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 (1, 2, 3, 4). Indeed, a study have suggested that women with Down syndrome (DS) may be less likely to express the insulin resistance syndrome*, and men and women with Down syndrome may possess fewer atherosclerotic risk factors than the comparison groups (5)
Confirming the results that DS individuals possess low levels of atherosclerosis a recent study have examined the relation between cardiovascular disease risk factors and intima-media thickness (IMT), a measure for atherosclerosis, in 52 adults with DS. The adults with DS possessed lower IMT, systolic blood pressure and diastolic blood pressure, than controls. The study’s conclusion was that the adults with DS may be protected against atherosclerosis despite elevated body fat and elevated cardiovascular risk factors (6).
It is interesting to note about the results from some studies demonstrating that at lower degrees of IMT, the thickening appears to reflect an equilibrium state in which the effects of pressure and flow on the arteries are in balance, given a characteristic relation between shear stress and local transmural pressure (7, 8).
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 (9, 10, 11). The reduced sympathetic response to stress in DS is supported by the low circulating catecholamines levels in response to incremental cycle ergometer exercise in individuals with DS (12).
In the acidity theory of atherosclerosis the sympathetic predominance is the primary step and shear stress is the last step in the cascade of events leading to the atherogenic process (13, 14)
Carlos Monteiro
*Note:
Insulin resistance may contribute to enhanced SNS activity (15) and SNS activity may similarly increase insulin resistance (16)

1. Ylä-Herttuala S, Luoma J, Nikkari T, Kivimäki T. Down's syndrome and atherosclerosis. Atherosclerosis. 1989 Apr;76(2-3):269-72.
2. Murdoch JC, Rodger JC, Rao SS, Fletcher CD, Dunnigan MG. Down's syndrome: an atheroma-free model? Br Med J. 1977 Jul 23;2(6081):226-8.
3. Moss TJ, Austin GE. Pre-atherosclerotic lesions in Down syndrome. J Ment Defic Res. 1980 Jun;24(2):137-41.
4. Chaney RH. Neurogenic atherosclerosis in mentally retarded persons. J Ment Defic Res. 1987 Sep;31 ( Pt 3):235-40
5. Draheim CC, McCubbin JA, Williams DP. Differences in cardiovascular disease risk between nondiabetic adults with mental retardation with and without Down syndrome. Am J Ment Retard. 2002 May;107(3):201-11
6. Draheim CC, Geijer JR, Dengel DR. Comparison of intima-media thickness of the carotid artery and cardiovascular disease risk factors in adults with versus without the Down syndrome. Am J Cardiol. 2010 Nov 15;106(10):1512-6
7. Gnasso A, et al. Association Between Intima-Media Thickness and Wall Shear Stress in Common Carotid Arteries in Healthy Male Subjects. Circulation. 1996;94:3257-3262
8. Bots M. L, et al. Increased Common Carotid Intima-Media Thickness. Adaptive Response or a Reflection of Atherosclerosis? Findings From the Rotterdam Study. Stroke. 1997;282442 .
9. Agiovlasitis S, Collier SR, et al. Autonomic response to upright tilt in people with and without Down syndrome. Res Dev Disabil. 2010 May-Jun;31(3):857-63.
10. Iellamo F, Galante A, et al. Altered autonomic cardiac regulation in individuals with Down syndrome. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2387-91.
11. Bo Fernhall and Mari Otterstetter. Attenuated responses to sympathoexcitation in individuals with Down syndrome. J Appl Physiol 94: 2158–2165, 2003.
12. Eberhard Y, Etarradossi J and Terminarias A. Biochemical changes and catecholamine response in Down’s syndrome adolescents in relation to incremental maximal exercise. J Ment Defic Res 35: 140-146, 1991
13. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
14. Sympathetic predominance: a primary factor in the cascade of events leading to the atherogenic spiraling, Carlos Monteiro, Monday, February 22, 2010 at http://aciditytheory.blogspot.com/2010/02/sympathetic-predominance-primary-factor.html
15. Pikkujamsa SM, Huikuri HV, Airaksinen KE, Rantala AO, Kauma H, Lilja M, Savolainen MJ, Kesaniemi YA. Heart rate variability and baroreflex sensitivity in hypertensive subjects with and without metabolic features of insulin resistance syndrome. Am J Hypertens 1998;11:523–31
16. Moan A, Nordby G, Rostrup M, Eide I, Kjeldsen SE. Insulin sensitivity, sympathetic activity, and cardiovascular reactivity in young men. Am J Hypertens 1995;8:268–75

Sympathetic predominance: The link between diabetes and cardiovascular disease?

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 can now be attributable to autonomic imbalance between the sympathetic and parasympathetic nervous system regulation of cardiovascular function (1)
It is also interesting to notice that plasma lactate was strongly associated with type 2 diabetes in older adults as demonstrated in a recent paper (2). According to the authors plasma lactate deserves greater attention in studies of oxidative capacity and diabetes risk.
Both lines of studies come in favour of our point of view (3, 4,5) where the sympathetic predominance represents the primary factor in the cascade of events leading to a higher lactic acid production that provokes an increased perfusion pressure and effects on contractility of coronary arteries resulting in changes in hemodynamic shear stress and atherosclerosis as consequence.
Carlos Monteiro
1. Vinik AI, Zieglert D. Autonomic imbalance: prophet of doom or scope for hope? Diabet. Med. 28, 643-651 (2011) Full free text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123705/
2. Stephen O Crawford et al, Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study. International Journal of Epidemiology 2010;1–9. Free full text at http://ije.oxfordjournals.org/content/early/2010/08/25/ije.dyq126.full.pdf+html
3. Sympathetic predominance: a primary factor in the cascade of events leading to the atherogenic spiraling, Carlos Monteiro, Monday, February 22, 2010 at http://aciditytheory.blogspot.com/2010/02/sympathetic-predominance-primary-factor.html
4. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
5. Association of lipid abnormalities with lactate and coronary artery disease progression. Carlos Monteiro, October 3, 2010 at http://aciditytheory.blogspot.com/2010/10/lactate-coronary-artery-disease-insulin.html

Some news.....

David M Diamond* made in public the following declaration in the THINCS Forum on June 22, 2011: “Carlos, your thesis on stress, acidic environment and CHD is brilliant. Particularly impressive is how you relate reduced pH to increased oxidation of LDL, which increases its atherogenicity”
* Ph.D, Professor, Depts of Psychology and Molecular Pharmacology and Physiology, Center for Preclinical and Clinical Research on PTSD. Director, University of South Florida, Neuroscience Collaborative)

Sympathetic Predominance: The link between erectile dysfunction, atherosclerosis and cardiovascular disease?

Erectile dysfunction affects 40% of men above 40 year old, in some degree, and two thirds of men over 70 have significant symptoms of ED.
The association between erectile dysfunction and coronary artery disease (CAD) was suggested years ago, by observational studies. More recently it was found that erectile dysfunction is an early marker of CAD, as the canary in the coal mine*.
Indeed some studies have demonstrated that coronary atherosclerosis is more severe in patients with vascular ED, with the authors considering that ED may be an additional, early warning sign of coronary atherosclerosis (1).
A recent meta-analysis of prospective cohort studies, involving 36,744 participants, have suggested that ED significantly increases the risk of cardiovascular disease, coronary heart disease, stroke, and all cause mortality, and the increase is probably independent of conventional risk factors (2)
Erection is initiated through the parasympathetic nervous system, activation of which overrides the sympathetic tone that maintains the penis in a nonerectile (flaccid) state. This state is maintained mainly through the release of norepinephrine from penile adrenergic nerves. Norepinephrine contracts the vasculature and cavernosal smooth muscle. Arousal/erection is associated with a decrease of norepinephrine release in the penis, with a release of nitric oxide, and with a reduction in penile smooth muscle tone. Thus, nitric oxide is a mediator of the parasympathetic vasodilation in erectile function (3). So, when the parasympathetic system is continuously disabled there is a reduced production of NO.
Lifestyle and nutrition have been increasingly recognized as central factors influencing vascular nitric oxide (NO) production and erectile function. ED is associated with smoking, excessive alcohol intake, abdominal obesity, diabetes, hypertension and decreased antioxidant defenses, all of which reduce NO production (4,). Recent studies have discussed about the benefits of lifestyle interventions like healthier eating habits, getting exercise and avoiding smoke for improving erectile dysfunction (5) and also targeting CAD risk factors reduction (4, 6).
It is interesting to note that ED and atherosclerosis have many risk factors in common like ageing, physical inactivity, improper diet, psychological stress, cigarette smoking, high blood pressure and diabetes. In relation to this point there are diverse studies showing that: a) increased sympathetic activity and mental stress may affect erectile function with studies suggesting that an elevated central sympathetic tone may be one of the causes of psychogenic impotence (7, 8, 9); b) a study suggested that drugs acting within the central nervous system that reduce the sympathetic antierectile flow and enhance the parasympathetic proerectile flow to the penis may restore penile erection in cases of erectile dysfunction of both psychogenic and organic origin (10); c) other study have demonstrated that patients complaining of daytime sexual dysfunction and found by sleep-related erection monitoring to suffer from organic erectile dysfunction, have altered cardiac autonomic balance during both stages of sleep (11); d) A study has shown that men with idiopathic ED have evidence of endothelial dysfunction in forearm resistance vessels, increased pulse pressure and impaired heart rate variability. According the authors this support the concept that erectile dysfunction is a predictor of cardiovascular dysfunction and a precursor of clinical cardiovascular disease (13). e) and, finally, a very recent study have shown that patients with ED exhibited different heart rate variability compared with normal controls. This suggested to the authors that the patients with ED may have some kind of imbalance in the autonomic nervous system (ANS) and it may be possible that general imbalance of the ANS is one of the causes of ED (12).
Taking in view the above studies and our postulation that sympathetic predominance is the primary factor in the cascade of events leading to the atherogenic spiraling (14, 15), we have to assume that it really is the link between ED and cardiovascular disease.
14. 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
15. Sympathetic predominance: a primary factor in the cascade of events leading to the atherogenic spiraling, Carlos Monteiro, Monday, February 22, 2010 at http://aciditytheory.blogspot.com/2010/02/sympathetic-predominance-primary-factor.html
Carlos Monteiro

*As long as the canary still singing, it is all ok. However, a dead canary is a warning of a larger problem.

References:
1. Chiurlia E et al. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol, 2005; 46:1503-6
2. Dong JY et al. Erectile dysfunction and risk of cardiovascular disease. Meta-analysis of prospective cohort studies. J Am Coll Cardiol, 2011; 58:1378-1385
3. Andersson K, Stief C. Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms. Am J Cardiol. 2000 Jul 20;86(2A):23F-26F
4. Meldrum DR et al. The link between erectile and cardiovascular health: the canary in the coal mine. Am J Cardiol. 2011 Aug 15; 108(4): 599-606
5. Horasanli K et al. Do lifestyle changes work for improving erectile dysfunction? Asian J Androl, 2008; 10(1):28-35
6. Gupta PB et al. The effect of lifestyle modification and cardiovascular risk factor reduction on erectile dysfunction: A systematic review and meta-analysis. Arch Intern Med, 2011. Published online September 12.
7. Junemann KP et al. Neurophysiological aspects of penile erection: the role of the sympathetic nervous system. Br J Urol, 1989 Jul;64(1):84-92
8. Pagani M. Hypertension, stress and erectile dysfunction: potential insights from the analysis of heart rate variability. Curr Med Res Opin, 2000; 16 Suppl1:s3-8
9. Diederichs W et al. The sympathetic role as an antagonist of erection. Urol Res. 1991;19(2):123-6
10. Allard J, Giuliano F. Central nervous system agents in the treatment of erectile dysfunction: how do they work? Curr Urol Rep 2001 Dec;2(6):488-94
11. Lavie P et al. Cardiac autonomic function during sleep in psychogenic and organic erectile dysfunction. J Sleep Res. 1999 Jun;8(2):135-42
12. Lee JY et al. Heart rate variability in men with erectile dysfunction. Int Neurourol J 2011;15:87-91. Full free text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138849/pdf/inj-15-87.pdf
13. Stuckey BG, Walsh JP ET al. Erectile dysfunction predicts generalised cardiovascular disease. Evidence from a case control study. Atherosclerosis 2007, 194(2):458-6414.

The positive impact of humor and negative of stress over the vascular function

Chronic stress is correlated with increases in stress hormones cortisol and cathecolamines. There is strong scientific evidence linking negative emotional states like depression, anxiety, or anger with increased risk for cardiovascular disease. However, much less is known about the association between positive emotional states, the so called eustress, like laughter and happiness. The nicest of all laughter types is associated with humor and it is specified as mirthful laughter.
In this respect there are some studies made by Berk and colleagues, from the Loma Linda University, demonstrating that in comparison with chronic stress mirthful laughter reduced the levels of Cortisol by 39%; adrenaline by 70% and dopac by 38%. The conclusion in one of their papers was that humor appears to attenuate catecholamines and MI recurrence and thus could be an effective adjunct in post-MI care (1, 2, 3).
On the other hand Michael Miller, from the University of Maryland, presented a study at the European Society of Cardiology in the 2011 Congress (4) highlighting the link between endothelial function and laughter. His study showed that when people laughed their major blood vessels dilated allowing for easier blood flow, that indicates a reduced risk of cardiac events.
Dr. Miller’s idea to study positive emotions such as laughter came after studies that had shown that mental stress caused blood vessels to constrict. His first study about sense of humor and coronary artery disease was published in 2001 (5). In other paper, published in 2009 (6), he told about the tests made to confirm the hypothesis that mirthful laughter also favorably affect endothelial dependent flow-mediated vasodilation (FMD). In this way volunteers were randomized for two different phases in a randomized-crossover design. One phase included watching a movie or segment of popular comedies (ex: Saturday Night Live) whereas a second phase was to view a movie known to promote mental stress (ex: The opening segment of “Saving Private Ryan”). The assessment of endothelial dependent vasoreactivity was performed using high resolution ultrasound of the brachial artery, also referred as brachial artery reactivity test (BART). A total of 160 BART measurements were performed and demonstrated a divergent effect after watching a movie provoking mental stress as compared to mirthful laughter. Specifically, a 35% reduction in FMD compared to baseline followed mental stress whereas a 22% increase in FMD occurred in response to laughter (7). In 2008, Dr. Miller and colleagues, in an oral presentation entitled “Positive emotions and the endothelium: Does joyful music improve vascular health?”, made at the American Association Scientific Sessions, on 11/11/2008, conclude that the cardiovascular benefits of music are similar to those found in their previous study of mirthful laughter (8)
Dr. Sugawara and colleagues in 2010 have confirmed the findings from Dr. Miller saying that their results suggest mirthful laughter elicited by comic movies induces beneficial impact on vascular function (9).
Again, in the presentation made by Dr. Miller at the ESC, 2011, volunteers watched segments of a funny movie, such as the farce “There's Something About Mary” on one day and on another day watched the opening segment of the stressful movie “Saving Private Ryan”. When study volunteers watched the stressful movie, their blood lining developed a potentially unhealthy response called vasoconstriction, reducing blood flow. Overall, in this time, more than 300 measurements were made with a 30-50% difference in blood vessel diameter between the laughter and mental stress phases (4).
We think the above studies give additional evidence to our acidity theory of atherosclerosis (10), that has the following sequence of events:
I. Sympathetic dominance by continuous stress plus
II. Deficiency in production of endogenous digitalis-like compounds (DLCs) with alterations of Na(+), K(+)-ATPase activity results in:
III. Lowered pH (acidity) that increases perfusion pressure and provokes effects on contractility of coronary arteries leading to changes in hemodynamic shear stress and atherosclerosis as consequence.
Sympathetic activation, metabolic acidosis and vascular reactivity The studies by Berk and Miller confirm previous studies suggesting that the sympathetic activation with elevation of circulating catecholamine (adrenaline, etc..), cause coronary vasoconstriction and consequent reduction in blood flow.
On the other hand it is interesting to notice that increased lactate (or decreased blood pH) may evoke vascular smooth muscle relaxation and increase of blood flow (11).
These opposite forces working in sequence - with the sympathetic overdrive leading to metabolic acidosis -, in our view, may be reconciled to partially explain the occurrence of the resulting abnormal stretching/relaxing of coronary arteries, in different directions, simultaneously, producing atherosclerosis (10).Carlos Monteiro

1. Berk LS, Tan SA and Berk B. Cortisol and cathecolamine stress hormone drecrease is associated with the behavior of perceptual anticipation of mirthful laughter. The FASEB Journal. 2008; 22;946.11
2. Tans SA, Berk LS et al. Humor as an adjunct therapy in cardiac rehabilitation, attenuates cathecolamines and myocardial infarction recurrence. Adv Mind Body Med 2007; 22(3-4): 8-12
3. Berk LS et al. The neuroendocrine and stress hormone changes during mirthful laughter. Am J Med Sci 1989;6:390-396
4. Miller M. Laughter and vascular function, ESC 2011.
5. Clark A, Seidler A, Miller M. Inverse association between sense of humor and coronary heart disease. Int J Cardiol. 2001 Aug; 80(1):87-8
6. Miller M, Fry WF. The effect of mirthful laughter on the human cardiovascular system. Med. Hypothesis 2009; 73(5):636 . Full free text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814549/pdf/nihms-154943.pdf
7. Miller M, Mangano C, Park Y, et al. Impact of cinematic viewing on endothelial function. Heart 2006; 92:261-262
8. Miller M, Beach V, Mangano C, Vogel RA. Positive emotions and the endothelium: Does joyful music improve vascular health? American Association Scientific Sessions, on 11/11/2008
9. Sugawara et al. Effect of mirthful laughter on vascular function. Am J Cardiol 106:856-9 (2010).
10. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
11. Celotto AC, Capellini VK et al. Effects of acid-base imbalance on vascular reactivity. Brazilian Journal of Medical and Biological Research (2008) 41:439-445 Full free text at http://www.scielo.br/pdf/bjmbr/v41n6/7099.pdf

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

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

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

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

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

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

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

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

Hemodynamic shear stress, calcification and atherosclerosis

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