The The AcidityAcidity TheoryTheory ofof AtherosclerosisAtherosclerosis

Fourth International Conference on Advanced Cardiac Sciences

King King ofof OrgansOrgans, 2012, 2012 KingdomKingdom ofof SaudiSaudi ArabiaArabia

Carlos MonteiroCarlos Monteiro

InfarctInfarct CombatCombat ProjectProject http://infarctcombat.orghttp://infarctcombat.org

In July 29, 2006, during a discussion in the internal forum at internet of In July 29, 2006, during a discussion in the internal forum at internet of the International Network of Cholesterol Skeptics (THINCS) , about the the International Network of Cholesterol Skeptics (THINCS) , about the role of mechanical forces in atherosclerosis, Melchior Meijer, a journalist role of mechanical forces in atherosclerosis, Melchior Meijer, a journalist specialized in medical area, noticed about the demonstration by scientists specialized in medical area, noticed about the demonstration by scientists from California that normal stretching/relaxing of an artery does not from California that normal stretching/relaxing of an artery does not produce atherosclerosis, while stretching/relaxing in different directions produce atherosclerosis, while stretching/relaxing in different directions simultaneously on every heart beat does.simultaneously on every heart beat does.

Dr. Paul Dr. Paul RoschRosch, participating in the discussion about these findings, told , participating in the discussion about these findings, told that in relation of the contribution of psychological stress his friend that in relation of the contribution of psychological stress his friend Meyer Meyer TexonTexon, the , the developer of the hemodynamic theory of developer of the hemodynamic theory of atherosclerosis, atherosclerosis, conceded conceded to him in to him in a a conversation that stress might conversation that stress might accelerate the development of atherosclerotic lesions by aggravating the accelerate the development of atherosclerotic lesions by aggravating the basic mechanism basic mechanism of shear stress, that of shear stress, that he felt was responsible. he felt was responsible.

Few Few days after, inspired by days after, inspired by the findings from the researchers in California the findings from the researchers in California and by the and by the information brought by information brought by Dr. Paul Dr. Paul RoschRosch, , I I came to came to the draft the draft about the acidity theory of atherosclerosisabout the acidity theory of atherosclerosis..

GaskettGaskett demonstrated in 1880 that acid solutions have demonstrated in 1880 that acid solutions have effects on effects on the the contractility of heart tissues and vascular smooth muscle, contractility of heart tissues and vascular smooth muscle, reasoning that reasoning that this was one important mechanism for the local this was one important mechanism for the local regulation of regulation of blood flow blood flow during increased metabolic during increased metabolic activity.activity.

(Gaskell (Gaskell WH. On the tonicity of the heart and blood vessels. J WH. On the tonicity of the heart and blood vessels. J PhysiolPhysiol 1880;3:481880;3:48--75)75)

ZsoterZsoter et al have shown in 1961 that reduction of blood pH increases blood et al have shown in 1961 that reduction of blood pH increases blood flow. flow.

((ZsoterZsoter, , BandemanBandeman L, L, ChappelChappel CL. The effect of local pH changes on blood flow in CL. The effect of local pH changes on blood flow in

the dog. Am Heart J. 1961;61: 777the dog. Am Heart J. 1961;61: 777--782)782)

In 1977 James In 1977 James P. Henry and Patricia M. Stephens were the first to P. Henry and Patricia M. Stephens were the first to

postulate postulate that chronic stress or the constantly heightened sympatheticthat chronic stress or the constantly heightened sympathetic--adrenomedullaryadrenomedullary activity may lead to activity may lead to atherosclerosis atherosclerosis and and cardiovascular cardiovascular disease*.disease*.

*J.P*J.P. Henry , P.M. Stephens. Stress, Health, and the Social Environment: A . Henry , P.M. Stephens. Stress, Health, and the Social Environment: A

SociobiologicSociobiologic Approach to Medicine. Springer; First edition, Dec 21 Approach to Medicine. Springer; First edition, Dec 21 19771977

Sequence Sequence of of events* events*

I. Sympathetic dominance by continuous stress plusI. Sympathetic dominance by continuous stress plus

II. Deficiency in production of endogenous digitalisII. Deficiency in production of endogenous digitalis--like like compounds compounds with with alterations of alterations of sodiumsodium--potassium pump potassium pump activity results inactivity results in

III. Lowered pH (acidity) that increases perfusion pressure and provokes III. Lowered pH (acidity) that increases perfusion pressure and provokes effects on contractility of coronary arteries, leading to changes in effects on contractility of coronary arteries, leading to changes in hemodynamic shear stress and atherosclerosis as hemodynamic shear stress and atherosclerosis as consequence.consequence.

*Carlos *Carlos ETB ETB MonteiroMonteiro, Acidic environment evoked by chronic stress: A novel , Acidic environment evoked by chronic stress: A novel

mechanism to explain mechanism to explain atherogenesisatherogenesis. Available from Infarct Combat Project, . Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdfJanuary 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf

The The heart is an organ of high metabolic activity heart is an organ of high metabolic activity that cannot rest as other that cannot rest as other body muscles, being susceptible to drops in pH during ischemia and body muscles, being susceptible to drops in pH during ischemia and hypoxia. hypoxia. The chronic or acute elevated catecholamine release, mainly The chronic or acute elevated catecholamine release, mainly from sympathetic nerve terminals in cardiac from sympathetic nerve terminals in cardiac tissue, may tissue, may accelerate the accelerate the myocardial myocardial glycolysisglycolysis leading to significant increase in lactate productionleading to significant increase in lactate production..

The The association of increased lipid levels with abnormal lactate association of increased lipid levels with abnormal lactate metabolism may provide a useful screening test for the detection of metabolism may provide a useful screening test for the detection of coronary artery coronary artery disease, according a study. Other study has demonstrated disease, according a study. Other study has demonstrated that that plasma lipid abnormalities and myocardial lactate production plasma lipid abnormalities and myocardial lactate production were were significantly associated with subsequent significantly associated with subsequent arteriographicarteriographic progression. The progression. The amount of lactate released by the myocardium has been shown to be amount of lactate released by the myocardium has been shown to be related to the severity of coronary artery disease.related to the severity of coronary artery disease.

In In our opinion the raise in plasma lipids presented in these studies might 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 be a response to injury of the arterial endothelium due to an increased release of release of lactate and the resulting changes in hemodynamic shear stress. lactate and the resulting changes in hemodynamic shear stress. The response to injury concept is supported by the acidity theory of The response to injury concept is supported by the acidity theory of atherosclerosis.atherosclerosis.

(G(G. Jackson, . Jackson, et al. et al. Diagnosis of coronary artery disease by estimation of coronary Diagnosis of coronary artery disease by estimation of coronary sinus lactate. British Heart Journal, 1978, 40, 979sinus lactate. British Heart Journal, 1978, 40, 979--983 983 ; Bemis ; Bemis CE, CE, GorlinGorlin R, et al. R, et al. Progression of coronary artery disease: A clinical Progression of coronary artery disease: A clinical arteriographicarteriographic study. Circulation, study. Circulation, VolVol XLVII, March XLVII, March 1973)1973)

TThe sympathetic activation with elevation of circulating catecholamine he sympathetic activation with elevation of circulating catecholamine ((adrenalineadrenaline, etc..), cause , etc..), cause coronarycoronary vasoconstrictionvasoconstriction andand consequentconsequent reductionreduction in in bloodblood flowflow..

On the other hand the increased lactate (or decreased blood pH) may evoke On the other hand the increased lactate (or decreased blood pH) may evoke vascular smooth muscle relaxation and increase of blood vascular smooth muscle relaxation and increase of blood flowflow..

These opposite forces working in sequence These opposite forces working in sequence -- with the sympathetic overdrive with the sympathetic overdrive leading to metabolic acidosis, in our view, may be reconciled to partially leading to metabolic acidosis, in our view, may be reconciled to partially explain the occurrence of the resulting abnormal stretching/relaxing of explain the occurrence of the resulting abnormal stretching/relaxing of coronary arteries, in different directions, simultaneously, producing changes coronary arteries, in different directions, simultaneously, producing changes in hemodynamic shear stress leading to atherosclerosis.in hemodynamic shear stress leading to atherosclerosis.

Book Acidity Theory of Atherosclerosis Book Acidity Theory of Atherosclerosis New Evidences, 2012New Evidences, 2012

Studies suggest that some risk factors for coronary artery disease, like Studies suggest that some risk factors for coronary artery disease, like stress (anxiety, hostility, stress (anxiety, hostility, extreme physical exertion extreme physical exertion , etc..), high , etc..), high carbohydrate diets and carbohydrate diets and smoke may raise smoke may raise total cholesterol and low density total cholesterol and low density lipoproteins lipoproteins levels.levels.

Also, it is interesting to notice that in stress conditions, high carbohydrate Also, it is interesting to notice that in stress conditions, high carbohydrate diets and cigarette smoking there is a significant elevation in blood diets and cigarette smoking there is a significant elevation in blood lactate levels.lactate levels.

As Dr. Malcolm Kendrick use to say: As Dr. Malcolm Kendrick use to say:

"Do cigarettes contain fat? No, not at all. So, how can smoking a cigarette, "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 containing no fat or cholesterol, end up depositing fat and cholesterol in the artery walls. What is the mechanism for that?artery walls. What is the mechanism for that?

References at the book: Acidity Theory of atherosclerosis References at the book: Acidity Theory of atherosclerosis New Evidences, 2012New Evidences, 2012

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

The The 5 specific psychosocial domains 5 specific psychosocial domains that contribute that contribute significantly to the significantly to the pathogenesis and expression of coronary artery pathogenesis and expression of coronary artery disease are:disease are:

Depression; Depression;

Anxiety; Anxiety;

Personality Personality factors and character factors and character traits; traits;

Social isolationSocial isolation;;

Chronic Chronic life stress.life stress.

(Alan (Alan RozanskiRozanski, James A. Blumenthal and Jay Kaplan. Impact of Psychological , James A. Blumenthal and Jay Kaplan. Impact of Psychological

Factors on the Pathogenesis of Cardiovascular Disease and Implications for Factors on the Pathogenesis of Cardiovascular Disease and Implications for Therapy. Circulation. 1999;99:2192Therapy. Circulation. 1999;99:2192--2217; 2217; VeithVeith RC et al. Sympathetic RC et al. Sympathetic nervous nervous system activity in major depression. Basal and system activity in major depression. Basal and desipraminedesipramine--induced alterations in induced alterations in plasma norepinephrine kinetics. plasma norepinephrine kinetics. Arch Arch Gen Psychiatry. 1994 May;51(5):Gen Psychiatry. 1994 May;51(5):411411--22)22)

Atherosclerosis Atherosclerosis and age are intimately linked, being the best example of an and age are intimately linked, being the best example of an ageage--related disease. related disease. It It isis generally generally accepted accepted that sympathetic nervous activity that sympathetic nervous activity increases progressively with age. Also that plasma noradrenaline levels increases progressively with age. Also that plasma noradrenaline levels increase may be mediated by the age related impairment of increase may be mediated by the age related impairment of baroreflexbaroreflex sensitivitysensitivity..

(Ziegler MG, Lake CR and (Ziegler MG, Lake CR and KopinKopin IJ. Plasma noradrenaline increases with age. Nature IJ. Plasma noradrenaline increases with age. Nature 261, 33 261, 33 --335 (27 May 1976); Shimada and all. Age335 (27 May 1976); Shimada and all. Age--related changes of related changes of baroreflexbaroreflex function, function, plasma norepinephrine , and blood pressure. Hypertension 7:113plasma norepinephrine , and blood pressure. Hypertension 7:113--117, 1985; 117, 1985; NarkiewiczNarkiewicz et al. Genderet al. Gender--selective interaction between aging, blood pressure and sympathetic selective interaction between aging, blood pressure and sympathetic nerve activity. Hypertension 2005;45:522nerve activity. Hypertension 2005;45:522--525)525)

A A recent study have demonstrated that sympathetic predominance may recent study have demonstrated that sympathetic predominance may favor the development of sustained hypertension and favor the development of sustained hypertension and hypercholesterolemia early in life, and lead to increased susceptibility to hypercholesterolemia early in life, and lead to increased susceptibility to vascular complications. vascular complications.

((PalatiniPalatini PP, et al. , et al. EvolutionEvolution ofof bloodblood pressurepressure andand cholesterolcholesterol in in stagestage 1 1 hypertensionhypertension: role : role ofof autonomicautonomic nervousnervous system system activityactivity. . JournalJournal ofof HypertensionHypertension 2006, 2006, 24:137524:1375--1381)1381)

Hypertension Hypertension is considered as an important risk factor for the is considered as an important risk factor for the development of atherosclerosis, with these processes sharing some development of atherosclerosis, with these processes sharing some common mechanisms. The endothelium is usually placed as the probable common mechanisms. The endothelium is usually placed as the probable central focus for the effects in both diseases, with evidences leading to the central focus for the effects in both diseases, with evidences leading to the postulation that hypertension predispose and accelerate atherosclerosis.postulation that hypertension predispose and accelerate atherosclerosis.

The sympathetic activation plays an important role in the regulation of The sympathetic activation plays an important role in the regulation of the blood the blood pressure. pressure.

((GrassiGrassi G, G, SeravalleSeravalle G et al. Sympathetic and G et al. Sympathetic and baroreflexbaroreflex cardiovascular control in cardiovascular control in hypertensionhypertension--related left ventricular dysfunction. Hypertension related left ventricular dysfunction. Hypertension 2009;53:2052009;53:205--209 ; 209 ; GrassiGrassi G, G, BertoliBertoli S, S, SeravalleSeravalle G. Sympathetic nervous system: role in hypertension G. Sympathetic nervous system: role in hypertension and in chronic kidney disease. and in chronic kidney disease. CurrCurr OpinOpin NephrolNephrol HypertensHypertens, 2010, Nov , 2010, Nov 10; Joyner 10; Joyner MJ, MJ, CharkoudianCharkoudian N and N and WallinWallin BG. Sympathetic nervous system and blood BG. Sympathetic nervous system and blood pressure in humans. Individualized patterns of regulation and their implications. pressure in humans. Individualized patterns of regulation and their implications. Hypertension 2010; Hypertension 2010; 56:1056:10--16)16)

Patients Patients with chronic kidney disease are at increased risk of with chronic kidney disease are at increased risk of atherosclerotic cardiovascular disease. atherosclerotic cardiovascular disease.

A marked increase in sympathetic neural discharge, as assessed via the A marked increase in sympathetic neural discharge, as assessed via the microneurographicmicroneurographic technique, has been shown to occur in the technique, has been shown to occur in the predialyticpredialytic stage of chronic renal failure. Recent evidence, however, indicates that stage of chronic renal failure. Recent evidence, however, indicates that also in the earlier clinical phases of kidney disease, sympathetic activation also in the earlier clinical phases of kidney disease, sympathetic activation is detectable. Further data show that sympathetic neural mechanisms is detectable. Further data show that sympathetic neural mechanisms participate in renal and/or hypertensive disease progression, participate in renal and/or hypertensive disease progression, favoring favoring the the development of target organ damage.development of target organ damage.

((GrassiGrassi G, G, BertolliBertolli S, S, SeravalleSeravalle G. Sympathetic nervous system: role in hypertension G. Sympathetic nervous system: role in hypertension

and in chronic kidney disease. and in chronic kidney disease. CurrCurr OpinOpin NephrolNephrol HypertensHypertens 2012 Jan;21(1):462012 Jan;21(1):46--5151.).)

Patients Patients with diabetes are at increased risk for with diabetes are at increased risk for atherosclerosis. atherosclerosis. It has long It has long been recognized that cardiac autonomic neuropathy increases morbidity been recognized that cardiac autonomic neuropathy increases morbidity and mortality in diabetes and may have greater predictive power than and mortality in diabetes and may have greater predictive power than traditional risk factors for cardiovascular events. Significant morbidity traditional risk factors for cardiovascular events. Significant morbidity and mortality and mortality in diabetes can in diabetes can now be attributable to autonomic imbalance now be attributable to autonomic imbalance between the sympathetic and parasympathetic nervous system regulation between the sympathetic and parasympathetic nervous system regulation of of cardiovascular function.cardiovascular function.

(Beckman (Beckman JA,CreagerJA,Creager MA, Libby P. Diabetes and Atherosclerosis. JAMA. 2002; MA, Libby P. Diabetes and Atherosclerosis. JAMA. 2002; 287(19):287(19):25702570--2581; 2581; VinikVinik AI, AI, ZieglertZieglert D. Autonomic imbalance: prophet of doom or D. Autonomic imbalance: prophet of doom or scope for hope? scope for hope? DiabetDiabet. Med. 28, 643. Med. 28, 643--651 (2011) 651 (2011)

Cigarette Cigarette smoking increases efferent sympathetic nerve traffic acutely, as smoking increases efferent sympathetic nerve traffic acutely, as

well norepinephrine and epinephrine releasewell norepinephrine and epinephrine release. . The acute The acute sympathoexcitatorysympathoexcitatory effects of smoking on the cardiovascular system are effects of smoking on the cardiovascular system are partially mediated by catecholamine release, muscle sympathetic nerve partially mediated by catecholamine release, muscle sympathetic nerve excitation and peripheral chemoreceptor sensitivity increase, consecutive excitation and peripheral chemoreceptor sensitivity increase, consecutive to nicotinic receptor stimulation in the autonomic nervous to nicotinic receptor stimulation in the autonomic nervous system. Both system. Both active smoking and exposure to active smoking and exposure to environmental environmental tobacco smoke are tobacco smoke are associated with the progression of atherosclerosis as indexed by intimalassociated with the progression of atherosclerosis as indexed by intimal--medial thickness of the carotid artery assessed by medial thickness of the carotid artery assessed by ultrasoundultrasound. Carotid . Carotid intimaintima--media media thickness is thickness is a valid surrogate measure for coronary a valid surrogate measure for coronary atherosclerosis.atherosclerosis.

Blood lactate levels are increased after passive smoking.Blood lactate levels are increased after passive smoking.

((NiedermaierNiedermaier ON, Smith ML. ON, Smith ML. Influence of cigarette smoking on human autonomic Influence of cigarette smoking on human autonomic function. Circulation 1993, 88:562function. Circulation 1993, 88:562--571 571 ; ; AdamopoulusAdamopoulus D, van de Borne P and D, van de Borne P and ArgachaArgacha JF, New insights into the sympathetic, endothelial and coronary effects of JF, New insights into the sympathetic, endothelial and coronary effects of nicotine. nicotine. ClinClin ExpExp PharmacolPharmacol PhysiolPhysiol 2008; 35(4): 2008; 35(4): 458458--63; Howard 63; Howard G et al, Cigarette G et al, Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA, 1998 Jan 14;279(2):119Communities (ARIC) Study. JAMA, 1998 Jan 14;279(2):119--24. 24. YarliogluesYarlioglues M. M. KayaKaya MG et al. DoseMG et al. Dose--dependent acute effects of passive smoking on left ventricular dependent acute effects of passive smoking on left ventricular cardiac function in health volunteers. J cardiac function in health volunteers. J InvestigInvestig Med 2012 , Feb; 60 (2): 517Med 2012 , Feb; 60 (2): 517--22)22)

A A recentrecent studystudy in in humanshumans havehave confirmedconfirmed thethe associationassociation ofof thethe exposureexposure to to ambientambient airair pollutionpollution andand atherosclerosisatherosclerosis, , throughthrough thethe progressionprogression ofof carotidcarotid arteryartery intimaintima--media media thicknessthickness . . AlsoAlso, some , some investigatorsinvestigators havehave demonstrateddemonstrated thatthat particulateparticulate airair pollutantspollutants continuouscontinuous expositionexposition decreasesdecreases thethe heartheart rate rate variabilityvariability andand may lead to may lead to anan impairedimpaired autonomicautonomic controlcontrol withwith potentialpotential accelerationacceleration in in thethe progressionprogression ofof atherosclerosisatherosclerosis..

(Nino (Nino KunzliKunzli et al. et al. ""AmbientAmbient Air Air PollutionPollution andand thethe ProgressionProgression ofof AtherosclerosisAtherosclerosis in in AdultsAdults." ." PloSPloS ONE 5(2): ONE 5(2): e9096, e9096, FebruaryFebruary 8, 8, 2010; 2010; DuanpingDuanping LiaoLiao et al. et al. AssociationAssociation ofof HigherHigher Levels Levels ofof AmbientAmbient CriteriaCriteria PollutantsPollutants withwith ImpairedImpaired CardiacCardiac AutonomicAutonomic ControlControl: A : A PopulationPopulation--basedbased StudyStudy, , AmAm J J EpidemiolEpidemiol 2004;159:7682004;159:768777; 777; C. C. ArdenArden Pope Pope III et al. III et al. AmbientAmbient ParticulateParticulate Air Air PollutionPollution, Heart Rate , Heart Rate VariabilityVariability, , andand BloodBlood MarkersMarkers ofof InflammationInflammation in a in a PanelPanel ofof ElderlyElderly SubjectsSubjects. Environmental . Environmental Health Perspectives, V 112; N 3: Health Perspectives, V 112; N 3: MarchMarch 2004; 2004; HeikkiHeikki V et al. V et al. Heart Rate Heart Rate VariabilityVariability andand ProgressionProgression ofof CoronaryCoronary AtherosclerosisAtherosclerosis. . ArteriosclerosisArteriosclerosis, , ThrombosisThrombosis, , andand Vascular Vascular BiologyBiology. . 1999;19:19791999;19:1979--1985)1985)

Road traffic and aircraft noise near airports causes stress reactions similar Road traffic and aircraft noise near airports causes stress reactions similar to other stressors in the occupational and ambient environment. In these to other stressors in the occupational and ambient environment. In these situations of sympathetic and endocrine arousal, concentrations of stress situations of sympathetic and endocrine arousal, concentrations of stress hormones in the blood are increased. Laboratory and epidemiological hormones in the blood are increased. Laboratory and epidemiological studies have demonstrated a link between noise and cardiovascular studies have demonstrated a link between noise and cardiovascular disease.disease.

((BabischBabisch W. Stress hormones in the research on cardiovascular effects of noise. W. Stress hormones in the research on cardiovascular effects of noise.

Noise Health 2003;5:1Noise Health 2003;5:1--11; 11; BabischBabisch W. Transportation noise and cardiovascular W. Transportation noise and cardiovascular risk: updated review and synthesis of epidemiological studies indicate that the risk: updated review and synthesis of epidemiological studies indicate that the evidence has increased. Noise Health 2006;8:1evidence has increased. Noise Health 2006;8:129; Eriksson C, 29; Eriksson C, RosenlundRosenlund M, M, PershagenPershagen G, G, HildingHilding A, A, OstensonOstenson C, C, BluhmBluhm G. Aircraft noise and incidence of G. Aircraft noise and incidence of hypertension. Epidemiology 2007;18:716hypertension. Epidemiology 2007;18:716721; 721; JarupJarup L, L, BabischBabisch W, W, HouthuijsHouthuijs D, D, PershagenPershagen G, G, KatsouyanniKatsouyanni K, K, CadumCadum E, Dudley M, E, Dudley M, SavignySavigny P, P, SeiffertSeiffert I, Swart W, I, Swart W, et al.et al. Hypertension and exposure to noise near airports: the HYENA Study. Hypertension and exposure to noise near airports: the HYENA Study. Environ Health Environ Health PerspectPerspect 2008;116:3292008;116:329333)333)

It It is well established that the is well established that the sympathetic nervous system sympathetic nervous system activity is also activity is also influenced by food ingestion, and that diet composition plays an influenced by food ingestion, and that diet composition plays an important role. important role. High High carbohydrate diets, particularly in the form of highcarbohydrate diets, particularly in the form of high--glycemic glycemic carbohydratecarbohydrate, have the ability to directly induce endothelial , have the ability to directly induce endothelial dysfunction, vascular inflammation and subsequent development of dysfunction, vascular inflammation and subsequent development of atherosclerosis. atherosclerosis. A study from 2009 defends A study from 2009 defends that the that the widespread use of widespread use of starchy food and sugars has brought about a new metabolic problem: a starchy food and sugars has brought about a new metabolic problem: a chronically chronically increased increased sympathetic nervous system activity, sympathetic nervous system activity, where the where the highhigh--glycemic index nutrition has been suggested to play a key role in the glycemic index nutrition has been suggested to play a key role in the pathogenesis of hypertension and pathogenesis of hypertension and atherosclerosis. On atherosclerosis. On the other side the other side protein or fat ingestion have no significant protein or fat ingestion have no significant sympathoexcitatorysympathoexcitatory effect. effect.

(Koop (Koop W. The W. The atherogenicatherogenic potential of dietary carbohydrate. Preventive Medicine 42 potential of dietary carbohydrate. Preventive Medicine 42 (2006): (2006): 336336--342; Koop 342; Koop W. Chronically increased activity of the sympathetic nervous W. Chronically increased activity of the sympathetic nervous system: our dietsystem: our diet--related evolutionary inheritance. The Journal of Nutrition, Health & related evolutionary inheritance. The Journal of Nutrition, Health & Aging Volume 13, Number 1, Aging Volume 13, Number 1, 2009; 2009; WelleWelle SS, et al , et al Thermic effect of feeding in men: Thermic effect of feeding in men: Increased plasma norepinephrine levels following glucose but not protein or fat Increased plasma norepinephrine levels following glucose but not protein or fat consumption. Metabolism 1981; 30: consumption. Metabolism 1981; 30: 953953--958; 958; TentolourisTentolouris et al. Differential effect of et al. Differential effect of highhigh--fat and high carbohydrate fat and high carbohydrate isoenergeticisoenergetic meals on cardiac autonomic nervous meals on cardiac autonomic nervous system activity system activity in lean in lean and obese women. Metabolism 2003; 52: and obese women. Metabolism 2003; 52: 14261426--32)32)

The The prevalence of coronary artery prevalence of coronary artery disease disease is 3 to 5 times higher in patients is 3 to 5 times higher in patients with with obstructive seep apnea (OSA) obstructive seep apnea (OSA) compared with control compared with control populations. populations. Increased carotid intimaIncreased carotid intima--media media thickness thickness and plaque occurrence was and plaque occurrence was reported in OSA patients without any other significant coreported in OSA patients without any other significant co--morbidity morbidity compared to matched compared to matched controls. controls. OSA patients experience intermittent OSA patients experience intermittent hypoxaemiahypoxaemia and CO2 retention that modify the autonomic and and CO2 retention that modify the autonomic and haemodynamichaemodynamic responses to responses to sleep. sleep. Chronic intermittent hypoxia may Chronic intermittent hypoxia may lead to sympathetic lead to sympathetic overactivityoveractivity..

(Marin (Marin JM, JM, CarrizoCarrizo SJ, Vicente E, SJ, Vicente E, AgustiAgusti AG. AG. LongLong--termterm cardiovascular cardiovascular outcomesoutcomes in in menmen withwith obstructiveobstructive sleepsleep apnoeaapnoeahypopnoeahypopnoea withwith oror withoutwithout treatmenttreatment withwith continuouscontinuous positive positive airwayairway pressurepressure: : anan observationalobservational studystudy. Lancet 2005; 365: . Lancet 2005; 365: 104610461053; 1053; SomersSomers VK, VK, DykenDyken ME, Mark AL, ME, Mark AL, AbboudAbboud FM. FM. SympatheticSympathetic nervenerve activityactivity duringduring sleepsleep in normal in normal subjectssubjects. N . N EnglEngl J J MedMed 1993; 328 : 1993; 328 : 303303--7; 7; Johnson, T. Johnson, T. SS. . andand allall. . Greenberg HE, Greenberg HE, andand allall. . ChronicChronic intermittentintermittent hypoxiahypoxia increasesincreases sympatheticsympathetic responsivenessresponsiveness toto hypoxiahypoxia andand hypercapniahypercapnia. J . J ApplAppl PhysiolPhysiol 1999; 86: 1999; 86: 298298305)305)

Some Some recent studies have demonstrated that coronary atherosclerosis is recent studies have demonstrated that coronary atherosclerosis is more severe in patients with vascular more severe in patients with vascular erectile dysfunction (ED), erectile dysfunction (ED), with with indications indications that ED may be an additional, early warning sign of coronary that ED may be an additional, early warning sign of coronary atherosclerosis. One of these atherosclerosis. One of these has shown that men with idiopathic ED have has shown that men with idiopathic ED have evidence of endothelial dysfunction in forearm resistance vessels, evidence of endothelial dysfunction in forearm resistance vessels, increased pulse pressure and impaired heart rate variability. Tincreased pulse pressure and impaired heart rate variability. The he authors authors say this say this support the concept that erectile dysfunction is a predictor of support the concept that erectile dysfunction is a predictor of cardiovascular dysfunction and a precursor of clinical cardiovascular cardiovascular dysfunction and a precursor of clinical cardiovascular disease. disease. A very recent study has demonstrated that patients with ED A very recent study has demonstrated that patients with ED exhibited different heart rate variability compared with normal controls, exhibited different heart rate variability compared with normal controls, confirming the results of other studies showing that patients with ED confirming the results of other studies showing that patients with ED may have excessive sympathetic may have excessive sympathetic activity.activity.

((ChiurliaChiurlia E et al. Subclinical coronary artery atherosclerosis in patients with erectile E et al. Subclinical coronary artery atherosclerosis in patients with erectile

dysfunction. J Am dysfunction. J Am CollColl CardiolCardiol, 2005; , 2005; 46:150346:1503--63; Stuckey 63; Stuckey BG, Walsh JP BG, Walsh JP et al. et al. Erectile dysfunction predicts Erectile dysfunction predicts generalisedgeneralised cardiovascular disease. Evidence from a cardiovascular disease. Evidence from a case control study. Atherosclerosis 2007, 194(2):case control study. Atherosclerosis 2007, 194(2):458458--64; Lee 64; Lee JY JY et et al. Heart rate al. Heart rate variability in men with erectile dysfunction. variability in men with erectile dysfunction. IntInt NeurourolNeurourol J J 2011;15:872011;15:87--91)91)

The The metabolic syndrome is associated with increased risk for metabolic syndrome is associated with increased risk for development of both cardiovascular disease and typedevelopment of both cardiovascular disease and type--2 diabetes in 2 diabetes in humans. Central obesity and insulin resistance are thought to represent humans. Central obesity and insulin resistance are thought to represent common underlying factors of the syndrome, which features a chronic common underlying factors of the syndrome, which features a chronic lowlow--grade inflammatory state grade inflammatory state . . Several markers of adrenergic drive, such Several markers of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals, heart rate and others, with sympathetic activation, have nerve terminals, heart rate and others, with sympathetic activation, have all shown an increase in the different conditions clustering in metabolic all shown an increase in the different conditions clustering in metabolic syndrome like obesity, hypertension and insulin resistance syndrome like obesity, hypertension and insulin resistance state.state.

((PaolettiPaoletti R, R, BolegoBolego C, Poli A, C, Poli A, andand CignarellaCignarella A. A. MetabolicMetabolic SyndromeSyndrome, , InflammationInflammation

andand AtherosclerosisAtherosclerosis. . VascVasc Health Health RiskRisk ManagManag. 2006 . 2006 JuneJune; 2(2): ; 2(2): 145145152;152; ManciaMancia G, G, BousquetBousquet P et al. The P et al. The sympatheticsympathetic nervousnervous system system andand thethe metabolicmetabolic syndromesyndrome. . JournalJournal ofof HypertensionHypertension 2007, 25 (5):2007, 25 (5):909909--920; Grassi 920; Grassi G, G, QuartiQuarti--TrevanoTrevano F et al. F et al. Cardiovascular Cardiovascular riskrisk andand adrenergicadrenergic overdriveoverdrive in in metabolicmetabolic syndromesyndrome. . NutrNutr MetabMetab CardiovascCardiovasc DisDis 2007, 17(6): 2007, 17(6): 473473--81)81)

Periodontal Periodontal disease, one the most common chronic bacterial infection, disease, one the most common chronic bacterial infection, may represent a favorable scenario to verify the connection of infection may represent a favorable scenario to verify the connection of infection and atherosclerosis/cardiovascular and atherosclerosis/cardiovascular disease. Several disease. Several studies are studies are suggesting an oral source for atherosclerotic plaque suggesting an oral source for atherosclerotic plaque -- associated bacteria associated bacteria with demonstration about the presence of viable periodontal pathogens with demonstration about the presence of viable periodontal pathogens in atherosclerotic in atherosclerotic plaques. plaques. In this regard an interesting hypothesis was In this regard an interesting hypothesis was proposed in 2004 that periodontal infection may lead to brief episodes of proposed in 2004 that periodontal infection may lead to brief episodes of bacteremia with inoculation of atherosclerotic plaque by periodontal bacteremia with inoculation of atherosclerotic plaque by periodontal pathogenspathogens. However, important information is left aside by most . However, important information is left aside by most investigators studying the connection between oral infection and investigators studying the connection between oral infection and atherosclerosis/coronary myocardial atherosclerosis/coronary myocardial disease. These investigators dont disease. These investigators dont take in consideration that the sympathetic nervous system is intensely take in consideration that the sympathetic nervous system is intensely activated during bacteremia. activated during bacteremia.

((GaettiGaetti--Jardim E et al. Jardim E et al. QuantitativeQuantitative detectiondetection ofof periodontopathicperiodontopathic bacteriabacteria in in atheroscleroticatherosclerotic plaques plaques fromfrom coronarycoronary arteriesarteries. J . J MedMed MicrobiolMicrobiol 58:156858:15681575, 20091575, 2009; ; LeinhardtLeinhardt DJ et al. DJ et al. Plasma NE Plasma NE concentrationsconcentrations do do notnot accuratelyaccurately reflectreflect sympatheticsympathetic nervousnervous system system activityactivity in in humanhuman sepsissepsis. . AmAm J J PhysiolPhysiol 1993; 1993; 265:E2848; 265:E2848; StraubStraub RH et al. RH et al. AblationAblation ofof thethe sympatheticsympathetic nervousnervous system system decreasesdecreases gramgram--negativenegative andand increasesincreases gramgram--positivepositive bacterialbacterial disseminationdissemination: : keykey roles for tumor roles for tumor necrosisnecrosis factorfactor//phagocytesphagocytes andand interleukininterleukin--4/4/lymphocyteslymphocytes. . InfectInfect DisDis. 2005 . 2005 AugAug 15;192(4):15;192(4):560560--72) 72)

ThereThere is is anan intense intense discussiondiscussion onon thethe benefitsbenefits andand potentialpotential harmharm ofof reducingreducing saltsalt intakeintake in in thethe general general populationpopulation. In . In ourour viewview, , bothboth restrictionrestriction andand high high saltsalt intakeintake may may resultresult in in coronarycoronary arteryartery diseasedisease*. The *. The reasonreason isis thatthat in in bothboth cases cases existsexists anan increasedincreased sympatheticsympathetic nervenerve activityactivity. .

(*Book Acidity theory of atherosclerosis (*Book Acidity theory of atherosclerosis New Evidences, by Carlos New Evidences, by Carlos MonteiroMonteiro. .

Chapter: Both Chapter: Both restriction and high salt intake may result in cardiovascular restriction and high salt intake may result in cardiovascular disease, 2012, Amazon.com; disease, 2012, Amazon.com; StolarzStolarz--SkrypekSkrypek K, et al. Fatal and nonfatal outcomes, K, et al. Fatal and nonfatal outcomes, incidence of incidence of hypertensionhypertension, and blood pressure changes in relation to urinary , and blood pressure changes in relation to urinary sodium excretion. JAMA 2011; sodium excretion. JAMA 2011; 305:1777305:1777--1785; Guido 1785; Guido GrassiGrassi, et al. Short, et al. Short-- and Longand Long--Term Term NeuroadrenergicNeuroadrenergic Effects of Moderate Dietary Sodium restriction in Essential Effects of Moderate Dietary Sodium restriction in Essential Hypertension. Circulation. 2002;106: 1957Hypertension. Circulation. 2002;106: 1957--1961; 1961; 'Volume'Volume--expandedexpanded' hypertension: ' hypertension: the effect of fluid overload and the role of the sympathetic nervous system in saltthe effect of fluid overload and the role of the sympathetic nervous system in salt--dependent hypertension, Journal of Hypertension, V30; N1: January dependent hypertension, Journal of Hypertension, V30; N1: January 2012) 2012)

Insomnia is characterized by a constant sympathetic hyperInsomnia is characterized by a constant sympathetic hyper--activation.activation.

In 1999 was hypothesized that insomnia may be related to continual In 1999 was hypothesized that insomnia may be related to continual stressors, reduced slowstressors, reduced slow--wave sleep, and autonomic dysfunction, which wave sleep, and autonomic dysfunction, which increase the risk of heart problems.increase the risk of heart problems.

(de (de ZambottiZambotti M, M, CovassinCovassin N, N, SarloSarlo M, De M, De MinMin Tona G, Tona G, TrinderTrinder J, J, StegagnoStegagno L. L. Nighttime cardiac sympathetic hyperNighttime cardiac sympathetic hyper--activation in young primary insomniacs. activation in young primary insomniacs. ClinClin AutonAuton ResRes.. 2013 Feb;23(1):492013 Feb;23(1):49--56; Schwartz S, McDowell Anderson W, Cole 56; Schwartz S, McDowell Anderson W, Cole SR, SR, CornoniCornoni--Huntley J, Hays JC, Blazer D. Insomnia and heart disease: a review of Huntley J, Hays JC, Blazer D. Insomnia and heart disease: a review of epidemiologic studies. J epidemiologic studies. J PsychosomPsychosom Res. 1999 Oct;47(4):313Res. 1999 Oct;47(4):313--33;)33;)

Studies have shown that longStudies have shown that long--term marathon runners may have term marathon runners may have increased coronary calcium and calcified plaque volume. Other studies increased coronary calcium and calcified plaque volume. Other studies support an increased awareness of atherosclerosis prevalence and support an increased awareness of atherosclerosis prevalence and cardiovascular risk factors in marathon runners.cardiovascular risk factors in marathon runners.

In our view the sympathetic activation and the resulted increase in blood In our view the sympathetic activation and the resulted increase in blood lactate levels may represent the biological mechanism leading to lactate levels may represent the biological mechanism leading to atherosclerosis in marathon runnersatherosclerosis in marathon runners.

(Schwartz JG, Merkel(Schwartz JG, Merkel--Kraus S, Duval S, et al. Does elite athleticism enhance or Kraus S, Duval S, et al. Does elite athleticism enhance or

inhibit coronary artery plaque formation. inhibit coronary artery plaque formation. AmericanAmerican CollegeCollege ofof CardiologyCardiology 2010 2010 ScientificScientific SessionsSessions; ; MarchMarch 16, 2010; Atlanta, GA; 16, 2010; Atlanta, GA; Kroger K et al. Carotid and Kroger K et al. Carotid and peripheral atherosclerosis in male marathon runners. Med peripheral atherosclerosis in male marathon runners. Med SciSci Sports Sports ExercExerc.. 2011 2011 Jul;43(7):1142Jul;43(7):1142--7; 7; Beth A Taylor Beth A Taylor etet al. al. Influence of chronic exercise on carotid Influence of chronic exercise on carotid atherosclerosis in marathon runners, atherosclerosis in marathon runners, BMJ Open 2014;4:e004498)BMJ Open 2014;4:e004498)

A A historyhistory ofof preeclampsiapreeclampsia havehave a a higherhigher riskrisk ofof cardiovascular cardiovascular diseasedisease andand mortalitymortality in in laterlater lifelife. . StudiesStudies havehave shownshown thatthat womenwomen withwith preeclampsiapreeclampsia hadhad significantlysignificantly more more atherosclerosticatherosclerostic plaques plaques thanthan parousparous controlscontrols. . TheThe carotidcarotid intimaintima--media media thicknessthickness in in thesethese womenwomen withwith prepre--eclampsiaeclampsia alsoalso tendedtended to to bebe higherhigher thanthan in in otherother groupsgroups..

TheThe autonomicautonomic nervousnervous system system appearsappears to play to play anan importantimportant role in role in thethe etiologyetiology ofof preeclampsiapreeclampsia wherewhere therethere is is increased sympathetic and decreased increased sympathetic and decreased parasympathetic control of heart rateparasympathetic control of heart rate. . TheThe lactatelactate dehydrogenasedehydrogenase levelslevels are are alsoalso significantlysignificantly elevatedelevated in in womenwomen withwith preeclampsiapreeclampsia..

((HaukkamaaHaukkamaa L, L, MoilanenMoilanen L, L, KattainenKattainen A, A, LuotoLuoto R et al. 2009. PreR et al. 2009. Pre--eclampsiaeclampsia is a risk factor of is a risk factor of

carotid artery atherosclerosis. carotid artery atherosclerosis. CerebrovascCerebrovasc DisDis 27(6): 59927(6): 599--607; 607; BlaauwBlaauw J, van J, van PampusPampus MG, MG, DoormalDoormal JV, et al. 2006. Increased JV, et al. 2006. Increased intimaintima--mediamedia--thickness after early onset of preeclampsia. thickness after early onset of preeclampsia. ObstetObstet GynecolGynecol 107(6): 1345107(6): 1345--51. N. 51. N. SharashkinaSharashkina etet al. al. Preeclampsia and pregnancy induced Preeclampsia and pregnancy induced hypertension and carotid artery atherosclerosis. Pregnancy Hypertension 2012,V2; I3: 294hypertension and carotid artery atherosclerosis. Pregnancy Hypertension 2012,V2; I3: 294--295; 295; Yang, Cheryl C. H., TeYang, Cheryl C. H., Te--Chang Chao et al. Chang Chao et al. PreeclampticPreeclamptic pregnancy is associated with pregnancy is associated with increased sympathetic and decreased parasympathetic control of HR. Am J increased sympathetic and decreased parasympathetic control of HR. Am J PhysiolPhysiol Heart Circ Heart Circ PhysiolPhysiol 2000, 2000, 278: 1269278: 12691273; 1273; He S, He S, BremmeBremme K, K, KallnerKallner A, et al. Increased concentrations of A, et al. Increased concentrations of lactate lactate dehydrogenasedehydrogenase in pregnancy with preeclampsia; a predictor for birth of small for in pregnancy with preeclampsia; a predictor for birth of small for gestational age infants. gestational age infants. GynecolGynecol ObstetObstet Invest. 1995;39:234Invest. 1995;39:2348; 8; Catanzerite VA, Steinberg SM, Catanzerite VA, Steinberg SM, Mosley CA, et al. Severe Mosley CA, et al. Severe preeclampsia with preeclampsia with fulminantfulminant and extreme elevation of and extreme elevation of aspartateaspartate aminotransferaseaminotransferase andand lactatelactate dehydrogenasedehydrogenase levelslevels. . AmAm J J PerinatolPerinatol. 1995;12:310. 1995;12:3103)3)

HyperhomocysteinemiaHyperhomocysteinemia has been reported to be associated with both has been reported to be associated with both

vascular structure alteration and increased cardiovascular risk. vascular structure alteration and increased cardiovascular risk. Some studies have shown a relationship Some studies have shown a relationship between between homocysteinehomocysteine and and

psychological risk factors for cardiovascular diseases, like hostility and psychological risk factors for cardiovascular diseases, like hostility and anger. However, a subsequent study revealed that there anger. However, a subsequent study revealed that there is no evidence is no evidence for an association between for an association between homocysteinehomocysteine levels and cardiovascular levels and cardiovascular autonomic function in either diabetic or autonomic function in either diabetic or nondiabeticnondiabetic subjects. subjects. So, So, according this later study the cardiovascular according this later study the cardiovascular autonomic dysfunction does autonomic dysfunction does not help not help to explain to explain why why hyperhomocysteinaemiahyperhomocysteinaemia is related to is related to cardiovascular mortalitycardiovascular mortality..

My take on the biological mechanism is that My take on the biological mechanism is that homocysteinehomocysteine and its acidic and its acidic derivatives might contribute to the acidic coronary blood flow that lead derivatives might contribute to the acidic coronary blood flow that lead to to increased increased perfusion pressure perfusion pressure and and effects on contractility of coronary effects on contractility of coronary arteries, arteries, resulting in resulting in changes in hemodynamic shear stress changes in hemodynamic shear stress that ends in that ends in atherosclerosis/coronary myocardial disease.atherosclerosis/coronary myocardial disease.

((StoneyStoney CM, CM, EngebretsonEngebretson TO. TO. Plasma Plasma homocysteinehomocysteine concentrations are positively concentrations are positively associated with hostility and anger. Life Sci. 2000;66(23):associated with hostility and anger. Life Sci. 2000;66(23):22672267--7575; ; SpoelstraSpoelstra--De Man De Man AM, AM, SmuldersSmulders YM et al. YM et al. HomocysteineHomocysteine levels are not associated with levels are not associated with cardiovascular autonomic function in elderly Caucasian subjects without or with cardiovascular autonomic function in elderly Caucasian subjects without or with type 2 diabetes mellitus: the Hoorn Studytype 2 diabetes mellitus: the Hoorn Study.. J Intern Med. 2005 Dec;258(6):536J Intern Med. 2005 Dec;258(6):536--4343.) .)

TheThe studiesstudies associatingassociating cardiovascular cardiovascular diseasedisease withwith thethe expositionexposition to to certaincertain chemicalschemicals likelike perfluorooctanoicperfluorooctanoic acid acid , , arsenicarsenic, lead , lead andand cadmiumcadmium besides some persistent organic pollutants,besides some persistent organic pollutants, remindsreminds me me thethe experimentsexperiments fromfrom thethe beginningbeginning ofof thethe lastlast centurycentury showingshowing thatthat acidacid--fedfed rabbitsrabbits andand dogsdogs developdevelop atheroscleroticatherosclerotic lesionslesions. In . In ourour opinionopinion thethe effectseffects generatinggenerating atheroscleroticatherosclerotic lesionslesions in in thesethese experimentsexperiments werewere causedcaused notnot onlyonly byby chronicchronic hyperacidityhyperacidity in in rabbitsrabbits andand dogsdogs butbut alsoalso relatedrelated to to anan intense intense activationactivation ofof thethe sympatheticsympathetic system system provokedprovoked byby acidacid ingestioningestion..

((ShankarShankar A, A, XiaoXiao J, J, DucatmanDucatman A. A. PerfluorooctanoicPerfluorooctanoic AcidAcid andand Cardiovascular Cardiovascular DiseaseDisease in in

US US AdultsAdults. . ArchivesArchives ofof InternalInternal Medicine, 2012; Medicine, 2012; HsiehHsieh YC, YC, LienLien LM et al. LM et al. SignificantlySignificantly increasedincreased riskrisk ofof carotidcarotid atherosclerosisatherosclerosis withwith arsenicarsenic exposureexposure andand polymorphismspolymorphisms in in arsenicarsenic metabolismmetabolism genes. genes. EnvironEnviron Res. 2011 Aug;111(6):Res. 2011 Aug;111(6):804804--10; 10; RevisRevis NW, NW, ZinsmeisterZinsmeister AR, Bull R. Atherosclerosis and hypertension induction by lead and cadmium ions: an AR, Bull R. Atherosclerosis and hypertension induction by lead and cadmium ions: an effect prevented by calcium ion. Proc effect prevented by calcium ion. Proc NatlNatl AcadAcad SciSci USA 1981; 78 : 6494USA 1981; 78 : 6494--8; 8; MessnerMessner B, B, KnoflachKnoflach M, M, SeubertSeubert A, A, RitschRitsch A, A, PfallerPfaller K, Henderson B, et al. Cadmium is a novel and K, Henderson B, et al. Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. independent risk factor for early atherosclerosis mechanisms and in vivo relevance. ArteriosclerArterioscler ThrombThromb VascVasc BiolBiol 2009; 2009; 29: 29: 1392 1392 1398; P. Monica Lind, Bert van 1398; P. Monica Lind, Bert van BavelBavel, , Samira Samira SalihovicSalihovic and Lars Lind. Circulating Levels of Persistent Organic Pollutants and Lars Lind. Circulating Levels of Persistent Organic Pollutants (POPs) and Carotid Atherosclerosis in the Elderly. Environ Health (POPs) and Carotid Atherosclerosis in the Elderly. Environ Health PerspectPerspect 120:38120:3843 43 (2012); (2012); LoebLoeb, O., , O., UeberUeber experimentelleexperimentelle ArterienveraenderArterienveraender ungenungen mitmit besondererbesonderer BeruecksichtigungBeruecksichtigung der der WirkungWirkung der der MilchsaeureMilchsaeure aufauf GrundGrund eigenereigener VersucheVersuche, , DeutschDeutsch. . med. med. WchnschrWchnschr., I913, ., I913, xxxixxxxix, I819; I. Adler, , I819; I. Adler, StudiesStudies in Experimental in Experimental atherosclerosisatherosclerosis -- A A preliminarypreliminary reportreport, The , The JournalJournal ofof Experimental Medicine, Experimental Medicine, 1913) 1913)

StudiesStudies alsoalso suggestsuggest thatthat chemotherapychemotherapy maymay bebe a a riskrisk factorfactor for for thethe developmentdevelopment ofof atherosclerosisatherosclerosis. .

((SajimaSajima T, T, TanabeTanabe A A etet al. al. ImpactImpact ofof platinumplatinum--basedbased chemotherapychemotherapy onon thethe

progressionprogression ofof atherosclerosisatherosclerosis. . ClimatericClimateric 2011 2011 FebFeb;14 (1): 31;14 (1): 31--40; 40; KalabovaKalabova H, H, MelicharMelichar B B etet al. Intimaal. Intima--media media thicknessthickness, , myocardialmyocardial perfusionperfusion andand laboratorylaboratory riskrisk factorsfactors ofof atherosclerosisatherosclerosis in in patientspatients withwith breastbreast cancercancer treatedtreated withwith anthracyclineanthracycline--basedbased chemotherapychemotherapy. . MedMed OncolOncol 2011 2011 DecDec; 28 (4): 1281; 28 (4): 1281--7)7)

RadiationRadiation maymay alsoalso induceinduce atherosclerosisatherosclerosis. . RecentRecent epidemiologicalepidemiological

studiesstudies providedprovided evidenceevidence thatthat anan excessexcess riskrisk ofof cardiovascular cardiovascular diseasedisease cancan bebe associatedassociated withwith moderatemoderate andand lowlow dose dose radiationradiation..

It is It is reconizedreconized for more for more thanthan 50 50 yearsyears thethe effectseffects ofof radiationradiation over over thethe nervousnervous system. In system. In thisthis relationshiprelationship W. O W. O CasterCaster fromfrom US US saidsaid in a in a SymposiumSymposium onon thethe EffectsEffects ofof IonizingIonizing RadiationRadiation onon thethe NervousNervous System System heldheld byby thethe InternationalInternational AtomicAtomic EnergyEnergy AgencyAgency (IAEA), in 1961:(IAEA), in 1961:

it it maymay turnturn out out thatthat a central a central nervousnervous system system responseresponse is is anan importantimportant underlyingunderlying factorfactor in in thethe causationcausation ofof manymany ofof thethe commoncommon manifestationsmanifestations ofof

radiationradiation damagedamage

(Andrea (Andrea BorghiniBorghini etet al. al. Ionizing radiation and atherosclerosis: Current knowledge Ionizing radiation and atherosclerosis: Current knowledge

and future challenges. Atherosclerosis 2013, V 230; I 1: 40 and future challenges. Atherosclerosis 2013, V 230; I 1: 40 47) 47)

Recent studies show that acute myocardial infarction leads to acceleration Recent studies show that acute myocardial infarction leads to acceleration of atherosclerosis. In our view this happens because the acute of atherosclerosis. In our view this happens because the acute sympathetic activity in AMI results in lactic acidosis and lactate sympathetic activity in AMI results in lactic acidosis and lactate accumulation leading to increased perfusion pressure and effects on accumulation leading to increased perfusion pressure and effects on contractility of coronary arteries ,with changes in hemodynamic shear contractility of coronary arteries ,with changes in hemodynamic shear stress ending in atherosclerosis as consequence. Mechanism supported by stress ending in atherosclerosis as consequence. Mechanism supported by the acidity theory of atherosclerosis.the acidity theory of atherosclerosis.

((DuttaDutta P, P, CourtiesCourties G, G, WeiWei Y, Y, LeuschnerLeuschner F, F, GorbatovGorbatov R, Robbins CS, Iwamoto Y, R, Robbins CS, Iwamoto Y, etet

al. al. MyocardialMyocardial infarctioninfarction acceleratesaccelerates atherosclerosisatherosclerosis. . NatureNature. 2012 Jul . 2012 Jul 19;487(7407):32519;487(7407):325--9; 9; HuiHui Wang, Daniel T. Wang, Daniel T. EitzmanEitzman. Acute myocardial infarction . Acute myocardial infarction leads to acceleration of atherosclerosis. Atherosclerosis, Volume 229, Issue 1 , Pages leads to acceleration of atherosclerosis. Atherosclerosis, Volume 229, Issue 1 , Pages 1818--22, July 2013)22, July 2013)

In In addition of diabetes and hypertension there are various diseases addition of diabetes and hypertension there are various diseases associated with associated with atherosclerosis/coronary artery disease atherosclerosis/coronary artery disease where the where the common denominator is the elevation of lactic acid or lactate, for common denominator is the elevation of lactic acid or lactate, for example: psoriasis, rheumatoid example: psoriasis, rheumatoid arthritis, osteoporosis arthritis, osteoporosis and migraine. and migraine. Certainly the raise in lactic acid/lactate levels might also Certainly the raise in lactic acid/lactate levels might also be related be related to to an an altered autonomic nervous system with sympathetic predominance.altered autonomic nervous system with sympathetic predominance.

(Stephen O Crawford et al, Association of blood lactate with type 2 diabetes: the (Stephen O Crawford et al, Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study. International Journal of Atherosclerosis Risk in Communities Carotid MRI Study. International Journal of Epidemiology 2010;1Epidemiology 2010;19; F. E. 9; F. E. DemartiniDemartini, P. J. Cannon, W. B. , P. J. Cannon, W. B. StasonStason, and J. H. , and J. H. LaraghLaragh. . Lactic Acid Metabolism in Hypertensive Patients. Science 11 June 1965, Vol. 148. no. Lactic Acid Metabolism in Hypertensive Patients. Science 11 June 1965, Vol. 148. no. 3676; 3676; GelfandGelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice mortality: cohort study using the General Practice Research DatabaseResearch Database. . EurEur Heart J. 2009 Heart J. 2009 Dec 27.; Dec 27.; MalinaMalina L, L, VolekVolek V, V, BielickyBielicky T. The activity of lactate dehydrogenase in the T. The activity of lactate dehydrogenase in the erythrocytes in psoriasis. Z Haut erythrocytes in psoriasis. Z Haut GeschlechtskrGeschlechtskr. 1969 Oct 1;44(19):877. 1969 Oct 1;44(19):877--9; Roman M. J, et 9; Roman M. J, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 2006; 144: 249Med. 2006; 144: 249--256; 256; GobeletGobelet C and C and GersterGerster J. C. Synovial fluid lactate levels in septic J. C. Synovial fluid lactate levels in septic and nonand non--septic septic arthritidesarthritides. Annals of the Rheumatic diseases, 1984, 43, 742. Annals of the Rheumatic diseases, 1984, 43, 742--745; 745; DekkersDekkers JC et al. Elevated sympathetic nervous system activity in patients with recently JC et al. Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. diagnosed rheumatoid arthritis with active disease. ClinClin ExpExp RheumatolRheumatol. 2004 Jan. 2004 Jan--Feb;22(1):63Feb;22(1):63--70. 70. LarusLarus S S GudmundssonGudmundsson, Ann I , Ann I ScherScher, Thor , Thor AspelundAspelund, et al. Migraine , et al. Migraine with aura and risk of cardiovascular and all cause mortality in men and women: with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study, BMJ 2010;341:c3966; Okada H, prospective cohort study, BMJ 2010;341:c3966; Okada H, AragaAraga S, S, TakeshimaTakeshima T, T, Nakashima K. Plasma lactic acid and pyruvic acid levels in migraine and tensionNakashima K. Plasma lactic acid and pyruvic acid levels in migraine and tension--type type headache. Headache. 1998 Jan;38(1):39headache. Headache. 1998 Jan;38(1):39--42)42)

Different Different necropsy studies have shown that the occurrence of necropsy studies have shown that the occurrence of atherosclerosis atherosclerosis is milder or nonis milder or non--existent in subjects with Down existent in subjects with Down syndrome. syndrome. A A reasonable explanation for the reduced incidence of reasonable explanation for the reduced incidence of atherosclerosis atherosclerosis is is the altered autonomic regulation in individuals with DS, with effects of the altered autonomic regulation in individuals with DS, with effects of smaller changes in smaller changes in baroreflexbaroreflex sensitivity and in sensitivity and in sympathosympatho--excitation excitation response. response. The reduced sympathetic response to stress in DS is supported The reduced sympathetic response to stress in DS is supported by the low circulating by the low circulating catecholaminescatecholamines levels in response to incremental levels in response to incremental cycle cycle ergometer exercise in individuals with ergometer exercise in individuals with DS.DS.

((YlYl--HerttualaHerttuala S, S, LuomaLuoma J, J, NikkariNikkari T, T, KivimkiKivimki T. Down's syndrome and T. Down's syndrome and atherosclerosis. atherosclerosis. Atherosclerosis, Atherosclerosis, 1989 Apr;76(21989 Apr;76(2--3):3):269269--72; Murdoch 72; Murdoch JC, Rodger JC, JC, Rodger JC, RaoRao SS, Fletcher CD, SS, Fletcher CD, DunniganDunnigan MG. Down's syndrome: an atheromaMG. Down's syndrome: an atheroma--free model? free model? Br Med J. 1977 Jul 23;2(6081):Br Med J. 1977 Jul 23;2(6081):226226--8; 8; IellamoIellamo F, F, GalanteGalante A, et al. Altered autonomic A, et al. Altered autonomic cardiac regulation in cardiac regulation in individuals individuals with Down syndrome. Am J with Down syndrome. Am J PhysiolPhysiol Heart Heart CircCirc Physiol. Physiol. 2005 Dec;289(62005 Dec;289(6):):H2387H2387--91; Bo 91; Bo FernhallFernhall and Mari and Mari OtterstetterOtterstetter. Attenuated . Attenuated responses to responses to sympathosympatho--excitation in individuals with Down syndrome. J excitation in individuals with Down syndrome. J ApplAppl PhysiolPhysiol 94: 215894: 21582165, 2003); 2165, 2003); EberhardEberhard Y, Y, EtarradossiEtarradossi J and J and TerminariasTerminarias A. A. Biochemical changes and catecholamine response in Downs syndrome adolescents Biochemical changes and catecholamine response in Downs syndrome adolescents in relation to incremental maximal exercise. J in relation to incremental maximal exercise. J MentMent DeficDefic Res 35: 140Res 35: 140--146, 146, 1991)1991)

Necropsy studies have shown that individuals Necropsy studies have shown that individuals suffering from alcoholism suffering from alcoholism have a significantly have a significantly lower degree of atherosclerosis in the coronary lower degree of atherosclerosis in the coronary arteries. arteries.

A paper published in 2002 may have the answer to this question. William A paper published in 2002 may have the answer to this question. William LovalloLovallo, one of the authors of this , one of the authors of this paper, paper, told in interview to told in interview to EurekAlertEurekAlert that::Before testing alcoholics for their responses to a publicthat::Before testing alcoholics for their responses to a public--speaking speaking task, researchers first needed to establish if their sympathetic nervous 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 system was able to respond at all. "This would tell us if their blunting was specific to psychological stressors like public speaking," said specific to psychological stressors like public speaking," said LovalloLovallo, "or , "or due to a generalized autonomic deficit." due to a generalized autonomic deficit."

The The patients reacted as if the social challenge of public speaking had no patients reacted as if the social challenge of public speaking had no special meaning for them. So, the sympathetic nervous system in the special meaning for them. So, the sympathetic nervous system in the patients looked normal, but their response to a psychological stressor was patients looked normal, but their response to a psychological stressor was almost absent. When faced with a socially meaningful stressor, neither almost absent. When faced with a socially meaningful stressor, neither part of their fightpart of their fight--flight mechanism was workingflight mechanism was working."."

((LearyLeary T. T. AtherosclerosisAtherosclerosis, , thethe importantimportant formform ofof arteriosclerosisarteriosclerosis, a , a metabolicmetabolic diseasedisease. . VolVol 104, N7. JAMA, 104, N7. JAMA, 1935; 1935; ThomsenThomsen JL. JL. AtherosclerosisAtherosclerosis in in alcoholicsalcoholics. . ForensicForensic SciSci Int. 1995 Int. 1995 OctOct 30;75(230;75(2--3):1213):121--31 31 andand in in UgeskrUgeskr LaegerLaeger. 1997 . 1997 FebFeb 3;159(6):7573;159(6):757--60; 60; TeraTera L. L. PankninPanknin, Stacey L. , Stacey L. DickensheetsDickensheets, Sara J. Nixon, William R. , Sara J. Nixon, William R. LovalloLovallo. . AttenuatedAttenuated Heart Rate Responses Heart Rate Responses toto PublicPublic SpeakingSpeaking in in IndividualsIndividuals WithWith AlcoholAlcohol DependenceDependence. . AlcoholAlcohol ClinClin. Exp. Res. 2002 . Exp. Res. 2002 JunJun; 26 (6): 841; 26 (6): 841

Studies Studies have shown that rhesus monkeys submitted to sympatholytic agents have shown that rhesus monkeys submitted to sympatholytic agents

like like betablockersbetablockers or bilateral surgical thoracic or bilateral surgical thoracic sympathectomysympathectomy have had a have had a marked reduction in the progression of marked reduction in the progression of atherosclerosis. The atherosclerosis. The first randomized first randomized trial showing that trial showing that betablockersbetablockers can reduce the rate of progression of carotid can reduce the rate of progression of carotid IMT in clinically healthy symptomIMT in clinically healthy symptom--free subjects with carotid plaque was free subjects with carotid plaque was published in published in 2001. A 2001. A recent pooled analysis data from 4 intravascular recent pooled analysis data from 4 intravascular ultrasonography trials involving 1,515 patients has confirmed that ultrasonography trials involving 1,515 patients has confirmed that betablockerbetablocker therapy is associated with reduced atheroma therapy is associated with reduced atheroma progression. A progression. A study by Strawn study by Strawn and colleagues in 1991 have indicated that social disruption is associated with and colleagues in 1991 have indicated that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial both sympathetic nervous system arousal and indexes of endothelial dysfunction, effects that may be prevented by dysfunction, effects that may be prevented by treatment treatment with Bwith B--adrenergic adrenergic blocking agent. blocking agent. Also interesting is the study showing a decrease in Also interesting is the study showing a decrease in glycogenolyticglycogenolytic rate, blood lactate concentration and lactate clearance after Brate, blood lactate concentration and lactate clearance after B--Adrenergic blockade with Adrenergic blockade with propranololpropranolol, probable a indirect effect of its , probable a indirect effect of its sympatholyticsympatholytic properties.properties.

((LichtorLichtor T et al. 1987.The T et al. 1987.The sympatheticsympathetic nervousnervous system system andand atherosclerosisatherosclerosis. J . J NeurosurgNeurosurg Dec;67(6):Dec;67(6):906906--14; 14; HedbladHedblad B et al. B et al. LowLow--dose dose metoprololmetoprolol CR/XL CR/XL andand fluvastatinfluvastatin slowslow progressionprogression ofof carotidcarotid intimaintima--mediamedia thicknessthickness: : MainMain resultsresults fromfrom thethe BetaBeta--BlockerBlocker CholesterolCholesterol--LoweringLowering AsymptomaticAsymptomatic Plaque Plaque StudyStudy (BCAPS). (BCAPS). CirculationCirculation. 2001 . 2001 AprApr 3;103(13):3;103(13):17211721--6.; 6.; SipahiSipahi I et al. 2007. I et al. 2007. BB--BlockersBlockers andand progressionprogression ofof coronarycoronary atherosclerosisatherosclerosis; ; PooledPooled analysisanalysis ofof 4 intravascular 4 intravascular trialstrials. . AnnalsAnnals ofof InternalInternal Medicine, 3 July, V147; Medicine, 3 July, V147; IssueIssue 1: 1: 1010--18; 18; StrawnStrawn WB WB andand allall. . EndothelialEndothelial dysfunctiondysfunction in response in response toto psychosocialpsychosocial stress in stress in monkeysmonkeys. . CirculationCirculation Research 1991; 68:1270Research 1991; 68:1270--1279; 1279; IssekutzIssekutz B Jr. Effect of betaB Jr. Effect of betaadrenergic blockade on lactate turnover in exercising dogs. J adrenergic blockade on lactate turnover in exercising dogs. J ApplAppl PhysiolPhysiol 1984; 57: 17541984; 57: 175459)59).

To our knowledge only one angiographic study assessed data on regression To our knowledge only one angiographic study assessed data on regression (15%), inalterability (62%) or progression (23%) of atherosclerosis in patients (15%), inalterability (62%) or progression (23%) of atherosclerosis in patients treated with cardiac glycosides. Indeed, cardiac glycosides at low treated with cardiac glycosides. Indeed, cardiac glycosides at low concentration may lead to stress reduction by the improvement of concentration may lead to stress reduction by the improvement of baroreceptorbaroreceptor function, function, sympathoinhibitorysympathoinhibitory effects, effects, vagomimeticvagomimetic effects and effects and decrease in heightened secretion of decrease in heightened secretion of catecholaminescatecholamines..

There are studies showing the existence of potential positive effects of cardiac There are studies showing the existence of potential positive effects of cardiac glycosides (glycosides (digoxindigoxin, , digitoxindigitoxin, etc) for the treatment of atherosclerosis., etc) for the treatment of atherosclerosis.

(Mesquita (Mesquita QHdeQHde, , etet al. Preservao funcional do miocrdio isqumico pelo al. Preservao funcional do miocrdio isqumico pelo cardiotonicocardiotonico a longo prazo: a longo prazo: recateterizaorecateterizao de 29 casos. Medicina de Hoje, maro 1978). de 29 casos. Medicina de Hoje, maro 1978). GheorghiadeGheorghiade M, Adams KF, M, Adams KF, ColucciColucci WS. WS. DigoxinDigoxin in the Management of Cardiovascular Disorders in the Management of Cardiovascular Disorders 20042004; ; 109109: : 29592959--2964; 2964; JagielskaJagielska J. et al. J. et al. DigitoxinDigitoxin elicits antielicits anti--inflammatory and inflammatory and vasoprotectivevasoprotective properties in endothelial cells: Therapeutic implications for the treatment properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis?, Atherosclerosis 2009 Oct;206(2):390of atherosclerosis?, Atherosclerosis 2009 Oct;206(2):390--6; 6; KolkhofKolkhof P et al. Cardiac P et al. Cardiac glycosides potently inhibit Cglycosides potently inhibit C--reactive protein synthesis in human reactive protein synthesis in human hepatocyteshepatocytes. . BiochemBiochem BiophysBiophys Res Res CommunCommun. 2010 Mar 26;394(1): 233. 2010 Mar 26;394(1): 233--9)9)

RRegression of egression of coronary coronary atherosclerosis atherosclerosis in women who were free of in women who were free of stress stress showed through the use of serial quantitative angiography;showed through the use of serial quantitative angiography;

DDecrease of ecrease of carotid carotid intima media thickness intima media thickness in African Americans with in African Americans with hypertension submitted to stress reduction through Transcendental hypertension submitted to stress reduction through Transcendental Meditation Meditation ; ;

Decrease Decrease in carotid in carotid intima media thickness in intima media thickness in older persons with multiple older persons with multiple factors for coronary heart disease submitted to the Maharishi factors for coronary heart disease submitted to the Maharishi Vedic Vedic Medicine Medicine treatment treatment ---- which also includes stress reduction through which also includes stress reduction through Transcendental Meditation Transcendental Meditation program; program;

Yoga Yoga intervention retards progression and increases regression of intervention retards progression and increases regression of coronary atherosclerosis in patients with severe coronary artery disease coronary atherosclerosis in patients with severe coronary artery disease ..

Slow breathing increases Slow breathing increases baroreflexbaroreflex sensitivity and reduce sympathetic sensitivity and reduce sympathetic nervous system with beneficial effects to coronary myocardial disease.nervous system with beneficial effects to coronary myocardial disease.

*Carlos *Carlos ETB ETB MonteiroMonteiro, Acidic environment evoked , Acidic environment evoked by chronic by chronic stress: A novel stress: A novel mechanism to explain mechanism to explain atherogenesisatherogenesis. Available . Available from Infarct from Infarct Combat Project, Combat Project, January 28, 2008 January 28, 2008 at httpat http://://www.infarctcombat.org/AcidityTheory.pdf; Book www.infarctcombat.org/AcidityTheory.pdf; Book Acidity Theory of Atherosclerosis: New Evidences, 2012Acidity Theory of Atherosclerosis: New Evidences, 2012

It It is interesting to notice is interesting to notice about the about the impairment or decrease of impairment or decrease of baroreflexbaroreflex sensitivity sensitivity in front of some key factors for atherosclerosis, in front of some key factors for atherosclerosis, coronary coronary myocardial disease myocardial disease and stroke, like in ageing, ingestion of sugars, and stroke, like in ageing, ingestion of sugars, in in special special highhigh--fructose diets, and smoking. fructose diets, and smoking. Indeed there Indeed there are some studies are some studies showing that in bilateral carotid atherosclerosis and in greater intimashowing that in bilateral carotid atherosclerosis and in greater intima--media thickness the media thickness the baroreflexbaroreflex sensitivity is reduced or impairedsensitivity is reduced or impaired..

On the other hand the result of the baroreceptor improvement On the other hand the result of the baroreceptor improvement is the is the inhibition of the sympathetic nervous system and activation inhibition of the sympathetic nervous system and activation of the of the parasympathetic nervous parasympathetic nervous system. system. Drugs Drugs like like BetablockersBetablockers and Digitalis and Digitalis glycosides may glycosides may enhance enhance baroreflexbaroreflex sensitivity sensitivity with with possible positivepossible positive

effects on effects on atherosclerosis. atherosclerosis.

(Nasr (Nasr N et al. N et al. BaroreflexBaroreflex sensitivity is impaired in bilateral carotid sensitivity is impaired in bilateral carotid atherosclerosis. atherosclerosis.

Stroke;36:1891Stroke;36:1891--1895; 1895; GianorosGianoros PJ et al. Greater intimaPJ et al. Greater intima--media thickness in the media thickness in the carotid bulb carotid bulb is associated is associated with reduced with reduced baroreflexbaroreflex sensitivity. Am J sensitivity. Am J HypertensHypertens. . 2002;15(62002;15(6): ): 486486--491491; ; TruijenTruijen J et al. J et al. BaroreflexBaroreflex sensitivity is higher during acute sensitivity is higher during acute psychological stress psychological stress in healthy subjects under Bin healthy subjects under B--adrenergic blockade. adrenergic blockade. ClinClin SciSci

((LondLond), Feb 2011; 120(4):161), Feb 2011; 120(4):161--167; 167; SchobelSchobel HP et al. 1991.Contrasting effects of HP et al. 1991.Contrasting effects of digitalis and digitalis and dobutaminedobutamine on on baroreflexbaroreflex sympathetic control in normal humans, sympathetic control in normal humans, Circulation Circulation V84,1118V84,1118--11291129..

A recent study confirm that the use of beta blockers do not appear to be of any 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 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); disease but no history of MI; those with a remote history of MI (one year or more); and those with coronary risk factors only. and those with coronary risk factors only.

Also, the effect of Also, the effect of betablockersbetablockers as a treatment for primary hypertension has been as a treatment for primary hypertension has been questioned. In a metaquestioned. In a meta--analysis study published at Lancet Journal in 2005 the analysis study published at Lancet Journal in 2005 the authors say that the effect of authors say that the effect of betablockersbetablockers compared to placebo is less than compared to placebo is less than optimum, with no difference for myocardial infarction but with a raised risk of optimum, with no difference for myocardial infarction but with a raised risk of stroke.stroke.

Moreover in a randomized trial study published in Lancet Journal in 2008 the Moreover in a randomized trial study published in Lancet Journal in 2008 the authors say that there were more deaths in the authors say that there were more deaths in the metoprololmetoprolol group than in the group than in the placebo group in patients undergoing nonplacebo group in patients undergoing non--cardiac surgery (129 versus 97 patients).cardiac surgery (129 versus 97 patients).

So, while So, while betablockersbetablockers seems useful in atherosclerosis its poor results in these seems useful in atherosclerosis its poor results in these clinical situations might be related to their effects of generalized clinical situations might be related to their effects of generalized hypocontractilityhypocontractility, , as suggested by Dr. as suggested by Dr. MesquitaMesquita in 1979.in 1979.

(Bangalore S, (Bangalore S, StegSteg PHG, PHG, DeedwaniaDeedwania P, et al. Beta blocker use and clinical outcomes in stable P, et al. Beta blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 2012; 308:1340outpatients with and without coronary artery disease. JAMA 2012; 308:1340--1349; 1349; LindholmLindholm LH, LH, CarlbergCarlberg B, Samuelsson O. Should B blockers remain first choice in the treatment of B, Samuelsson O. Should B blockers remain first choice in the treatment of primary hypertension? A metaprimary hypertension? A meta--analysis. Lancet 2005;366:1545analysis. Lancet 2005;366:1545--53; POISE study group. Effects 53; POISE study group. Effects of extendedof extended--release release metoprololmetoprolol succinatesuccinate in patients undergoing nonin patients undergoing non--cardiac surgery (POISE cardiac surgery (POISE Trial): a randomized controlled trial. Lancet 2008; 371: 1839Trial): a randomized controlled trial. Lancet 2008; 371: 1839--47; 47; MesquitaMesquita, QH, Book , QH, Book MyogenicMyogenic Theory of Myocardial Infarction, 1979) Theory of Myocardial Infarction, 1979)

BaldnessBaldness SSevereevere vertex pattern of vertex pattern of androgeneticandrogenetic alopecia is considered to have an alopecia is considered to have an

increased risk of subclinical atherosclerosisincreased risk of subclinical atherosclerosis. . There is a postulation made in 1997 by Marino There is a postulation made in 1997 by Marino SalinSalin, from Italy, telling if , from Italy, telling if

there is excess adrenergic tone in the metabolic system, then there is also there is excess adrenergic tone in the metabolic system, then there is also vasoconstriction, ischemia and hypoxia and if there is hypoxia, vasoconstriction, ischemia and hypoxia and if there is hypoxia, glycolysisglycolysis leads to lactic acid that causes caustic damage to the inner sheath and this leads to lactic acid that causes caustic damage to the inner sheath and this sheath seems to be raised above the hair cuticle.sheath seems to be raised above the hair cuticle.

Earlobe CreaseEarlobe Crease Diagonal earlobe crease is another external marker for coronary artery Diagonal earlobe crease is another external marker for coronary artery

disease. Interesting is that the earlobe is one local to determine blood 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 lactate concentration that may be in our opinion the culprit for the earlobe wrinkle.wrinkle.

(Dogramaci AC et al. Is androgenetic alopecia a risk for atherosclerosis? J Eur Acad Dermatol Venereol. 2009 Jun;23(6):673-7.; Marino Salin e Andrea Marliani,, TricoItalia (Firenze) marzo 1997, Bolletino della Societ 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. 1987 Mar;8(1):9-11)

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In In thisthis book book wewe explore in explore in depthdepth thethe riskrisk factorsfactors andand pathophysiologicalpathophysiological explanationsexplanations ofof atherosclerosisatherosclerosis, , underunder thethe acidityacidity theorytheory point point ofof viewview..

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