Johannes A. Schaar

Characterizing Vulnerable Plaque Features With Intravascular Elastography

Background—In vivo detection of vulnerable plaques is presently limited by a lack of diagnostic tools. Intravascular ultrasound elastography is a new technique based on intravascular ultrasound and has the potential to differentiate between different plaques phenotypes. However, the predictive value of intravascular elastography to detect vulnerable plaques had not been studied. Methods and Results—Postmortem coronary arteries were investigated with intravascular elastography and subsequently processed for histology. In histology, a vulnerable plaque was defined as a plaque consisting of a thin cap (<250 &mgr;m) with moderate to heavy macrophage infiltration and at least 40% of atheroma. In elastography, a vulnerable plaque was defined as a plaque with a high strain region at the surface with adjacent low strain regions. In 24 diseased coronary arteries, we studied 54 cross sections. In histology, 26 vulnerable plaques and 28 nonvulnerable plaques were found. Receiver operator characteristic analysis revealed a maximum predictive power for a strain value threshold of 1.26%. The area under the receiver operator characteristic curve was 0.85. The sensitivity was 88%, and the specificity was 89% to detect vulnerable plaques. Linear regression showed high correlation between the strain in caps and the amount of macrophages (P <0.006) and an inverse relation between the amount of smooth muscle cells and strain (P <0.0001). Plaques, which are declared vulnerable in elastography, have a thinner cap than nonvulnerable plaques (P <0.0001). Conclusions—Intravascular elastography has a high sensitivity and specificity to detect vulnerable plaques in vitro.

The role of shear stress in the destabilization of vulnerable plaques and related therapeutic implications

American Heart Association type IV plaques consist of a lipid core covered by a fibrous cap, and develop at locations of eccentric low shear stress. Vascular remodeling initially preserves the lumen diameter while maintaining the low shear stress conditions that encourage plaque growth. When these plaques eventually start to intrude into the lumen, the shear stress in the area surrounding the plaque changes substantially, increasing tensile stress at the plaque shoulders and exacerbating fissuring and thrombosis. Local biologic effects induced by high shear stress can destabilize the cap, particularly on its upstream side, and turn it into a rupture-prone, vulnerable plaque. Tensile stress is the ultimate mechanical factor that precipitates rupture and atherothrombotic complications. The shear-stress-oriented view of plaque rupture has important therapeutic implications. In this review, we discuss the varying mechanobiologic mechanisms in the areas surrounding the plaque that might explain the otherwise paradoxical observations and unexpected outcomes of experimental therapies.

Identification of Atherosclerotic Plaque Components With Intravascular Ultrasound Elastography In Vivo A Yucatan Pig Study

Background—Intravascular ultrasound elastography assesses the local strain of the atherosclerotic vessel wall. In the present study, the potential to identify different plaque components in vivo was investigated. Methods and Results—Atherosclerotic external iliac and femoral arteries (n=24) of 6 Yucatan pigs were investigated. Before termination, elastographic data were acquired with a 20-MHz Visions catheter. Two frames acquired at end-diastole with a pressure differential of ≈4 mm Hg were acquired to obtain the elastograms. Before dissection, x-ray was used to identify the arterial segments that had been investigated by ultrasound. Specimens were stained for collagen, fat, and macrophages. Plaques were classified as absent, early fibrous lesion, early fatty lesion, or advanced fibrous plaque. The average strains in the plaque-free arterial wall (0.21%) and the early (0.24%) and advanced fibrous plaques (0.22%) were similar. Higher average strain values were observed in fatty lesions (0.46%) compared with fibrous plaques (P =0.007). After correction for confounding by lipid content, no additional differences in average strain were found between plaques with and without macrophages (P =0.966). Receiver operating characteristic analysis revealed a sensitivity and a specificity of 100% and 80%, respectively, to identify fatty plaques. The presence of a high-strain spot (strain >1%) has 92% sensitivity and 92% specificity to identify macrophages. Conclusions—To the best of our knowledge, this is the first time that intravascular ultrasound elastography has been validated in vivo. Fatty plaques have an increased mean strain value. High-strain spots are associated with the presence of macrophages.

Incidence of High-Strain Patterns in Human Coronary Arteries Assessment With Three-Dimensional Intravascular Palpography and Correlation With Clinical Presentation

Background—Rupture of thin-cap fibroatheromatous plaques is a major cause of acute myocardial infarction (AMI). Such plaques can be identified in vitro by 3D intravascular palpography with high sensitivity and specificity. We used this technique in patients undergoing percutaneous intervention to assess the incidence of mechanically deformable regions. We further explored the relation of such regions to clinical presentation and to C-reactive protein levels. Method and Results—Three-dimensional palpograms were derived from continuous intravascular ultrasound pullbacks. Patients (n= 55) were classified by clinical presentation as having stable angina, unstable angina, or AMI. In every patient, 1 coronary artery was scanned (culprit vessel in stable and unstable angina, nonculprit vessel in AMI), and the number of deformable plaques assessed. Stable angina patients had significantly fewer deformable plaques per vessel (0.6±0.6) than did unstable angina patients (P = 0.0019) (1.6±0.7) or AMI patients (P < 0.0001) (2.0±0.7). Levels of C-reactive protein were positively correlated with the number of mechanically deformable plaques (R2 = 0.65, P < 0.0001). Conclusions—Three-dimensional intravascular palpography detects strain patterns in human coronary arteries that represent the level of deformation in plaques. The number of highly deformable plaques is correlated with both clinical presentation and levels of C-reactive protein. Further studies will assess the potential role of the technique to identify patients at risk of future clinical events

Fully automatic luminal contour segmentation in intracoronary ultrasound imaging-a statistical approach

In this paper, a fully automatic method for luminal contour segmentation in intracoronary ultrasound imaging is introduced. Its principle is based on a contour with a priori properties that evolves according to the statistics of the ultrasound texture brightness, which is generally Rayleigh distributed. The main interest of the technique is its fully automatic character. This is insured by an initial contour that is not set by the user, like in classical snake-based algorithms, but estimated and, thus, adapted to each image. Its estimation combines two pieces of information extracted from the a posteriori probability function of the contour position: the function maximum location (or maximum a posteriori estimator) and the first zero-crossing of its derivative. Then, starting from the initial contour, a region of interest is automatically selected and the process iterated until the contour evolution can be ignored. In vivo coronary images from 15 patients, acquired with the 20-MHz central frequency Jomed Invision ultrasound scanner, were segmented with the developed method. Automatic contours were compared to those manually drawn by two physicians in terms of mean absolute difference. The results demonstrate that the error between automatic contours and the average of manual ones is of small amplitude, and only very slightly higher (0.099/spl plusmn/0.032 mm) than the interexpert error (0.097/spl plusmn/0.027 mm).

Strain distribution over plaques in human coronary arteries relates to shear stress

Once plaques intrude into the lumen, the shear stress they are exposed to alters with hitherto unknown consequences for plaque composition. We investigated the relationship between shear stress and strain, a marker for plaque composition, in human coronary arteries. We imaged 31 plaques in coronary arteries with angiography and intravascular ultrasound. Computational fluid dynamics was used to obtain shear stress. Palpography was applied to measure strain. Each plaque was divided into four regions: upstream, throat, shoulder, and downstream. Average shear stress and strain were determined in each region. Shear stress in the upstream, shoulder, throat, and downstream region was 2.55+/-0.89, 2.07+/-0.98, 2.32+/-1.11, and 0.67+/-0.35 Pa, respectively. Shear stress in the downstream region was significantly lower. Strain in the downstream region was also significantly lower than the values in the other regions (0.23+/-0.08% vs. 0.48+/-0.15%, 0.43+/-0.17%, and 0.47+/-0.12%, for the upstream, shoulder, and throat regions, respectively). Pooling all regions, dividing shear stress per plaque into tertiles, and computing average strain showed a positive correlation; for low, medium, and high shear stress, strain was 0.23+/-0.10%, 0.40+/-0.15%, and 0.60+/-0.18%, respectively. Low strain colocalizes with low shear stress downstream of plaques. Higher strain can be found in all other plaque regions, with the highest strain found in regions exposed to the highest shear stresses. This indicates that high shear stress might destabilize plaques, which could lead to plaque rupture.

Contrast harmonic intravascular ultrasound: A feasibility study for vasa vasorum imaging

Objective:We sought to investigate feasibility of vasa vasorum imaging using the novel technique of contrast harmonic intravascular ultrasound. Methods:Prototype intravascular ultrasound (IVUS) instrumentation was developed for the sensitive detection of microbubble contrast agents. The technique, “harmonic” imaging, involves transmitting ultrasound at 20 MHz (fundamental) and detecting contrast signals at 40 MHz (second harmonic). Phantom experiments were conducted to investigate the detection of a small vessel in the wall surrounding a larger vessel. In vivo experiments were conducted in atherosclerotic rabbit abdominal aortas. Results:The phantom experiments showed improved small vessel detection in harmonic mode relative to fundamental mode. For the in vivo experiments, harmonic imaging enabled the visualization of contrast agent outside the aortic lumen through a statistically significant (P < 0.001) enhancement of image power, consistent with the detection of adventitial microvessels. These microvessels were not detected in fundamental imaging mode. Conclusions:These results indicate the feasibility of contrast harmonic intravascular ultrasound as a new technique for vasa vasorum imaging.

Current diagnostic modalities for vulnerable plaque detection

Rupture of vulnerable plaques is the main cause of acute coronary syndrome and myocardial infarction. Identification of vulnerable plaques is therefore essential to enable the development of treatment modalities to stabilize such plaques. Several diagnostic methods are currently tested to detect vulnerable plaques. Angiography has a low discriminatory power to identify the vulnerable plaque, but does provide information about the entire coronary tree and serves as guide for invasive imaging techniques and therapy. Angioscopy offers a direct visualization of the plaque surface and intra-luminal structures like thrombi and tears. However, angioscopy is difficult to perform, invasive and only the proximal part of the vessels can be investigated. IVUS (intravascular ultrasound) provides some insight into the composition of plaques. The detection of vulnerable plaques is mainly based on series of case reports with a lack of prospectivity and follow-up. Palpography, an IVUS derived technique, reveals information, which is not recognizable in IVUS. It can differentiate between deformable and non-deformable tissue, which enables the technique to detect vulnerable plaques with a positive predictive value. The clinical value of palpography is currently under investigation. Thermography assesses the temperature heterogeneity as an indicator of the metabolic state of the plaque. A coincidence of temperature rise and localization of vulnerable plaque was suggested. OCT (optical coherence tomography) can provide images with ultrahigh resolution utilizing the back-reflection of near-infrared light from optical interfaces in tissue. Drawbacks are the low penetration depth into tissue and the absorbance of light by blood. Raman spectroscopy can provide quantification about the molecular composition of the plaque. Long acquisition time, the low penetration depth and light absorbance by blood limit the performance of the technique. Another light emitting technique is NIR (near infrared spectroscopy), which identifies lipid loaded plaques and is tested currently in clinical trials. Non-invasive MRI (magnetic resonance imaging) and multislice spiral computed tomography (MSCT), with their excellent ability to identify lipid-rich tissue, have been utilized to characterize potentially vulnerable plaques foremost in non-moving structures like the carotid arteries. Due to the resolution of the techniques small plaque structure cannot be assessed. The role of non-invasive imaging in vulnerable plaque detection is currently under investigation. Several invasive and non-invasive techniques are currently under development to assess the vulnerable plaque. Most of the techniques show exiting features, but none have proven their value in an extensive in vivo validation and all have a lack of prospective data.

Intravascular palpography for high-risk vulnerable plaque assessment.

Background:The composition of an atherosclerotic plaque is considered more important than the degree of stenosis. An unstable lesion may rupture and cause an acute thrombotic reaction. Most of these lesions contain a large lipid pool covered by an inflamed thin fibrous cap. The stress in the cap increases with decreasing cap thickness and increasing macrophage infiltration. Intravascular ultrasound (IVUS) palpography might be an ideal technique to assess the mechanical properties of high-risk plaques.Technique:Palpography assesses the local mechanical properties of tissue using its deformation caused by the intraluminal pressure.In Vitro Validation:The technique was validated in vitro using diseased human coronary and femoral arteries. Especially between fibrous and fatty tissue, a highly significant difference in strain (p = 0.0012) was found. Additionally, the predictive value to identify the vulnerable plaque was investigated. A high-strain region at the lumen-vessel wall boundary has an 88% sensitivity and 89% specificity for identifying such plaques.In Vivo Validation:In vivo, the technique was validated in an atherosclerotic Yucatan minipig animal model. This study also revealed higher strain values in fatty than fibrous plaques (p < 0.001). The presence of a high-strain region at the lumenplaque interface has a high predictive value to identify macrophages.Patient Studies:Patient studies revealed high-strain values (1–2%) in thin-cap fibrous atheroma. Calcified material showed low strain values (0–0.2%). With the development of three-dimensional (3-D) palpography, identification of highstrain spots over the full length of a coronary artery becomes available.Conclusion:Intravascular palpography is a unique tool to assess lesion composition and vulnerability. The development of 3-D palpography provides a technique that may develop into a clinical tool to identify the high-risk plaque.Hintergrund:Die Zusammensetzung einer atherosklerotischen Plaque wird als wichtiger erachtet als deren Stenosegrad. Eine instabile Läsion kann aufbrechen und eine thrombotische Reaktion auslösen. Die Mehrzahl dieser Läsionen enthält einen großen lipidreichen Kern, der von einer dünnen entzündeten Kappe bedeckt ist. Der Stress in der Kappe erhöht sich mit abnehmender Dicke der Kappe und zunehmender Makrophageninfiltration. Die intravaskuläre Ultraschall- (IVUS-)Palpographie könnte die ideale Technik zur Beurteilung der mechanischen Eigenschaften von Hochrisikoplaques darstellen.Technik:Die Palpographie erfasst die lokalen mechanischen Eigenschaften von Gewebe mit Hilfe der durch den intravaskulären Druck erzeugten Deformation.In-vitro-Validierung:Die Methode wurde durch Untersuchung erkrankter Koronar- und Femoralarterien validiert. Insbesondere zwischen fibrösem und fetthaltigem Gewebe ließ sich ein hochsignifikanter Unterschied bezüglich der Gewebsdehnung feststellen (p = 0,0012). Zudem wurde der prädiktive Wert für die Diagnose einer vulnerablen Plaque untersucht. Eine Stelle mit hoher Dehnung an der Gefäßoberfläche hat eine Sensitivität von 88% und eine Spezifität von 89% für die Erkennung solcher Plaques.In-vivo-Validierung:In vivo wurde die Technik in einem atherosklerotischen Yucatan-Minischwein-Modell validiert. Auch diese Untersuchung zeigte höhere Dehnungswerte in fetthaltigen gegenüber fibrösen Plaques (p < 0,001). Zudem hat das Vorliegen hoher Dehnungswerte an der Plaqueoberfläche einen hohen prädiktiven Wert für die Erkennung von Makrophagen.Patientenstudien:Patientenstudien ergaben hohe Dehnungswerte (1–2%) in fetthaltigen Plaques mit dünner Kappe. Kalzifiziertes Material zeigte niedrige Dehnungswerte (0–0,2%). Durch die Entwicklung der dreidimensionalen (3-D) Palpographie wird die Identifikation von Stellen mit hohen Dehnungswerten im kompletten Koronarsystem möglich.Schlussfolgerung:Wie keine andere Methode gestattet die intravaskuläre Palpographie, Zusammensetzung und Vulnerabilität einer Läsion zu beurteilen. Die Entwicklung der 3-D-Palpographie stellt eine Technik zur Verfügung, die sich zu einem klinischen Hilfsmittel zur Identifizierung von Hochrisikoplaques entwickeln könnte.

Tissue Doppler Imaging: A New Technique for Assessment of Pseudonormalization of the Mitral Inflow Pattern

Left ventricular diastolic dysfunction (LVDD) is a frequent cause of heart failure. Doppler echocardiography has become the method of choice for the noninvasive evaluation of LVDD. However, pseudonormalization (PN) of the mitral inflow often presents a diagnostic challenge in clinical practice. In this setting, we sought to define the role of tissue Doppler imaging (TDI) of the septal mitral annulus. Echocardiography was performed in 36 consecutive subjects (age 59 ± 10 years). Eighteen of these had diagnosed coronary artery disease (CAD) with recent onset of symptoms (within 3 months), 18 had clinical suspicion of CAD, and 15 had symptoms of heart failure (New York Heart Association [NYHA] Class 2.4 ± 0.5). The mitral inflow profile (E, A, E/A) was measured by pulsed Doppler, and the deceleration time (DT) and the isovolumic relaxation time (IVRT) were calculated. Peak diastolic velocities of the septal mitral annulus (ET, AT, ET/AT) and the time interval from Q in the ECG to the onset of ET were derived from pulsed TDI. Left heart catheterization was performed for direct measurement of left ventricular end‐diastolic pressure (LVEDP). PN defined by an E/A ratio > 1 and an LVEDP ≥ 16 mmHg was found in nine patients. All patients with PN had symptoms of heart failure (NYHA Class 2.8 ± 0.5). Patients with and without PN did not differ with respect to the E/A ratio (1.29 ± 0.44 vs 1.16 ± 0.23, P = ns), DT (182 ± 38 msec vs 205 ± 42 msec, P = ns), and IVRT (88 ± 24 msec vs 92 ± 18 msec, P = ns). In the group with PN, a significant reduction of ET (5.6 ± 1.8 cm/sec vs 8.8 ± 2.9 cm/sec, P < 0.05) and ET/AT (0.5 ± 0.16 vs 0.82 ± 0.37, P < 0.05) was detected. In the PN group, the Q‐ET interval was prolonged (404 ± 48 msec vs 346 ± 50 msec, P < 0.05). Receiver operating characteristic curve analysis for ETyielded an area under the curve of 0.78 ± 0.06 (P = 0.034) for separating patients with versus without PN. When the combination of ET < 7 cm/sec and ET/AT < 1 was used as cutpoint, PN could be identified with a sensitivity of 83% and a specificity of 79%. There was no significant relation between LVEDP and either ET (r = 0.32, P > 0.2) or the Q‐ET interval (r = 0.14, P > 0.5). In conclusion, ET and the Q‐ET interval appear to be useful parameters for assessing LV diastolic dysfunction in symptomatic patients with a pseudonormal mitral inflow pattern and elevated filling pressures.