NEW YORK, October 3, 2006 – An interdisciplinary team of researchers from The Grove School of Engineering at The City College of New York (CCNY) and other institutions has confirmed the presence of minute calcifications in the fibrous thin cap that forms between lipid-filled lesions and the bloodstream.
The discovery supports a new hypothesis developed by the team to explain what causes the thin cap to rupture, triggering catastrophic coronary events that kill over 300,000 Americans annually. The findings were reported September 26 in the Proceedings of the National Academy of Science.
Of the more than 500,000 yearly sudden coronary deaths in the United States, 60 percent result from ruptures of the thin cap, which results in formation of a thrombosis that causes a sudden fatal blockage. These life-threatening atheroma often go undetected because the ruptures often occur in arteries that are constricted by 50 percent or less and are asymptomatic.
The theory advanced by the researchers posits that calcifications that become lodged in the thin cap layer can cause the thin cap to rupture when they become de-bonded, or detached, by stress-induced cavitation (small bubbles) that form at the interface between the calcific particle and the surrounding tissue. The calcifications, which are the size of a single cell or 10 microns – one fifth the thickness of a human hair – cannot be detected through conventional in vivo imaging techniques such as MRI, IVUS (intravenous ultrasound) or OCT (optical coherence tomography).
The team confirmed the presence of the tiny particles through two in vitro micro-imaging techniques they developed. The technologies used have superior resolution than those used for in vivo studies.
Using confocal microscopy, they observed the presence of calcifications in tissue samples to which a stain that highlights the presence of calcium, Alizarin Red S, had been applied. In cross sections of the samples observed using microcomputer tomography (micro CT), the calcifications were seen in greater clarity.
“The micro CT images picked out the calcified cells like stars in the sky,” said Dr. Sheldon Weinbaum, CCNY Distinguished Professor of Biomedical Engineering and Mechanical Engineering, the team’s communicating author.
Five advanced atheromatous lesions with fibrous caps and lipid cores were detected in the 24 samples scanned with micro CT. Micro-calcifications were found in the fibrous cap overlying one of the cores.
The micro-calcifications are most likely single macrophage cells that devour LDL cholesterol within necrotic lipid cores, die a natural death and then get stuck in the fibrous cap when they try to migrate back to the blood stream, Professor Weinbaum explained. “Had they remained in the lipid core, they would not pose problems and would most likely eventually become stable,” he added.
The team theorizes that the thin cap – less than 65 microns in thickness – ruptures due to stress around the trapped calcified particles, which causes them to de-bond or become loose within the cap. This is similar to the effect that impurities had in causing rubber tires to fail observed in a classic study done in 1933.
Subsequent experiments showed that the de-bonding occurred at the interface between the solid impurity and the rubber because of the large mismatch in the hardness of the materials and the local stress concentrations that develop at the poles of the impurity along the tensile axis as a result of this mismatch.
A theoretical model developed to support the hypothesis predicts a near doubling of interface stress at the poles of calcifications lodged in the fibrous thin cap. Presence of a calcification within fibrous caps of less than 65 microns would result in an increase in peak circumferential stress to 600 kPa (kilo Pacscals) from 300kPa, exceeding the 545 kPa threshold at which a rupture is likely to occur. . One hundred kilo Pascals equates to normal atmospheric pressure.
The location of the calcification within the cap was found to have only modest affect on the stress buildup. In previous studies, it had been shown that 40 percent of ruptures occur in the center of the cap, even though computational finite element (FEM) analysis had predicted maximum stress would have occurred at the shoulders of the lipid core.
The researchers emphasize that their theoretical analysis does not incorporate de-bonding per se but, rather, demonstrates the possibility that it can occur. Future steps would include more extensive studies to determine the frequency and location of calcifications within the fibrous cap and a demonstration that stress-induced cavitation would cause interfacial de-bonding, Professor Weinbaum said.
Members of the research team in addition to Professor Weinbaum were:
In addition, Dr. Stephen Cowin, CCNY Distinguished Professor of Biomedical Engineering and Mechanical Engineering, Dr. John Tarbell, CCNY Distinguished Professor of Biomedical Engineering, and Dr. Lucas Parra, CCNY Associate Professor of Biomedical Engineering, consulted on the project, which was conducted without an external grant, according to Professor Weinbaum.
About The Grove School of Engineering at CCNY
The Grove School of Engineering at The City College of New York, formerly the CCNY School of Engineering, is the only public engineering school within New York City. It offers Bachelors, Masters and Ph.D. degrees in seven fields: biomedical, chemical, civil, computer, electrical, and mechanical engineering and computer science. The School is recognized nationally for the excellence of its instructional and research programs and ranks among the most diverse engineering schools in the country. On November 28, 2005, the CUNY Board of Trustees named the School in honor of Dr. Andrew S. Grove, a member of the CCNY Class of 1960, and a co-founder and former chairman of Intel Corp., the world’s leading producer of microprocessors.
About The City College of New York
For over 159 years, The City College of New York has provided low-cost, high-quality education for New Yorkers in a wide variety of disciplines. Over 13,000 students pursue undergraduate and graduate degrees in the College of Liberal Arts and Science, the School of Architecture, the School of Education, the Grove School of Engineering, the Center for Worker Education and the Sophie Davis School of Biomedical Education.
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