Author + information
- Robert A. Vogel, MD∗ ()
- Cardiology Section, Department of Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado
- ↵∗Address for correspondence:
Dr. Robert A. Vogel, Cardiology Section (111B), Department of Veterans Affairs Medical Center, University of Colorado Denver, 1055 Clermont Street, Denver, Colorado 80220.
Designating angiographic coronary stenosis as ≥70% has important implications, namely categorization of the disease as “significant,” consideration of percutaneous or surgical revascularization, and initiation of aggressive secondary preventive measures (1). Despite its importance in cardiology, however, the visual designation of coronary stenosis severity as ≥70% has distinct limitations. I recently saw a patient whose clinical course nicely highlights one of the most important of these limitations. The patient had experienced 6 myocardial infarctions over a 20-year period, resulting in ischemic cardiomyopathy. He had never experienced chest pain other than in the setting of infarction. Although a review of his multiple angiographic studies revealed diffuse disease, none of his infarctions had occurred at a site of prior >70% stenosis. His moderate to severe disease was certainly “significant,” although not >70%. The poor correlation between individual lesion severity and stability is well documented (2). High-grade disease is more likely to produce ischemia and necessitate revascularization, but its prognostic value stems from its association with more extensive disease.
Characteristics of unstable plaques include moderate stenosis severity, positive remodeling, necrotic lipid-rich cores, thin fibrous caps, and active local and systemic inflammation (3,4). Other than having less compensatory remodeling, high-grade stable disease has been less well characterized. An important goal in cardiology is to noninvasively identify individuals with both stable and unstable coronary artery disease (CAD) so that secondary preventive measures can be instituted. Of the 2 factors, however, identification of unstable patients before their potentially devastating initial presentation is the more important.
Several means for estimating coronary heart disease risk and noninvasively detecting CAD have evolved, including: global risk (Framingham-type) scores; computed tomography coronary calcium detection; and systemic biomarkers (5). Proposed blood biomarkers range from single factors, such as C-reactive protein, to panels of multiple proatherogenic proteins, ribonucleic acid messengers, and genes.
In this issue of the Journal, Ibrahim et al. (6) present a novel composite scoring approach that combines clinical parameters (sex, prior percutaneous coronary intervention [PCI]) and blood biomarkers (midkine, adiponectin, apolipoprotein C-I, and kidney injury molecule [KIM]-1) designed to identify patients with high-grade disease (≥70% stenosis) in at least 1 vessel. Unlike previous approaches for detecting disease of any severity, the specific goal of this project was to find “significant” disease that would have the potential to cause coronary ischemia and might necessitate PCI or surgical intervention. The score had an area under the receiver-operating characteristic curve of 0.87, with 77% sensitivity and 84% specificity for detecting high-grade disease in patients referred for coronary angiography. Higher scores were associated with greater severity of angiographic stenosis and correlated better with high-grade disease than did cardiac stress testing (area under the receiver-operating characteristic curve 0.87 vs. 0.52). The scoring system independently predicted incident acute myocardial infarction over a mean follow-up period of 3.6 years with a modest hazard ratio of 2.23.
Novel aspects of this study (6) included its goal of detecting specifically high-grade disease, its use of both clinical and blood biomarkers, and its identification of midkine as a biomarker of atherosclerosis. This study begs the question of whether high-grade coronary disease is associated with unique biomarkers apart from those associated with coronary atherosclerosis in general. It did not answer this question because it did not provide the performance of the selected biomarkers in separating those patients with and without any disease. Assigning patients to the “nonsignificant” category of coronary disease, as opposed to “no angiographic disease,” is a disservice to patients because they have almost the same risk for major coronary events, and secondary preventive measures are usually not suggested with the same vigor as for those with significant disease. Nor did the study compare its performance with biomarkers identified in other studies, although no prior investigation has focused on stenosis severity. For comparison, the single biomarker high-sensitivity C-reactive protein discriminates major cardiovascular event risk about as well (7).
Beyond the biological limitations of percent stenosis, visually assessed stenosis severity, as was done in this study (6), is remarkably inaccurate and imprecise. One SD of interobserver variability is 14.5%, even without the observer bias associated with patient management (8). Visually assessed percent diameter stenosis narrowing correlates only moderately (r = 0.74) with quantitative measurements and poorly with digitally assessed coronary flow reserve (9). It should be no surprise, therefore, that routine measurement of the more objective and physiologically relevant fractional flow reserve reduces the rate of major cardiovascular events in patients with multivessel CAD undergoing PCI (10).
The study score’s combination of clinical and biomarker parameters mimics clinical judgment (6). Surprisingly, only sex and previous PCI proved useful, but the score performed as well in those patients who had not undergone previous intervention as in those who did. Of >100 biomarkers evaluated, 4 were useful: midkine (promotes migration of leukocytes, induction of chemokines, and suppression of regulatory T cells); adiponectin (regulates glucose and fatty acid metabolism); apolipoprotein C-I (regulates fasting and postprandial triglyceride levels); and KIM-1 (a proximal renal tubular marker linked to acute kidney injury). Midkine and KIM-1 have not previously been linked to coronary atherosclerosis. It is interesting that none of the 4 biomarkers identified is a marker of inflammation as would be expected if the goal had been determining unstable disease.
To date, there seems to be little consensus on useful protein biomarkers for coronary atherosclerosis. The lack of consensus might be due to the characteristics of the populations studied, an important consideration for the development of any screening test. The findings of this study by Ibrahim et al. (6) must be considered preliminary because the investigators chose to divide a single population of patients referred for coronary angiography into training and validation groups. Discriminatory clinical and blood biomarkers were determined in the training group and then retested in the similar validation group. Validation of the scoring system in an independent population selected with more varied inclusion criterion would give the current study more certainty, a criticism acknowledged by the investigators.
In general, the development of more universally applicable biomarker screening tests for both early and high-grade CAD would potentially benefit from collaborative efforts as used by the Emerging Risk Factors Collaboration (11). My patient with ischemic cardiomyopathy is a good example of why cardiology urgently needs better approaches to screening for this important disease.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Vogel has reported that he has no relationships relevant to the contents of this paper to disclose.
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