Regional Mechanics of Demand Ischemia During Cardiac Stress Testing

Currently, the most effective non-invasive method for early diagnosis of coronary artery disease is the cardiac stress test. In this test, stress is induced by treadmill exercise or with a pharmacologic agent such as dobutamine, and myocardium with insufficient coronary flow reserve, usually caused by coronary stenosis, experiences an imbalance between oxygen supply and demand known as demand ischemia. This causes altered mechanical and electrical behavior that is often identified using cardiac imaging. The mechanical movement of the left ventricular (LV) wall, characterized clinically as “wall motion”, is currently assessed qualitatively to identify abnormally-moving ischemic regions which may benefit from angioplasty. Advances in ultrasound and MRI may improve diagnosis by allowing more quantitative measures such as strain, wall thickening, or endocardial fractional shortening. However, little is understood about how these measures are affected by the severity of demand ischemia, coupling to adjacent myocardium, or the presence of previously-unrecognized myocardial infarction. A greater understanding of the factors that influence regional mechanics during stress testing would help determine the best way to detect the altered mechanics that indicate demand ischemia and coronary stenosis. The goal of this dissertation is to understand how regional demand ischemia affects regional mechanics and apply that knowledge to improve clinical stress testing.

A finite element model of the heart was used to examine how reduced force generation in the ischemic region, ischemic region size, and coupling to myocardium with increased contractility separately and jointly impact various measures of regional mechanics. Area strain and a measure of wall motion developed in our lab, three-dimensional fractional shortening (3DFS), were most sensitive to reduced force generation, while radial strain was affected most by the contractility of remote myocardium. The model also predicted that a novel measure of wall motion bulging, dyskinesia severity index (DSI), can separate infarcts from demand ischemia during stress testing. The ability of strain and 3DFS to detect a critical stenosis was evaluated in experimental canine dobutamine stress tests. The three-dimensional (3D) measures of area strain and 3DFS detected critical stenoses better than two-dimensional (2D) strain. Finally, 3DFS measured during clinical stress testing in patients at low risk for coronary artery disease displayed low variability, suggesting 3DFS may be effective for detecting demand ischemia in patients.

Another application in which the cardiac mapping techniques described here could improve treatment is in evaluating cardiac resynchronization therapy (CRT) nonresponders, which compromise 30-40% of CRT patients. The relationship between LV lead location and scar or regional mechanical function measured from pre-CRT cardiac imaging likely has an important impact on CRT response. A method to reconstruct the 3D coordinates of the lead from 2D fluoroscopic images and then map the LV lead position onto a pre-CRT imaging study was developed. The accuracy of the average mapped lead position was within 1.5cm. This method will allow clinicians to evaluate nonresponders and test hypotheses to quantitatively optimize LV lead location without specialized cardiac mapping equipment.

The work of this dissertation improves our understanding of the mechanical consequences of demand ischemia and interpretation of the functional stress test, and enables more quantitative image analysis during both stress testing and CRT evaluation. A more quantitative and empirical method for stress test interpretation and CRT evaluation will not only improve diagnostic utility, but enable better training, center-to-center repeatability, and clinical research methods for publishing regional function data. The significance of this work is that it will increase understanding of regional mechanical behavior during cardiac stress testing, and improve the diagnostic capability of the cardiac stress test by enabling quantitative diagnosis of mechanical dysfunction.