Inflammation in atrial fibrillation and atherosclerosis: pearls and pitfalls in the theorising process

To the Editor: While maintaining a degree of scientific equipoise, Boos and Lip (1) give credence to the idea that systemic markers of inflammation have a distinct and possibly pathogenetic role in cardiovascular disorders such as atrial fibrillation (AF) and human coronary artery disease. Any comprehensive theory must satisfy three criteria: (i) it must explain the major manifestations of the disorder or phenomenon by means of a model that contains only a few arbitrary elements; (ii) it must generalise the phenomenon to similar or related entities; and (iii) it must include hypotheses that can be supported, refuted or improved (2, 3). Fundamentally, the human coronary artery disease model is histopathologically a very well-defined disease entity. It is a tribute to the human spirit that we continue to improve upon what we already know; this spirit has been perhaps best captured by Popper: ‘No idea cannot be improved upon’ (4). Much of the current focus on the putative role of C-reactive protein (CRP) in atherosclerosis, nevertheless, is based on unequivocal demonstration on immunohistochemical staining of CRP in the vascular wall of active atherosclerotic plaques (1, 5). Unless a determined effort is made to understand the reductionist nature of the laboratory, we remain prone to oversimplification. The active atheromatous plaque, in contrast to solid organs such as liver, kidney, lung or brain, is freely bathed in circulating blood. Axiomatically, any and all components of the blood as well as organisms and antigens circulating in the blood can be found in the tissues surrounding the atheromatous plaque. A typical example of this phenomenon is the variable detection of Chlamydia pneumoniae in atheromatous lesions (6). As C. pneumoniae neither affects plaque instability nor accelerates atherogenic changes in the aortic root of apolipoprotein E-deficient mice, the task of concluding a definitive role for C. pneumoniae in the pathogenesis of atherosclerosis is truly formidable (7). The most likely explanation for variable detection of C. pneumoniae in parallel with the natural distribution of atheromatous lesions is that in the phase of bloodstream dissemination during the original infection (clinical or subclinical) the organism is rheologically deposited (seeded or embedded) in those atheromatous plaques that do not have an intact intima at that point of time (7). Because randomisation is not a scientific method but does enable investigative clinicians to do scientifically credible research without having to discern crucial clinical phenomena (8), it is understandable – but disquieting – why, even while the mechanism(s) of contribution of C. pneumoniae to the pathogenesis of atherosclerosis remains unknown, prophylactic antibiotic trials are being conducted for people at high risk of coronary disease and abdominal aortic aneurysm (7). The distributive parallel between CRP and C. pneumoniae in atheromatous plaques is not difficult to comprehend. Against this background, colocalisation of the terminal complement complex with CRP in atheromatous plaques (1) is practically inconsequential. More importantly, there is a clearly defined spectrum of clinical illnesses that are unambiguously associated with sustained rises of CRP for decades; there is no evidence to suggest that an accelerated atherosclerosis commonly accompanies the several autoimmune diseases (such as rheumatoid arthritis, rheumatic heart disease and sarcoidosis) that serve as a natural human model for studying the putative atherogenic role of CRP. Finally, statin therapy concomitantly decreases low-density lipoprotein (LDL) cholesterol and CRP (9). Biologically – but not statistically – it is impossible to distinguish between the effects on the progression of atherosclerosis of simultaneous reduction of LDL cholesterol and CRP. The link between systemic inflammation and AF is a far more complex affair. The clinical course of AF is highly variable. Lone AF has inexplicable reversions to normal sinus rhythm as well as recurrences; the occurrence of thromboembolism in AF is equally unpredictable. Spontaneous reversions of AF to normal sinus rhythm indicate that any ‘atrial remodelling’ is reversible and adaptive rather than being pathogenetic. Wijffels et al. (10) reported that all electrophysiological changes induced in five goats after 2–4 weeks of sustained AF were reversed within 1 week after sinus rhythm was restored. The idea that ‘AF begets AF’ is not akin to ‘mitral regurgitation begets mitral regurgitation’; Wijffels et al. (10) did not describe structural alterations attributable to AF in their animal model. Second, the attempt to link systemic alterations in CRP to localised pathological changes in the atrium is debatable (1). Atrial inflammatory infiltrates, oxidative damage or occult myocarditis in patients with lone AF (11, 12) certainly indicates a low-grade inflammatory process, but to even speculate about a direct involvement of CRP in the pathogenesis of such lesions – and therefore AF – without having seen CRP in atrial tissue requires complete suspension of clinical disbelief. Even in rheumatic pancarditis, where the occurrence of CRP elevation as part of systemic inflammation is a diagnostic feature, CRP has not been seen in cardiac tissues. Third, to conclude that the concurrence of peak of CRP elevation after coronary artery bypass grafting (CABG) surgery and AF indicates a pathogenetic link between CRP and AF (1, 9) is erroneous. Boos and Lip (1) do not underscore that CRP is routinely elevated for 1–4 days after all surgical procedures in proportion to the degree of surgical trauma (13). CRP is simply a marker of the acute inflammatory response; surgery that involves the destruction and reconstruction of tissues is a classic form of acute inflammation. The fact that AF is not associated with noncardiac surgeries indicates that any link or causal relation to CRP is not straightforward. Because postsurgical pericardial injury is an invariable concomitant of cardiac surgeries, the link between localised pericardial inflammation and AF needs to be explored. Fourth, AF in the end-stage renal disease (14) appears to have no link with CRP. Fifth, autonomic dysfunction appears to have a prominent role in the development of AF after CABG surgery (15). Sixth, the link between CRP and microalbuminuria in the genesis of AF (1, 16) is a further digression from common sense. Microalbuminuria is not a marker for systemic inflammation. Also, while diabetes mellitus is the largest cohort linked to microalbuminuria, there is no definitive predilection for uncomplicated diabetic patients without other cardiovascular disorders to develop AF. Finally, AF is a largely asymptomatic arrhythmia; however, the occurrence or relapse of such an arrhythmia would activate the body's intrinsic defence mechanisms much before subjective awareness of the disorder. The rise and fall of markers of systemic inflammation following relapse or remission of AF, respectively (17), should not be construed to show a pathogenetic link. While speculation is indeed the engine that carries medical research forward (18), it must not be allowed to leave the station without the bogies of generalisation, prediction and common sense. Speculation in the absence of readiness to question favoured paradigms is nothing but a recipe for disaster or, at best, seeing the trees for the wood indefinitely. The real gem in the analysis (1) is the role of low-dose glucocorticoid therapy in improving the efficacy of sinus rhythm maintenance postcardioversion (19). Corticosteroids reduce CRP whenever they are used; the reduction of CRP levels while using corticosteroids in AF must not be extrapolated back to the origin of the disorder. The research challenge is to identify the underlying pathophysiological process in AF that is so exquisitely sensitive to low-dose corticosteroid therapy. To maintain this focus, we have to address and eliminate the many ideas and theories that clutter our thinking about the pathogenetic role of CRP in cardiovascular disorders.