics for their responses to a public-speaking task, researchers first needed to establish if their sympathetic nervous system was able to respond at all. "This would tell us if their blunting was specific to psychological stressors like public speaking," said Lovallo, "or due to a generalized autonomic deficit." The patients reacted as if the social challenge of public speaking had no special meaning for them. So, the sympathetic nervous system in the patients looked normal, but their response to a psychological stressor was almost absent. When faced with a socially meaningful stressor, neither part of their fight-flight mechanism was working." (Leary T. Atherosclerosis, the important form of arteriosclerosis, a metabolic disease. Vol 104, N7. JAMA, 1935; Thomsen JL. Atherosclerosis in alcoholics. Forensic Sci Int Oct 30;75(2-3): and in Ugeskr Laeger Feb 3;159(6):757-60; Tera L. Panknin, Stacey L. Dickensheets, Sara J. Nixon, William R. Lovallo. Attenuated Heart Rate Responses to Public Speaking in Individuals With Alcohol Dependence. Alcohol Clin. Exp. Res Jun; 26 (6): 841

38 reversion or lower progression of Atherosclerosis

39 Sympatholytic agents may reduce progression of atherosclerosis
Studies have shown that rhesus monkeys submitted to sympatholytic agents like betablockers or bilateral surgical thoracic sympathectomy have had a marked reduction in the progression of atherosclerosis. The first randomized trial showing that betablockers can reduce the rate of progression of carotid IMT in clinically healthy symptom-free subjects with carotid plaque was published in A recent pooled analysis data from 4 intravascular ultrasonography trials involving 1,515 patients has confirmed that betablocker therapy is associated with reduced atheroma progression. A study by Strawn and colleagues in 1991 have indicated that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial dysfunction, effects that may be prevented by treatment with B-adrenergic blocking agent. Also interesting is the study showing a decrease in glycogenolytic rate, blood lactate concentration and lactate clearance after B-Adrenergic blockade with propranolol, probable a indirect effect of its sympatholytic properties. (Lichtor T et al The sympathetic nervous system and atherosclerosis. J Neurosurg Dec;67(6):906-14; Hedblad B et al. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation Apr 3;103(13): ; Sipahi I et al B-Blockers and progression of coronary atherosclerosis; Pooled analysis of 4 intravascular trials. Annals of Internal Medicine, 3 July, V147; Issue 1: 10-18; Strawn WB and all. Endothelial dysfunction in response to psychosocial stress in monkeys. Circulation Research 1991; 68: ; Issekutz B Jr. Effect of beta–adrenergic blockade on lactate turnover in exercising dogs. J Appl Physiol 1984; 57: 1754–59).

40 Sympatholytic agents may reduce progression of atherosclerosis
To our knowledge only one angiographic study assessed data on regression (15%), inalterability (62%) or progression (23%) of atherosclerosis in patients treated with cardiac glycosides. Indeed, cardiac glycosides at low concentration may lead to stress reduction by the improvement of baroreceptor function, sympathoinhibitory effects, vagomimetic effects and decrease in heightened secretion of catecholamines. There are studies showing the existence of potential positive effects of cardiac glycosides (digoxin, digitoxin, etc) for the treatment of atherosclerosis. (Mesquita QHde, et al. Preservação funcional do miocárdio isquêmico pelo cardiotonico a longo prazo: recateterização de 29 casos. Medicina de Hoje, março 1978). Gheorghiade M, Adams KF, Colucci WS. Digoxin in the Management of Cardiovascular Disorders 2004; 109: ; Jagielska J. et al. Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis?, Atherosclerosis 2009 Oct;206(2):390-6; Kolkhof P et al. Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes. Biochem Biophys Res Commun Mar 26;394(1): 233-9)

41 Stress reduction show reversion or lower progression of atherosclerosis
Regression of coronary atherosclerosis in women who were free of stress showed through the use of serial quantitative angiography; Decrease of carotid intima media thickness in African Americans with hypertension submitted to stress reduction through Transcendental Meditation ; Decrease in carotid intima media thickness in older persons with multiple factors for coronary heart disease submitted to the Maharishi Vedic Medicine treatment -- which also includes stress reduction through Transcendental Meditation program; Yoga intervention retards progression and increases regression of coronary atherosclerosis in patients with severe coronary artery disease . Slow breathing increases baroreflex sensitivity and reduce sympathetic nervous system with beneficial effects to coronary myocardial disease. *Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at Book “Acidity Theory of Atherosclerosis: New Evidences”, 2012

42 The baroreflex function and the autonomic nervous system
It is interesting to notice about the impairment or decrease of baroreflex sensitivity in front of some key factors for atherosclerosis, coronary myocardial disease and stroke, like in ageing, ingestion of sugars, in special high-fructose diets, and smoking. Indeed there are some studies showing that in bilateral carotid atherosclerosis and in greater intima-media thickness the baroreflex sensitivity is reduced or impaired. On the other hand the result of the baroreceptor improvement is the inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system. Drugs like Betablockers and Digitalis glycosides may enhance baroreflex sensitivity with possible positive effects on atherosclerosis. (Nasr N et al. Baroreflex sensitivity is impaired in bilateral carotid atherosclerosis. Stroke;36: ; Gianoros PJ et al. Greater intima-media thickness in the carotid bulb is associated with reduced baroreflex sensitivity. Am J Hypertens. 2002;15(6): ; Truijen J et al. Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under B-adrenergic blockade. Clin Sci (Lond), Feb 2011; 120(4): ; Schobel HP et al Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans, Circulation V84,

43 β blockers, a double edged sword?
A recent study confirm that the use of beta blockers do not appear to be of any benefit in three distinct groups of stable outpatients: those with coronary artery disease but no history of MI; those with a remote history of MI (one year or more); and those with coronary risk factors only. Also, the effect of betablockers as a treatment for primary hypertension has been questioned. In a meta-analysis study published at Lancet Journal in 2005 the authors say that the effect of betablockers compared to placebo is less than optimum, with no difference for myocardial infarction but with a raised risk of stroke. Moreover in a randomized trial study published in Lancet Journal in 2008 the authors say that there were more deaths in the metoprolol group than in the placebo group in patients undergoing non-cardiac surgery (129 versus 97 patients). So, while betablockers seems useful in atherosclerosis its poor results in these clinical situations might be related to their effects of generalized hypocontractility, as suggested by Dr. Mesquita in 1979. (Bangalore S, Steg PHG, Deedwania P, et al. Beta blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 2012; 308: ; Lindholm LH, Carlberg B, Samuelsson O. Should B blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366: ; POISE study group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE Trial): a randomized controlled trial. Lancet 2008; 371: ; Mesquita, QH, Book Myogenic Theory of Myocardial Infarction, 1979)

44 External Risk Markers for Atherosclerosis
Baldness Severe vertex pattern of androgenetic alopecia is considered to have an increased risk of subclinical atherosclerosis. There is a postulation made in 1997 by Marino Salin, from Italy, telling if there is excess adrenergic tone in the metabolic system, then there is also vasoconstriction, ischemia and hypoxia and if there is hypoxia, glycolysis leads to lactic acid that causes caustic damage to the inner sheath and this sheath seems to be raised above the hair cuticle. Earlobe Crease Diagonal earlobe crease is another external marker for coronary artery disease. Interesting is that the earlobe is one local to determine blood lactate concentration that may be in our opinion the culprit for the earlobe wrinkle. (Dogramaci AC et al. Is androgenetic alopecia a risk for atherosclerosis? J Eur Acad Dermatol Venereol Jun;23(6):673-7.; Marino Salin e Andrea Marliani,, “TricoItalia” (Firenze) marzo 1997, Bolletino della Società Italiana di Tricologia, La Teoria e la Clinica delle “Incidenze” nelle Alopecie. Cumberland GD et al. Earlobe creases and coronary atherosclerosis. The view from forensic pathology. Am J Forensic Med Pathol Mar;8(1):9-11)

45 Video and Powerpoint presentations on the Acidity Theory of Atherosclerosis
You can find recent videos and powerpoint presentations as well articles and other information about the acidity theory at:

46 Book “Acidity Theory of Atherosclerosis – New Evidences”, 2012
In this book we explore in depth the risk factors and pathophysiological explanations of atherosclerosis, under the acidity theory point of view. Our book is being offered for Kindle readers and in paperback by The printed edition is also being distributed by Barnes and Noble and other bookstores at Internet

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