Author + information
- Stephen J. Nicholls, MBBS, PhD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Stephen J. Nicholls, Department of Cardiovascular Medicine, Heart and Vascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195
- cardiovascular risk factors
- coronary artery disease
- plaque vulnerability
- virtual histology–intravascular ultrasound
For more than half a century, angiography has been widely used to diagnose and quantify the extent of obstructive disease within the coronary arteries. As a result, angiography is used to triage patients to a range of medical and revascularization strategies. This has largely been fueled by advances in bypass surgery and percutaneous coronary intervention (PCI), and by the observation of a relationship between the extent of angiographic disease and clinical outcome. Accordingly, coronary angiography has become an essential clinical tool for the cardiologist in the evaluation of patients with ischemic symptoms.
At the same time, however, we began to appreciate that angiography has its limitations. It involves an invasive procedure, thus limiting its use to patients with suspected ischemic symptoms. Numerous reports emerged that many patients with myocardial infarction had culprit lesions that were minimally diseased on angiography (1). This was largely explained by the importance of plaque composition in determining the propensity to develop acute ischemic events and by the understanding that angiography only images the lumen and fails to visualize the vessel wall, the site where plaque accumulates. Immense interest subsequently developed in the need to develop novel imaging modalities that could provide potentially more important insights.
Developing new imaging modalities has had 2 major objectives. First, can we perform imaging in a noninvasive fashion? This would theoretically broaden the scope of individuals who could be imaged, potentially including those who are deemed to be of intermediate risk by conventional risk prediction algorithms. Developments in carotid intimal medial thickness and coronary calcification have been reported to provide incremental risk prediction, stimulating a proliferation of their use without any robust evidence from clinical trials that their use is either cost-effective or makes a definitive change to the management or outcome of patients. A positive finding from such a study would represent a major advance for the cause of integrating noninvasive arterial imaging into risk prediction algorithms. In a similar fashion, there has been interest in the development of computed tomography and magnetic resonance imaging to noninvasively image atherosclerotic plaque, although limited resolution continues to plague their ability to visualize coronary plaque with the accuracy required by a useful clinical tool. Nevertheless, there remains optimism that ongoing advances may overcome these challenges.
The second major objective in advancing arterial wall imaging has been the ability to characterize plaque composition. Moving beyond demonstrating plaque burden to image its individual components is based on the premise that a plaque containing greater amounts of lipids, inflammatory cells, and necrotic material is more likely to rupture and promote acute ischemia (2). Intravascular ultrasound permits imaging of the full extent of plaque in the artery wall and has provided important insights into the vascular changes following PCI and factors that slow progression of atherosclerosis. Yet, the inability to optimally characterize plaque composition has limited its ability to precisely characterize the compositional changes within the artery wall.
Technological advances in radiofrequency analysis of ultrasound backscatter enable generation of a spectral tissue map that separates plaque into fatty, fibrofatty, necrotic, and calcific components. The early experience imaging human coronary arteries ex vivo revealed good correlation between the features demonstrated by the virtual histology–intravascular ultrasound (VH-IVUS) approach and histology (3). This finding stimulated considerable optimism that this approach would become a useful tool to the clinician, vascular biologist, and drug developer in their evaluation of coronary atherosclerosis.
Since its development, VH-IVUS has been increasingly used in case-control studies to characterize the relationship between clinical characteristics and plaque components. These reports have demonstrated the presence of more necrotic material in patients with acute coronary syndromes compared with patients with stable symptoms and in patients with a greater number of comorbid cardiovascular risk factors (4). Such volumetric measures have been incorporated in clinical trials to demonstrate potential efficacy of a novel anti-inflammatory therapy (5). An alternative approach has been to classify focal lesions into a number of plaque subtypes, the most clinically important proposed to be the virtual histology–intravascular ultrasound-derived thin-cap fibroatheroma (VH-TCFA), identified on the basis of large plaque burden and necrotic core size, with no overlying fibrous tissue demonstrable (6). Therefore, VH-IVUS has evolved to provide a range of methods to characterize plaque composition in different clinical and therapeutic settings.
In this issue of JACC: Cardiovascular Interventions, Zheng et al. (7) provide further insights into the findings of VH-IVUS in patients with the metabolic syndrome. Multivessel ultrasonic imaging was performed in 63 patients with angiographic coronary artery disease at a single center. Although the number of subjects was relatively small, patients with either diabetes or the metabolic syndrome were found to have not only more atherosclerotic plaque, but, in particular, more necrotic and calcific material and plaques classified as VH-TCFA. These are interesting observations that provide further mechanistic support linking the metabolic syndrome to adverse cardiovascular outcomes. However, the challenge remains to determine whether these features relate specifically to the presence of the metabolic syndrome or whether they simply reflect the presence of its individual components. The findings of similar reports that have focused on either plaque burden or cardiovascular outcomes would suggest that it simply represents the impact of multiple risk factors, rather than an independent entity (8,9). Regardless, the findings support the concept that patients meeting the diagnostic criteria for the metabolic syndrome warrant more intensive management of their global cardiovascular risk.
So how does one interpret the findings of studies such as these? In many of these reports, the differences in the size of necrotic core appear relatively small, while maintaining statistical significance. The question is to what degree does that translate to clinical significance? The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial (10) investigators recently aimed to provide clarity with regard to this issue. In a report of 697 patients undergoing multivessel imaging following PCI for an acute coronary syndrome, the presence of a VH-TCFA was associated with a more than 3-fold greater likelihood of subsequent major adverse cardiovascular event (10). Though this provides some degree of clinical link to the imaging findings, it is important to note that this reflected observations of very focal lesions, whereas most reports using VH-IVUS, such as reported by Zheng et al. (7) focus on the percentage of plaque occupied by various components throughout a segment of vessel. The degree to which small differences in these parameters relate to clinical outcome remains to be determined. Given the immense interest in use of this technology to evaluate novel antiatherosclerotic therapies in early stages of clinical development, this will be important to establish and quickly!
The increasing use of VH-IVUS in clinical trials presents a number of ongoing challenges. Use of volumetric measures may seem relatively straightforward, but with no robust evidence of a clear link between small changes in individual components and clinical outcome, it remains to be determined how to interpret these findings. In contrast, a focal approach may potentially have more evidence supporting a correlation with clinical outcome; the difficulty matching focal lesions and finding that these lesions often “disappear” on serial evaluation makes it difficult to know what information this will provide. More serial clinical data are clearly required linking changes of these parameters to changes in established biochemical parameters, measures of plaque burden, and clinical events.
More important, how does one integrate such findings into their clinical practice? Does the presence of more necrotic material or a VH-TCFA make an argument for intensification of medical therapy or use of experimental, focally based therapeutic approaches? The trend toward more aggressive use of lipid-lowering therapy would suggest that radiofrequency analysis is unlikely to be necessary for this. Similarly, more aggressive use of PCI or experimental intravascular therapies requires definitive evidence from clinical trials that they reduce cardiovascular morbidity before they can be advocated. For the time being, it would appear that although the virtual world can provide important insights into reality, much more work is needed for us to know what to do with these findings.
Dr. Nicholls has received research support from AstraZeneca, Roche, LipoScience, Eli Lilly, Novartis, Anthera, and Resverlogix; and he has received honoraria and consulting fees from AstraZeneca, Merck, Roche, Takeda, Anthera, Omthera, and Eli Lilly.
↵⁎ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
- American College of Cardiology Foundation
- Ambrose J.A.,
- Tannenbaum M.A.,
- Alexopoulos D.,
- et al.
- Falk E.,
- Shah P.K.,
- Fuster V.
- Nair A.,
- Kuban B.D.,
- Tuzcu E.M.,
- Schoenhagen P.,
- Nissen S.E.,
- Vince D.G.
- Garcia-Garcia H.M.,
- Gonzalo N.,
- Regar E.,
- Serruys P.W.
- Serruys P.W.,
- Garcia-Garcia H.M.,
- Buszman P.,
- et al.,
- Integrated Biomarker and Imaging Study-2 Investigators
- Zheng M.,
- Choi S.-Y.,
- Tahk S.-J.,
- et al.
- Mente A.,
- Yusuf S.,
- Islam S.,
- et al.,
- INTERHEART Investigators