Infections May Cause Arterial Inflammation, Atherosclerosis, Myocarditis and Cardiovascular Disease
Main Article Content
Abstract
Effective prevention and treatment of atherosclerosis and cardiovascular disease (CVD), the commonest cause of death in most countries, is still lacking. For many years we have studied the cholesterol hypothesis and found that there are many contradictions to this hypothesis. For instance, no trial has shown exposure response; the lipid values are not associated with degree of atherosclerosis, and people with high LDL-C live just as long or longer than people with low LDL-C. These facts together with the observation that inflammation is a common finding in atherosclerotic arteries have probably contributed to the hypothesis that CVD may be caused by inflammation. However, several trials with anti-inflammatory drugs have shown that such treatment increases the risk of CVD. Therefore, a relevant hypothesis is whether it is infections which cause the inflammation and whether CVD may be caused by infections because many human observations and animal experiments are in accordance with this idea. As cholesterol-lowering treatment is ineffective and may cause serious side effects, we believe that future research should elucidate the importance of infections in the etiology of CVD. A relevant method would be to perform a blood culture on all patients with an acute AMI and if it is positive, to treat the patient with an appropriate antibiotic.
Keywords:
Adventitia, anti-inflammatory drugs, atherosclerosis, cardiovascular disease, infections, inflammation, LDL-cholesterol, macrophages, myocardial infarction, myocarditis, vasa vasorum
Article Details
How to Cite
RAVNSKOV, Uffe; ALABDULGADER, Abdullah; MCCULLY, Kilmer S..
Infections May Cause Arterial Inflammation, Atherosclerosis, Myocarditis and Cardiovascular Disease.
Medical Research Archives, [S.l.], v. 11, n. 5, may 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3866>. Date accessed: 23 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i5.3866.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Ravnskov U, de Lorgeril M, Diamond DM, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Exp Rev Clin Pharm. 2018;11(10):959-970. [PubMed]
2. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016, 6:e010401. [PubMed].
3. Ravnskov U, de Lorgeril M, Diamond DM, et al. The LDL paradox: higher LDL-cholesterol is associated with greater longevity. Ann Epidemiol Pub Health 2000;3(1):1040-1047. [PubMed]
4. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Importance of coagulation factors as critical components of premature cardiovascular disease in familial hypercholesterolemia. Int J Mol Sci 2022;23(16):9146. [PubMed]
5. Mori, Y.; Wada, H.; Nagano, Y, et al. Hypercoagulable state in the Watanabe heritable hyperlipidemic rabbit, an animal model for the progression of atherosclerosis. Effect of probucol on coagulation. Thromb Haemost. 1989;61(1):140-143. [PubMed]
6. Raggi P, Genest J, Giles JT, et al. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic Interventions. Atherosclerosis 2018;276(Sept):98-108. [PubMed]
7. Choi SH, Chae A, Miller E, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma volume: observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Amer Coll Cardiol. 2008;52(1):24-32 [PubMed].
8. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroid-anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330(7504):1366. [PubMed].
9. Johnsen SP, Larsson H, Tarone RE. et al. Risk of hospitalization for myocardial infarction among users of refecoxib, celecoxib, and other NSAIDS. Arch Intern Med 2005;165(9):9789-84. [PubMed]
10. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials. Lancet 2013;382(9894):769-779. [PubMed].
11. Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ 2017;357:j1909. [PubMed].
12. Wudexi I, Shokri E, Abo-Aly M, Shindo K, Abdel-Latif A. Comparative effectiveness of anti-inflammatory drug treatments in coronary heart disease patients: A systematic review and network meta-analysis. Mediators Inflamm. 2021;5160728. [PubMed].
13. Niu Y, Bai N, Ma V, et al. Safety and efficacy of anti‑inflammatory therapy in patients with coronary artery disease: a systematic review and meta‑analysis. BMC Cardiovasc Disord 2022;22:84-95. [PubMed].
14. Higuchi ML, Gutierrez PS, Bezerra HG, et al. Comparison between adventitial and intimal inflammation of ruptured and nonruptured atherosclerotic plaques in human coronary arteries. Arq Bras Cardiol. 2002;79(1):20-24. [PubMed].
15. Higuchi ML, Sambiase N, Palomino S, et al. Detection of mycoplasma pneumoniae and chlamydia pneumoniae in ruptured atherosclerotic plaques. Braz J Med Biol Res 2000; 33(9):1023-1026. [Pub Med].
16. Maiellaro K, Taylor WR. The role of the adventitia in vascular inflammation. Cardiovasc Res 2007;75(4):640-648. [PubMed].
17. Hirata Y, Tabata M, Kurobe H, et al. Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Amer Coll Cardiol 2011;58:248-25. DOI: 10.1016/j.jacc.2011.01.048 [PubMed].
18. Ito H, Wakatsuki T, Yamaguchi K, et al. Atherosclerotic coronary plaque is associated with adventitial vasa vasorum and local inflammation in adjacent epicardial adipose tissue in fresh cadavers. Circ J. 2020;84(5),769-775 [PubMed].
19. Thayer WS. On the cardiac and vascular complications and sequels of typhoid fever. Bull Johns Hopkins Hosp. 1904, Oct, 323-340.
20. Osler, W. Diseases of the arteries. In: Modern Medicine: Its practice and theory (Osler W, Ed), Lea & Fibiger, Philadelphia, 1908; pp 426-447.
21. Klotz O, Manning MF. Fatty streaks in the intima of arteries. J Pathol Bacteriol. 1911;16(1):211-220 [PubMed].
22. Pesonen, E. Infection and intimal thickening: evidence from coronary arteries in children. Eur Heart J 1994;15(Suppl C):57-61 [PubMed].
23. Liuba P, Persson J, Luoma J, Yla-Hertuala S, Pesonen E. Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL, and are followed by thickening of carotid intima-media. Eur Heart J. 2003;24(6):515-521 [PubMed].
24. Piconi S, Trabattoni D, Luraghi C, et al. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J. 2009;23:1196-1204 [PubMed].
25. Zeng XT, Leng WD, Lam YY. Periodontal disease and carotid atherosclerosis: A meta-analysis of 17,330 participants. Int J Cardiol. 2016;203:1044-1051. [PubMed].
26. Sanz, M.; Marco Del Castillo, A.; Jepsen, S, et al. Periodontitis and cardiovascular diseases: consensus report. J Clin Periodontol. 2020;47(3),268–288 [PubMed].
27. Zemedikun DT, Chandan JS , Raindi D, et al. Burden of chronic diseases associated with periodontal diseases: a retrospective cohort study using UK primary care data. BMJ Open 2021;11:e048296. [PubMed]
28. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci. 2009;39(1):3-16 [PubMed].
29. Ravnskov U; McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Amer J Med Sci. 2012;344(5):391-394 [PubMed].
30. Pak A, Eisen DP, McBryde ES, Adegboye OA. Hospitalisation for lower respiratory tract infection is associated with an increased incidence of acute myocardial infarction and stroke in tropical Northern Australia. Sci Reports. 2021;11(1):6828 [PubMed].
31. McNamara JF, Harris PNA, Chatfield MD, Paterson DL. Acute myocardial infarction and community-acquired staphylococcus aureus bloodstream infection: An observational cohort study. Clin Infect Dis. 2021;73(9):e2647–e2655. [PubMed]
32. Angriman F, Rosella LC, Lawler PR, et al. Sepsis hospitalization and risk of subsequent cardiovascular events in adults: a population-based matched cohort study. Intens Care Med. 2022;48:448-457. [PubMed]
33. We KC, Sy CL, Wang WH. Major acute cardiovascular events after dengue infection – A population-based observational study. PLoS Negl Trop Dis. 2022; 6(2):e0010134 2022. [PubMed]
34. Ott SJ, El Mokhtari NE, Musfeldt M, et al. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation 2006;113(7):929-937 [PubMed].
35. Shi Y, Tokunaga O. Chlamydia pneumoniae and multiple infections in the aorta contribute to atherosclerosis. Pathol Int. 2002;52(12):755-763. [PubMed]
36. Chatzidimitriou D, Kirmizis D, Gavriilaki E, Chatzidimitriou M, Malisiovas N. Atherosclerosis and infection: is the jury still not in? Future Microbiol 2012;7(10): 1217–1230. [PubMed]
37. Birck MM, Pesonen E, Odermarsky M, et al. Infection-induced coronary dysfunction and systemic inflammation in piglets are dampened in hypercholesterolemic milieu. Amer J Physiol. Heart Circ Physiol. ;300(5):H1595-1601. [PubMed].
38. Syada K, Yokota K, Hirai K, et al. Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis. Lupus 2009;18(13):1154-1168. [PubMed]
39. Piconi S, Trabattoni D, Luraghi C, et al. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J 2009;23:1196-1204. [PubMed]
40. McCully KS. Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci. 2009;39(3):219-232. [PubMed]
41. Madjid, M.; Naghavi, M; Malik BA, et al. Thermal detection of vulnerable plaque. Amer. J. Cardiol. 2002;90(10C):36L-39L. [PubMed].
42. Hammadah M, Mheid IA, Wilmot K, Ramadan R, Shah AJ, Sun Y, et al. The mental stress ischemia prognosis study: Objectives, study design, and prevalence of inducible ischemia. Psychosom Med 2007;79:311-17. doi: 10.1097/PSY.0000000000000442 [PubMed].
43. Grignani G, Soffiantino F, Zucchella M, et al. Platelet activation by emotional stress in patients with coronary artery disease. Circulation 1991;83(4 Suppl):128-136. PubMed]
44. Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med. 1982;44(5):413-430. [PubMed]
45. Rosenman RH. Relationships of neurogenic and psychological factors to the regulation and variability of serum lipids. Stress Med 1993;9(3):133-140. [PubMed]
46. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev Clin Pharmacol 2015;8/2):201–210. [PubMed],
47. Kohsaka S, Menon V, Lowe AM, et al. Systemic inflammation response syndrome after acute myocardial infection complicated by cardiogenic shock. Arch Intern Med. 2005; 165(14):1643-1650. [PubMed].
48. Ravnskov U, Alabdulgader A, de Lorgeril M, et al. The new European guidelines for prevention of cardiovascular disease are misleading. Exp Rev Clin Pharmacol. 2020;13(12):1289-1294. [PubMed]
2. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016, 6:e010401. [PubMed].
3. Ravnskov U, de Lorgeril M, Diamond DM, et al. The LDL paradox: higher LDL-cholesterol is associated with greater longevity. Ann Epidemiol Pub Health 2000;3(1):1040-1047. [PubMed]
4. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Importance of coagulation factors as critical components of premature cardiovascular disease in familial hypercholesterolemia. Int J Mol Sci 2022;23(16):9146. [PubMed]
5. Mori, Y.; Wada, H.; Nagano, Y, et al. Hypercoagulable state in the Watanabe heritable hyperlipidemic rabbit, an animal model for the progression of atherosclerosis. Effect of probucol on coagulation. Thromb Haemost. 1989;61(1):140-143. [PubMed]
6. Raggi P, Genest J, Giles JT, et al. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic Interventions. Atherosclerosis 2018;276(Sept):98-108. [PubMed]
7. Choi SH, Chae A, Miller E, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma volume: observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Amer Coll Cardiol. 2008;52(1):24-32 [PubMed].
8. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroid-anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330(7504):1366. [PubMed].
9. Johnsen SP, Larsson H, Tarone RE. et al. Risk of hospitalization for myocardial infarction among users of refecoxib, celecoxib, and other NSAIDS. Arch Intern Med 2005;165(9):9789-84. [PubMed]
10. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials. Lancet 2013;382(9894):769-779. [PubMed].
11. Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ 2017;357:j1909. [PubMed].
12. Wudexi I, Shokri E, Abo-Aly M, Shindo K, Abdel-Latif A. Comparative effectiveness of anti-inflammatory drug treatments in coronary heart disease patients: A systematic review and network meta-analysis. Mediators Inflamm. 2021;5160728. [PubMed].
13. Niu Y, Bai N, Ma V, et al. Safety and efficacy of anti‑inflammatory therapy in patients with coronary artery disease: a systematic review and meta‑analysis. BMC Cardiovasc Disord 2022;22:84-95. [PubMed].
14. Higuchi ML, Gutierrez PS, Bezerra HG, et al. Comparison between adventitial and intimal inflammation of ruptured and nonruptured atherosclerotic plaques in human coronary arteries. Arq Bras Cardiol. 2002;79(1):20-24. [PubMed].
15. Higuchi ML, Sambiase N, Palomino S, et al. Detection of mycoplasma pneumoniae and chlamydia pneumoniae in ruptured atherosclerotic plaques. Braz J Med Biol Res 2000; 33(9):1023-1026. [Pub Med].
16. Maiellaro K, Taylor WR. The role of the adventitia in vascular inflammation. Cardiovasc Res 2007;75(4):640-648. [PubMed].
17. Hirata Y, Tabata M, Kurobe H, et al. Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Amer Coll Cardiol 2011;58:248-25. DOI: 10.1016/j.jacc.2011.01.048 [PubMed].
18. Ito H, Wakatsuki T, Yamaguchi K, et al. Atherosclerotic coronary plaque is associated with adventitial vasa vasorum and local inflammation in adjacent epicardial adipose tissue in fresh cadavers. Circ J. 2020;84(5),769-775 [PubMed].
19. Thayer WS. On the cardiac and vascular complications and sequels of typhoid fever. Bull Johns Hopkins Hosp. 1904, Oct, 323-340.
20. Osler, W. Diseases of the arteries. In: Modern Medicine: Its practice and theory (Osler W, Ed), Lea & Fibiger, Philadelphia, 1908; pp 426-447.
21. Klotz O, Manning MF. Fatty streaks in the intima of arteries. J Pathol Bacteriol. 1911;16(1):211-220 [PubMed].
22. Pesonen, E. Infection and intimal thickening: evidence from coronary arteries in children. Eur Heart J 1994;15(Suppl C):57-61 [PubMed].
23. Liuba P, Persson J, Luoma J, Yla-Hertuala S, Pesonen E. Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL, and are followed by thickening of carotid intima-media. Eur Heart J. 2003;24(6):515-521 [PubMed].
24. Piconi S, Trabattoni D, Luraghi C, et al. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J. 2009;23:1196-1204 [PubMed].
25. Zeng XT, Leng WD, Lam YY. Periodontal disease and carotid atherosclerosis: A meta-analysis of 17,330 participants. Int J Cardiol. 2016;203:1044-1051. [PubMed].
26. Sanz, M.; Marco Del Castillo, A.; Jepsen, S, et al. Periodontitis and cardiovascular diseases: consensus report. J Clin Periodontol. 2020;47(3),268–288 [PubMed].
27. Zemedikun DT, Chandan JS , Raindi D, et al. Burden of chronic diseases associated with periodontal diseases: a retrospective cohort study using UK primary care data. BMJ Open 2021;11:e048296. [PubMed]
28. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci. 2009;39(1):3-16 [PubMed].
29. Ravnskov U; McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Amer J Med Sci. 2012;344(5):391-394 [PubMed].
30. Pak A, Eisen DP, McBryde ES, Adegboye OA. Hospitalisation for lower respiratory tract infection is associated with an increased incidence of acute myocardial infarction and stroke in tropical Northern Australia. Sci Reports. 2021;11(1):6828 [PubMed].
31. McNamara JF, Harris PNA, Chatfield MD, Paterson DL. Acute myocardial infarction and community-acquired staphylococcus aureus bloodstream infection: An observational cohort study. Clin Infect Dis. 2021;73(9):e2647–e2655. [PubMed]
32. Angriman F, Rosella LC, Lawler PR, et al. Sepsis hospitalization and risk of subsequent cardiovascular events in adults: a population-based matched cohort study. Intens Care Med. 2022;48:448-457. [PubMed]
33. We KC, Sy CL, Wang WH. Major acute cardiovascular events after dengue infection – A population-based observational study. PLoS Negl Trop Dis. 2022; 6(2):e0010134 2022. [PubMed]
34. Ott SJ, El Mokhtari NE, Musfeldt M, et al. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation 2006;113(7):929-937 [PubMed].
35. Shi Y, Tokunaga O. Chlamydia pneumoniae and multiple infections in the aorta contribute to atherosclerosis. Pathol Int. 2002;52(12):755-763. [PubMed]
36. Chatzidimitriou D, Kirmizis D, Gavriilaki E, Chatzidimitriou M, Malisiovas N. Atherosclerosis and infection: is the jury still not in? Future Microbiol 2012;7(10): 1217–1230. [PubMed]
37. Birck MM, Pesonen E, Odermarsky M, et al. Infection-induced coronary dysfunction and systemic inflammation in piglets are dampened in hypercholesterolemic milieu. Amer J Physiol. Heart Circ Physiol. ;300(5):H1595-1601. [PubMed].
38. Syada K, Yokota K, Hirai K, et al. Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis. Lupus 2009;18(13):1154-1168. [PubMed]
39. Piconi S, Trabattoni D, Luraghi C, et al. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J 2009;23:1196-1204. [PubMed]
40. McCully KS. Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci. 2009;39(3):219-232. [PubMed]
41. Madjid, M.; Naghavi, M; Malik BA, et al. Thermal detection of vulnerable plaque. Amer. J. Cardiol. 2002;90(10C):36L-39L. [PubMed].
42. Hammadah M, Mheid IA, Wilmot K, Ramadan R, Shah AJ, Sun Y, et al. The mental stress ischemia prognosis study: Objectives, study design, and prevalence of inducible ischemia. Psychosom Med 2007;79:311-17. doi: 10.1097/PSY.0000000000000442 [PubMed].
43. Grignani G, Soffiantino F, Zucchella M, et al. Platelet activation by emotional stress in patients with coronary artery disease. Circulation 1991;83(4 Suppl):128-136. PubMed]
44. Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med. 1982;44(5):413-430. [PubMed]
45. Rosenman RH. Relationships of neurogenic and psychological factors to the regulation and variability of serum lipids. Stress Med 1993;9(3):133-140. [PubMed]
46. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev Clin Pharmacol 2015;8/2):201–210. [PubMed],
47. Kohsaka S, Menon V, Lowe AM, et al. Systemic inflammation response syndrome after acute myocardial infection complicated by cardiogenic shock. Arch Intern Med. 2005; 165(14):1643-1650. [PubMed].
48. Ravnskov U, Alabdulgader A, de Lorgeril M, et al. The new European guidelines for prevention of cardiovascular disease are misleading. Exp Rev Clin Pharmacol. 2020;13(12):1289-1294. [PubMed]