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Vascular applications of quantitative optical coherence tomography
van der Meer, F.J.
Publication date
2005
Link to publication
Citation for published version (APA):
van der Meer, F. J. (2005). Vascular applications of quantitative optical coherence
tomography.
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C
ardiovascular disease is the leading cause of death in developed countries and is rapidly becoming the number one killer in the developing countries.' In 2002, it accounted for 34% of all mortality in the Netherlands, translating to 134 deaths per day.2 Moreover, 231 patients per day were submitted to a hospital with a cardiac event in that year. Atherosclerosis, a disease that can lead to these chronic vascular obstruction and acute coronary and cerebrovascular syndromes, damages the lining of the coronary arteries, making them susceptible to the formation of blood clots and stenoses. Atherosclerotic plaque can build up for years before vessel narrowing becomes apparent: a debilitating or fatal heart attack is often the first indication of the underlying disease.ATHEROSCLEROSIS
Previously, atherosclerosis was regarded as a straightforward plumbing problem: fat deposits on the surface of static arterial walls, eventually blocking the pipe.' Nowadays it is recognized that the lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the arterial wall.4'5 Atherosclerotic lesions do not occur in a random fashion; the coronary arteries, the major branches of the aortic arch, the abdominal aorta and its visceral and major lower extremity branches are particularly susceptible sites. Hemodynamic forces interacting with an active vascular endothelium are responsible for localizing lesions in this nonrandom pattern of distribution. Shear stress and cyclic circumferential strain are the predominant forces that for example modify the endothelial cell structure and function/'
The normal arterial wall (figure 1-1 A) is composed of three layers, which are separated by elastic laminas. The innermost layer, the intima, is separated from the blood stream by endothelial cells and is in normal condition a thin layer of extracellular matrix and an
CHAPTER 1 adventitia media intima lipid pool calcification • • thrombus •*• macrophages
F i g u r e 1-1. S c h e m a t i c d r a w i n g of t h e n o r m a l arterial wall A and of
atherosclerotic lesions, showing lipid accumulation (B), ruptured lipid rich plaque with n o n - o c c l u s i v e t h r o m b u s (C), t h r o m b o s i s due to e r o s i o n , endothelial denudation (D), calcification (E) and chronic occlusion I .
i n c i d e n t a l s m o o t h m u s c l e cell (SMC). The i n t i m a is s e p a r a t e d from the m e d i a by t h e i n t e r n a l elastic lamina. T h e m e d i a c o n s i s t of S M C s , b u n d l e s of collagen fibers and elastic fibrils, e m b e d d e d in an extracellular matrix, li is separated from the o u t e r m o s t a d v e n t i t i a b\ t h e e x t e r n a l elastic l a m i n a . T h e adventitia is a layer of c o n n e c t i v e tissue, collagen a n d elastic l i b e r s e m b e d d i n g the e n u r e vessel within its s u r r o u n d i n g s .
In g e n e r a l , a t h e r o s c l e r o s i s starts w i t h lipid d e p o s i t i o n in the intima, the so-called 'fatty s t r e a k ' . T h e lipid d e p o s i t i o n gradually increases and the i n t i m a t h i c k e n s d u e to m i g r a t i n g S M C s t r o m the m e d i a a n d m o n o c y t e s t h a t e n t e r from t h e b l o o d . T h e m o n o c y t e s differentiate into m a c r o p h a g e s that internalize the lipid d e p o s i t i o n , b e c o m i n g lipid loaden f o a m cells, w h e r e a s S M C c h a n g e from migrating i n t o a s e c r e t i n g p h e n o t y p e , p r o d u c i n g c o l l a g e n to f o r m a p r o t e c t i v e cap figure 1 - I B ) . D u e t o c o m p e n s a t o r } e n l a r g e m e n t of t h e
vessel, early lesions can c o n t i n u e to develop without c o m p r o m i s i n g the lumen ('remodeling').7 However, some plaques with a large lipid core, which by now contain both apoptotic and necrotic cells and cellular debris and have a thin fibrous cap, are prone to rupture. Further lipid deposition and necrosis of foam cells result in a lipid pool, which thrombogenic contents cause thrombus formation when cap rupture occurs (figure 1-1C). Thrombus formation may also occur when the endothelial lining is damaged (erosion) (figure 1-1D). The thrombus can embolize in other vessels causing symptoms of acute syndromes, such as the abrupt reduction in flow to a region of the myocardium (myocardial infarction), or strokes. Further advanced plaques show calcifications (figure 1-1E) which can result in thrombus formation by protruding into the lumen through a disrupted thin fibrous cap. Healing of cap rupture and further accumulation of lipid, calcifications, SMCs and fibrous tissue can eventually compromise the vascular lumen (figure 1-1F).
V U L N E R A B L E PLAQUE
Vulnerable plaques have been defined as precursors to lesions that rupture. A large number of vulnerable plaques are relatively uncalcified, relatively nonstenotic, and similar to type IV atherosclerotic lesions described in the American Heart Association classification.'' They are morphologically characterized by a lipid core covered by a thin fibrous cap (thickness < 65/um).l o r > These unstable plaques are very prone to rupture or fissure, especially in the
Morphology/structure Activity/'function
Cap thickness I jpid core size Stenosis Remodelling Color
Collagen content vs. lipid content, mechanical stability
Calcification burden and pattern Shear stress
Inflammation (macrophage density) Endothelial denudation or dysfunction Plaque oxidative stress
Superficial platelet aggregation/fibrin deposition
Rate of apoptosis
Angiogenesis, intraplaque hemorrhage, leaking vasa vasorum
Matrix-digesting enzyme activity (MM I') Certain microbial agents (HSP60, C. Pneumoniae)
Adapted from ret. H
Table 1-1 O v e r v i e w of m a r k e r s for plaque vulnerability, c a t e g o r i z e d into
CHAPTER 1
s h o u l d e r s o f t h e fibrous cap, with s u b s e q u e n t e x p o s u r e o f the t h r o m b o g e n i c lipid c o r e t o t h e f l o w i n g b l o o d , r e s u l t i n g in t h r o m b o s i s . H o w e v e r , different types o f v u l n e r a b l e p l a q u e exist. C o r o n a r y t h r o m b o s i s m a y o c c u r from o t h e r lesions like p l a q u e e r o s i o n and calcified n o d u l e s , a l t h o u g h to a lesser frequency than c a p r u p t u r e . I n a r e c e n t p u b l i c a t i o n , N a g h a v i
i't a/, s u m m a r i z e d t h e c h a r a c t e r i s t i c s o f a t h e r o s c l e r o t i c lesions t h a t r e s u l t e d in v a s c u l a r
o c c l u s i o n and o t h e r clinical s y m p t o m s (table 1-1).u
IMAGING OF THE VULNERABLE PLAQUE
S e v e r a l i m a g i n g t e c h n i q u e s a r e currently available for t h e d e t e c t i o n o f s t e n o s i s a n d p l a q u e s , r a n g i n g f r o m n o n i n v a s i v e t o c a t h e t e r b a s e d i n v a s i v e s y s t e m s , u s i n g e l e c t r o -m a g n e t i c o r u l t r a s o u n d waves.13"18 For non-invasive imaging, the radiation w h i c h is minimally
a b s o r b e d by t i s s u e c a n b e u t i l i z e d . I n figure 1-2, t h e a b s o r p t i o n s p e c t r u m o f w a t e r for e l e c t r o - m a g n e t i c w a v e s is p l o t t e d . F r o m this g r a p h it is clear that for X-rays, y-rays a n d r a d i o w a v e s t h e a b s o r p t i o n c o e f f i c i e n t is smaller t h a n 1 cm"' a n d t h e r e f o r e t h e s e are very s u i t a b l e for i m a g i n g t h r o u g h c e n t i m e t r e s o f tissue. X-rays h a v e b e e n utilized for m o r e t h a n h u n d r e d years for n o n - i n v a s i v e imaging. T h e c o n t r a s t is b a s e d o n d i f f e r e n c e s in a b s o r p t i o n for t h e X-rays by t h e t i s s u e . H o w e v e r , d u e t o t h e l o w a b s o r p t i o n d i f f e r e n c e s b e t w e e n b l o o d a n d vascular wall c o m p o n e n t s , highly a b s o r b i n g c o n t r a s t agents h a v e to b e i n j e c t e d t o visualize t h e l u m e n . C o n s e q u e n t l y , a n g i o g r a p h y visualizes, albeit with a g o o d r e s o l u t i o n , t h e v a s c u l a r l u m e n b u t is n o t able to i m a g e t h e v a s c u l a r wall and its c o n t e n t s . D u e t o t h e fact t h a t v u l n e r a b l e p l a q u e s are o f t e n h e m o d y n a m i c a l l v insignificant, they a r e difficult t o d e t e c t with angiography.v>~" Still, a n g i o g r a p h y w a s the gold standard for c o r o n a r y
i m a g i n g l o r d e c a d e s . C o m p u t e d t o m o g r a p h y o f m u l t i d i r e c t i o n a l X-ray p r o j e c t i o n s (CT) a l l o w s 3 D v i s u a l i z a t i o n o f m o r p h o l o g i c s t r u c t u r e s . H o w e v e r , d u e t o limited r e s o l u t i o n ( u p t o 0.6 x 0.75 m m ) a n d limited contrast, a l t h o u g h m u c h b e t t e r than for X-ray p r o j e c t i o n i m a g i n g , only c a l c i f i c a t i o n s c a n b e clearly d e t e c t e d . 2I F o r t h e m o r e e n e r g e t i c p a r t o f t h e
e l e c t r o - m a g n e t i c s p e c t r u m , t h e i m a g i n g techniques like P E T a n d S P E C T a r e h a m p e r e d by t h e i r l o w r e s o l u t i o n ( a p p r o x i m a t e l y 3-10 m m ) . ~
A t t h e o t h e r side o f t h e s p e c t r u m , radio w a v e s in c o m b i n a t i o n with a high m a g n e t i c field are u s e d t o n o n - i n v a s i v e l y i m a g e tissues. In this so called nuclear m a g n e t i c r e s o n a n c e i m a g i n g ( M R I ) , r a d i o w a v e s are u s e d t o excite t h e m a g n e t i c field i n d u c e d split g r o u n d state o f h y d r o g e n a t o m s in t h e t i s s u e . A f t e r excitation, r a d i o w a v e s are e m i t t e d w h i c h can b e c h a r a c t e r i z e d t h r e e p a r a m e t e r s : t h e signal s t r e n g t h , w h i c h d e p e n d s o n t h e d e n s i t y o f t h e p r o t o n s , t h e t i m e T , n e e d e d for r e c o v e r y o f t h e e x c i t e d spins t o the e q u i l i b r i u m , w h i c h d e p e n d s o n t h e s p i n - l a t t i c e i n t e r a c t i o n and t h e d e c a y t i m e T7 o f t h e R F signal, w h i c h
d e p e n d s o n the s p i n - s p i n i n t e r a c t i o n . T h e s e p a r a m e t e r s are tissue specific a n d t h e r e f o r e c a n b e u s e d t o d i f f e r e n t i a t e t h e tissue c o m p o n e n t s . T h u s M R I h a s t h e p o t e n t i a l t o d i s t i n g u i s h a t h e r o s c l e r o t i c p l a q u e a n d t o d e t e r m i n e its c o m p o s i t i o n a n d m i c r o a n a t o m y2' .
I n p a t i e n t s , M R I is able t o identify u n s t a b l e p l a q u e s in t h e aorta.2 4 H o w e v e r , t h e
Frequency [Hz]
FIGURE 1-2 The absorption coefficient of water as a function of the frequency of the electro magnetic waves. Note the logarithmic scales and the regions in which the absorption coefficient is less than 1 cm"1: Radio waves, visible light, X and y rays.
thickness,2526 and the imaging time (several minutes) limit its application for the detection of the specific morphological characteristics of unstable plaques in coronary arteries.2
Tn the visible part of the electro-magnetic spectrum, the absorption by water is also low (figure 1 -2). However, in this part the scattering of the light by the tissue constituents hampers the utilisation of these electro-magnetic waves for non-invasive imaging. Using fiber-optics, light can be used in catheter based systems for intravascular imaging. In angioscopy, via a coherent bundle of optical fibers, an intra-luminal image is obtained while the blood is removed with flushing saline or C O , gas.28 Angioscopy is a straight-forward imaging technique that only provides information on the morphology of the endo-luminal surface and is therefore, like angiography, unable to identify the extent of an atherosclerotic plaque into the vessel wall. In some cases, angioscopy can indirectly detect the position of a fibroatheromatous plaque.2'' The yellow color intensity of plaque determined by angioscopy can indicate the prevalence of thrombosis on the plaque and thus be a marker of plaque vulnerability.1" Finally, the plaque cap thickness is a determinant of plaque color and quantitative colorimetry might be useful for the detection of vulnerable plaques.''Instead of electro-magnetic waves, also acoustic waves can be used for medical imaging. In ultrasound (US) imaging, the intensity of back-reflected acoustic pulses is depicted as a function of the time of flight. The contrast of US imaging is based on differences in the acoustic impedance of the different tissue layers. Both the axial resolution and the attenuation of the US in tissue are proportional to the frequency of the US waves
C H M M ! K 1
(figure 1 -3). Therefore, for high resolution imaging of the arterial wall, the I S signals of frequencies around 311 MI 1/ have t< > be delivered and detected intravascular. This intravascular ultrasound (IVUS) imaging, which lias an axial resolution of approximately 100 fivn, currently represents the gold standard in the assessment of atherosclerotic disease. [VI S facilitated in-depth understanding of coronary artery disease. like arterial remodelling and therapeutic strategies like stent implantation and coronary brachv ihcrapv. [VUS imaging, although being able to image the vascular wall, is limited in specifically identifying lipid-rich plaques, thus the contrast and the res. >lution are not suitable for directly detecting the vulnerable plaque.
I sing a sophisticated analysis of the I S signals obtained during systole, the local mechanical properties can be assessed. This so called elastography can distinguish the weaker and stiffer regions in the arterial wall and therefore can identify the vulnerable plaque. Intravascular elastography is a unique tool to assess lesion composition and vulnerability, '; S(' which has proven to detect vulnerable plaques in v i t r ov With the development of three-dimensional elastography, palpography, in vivo identification of weak spots over the full length of human coronary arteries has become possible."
An entirely different approach to deteel plaque vulnerability is the measurement of the temperature of the arterial wall, which may be increased by the local inflammation. With a precise thermography catheter, the heal or metabolic activity can be localised and correlated with plaques at high risk to rupture or thrombosis. Indeed, an increased thermal heterogeneity within human atherosclerotic coronan arteries was observed in patients
SE"
CL Q o — w E 5, o. 0) D 10 0.1 10 0 1 Tomography: SPECT & PETUS: 3-5 Mhz US: 7.5-20 Mhz . ^ 20-40 Mhz ^ C^ 1 10 100 Depth \prr\] 1 10 100 Depth [mm] 1000
Figure 1-3 Axial (depth) resolution and obtainable imaging depth for I S imaging
devices with different frequencies compared with other imaging techniques as SPECT, PET, CT, MR1. I S, OCT and (confocal) microscopy C)M .
w i t h u n s t a b l e a n g i n a a n d a c u t e m y o c a r d i a l i n f a r c t i o n , s u g g e s t i n g t h a t it m a y be related to t h e p a t h o g e n e s i s .4" H o w e v e r , t h e spatial r e s o l u t i o n ( a p p r o x i m a t e l y 0.5 m m ) and t h e
p o t e n t i a l in v i v o u n d e r e s t i m a t i o n o f h e a t p r o d u c t i o n locally in h u m a n a t h e r o s c l e r o t i c p l a q u e d u e t o t h e " c o o l i n g effect" o f c o r o n a r y b l o o d flow41 currently limits the applicability
o f this t e c h n i q u e .
T h e r e a r e t w o f a c t o r s t h a t h a m p e r t h e d e t e c t i o n o f t h e v u l n e r a b l e p l a q u e using t h e a b o v e d e s c r i b e d t e c h n i q u e s : t h e y are e i t h e r (1) en face i m a g i n g t e c h n i q u e s , w h i c h are n o t a b l e t o s h o w t h e d e p t h r e s o l v e d m o r p h o l o g y ( a n g i o s c o p y , t h e r m o g r a p h y ) or (2) h a v e a r e s o l u t i o n t h a t d o e s n o t p e r m i t detailed i m a g i n g ( I V U S , M R I a n d C T ) . T h e n e e d f o r a high r e s o l u t i o n i m a g i n g t e c h n i q u e that can d e t e c t u n s t a b l e c o r o n a r y a t h e r o s c l e r o t i c p l a q u e s b e f o r e t h e y b e c o m e clinically significant is p a r a m o u n t . T h i s i m a g i n g lacuna c o u l d be filled by optical c o h e r e n c e t o m o g r a p h y ( O C T ) . I n t r a v a s c u l a r O C T may plav an i m p o r t a n t role in g u i d i n g t h e r a p e u t i c i n t e r v e n t i o n s , d i a g n o s i n g a t h e r o s c l e r o s i s a n d r e s e a r c h i n g t h e c a u s e s o f c o r o n a r y artery d i s e a s e .
OCT
S i n c e its i n t r o d u c t i o n in t h e early 1990s, O C T has b e c o m e a p o w e r f u l m e t h o d f o r i m a g i n g t h e i n t e r n a l s t r u c t u r e o f b i o l o g i c a l s y s t e m s a n d m a t e r i a l s .4 2 O C T is a n a l o g o u s t o
B - m o d e u l t r a s o u n d , e x c e p t t h a t it uses light r a t h e r t h a n s o u n d . W h e r e a s in u l t r a s o u n d t h e l o c a t i o n o f r e f l e c t i n g o b j e c t is d e t e r m i n e d by m e a s u r i n g e c h o delay t i m e s , in O C T d e p t h r e s o l v e d m e a s u r e m e n t o f t h e b a c k s c a t t e r e d light is a c h i e v e d t h r o u g h l o w - c o h e r e n c e i n t e r f e r o m e t r y . T h e h e a r t o f the O C T s e t u p is a M i c h e l s o n i n t e r f e r o m e t e r (figure 1-4); light e m i t t e d by a light s o u r c e is split by a b e a m splitter in t w o b e a m s . O n e is d i r e c t e d i n t o t h e r e f e r e n c e a r m a n d is r e f l e c t e d by a t r a n s l a t i n g r e f e r e n c e m i r r o r . T h e o t h e r b e a m is d i r e c t e d i n t o t h e s a m p l e a r m a n d is reflected b y a tissue s a m p l e . T h e b a c k reflected b e a m s r e c o m b i n e a t t h e b e a m s p l i t t e r a n d are g u i d e d to a d e t e c t o r . It is i m p o r t a n t to n o t e t h a t i n t e r f e r e n c e b e t w e e n t h e t w o light b e a m s will o n l y b e d e t e c t e d w h e n t h e difference in o p t i c a l p a t h l e n g t h s travelled by the light in b o t h a r m s is less t h a n t h e so-called c o h e r e n c e l e n g t h o f t h e light s o u r c e . T h i s p h e n o m e n o n is used t o d e t e r m i n e t h e o p t i c a l p a t h l e n g t h t h e light h a s travelled in t h e s a m p l e a r m : if i n t e r f e r e n c e is o b s e r v e d while s c a n n i n g t h e p a t h l e n g t h in t h e r e f e r e n c e a r m (i.e. m o v i n g t h e r e f e r e n c e m i r r o r ) , the back scattered light f r o m d i f f e r e n t p o s i t i o n s w i t h i n t h e s a m p l e (i.e. in d e p t h ) c a n b e m e a s u r e d ( ' c o h e r e n c e g a t i n g ' ) . C o n s e q u e n t l y , t h e axial r e s o l u t i o n is directly related t o the c o h e r e n c e length ( / ) o f the light s o u r c e (with a c e n t e r w a v e l e n g t h Xr), w h i c h is i n v e r s e l y related t o t h e b a n d w i d t h
(ZlA) o f t h e light s o u r c e ( e q u a t i o n 1-1).
CHAPTER 1 reference arm m
-Is RM BS
*->
EH
sample a n dFigure 1-4 A schematic drawing of an OCT setup. Light emitted by a light source (Is) is split by a beam splitter (BS) into two beams, travelling through the reference arm or the sample arm. Via mirror (m), the light in the sample arm, is focused into a sample (S) using a lens (L). In the reference arm, the light is directed to a translating reference mirror (RM). Back reflected light from both arms is recombined by the beam splitter (BS) and the interference signal is monitored bv the detector (d).
The transverse resolution for O C T imaging is determined by the focused spot size, as in microscopy. In contrast to conventional microscopy, the lateral resolution is decoupled from the axial resolution. Furthermore, OCT provides cross-sectional images of structure below the tissue surface in analogy to histopathology. Standard-resolution O C T can achieve axial resolutions of 10-15 /urn.
In accordance with the terminology of ultrasound imaging, a measurement of reflectivity vs. depth is called an scan. The O C T image, or B-scan, is constructed from adjacent A-scans, with the reflectivity now plotted as a grey or color scale. The contrast of an O C T image is determined by differences in the optical properties (e.g. scattering and absorption) of different tissue layers and their components. T h e imaging depth is also determined by the optical properties of the tissue. Using wavelengths in the near infrared, where hemoglobin and melanin absorption arc low and scattering is reduced, permits imaging depths of up to 2 mm in tissues.43-4"1 Although this depth is shallow compared with other clinical imaging techniques like US (figure 1-3), the image resolution of O C T is 1 to 2 orders of magnitude better than conventional ultrasound imaging, magnetic resonance imaging or computed tomography. Recently, using state-of-the-art lasers as light sources,
ultrahigh-resolution imaging with axial r e s o l u t i o n s as fine as 1— 2ium h a s b e e n d e m o n s t r a t e d
(table 1-2).
45VASCULAR APPLICATION O F O C T
T o d a t e , O C T i m a g i n g is r o u t i n e l y u s e d in o p h t h a l m o l o g y ,4 6'1 b u t has g r e a t p o t e n t i a l
as a n ' o p t i c a l b i o p s y ' t o o l in o t h e r fields o f m e d i c i n e , i.e. g a s t r o - e n t e r o l o g y ,4 8"5
d e r m a t o l o g y ,M urology,5 2'5 4 gynaecology,"'"' a n d cardiology."''' A p a r t from a p p l i c a t i o n as a
d i a g n o s t i c t o o l , O C T can also b e u s e d for feedback d u r i n g surgical p r o c e d u r e s '1" e.g. in
laser a b l a t i o n o f t i s s u e s ,, x a n d for g u i d a n c e in c l e a r i n g a totally o c c l u d e d vessel."'9 I n
c a r d i o l o g y , O C T c o u l d b e u s e d t o d e t e c t a n d analyze a t h e r o s c l e r o t i c l e s i o n s , d u e to its capacity o f high r e s o l u t i o n i m a g i n g o f superficial s t r u c t u r e s . A s P a s t e r k a m p et al. s t a t e , t h i c k n e s s o f t h e c a p as well as t h e size a n d c o m p o s i t i o n o f t h e u n d e r l y i n g a t h e r o m a t o u s lipid c o r e , are m a j o r c o n t r i b u t o r s t o p l a q u e vulnerability, a n d O C T is t h e o n l y i m a g i n g m o d a l i t y c a p a b l e o f m e a s u r i n g this c a p t h i c k n e s s .6 0 By accurately m e a s u r i n g t h e c a p
t h i c k n e s s , O C T c o u l d b e a t o o l i n d e t e c t i o n o f r u p t u r e - p r o n e v u l n e r a b l e p l a q u e s .6 i r'2
I n 1 9 9 6 , B r e z i n s k i et al. w e r e t h e first t o r e p o r t t h e u s e o f O C T for i m a g i n g v a s c u l a r pathology.6 1 , 6 3 T h i s g r o u p also d e v e l o p e d d e v e l o p m e n t o f an e x p e r i m e n t a l c a t h e t e r for in
vivo imaging.6 4 T h e c a t h e t e r - b a s e d i m a g e s w e r e p r o v e n t o identify p l a q u e s b o t h in vitro,65
a n d in vivo.1'''-'' I n a n in vitro e x p e r i m e n t , Y a b u s h i t a et al. d e m o n s t r a t e d the abilitv o f O C T
t o d e t e c t d i f f e r e n t types o f a t h e r o s c l e r o t i c l e s i o n s , d e f i n e d as fibrous, fibrocalcific a n d lipid-rich a t h e r o m a ' s .6" U s i n g a p r o t o t y p e c a t h e t e r , J a n g et al. r e c e n t l y s h o w e d t h a t in vivo i n t r a c o r o n a r y O C T a p p e a r s t o b e feasible a n d safe.6" W i t h O C T they i d e n t i f i e d m o s t
a r c h i t e c t u r a l features d e t e c t e d by I V U S a n d s u g g e s t e d t h a t O C T may p r o v i d e a d d i t i o n a l detailed s t r u c t u r a l i n f o r m a t i o n . l i g h t s o u r c e SLD SLD AF Ti:Al203 "k ( n m ) 825 1300 1300 800 Ak ( n m ) - 2 5 - 50 - 60 - 100 - 250 Pm ,x ( m W ) - 5 - 5 - 2 0 - 1000 /c (Mm) - 12 - 15 - 12 - 1 - 3 d\ ( m m ) 0 . 5 - 1.0 1.0-2.0 1.0-2.0 0 . 5 - 1.5
T a b l e 1-2 O v e r v i e w of light sources and their specifications. T h e c e n t e r wavelength (A) is proportional to the imaging depth (d). The bandwidth of the light source (AX) is inversely proportional to the coherence length (/.). The maximal power (P|llaJ is also given. SLD: super luminescent diode; AF: autofluorescent fiber; T i : A l , 0 . : titanium sapphire laser
CHAPTER 1
SCOPE OF THIS THESIS
Currently, the interpretation of vascular O C T images is based on the qualitative interpretation of the O C T images, without further quantitative data analysis of the O C T signals. In this thesis, the possibilities of quantitative analysis of vascular O C T signals are explored for the identification of vulnerable plaques. To distinguish the constituents of these plaques, reflection spectroscopy on components will be performed, furthermore, the effect of the light source, with consequently the effect of axial resolution and contrast, on the O C T data analysis is studied.
In CHAPTER 2 we explore the possibility to extract quantitative data from the O C T image, i.e. the attenuation coefficient (ju ). Subsequently, the algorithm for measurement of fx is applied to O C T images of human atherosclerotic tissue and the possibility of discrimination of plaque components, based on the quantitative basis is explored. The results are presented in CHAPTER 3. A comparison between two O C T setups, operating with different light sources (and thus different contrast and resolution), the effect on quantitative measurement is presented in CHAPTER 4 as well as the correlation between O C T and histology. To determine the effect of the surrounding tissue and to further quantify the optical properties precisely, ,a and the index of refraction (n) was measured in isolated vessel wall and plaque components (CHAPTER 5). The dependence on temperature of /u and n, important to relate in vitro and /'// vivo measurements, was also determined. In CHAPTER 6, the measurement of// is applied to living, apoptotic and necrotic cells. Since the morphological changes during necrosis and apoptosis would result in changes of ji , enabling detection of cellular death using OCT. Finally, in CI IAPTER 7 a general discussion on the role of vascular O C T is given.
REFERENCES
1. Yusuf, $., Rcddv, S., Ounpuu, S. et a/., "Global Burden of Cardiovascular Diseases: Part I: General Considerations, the Epidemiologic Transition, Risk Factors, and Impact o f Urbanization," Circulation. 104, 2746-2753 (2001).
2. The Netherlands Heart Foundation, "Hart- En Vaatziekten: Cijfers E n Feiten," (2004). 3. Libby, P., "Atherosclerosis: the New View," Sci.Aw. 286, 28-37 (2002).
4. Ross, R., "The Pathogenesis of Atherosclerosis: a Perspective for the 1990s," Nature 362, 801-809 (1993).
5. Libby, P., "Vascular Biology of Atherosclerosis: Overview and State of the Art,"
Am.J.Cardiol. 9 1 , 3A-6A (2003).
6. Frangos, S. G , Gahtan, V., and Sumpio, B., "Localization of Atherosclerosis: Role o f Hemodynamics," Arch.Surg. 134, 1142-1149 (1999).
7. Glagov, S., Weisenberg, E., Zarins, C. K. at a/., "Compensatory Enlargement of Human Atherosclerotic Coronary Arteries," 7\.Eng/.J.Med. 316, 1371-1375 (1987).
8. Naghavi, M., I.ibhv, P., Falk, E. et a/., " f r o m Vulnerable Plaque to Vulnerable Patient: a Call for New Definitions and Risk Assessment Strategies: Part I," Circulation. 108, 1664-1672 (2003).
9. Starv, H. C , Chandler, A. B., Dinsmore, R. E. et a/., "A Definition ot Advanced Types o f Atherosclerotic Lesions and a Histological Classification ot Atherosclerosis. A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association," Circulation. 92, 1355-1374 (1995).
1 0. Fuster, V , Fayad, Z. A., and Badimon, J. J., "Acute Coronary Syndromes: Biology," Lancet 353 Suppl 2,\SII5-SII9 (1999).
1 1 . Kleber, F. X., Dopfmer, S., and Thieme, T , "Invasive Strategies to Discriminate Stable and Unstable Coronary Plaques," Eur.Heart.J 19 Suppl C, C44-C49 (1998).
12. Kolodgie, F. D., Burke, A. P., Farb, A. et a/., "The Thin-Cap Fibroatheroma: a Type o f Vulnerable Plaque - T h e Major Precursor Lesion to Acute C o r o n a r y S y n d r o m e s , "
Curr.Opin.Cardiol. 16, 285-292 (2001).
13. Virmani, R., Burke, A. P., Kolodgie, E D eta!, "Vulnerable Plaque: the Pathology o f Unstable Coronary Lesions," J.Iuterr.Cardiol. 15, 439-446 (2002).
14. Naghavi, M., Libby, P., balk, E. eta/., "From Vulnerable Plaque to Vulnerable Patient: a Call tor New Definitions and Risk Assessment Strategies: Part I," Circulation. 108, 1664-1672 (2003).
15. Kleber, F. X., Dopfmer, S., and Thieme, T , "Invasive Strategies to Discriminate Stable and Unstable Coronary Plaques," Eur.Heart.J 19 Suppl C, C44-C49 (1998).
16. MacNeill, B. D., Lowe, H. C , Takano, M. et a!, "Intravascular Modalities for Detection of Vulnerable Plaque: C u r r e n t Status," Arterioscler.Thromb.Vasc.Biol. 2 3 , 1333-1342 (2003).
17. Ncmirovskv, D , "Imaging of High-Risk Plaque," Cardiology 100, 160-175 (2003). 18. Naghavi, M., Madjid, M.. Khan, M. R. eta/., "New D e \ e l o p m e n t s in the Detection of
Vulnerable Plaque," Cnrr.Atberosc/er.Kep. 3, 125-135 (2001).
19. Fuster, V., "Mechanisms Leading to Myocardial Infarction: Insights From Studies of Vascular Biology," Circulation. 90, 2126-2146 (1994).
20. Kleber, !•'. X., Dopfmer, S., and Thieme, T , "Invasive Strategies to Discriminate Stable and Unstable Coronary Plaques," Eur.Heart.J 19 Suppl C, C44-C49 (1998).
2 1 . K o p p , A. 1., Schroeder, S., Baumbach, A. et a/., "Non-Invasive Characterisation o f Coronary Lesion Morphology and C o m p o s i t i o n by Multislice CT: First Results in Comparison With Intracoronary Ultrasound," Eur.Radioi. 11, 1607-1611 (2001).
22. Sanchez-Crespo, A., Andreo, P., and Larsson, S. A., "Positron Flight in Human Tissues and Its Influence on PET Image Spatial Resolution," Eur.J.Nuc/.Med.Mo/Jmagifig 31, 44-51 (2004).
2 3 . C h o u d h u r y , R. P., l u s t e r , V., B a d i m o n , J. J. et al., " M R ! and C h a r a c t e r i z a t i o n of A t h e r o s c l e r o t i c P l a q u e : E m e r g i n g A p p l i c a t i o n s and M o l e c u l a r I m a g i n g , "
Arterioscler.Tbromb.Vasc.hio/. 22, 1065-1074 (2002).
24. Fuster, V, "Mechanisms Leading to Myocardial Infarction: Insights From Studies of Vascular Biology," Circulation. 90, 2126-2146 (1994).
CHAPTER 1
2 5 . Fayad, Z. A., Fuster, V., Fallon, J. T. eta/., "Noninvasive in Vivo Human Coronarv Arterv Lumen and Wall Imaging Using Black-Blood Magnetic Resonance Imaging," Circulation.
1(12, 506-510 (2000)'.
2 6 . Fayad, Z. A., "MR Imaging for the Noninvasive Assessment ot A t h e r o t h r o m b o t i c Plaques," Magn.Keson.lmaging Clin.K.Am. 11, 101-113 (2003).
2 ~ . MacNeill. B. D., I.owe. II. C , Takano, M. et a/., "Intravascular Modalities for Detection of Vulnerable Plaque: C u r r e n t Status," Arterioscler.Thromb.Vasc.hiol. 2 3 , 1333-1342 (2003).
2 8 . Smits, P. C , Post, M. [., Velema, E. et a/., " P e r c u t a n e o u s Coronarv and Peripheral Angioscopv With Saline Solution and Carbon-Dioxide Gas in Porcine and Canine Arteries,"
Am.Heart.J. 122, 1315-1322 (1991).
2 9 . Kleber, 1. X., Dopfmer, S., and Thicme, T., "Invasive Strategies to Discriminate Stable and Unstable Coronary Plaques," Eur.Heart.J 19 Suppl C, C44-C49 (1998).
3 0 . Ueda, Y., O h t a n i , T., Shimizu, M. et a/., "Assessment of Plaque Vulnerability by Angioscopic Classification of Plaque Color," Am.Heart.J. 148, 333-335 (2004). 3 1. Miyamoto, A., Prieto, A. R., Friedl, S. E. eta/., "Atheromatous Plaque Cap Thickness Can
Be Determined by Quantitative Color Analvsis During Angioscopv: Implications for Identifying the Vulnerable Plaque," Clin.Cardiol. 27, 9-15 (2004).
3 2 . Regar, E. and Serruvs, P. W.. "Ten Years Alter Introduction of Intravascular Ultrasound in the Catheterization Laboratory: Tool or Toy?," Z.Kardiol. 91 Suppl 3, 89-97 (2002). 3 3 . Kleber, 1. X., Dopfmer, S., and Thieme, T , "Invasive Strategies to Discriminate Stable
and Unstable Coronarv Plaques," Eur.HeartJ 19 Suppl C, C44-C49 (1998).
3 4 . de Korte, C. I.., Schaar, |. A., Mastik, F. et a/., "Intravascular Elastographv: from Bench to Bedside," J.Interv.Cardiol. 16, 253-259 (2003).
3 5 . de Korte, C. I... Sierevogel. M. J., Mastik, F. et a/., "Identification of Atherosclerotic Plaque C o m p o n e n t s With Intravascular Ultrasound Hlastographv in Vivo: a Yucatan Pig Study." Circulation. 105, L627-1630 (2002).
3 6 . de Korte, C. 1.., Cespedes, L. I., van der Steen, A. F. et a/., 'intravascular Ultrasound Elastographv: Assessment and Imaging of Llastic Properties of Diseased Arteries and Vulnerable Plaque," Eur.].Ultrasound7', 219-224 (1998).
3 7 . Schaar, ). A., de Korte, C. 1.., Mastik, L etui., "Characterizing Vulnerable Plaque features With Intravascular Elastographv," Circulation. 108, 2636-2641 (2003).
3 8 . Schaar, J. A., Regar, L.. Mastik, F. eta/., "Incidence of High-Strain Patterns in Human Coronarv Arteries: Assessment With Three-Dimensional Intravascular Palpographv and Correlation With Clinical Presentation," Circulation. 109, 2716-2719 (2004)"
39. Casscells, W , Harhorn, B , David, M. et ah, "Thermal Detection of Cellular Infiltrates in Living A t h e r o s c l e r o t i c P l a q u e s : Possible I m p l i c a t i o n s for Plaque R u p t u r e and T h r o m b o s i s , " Lancet 3 47, 1447-1451 (1996).
4 0 . Stefanadis, C , Diamantopoulos, 1.., Vlachopoulos, C. et a/., "Thermal Heterogeneity Within Human Atherosclerotic Coronary Arteries Detected in Vivo: A New Method of Detection bv Application of a Special Thermographv Catheter," Circulation. 99, 1965-1971 (1999).
4 1. Stefanadis, C , Toutouzas, K., Tsiamis, E. et a/., "Thermal Heterogeneity in Stable Human Coronarv Atherosclerotic Plaques Is Underestimated in Vivo: the "Cooling Effect" of Blood Flow," J.Aw.CoI/.Cardiol. 4 1 , 4 0 3 - 4 0 8 (2003).
4 2 . Huang, D., Swanson, E. A., Lin, C. P. et a/., "Optical Coherence Tomography," Science 254, 1178-81 (1991).
4 3 . Fujimoto, J. G., Brezinski, M. E., Tearney, G. J. et a/., "Optical Biopsv and Imaging Using Optical Coherence Tomography," NatMed. 1, 970-972 (1995).
4 4 . Schmitt, J. M., Knuttel, A., Yadlowskv, M. el <//., "Optical-Coherence Tomography of a D e n s e Tissue: Statistics ot Attenuation and Backscattering," Vhys.Med.Biol. 39, 1705-1720 (1994).
4 5 . Drexler, W , Morgner, U., Kartner, 1'. X. et <//., "/// I 'iro Ultrahigh-Resolution Optical Coherence Tomography," Opt.Lett. 24, 1221-1223 (1999).
4 6 . Swanson, E. A., Izatt, ]. A., Flee, M. R. et a/., "In-Vivo Retinal Imaging bv Optical Coherence Tomography," Opt.Lett. 18, 1864-1866 (1993).
4 7 . Thomas, D. and Duguid, G., "Optical Coherence Tomography—a Review of the Principles and Contemporary Uses in Retinal Investigation," l.iye 18, 561-570 (2004).
4 8 . Sivak, M. V., Jr., Kobayashi, K., Izatt, J. A. etal., "High-Resolution Endoscopic Imaging of the GI Tract Using Optical Coherence Tomography," Gastrointest.Endosc. 51, 474-479 (2000).
49. Shcn, B., Zuccaro, G., Jr., Gramlich, T. L. eta/., "In Vivo Colonoscopic Optical Coherence T o m o g r a p h y for T r a n s m u r a l I n f l a m m a t i o n in I n f l a m m a t o r y Bowel D i s e a s e , "
Clin.GastroenteroLHepatol. 2, 1080-1087 (2004).
50. Tearney, G. J., Brezinski, M. E., S o u t h e r n , J. F. et al., "Optical Biopsy in H u m a n Pancreatobiliarv Tissue Using Optical Coherence Tomography," Dig.Dis.Sci. 43, 1193-1199 (1998).
5 1. Welzel, )., "Optical Coherence Tomography in Dermatology: a Review," Skin Res.TechnoI. 7, 1-9 (2001).
52. |esser, C. A., Boppart, S. A., Pitris, C. et al, "High Resolution Imaging of Transitional Cell Carcinoma With Optical Coherence Tomography: Feasibility for the Evaluation of Bladder Pathology," Br.J.RadioI. 72, 1170-1176 (1999).
5 3 . Tearney, G. [., Brezinski, M. E., Southern, J. F et al., "Optical Biopsy in Human Urologie Tissue'Using Optical Coherence Tomography," J.Urol. 157, 1915-1919 (1997). 54. Zagaynova, E. V., Streltsova, O. S., Gladkova, N. D. et al., "In Vivo Optical Coherence
Tomography Feasibility for Bladder Disease," J.Urol. 167, 1492-1496 (2002).
5 5 . Escobar, P. F , Belinson,}. L., White, A. et al, "Diagnostic Efficacy of Optical Coherence Tomography in the Management of Preinvasive and Invasive Cancer of Uterine Cervix and Vulva," Int.J.Gyneco/.Cancer 14, 470-474 (2004).
56. [ang, I. K., Tearney, G. (., MacNeill, B. et al., "In Vivo Characterization of Coronary Atherosclerotic Plaque by Use of Optical Coherence Tomography," Circulation. I l l , 1551-1555 (2005).
57. Brezinski, M. E., Tearney, G. )., Boppart, S. A. et al., "Optical Biopsy With Optical Coherence Tomography: Feasibility for Surgical Diagnostics," / Surg Res 7 1 , 32-40 (1997). 5 8 . Patel, N. A., Li, X., Stamper, D. L. et al., "Guidance of Aortic Ablation Using Optical
Coherence Tomography," Int.j.CardiovascImaging 19, 171-178 (2003).
59. Morales, P. A. and Heuser, R. R., "Chronic Total Occlusions: Experience With Fiber-Optic Guidance Technology—Fiber-Optical Coherence R e f l e c t o m c t n , " J.Interv.Cardiol. 14, 611-616 (2001).
60. Pasterkamp, G , lalk, E., Woutman, FI. et al., "Techniques Characterizing the Coronary Atherosclerotic Plaque: Influence on Clinical Decision Making," J.Am.Coll.Cardiol. 36, 13-21 (2000).
6 1. Brezinski, M. E., Tearney, G. ]., Bouma, B. E. et al., "Optical Coherence Tomography for Optical Biopsy - Properties and Demonstration of Vascular Pathology," Circulation. 93, 1206-1213 (1996).
62. Perree, J., Van Leeuwen, T G , Pasterkamp, G et al., "Imaging of Atherosclerotic Plaques by Optical Coherence Tomography (OCT)," Proc.SPIE 3907, 522-527 (2000).
6 3 . Brezinski, M. E., Tearney, G )., Bouma, B. E. et a/., "Imaging of Coronary Artery Microstructure (in Vitro) With Optical Coherence Tomography," Aw.].Cardiol. 77, 92-3 (1996).
64. Fujimoto, ƒ. G , Boppart, S. A., Tearney, G. J. el al., "High Resolution in Vivo Intra-Arterial Imaging With Optical Coherence Tomography," Heart 82, 128-133 (1999). 65. Yabushita, H . , B o u m a , B. F . , H o u s e r , S. 1.. et al., " C h a r a c t e r i z a t i o n o f Human
Atherosclerosis by Optical Coherence Tomography," Circulation. 106, 1640-1645 (2002). 66. fang, 1. K., Bouma, B. E., Kang, D. H. et al., "Identification of Different Coronary
Plaque Types in Living Patients Using Optical Coherence Tomography," Circulation. 102, 1997-(2000).
67. fang, I. K., Bouma, B. E., Kang, D. H. et al., "Visualization of Coronary Atherosclerotic Plaques in Patients Using Optical Coherence Tomography: Comparison With Intravascular Ultrasound," J.Aw.Cotl.Cardiol. 39, 604-609 (2002).
6 8 . Yabushita, 11., B o u m a , B. F . , H o u s e r , S. I., et al., " C h a r a c t e r i z a t i o n of Human Atherosclerosis by Optical Coherence Tomography," Circulation. 106, 1640-1645 (2002).
