Positive Health Online

Introduction

During the nineties, in a conversation with Quintiliano H de Mesquita - my father in law, a brilliant cardiologist and professor -  I asked to him to express his thoughts about cholesterol (The Lipid Hypothesis), whether it was the culprit or not for coronary artery disease. Dr Mesquita was my mentor in medical science who has developed, among other pioneer advances in medicine, the myogenic theory of myocardial infarction in 1972, about which I have had the great honour and gratification to make a recent review. It was entitled Stress as Cause of Heart Attacks - The Myogenic Theory.[1]

In reality the question I made to Dr Mesquita had origin in my knowledge that some important researchers like Drs Uffe Ravsnkov and George Mann pointed many flaws to the whole cholesterol idea.

The approximate answer from Dr Mesquita was: “Carlos, I don’t believe the cholesterol is the enemy. In my view, it represents just a healing agent to repair the injury suffered by the arterial endothelium. In reality, I think the cholesterol theory reasoning is very simplistic, limited and superficial.”  Then I went back to ask: What causes atherosclerosis in your opinion? His response to this question was: “Carlos, I do not have any alternative explanation, so I prefer to say I do not know.” This has shaped my mind that atherosclerosis could be a response to injury, and the lipid hypothesis a delusion.

We could not fail to quote the following excerpt from the chapter ‘How evolves coronary disease’ from the book How to escape coronary bypass surgery and myocardial infarction only with a remedy, originally published in the Portuguese language, written in 1991 by Dr Quintiliano H de Mesquita.

"The natural tendency of the too little known atherosclerotic process is evolutionary, gradual and inexorable, in which the arterial walls are transformed, becoming hardened without elasticity and reduced vascular caliber throughout its course. When coincides with sharp deviations from the metabolism of fat (total lipids, triglycerides, cholesterol, etc.) and carbohydrates, that require therapeutics and dietary control, sets up an apparent relation of cause and effect. However, often we observe atherosclerotic coronaries without any deviations from those elements measured in blood, which seems to complicate and undermine the traditional concepts as cause of atherosclerosis."

In July 29, 2006 I participated, as a recent member, in a discussion inside the internal forum at internet of the International Network of Cholesterol Skeptics (THINCS), regarding the role of mechanical forces in atherosclerosis. Melchior Meijer, a journalist specialized in medical areas, noticed 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.[2, 3, 4]. 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, which he felt was responsible.

A 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 presenting my proposal for its pathophysiological mechanism and sequence of events at the THINCS forum, on August 2, 2006. The acidity theory of atherosclerosis was in line with some scientific medical matters that I was researching at the time. After 16 months, a period during which we gathered several studies giving scientific support to the pathophysiological mechanism proposed in the Acidity Theory of Atherosclerosis, I wrote  the manuscript Acidic Environment Evoked by Chronic Stress: A Novel Mechanism to Explain Atherogenesis. [5]

In 2009 I launched the blog New Evidences: Acidity Theory of Atherosclerosis[6] which became the basis for my book Acidity Theory of Atherosclerosis - New Evidences, launched in early 2012.[7] A few months later I was invited by Professor Dr Paul Rosch, the president of the American Institute of Stress, as one of speakers for the IV International Conference of Advanced Cardiac Sciences - The King of Organs Conference, November 2012[8], in Saudi Arabia. Dr Paul Rosch, who also is a remarkable researcher, well-known and respected for his scientific integrity, started to fight for stress as the main risk factor for coronary heart disease more than 3 decades ago. Meanwhile he was a strong opponent to the Lipid Hypothesis. Dr Paul Rosch belonged to the scientific committee of this event. In his letter to Dr Abdullah Alabdulgader, the President of The King of Organs Conference, he said:

“Carlos Monteiro, another of our fellows who is based in Brazil just published Acidity Theory of Atherosclerosis. It is a fascinating book that extends Dr De Mesquita’s myogenic theory of myocardial infarction and its focus on the crucial role of the sympathetic nervous system and stress in the pathogenesis of atherosclerotic heart disease. I feel confident that he could give one or more presentations that would be cutting edge and informative to this audience”

During the King of Organs Conference I delivered to Dr Paul Rosch my book with the following inscription:

“To my friend Dr Paul Rosch, one of the greatest medical teachers I have known, and who gave us the initial inspiration for the development of the acidity theory of atherosclerosis. Paul, I have to thank you greatly about this and for your decisive support about our proposal to be effectively recorded and discussed within the medical community, as is happening in King of Organs Conference. Please accept our book with the compliments from your friend who much admires you.”

I have given two lectures at The King of Organs Conference. The first speech was about the Myogenic Theory of Myocardial Infarction (Powerpoint presentation and video) and the second about the Acidity Theory of Atherosclerosis (Powerpoint presentation and video).

Members from the International Network of Cholesterol Skeptics - THINCS at the
Fourth International Conference of Advanced Cardiac Sciences (The King of Organs Conference), November 2012.
L-R: David Diamond, Malcolm Kendrick, Carlos Monteiro, Paul Rosch. 
Some topics presented by our group: 1. The demise of lipid hypothesis;
2. Why stress is more important than cholesterol; 3. Stress, atherosclerosis and coronary heart disease;
4. Why statins are not solution to coronary heart disease - or anything else.

One of the subjects I have presented in “The King of Organs Conference” was “What causes the elevation of cholesterol levels in blood?” In it I have pointed to studies showing that some risk factors for coronary artery disease, like stress (anxiety, hostility, extreme physical exertion, etc..), high carbohydrate diets, smoke and exposition to some chemicals like perfluorooctanoic acid might lead to a raise in total cholesterol and low density lipoproteins  levels. It should also be noticed that in stress conditions, high carbohydrate diets and cigarette smoking there is a significant elevation in blood lactate levels.

Particularly interesting was the declaration from Dr Malcolm Kendrick in one of his speeches at “The King of Organs Conference, 2012”: 

"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?“

Our Hypothesis

The myogenic theory, developed by Dr Mesquita, became the template for the acidity theory of atherosclerosis. In his point of view the heart disease process involves two distinct pathologies, one for coronary artery disease/atherosclerosis, the  other for the myocardial disease, what led to his adoption of the terms ‘coronary-cardiomyopathy’ or ‘coronary-myocardial disease’, instead of "coronary heart disease" and the term ‘acute myocardial syndromes’ instead of  ‘acute coronary syndromes’. His reasoning was contrary to the currently accepted thinking which has its cause and effect relationship based in the thrombocentric coronary heart disease model.

Noteworthy is the citation from Dr George E Burch, a shaper of modern cardiology, which goes strikingly to the point:

“The coronary patient does not die from coronary disease
he dies from myocardial disease." (1972)[9]

Indeed our acidity theory of atherosclerosis fits perfectly with the myogenic theory of myocardial infarction concept. The myogenic theory accepts that stress or emotion affects the cardiac muscle dependent on the affected coronary artery, compromising the myocardial structure. In his book about the myogenic theory (1979) he says: Thus, the coronary disease contributes to the deterioration of the ventricular segment, constituting areas of myocardial sclerosis or segmental myocardial disease, the possible future site of the myocardial infarction”.[10]

Here are the sequence of events to explain atherogenesis, inside the acidity theory of atherosclerosis concept:

1. Sympathetic dominance by continuous stress plus;
2. Deficiency in production of endogenous digitalis-like compounds (DLCs) with alterations of Na(+), K(+)-ATPase activity results in;
3. Lowered pH (acidosis) that increases perfusion pressure and provokes effects on contractility of coronary arteries leading to changes in hemodynamic shear stress and atherosclerosis as consequence.

Some Fundamentals about the Acidity Theory of Atherosclerosis:

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 elevated catecholamine release, triggered by sympathetic dominance, 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. It was 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.[11,12,13]

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 triggered by sympathetic activation resulting in changes on hemodynamic shear stress.

Note: Findings from studies in human beings and animals have shown that epinephrine increases lactate formation by an increase in the Na+K+ ATPase activity.[14] This can be inhibited through digitalis or strophanthin/ouabain that are sodium pump inhibitors.[15]  Perturbation of the endogenous digitalis-like compounds (DLCs) system has been implied in pathological conditions including cardiac arrhythmias, hypertension, cancer and depressive disorders.[16, 17]  Stress situations may affect the release of endogenous DLCs by the adrenal gland.[18] Also, the extracellular acidification may affect the signaling and transport of endogenous DLCs.[19, 20] This raises the possibility that an insufficient production of endogenous DLCs to attend the demand in some medical conditions, like coronary-myocardial disease, hypothetically can be resolved through the use of cardiac glycosides at low concentration, as a supplement. This is confirmed by clinical studies using digitalis and strophanthin / ouabain, with largely positive effects in prevention of acute coronary syndromes.[1, 21] Low therapeutic doses of digitalis or strophanthin/ouabain have specific sympatho-inhibitory response by blocking the overproduction of catecholamine. This property is unrelated to the positive inotropic action of cardiac glycosides.[1) We hypothesize that endogenous digitalis-like compounds may have similar action on neurohormonal levels.[5]

The Link Between Sympathetic Dominance and Changes in Hemodynamic Shear Stress

The sympathetic activation with elevation of circulating catecholamine (epinephrine, etc..), causes 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 represent one of the explanations for the occurrence of the resulting abnormal stretching/relaxing of coronary arteries, in different directions, simultaneously, demonstrated by scientists from California , producing changes in hemodynamic shear stress and ultimately leading to atherosclerotic disease.[7]

The Most Important Scientific Advances by Researchers that Paved the Way for our Acidity Theory of Atherosclerosis

1. Walter Holbrook Gaskell demonstrated in 1880 that acid solutions have effects on the contractility of heart tissues and vascular smooth muscle, representing an important mechanism for the local regulation of blood flow during increased metabolic activity.[22]
2. Rudolph Virchow in 1856 described atherosclerosis as “endarteritis deformans” meaning that the atheroma was a product of vascular injury inducing inflammation within the intima of the artery wall.[23]
3. Carl F Cori in 1925 was the first to observe the influence of adrenaline on lactic acid production.[24]
4. Meyer Texon in 1957 postulated that forces such as those derived from changes in hemodynamic shear stress might cause atherosclerosis.[25]
5. Zsotér et al have demonstrated in 1961 that reduction of blood pH increases blood flow.[26] 
6. James P. Henry and Patricia M. Stephens, in 1977, postulated that chronic stress or the constantly heightened sympathetic-adrenomedullary activity might lead to atherosclerosis and cardiovascular disease*.[27]
7. Redford B. Williams, in 1978, postulated that recurrent physiologic actions involving exaggerated heart rate and pressor responses to behavioral stimuli might promote arterial injury via hemodynamic forces such as turbulence and shear stress. [28]

Risk Factors for Atherosclerosis/Coronary Artery Disease

Most risk factors for atherosclerosis have as common denominator the dysregulation of the autonomic nervous system, related with sympathetic dominance, through sympathetic over-activity or withdrawal of the parasympathetic system.

1. 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 and Chronic life stress.[29,30]
2. 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.[31,32,33]
3. Hypercholesterolemia:  Sympathetic dominance may favor hypertension and hypercholesterolemia early in life, and lead to increased susceptibility to vascular complications.[34]
4. Hypertriglyceridemia: Elevated levels of triglycerides are associated with atherosclerosis. Recent studies found that the sympathetic nervous system play an important role in control of triglyceride metabolism.[35,36]
5. 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.[37,38,39]
6. Chronic kidney disease: Patients with chronic kidney disease are at increased risk of atherosclerotic cardiovascular disease. A marked increase in sympathetic neural discharge, as accessed 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, favouring the development of target organ damage.[40]
7. 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.[41,42]
8. Cigarette smoking: Cigarette smoking increases efferent sympathetic nerve traffic acutely, as well norepinephrine and epinephrine release. The acute sympatho-excitatory 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.[43-46]
9. Air pollution: Studies in humans have confirmed the association of the exposure to ambient air pollution and atherosclerosis, through the progression of carotid artery intima-media thickness. It was 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.[47-50]
10. Noise:  Living near main roads 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 blood are increased. Laboratory and epidemiological studies have demonstrated a link between noise and cardiovascular disease. A large study recently published found that long-term exposure to fine particulate matter and night-time traffic noise are both independently associated with subclinical atherosclerosis.[51-55]
11. 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 advocates that the widespread use of starchy food and sugars has brought a new metabolic problem: a chronically increased sympathetic nervous system activity, where the high glycaemic 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 sympatho-excitatory effect.[56-59]
12. 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 hemodynamic responses to sleep. Chronic intermittent hypoxia may lead to sympathetic over-activity.[60-63]
13. Erectile dysfunction: 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 studies 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 of this study say that this supports the concept that erectile dysfunction is a predictor of cardiovascular dysfunction and a precursor of clinical cardiovascular disease. Another recent study has demonstrated that patients with ED exhibited different heart rate variability compared with normal controls, confirming the results of other findings showing that patients with ED may have excessive sympathetic activity.[64-66]
14. 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.[67-69]
15. 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.[70-72]
16. 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 exist an increased sympathetic nerve activity.[7, 73-75]
17. Insomnia: Insomnia is characterized by a constant sympathetic hyper-activation. In 1999 it was hypothesized that insomnia may be related to continual stressors, reduced slow-wave sleep, and autonomic dysfunction, which increase the risk of heart problems.[76-77]
18. Extreme physical exertion:  Studies have shown that long-term marathon runners may have increased coronary calcium and calcified plaque volume. Other findings 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.[78-80]
19. Vitamin D deficiency: Vitamin D deficiency is a risk factor for atherosclerosis. It has been shown that vitamin D deficiency alters activity of the cardiovascular system and related pressor responses and may lead to dysfunction of the cardiac autonomic nervous system.[81-82]
20. Preeclampsia:  A history of preeclampsia has a higher risk of cardiovascular disease and mortality later in life. Studies have shown that women with preeclampsia had significantly more atherosclerotic plaques than parous controls. The carotid intima-media thickness in these women with preeclampsia 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.[83-88]
21. 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. Studies also suggest that chemotherapy may be a risk factor for the development of atherosclerosis.[7, 89-97]
22. 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 recognized for more than 50 years the effects of radiation over the nervous system. This may also include radiation from wireless technology.[98-99]
23. 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.[100-101]
24. Associated Diseases with 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 and migraine. Certainly the raise in lactic acid/lactate levels might also be related to an altered autonomic nervous system with sympathetic predominance. Incidentally, blood lactate was also found recently to be associated with carotid atherosclerosis.[102-113]

Individuals with Lower Degree or Absence of Atherosclerosis

1. 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 catecholamine levels in response to incremental cycle ergometer exercise in individuals with DS.[114-118]
2. 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: “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."[119-121]

Reversion or Lower Progression of Atherosclerosis

1. Beta blockers and  sympathectomy 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 2001. A 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 an indirect effect of its sympatholytic properties.[122-125]
2. Cardiac glycosides like digoxin, digitoxin, etc… 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, sympatho-inhibitory 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.[127-130]
3. Stress reduction shows reversion or lower progression of atherosclerosis
   Regression of coronary atherosclerosis in women who were free of stress demonstrated 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; Aerobic physical exercise did not attenuate progression of atherosclerosis, except in a subgroup of men not taking statins.[131-135]
4. 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. [136-139]

External Risk Markers for Atherosclerosis

1. 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.[140-142]
2. 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 which, when elevated, may be the culprit for the earlobe wrinkle. A recent study confirmed that diagonal bilateral Earlobe crease is independently associated with cardiovascular events in the hospitalized population. An independent association with ischemic stroke has also been demonstrated for the first time.[143-144]

Final Considerations

The present article presents the main points and arguments in favor of the Acidity Theory of Atherosclerosis. However, there are additional information that you may find useful in our short (100 pages) and low cost book from 2012,[7] that includes our manuscript from 2008.[5]

It comprises, for example, the following information:

1. Findings demonstrating that approximately two-thirds of the atherosclerotic plaques show lactate dehydrogenase isoenzyme shifts significantly above the media and intima;
2. Findings about the relation of reduced pH to increased oxidation of LDL;
3. Among others the article “What causes the elevation of cholesterol levels in blood?” with 23 references;
4. and more….

References

1. Carlos Monteiro. Stress as Cause of Heart Attacks - The Myogenic Theory originally published in the Wise Traditions Journal (Fall edition, 2014) from Weston A. Price Foundation. Reproduced in Positive Health Online (Issue 222, May 2015), at www.positivehealth.com/article/heart/stress-as-cause-of-heart-attacks-the-myogenic-theory
2. Press release. 2006. Beyond Lipids: Understanding the Mechanics of Atherosclerosis (press release). UCSD News, July 12. At http://www.jacobsschool.ucsd.edu/news/news_releases/release.sfe?id=554
3. Kaunas R, Usami S, Chien S. Regulation of stretch-induced JNK activation by stress fiber orientation. Cellular Signalling, Nov;18(11):1924-31 at http://www.ncbi.nlm.nih.gov/pubmed/16581230   2006.
4. Haga JH, Li Yi-Shuan J. and Chien S. Molecular basis of the effects of mechanical stretch on vascular smooth muscle cells, Journal of Biomechanics, 40(5):947-60. 2007.
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
6. The blog “New Evidences: Acidity Theory of Atherosclerosis” is at http://aciditytheory.blogspot.com.br/
7. Book “Acidity Theory of Atherosclerosis – New Evidences”. It can be found for Kindle readers and in paperback at Amazon.com. The printed edition is also being distributed by Barnes and Noble and other bookstores. 2012
8. The King of Organs Conference 2012 was reported by the American Institute of Stress at AIS Health and Stress Newsletter (http://www.stress.org/) , December 2012
9. Burch GE and col. Ischemic cardiomyopathy, Am Heart J. March, 83(3): 340-50. 1972.
10. Quintiliano H. de Mesquita. Book “Myogenic Theory of Myocardial Infarction”, 1979. Summary in English at http://www.infarctcombat.org/LivroTM/parte8.htm
11. 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, 40, 979-983. 1978. Full free text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC483520/ 
12. 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 
13. 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 
14. Mercedes Garcia Alvarez, Paul Marik, Rinaldo Bellomo. Stress hyperlactataemia: present understanding and controversy. The Lancet Diabetes & Endocrinology, November 29, 2013.
15. Gibot S . On the origin of lactate during sepsis, Critical Care 2012, 16: 151 at http://ccforum.com/content/16/5/151
16. Nesher M, Shpolansky U, Rosen H, Lichtstein D. 2007.The digitalis-like steroid hormones: New mechanisms of action and biological significance. Life Sci. May 15;80(23):2093-107
17. Rose AM, Valdes RJ. 1994. Understanding the sodium potassium pump and its relevance to disease, Clin. Chem. 40/9: 1674-1685. Full free paper at http://www.clinchem.org/cgi/reprint/40/9/1674
18. Weidemann H et al. 2004. Diverse effects of stress and additional adrenocorticotropic hormone on digitalis-like compounds in normal and nude mice, Journal of Neuroendocrinology, Vol 16, 458-463.
19. Vasilyev A, Khater K, and Rakowski RF. 2004. Effect of Extracellular pH on Presteady-State and Steady- State Current Mediated by the Na+/K+ Pump,. J Membr Biol. March 15; 198(2):65–76. Full free paper at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1357233
20. Li C, Geering K, Horisberger JD. 2006. The Third Sodium Binding Site of Na,K-ATPase Is Functionally Linked to Acidic pH-Activated Inward Current. Membr Biol. 213(1):1-9
21. Kern B.  Der Myokard-Infarkt. Haug-Verlag, Heidelberg. 1970.
22. Gaskell WH. On the tonicity of the heart and blood vessels. J Physiol 1880;3:48-75
23. Rudolph Virchow. Book “Celular Pathology”: as based upon Physiological and Pathological Histology: Twenty lectures delivered in the Pathology Institute of Berlin, 1858.
24. Cori CF and Cori GT. The mechanism of epinephrine action IV: The influence of epinephrine on lactic acid production and blood sugar utilization. J Biol Chem 84: 683 – 698. 1929. Full text at http://www.jbc.org/content/84/2/683.full.pdf+html
25. Texon M.  A hemodynamic concept of atherosclerosis, with particular reference to coronary occlusion. Arch Intern Med 99:418–427. 1957.
26. Zsotér T, Bandeman L, Chappel CL. The effect of local pH changes on blood flow in the dog. Am Heart J.  61: 777-782. 1961.
27. Henry J.P., Stephens P.M.. Stress, Health, and the Social Environment: A Sociobiologic Approach to Medicine. Springer; First edition, Dec 21 1977.
28. Williams RB: Psychophysiological process, the coronary prone behavior pattern, and coronary heart disease. In Dembroski TM, Weiss SM, Shields JL, Haynes SG, Feinleib M (eds), Coronary Prone Behavior. New York, Springer, pp 141-146. 1978.
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