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INFLUENCIA DE LA INFECCIÓN POR CHLAMYDIA PNEUMONIAE EN LA ARTERIOSCLEROSIS EN PACIENTES CON HIPERLIPEMIA.

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Aunque no parece haber asociación entre la presencia de anticuerpos contra clamidias y la arteriosclerosis de carótida, la infección por C. pneumoniae reduce la eficacia de la terapia hipolipemiante.
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Autor:
Jun Hayashi
Columnista Experto de SIIC
Institución:
Department of Environmental Medicine and Infectious Diseases, Faculty of Medical Sciences, Kyushu University.
Artículos publicados por Jun Hayashi
Coautores
Yasunori Sawayama M.D.Ph.D.*  Naoyasu Maeda M.D., Ph.D.*  Masafumi Tatsukawa M.D.**  Kensuke Kikuchi M.D.**  Kyoko Okada M.D.** 
Department of General Medicine, Kyushu University Hospital.*
Department of Environmental Medicine and Infectious Diseases, Faculty of Medical Sciences, Kyushu University.**
Recepción del artículo
5 de noviembre, 2003 		Primera edición
12 de julio, 2004 		Segunda edición, ampliada y corregida
7 de junio, 2021
Resumen
La relación entre arteriosclerosis e infección por Chlamydia pneumoniae es controvertida. Si bien la modificación de los factores de estilo de vida es una medida eficaz para retrasar la progresión de la enfermedad de carótida, el probucol y la pravastatina son más eficaces en reducir el nivel de colesterol total y en la estabilización de la placa de ateroma en sujetos con hipercolesterolemia, fenómenos que probablemente expliquen la disminución en la incidencia de eventos coronarios. En más de la mitad de la población adulta de todo el mundo se han encontrado anticuerpos contra C. pneumoniae por enzimoinmunoensayo. No pudimos demostrar una asociación entre la presencia de dichos anticuerpos y la arteriosclerosis de carótida en la población general y en sujetos en plan de hemodiálisis. Sin embargo, la infección por C. pneumoniae reduce la eficacia de la terapia hipolipemiante en la aterosclerosis carotídea. La terapia combinada con probucol y levofloxacina podría ser útil en la estabilización de la placa en pacientes con infección por C. pneumoniae.

Palabras clave
Arteriosclerosis de carótida, Chlamydia pneumoniae, probucol, pravastatina, levofloxacina

Abstract
The relation of atherosclerosis and Chlamydia pneumoniae (C. pneumoniae) infection is controversial. Although lifestyle modification is an effective measure for retarding the progression of carotid IMT, probucol and pravastatin are more effective in reducing the TC level and stabilizing plaque in hypercholesterolemic patients, which probably explains a reduction in the incidence of cardiac events. Specific antibodies to C. pneumoniae have been found in more than half of the adult population by enzyme-linked immunosorbent assay in the world. We have failed to demonstrate an association between the presence of C. pneumoniae antibodies and carotid atherosclerosis in the general population and in hemodialysis paitents. However, C. pnemoniae infection reduced the effectiveness of lipid-lowering therapy for carotid atherosclerosis. The combination therapy of purobucol and levofloxacin may be a useful tool for the stabilization of plaque among patients with C. pnemoniae infection.

Key words
Carotid atherosclerosis, Chlamydia pneumoniae, probucol, pravastatín; levofloxacin

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  Relacionadas: Diagnóstico por Laboratorio, Epidemiología, Medicina Interna

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Artículo completo

INFLUENCE OF CHLAMYDIA PNEUMONIAE INFECTION ON THE ATHEROSCLEROSIS OF PATIENTS WITH HYPERLIPIDEMIA



Introduction
Measurement of the carotid artery intima-media thickness (IMT) by high-resolution B-mode ultrasonography has been used for the noninvasive detection of early carotid atherosclerosis. The IMT is also a reliable end point for intervention trials assessing disease progression. Ultrasonography can directly quantify early atherosclerotic changes and the response to risk factor modification. Measurement of carotid artery IMT by high-resolution ultrasound shows less variability than angiographic measurement of the carotid arteries,1 so only a small sample size is necessary to determine the benefits of treatment or to accurately assess the presence of early atherosclerosis.Probucol has been reported to prevent atherogenesis by acting as an antioxidant and suppressing the oxidative modification of low-density lipoprotein (LDL) cholesterol, in addition to its recongnized action in lowering cholesterol levels.2 It has been shown to cause marked regression of cutaneous3 and tendon4 xanthoma in familial hypercholesterolemia. Retardation of the progression of coronary5 and femoral6 atherosclerosis has been related to a decrease of LDL cholesterol and an increase of high-density lipoprotein (HDL) cholesterol levels, in agreement with the general concept of the role of HDL in reverse cholesterol transport.7 Because probucol is known to decrease HDL cholesterol, it seems important to study the effect of this drug on atherosclerosis.It has recently been suggested that infectious agents may trigger a cascade of biological and biochemical reactions leading to inflammation, atherogenesis, and vascular thrombosis. Chlamydia pneumoniae (C.pneumoniae) is a recognized human pathogen, first isolated from patients with respiratory infections in 1986.8 A subsequent epidemiologic study showed that it was the cause of 5-10% of respiratory infections in adults and children, making it the third most common etiologic agent.9 Antibody prevalence studies suggest that over 50% of adults world-wide have been exposed to C. peumoniae.10 There have been reports of an association between the circulating C. pneumoniae antibody titer and coronary artery disease, as well as several studies that gave negative results. Therefore, we conducted a large scale epidemiologic study of C.pneumoniae infection, evaluated the association between C. pneumoniae infection and the prevalence of carotid atherosclerosis and demonstrated the effectiveness of lipid-lowering drugs for carotid atherosclerosis in relation to C. peumoniae infection status. Moreover, we tested levofloxacin (LVFX) for the treatment of C. pneumoniae antibody-positive patients with no significant regression of carotid atherosclerosis by lipid-lowering drugs alone.

The effects of lipid-lowering drugs on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia

A total of 246 asymptomatic patients with hypercholesterolemic (mean age 66 years) were randomized to either probucol (500 mg/day, n = 82) or pravastatin (10 mg/day, n = 83) or to a control group (diet alone, n = 81) and followed for two years. Randomization was done by the minimization method, controlling for the following four factors: total cholesterol (TC), age, gender and IMT. The primary end point was the rate of progression of carotid atherosclerosis, which was measured as the slope of the change in the mean IMT of six carotid segments (3 sites each in the left and right common carotid arteries, which were 2, 2.5 and 3 cm proximal to the carotid bifurcation) on ultrasound examination.Over the 24-month period, serum TC was significantly reduced in the pravastatin (23.0%) and probucol groups (24.1%) (both p < 0.001). In the control group, the TC level was reduced at the end of the study, but the difference was not significant. Serum LDL cholesterol was significantly reduced in the pravastatin (36%), probucol (29%) and control groups (12%) (p < 0.0001, p < 0.0001 and p < 0.05, repectively). The serum HDL cholesterol level of the pravastatin group was increased significantly (by 6.4%) after 24 months (p < 0.05). In the control group, HDL cholesterol also increased (by 5.4%), but the change was not significant. In contrast, the HDL cholesterol level of the probucol group was significantly reduced (20.7%; p < 0.05).In the probucol group, IMT was significantly reduced after 12 months of therapy (8.3%; p < 0.01). After 24 months therapy, there was a further significant reduction, for a total reduction of 13.9%, compared with baseline (p < 0.01). No significant reduction in IMT was found during the first 18 months of therapy in the pravastatin group, but there was a significant reduction, by 13.9%, after 24 months (p < 0.01). In the control group, IMT increased significantly by 23.3% after 24 months (p < 0.05). The change in IMT was significantly greater in the probucol and pravastatin groups than in the control group (both p < 0.001).Forward stepwise multiple linear regression analysis was done to assess the factors influencing IMT regression. Lipid-lowering therapy was found to be the most important independent factor associated with the rate of IMT regression (p < 0.0001). The reduction of LDL cholesterol after 24 months of treatment was also independently associated with the rate of IMT regression (p < 0.001). In contrast, age showed an independent association with the rate of IMT progression (p < 0.001).A weak but significant, positive correlation was found between the absolute change in IMT and the change in LDL cholesterol in the pravastatin group (r = 0.363, p = 0.0051), but there was no such correlation in the probucol or control group (r = 0.363, p = 0.0051 and r = 0.130, p = 0.3321).11Probucol has been shown to modify vascular remodeling after balloon angioplasty, and remodeling is an important component of the restenotic process.12 In addition, probucol has a radical-scavenging effect and inhibits the production of platelet-derived growth factor and interleukin-1, giving it an anti-inflammation effect.13 Such reports suggest that probucol may not only have a lipid-lowering effect, but may also stabilize plaque.Among the 82 patients in the probucol group, two had a major cardiovascular event compared with 4 of the 83 patients in the pravastatin group and 11 of the 81 patients in the control group. A significantly lower incidence of cardiac events was seen in the probucol group than in the control group (p < 0.05).Although lifestyle modification is an effective measure for retarding the progression of carotid IMT,14 probucol and pravastatin are more effective in reducing the TC level and stabilizing plaque in hypercholesterolemic patients, which probably explains a reduction in the incidence of cardiac events.

The association of Chlamydia pneumoniae antibody and the effectiveness of statins in lowering cholesterol

Chlamydia pneumoniae, an obligate intracellular pathogen, is a common cause of respiratory tract infection in all age groups.9 We surveyed for the prevalence of antibody to C. pneumoniae in 4 050 residents from Japan, 276 from the Solomon Islands and 602 from Nepal by enzyme-linked immunosorbent assay. The prevalences of IgG and IgA antibodies were 53.6% and 42.4% in Japan, 64.9% and 82.2% in the Solomon Islands and 73.1% and 69.8% in Nepal. Specific antibodies to C. pneumoniae have been found in more than half of the adult population by enzyme-linked immunosorbent assay in the world.15 Epidemiological and pathological studies since 1988 have suggested a possible association between C. pneumoniae infection and CAD or CVD.16 Our recent reports have failed to demonstrate an association between the presence of C. pneumoniae antibodies and carotid atherosclerosis in the general population17 and in hemodialysis patients.18 In multivariate logistic regression analysis, independent risk factors for carotid atherosclerosis were confirmed with age and triglycerides in men and age, systolic blood pressure, pack-years of smoking, and LDL colesterol.17 On the other hand, C. pneumoniae has been detected within atherosclerotic tissue by immunocytochemistry, polymerase chain reaction, electron microscopy19 and bacterial culture.20To investigate the association between C. pneumoniae infection and atheroscrelosis, we compared the effect of lipid-lowering drugs on IMT between patients who were positive and negative for C. pneumoniae antibodies. Significant reductions of serum TC (21%) and LDL cholesterol (26%) occurred between baseline and 24 months of therapy in 50 C. peumoniae antibody-negative patients versus 21% and 28% in 115 antibody-positive patients (all p < 0.001).Over the 24-month period, the antibody-negative patients showed significant reduction of IMT progression (-19%, p < 0.01), while no significant change of IMT was noted in the antibody-positive patients (-6%). Moreover, significant inverse associations were found between the reduction of IMT progression and the C. pneumoniae IgA- and IgG-antibody index (p < 0.01 and p < 0.01, respectively). Forward stepwise multiple linear regression analysis was done to estimate P- and F- values for the patients. Chlamidya pneumoniae infection was found to be the most important unfavorable independent factor associated with the rate of IMT progression (F = 13.02, p < 0.0001). Age and a history of diabetes mellitus were other unfavorable factors for IMT progression (F = 6.61, p < 0.05; F = 5.48, p < 0.05, respectively).21Our previous studies revealed that C. pneumoniae infection was not a risk factor for carotid atherosclerosis in asymptomatic patients.16,17 However, C. pneumoniae infection reduces the effectiveness of lipid-lowering therapy for carotid atherosclerosis. The prevalence of C. pneumoniae IgA antibody was higher in patients with acute (61.5%, p < 0.01) or chronic coronary syndrome (62.5%, p < 0.05) than in controls (25.9%) (unpublished data). These results indicate that C. pneumoniae infection may play a role in atherogenesis. Whether or not C. pneumoniae antibodies truly show infection with this organism controversial. The rate of C. pneumoniae DNA detection in peripheral blood mononuclear cells was significantly higher in seropositive (36.2%) than in negative patients (16.9%) (p < 0.01) unpublished data), result suggesting that patients with C. pneumoniae antibodies are probably infected with C. pneumoniae.

The effect of levofloxacin for carotid atherosclerosis

We prescribed LVFX to 15 patients (mean age 65 years) in whom serum TC levels were normalized by 2-years of probucol treatment, but for whom carotid atherosclerosis progression was not retarded. Of 15 patients positive for C. pneumoniae IgA or IgG antibody, 6 had hypertension and none had diabetes mellitus. LVFX of 400 mg was administered every 2 weeks for 3 months to patients taking probucol at 500 mg/day. After 12 months of therapy, IMT was significantly reduced in 12 of the 15 patients (p < 0.05). The plaque score, calculated by the total thickness of plaques, was also significantly reduced in 13 patients (p < 0.05). The serum TC level was relatively reduced after the combination therapy with probucol and LVFX, while C. pneumoniae IgA and IgG antibody index was not reduced, indicating that the mechanism of reduction of carotid IMT levels may not be the anti-bacterial effect to C. pneumoniae. These data suggest a synergistic effect of the two compounds, a combination of an anti-inflammation effect by LVFX22 and a radical-scavenging effect by probucol.13 Muhlestein et al23failed to demonstrate an effect for azithromycin on early reduction at ischemic events. Large-scale trials examining atherosclerosis lesions are needed to properly assess the effects of antibiotic treatment.

Conclusión
Lipid-lowering therapy is useful for the improvement of hyperlipidemia and for retarding the progression of atherosclerosis. Especially, probucol is effective in stabilizing plaque, even though it does not reduce LDL cholesterol. Although C. pneumoniae seropositibity was not an independent risk factor for early carotid atherosclerosis, infection interferes with the effectiveness of lipid-lowering drugs for the treatment of atherosclerosis. C. pneumoniae has been shown to accelerate the development of atherosclerotic lesions development in hyperlipidemic animals.24 Hyperlipidemia may initiate artery damage, followed by C. pneumoniae infection that may activate and promote the process of atherosclerosis. LVFX administration may be a useful tool for the stabilization of plaque among patients with C. pneumoniae infection.
Bibliografía del artículo
  1. Riley WA, Barnes RW, Applegate WB, et al. Reproducibility of noninvasive ultrasonic measurement of carotid atherosclerosis: the Asymptomatic Carotid Artery Plaque study. Stroke 1999;23:1062-1068.
  2. Strandberg A, Tilvis RS. Probucol: physiological and pharmacological regulation of amall intestinal cholesterol synthesis. Gen Pharmacol 1988;19:321-329.
  3. Yamamoto A, Matsuzawa Y, Kishino B, et al. Effects of probucol on homozygous cases of familial hypercholesterolemia. Atherosclerosis 1983;48:157-166.
  4. Yamamoto A, Matsuzawa Y, Yokoyama S, et al. Effect of probucol on xanthomata regression familial hypercholesterolemia. Am J Cardiol 1986;57:29H-35H.
  5. Brown BG, Zhao XQ, Sacco DE, et al. Lipid lwering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993;87:1781-1791.
  6. Blankenhorn DH, Azen SP, Crawford DW, et al. Effects of colestipol-niacin therapy on human femoral atherosclerosis. Circulation 1991;83:438-441.
  7. Miller NE. HDL metabolism and its role in lipid transport. Eur Heart J 1990;11 Suppl H:1-3.
  8. Grayston JT, Kuo CC, Wang SP, et al. A new Chlamydia psittaci strain TWAR, solated in acute respiratory tract infections. N Engl J Med 1986; 315:161-168.
  9. Grayston JT, Campbell LA, Kuo CC, et al. A new respiratory tract pathogen:Chlamydia pneumoniae strain TWAR. J Infect Dis 1990;161:618-625.
  10. Aldous MB, Grayston JT, Wang SP, et al. Seroepidemiology of Chlamidia pneumoniae TWAR infection in Seattle families, 1966-1979. J Infect Dis 1992;166:646-649.
  11. Sawayama Y, Shimizu C, Maeda N, et al. Effects of probucol and plavastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia-Fukuoka Atherosclerosis Trial (FAST). J Am Coll Cardiol 2002;39:610-616.
  12. Tardif JC, Cote G, Lesperance J, et. al. Probucol and multivitamins in the prevention of restenosis after coronary angiography. N Engl J Med 1997;337:365-372.
  13. Chang MY, Sasahara M, Chait A, et al. Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. II. Cellular composition and proliferation. Arterioscler Thromb Vasc Biol 1995;15:1631-1640.
  14. Okada K, Maeda N, Tatsukawa M, et al. The influence of lifestyle modification with and without lipid lowering therapy on carotid artery intima-media thikness in a suburban Japanese population. Atherosclerosis 2004;173:327-335.
  15. Shimizu C, Nabeshima A, Kikuchi K, et al. Prevalence of antibody to Chlamydia peumoniae in residents of Japan, the Solomon Islands, and Nepal. Am J Trop Med Hyg 2002;67:170-175.
  16. Saikku P, Leinonen M, Mallita K, et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1998;8618:983-986.
  17. Maeda N, Sawayama Y, Tatsukawa M, et al. Chlamydia pneumoniae seropositivity and early carotid atherosclerosis in a suburban Japanese population. Atherosclerosis 2002;164:313-319.
  18. Maeda N, Sawayama Y, Tatsukawa M, et al. Carotid artery lesions and atherosclerotic risk factor in Japanese hemodialysis patients. Atherosclerosis 2003;169:183-192.
  19. Grayston JT, Kuo CC, Coulson AS, et al. Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation 1995;125:979-982.
  20. Ramirez JA. Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. The Chlamydia pneumoniae/Atherosclerosis Study Group. Ann Intern Med 1996;125:979-982.
  21. Sawayama Y, Tatsukawa M, Okada K, et al. Association of Chlamydia pneumoniae antibody with the cholesterol-lowering effect of statin. Atherosclerosis 2003;171:281-285.
  22. Kutlin A, Robin PM, Hammerschlag MR. Effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on Chlamydia pneumoniae in a continuous-infection model. Antimicrob Agents Chemother 2002;46:409-412.
  23. O'Conner CM, Dunne MW, Pfeffer MA, et al. Azithromycin for the secondary prevention of coronary heart disease events. The WIZARD study: a randomized controlled trial. JAMA 2003;290:1459-1466.
  24. Blessing E, Campbell LA, Rosenfeld ME, et al. Chlamydia pneumoniae and hyperlipidemia are co-risk factors for atherosclerosis: Infection prior to induction of hyperlipidemia does not accelerate development of atherosclerotic lesions in C57BL/6J mice. Infect Immun 2002;70:5332-5334.

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