Chris L. de Korte

From Vulnerable Plaque to Vulnerable Patient: A Call for New Definitions and Risk Assessment Strategies: Part II

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term vulnerable patient may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Intravascular elasticity imaging using ultrasound: Feasibility studies in phantoms

A technique is described for measuring the local hardness of the vessel wall and atheroma using intravascular ultrasound. Strain images were constructed using the relative local displacements, which are estimated from the time shifts between gated echo signals acquired at two levels of intravascular pressure. Time shifts were estimated using one-dimensional correlation with bandlimited interpolation around the peak. Tissue-mimicking phantoms with typical morphology and hardness topology of some atherosclerotic vessels were constructed. Hard and soft regions could be distinguished on the strain image, independently of their contrast in echogenicity. Thus, the potential of ultrasonic hardness imaging to provide information that may be unavailable from the echogram alone was demonstrated. The strain images of the homogeneous and layered phantoms showed some artifacts that need to be corrected for, to obtain images of the modulus of elasticity. For in vitro and in vivo experiments, the spatial resolution of the technique needs to be improved. Furthermore, two-dimensional correlation techniques may be necessary in case of nonradial expansion and an off-centre catheter position.

Characterization of plaque components and vulnerability with intravascular ultrasound elastography

Intravascular ultrasound elastography is a method for measuring the local elastic properties using intravascular ultrasound (IVUS). The elastic properties of the different tissues within the atherosclerotic plaque are measured through the strain. Knowledge of these elastic properties is useful for guiding interventional procedures (balloon dilatation, ablation) and detection of the vulnerable plaque. In the last decade, several groups have applied elastography intravascularly with various levels of success. In this paper, the approaches of the different research groups will be discussed. The focus will be on our approach to the application of intravascular elastography. Elastograms were acquired in vitro and in vivo using the relative local displacements between IVUS images acquired at two levels of intravascular pressure with a 30 MHz mechanical or a 20 MHz array echo catheter. These displacements were estimated from the time shift between gated radiofrequency echo signals using cross-correlation algorithms with interpolation around the peak. Experiments on gel-based phantoms mimicking atherosclerotic vessels demonstrated the capability of elastography to identify soft and hard tissues independently of the echogenicity contrast. In vitro experiments on human arteries have demonstrated the potential of intravascular elastography to identify different plaque types based on their mechanical properties. These plaques could not be identified using the IVUS image alone. In vivo experiments revealed that reproducible elastograms could be obtained near end-diastole. Partial validation using the echogram was performed. Intravascular elastography provides information that is frequently unavailable or inconclusive from the IVUS image and which may therefore assist in the diagnosis and treatment of atherosclerotic disease.

Intravascular ultrasound elastography in human arteries: Initial experience in vitro

Intravascular elastography is a new technique to obtain the local mechanical properties of the vessel wall and its pathology using intravascular ultrasound (IVUS). Knowledge of these mechanical properties may be useful for guiding interventional procedures. An experimental set-up is described for assessment of the strain data of arteries. Using a 30-MHz IVUS catheter, radio frequency data are acquired with a custom-made high-performance data acquisition system. High-resolution, local tissue displacement estimation by cross-correlation is followed by computation of local strain. An algorithm that uses a priori knowledge of the correlation coefficient function was applied to filter the obtained strain data. With this experimental set-up, intravascular elastograms containing 400 angles/revolution with a radial resolution of 200 microns can be produced. The feasibility of intravascular elastography with this experimental set-up is demonstrated using two diseased human femoral arteries. Qualitative comparison of the elastograms with the echograms and the histology demonstrates the potential of intravascular elastography to obtain mechanical information from the vessel wall and from plaque.

Intravascular ultrasound elastography: an overview.

The composition and morphology of the atherosclerotic lesion are currently considered more important determinants of acute coronary ischemic syndromes than the degree of stenosis. When a lesion is unstable, it may rupture and cause an acute thrombotic reaction. A rupture prone plaque contains a large lipid pool covered by a thin fibrous cap. The stress in the cap increased with decreasing thickness. Additionally, it may be weakened by macrophage infiltration. Intravascular ultrasound elastography might be an ideal technique to assess the presence of lipid pools and identify high stress regions. Elastography is a technique to assess local mechanical properties of tissue. The underlying principle is that the deformation of tissue by a mechanical excitation is a function of its mechanical properties. The deformation of the tissue is determined using ultrasound. For intravascular purposes, the intraluminal pressure is used as the excitation force. The radial strain in the tissue is obtained by cross-correlation techniques on the radio frequency (rf) signal. The strain is colour-coded and plotted as a complimentary image to the IVUS echogram. Elastography was validated in vitro using diseased human coronary and femoral arteries. After the ultrasound experiments, the specimens were processed for routine histology to counterstain collagen, smooth-muscle cells, and macrophage activity. Regions were segmented in the elastograms based on their strain values. Next, the dominant plaque type (fibrous, fibro-fatty or fatty) was defined by observers blinded to the elastographic result. These experiments demonstrate that the strain in the three plaque types is different (Kruskall-Wallis p < 0.001). Especially between fibrous and fatty tissue, a highly significant difference (Wilcoxon p < 0.001) was found. In vivo, the technique is validated in an atherosclerotic Yucatan mini-pig animal model. High-resolution echo frames (30 frames per second) were acquired near end-diastole. In this phase of the pressure cycle, catheter motion was minimal. Frames with a pressure difference of approx. 5 mm Hg were taken to determine the elastograms. This in vivo validation study in Yucatan mini-pigs revealed higher strain values in fatty material (ANOVA p < 0.001). All cross-sections with a fatty plaque were identified with the elastogram by the presence of high strain values. Additionally, data are acquired in patients referred for Percutaneous Transluminal Coronary Angioplasty with the same set-up as tested in the animal study. Ultrasound data of soft, fibrous, calcified and stented plaques are acquired near end-diastole. The elastogram of soft plaques. as identified from the deformation during the pressure cycle, reveals strain values of 1% with increased strain up to 2% at the shoulders of the plaque. Calcified material, as identified from the echogram, shows low strain values of 0-0.2%. The elastogram of stented plaques reveals very low strain values, except for two regions: these are between the stent struts and at the shoulders of the plaque. In conclusion, intravascular elastography appears to be a unique tool to determine local mechanical properties in atherosclerotic lesions to identify fibrous and fatty tissue. Experiments have demonstrated the feasibility of this technique to be applied in vivo.

Intravascular ultrasound elastography : assessment and imaging of elastic properties of diseased arteries and vulnerable plaque

OBJECTIVEnIntravascular elastography is concerned with methods for measuring the local elastic properties using intravascular ultrasound (IVUS). The elastic properties of the vessel wall and atheroma can be measured through the strain. Knowledge of these mechanical properties is useful for guiding interventional procedures (balloon dilatation, ablation) and detection of plaque vulnerability.nnnMETHODSnElastograms and palpograms (images of strain) were constructed using the relative local displacements between IVUS images acquired at two levels of intravascular pressure with a 30-MHz echo catheter. These displacements were estimated from the time shift between gated radio-frequency echo signals using cross-correlation algorithms with interpolation around the peak.nnnRESULTSnExperiments on gel-based phantoms mimicking atherosclerotic vessels demonstrated the capability of elastography to identify soft and hard plaques independently of the echogenicity contrast. In vitro experiments on human arteries have demonstrated the potential of intravascular elastography to identify different plaque types based on the mechanical properties. These plaques could not be identified using the IVUS image alone. Regions with elevated mechanical stress could also be detected. These stress concentrations are related to plaque fracture.nnnCONCLUSIONnIntravascular elastography provides information that is frequently unavailable or inconclusive from the IVUS image and therefore may assist in the diagnosis and treatment of atherosclerotic disease.

Intravascular palpography for high-risk vulnerable plaque assessment.

Background:The composition of an atherosclerotic plaque is considerednmore important than the degree of stenosis. An unstable lesionnmay rupture and cause an acute thrombotic reaction. Most ofnthese lesions contain a large lipid pool covered by an inflamednthin fibrous cap. The stress in the cap increases withndecreasing cap thickness and increasing macrophage infiltration.nIntravascular ultrasound (IVUS) palpography might be an idealntechnique to assess the mechanical properties of high-risknplaques.Technique:Palpography assesses the local mechanical properties ofntissue using its deformation caused by the intraluminalnpressure.In Vitro Validation:The technique was validated in vitro using diseased humanncoronary and femoral arteries. Especially between fibrous andnfatty tissue, a highly significant difference in strain (p =n0.0012) was found. Additionally, the predictive value tonidentify the vulnerable plaque was investigated. A high-strainnregion at the lumen-vessel wall boundary has an 88% sensitivitynand 89% specificity for identifying such plaques.In Vivo Validation:In vivo, the technique was validated in an atheroscleroticnYucatan minipig animal model. This study also revealed highernstrain values in fatty than fibrous plaques (p < 0.001). Thenpresence of a high-strain region at the lumenplaque interfacenhas a high predictive value to identify macrophages.Patient Studies:Patient studies revealed high-strain values (1–2%) innthin-cap fibrous atheroma. Calcified material showed low strainnvalues (0–0.2%). With the development of three-dimensional (3-D)npalpography, identification of highstrain spots over the fullnlength of a coronary artery becomes available.Conclusion:Intravascular palpography is a unique tool to assessnlesion composition and vulnerability. The development of 3-Dnpalpography provides a technique that may develop into anclinical tool to identify the high-risk plaque.Hintergrund:Die Zusammensetzung einer atherosklerotischen Plaque wirdnals wichtiger erachtet als deren Stenosegrad. Eine instabilenLäsion kann aufbrechen und eine thrombotische Reaktion auslösen.nDie Mehrzahl dieser Läsionen enthält einen großen lipidreichennKern, der von einer dünnen entzündeten Kappe bedeckt ist. DernStress in der Kappe erhöht sich mit abnehmender Dicke der Kappenund zunehmender Makrophageninfiltration. Die intravaskulärenUltraschall- (IVUS-)Palpographie könnte die ideale Technik zurnBeurteilung der mechanischen Eigenschaften von Hochrisikoplaquesndarstellen.Technik:Die Palpographie erfasst die lokalen mechanischennEigenschaften von Gewebe mit Hilfe der durch den intravaskulärennDruck erzeugten Deformation.In-vitro-Validierung:Die Methode wurde durch Untersuchung erkrankter Koronar-nund Femoralarterien validiert. Insbesondere zwischen fibrösemnund fetthaltigem Gewebe ließ sich ein hochsignifikanternUnterschied bezüglich der Gewebsdehnung feststellen (p =n0,0012). Zudem wurde der prädiktive Wert für die Diagnose einernvulnerablen Plaque untersucht. Eine Stelle mit hoher Dehnung annder Gefäßoberfläche hat eine Sensitivität von 88% und einenSpezifität von 89% für die Erkennung solcher Plaques.In-vivo-Validierung:In vivo wurde die Technik in einem atherosklerotischennYucatan-Minischwein-Modell validiert. Auch diese Untersuchungnzeigte höhere Dehnungswerte in fetthaltigen gegenüber fibrösennPlaques (p < 0,001). Zudem hat das Vorliegen hohernDehnungswerte an der Plaqueoberfläche einen hohen prädiktivennWert für die Erkennung von Makrophagen.Patientenstudien:Patientenstudien ergaben hohe Dehnungswerte (1–2%) innfetthaltigen Plaques mit dünner Kappe. Kalzifiziertes Materialnzeigte niedrige Dehnungswerte (0–0,2%). Durch die Entwicklungnder dreidimensionalen (3-D) Palpographie wird die Identifikationnvon Stellen mit hohen Dehnungswerten im kompletten Koronarsystemnmöglich.Schlussfolgerung:Wie keine andere Methode gestattet die intravaskulärenPalpographie, Zusammensetzung und Vulnerabilität einer Läsion zunbeurteilen. Die Entwicklung der 3-D-Palpographie stellt einenTechnik zur Verfügung, die sich zu einem klinischen Hilfsmittelnzur Identifizierung von Hochrisikoplaques entwickelnnkönnte.

Three-Dimensional Palpography of Human Coronary Arteries

Background:Rupture of thin-cap fibroatheroma is a major cause of acute myocardial infarction and stroke. Identification of these plaques is one of the major challenges in cardiovascular medicine. At present, techniques with sufficient sensitivity and specificity to identify these unstable plaques are not clinically available. This paper describes a new technique to identify these plaques.Methods and Results:Three-dimensional intravascular ultrasound palpography is a catheter-based technique that visualizes radial strain (deformation) of vascular tissue induced by physiological variations in intraluminal pressure. A three-dimensional palpogram of these cross sections can be constructed by performing a continuous pullback of the catheter. Phantom and animal experiments revealed feasibility and good reproducibility of three-dimensional palpography. Increased strain values were observed in areas with reduced cap thickness and increased macrophage accumulation. In patients (n = 2) three-dimensional palpography is feasible and identifies areas with high and low strain.Conclusion:Three-dimensional palpography allows scanning of coronary arteries in patients to identify and localize highly deformable regions.Hintergrund:Das Aufbrechen eines Fibroatheroms mit dünner Kappe ist die Hauptursache für einen Myokardinfarkt oder Schlaganfall. Die Erkennung dieser Plaques gehört zu den großen Herausforderungen der kardiovaskulären Medizin. Derzeit stehen keine Techniken, die eine dieser instabilen Plaques mit hoher Sensitivität und Spezifität erkennen, zur Verfügung. Der Artikel beschreibt eine neue Technik, die versucht, diese Plaques zu identifizieren.Methodik und Ergebnisse:Die dreidimensionale intravaskuläre Ultraschallpalpographie ist eine katheterbasierte Technik, die radialen Strain (Deformation) der Gefäßwand visualisiert. Strain wird durch physiologische Variationen des intraluminalen Drucks erzeugt. Ein dreidimensionales Palpogramm von Gefäßquerschnitten kann bei einem kontinuierlichen Katheterrückzug konstruiert werden. Untersuchungen am Phantom und im Tierexperiment zeigten eine gute Durchführbarkeit und Reproduzierbarkeit der dreidimensionalen Palpographie. Erhöhte Strain-Werte wurden in Bereichen mit Fibroatherom, die eine dünne Kappe und eine erhöhte Makrophagendichte aufwiesen, beobachtet. Auch bei Patienten (n = 2) ist die dreidimensionale Palpographie möglich und weist Bereiche mit hoher und niedrigem Strain nach.Schlussfolgerung:Die dreidimensionale Palpographie erlaubt die Untersuchung von koronaren Gefäßen, um deutlich deformierbare Bereiche zu identifizieren.

Vascular tissue characterisation with IVUS elastography.

Knowledge about the mechanical properties of the vessel wall and plaque is important for guiding intravascular interventional procedures and detection of plaque vulnerability. Rupture of atherosclerotic plaques is associated with acute myocardial infarction and unstable angina pectoris. In a plaque with a lipid core, the stress due to the arterial pulsation will be concentrated in the cap and a thin cap may be unable to bear this stress. In this study, the potential of intravascular elastography to characterise fibrous, fibro-fatty and fatty tissue based on their mechanical properties was investigated. Using a custom-made set-up, intravascular echograms and elastograms of excised human femoral arteries were determined. High frequency r.f. data (30 MHz) were acquired using an intravascular catheter. The tissue was compressed using intravascular pressures of 80 and 100 mmHg. The cross-sections of interest were marked with a needle for matching with histology. Using cross-correlation estimation of gated echosignals, elastograms (images of the local strain) were determined. After the intravascular experiments, the specimens were fixed in formaldehyde and processed for paraffin embedding. Sections were stained with picrosirius red and alpha-actin to counterstain collagen and smooth muscle cells (SMC), respectively. Results of vessel cross-sections with fibrous and fatty plaque regions will be presented. The elastograms of these specimens show that the strain in fatty tissue is higher than the strain in fibrous material. In conclusion, these in vitro experiments on human femoral arteries indicate the potential of intravascular elastography to characterise different plaque components.

Quantitative IVUS blood flow: validation in vitro, in animals and in patients.

In recent years, a new method to measure transverse blood flow based on the decorrelation of the radiofrequency (RF) signals of intravascular ultrasound (IVUS) rotating single-element scanners was introduced. We report here in vitro, animal and patient testing to evaluate the correlation-based method using an IVUS array catheter. A new correlation-based method to dynamically correct the correlation coefficients for noise is implemented. The decorrelation due to noise was estimated from the correlation coefficients from flowing blood obtained at increasing time lags. First, blood flow experiments were carried out with different catheters in a tissue-mimicking flow phantom with an inner diameter ranging from 3.0 to 5.0 mm. A calibrated electromagnetic flow meter (EMF, range: 0 to 250 cc/min) was used as a reference. Good linear relationships were found between the IVUS-derived flow and the calibrated EMF (all R(2)> 0.96). The catheter position within the flow phantom and the size of the ring-down were theoretically analyzed. These elements, and noise in the RF signals, have an important influence on the IVUS blood flow measurements reflected by the offset and the slope of the linear relationships. By placing the IVUS catheter outside the flow phantom, parabolic blood flow profiles were also measured. Second, IVUS blood flow measurements were performed in the carotid artery of two Yorkshire pigs, which showed linear relationships (all R(2)> 0.85) between the IVUS-derived flow and the calibrated EMF. Experimentally, the offset was lower than 3 mL/min and the slope was close to 1. Third, IVUS blood flow measurements were performed in coronary arteries in patients. Preliminary results for the coronary flow reserve (CFR = high flow/baseline flow) in patients using the decorrelation method of RF signals of an array IVUS scanner were comparable with CFR based on Doppler measurements.