Division of Neurology, Department of Medicine, Brain Research and Treatment Center, Scripps Clinic, La Jolla, CA, USA
Medical Director, Division of Neurology, Department of Medicine, Brain Research and Treatment Center, Scripps Clinic, La Jolla, CA, USA Tel.: +1-858-554-8892; fax: +1-858-554-6214
Division of Hematopathology and Immunopathology, Department of Pathology, Scripps Clinic, La Jolla, CA, USA
Head, Division of Infectious Diseases, Department of Medicine, Scripps Clinic, La Jolla, CA, USA
E-mail address: sotis{at}scrippsclinic.com
To the Editor
One investigative approach to linking periodontal disease to atherosclerotic cardiovascular disorders is demonstrating a shared risk factor with the potential for actually mediating cardiovascular disease. In this regard, the Buhlin et al.,1 report comparing cardiovascular risk factors between patients with severe periodontal disease (without known history of cardiovascular disorders) and healthy individuals suggests discovery of an important relationship. Their meticulous and innovative investigation discloses that a unique haematological index, the peripheral blood monocyte count, associates strongly with severe periodontal disease. Yet the investigators dismiss any potential for clinical relevance of this finding on the stated ground that the monocyte levels were within the "normal" range, and consequently they excluded this variable from their reported multivariable models and analyses.
The discovery of novel risk factors in exploratory studies like the Buhlin study requires entertaining scenarios beyond the entrenched paradigms. Moreover, several bases do exist to support an inference that peripheral blood monocyte indices, within today's reference range, may in fact operate to confer substantial cardiovascular disease risk. The true healthy range for peripheral blood monocyte levels vis à vis cardiovascular disease is not known. This conundrum persists because an appropriate reference population cannot be constituted. Present day technology does not enable physicians to validate the absence of underlying atherosclerosis. Therefore the statistical approach used today to define the reference range, for example, as two standard deviations above and below the mean is problematic in that it relies on a group of apparently healthy individuals. However a more meaningful approach, defining abnormal values as those associated with adverse physiological or clinical consequences, is feasible. Several initial developments in this direction are reported. First, the available longitudinal epidemiological studies indicate that minor increments in monocyte counts and proportions (that fall well within their reference ranges) do convey long-range predictive value for clinical cardiovascular disease and mortality.24 Second, the available longitudinal clinical imaging studies show that minor incremental differences in monocyte counts or proportions within today's reference range associate with near-term augmentation in rates of atherosclerotic vascular lesion progressions. The putative atherogenic effect of circulating monocytes manifests at native lesions in non-manipulated arteries5 as well as at iatrogenically triggered lesions such as restenosis after angioplasty or endovascular stent placement.67
In summary, this cumulative evidence enables the conclusion that it is both valid scientifically and clinically relevant for investigators to pursue evaluating monocyte levels in future risk factor analyses of cardiovascular disease. This logic is germane to the aim of the Buhlin study seeking to identify independent risk factors for periodontal disease that might be shared with cardiovascular diseases. Therefore the inclusion of peripheral blood monocyte indices (absolute count and relative proportion) as variables into their multivariate models is warranted. This more comprehensive modelling might also serve to illuminate interactions between circulating monocytes and the inflammatory mediators and biomarkers discussed (e.g., C-reactive protein, TNF- receptor 1, IL-6), where such physiological relationships in vivo have yet to be articulated.
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