Inflammation plays a crucial role in the pathogenesis of arteriosclerosis, especially in acute coronary syndromes such as happen with a heart attack. And it was the very inability of ‘established’ risk factors such as high blood cholesterol (hypercholesterolemia), high blood pressure (hypertension) and smoking to fully explain the incidence of cardiovascular disease that has resulted in historically repeated calls to search out an infectious cause and the specific microbe behind it. Today, half of US heart victims have acceptable cholesterol levels, including HDL and LDL fractions, and 25% or more have none of the “risk factors” associated with heart disease, including smoking, high blood pressure or obesity, most of which are not inconsistent with being caused by infection to begin with. [1,2] Cholesterol itself was on the rise in Japanese blood during the very decade (1980-1989) when its incidence in coronary heart disease was on its way down.  So Nieto stressed the need to continue to look for an infectious disease behind heart disease. [3}
Ever since a 1988 report of raised antibodies against Chlamydia pneumoniae in patients with heart disease, it was hoped that this microbe might be behind heart disease and atherosclerosis  Hurting this was the low incidence of atherosclerosis in the tropics despite Chlamydia’s high frequency there. . Also Loehe, Bittman and other groups concluded that although Chlamydia, on occasion, might be present, it was not a causative factor in heart disease , because there was no correlation between the severity or extent of atherosclerosis and the involvement of chlamydial infection. Recently the Chlamydial hypothesis has been subject to a flurry of antibiotic trials, with mixed results, leaving some investigators to conclude that possibly Chlamydia doesn’t even play a role in atherosclerosis.  Certainly this was born out in two sizeable trials, one of which  had 1,187 participant. In neither trial  could any of the commonly thought of bacterial causes of heart problems – Chlamydia pneumonia and Helobacter pylori be correlated with cardiovascular disease. Nor could a virus. Also, in those trials which did show benefit antibiotics used (Azithromycin, Clarithromycin) are first line agents against certain forms of tuberculosis (fowl tuberculosis or Mycobacterium avium). Contrary to common belief, TB infections occur as a mixed infection with “atypical” TB in up to 11% of cases, even in HIV free individuals.  Today the antibiotic Rapamycin is used to coat coronary stents.  Rapamycin enhances the killing of mycobacteria like tuberculosis by human white blood cells called macrophages. 
The association between active pulmonary tuberculosis and Acute Myocardial Infarction or heart attack has been reported and stubbornly ignored for around four and a half decades. Certainly, TB shares a more striking connection to heart disease than its nearest competitor, Chlamydia pneumonia. CDC maps for cardiovascular disease case rates bear a striking resemblance to comparable state and regional tuberculosis maps. [4,5]
Long before there was such a thing as a ‘heart specialist’ The National Tuberculosis Association created an offshoot called the American Heart Association (AHA). In one of its first bulletins, the American Heart Association came up with a long list of similarities between tuberculosis and heart disease.  And Ellis’s 1977 New England Journal of Medicine article , confirmed that the mortality rate for TB and heart disease were curiously about the same: 200 to 300 persons per 100,000.
By 1965, Rutgers investigators Livingston and Alexander-Jackson, working with sterile, post-catastrophic coronary artery and muscle specimens, established low-grade tubercular infection, staining ‘acid-fast’ (stains which did not decolorize when acid-alcohol was added) occuring in all ischemic heart specimens.  In that same year Russian investigators began generating their own proof that tuberculosis was causative in both atherosclerotic heart disease [18,19,20,21] and acute myocardial infarction (a heart attack) itself. [13,14,15].
Measuring Heart Trouble With Cardiac Enzymes In The Blood
Cases were soon on record of individuals with no cardiac risk factors, presenting with acute onset chest pain, ST elevation on their electrocardiogram (EKG), and elevated cardiac enzymes – all indicative of a heart attack with no other involvement than pulmonary tuberculosis . As with its predecessor creatine kinase (CK-MB), today’s new enzymatic gold standard for detecting a heart attack, the troponins, are elevated in disseminated tuberculosis, an example of which can be found in TB’s role in acute pericarditis. . Acute pericarditis, often not detected either until death was historically linked most commonly to Mycobacterium tuberculosis. In 1951, Christian  suggested that viral infection was more responsible for “idiopathic” (of unknown cause) or “benign” pericarditis. Such a viral cause, however, was never substantiated in many cases. Also, when it was found that the fatty substance (phospolipid) phosphatidylinositol was not only housed itself inside TB’s cell wall, but was a potent coagulant and thrombin former as well – it further raised the question as to whether M. tuberculosis, by its very nature, lays down the conditions for the vessel clogging atherosclerosis behind heart disease and myocardial infarctions or heart attacks. 
Livingston and Alexander-Jackson  were far from the first ones to document lab evidence that TB can cause heart disease. Hektoen , Osler , and Schwartz , all documented lab and animal evidence to this effect. MacCallum  claimed that of all the infectious causes of heart disease, one one, tuberculosis, caused arteriosclerosis. At autopsy MacCallum cited 101 cases of advance tuberculous arteriosclerosis. In separate studies, Kossowsky , Tarakanova  and Ferrari-Sacco  all directly linked heart attacks with pulmonary tuberculosis.
There can no longer be any doubt that tubercular protein HSP-65 is involved in atherosclerosis. Xu  used it to cause experimental atherosclerosis in laboratory animals with normal cholesterol. George and Shoenfeld found it not only in atherosclerosis but fatty streak formation in cardiovascular blood vessels.  Mukherjee and De Benedictis showed also that the higher the antibodies against such tubercular protein in the body, the higher the possibility of “restenosis” or future closure of heart vessels. Also Afek proved that the higher the amount of tuberculoprotein (HSP-65) administered, the larger the area of vessel clogging atherosclerosis, even despite a low-fat diet.  Xu saw similar changes in New Zealand White Rabbits.  Xu’s rabbits had normal serum cholesterol, but when injected with tubercular protein, their arteries soon developed the classic features of arteriosclerosis in humans – both with regards to inflammatory cell accumulation and smooth cell proliferation. [IBID]. The only finding missing from Xu’s animals were “foam cells” – fat laden tissue white blood cells called macrophages in which tuberculosis lives and thrives. Xu remedied this by subjecting his animals to a cholesterol rich diet in addition to tubercular protein. this combination produced classic human heart disease, with foam cells. Xu continued to find sustained antibodies to HSP-65 in human subjects with the severe atherosclerosis predictive of mortality.  By 2004 Mandal and Xu even confirmed a positive association between high levels of antibodies to HSP-65, which are cytotoxic, and the vexing atrial fibrillation that often accompanies cardiac surgery. 
Present day heart disease “markers” have been suggest as indicators of possible heart disease, even in the 25 million US patients who have none of its “risk factors”. These include blood test for C-Reactive Protein (CRP), interleukin-6 and homocysteine  – all of which are similarly elevated in tuberculosis. [32,33,34,40,36].
Although blood cholesterol seems an imperfect criterion by itself for determining coronary heart disease, its intimate interaction with TB is unique. Tuberculosis is the only microorganism to depend on cholesterol for its destructive pathogenesis, and it relies upon cholesterol to enter the body’s white blood cell macrophages.  The tuberculous bacilli alone is able to produce , esterify , take up, modify, accumulate , and promote the deposition of, and release  of cholesterol. The statins, among the most popular drugs in America (Lipitor), inhibit Coenzyme-A compounds, and as such lower serum cholesterol levels. But they do more. Specifically, when macrophages were depleted of cholesterol by these agents, it hinders tuberculosis’s entrance into the body’s macrophages that TB likes to house in, thrive in, and depends upon. 
Nieto concludes that the introduction of antibiotic therapies in the 1940’s and 1950’s could have contributed to the decline of heart disease and heart attacks, and so, by 2000, the CDC found that 14% of the cardiologists in Alaska and West Virginia treated heart patients with antibiotics for angina, heat attacks, angioplasty or after by-pass surgery.
In Tuberculosis in Disguise, Rab and Rahman report cases of congestive heart failure and ischemic heart disease (IHD) with chest pain, raised erythrocyte sedimentation rate, leukocytosis (elevated white cell count) and inverted T-waves across the chest leads in an Electrocardiogram – otherwise indistinguishable from a heart attack, which turned out to be miliary (systemic) tuberculosis. 
Though more than 120 years have passed since its discovery Mycobacterium tuberculosis is still the leading cause of infectious death globally due to a single infectious agent. At least a staggering 1.7 million around the globe die of tuberculosis each year, while another 1.9 million are infected and at risk for active tubercular disease.  The World Health Organization [WHO] estimates that 1/3 of the planet has contracted TB. It would take such a disease of such magnitude to adequately explain the scope of cardiovascular disease, which affects, according to the CDC (Centers for Disease Control) about 61 million people, or almost one-fourth of the population of the US alone. Almost 6 million US hospitalizations each year are due to cardiovascular disease, which has become an equal opportunity disease that is now both the leading cause of death among women as well as the general US population.
There is at least as much, and probably much more evidence that Mycobacteria, particularly Mycobacterium tuberculosis causes cardiovascular disease than there is regarding Chlamydia Pneumoniae. Yet oddly, to this point Chlamydia has been pursued in therapeutic antibiotic trial after trial…………with not one such trial directed towards tuberculosis.
1. Benson RL, Smith KG. Experimental arteritis and arteriosclerosis associated with streptococcal inoculations. Arch Pathol 1931;12:924–40.
2. Thom DH, Grayston JT. Association of prior infection with Chlamydia pneumoniae and angiographically demonstrated coronary artery disease. JAMA 1992;268:68–72.
3. Nieto FJ. Infections and atherosclerosis: new clues from an old hypothesis. Am J Epidemiol 1998;148(10):937–48.
4. CDC Map: TB case rates, United States, 2001. Atlanta Georgia: US Department of Health, Education and Welfare CDC; 2001.
5. CDC Map total cardiovascular disease – 1995 death rate. Atlanta Georgia: US Department of Health, Education Welfare CDC; 1995.
6. Ellis JG. Plague tuberculosis and plague atherosclerosis. The New England J Med 1977;296(12):695.
7. Hektoen L. The vascular changes of tuberculous meningitis. J Exper Med 1986:112.
8. Osler W. Diseases of the arteries. In: Osler W, MacCrae T, editors. Modern medicine Its theory and practice in original contributions by Americans and foreign authors, vol. 4. Philadelphia, PA: Lea & Fabiger; 1908. p. 426–47.
9. MacCallum WG. Acute and chronic infections as etiological factors in arteriosclerosis. In: Cowdry EV, editor. Arteriosclerosis A survey of the problem. New York: MacMillan Co; 1933. p. 355–62.
10. Schwartz P. Amyloid degeneration and tuberculosis in the aged. Gerontologia 1972;18(5-6):321–62.
11. Livingston V. Cancer: a new breakthough. Los Angeles: Nash Publishing; 1972.
12. Xu Q. Dietrich Induction of arteriosclerosis in normocholesterolemic mice and rabbits by immunization with heat shock protein 65. Arterioscler Thromb 1992;12:789–99.
13. Kossowsky WA, Rafii S. Letter: acute myocardial infarction in miliary tuberculosis. Ann Intern Med 1975;82(6):813–4.
14. Tarakanova KN, Terent’eva GM. Myocardial infarct in patients with pulmonary tuberculosis. Probl Tuberk 1972;50(4):90–1.
15. Ferrari-Sacco A, Ferraro U. Myocardial Infarct and Pulmonary Tuberculosis. Discussion of 2 cases of myocardiocoronary disease appearing during hospitalization in a sanatorium. Minerva Cardioangiol 1966;14(8):465–75.
16. Dye C, Scheele S. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999;282:677–86.
17. AHA Similarity of tuberculosis and heart disease. Bull Am Heart Assoc 1927;2(5):22.
18. Bruade VI. Cardiovascular diseases in conjunction with pulmonary tuberculosis (pathological-anatomical findings). Sov Med 1966;29(12):104–7.
19. Kamyshnikova VS, Kolb VG. Biochemical factors involved in atherogenesis in pulmonary tuberculosis. Probl Tuberk 1984;11:48–52.
20. Kazykhanov NS. Lung tuberculosis in patients with atherosclerosis. Sov Med 1965;28(8):37–44.
21. Kazykhanov NS. Arteriosclerosis in patients with pulmonary tuberculosis. Kardiologiia 1967;7(10):137.
22. Okayama A. Ueshima changes in total serum cholesterol and other risk factors for cardiovascular disease in Japan, 1980–1989. Int J Epidemiol 1993;22:1038–47.
23. Gatfield J, Pieters J. Essential role for cholesterol in entry of mycobacteria in macrophages. Science 2000;288:1647–750.
24. Lamb DC, Kelly DE. A sterol biosynthetic pathway in mycobacterium. FEBS Lett 1998;437(1-2):142–4.
25. Kondo E, Kanai K. Accumulation of cholesterol esters in macrophages incubated with mycobacteria in vitro. Jpn J Med Sci Biol 1976;29(3):123–37.
26. Av-Gay Y, Sobouti R. Cholesterol is accumulated by mycobacteria but its degradation is limited to non-pathogenic Heart disease: the greatest ‘risk’ factor of them all 777 fast growing mycobacteria. Can J Microbiol 2000;46(9):826–31.
27. Kamyshnikov VS, Kolb VG. Lipid metabolism and atherogenesis in tuberculosis in experimental animals. Probl Tuberk 1993;4:53–5.
28. Gurfinkel E, Bozovich G. Chlamydia pneumoniae: inflammation and instability of the atherosclerotic plaque. Atherosclerosis 1998;140(Suppl 1):31–5.
29. Stille W, Dittmann R. Arteriosclerosis as a sequela of chronic Chlamydia pneumoniae infection. Herz 1998;23(3):185–92.
30. Loehe F, Bittmann I. Chlamydia pneumoniae in atherosclerotic lesions of patients undergoing vascular surgery. Ann Vasc Surg 2002;16(4):467–73.
31. Rota S Rota S Mycobacterium tuberculosis Complex in Atherosclerosis Acta. Med. Okayama 59:6 pp.247-251 2005
32. George J, Shoenfeld Y. Enhanced fatty streak formation in C57BL/6J Mice by immunization with heat shock protein-65 arteriosclerosis. Thromb Vasc Biol 1999;19:505–10.
33. Mukherjee M. De Benedictis association of antibodies to heat-shock protein-65 with percutaneous transluminal coronary angioplasty and subsequent restenosis. Thromb Haemost 1996;75(2):258–60.
34. Afek A, George J. Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis. J Autoimmun 2000;14(2):115–21.
35. Xu Q, Kleindienst R. Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65. J Clin Invest 1993;91:2693–702.
36. Markkansen T, Levanto A. Folic acid and vitamin B12 in tuberculosis. Scand J Haemat 1967;4:283–91.
37. Bakalli A Osmani B Acute myocardial infarction and pulmonary tuberculosis in a young female patient: a case report Cases Journal 1: 246 2008
38. Rab SM, Rahman M. Tuberculosis in disguise. Brit J Dis Chest 1967;61:90–4.
39. Wilson PW. Homocysteine and coronary heart disease: how great is the hazard? JAMA 2002;288(16):2042–3.
40. Bajaj G, Rattan A. Prognostic value of ‘C’ reactive protein in tuberculosis. Indian Pediatr 1989;26(10):1010–3.
41. Tsukamura M, Mizuno S. Occurrence of Mycobacterium tuberculosis and strains of the Mycobacterium avium- M. intracellulare complex together in the sputum of patients with pulmonary tuberculosis. Tubercle 1981;62:43-46.
42. Pislru S Van de Werf F Editorial: Antibiotic Therapy for Coronary Artery Disease. Can Wizard Change It All? JAMA. 2003;290: 1515-1516
43. Imazio M Demichelis B Cardiac Troponin I in Acute Pericarditis Journal of the American College of Cardiology Vol.42, No. 12 pp. 2144-2148 2003
44. Christian HA Nearly ten decades of interest in idiopathic pericarditis Am. Heart J. 42:654 1961
45. Li YL Wan Z Comparison of Sirolimus- and Paclitaxel-Eluting Stents in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction: A Meta-analysis of Randomized Trials. Clin Cardiol. 2010 Sep;33(9):583-90.
46. Floto AF Sarkar S Perlstein EO Addendum: Small Molecule Enhancers of Rapamycin-Induced TOR Inhibition Promote Autophagy, Reduce Toxicity in Huntington’s Disease Models and Enhance Killing of Mycobacteria by Macrophages. Autophagy Landes Bioscience 3:6, 620-622; November/December 2007.
47. Haider AW Wilson PW The association of seropositivity to Helicobacter pylori, Chlamydia pneumonia, and cytomegalovirus with risk of cardiovascular disease: a prospective study. J. Am Coll Cardiol. 2002 Oct 16;40(8):1408-13.
48. Ridker PM Kundsin RB Prospective study of Chlamydia pneumonia IgG seropositivity and risks of future myocardial infarction. Circulation 1999 Mar 9;99(9):1161-4.
49. Xu Q Kiechl S Association of Serum Antibodies to Heat-Shock Protein 65 With Carotid Atherosclerosis – Clinical Significance Determined in a Follow-Up Study Circulation 1999;100:1169-1174.
50. Mandal K Jahangiri M Association of Anti-Heat Shock Protein 65 Antibodies With Development of Postoperative Atrial Fibrillation. Circulation 2004;110:2588-2590.