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Prof. Gerard Pasterkamp,
Interview with Dr. Pasterkamp
Q: Dr. Pasterkamp, your group continues to present remarkable studies just like the one published in Circulation in May 2010. It is on a very important and timely topic, namely the vulnerable patient and its plaque phenotype. Before we go there though, would you mind taking the first step by briefly summarizing the highlights of this study, which is part of the Athero-Express project?
A: Highlight is that this discovery follow a new concept. It shows that plaque characteristics at one location does contain information of the entire vascular system. This suggests that some plaque characteristics are more homogeneously distributed within the arterial system and also related with plaque progression. This new concept does not challenge the traditional concepts of the vulnerable plaque (thin capped inflammatory atheromatous plaques): that concepts follows the idea that the local plaque with these features have a higher risk for local rupture. In our case it was studied whether removed plaques contained predictive value for plaques that resided in the vascular system.
Q: As it stands, more than some or all of us would have thought, plaque neovessels and hemorrhage are important for the clinical outcome of atherosclerotic plaques. Are they maybe even more important than the standard vulnerable plaque features, that is to say are they THE vulnerable plaque feature? What would you say, where would you rank plaque neovessels and plaque hemorrhage relative to the conventional characteristic features of vulnerable plaque such as lipid core size and cap thickness, even inflammation?
A: As mentiond in my previous answer this is difficult to answer. It might well be that the other plaque characteristics are Justas or even more important for local plaque destabilization. This study shows that local plaque hemorraghe has predictive value: it does not tell anything related with causality. It may suggest this but it is not hard proof.
Q: Which of the two is prognostically more important – plaque vessel density or plaque hemorrhage, or are they equally important?
A: I think they are just as important. Looking at the graph, it seems that neovessels predict early and local plaque bleeding more late events. Q: What is the correlation between the two? Is there a threshold phenomenon that the risk of plaque hemorrhage goes up steeply once a certain plaque neovessel density is reached? Do some plaques develop more fragile vessels, which are more prone to rupture?
A: A correlation existed, it was weak however. Anwering questions regarding causality and mechanisms is difficult. This was a cross-sectional study which makes causal inferences impossible. If you ask my personal opinion, the answer on the last question would be yes. I do think that some individuals at a certain moment in life house plaques with more fragile vessels that have a higher risk for plaque bleeding.
Q: In a specimen-based study, it is sometimes difficult to ascertain in vivo plaque hemorrhage – how did you verify it was not due to dissection?
A: Good question. We did a fibrin stain and also examined whether bleedings were organized. In case many RBCs were present and dissection artifact were suspected we did not consider it to be an intraplaque bleeding.
Q: Were you able to identify “predictors” of plaque vessel density and hemorrhage in this study cohort?
Q: Dr. Renu Virmani forwarded the view that plaque neovessels, by allowing extravasation of RBCs with subsequent “lipid loading” of the plaque to contribute to the lipid pool and hence plaque progression and complication. However, in your study you did not see that a large lipid pool was an independent predictor for outcome. Can we conclude then that the predictive nature of plaque neovessels for events is independent from its putative contributory role to lipid core formation, even though the two lipid core size and plaque hemorrhage formally correlate on CEA analysis?
A: No we cannot conclude that. I think that the theory that intraplaque bleeding may serve as a basis for the formation of a lipid lake makes sense. In many sections fibrin stain and lipid stains are co-localized. Also glycophorin A is abundant in these lipid cores. The predictive value is a snap view: one moment in time. The subsequent progression of lipid pool formation may take different time frames. For example. When a tuberculosis outbreak is present then it is evident that there is a chance that a cough and fever is caused by this disease and complications may occur. However, a consequence of this (scarred lung tissue) will be present for ever and does provide less information if the patients may acutely suffer from complications from TBC.
Q: Plaque angiogenesis has been frequently associated plaque inflammation; in fact, the current study data corroborate this, and you and others have pointed out the significance of plaque inflammation. However, here, in this study, plaque macrophages were not as important for outcome? Any explanation why not?
A: There was a correlation between macrophages and the presence of vessels in the plaque. I do not have an explanation for this except a statistical argument.
Q: As a summarizing concept, how do you view the pathological sequence of events – how do plaque neovessels and in particularly plaque hemorrhage lead to cardiovascular events?
A: I can only speculate on this. I think neovessels may be leaky and that in the plaque a bruise may occur suddenly leading to a fast progression of “plaque size”. In addition, the bleeding may induce inflammation which destabilizes the lesion.
Q: Among the components of the composite endpoint, which one was the “driving factor” for the correlation between plaque vessels and outcome? Did any analyses for individual outcome parameters show any significant trends for association with any plaque components?
A: We did not identify such a driving factor. Q: By design, any prospective cohort study starts with a snapshot but then changes may occur over time that could influence outcome including those of the atherosclerotic plaque. Any word on these, if they should be tracked, of they could be tracked by imaging modalities or biomarker profiling? Did you include any in your study?
A: This was study on secondary manifestations. Most patients suffered from risk factors and took medication. Changes are likely to be many (new medication, life style changes) that have not been recorded. Personally I do not think any of these changes could have been detected with imaging of biomarker profiling.
Q: Another aspect of your study is the “vulnerable patient” concept. You assessed carotid artery plaques but follow-up events were not limited to this vascular territory. Does your study support the view that some patients develop a more aggressive phenotype throughout the vasculature and that one part will let you about the entire system? If so, which plaque characteristic was it that you found to be so telling? Vulnerable plaque – vulnerable patient – are we one step closer?
A: Yes, indeed we think that some patients do have a vascular system that houses more vulnerable plaques. The plaque bleeding may be a more consistent marker for that. Macrophages and protease activity may also be important in the pathogenetic process but may be more fluctuating which increases the variability.
Q: Given the importance of plaque hemorrhage, would you recommend we should start looking into this more in the future and if so how? MRI is a great tool to detect iron deposition – would this be a screening tool? How can we modify the process?
A: Good suggestion.
Q: Thank you so, so much again for this interview. It is always great, a real privilege, to discuss studies with you. As it has been our practice, in case someone has further discussion points, may we forward them via my E-mail (email@example.com) or may they contact you directly at your E-mail address?
Circulation. 2010 May 4;121(17):1941-50.
Expert Comment from Dr. Renu Virmani, President and Medical Director: CVPath, international Registry of Pathology in Gaithersburg, MD: I think Pasterkamp et al. have done a masterful job at slowly trying to understand how to find appropriate markers to detect individual patients at increased risk of future events.. They could not have chosen a better territory to look at i.e., the carotid artery as it is possible to image this territory noninvasively and it is also removed during surgery in individuals who present with cerebro-vascular symptoms or who are asymptomatic but have severe narrowing. Their collection of hundreds of cases gives them the power to study both large and small changes with sophisticated tools which exist today such as immunohistochemistry, proteins and mRNA along with a great follow-up to determine which markers may be more important and can be predictors of future events in individual patients which we have lacked so far. I congratulate him and his coworkers for the hard work and insightful thinking that will bring us closer to understanding plaque progression and regression as well us one day even help us develop new treatments to overcome the burden of atherosclerotic disease that is plaguing the western and the developing world.
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