The importance of LDL-cholesterol and infection in the etiology of cardiovascular disease: a meta-analysis of COVID-19 survivors and non-survivors
Main Article Content
Abstract
Object: As cardiovascular mortality has increased during the COVID-19 epidemic, and as low-density-lipoprotein cholesterol (LDL-C) participates in the immune system, we examined whether infection is a more serious risk factor for cardiovascular disease (CVD) than elevated LDL-C.
Method: In a systematic search identifying cohort studies of COVID-19 patients we identified 21 studies including 25.647 patients with COVID-19 where LDL-cholesterol was compared with mortality.
Results: In 20 of the 21 cohorts where LDL-C was compared with mortality, LDL-C was lowest among the non-survivors and with statistical significance in 19 of the studies. LDL-C was highest among non-survivors in one cohort that included only 250 patients and the difference was not statistically significant. In three reviews, the authors found that severity of COVID-19 was also more prominent among patients with low LDL-C.
Conclusions: The results are in accordance with the hypothesis that LDL-C participates in the immune system by adhering to and inactivating almost all kinds of microorganisms and their toxic products. The results contradict the general view that low LDL-C protects against CVD. Obviously, infection is a more serious risk factor for CVD than high LDL-C. To verify this hypothesis, blood cultures should be performed in all patients with acute myocardial infarction (AMI) and if positive, appropriate antibiotic therapy should be administered.
Keywords:
LDL-cholesterol • COVID-19 • inflammation • infection • hypothesis • statin • cardiovascular disease • ox-LDL • bacteremia • sepsis • mortality
Article Details
How to Cite
RAVNSKOV, Uffe; MCCULLY, Kilmer S..
The importance of LDL-cholesterol and infection in the etiology of cardiovascular disease: a meta-analysis of COVID-19 survivors and non-survivors.
Medical Research Archives, [S.l.], v. 12, n. 5, may 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5363>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i5.5363.
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
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2. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Exp Rev Clin Pharm 2015;8:201–210.
3. Dubroff R. Cholesterol paradox: a correlate does not a surrogate make. BMJ Evidence-Based Med 2017;22:15-19.
4. Okuyama H, Hamazaki T, Hama R, et al. A critical review of the consensus statement from the European atherosclerosis society consensus panel 2017. Pharmacology 2018;101:184–218.
5. 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;11:959–970.
6. Byrne P, Demasi M, Jones M, et al. Evaluating the association between low-density lipoprotein cholesterol reduction and relative and absolute effects of statin treatment. A systematic review and meta-analysis. JAMA Intern Med 2022;182:474-481.
7. Nilsson G, Leppert J, Ohrvik J. Enigma of the cholesterol paradox in acute myocardial infarction: lessons from an 8-year follow-up of all-cause mortality in an age-matched and sex-matched case–control study with controls from the patients’ recruitment area. BMJ Open 2022;12:e057562.
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9. Durai V., Redberg R. Statin therapy for the primary prevention of cardiovascular disease: Cons. Atherosclerosis 2022;356:46-49.
10. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Importance of coagulation factors as critical components of premature cardiovascular disease in familial hypercholesterolemia. Internat J Mol Sci. 2022;23:9146
11. 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].
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13. Ridker PM, Bhatt DL, Pradhan AD. et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023;401:1293-1301.
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16. Johnsen SP, Larsson H, Tarone R, et al. Risk of hospitalization for myocardial infarction among users of refecoxib, celecoxib, and other NSAIDS. Arch Intern Med. 2005;165:978-984.
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18. 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
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20. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Amer J Med Sci. 2012;344;391-394.
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27. Mahat RK, Rathore V, Singh N, et al. Lipid profile as an indicator of COVID-19 severity: A systematic review and meta-analysis. Clin Nutr ESPEN. 2021, 45, 91-101.
28. Zinellu A, Paliogiannis P, Fois AG, et al. Cholesterol and triglyceride concentrations, COVID-19 severity, and mortality: A systematic review and meta-analysis with meta-regression. Front Pub Health. 2021, 9, 705916.
29. Chidambaram V, Geetha HS, Kumar A, et al. Association of lipid levels with COVID-19 infection, disease severity and mortality: a systematic review and meta-analysis. Front Cardiovasc Med 2022, 9, 862999.
30. Anushiravani A, Khosravi B, Saberzadeh-Ardestani B, et al. A reliable prognostic marker for liver dysfunction in COVID-19 infection. Middle East Digest Dis. 2021;13:193-199
31. Aparisi A, Iglesias-Echeverria C, Ybarra-Falcón C, et al. Low-density lipoprotein cholesterol levels are associated with poor clinical outcomes in COVID-19. Nutrit Metabol Cardiovasc Dis 2021;31,2619-2627.
32. Aydin SS, Aksakal E, Aydinyilomaz F, et al. Relationship between blood lipid levels and mortality in hospitalized COVID-patients. Angiology 2022;73:724-733.
33. Barman HA, Pala AS, Dogan O, et al. Prognostic significance of temporal changes of lipid profile in COVID-19 patients. Obes Med. 2021;28:34671707
34. Chen FF, Zhong M, Liu Y, et al. The characteristics and outcomes of 681 severe cases with COVID-19 in China. J Crit Care. 2020;60:32-37.
35. Fabre B, Machulsky NF, Olano C, et al. Remnant cholesterol levels are associated with severity and death in COVID-19 patients. Sci Reports. 2022;12:17584.
36. Fan J, Wang H, Ye G, et al. Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019. Metabolism 2020;107:154243.
37. Khalilzadeh F, Sakhaee F, Sotoodehnejadnematalahi F, et al. Angiotensin‐converting enzyme 2 rs2285666 polymorphism and clinical parameters as the determinants of COVID‐19 severity in Iranian population. Internat J Immunogen 2022;49: 325-332.
38. Li Y, Zhang Y. Dai M, et al. Lipid metabolism changes in patients with severe COVID-19. Clin Chim Acta 2021;517:66-73.
39. Mink S, Saely CH, Frick M, et al. Association between lipid levels, anti-SARS-CoV-2 spike antibodies and COVID-19 mortality: A prospective cohort study. J Clin Med. 2023;12:5068.
40. Mohammadshahi J, Ghobadi H, Matinfar G, et al. Role of lipid profile and its relative ratios (cholesterol/HDL-C, triglyceride/HDL-C, LDL-C/HDL-C, WBC/HDL-C, and FBG/HDL-C) on admission predicts in-hospital mortality COVID-19. J Lipids. 2023: Article ID 6329873
41. Parra S, Saballs M, DiNubile M, et al. Low HDL-C levels at admission are associated with greater severity and worse clinical outcomes in patients with COVID-19 disease. Atherosclerosis Plus 2023;50:1-8.
42. Rohani-Rasaf M, Mirjalili K, Vatannejad A, et al. Are lipid ratios and triglyceride-glucose index associated with critical care outcomes in COVID-19 patients? PLoS One 2022;17: e0272000.
43. Salari A, Mahdavi-Roshan M, Ghorbani Z, et al. An investigation of risk factors of in-hospital death due to COVID-19: a case-control study in Rasht, Iran. Irish J Med Sci. 2021;190:1321–1333.
44. Sampedro-Nuñez M, Aguirre-Moreno N, García-Fraile Fraile L. et al. Finding answers in lipid profile in COVID-19 patients. Endocrine 2021;74:443-454.
45. Senol A, Orhan D. The relationship of lipid profile with severity of disease and mortality in patients with COVID-1. Bratislava Med J 2022;123:589-593
46. Tanaka S, De Tymowski C, Assadi M, et al. Lipoprotein concentrations over time in the intensive care unit COVID-19 patients: Results from the ApoCOVID study. PLoS One 2020;15:e0239573.
47. Wu B, Zhou J, Wang W, et al. Association analysis of hyperlipidemia with the 28-day all-cause mortality of COVID-19. Clin Med Sci J. 2021;36:17-26.
48. Yan X, Li F, Wang X, et al. Neutrophil to lymphocyte ratio as prognostic and predictive factor in patients with coronavirus disease 2019: A retrospective cross‐sectional study. J Med Virol. 2020;92:2573-2581.
49. Yildirim ÖT, Kaya S. The atherogenic index of plasma as a predictor of mortality in patients with COVID-19. Heart & Lung 2021; 50:329-333.
50. Yue J, Xu H, Zhou Y, et al. Dyslipidemia is related to mortality in critical patients with coronavirus disease 2019: A retrospective study. Endocrinology 2021;12:611526.
51. Espinola-Klein C, Rupprecht HJ, Blankenberg S, et al. Impact of infectious burden on progression of carotid atherosclerosis. Stroke 2002;33:2581-2586.
52. Kohsaka S, Menon V, Lowe AM, et al. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005;165:1643-1650.
53. 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: 929-937.
54. Shi Y, Tokunaga O. Herpesvirus (HSV-1, EBV and CMV) infections in atherosclerotic compared with non-atherosclerotic aortic tissue. Pathol Internat. 2002;52:31-39.
55. Madjid M, Naghavi M, Malik BA, et al. Thermal detection of vulnerable plaque. Am J Cardiol 2002;90:36L-39L.
56. Sijbrands EJ, Westendorp RG, Defesche JC, et al. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: Family tree mortality study. BMJ 2001;322: 1019–1022.
57. Liuba P, Persson J, Luomac J, et al. Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima–media. Eur Heart J 2003;24:515–521.
58. Fabricant CG, Fabricant J, Litrenta MM, Minick CR. Virus-induced atherosclerosis. J Exp Med. 1978;148:335-40.
59. Damy SB, Higuchi ML, Timenetsky J, et al. Mycoplasma pneumoniae and/or Chlamydophila pneumoniae inoculation causing different aggravations in cholesterol-induced atherosclerosis in apoE KO male mice. BMC Microbiol. 2009;9:194-201
60. Birck MM, Pesonen E, Odermarsky M. et al. Infection-induced coronary dysfunction and systemic inflammation in piglets are dampened in hypercholesterolemic milieu. Am J Physiol - Heart Circul Physiol. 2011;300: 1595–1601.
61. Rothstein NM, Quinn TC, Madico G, et al. Effect of azithromycin on murine arteriosclerosis exacerbated by Chlamydia pneumoniae. J Infect Dis. 2001;183:232–238.
62. Ayada K, Yokota K, Hirai K, et al. Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis. Lupus 2009; 18:1154–1168.
63. Amar S, Wu SC, Madan M. Is Porphyromonas gingivalis cell invasion required for atherogenesis? Pharmacotherapeutic implications. J Immunol. 2009;182:1584–1592.
64. Feingold KR, Funk JL,Moser AH, et al. Role for circulating lipoproteins in protection from endotoxin toxicity. Infect Immun. 1995; 63:2041-2046.
65. Naruszewicz M, Mirkiewicz E, Olszewski AJ, McCully KS. Thiolation of low-density lipoprotein by homocysteine thiolactone causes increased aggregation and altered interaction with cultured macrophages. Nutr Metabol Cardiovasc Dis. 1994;4:70-77.
66. McCully KS. Infections, hyperhomocysteinemia, suppressed immunity and alteration of oxidative metabolism in atherosclerosis and dementia. Front Aging Neurosci. 2017;9:324.
67. Burgess S, Timpson NJ, Ebrahim S, et al. Mendelian randomization: where are we now and where are we going? Int J Epidemiol. 2015;44:379–388.
2. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Exp Rev Clin Pharm 2015;8:201–210.
3. Dubroff R. Cholesterol paradox: a correlate does not a surrogate make. BMJ Evidence-Based Med 2017;22:15-19.
4. Okuyama H, Hamazaki T, Hama R, et al. A critical review of the consensus statement from the European atherosclerosis society consensus panel 2017. Pharmacology 2018;101:184–218.
5. 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;11:959–970.
6. Byrne P, Demasi M, Jones M, et al. Evaluating the association between low-density lipoprotein cholesterol reduction and relative and absolute effects of statin treatment. A systematic review and meta-analysis. JAMA Intern Med 2022;182:474-481.
7. Nilsson G, Leppert J, Ohrvik J. Enigma of the cholesterol paradox in acute myocardial infarction: lessons from an 8-year follow-up of all-cause mortality in an age-matched and sex-matched case–control study with controls from the patients’ recruitment area. BMJ Open 2022;12:e057562.
8. Georgoulis M, Chrysohoou C, Georgousopoulou E, et al. Long‑term prognostic value of LDL‑C, HDL‑C, Lp(a) and TG levels on cardiovascular disease incidence, by body weight status, dietary habits and lipid‑lowering treatment: the ATTICA epidemiological cohort study (2002–2012). Lipids Health Dis 2022;21:141-153.
9. Durai V., Redberg R. Statin therapy for the primary prevention of cardiovascular disease: Cons. Atherosclerosis 2022;356:46-49.
10. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Importance of coagulation factors as critical components of premature cardiovascular disease in familial hypercholesterolemia. Internat J Mol Sci. 2022;23:9146
11. 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].
12. 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;3:1040-1047.
13. Ridker PM, Bhatt DL, Pradhan AD. et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023;401:1293-1301.
14. Choi SH, Chae A, Miller E, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma volume. J Amer Coll Cardiol 2008;52:24-32.
15. 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;330:1366.
16. Johnsen SP, Larsson H, Tarone R, et al. Risk of hospitalization for myocardial infarction among users of refecoxib, celecoxib, and other NSAIDS. Arch Intern Med. 2005;165:978-984.
17. 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;382:769-779.
18. 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
19. Ravnskov U, McCully KS. Review and hypothesis: 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;39:3-16.
20. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Amer J Med Sci. 2012;344;391-394.
21. Ravnskov U, Alabdulgader A, McCully KS. Infections may cause arterial inflammation, atherosclerosis, myocarditis and cardiovascular disease. Med Res Arch. 2023;11,1-8.
22. Changal K, Veria S, Mack S, et al. Myocardial injury in hospitalized COVID-19 patients: a retrospective study, systematic review, and meta-analysis. BMC Cardiovasc Disord 2021;21:626.
23. Chang W-T, Toh HST, Liao CT, Yu WL. Cardiac involvement of COVID-19: A comprehensive review. Amer J Med Sci. 2021;361:14-20.
24. Gharibzadeh A, Shahsanaei F, Petrudi NR. Clinical and cardiovascular characteristics of patients suffering st-segment elevation myocardial infarction after Covid-19: A systematic review and meta-analysis. Curr Probl Cardiol. 2023;48:101045
25. Zuin M, Rigatelli G, Battisti V, et al. Increased risk of acute myocardial infarction after COVID-19 recovery: A systematic review and meta-analysis. Internat J Cardiol 2023; 372:138-143.
26. Tolu-Akinnawo O, Poku FA, Elimihele T, et al. Acute cardiovascular complications of COVID-19: A systematic review. Cureus 2023;15:e38575.
27. Mahat RK, Rathore V, Singh N, et al. Lipid profile as an indicator of COVID-19 severity: A systematic review and meta-analysis. Clin Nutr ESPEN. 2021, 45, 91-101.
28. Zinellu A, Paliogiannis P, Fois AG, et al. Cholesterol and triglyceride concentrations, COVID-19 severity, and mortality: A systematic review and meta-analysis with meta-regression. Front Pub Health. 2021, 9, 705916.
29. Chidambaram V, Geetha HS, Kumar A, et al. Association of lipid levels with COVID-19 infection, disease severity and mortality: a systematic review and meta-analysis. Front Cardiovasc Med 2022, 9, 862999.
30. Anushiravani A, Khosravi B, Saberzadeh-Ardestani B, et al. A reliable prognostic marker for liver dysfunction in COVID-19 infection. Middle East Digest Dis. 2021;13:193-199
31. Aparisi A, Iglesias-Echeverria C, Ybarra-Falcón C, et al. Low-density lipoprotein cholesterol levels are associated with poor clinical outcomes in COVID-19. Nutrit Metabol Cardiovasc Dis 2021;31,2619-2627.
32. Aydin SS, Aksakal E, Aydinyilomaz F, et al. Relationship between blood lipid levels and mortality in hospitalized COVID-patients. Angiology 2022;73:724-733.
33. Barman HA, Pala AS, Dogan O, et al. Prognostic significance of temporal changes of lipid profile in COVID-19 patients. Obes Med. 2021;28:34671707
34. Chen FF, Zhong M, Liu Y, et al. The characteristics and outcomes of 681 severe cases with COVID-19 in China. J Crit Care. 2020;60:32-37.
35. Fabre B, Machulsky NF, Olano C, et al. Remnant cholesterol levels are associated with severity and death in COVID-19 patients. Sci Reports. 2022;12:17584.
36. Fan J, Wang H, Ye G, et al. Low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019. Metabolism 2020;107:154243.
37. Khalilzadeh F, Sakhaee F, Sotoodehnejadnematalahi F, et al. Angiotensin‐converting enzyme 2 rs2285666 polymorphism and clinical parameters as the determinants of COVID‐19 severity in Iranian population. Internat J Immunogen 2022;49: 325-332.
38. Li Y, Zhang Y. Dai M, et al. Lipid metabolism changes in patients with severe COVID-19. Clin Chim Acta 2021;517:66-73.
39. Mink S, Saely CH, Frick M, et al. Association between lipid levels, anti-SARS-CoV-2 spike antibodies and COVID-19 mortality: A prospective cohort study. J Clin Med. 2023;12:5068.
40. Mohammadshahi J, Ghobadi H, Matinfar G, et al. Role of lipid profile and its relative ratios (cholesterol/HDL-C, triglyceride/HDL-C, LDL-C/HDL-C, WBC/HDL-C, and FBG/HDL-C) on admission predicts in-hospital mortality COVID-19. J Lipids. 2023: Article ID 6329873
41. Parra S, Saballs M, DiNubile M, et al. Low HDL-C levels at admission are associated with greater severity and worse clinical outcomes in patients with COVID-19 disease. Atherosclerosis Plus 2023;50:1-8.
42. Rohani-Rasaf M, Mirjalili K, Vatannejad A, et al. Are lipid ratios and triglyceride-glucose index associated with critical care outcomes in COVID-19 patients? PLoS One 2022;17: e0272000.
43. Salari A, Mahdavi-Roshan M, Ghorbani Z, et al. An investigation of risk factors of in-hospital death due to COVID-19: a case-control study in Rasht, Iran. Irish J Med Sci. 2021;190:1321–1333.
44. Sampedro-Nuñez M, Aguirre-Moreno N, García-Fraile Fraile L. et al. Finding answers in lipid profile in COVID-19 patients. Endocrine 2021;74:443-454.
45. Senol A, Orhan D. The relationship of lipid profile with severity of disease and mortality in patients with COVID-1. Bratislava Med J 2022;123:589-593
46. Tanaka S, De Tymowski C, Assadi M, et al. Lipoprotein concentrations over time in the intensive care unit COVID-19 patients: Results from the ApoCOVID study. PLoS One 2020;15:e0239573.
47. Wu B, Zhou J, Wang W, et al. Association analysis of hyperlipidemia with the 28-day all-cause mortality of COVID-19. Clin Med Sci J. 2021;36:17-26.
48. Yan X, Li F, Wang X, et al. Neutrophil to lymphocyte ratio as prognostic and predictive factor in patients with coronavirus disease 2019: A retrospective cross‐sectional study. J Med Virol. 2020;92:2573-2581.
49. Yildirim ÖT, Kaya S. The atherogenic index of plasma as a predictor of mortality in patients with COVID-19. Heart & Lung 2021; 50:329-333.
50. Yue J, Xu H, Zhou Y, et al. Dyslipidemia is related to mortality in critical patients with coronavirus disease 2019: A retrospective study. Endocrinology 2021;12:611526.
51. Espinola-Klein C, Rupprecht HJ, Blankenberg S, et al. Impact of infectious burden on progression of carotid atherosclerosis. Stroke 2002;33:2581-2586.
52. Kohsaka S, Menon V, Lowe AM, et al. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005;165:1643-1650.
53. 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: 929-937.
54. Shi Y, Tokunaga O. Herpesvirus (HSV-1, EBV and CMV) infections in atherosclerotic compared with non-atherosclerotic aortic tissue. Pathol Internat. 2002;52:31-39.
55. Madjid M, Naghavi M, Malik BA, et al. Thermal detection of vulnerable plaque. Am J Cardiol 2002;90:36L-39L.
56. Sijbrands EJ, Westendorp RG, Defesche JC, et al. Mortality over two centuries in large pedigree with familial hypercholesterolaemia: Family tree mortality study. BMJ 2001;322: 1019–1022.
57. Liuba P, Persson J, Luomac J, et al. Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima–media. Eur Heart J 2003;24:515–521.
58. Fabricant CG, Fabricant J, Litrenta MM, Minick CR. Virus-induced atherosclerosis. J Exp Med. 1978;148:335-40.
59. Damy SB, Higuchi ML, Timenetsky J, et al. Mycoplasma pneumoniae and/or Chlamydophila pneumoniae inoculation causing different aggravations in cholesterol-induced atherosclerosis in apoE KO male mice. BMC Microbiol. 2009;9:194-201
60. Birck MM, Pesonen E, Odermarsky M. et al. Infection-induced coronary dysfunction and systemic inflammation in piglets are dampened in hypercholesterolemic milieu. Am J Physiol - Heart Circul Physiol. 2011;300: 1595–1601.
61. Rothstein NM, Quinn TC, Madico G, et al. Effect of azithromycin on murine arteriosclerosis exacerbated by Chlamydia pneumoniae. J Infect Dis. 2001;183:232–238.
62. Ayada K, Yokota K, Hirai K, et al. Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis. Lupus 2009; 18:1154–1168.
63. Amar S, Wu SC, Madan M. Is Porphyromonas gingivalis cell invasion required for atherogenesis? Pharmacotherapeutic implications. J Immunol. 2009;182:1584–1592.
64. Feingold KR, Funk JL,Moser AH, et al. Role for circulating lipoproteins in protection from endotoxin toxicity. Infect Immun. 1995; 63:2041-2046.
65. Naruszewicz M, Mirkiewicz E, Olszewski AJ, McCully KS. Thiolation of low-density lipoprotein by homocysteine thiolactone causes increased aggregation and altered interaction with cultured macrophages. Nutr Metabol Cardiovasc Dis. 1994;4:70-77.
66. McCully KS. Infections, hyperhomocysteinemia, suppressed immunity and alteration of oxidative metabolism in atherosclerosis and dementia. Front Aging Neurosci. 2017;9:324.
67. Burgess S, Timpson NJ, Ebrahim S, et al. Mendelian randomization: where are we now and where are we going? Int J Epidemiol. 2015;44:379–388.