Lactate as cause of secondary damage in acute ischemic stroke

Atherosclerosis of the carotid arteries is a leading cause of ischemic stroke. Increased carotid artery intima-media thickness (IMT) is a marker of atherosclerosis and also a predictor for ischemic stroke that represents more than 80% of strokes, with the remainder due to hemorrhage.
Recent study involving 187 patients with acute ischemic stroke or transient ischemic attack (1) have indicated that lactate in cerebrospinal fluid, but not in blood, is a reliable marker for the metabolic crisis in acute ischemic stroke and a possible cause of secondary neuronal damage in cortical infarction resulting in unfavourable evolution in the sub acute phase of stroke and poor long-term outcome.
However, some researchers believe that whole blood lactate, as measured in this study, unlike serum lactate, is an unreliable measure of systemic lactate (2).
It is interesting to note that a study from 2004 found ischemic stroke acidosis-mediated activation of acid-sensing ion channels may play a role to ischemic damage of brain tissue (3).
Most interesting is that cardiac glycosides, besides its anti-atherosclerotic effects as discussed recently in this blog (4, 5), also can provide cerebral neuroprotection in front of ischemic stroke and in prevention of its occurrence (6).

1) Evaluation of lactate as a marker of metabolic stress and cause of secondary damage in acute ischemic stroke or TIA, Brouns R, Sheorajpanday R, Wauters A, Surgeloose DD, Mariën P, DE Deyn PP. Clinica Chimica Acta 397 (2008) 27–31
2) The Lactic Acid Response to Alkalosis in Panic Disorder: An Integrative Review Richard J. Maddock, M.D.J Neuropsychiatry Clin Neurosci 13:1, Winter 2001. Full free paper at http://neuro.psychiatryonline.org/cgi/content/full/13/1/22
3) Huang Y, McNamara JO. 2004. "Ischemic Stroke: “Acidotoxicity” Is a Perpetrator", Cell, Volume 118, Issue 6 , 17 September, Pages 665-666
4) The anti-atherosclerotic effects of cardiac glycosides, Carlos Monteiro at http://aciditytheory.blogspot.com/2009/11/anti-atherosclerotic-effects-of-cardiac_27.html
5) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
6) Cardiac Glycosides in Prevention of Stroke, Carlos Monteiro, ICP, July 10, 2006, Full text at http://www.infarctcombat.org/media/071006.html

Stress, lactic acid, hypertension, atherosclerosis and hair loss

The last weekend I have read an article in New York Times Journal, entitled “The Claim: High Blood Pressure Will Increase People’s Risk of Losing Their Hair.” (http://www.nytimes.com/2009/12/08/health/research/08real.html), which caught my attention.
NYT have discussed the results and linked to some of the studies suggesting that hair loss may indicate an increased risk of high blood pressure and heart disease.
Curious about this information I have searched at Pubmed were I found a recent paper linking hair loss also to atherosclerosis, with the conclusion by the authors that severe vertex pattern of androgenetic alopecia should be considered to have an increased risk of subclinical atherosclerosis (1).
Going deeper I have found a postulation made in 1997 by Marino Salin, from Italy, telling if there is excess adrenergic tone in the metabolic system, then there is also vasoconstriction, ischemia and hypoxia and if there is hypoxia, glycolysis leads to lactic acid that causes caustic damage to the inner sheath and this sheath seems to be raised above the hair cuticle (2).
This postulation coincides with our thoughts about the acidity theory of atherosclerosis (3).
References
1) Dogramaci AC et al,Is androgenetic alopecia a risk for atherosclerosis? J Eur Acad Dermatol Venereol. 2009 Jun;23(6):673-7.
2) Marino Salin e Andrea Marliani, EDIZIONI ELETTRONICHE “TricoItalia” (Firenze) marzo 1997, BOLLETTINO della Società Italiana di Tricologia, La Teoria e la Clinica delle “INCIDENZE” nelle Alopecie. Full paper in Italian language at http://www.calvizieinfo.com/bollettino.pdf
3)Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf

Hypertension, atherosclerosis, stress and lactic acid

Hypertension is considered as an important risk factor for the development of atherosclerosis, with these processes sharing some common mechanisms. The endothelium is placed usually as a probable central focus for the effects in both diseases, with evidences leading to the postulation that hypertension predispose and accelerate atherosclerosis. Coronary myocardial-disease is the main death cause in hypertensive patients.
Stress is one of the suggested factors for the hypertension origin and its reduction may help to reduce an elevated blood pressure. Coincidently stress can also contribute for the development and subsequent complications of atherosclerosis what is evidenced in many studies (1).
The key mechanism according the acidity theory of atherosclerosis (1) as the triggering factor for hypertension and atherosclerosis, is the elevation of the lactic acid production in blood. It is interesting to note that lactic acid in blood plasma can have a significant elevation during stress situations , serving as an indicator of stress levels (2, 3). Also, high carbohydrate diet may increase significantly the activity of serum lactate dehydrogenase (4,5). On the other side the concentration of lactic acid in both venous and arterial blood may be significantly elevated in hypertension as showed a study published 45 years ago (6), which results were confirmed recently by the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study, that measured plasma lactate in 2066 older adults. This study came to the conclusion that high plasma lactate was independently associated with the odds of hypertension (7).
1) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
2) Sharda S, Gupta SN and Khuteta KP. 1975. Effect on mental stress on intermediate carbohydrate-and lipid-metabolism. Indian J Physiol Pharmacol. Apr-Jun;19(2):86-9.
3) Hall JB, Brown DA. 1979. Plasma glucose and lactic acid alterations in response to a stressful exam. Biol Psychol. May;8(3):179-88.
4) Marshall MW and Iacono JM (1976). Changes in lactate dehydrogenase, LDH isoenzymes, lactate, and pyruvate as a result of feeding low fat diets to healthy men and women. Metabolism. 1976 Feb;25(2):169-78.
5)Yoshimura T, Miyoshi T, et al. (1986). Effect of high carbohydrate diet on serum lactate dehydrogenase isozyme pattern in Japanese young men. Acta Biol Hung. 1986;37(3-4):243-8.
6) F. E. Demartini, P. J. Cannon, W. B. Stason, and J. H. Laragh. 1965. Lactic Acid Metabolism in Hypertensive Patients. Science 11 June, Vol. 148. no. 3676, pp. 1482 – 1484 em http://www.sciencemag.org/cgi/content/abstract/148/3676/1482
7) Abstract 5003: Association of Blood Lactate with Hypertension: The Atherosclerosis Risk in Communities Carotid MRI Study. J Hunter Young; Stephen O Crawford; Frederick L Brancati; Ron C Hoogeveen; Muhammad Amer; Christie M Ballantyne; Maria I Schmidt; Brad C Astor; Josef Coresh, Circulation. 2008;118:S_1129.), http://circ.ahajournals.org/cgi/content/meeting_abstract/118/18_MeetingAbstracts/S_1129-a

The anti-atherosclerotic effects of cardiac glycosides

A recent study has showed that cardiac glycosides have anti-atherosclerotic effects (1). This was foreseen in the acidity theory of atherosclerosis, because these cardiotonics have properties of reduction of lactic acid concentration in blood and a specific sympathoinhibitory response by blocking the overproduction of catecholamine. (2). Also compatible with the acidity theory concept is the conclusion from the authors of the present study telling that low concentrations of digitoxin would help to avoid side effects and might represent a specific therapeutically option for the treatment of inflammatory cardiovascular disease, such as atherosclerosis.
1) Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis?, Joanna Jagielska, Gustavo Salguero, Bernhard Schieffer, Udo Bavendiek, doi:10.1016/j.atherosclerosis.2009.03.019
2) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf

The potential anti-atherosclerotic effects of proton pump inhibitors

A recent study has shown that calcium phosphate crystals of approximately 1 micron or less in diameter caused rapid rises in intracellular calcium concentration, an effect that was inhibited by the lysosomal proton pump inhibitor, bafilomycin A1 which also blocked vascular smooth muscle cell death. This suggested to the authors that calcium phosphate crystals are rapidly degraded in lysosomes and subsequent acidification leads to the release of calcium into the cell (1)
A study looking to demonstrate that when subintimal macrophages come into contact with LDL aggregates, an extracellular, acidic, hydrolytic compartment (a lysosomal synapse) is formed., with bafilomycin A1 blocking the free cholesterol production in this compartment (2)
Another study has discussed about the potential anti-atherosclerotic effects of proton pump inhibitors (3).
The above studies give great support to the acidity theory of atherosclerosis concept (4)
1) Calcium Phosphate Crystals Induce Cell Death in Human Vascular Smooth Muscle Cells: A Potential Mechanism in Atherosclerotic Plaque Destabilization, Alexandra E. Ewence et al, Circ. Res. 2008;103;e28-e34; at http://circres.ahajournals.org/cgi/content/full/103/5/e28
2) Macrophages Create an Acidic Extracellular Hydrolytic Compartment to Digest Aggregated Lipoproteins, Haka, A.S., I. Grosheva, E. Chiang, A.R. Buxbaum, B.A. Baird, L.M. Pierini and F.R. Maxfield. Mol. Biol. Cell, in press 2009, at http://www.molbiolcell.org/cgi/reprint/E09-07-0559v1
3) The potential anti-xanthoma and anti-atherosclerotic effects of proton pump inhibitors, M. R. Namazi, MD and M. Sharifian, MD. Journal of Clinical Pharmacy and Therapeutics (2008) 33, 579–580
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

LDL oxidation occurs within lysosomes in cells

Recent evidence showed that LDL oxidation occurs not within the interstitial fluid of atherosclerotic lesions but within lysosomes in macrophages in atherosclerotic lesions. Most important, the study found that this oxidative modification was inhibited by the drug chloroquine, which increases the pH of lysosomes, as oxidation can be promoted by acidic pH (1, 2)
1) Low Density Lipoprotein Undergoes Oxidation Within Lysosomes in Cells, Yichuan Wen and David S. Leake, Circ. Res. 2007;100;1337-1343; em http://circres.ahajournals.org/cgi/content/full/100/9/1337
2) 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