The conventional ideas about plaque formation and rupture are wrong, according to Keith A.A. Fox, MB, ChB, who presented the Paul Dudley White International Lecture on Tuesday at Scientific Sessions.
Plaque does not build over time, rupture catastrophically and generate a thrombus that blocks the artery. Plaque does build over time, but small ruptures are common occurrences that pose little risk, he said. Only selected plaques are vulnerable to catastrophic rupture with potentially fatal consequences.
“Blockage of arteries is a stochastic progression with abrupt, destabilizing changes sometimes resulting in death,” said Fox, the Duke of Edinburgh Professor of Cardiology at the University of Edinburgh in Scotland. “We have a series of small ruptures all the time. In most of us, the balance is tipped toward repair. In vulnerable plaques, repair cannot keep pace and we die.”
The concept of vulnerable plaque is hardly new, Fox noted in his lecture, “Identification of the Vulnerable Plaque: From Bench to Bedside.” The first recorded observation of plaque rupture dates back to an 1844 autopsy in Denmark.
What’s new is the realization that plaque is ubiquitous and rupture is only sometimes catastrophic. Data from heart donors show increasing atherosclerosis with increasing age. Most older individuals in developed economies have atheromatous plaques, and most plaques are benign and asymptomatic.
That benign profile changes in cardiovascular disease. Not all coronary lesions are equally prone to catastrophic rupture, Fox explained. But standard imaging techniques cannot distinguish between vulnerable plaque and asymptomatic plaque.
The need for improved imaging techniques comes into sharp focus when seen through the lens of long-term survival from acute coronary syndromes. ST elevation is responsible for most deaths during the acute phase. But ST depression is the leading cause of death beyond the first 15 days, Fox noted.
Data from the Global Registry of Acute Coronary Events (GRACE) show roughly similar five-year death rates from STEMI, non-STEMI and unstable angina. But the proportion of post-discharge deaths is significantly higher for both non-STEMI and unstable angina than for STEMI events. Data on recurrent events from the U.K. cohort of GRACE showed significant numbers of readmissions for recurrance of the index event: 12.7 percent had at least one recurrent MI, 7.7 percent had at least one recurrent stroke and 53.6 percent had one or more ACS readmissions.
“Much has been done to improve outcomes in the acute phase,” Fox said. “I want us to refocus on longer-term outcomes. The acute phase is only the start of the problem. Some 86 percent of deaths occur after the acute phase, after the initial discharge.”
Cardiovascular events after an initial ACS are almost evenly divided between events related to the culprit lesion and events not related to the culprit lesion. That makes it even more important to devise methods to identify and treat vulnerable plaque.
Fox has devised ultrasound microbubbles that can be linked to monoclonal antibodies to target activated endothelial cells by CD54 on cells that have been activated by TNF. The microbubbles selectively attach to activated endothelial cells to enhance imaging. The same technique might be used to deliver therapeutic agents directly to target cells. Oncologic researchers are developing similar techniques to target, identify and treat specific tumor types.
New imaging techniques are being developed that can identify deposits of vulnerable plaque. One such technique, 18fluro-deoxy glucose PET, can identify pockets of aortic inflammation but it is less useful in picking out inflamed coronary lesions. Peak plasma troponin correlates well with aortic 18F-FDG uptake, but the technique does not work for coronary arteries because myocardial uptake of glucose obscures the culprit plaque in most images.
A newer technique, sodium 18F-fluoride, highlights calcification activity. In patients with myocardial infarction, 18F-fluoride clearly distinguished the culprit lesion from the highest non-culprit lesion in both ex vivo and in vivo experiments.
“There is progress in identifying the pathways leading to plaque rupture and progression,” Fox said. “But we need more research into patient phenotypes, identifying and imaging those vulnerable plaques and finding novel targets to limit progression.”