From the University of Utah, LDS Hospital, Salt Lake City, Utah.
Correspondence to Joseph B. Muhlestein, MD, Assistant Professor of Medicine, University of Utah, LDS Hospital, 8th Ave & C St, Salt Lake City, UT 84143.
Background—Chlamydia
pneumoniae infection has been associated with
atherosclerosis by serological studies and detection of
bacterial antigen within plaque. We sought to evaluate a possible
causal role in an animal model.
Methods and Results—Thirty New Zealand White rabbits were given
three separate intranasal inoculations of either C
pneumoniae (n=20) or saline (n=10) at 3-week intervals and fed
chow enriched with a small amount (0.25%) of cholesterol.
Immediately after the final inoculation, infected and control rabbits
were randomized and begun on a 7-week course of azithromycin or no
therapy. Three months after the final inoculation, rabbits were
euthanatized and sections of thoracic aortas were blindly evaluated
microscopically for maximal intimal thickness (MIT), percentage of
luminal circumference involved (PLCI), and plaque area index (PAI) of
atherosclerosis. Vascular chlamydial antigen was
assessed by direct immunofluorescence. MIT differed
among treatment groups (P=.009), showing an increase in
infected rabbits (0.55 mm; SE=0.15 mm) compared with
uninfected controls (0.16 mm; SE=0.06 mm) and with infected
rabbits receiving antibiotics (0.20 mm; SE=0.03 mm) (both
P<.025), whereas MIT in infected/treated versus control
rabbits did not differ. PLCI also tended to differ
(P<.1) and PAI differed significantly
(P<.01) among groups with a similar pattern. Chlamydial
antigen was detected in 2 untreated, 3 treated, and 0 control
animals.
Conclusions—Intranasal C pneumoniae infection
accelerates intimal thickening in rabbits given a modestly
cholesterol-enhanced diet. In addition, weekly treatment
with azithromycin after infectious exposure prevents accelerated
intimal thickening. These findings strengthen the etiologic link
between C pneumoniae and atherosclerosis
and should stimulate additional animal and human studies, including
clinical antibiotic trials.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Infection With Chlamydia pneumoniae Accelerates the Development of Atherosclerosis and Treatment With Azithromycin Prevents It in a Rabbit Model
Key Words: atherosclerosis • azithromycin • Chlamydia pneumoniae
This article has been cited by other articles:
 |
|
 |
|
  H. Loppnow, K. Werdan, and M. Buerke Invited review: Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms Innate Immunity, April 1, 2008; 14(2): 63 - 87. [Abstract] [PDF]
|
|
|
|
 |
|
 E. K.-H. Chow, B. Razani, and G. Cheng Innate immune system regulation of nuclear hormone receptors in metabolic diseases J. Leukoc. Biol., August 1, 2007; 82(2): 187 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. L. Baker and K. A. Couch Azithromycin for the secondary prevention of coronary artery disease: A meta-analysis Am. J. Health Syst. Pharm., April 15, 2007; 64(8): 830 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Volanen, M. J. Jarvisalo, R. Vainionpaa, M. Arffman, K. Kallio, S. Angle, T. Ronnemaa, J. Viikari, J. Marniemi, O. T. Raitakari, et al. Increased Aortic Intima-Media Thickness in 11-Year-Old Healthy Children With Persistent Chlamydia pneumoniae Seropositivity Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 649 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S.V. Elkind, M. L. C. Tondella, D. R. Feikin, B. S. Fields, S. Homma, and M. R. Di Tullio Seropositivity to Chlamydia pneumoniae Is Associated With Risk of First Ischemic Stroke Stroke, March 1, 2006; 37(3): 790 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yang, D. Coriolan, K. Schultz, D. T. Golenbock, and D. Beasley Toll-Like Receptor 2 Mediates Persistent Chemokine Release by Chlamydia pneumoniae-Infected Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2308 - 2314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R-S Koskela, P Mutanen, J-A Sorsa, and M Klockars Respiratory disease and cardiovascular morbidity Occup. Environ. Med., September 1, 2005; 62(9): 650 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Andraws, J. S. Berger, and D. L. Brown Effects of Antibiotic Therapy on Outcomes of Patients With Coronary Artery Disease: A Meta-analysis of Randomized Controlled Trials JAMA, June 1, 2005; 293(21): 2641 - 2647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Blessing, L. A. Campbell, M. E. Rosenfeld, B. Chesebro, and C.-C. Kuo A 6 week course of azithromycin treatment has no beneficial effect on atherosclerotic lesion development in apolipoprotein E-deficient mice chronically infected with Chlamydia pneumoniae J. Antimicrob. Chemother., June 1, 2005; 55(6): 1037 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Grayston, R. A. Kronmal, L. A. Jackson, A. F. Parisi, J. B. Muhlestein, J. D. Cohen, W. J. Rogers, J. R. Crouse, S. L. Borrowdale, E. Schron, et al. Azithromycin for the Secondary Prevention of Coronary Events N. Engl. J. Med., April 21, 2005; 352(16): 1637 - 1645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Cannon, E. Braunwald, C. H. McCabe, J. T. Grayston, B. Muhlestein, R. P. Giugliano, R. Cairns, A. M. Skene, and the Pravastatin or Atorvastatin Evaluation and Inf Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome N. Engl. J. Med., April 21, 2005; 352(16): 1646 - 1654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Charakida, A. E. Donald, M. Terese, S. Leary, J. P. Halcox, A. Ness, G. D. Smith, J. Golding, P. Friberg, N. J. Klein, et al. Endothelial Dysfunction in Childhood Infection Circulation, April 5, 2005; 111(13): 1660 - 1665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. F. Berg, B. Maraha, A. van der Zee, S. K. Gielis, P. J. M. Roholl, G.-J. Scheffer, M. F. Peeters, and J. A. J. W. Kluytmans Effect of Clarithromycin Treatment on Chlamydia pneumoniae in Vascular Tissue of Patients with Coronary Artery Disease: a Randomized, Double-Blind, Placebo-Controlled Trial J. Clin. Microbiol., March 1, 2005; 43(3): 1325 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Opitz, S. Forster, A. C. Hocke, M. Maass, B. Schmeck, S. Hippenstiel, N. Suttorp, and M. Krull Nod1-Mediated Endothelial Cell Activation by Chlamydophila pneumoniae Circ. Res., February 18, 2005; 96(3): 319 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. de Kruif, E. C.M. van Gorp, T. T. Keller, J. M. Ossewaarde, and H. ten Cate Chlamydia pneumoniae infections in mouse models: relevance for atherosclerosis research Cardiovasc Res, February 1, 2005; 65(2): 317 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Michelsen, T. M. Doherty, P. K. Shah, and M. Arditi TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis J. Immunol., November 15, 2004; 173(10): 5901 - 5907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Wells, A. G. Mainous III, and L. M. Dickerson Antibiotics for the Secondary Prevention of Ischemic Heart Disease: A Meta-analysis of Randomized Controlled Trials Arch Intern Med, October 25, 2004; 164(19): 2156 - 2161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Tormakangas, H. Alakarppa, D. B. David, M. Leinonen, and P. Saikku Telithromycin Treatment of Chronic Chlamydia pneumoniae Infection in C57BL/6J mice Antimicrob. Agents Chemother., October 1, 2004; 48(10): 3655 - 3661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Gold, R. M. Simmons, T. W. Petersen, L. A. Campbell, C.-C. Kuo, and A. Aderem Amphiphysin IIm Is Required for Survival of Chlamydia pneumoniae in Macrophages J. Exp. Med., September 7, 2004; 200(5): 581 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Netea, B. J. Kullberg, L. E. H. Jacobs, T. J. G. Verver-Jansen, J. van der Ven-Jongekrijg, J. M. D. Galama, A. F. H. Stalenhoef, C. A. Dinarello, and J. W. M. Van der Meer Chlamydia pneumoniae Stimulates IFN-{gamma} Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release J. Immunol., July 15, 2004; 173(2): 1477 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Vielma, M. Mironova, J.-R. Ku, and M. F. Lopes-Virella Oxidized LDL further enhances expression of adhesion molecules in Chlamydophila pneumoniae-infected endothelial cells J. Lipid Res., May 1, 2004; 45(5): 873 - 880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sander, K. Winbeck, J. Klingelhofer, T. Etgen, and B. Conrad Progression of Early Carotid Atherosclerosis Is Only Temporarily Reduced After Antibiotic Treatment of Chlamydia pneumoniae Seropositivity Circulation, March 2, 2004; 109(8): 1010 - 1015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Umehara, E. T. Bloom, T. Okazaki, Y. Nagano, O. Yoshie, and T. Imai Fractalkine in Vascular Biology: From Basic Research to Clinical Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 34 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Lindsberg and A. J. Grau Inflammation and Infections as Risk Factors for Ischemic Stroke Stroke, October 1, 2003; 34(10): 2518 - 2532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. O'Connor, M. W. Dunne, M. A. Pfeffer, J. B. Muhlestein, L. Yao, S. Gupta, R. J. Benner, M. R. Fisher, and T. D. Cook Azithromycin for the Secondary Prevention of Coronary Heart Disease Events: The WIZARD Study: A Randomized Controlled Trial JAMA, September 17, 2003; 290(11): 1459 - 1466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Pislaru and F. Van de Werf Antibiotic Therapy for Coronary Artery Disease: Can a WIZARD Change It All? JAMA, September 17, 2003; 290(11): 1515 - 1516. [Full Text] [PDF]
|
|
|
|
 |
|
 C. H. Selzman, M. G. Netea, M. A. Zimmerman, A. Weinberg, L. L. Reznikov, F. L. Grover, and C. A. Dinarello Atherogenic effects of Chlamydia pneumoniae: refuting the innocent bystander hypothesis J. Thorac. Cardiovasc. Surg., September 1, 2003; 126(3): 688 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Karter, D. H. Thom, J. Liu, H. H. Moffet, A. Ferrara, and J. V. Selby Use of Antibiotics Is Not Associated With Decreased Risk of Myocardial Infarction Among Patients With Diabetes Diabetes Care, July 1, 2003; 26(7): 2100 - 2106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. May, V. Redecke, S. Gruner, R. Schmidt, S. Massberg, T. Miethke, B. Ryba, C. Prazeres da Costa, A. Schomig, and F.-J. Neumann Recruitment of Chlamydia pneumoniae-Infected Macrophages to the Carotid Artery Wall in Noninfected, Nonatherosclerotic Mice Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 789 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bea, M. H. Puolakkainen, T. McMillen, F. N. Hudson, N. Mackman, C. C. Kuo, L. A. Campbell, and M. E. Rosenfeld Chlamydia pneumoniae Induces Tissue Factor Expression in Mouse Macrophages via Activation of Egr-1 and the MEK-ERK1/2 Pathway Circ. Res., March 7, 2003; 92(4): 394 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V Pislaru, M. Van Ranst, C. Pislaru, Z. Szelid, G. Theilmeier, J.M Ossewaarde, P. Holvoet, S. Janssens, E. Verbeken, and F. J Van de Werf Chlamydia pneumoniae induces neointima formation in coronary arteries of normal pigs Cardiovasc Res, March 1, 2003; 57(3): 834 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Spence and J. Norris Infection, Inflammation, and Atherosclerosis Stroke, February 1, 2003; 34(2): 333 - 334. [Full Text] [PDF]
|
|
|
|
|
|
J. B. Muhlestein and J. L. Anderson Infectious Serology and Atherosclerosis: How Burdensome Is the Risk? Circulation, January 21, 2003; 107(2): 220 - 222. [Full Text] [PDF]
|
|
|
|
|
|
M. V. Kalayoglu, P. Libby, and G. I. Byrne Chlamydia pneumoniae as an Emerging Risk Factor in Cardiovascular Disease JAMA, December 4, 2002; 288(21): 2724 - 2731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Nieto Commentary: The epidemiology of self-deprecation Int. J. Epidemiol., December 1, 2002; 31(6): 1124 - 1127. [Full Text]
|
|
|
|
|
|
F.-J. Neumann Chlamydia pneumoniae-Atherosclerosis Link: A Sound Concept in Search for Clinical Relevance Circulation, November 5, 2002; 106(19): 2414 - 2416. [Full Text] [PDF]
|
|
|
|
|
|
K. P. Karunakaran, J. F. Blanchard, A. Raudonikiene, C. Shen, A. D. Murdin, and R. C. Brunham Molecular Detection and Seroepidemiology of the Chlamydia pneumoniae Bacteriophage ({Phi}Cpn1) J. Clin. Microbiol., November 1, 2002; 40(11): 4010 - 4014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S.V. Elkind, R. Sciacca, B. Boden-Albala, S. Homma, and M. R. Di Tullio Leukocyte Count Is Associated With Aortic Arch Plaque Thickness Stroke, November 1, 2002; 33(11): 2587 - 2592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Ezzahiri, H.J.M.G Nelissen-Vrancken, H.A.J.M Kurvers, F.R.M Stassen, I Vliegen, G.E.L.M Grauls, M.M.L van Pul, P.J.E.H.M Kitslaar, and C.A Bruggeman Chlamydophila pneumoniae (Chlamydia pneumoniae) accelerates the formation of complex atherosclerotic lesions in Apo E3-Leiden mice Cardiovasc Res, November 1, 2002; 56(2): 269 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Blessing, L. A. Campbell, M. E. Rosenfeld, and C.-c. Kuo 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., September 1, 2002; 70(9): 5332 - 5334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh Effects of estrogen on the vascular wall: vasomotor function and inflammation Cardiovasc Res, September 1, 2002; 55(4): 714 - 726. [Full Text] [PDF]
|
|
|
|
|
|
I. W. Fong, B. Chiu, E. Viira, D. Jang, and J. B. Mahony Influence of Clarithromycin on Early Atherosclerotic Lesions after Chlamydia pneumoniae Infection in a Rabbit Model Antimicrob. Agents Chemother., August 1, 2002; 46(8): 2321 - 2326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kiechl, E. Lorenz, M. Reindl, C. J. Wiedermann, F. Oberhollenzer, E. Bonora, J. Willeit, and D. A. Schwartz Toll-like Receptor 4 Polymorphisms and Atherogenesis N. Engl. J. Med., July 18, 2002; 347(3): 185 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Wiesli, W. Czerwenka, A. Meniconi, F. E. Maly, U. Hoffmann, W. Vetter, and G. Schulthess Roxithromycin Treatment Prevents Progression of Peripheral Arterial Occlusive Disease in Chlamydia pneumoniae Seropositive Men: A Randomized, Double-Blind, Placebo-Controlled Trial Circulation, June 4, 2002; 105(22): 2646 - 2652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. W. FONG Infections and their role in atherosclerotic vascular disease J Am Dent Assoc, June 1, 2002; 133(suppl_1): 7S - 13S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Parchure, E. G. Zouridakis, and J. C. Kaski Effect of Azithromycin Treatment on Endothelial Function in Patients With Coronary Artery Disease and Evidence of Chlamydia pneumoniae Infection Circulation, March 19, 2002; 105(11): 1298 - 1303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lehto, L. Niskanen, M. Suhonen, T. Ronnemaa, P. Saikku, and M. Laakso Association Between Chlamydia pneumoniae Antibodies and Intimal Calcification in Femoral Arteries of Nondiabetic Patients Arch Intern Med, March 11, 2002; 162(5): 594 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Glurich, S. Grossi, B. Albini, A. Ho, R. Shah, M. Zeid, H. Baumann, R. J. Genco, and E. De Nardin Systemic Inflammation in Cardiovascular and Periodontal Disease: Comparative Study Clin. Vaccine Immunol., March 1, 2002; 9(2): 425 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wilhelmsen Inflammation, infection, and coronary heart disease Eur. Heart J., March 1, 2002; 23(5): 343 - 344. [Full Text] [PDF]
|
|
|
|
|
|
A. G. Pockley Heat Shock Proteins, Inflammation, and Cardiovascular Disease Circulation, February 26, 2002; 105(8): 1012 - 1017. [Full Text] [PDF]
|
|
|
|
|
|
M. L. C. Tondella, D. F. Talkington, B. P. Holloway, S. F. Dowell, K. Cowley, M. Soriano-Gabarro, M. S. Elkind, and B. S. Fields Development and Evaluation of Real-Time PCR-Based Fluorescence Assays for Detection of Chlamydiapneumoniae J. Clin. Microbiol., February 1, 2002; 40(2): 575 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Bulut, E. Faure, L. Thomas, H. Karahashi, K. S. Michelsen, O. Equils, S. G. Morrison, R. P. Morrison, and M. Arditi Chlamydial Heat Shock Protein 60 Activates Macrophages and Endothelial Cells Through Toll-Like Receptor 4 and MD2 in a MyD88-Dependent Pathway J. Immunol., February 1, 2002; 168(3): 1435 - 1440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Boman and M. R. Hammerschlag Chlamydia pneumoniae and Atherosclerosis: Critical Assessment of Diagnostic Methods and Relevance to Treatment Studies Clin. Microbiol. Rev., January 1, 2002; 15(1): 1 - 20. [Abstract] [Full Text]
|
|
|
|
|
|
X. H. Xu, P. K. Shah, E. Faure, O. Equils, L. Thomas, M. C. Fishbein, D. Luthringer, X.-P. Xu, T. B. Rajavashisth, J. Yano, et al. Toll-Like Receptor-4 Is Expressed by Macrophages in Murine and Human Lipid-Rich Atherosclerotic Plaques and Upregulated by Oxidized LDL Circulation, December 18, 2001; 104(25): 3103 - 3108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Streblow, S. L. Orloff, and J. A. Nelson Do Pathogens Accelerate Atherosclerosis? J. Nutr., October 1, 2001; 131(10): 2798S - 2804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Momiyama, R. Hirano, H. Taniguchi, H. Nakamura, and F. Ohsuzu Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection J. Am. Coll. Cardiol., September 1, 2001; 38(3): 712 - 717. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Virok, Z. Kis, L. Karai, L. Intzedy, K. Burian, A. Szabo, B. Ivanyi, E. Gonczol, and M. S. Elkind Chlamydia pneumoniae in Atherosclerotic Middle Cerebral Artery Editorial Comment Stroke, September 1, 2001; 32(9): 1973 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Caligiuri, M. Rottenberg, A. Nicoletti, H. Wigzell, and G. K. Hansson Chlamydia pneumoniae Infection Does Not Induce or Modify Atherosclerosis in Mice Circulation, June 12, 2001; 103(23): 2834 - 2838. [Abstract] [Full Text] [PDF]
|
|