Contemporary advances in cardiovascular imaging have contributed to improvements in the detection of clinically important coronary artery disease. Nevertheless, recurrent adverse events continue to persist in a substantial proportion of cases. Although coronary angiography is considered to be the gold standard for detecting coronary artery disease, it is incapable of assessing the vessel wall and, by extension, is insensitive in detecting and quantifying coronary atherosclerosis. On the other hand, intravascular ultrasound (IVUS) provides exquisite detail of the vessel wall and is currently the gold standard for quantifying coronary atherosclerosis. IVUS is also commonly used during clinical care as an adjunct to angiography and percutaneous coronary intervention (PCI). IVUS quantifies percentage stenosis and also facilitates description of the lumen and intima. Its use in clinical research has increased dramatically in recent years, including trials assessing the antiatherogenic effect of statins, angiotensin-converting enzyme inhibitors, and antidiabetes therapy.1-4 Furthermore, IVUS is frequently used to assist operators with stent sizing, lesion coverage, and postdilation balloon sizing. Although conventional grayscale IVUS has been commercially available for the past 2 decades, recent innovations in IVUS technology are leading to a better understanding of atherosclerosis progression and its association with future clinical events, namely through detection of plaque composition.

CONVENTIONAL GRAYSCALE VERSUS RADIOFREQUENCY IVUS

An IVUS image is generated when a transducer at the end of an IVUS catheter emits ultra-high-frequency sound waves, which are subsequently reflected by the surrounding tissue. In turn, the catheter receives the ultrasound backscatter and sends it to a processor for real-time display as a two-dimensional image of the artery.5 In conventional grayscale IVUS, images are derived from the amplitude of the reflected ultrasound signal; however, much information in the reflected ultrasound signal is not used.5

Various mathematical methods to process the unused radiofrequency backscatter signal have been developed, which are capable of generating sophisticated images of atherosclerotic tissue composition. One of these, termed virtual histology (VH, Volcano Corporation, San Diego, CA), uses autoregressive modeling to analyze the IVUS radiofrequency spectrum and construct a tissue map according to the presence of four distinct compositional elements.6-10 Autoregressive modeling is a procedure that converts the radiofrequency data into a power spectrum graph, plotting the magnitude and frequency of the signal backscatter. Linear regression is performed to identify parameters used by statistical classification trees to assign the radiofrequency data to one of the four tissue components.10

Each tissue characteristic is assigned a color on a VH IVUS image that corresponds with a known histological component. Fibrous tissue consists of densely packed bundles of collagen fibers without lipid or macrophage accumulation (green on VH IVUS, dark green/yellow on histology). Fibrofatty tissue contains loosely packed bundles of collagen fibers with minimal lipid deposition and without cholesterol clefts or necrosis (light green on VH IVUS, turquoise on histology). Dense calcium contains focal areas of calcium deposits without adjacent necrosis (white on VH IVUS, purple on histology). Necrotic core contains high lipid content as well as areas of necrosis with foam cells and dead lymphocytes but no visible collagen fibers8 (red on VH IVUS) (Figure 1).8

Algorithms to detect composition using VH IVUS have been validated in histology and clinical studies. In a series of 51 explanted left anterior descending coronary arteries, the sensitivity, specificity, and predictive accuracy of VH IVUS for the four plaque components ranged from 80% to 93%.8 In a separate study including 30 stable angina and acute coronary syndrome (ACS) patients, VH IVUS showed predictive accuracy of 87% for fibrous, 87% for fibrofatty, 88% for necrotic core, and 97% for calcium regions when compared with corresponding histological cross-sections obtained via directional coronary atherectomy.11

VH IVUS detection of plaque composition also permits advanced identification of plaque phenotypes in living patients. This process emulates a simplified American Heart Association morphological classification system for atherosclerotic lesions.12 In this system, nonatherosclerotic deposits containing foam cells without necrosis or a fibrous cap are described as intimal xanthoma. Atherosclerotic lesions are progressively classified as: (1) pathological intimal thickening (containing lipid without areas of necrosis); (2) fibrous cap atheroma (containing a well-formed necrotic core underlying a fibrous cap); (3) thin-cap fibroatheroma (TCFA) (necrotic core underlying a thin [< 65 µm] fibrous cap infiltrated by macrophages and lymphocytes); (4) fibrocalcific or abundant areas of calcium (few inflammatory cells with or without areas of necrosis). Each phenotype is defined in the VH IVUS–Derived Classification System for Plaque Phenotypes sidebar, along with a corresponding representative VH IVUS image.

Of the five lesion phenotypes, TCFA is associated with plaque vulnerability, rupture, and sudden cardiac death.13 The central role of TCFA in sudden cardiac death has been investigated in histopathology studies including high-risk subjects. In a series of autopsy specimens from more than 200 sudden cardiac death cases, Virmani and colleagues reported that > 60% of acute thrombi resulted from TCFA rupture.12 In a separate investigation of sudden cardiac death subjects, Burke and colleagues found more necrotic core in type 1 and 2 diabetes subjects than in those without diabetes matched on age, race, and sex.14 Thus, the clinical significance of phenotyping plaque composition is derived from these histopathologic observations that vulnerable plaque is frequently TCFA and often results in ACS and sudden cardiac death.

CLINICAL STUDIES WITH VH IVUS

Since its approval for commercial use within the last decade, VH IVUS has been the preferred imaging platform in many prospective studies that have advanced the understanding of coronary atherosclerosis.

PCI Complications
In early work, VH IVUS detection of necrotic core was associated with distal embolization after PCI. In a cohort of consecutive patients with ST-elevation myocardial infarction, Kawaguchi and colleagues performed PCI with VH IVUS on an infarct-related artery.15 ST-segment scores were evaluated before and after the procedure, with a > 2-mm increase in ST elevation immediately after stenting that was used to identify distal embolization. Necrotic core volume was significantly greater in patients with rather than without evidence of distal embolization (32.9 ± 14.1 mm3 vs 20.4 ± 19.1 mm3; P < .04), whereas there were no differences in volume of total plaque or other composition types. In a sensitivity analysis, necrotic core volume of 33.4 mm3 had a sensitivity of 82% and specificity of 64% for prediction of ST re-elevation. In other work, Kawamoto and colleagues studied stable angina patients undergoing elective PCI.16 Doppler ultrasound was used to detect microembolic particles as indicated by the presence of high-intensity transient signals. Patients in the highest signal tertile had significantly greater areas of necrotic core than patients in the lowest tertile (1.8 + 1 mm2 vs 0.5 + 0.4 mm2; P < .001). Necrotic core area was the only independent predictor of distal embolization (odds ratio, 4.41; 95% confidence interval, 1.03–18.81; P = .05). Both of these studies showed necrotic core to be linked to distal embolization, which is the likely mechanism for no-reflow and post-PCI myocardial infarction.

TCFA Studies
Investigators have used VH IVUS to demonstrate a higher than expected frequency of TCFA in patients presenting with ACS. In a single-center study of 21 consecutive ACS patients undergoing PCI followed by three-vessel VH IVUS, Garcia-Garcia and colleagues found a total of 42 TCFAs, including 13 patients with ≥ 1 TCFA in their coronary tree and 23 of the 63 vessels analyzed with ≥ 1 TCFA.17 In another prospective study, Rodriguez-Granillo and colleagues evaluated nonculprit lesions with < 50% occlusion in 55 stable angina and ACS patients. TCFA was observed to be more prevalent in the ACS cohort, whereas there were no statistically significant differences between the ACS and stable angina cohort in percent atheroma volume (57% vs 55%; P = .34) or percent necrotic core (20% vs 18%; P = .21).18

The association between TCFA and the risk of adverse cardiovascular events has also been described in high-risk subsets, including patients with greater future risk of myocardial infarction or cardiac death19 and diabetes.20,21 In the former category, patients from the Global VH IVUS Registry (n = 531) were classified by their 10-year risk for a coronary heart disease event by Framingham risk score. Patients with ≥ 20% risk had a twofold higher frequency of TCFA in the most diseased 10-mm segment than patients at < 10% risk (21.4% vs 11.3%; P = .008). This registry also suggested a higher proportion of TCFA in the most diseased 10-mm segment of patients with diabetes mellitus (21.6% vs 13.6%; P = .01). The duration of diabetes appears to be a potent driver of TCFA formation. In a separate study, patients with diabetes duration ≥ 10 years had a fivefold higher frequency of TCFA in the most diseased segment (54.4% vs 10.8%; P = .009).20

TCFA AND CLINICAL EVENTS: THE PROSPECT TRIAL

Although previous studies using VH IVUS provided valuable insights on plaque morphology and coronary risk, they were all limited by a lack of prospective longterm follow-up. In contrast, the PROSPECT trial was a prospective, multicenter, natural history study that used three-vessel multimodal imaging in ACS patients to study clinical events due to atherosclerosis progression and identify lesions associated with subsequent events.22 All patients underwent quantitative coronary angiography as well as grayscale and VH IVUS of the left main and the proximal 6 to 8 cm of each major epicardial coronary artery after successful PCI. Baseline angiograms and IVUS images were independently analyzed offline by trained investigators who were blinded to subsequent events. Subsequent major adverse cardiovascular events (MACE) consisting of cardiac death or arrest, nonfatal myocardial infarction, and rehospitalization for progressive or unstable angina, were adjudicated as occurring at either the culprit (treated) lesion or nonculprit (untreated) lesion site during median follow-up of 3.4 years.

Among the 697 patients enrolled in PROSPECT, the median age was 58 years, and 17% had diabetes. There were 3,160 nonculprit lesions that were identified by IVUS after PCI; 596 of these were identified as TCFA by VH IVUS in 313 patients. On average, there was one TCFA lesion identified per patient (range, 0–7). The cumulative 3-year rate of MACE was 20.4%, which was adjudicated to culprit lesions in 12.9% and nonculprit lesions in 11.6%.

Among nonculprit MACE lesions, a subset (n = 51) were imaged by VH IVUS. Independent predictors of nonculprit lesion MACE were minimal luminal area ≥ 4 mm2, plaque burden ≥ 70%, and presence of TCFA. There were 26 (51%) classified as TCFA, and eight (31%) of these had a minimal luminal area ≥ 4 mm2 and plaque burden ≥ 70%. In lesions with versus without all three of these characteristics present, the recurrent MACE rate was ninefold greater (18.2% vs 1.9%; hazard ratio, 11.05; 95% confidence interval, 4.39–27.82; P < .001).

TRANSPLANT VASCULOPATHY APPLICATIONS

Additional ongoing novel applications incorporating VH IVUS include studying cardiac allograft vasculopathy (CAV), a serious complication after heart transplant occurring in as many as 8% of patients within 1 year and is responsible for 33% of deaths within 5 years. The progression of CAV, an immune-mediated panarterial disease characterized by diffuse, longitudinal intimal thickness, 23 is not affected by preexisting donor-related atherosclerosis within the first few years after transplant.24

Coronary angiography is suboptimal in detecting CAV and donor atherosclerosis at earlier stages.25 Studies have shown that VH IVUS is a more sensitive tool in assessing changes in CAV. In a single-center study of 24 transplant patients, Rao and colleagues performed VH IVUS at baseline and 1 year after transplant.25 At baseline, 58% of patients had donor atherosclerosis (intimal thickness > 0.5 mm) and 25% developed CAV. At 1 year, there was a four-fold increase in percentage necrotic core in IVUS frames showing CAV (6.5% ± 15% vs 25% ± 13%; P = .0003). Representative angiographic, grayscale, and VH IVUS images from a CAV case analyzed at our imaging core laboratory are shown in Figure 2. In this case of a 50-year-old woman, there was a substantial increase in plaque thickness noted between baseline and follow-up at 1 year.

In 18 transplant patients with normal coronary angiograms within 90 days, König and colleagues showed six to have CAV with VH IVUS and plaque composed mostly of fibrotic tissue.26 In other work, these investigators studied time-dependent differences in plaque composition and phenotype using VH IVUS in 56 transplant patients.27 Patients were divided into three groups based on time from transplant (1–3 months, 1–5 years, and 5–15 years). Whereas fibrolipidic and fibrocalcific plaques were uniformly distributed throughout groups, TCFAs were mostly found in the 5 to 15 years group. This time-dependent relationship between CAV and plaque composition has also been shown by others,23 which has also shown donor age and presence of cardiovascular risk factors as influences.

ONGOING VH IVUS STUDIES

Today, research on the clinical utility of VH IVUS continues to evolve. In the BLAST (Bifurcation Lesion Analysis and Stenting) trial, investigators hypothesize that PCI with VH IVUS guidance for drug-eluting stent deployment in bifurcation lesions will lead to better postprocedural outcomes than angiographic guidance alone. This randomized, multinational trial is enrolling more than 200 patients who are scheduled to undergo PCI for bifurcation lesions and will include follow-up for MACE for up to 2 years. Another trial, VERDICT (Vascular Evaluation for Revascularization: Defining the Indications for Coronary Therapy), is a pilot study seeking to establish the prognostic utility of fractional flow reserve and VH IVUS–derived parameters of atherosclerosis in intermediate coronary lesions (40%–80% angiographic diameter stenosis). Lesion-related MACE will be assessed for up to 3 years in approximately 300 patients. In summary, these trials and results from other studies to date show VH IVUS to be a promising imaging modality that will likely be used in clinical practice and research well into the future.

Adnan Khalid, MD, is a postdoctoral cardiovascular diseases fellow with Saint Luke's Mid America Heart and Vascular Institute, and the University of Missouri-Kansas City in Kansas City, Missouri. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein.

Steven P. Marso, MD, is an interventional cardiologist at Saint Luke's Mid America Heart and Vascular Institute, and is Professor of Medicine at the University of Missouri- Kansas City in Kansas City, Missouri. He has disclosed that he has had no personal conflicts of interest during the previous 12 months. All compensation for his research activities, including research grants and consulting fees from The Medicines Company, Novo Nordisk, Abbott Vascular, Amylin Pharmaceuticals, Inc., Boston Scientific Corporation, Volcano Corporation, and Terumo Interventional Systems, is paid directly to the Saint Luke's Hospital Foundation. Dr. Marso may be reached at (816) 932-5773; smarso@cc-pc.com.

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