This application addresses broad Challenge Area (05): Comparative Effectiveness Research;Challenge Topic 05-HL-104 Reducing cardiovascular risk in moderate-risk and asymptomatic patients. More than half of the 500,000 coronary artery deaths each year in the U.S. from acute coronary syndrome are due to the rupture of the thin fibrous cap overlying the necrotic core of the lesion and the formation of a thrombus. The mechanism as to why some thin caps rupture and others do not is very likely the single most important unanswered question in life threatening atherothrombotic lesions. We recently proposed a new paradigm of thin cap fibroatheroma (TCFA) rupture, suggesting that minute calcifications located in the cap itself increase tissue stress concentration and plaque vulnerability. Microcalcifications can lead to cavitation induced debonding, a process in which the tissue in the cap will pull away from the calcified inclusion and tear when tensile stress in the tissue due to blood pressure becomes too large. The first experimental evidence for this new paradigm was recently provided using confocal microscopy and high resolution micro computed tomography.
In Aim 1 we will use a high resolution micro-CT imaging system to examine a much broader sample of ruptured and non-ruptured human thin cap fibroatheroma and statistically analyze the frequency, size, shape and spatial distribution of the cellular-level microcalcifications.
In Aim 2 we quantitatively evaluate the impact of the microcalcifications on the biomechanical stability of the cap using a three-dimensional (3D) multi-level finite element model (FEM) of realistic 3D geometries of human coronary lesions based on high resolution micro-CT imaging. We will investigate the stress concentration effect produced by the size, shape and presence of multiple microcalcifications in close proximity within a region of high peak circumferential stress (PCS), on the biomechanics of cap rupture. This multi-level micro-CT based approach has the ability to include the fine grain structure required to imbed local solutions in the vicinity of the microinclusions, which is critical to determine the PCS amplification leading to fibroatheroma rupture. These studies, if successful, could resolve the long-standing mystery as to why some vulnerable plaque lesions are more prone to rupture than others and, as a result, provide vital new criteria for the detection and treatment of vulnerable plaque.

Public Health Relevance

The rupture of the thin fibrous cap overlying the necrotic core of a vulnerable plaque is the principal cause of acute coronary syndrome. Unfortunately, the mechanism of vulnerable plaque rupture has remained a mystery. We proposed that the rupture of thin cap fibroatheroma may be caused by minute calcifications in the cap itself due to tissue stress concentration and provided the first experimental evidence for this new paradigm. We will investigate the impact of microcalcifications on cap rupture using a three-dimensional (3D) multi-level finite element model of realistic 3D geometries of human coronary lesions based on high resolution micro-CT imaging. If successful, this study may provide important insights on the rupture of fibrous cap atheromas responsible for more than half of the 500,000 coronary artery disease deaths in US every year.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
5RC1HL101157-02
Application #
7937740
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (58))
Program Officer
Cooper, Lawton S
Project Start
2009-09-30
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$356,588
Indirect Cost
Name
City College of New York
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
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Cardoso, Luis; Kelly-Arnold, Adreanne; Maldonado, Natalia et al. (2014) Effect of tissue properties, shape and orientation of microcalcifications on vulnerable cap stability using different hyperelastic constitutive models. J Biomech 47:870-7
Maldonado, Natalia; Kelly-Arnold, Adreanne; Cardoso, Luis et al. (2013) The explosive growth of small voids in vulnerable cap rupture; cavitation and interfacial debonding. J Biomech 46:396-401
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