Virtual histology in cardiology?

| September 10, 2007

On a recent search of PubMed for "virtual histology"  I was surprised how many articles were found dealing with "virtual histology" in cardiology.  Investigators trying to quantify histopathologic changes in-vivo beyond what can be done with conventional cardiac catherization currently.  The below abstract and editorial appeared in Heart in May.  Published online 13 May 2007 (omitted numbered references):


As a luminogram, coronary angiography provides a good overview of the coronary artery tree. Using quantitative coronary measurements, the degree of coronary obstruction can be determined. The limitation of coronary angiography is that it does not provide information on the arterial wall structure and therefore cannot assess the extent of atherosclerosis. Knowledge about adaptive coronary remodelling processes as compensatory enlargement of the coronary artery has focused diagnostic interest on the non-stenotic lesions of the coronary tree. Intravascular ultrasound (IVUS) can reveal discrepancies between the extent of coronary atherosclerosis and angiography imaging by in vivo plaque imaging. Spectrum analysis of IVUS-derived radiofrequency (RF) data enables a more detailed analysis of plaque composition and morphology. Preliminary in vitro studies correlated four histological plaque components with a specific spectrum analysis of the RF data. The different components (fibrous, fibrofatty, necrotic core and dense calcium) are colour coded. Coronary tissue maps were reconstructed from RF data using IVUS–Virtual Histology (VH IVUS) software (Real-Time VH, Volcano Corporation, Rancho Cordova, California, USA).

VH IVUS has the potential to detect high-risk lesions and can provide new insights into the pathophysiology of coronary artery disease. VH IVUS allows the differentiation of different lesion types based on information derived from histopathology. The in vivo specific histological analysis of coronary atherosclerosis may allow better stratification of treatment of patients with coronary artery disease.


Cardiovascular disease is the principal cause of death in developed countries. Rupture of the atherosclerotic plaque is the pathological substrate underlying up to 75% of episodes of acute coronary syndromes and the most common cause of sudden death. Although pathological findings at autopsy have helped our understanding of the various types of coronary plaques underlying thrombosis, clinically we have been unable to detect lesions prior to rupture. Therefore, intervention strategies have focused on the management of acute coronary syndrome following thrombosis or at sites of severe narrowing.

As most rupture-prone or vulnerable plaques have <75% cross-sectional area luminal narrowing (ie, <50% diameter stenosis), angiography is not useful in early detection. What distinguish these lesions from others in the coronary arteries are their morphological features, which consist of a thin fibrous cap infiltrated by macrophages and a large necrotic core. The development of new modalities to identify vulnerable plaques on the basis of morphological features is beginning to offer the possibility of identifying these lesions in vivo. One of those modalities, virtual histology (VH) intravascular ultrasound (IVUS), is based on spectral analysis of radiofrequency data and has begun to provide detailed assessment of plaque composition in vivo.

The concept that human coronary arteries dilate as plaque size increases in order to preserve luminal diameter was initially reported by Glagov et al. Two studies on the pathological features of patients dying due to coronary artery disease demonstrated a relationship between positive remodelling and morphological features of plaque vulnerability such as high lipid content, increased macrophage infiltration and less fibrous tissue. Previous in vivo studies using IVUS supported the concept that positive coronary arterial remodelling predominantly occurs in plaques of patients with acute coronary syndromes. Surmely et al confirm this observation in a larger series of patients by using VH-IVUS. In a series of 85 patients, 25% of patients with negative remodelling by IVUS presented with acute coronary syndrome compared with 52% of patients whose plaque had evidence of positive remodelling (p = 0.02).

As the advantage of VH-IVUS over grey-scale IVUS is the possibility of more accurate characterisation of plaque components, the authors also report on the differences in plaque morphology in negatively remodelled lesions compared with positively remodelled lesions. By VH-IVUS, there was a striking disparity between the authors’ findings regarding plaque morphology stratified by remodelling index and previous pathological findings. They report that lesions with positive remodelling had less percentage of necrotic core and more fibrous tissue at the minimal lumen diameter compared with intermediate/negative remodelling lesions. These data agreed with one previous IVUS study but were conflicted with another. Although differences in patient selection, definition of positive/negative remodelling and resolution of VH-IVUS compared with histological features might help explain these differences, studies such as this one are obviously limited by the fact that verification of the findings is not possible because of lack of histopathological evidence. Moreover, previous validation of VH-IVUS in ex vivo specimens may be biased by lesion selection and by tightly controlled experimental conditions, which may not be reliably translated in vivo.5 In addition, VH-IVUS has trouble distinguishing necrotic core from calcification and, indeed, in the initial study by Nair et al5 these were combined into a single colour and were called calcified necrosis, a terminology that does not distinguish between necrotic core and calcification. Pathological studies have clearly shown that there are definite areas of necrotic core that lack calcifications.

Despite these limitations, studies such as this one demonstrate the potential of in vivo plaque characterisation to begin to identify high-risk plaques. In previous times, we were limited to autopsy findings to study the relationship between arterial remodelling and coronary atherosclerosis, but this type of technology allows us to understand how such data compare with what is possible in the clinical setting. Moreover, autopsy data may not be applicable to living patients, especially those with acute coronary syndrome. However, there is little doubt that the larger necrotic core is more likely to be positively remodelled. This was also confirmed by greyscale IVUS data analysis in the current study by Surmely et al in this issue of Heart.

However, this acknowledgement should not be taken as an endorsement of the reliability of VH-IVUS to define plaque characteristics with high accuracy. Newer modalities and improvement in the existing technology for evaluating coronary plaques that can better distinguish plaque morphology are needed. As the pathological definition of vulnerable plaque is characterised by a necrotic core with an overlying fibrous cap of <65 µm, better imaging capability using higher-resolution devices is the only way to identify these plaques more accurately. Probably, the virtual histological definition of vulnerable plaque is not accurate as it has not been validated against histopathological features, and the spatial resolution of VH-IVUS (ie, 100–200 µm) is far below that needed to detect these plaques using the histological definition. Currently, optical coherence tomography yields a higher spatial resolution (10–20 µm), and offers the potential to provide more accurate information on coronary plaques. However, optical coherence tomography is limited by its inability to image through blood, which makes this technology cumbersome and often not reproducible except in the most skilled hands.

Nonetheless, what we should note from studies such as this one is that we are entering a new age in cardiology where precise identification of plaque composition may, one day, allow us to identify high-risk plaques before they rupture, and thereby save lives.

Category: Histology, In-vivo

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