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The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis

BMJ 2013; 347 doi: (Published 30 October 2013) Cite this as: BMJ 2013;347:f6187

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Re: The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis

Francesco Cappello,MD,1,2,3,4 Giovanni Zummo,MD,2 Everly Conway de Macario,PhD,5 and Alberto JL Macario, MD,2,5

1 Human Anatomy Section, BIONEC Department, University of Palermo, Palermo, Italy
2 Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
3 Institute of Biophysics, National Research Council, Palermo, Italy
4 Institute “Paolo Sotgiu”, University, Lugano, Switzerland
5 Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore; and IMET, Columbus Center, Baltimore, MD, USA.


Dear Editor,

In their paper titled “The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis” [1], Ravi and coll. performed a propensity matched landmark analysis in a population cohort with advanced hip or knee osteoarthritis (OA) and found a cardioprotective benefit of primary elective total joint arthroplasty. They concluded that their study provides further justification for increased attention to the impact of treatments directed towards OA-related disability in the prevention and management of other common chronic conditions such as cardiovascular (CV) disease. Among the potential explanations for these findings, the authors include: an improved capability for physical activity; a relieved pain and, in turn, psychosocial stress and depression; and a reduced use of non-steroidal anti-inflammatory drugs (NSAIDs). All these may reduce the CV risk. In our opinion, they should have also included another explanation, which should not be disregarded by physicians nowadays.

OA is characterized histologically by a progressive cartilage loss [2], which causes pain [3]. The histological changes alter the physiologic shear stress responsible for the maintenance of articular cartilage homeostasis [4] and induce pathologic stress. Heat Shock Proteins (HSPs), many of which are molecular chaperones, are the most important class of anti-stress molecules [5]. They confer cell resistance to a number of stressors, including physical ones, by preventing misfolding and by inducing refolding of damaged intracellular proteins [6]. In addition to their intracellular localization and functions, HSPs can be actively secreted by cells, via various pathways [7] and reach the circulation [8]. Circulating HSPs can have pro-inflammatory effects either directly, by stimulating immune cells to produce cytokines [9,10], or indirectly, because they are highly immunogenic and, thus, able to elicit the production of anti-HSPs antibodies [10]. The latter can recognize HSPs that are abnormally expressed on the plasma membrane in various pathophysiologic conditions. A classic example of the latter is hypertension. In it, Hsp60 is expressed on the surface of endothelial cells, thus generating an autoimmune response on the vessels and increasing the risk of cardiovascular disease [11,12]. Under the light of these findings, the term “chaperonopathies by mistake” has been coined for those pathological conditions in which chaperones are apparently not altered in their structure (at least according to present day detection methods) but they work to the advantage of the disease rather than to that of the host [13].

HSPs/molecular chaperones are abundantly expressed in connective tissues of patients with degenerative joint diseases [14] and in OA [15]. Furthermore, specific humoral antibodies in sera from patients with temporomandibular joint OA cross-react with recombinant Hsp47 [16], one of the most important stress proteins for normal articular chondrocyte homeostasis [17]. However, at the best of our knowledge, direct release of HSPs/chaperones in circulation by OA tissues has not been demonstrated and no systematic studies have been reported on circulating levels of HSPs/chaperones in populations with OA. Our view is that osteoarthritic joints can be the source of circulating HSPs/chaperones that, in turn, determine an increase in the CV risk in these patients [18-21]. As concluded by Ravi [1], elective total joint arthroplasty may have a cardioprotective effect in these patients. In this regard, the hypothesis that HSPs are crucial in determining the CV risk in OA patients before and after intervention, is a very promising avenue for investigation.

1. Ravi B, Croxford R, Austin PC, Lipscombe L, Bierman AS, Harvey PJ, Hawker GA. The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis. BMJ. 2013 Oct 30;347:f6187.
2. Eckstein F, Cicuttini F, Raynauld JP, Waterton JC, Peterfy C. Magnetic resonance imaging (MRI) of articular cartilage in knee osteoarthritis (OA): morphological assessment. Osteoarthritis Cartilage. 2006;14 Suppl A:A46-75.
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4. Lane Smith R, Trindade MC, Ikenoue T, Mohtai M, Das P, Carter DR, Goodman SB, Schurman DJ. Effects of shear stress on articular chondrocyte metabolism. Biorheology. 2000;37(1-2):95-107.
5. Hartl FU. Molecular chaperones in cellular protein folding. Nature. 1996 Jun 13;381(6583):571-9.
6. Macario AJL, Conway de Macario E. Sick chaperones, cellular stress, and disease. N Engl J Med. 2005 Oct 6;353(14):1489-501.
7. De Maio A. Extracellular heat shock proteins, cellular export vesicles, and the Stress Observation System: a form of communication during injury, infection, and cell damage. It is never known how far a controversial finding will go! Cell Stress Chaperones. 2011 May;16(3):235-49.
8. Henderson B, Pockley AG. Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases. Cell Stress Chaperones. 2012 May;17(3):303-11.
9. Macario AJL, Cappello F, Zummo G, Conway de Macario E. Chaperonopathies of senescence and the scrambling of interactions between the chaperoning and the immune systems. Ann N Y Acad Sci. 2010 Jun;1197:85-93.
10. Winfield JB, Jarjour WN. Stress proteins, autoimmunity, and autoimmune disease. Curr Top Microbiol Immunol. 1991;167:161-89.
11. Wick G. Atherosclerosis--an autoimmune disease due to an immune reaction against heat-shock protein 60. Herz. 2000 Mar;25(2):87-90.
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13. Macario AJL, Conway de Macario E, Cappello F. The Chaperonopathies. Diseases with defective molecular chaperones. Springer Dordrecht Heidelberg. New York, 2013. Available at:
14. Lambrecht S, Juchtmans N, Elewaut D. Heat-shock proteins in stromal joint tissues, innocent bystanders or disease-initiating proteins? Rheumatology (Oxford). 2013 Aug 16.
15. Takahashi K, Kubo T, Arai Y, Imanishi J, Kawata M, Hirasawa Y. Localization of heat shock protein in osteoarthritic cartilage. Scand J Rheumatol. 1997;26(5):368-75.
16. Kuboki T, Hattori T, Mizushima T, Kanyama M, Fujisawa T, Yamashita A, Takigawa M. Detection of specific antibodies against human cultured chondrosarcoma (HCS-2/8) and osteosarcoma (Saos-2) cells in the serum of patients with osteoarthritis of the temporomandibular joint. Arch Oral Biol. 1999 May;44(5):403-14.
17. Ruiz-Romero C, López-Armada MJ, Blanco FJ. Proteomic characterization of human normal articular chondrocytes: a novel tool for the study of osteoarthritis and other rheumatic diseases. Proteomics. 2005 Aug;5(12):3048-59.
18. Rizzo M, Macario AJL, Conway de Macario E, Gouni-Berthold I, Berthold HK, Rini GB, Zummo G, Cappello F. Heat shock protein-60 and risk for cardiovascular disease. Curr Pharm Des. 2011 Nov;17(33):3662-8.
19. Xu Q, Metzler B, Jahangiri M, Mandal K. Molecular chaperones and heat shock proteins in atherosclerosis. Am J Physiol Heart Circ Physiol. 2012 Feb 1;302(3):H506-14.
20. Ghayour-Mobarhan M, Rahsepar AA, Tavallaie S, Rahsepar S, Ferns GA. The potential role of heat shock proteins in cardiovascular disease: evidence from in vitro and in vivo studies. Adv Clin Chem. 2009;48:27-72.
21. Lamb DJ, El-Sankary W, Ferns GA. Molecular mimicry in atherosclerosis: a role for heat shock proteins in immunisation. Atherosclerosis. 2003 Apr;167(2):177-85.

Competing interests: No competing interests

04 November 2013
Francesco Cappello
Associate Professor of Human Anatomy,
& Giovanni Zummo, Everly Conway de Macario, Alberto JL Macario (see other affiliations)
University of Palermo, Palermo, Italy
via del Vespro 129, 90127, Palermo, Italy