Clinical Application of Contrast Agents with Echocardiography: Implications for Diagnosis and Treatment of Heart Disease

Moir, William Stuart (2007). Clinical Application of Contrast Agents with Echocardiography: Implications for Diagnosis and Treatment of Heart Disease PhD Thesis, School of Medicine, University of Queensland.

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Author Moir, William Stuart
Thesis Title Clinical Application of Contrast Agents with Echocardiography: Implications for Diagnosis and Treatment of Heart Disease
School, Centre or Institute School of Medicine
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Supervisor Professor Thomas Marwick
Abstract/Summary Contrast echocardiography has an established role for enhancement of the right heart Doppler signals, the detection of intra-cardiac shunts, and most recently for left ventricular cavity opacification (LVO). Over the past decade, because of the simultaneous evolution of micro-bubble engineering and contrast specific imaging modalities, the use of intravenously administered micro-bubbles to traverse the myocardial microcirculation in order to outline myocardial viability and perfusion has become a reality. The overall hypothesis of the studies undertaken in this thesis was that utilizing contrast agents during clinical echocardiographic studies can overcome the known limitations of non contrast echo imaging, facilitate the evaluation of novel diagnostic strategies and improve the accuracy of various echocardiographic techniques for diagnosis of clinical cardiac abnormalities. Further, this thesis hypothesises that the use of quantitative myocardial contrast echocardiography will enable further understanding of the pathophysiologic mechanisms involved in development of myocardial dysfunction in sub clinical cardiac diseases (eg patients with diabetes). The thesis initially reviews the evolution and development of contrast echocardiography, with focus on the clinical utility and technical aspects of qualitative and quantitative interpretation of contrast specific imaging. A number of unresolved clinical and technical issues are discussed, and will be addressed/investigated in this thesis. The second chapter describes the methodologies used in this thesis, with particular emphasis on new technologies used in the studies. Chapters 3 and 4 are studies which address the potential clinical utility of contrast agents for left ventricular opacification (LVO). Chapter 3 evaluates the benefit of LVO for calculation of left ventricular volumes and ejection fraction (EF), using magnetic resonance imaging (MRI) examination as a gold standard. Thirty patients with a previous history of ST elevation myocardial infarction underwent 2 dimensional (2DE) and three dimensional (3DE) echocardiography, with and without contrast for LVO. There was a significant improvement in accuracy for calculation of volumes and EF for 2DLVO and standard 3DE compared with standard 2DE, with 2DLVO and 3DE demonstrating comparable results. Overall 3DLVO demonstrated the closest accuracy, correlation and limits of agreement for all parameters. These results confirm previous studies which have demonstrated utility of both 2DLVO and non-contrast 3D for calculation of LV volumes and EF, although this is the first to address both modalities in a single cohort of patients. Additionally we have introduced a new, highly accurate modality, contrast 3D echocardiography which was the best predictor of MRI parameters. One limitation of stress echocardiography is reliance on image quality. Chapter 4 examines the incremental benefit and cost effectiveness of adding contrast for LVO to stress echo studies for diagnosis of CAD, using angiography as a gold standard. We prospectively recruited 135 patients planned to undergo coronary angiography, who were studied with pharmacologic and or exercise stress, with rest and peak/post stress images performed with and without contrast. Contrast significantly increased the sensitivity for overall diagnosis of coronary artery disease (CAD), recognition of single vessel CAD as well as extent of CAD. Unfortunately a cost benefit analysis based on published outcomes of patients having undergone stress echocardiography suggested the utility of this approach was not cost effective Chapters 5-8 are studies investigating use of contrast agents for qualitative and quantitative myocardial perfusion imaging. Reliance on ischaemia has been a documented limitation of stress echocardiography, with wall motion abnormalities developing late in the ischaemic cascade. Chapter 5 further advances the work of chapter 4, investigating the incremental diagnostic benefit of adding myocardial perfusion imaging to both standard and LVO for diagnosis of CAD, using a novel stress protocol (combining dipyridamole and exercise) to maximize acquisition and assessment of wall motion and perfusion images. We studied 70 patients planned for clinically indicated angiography, and 15 normal controls. Addition of contrast for myocardial perfusion (assessed qualitatively) to standard wall motion analysis and LVO significantly improved the diagnostic sensitivity for recognition of CAD and disease extent, with an insignificant reduction in specificity. This study provides further support for adding contrast to all stress echo studies, and demonstrates the diagnostic utility of assessing for ischemia earlier in the ischemic cascade, using technology with high spatial resolution. Another significant limitation of standard stress echo has been the qualitative nature of interpretation. Chapter 6 explores the use of a pure quantitative approach to stress echo, using myocardial contrast echocardiography. Stress MCE (using combined exercise-dipyridamole protocol) was performed in 90 patients undergoing angiography, with quantification of myocardial blood flow reserves for the left anterior descending and non-LAD coronary territories. Pure quantitative MCE was feasible and accurate for diagnosis of CAD, particularly in the LAD territory. Chapter 6 also investigates the contribution of dipyridamole to hyperaemia at the time of image acquisition in our protocol. A sub group of 18 patients from the study group were re-tested with exercise stress alone, and demonstrated significantly lower MBF reserve with exercise than with combined stress, enabling us to conclude that inclusion of dipyridamole was a critical component of the protocol. Patients with diabetes and no known coronary disease have been demonstrated to have impaired coronary flow reserve when tested invasively. Chapter 7 investigates whether this phenomenon is demonstrable with myocardial contrast echocardiography, and if present whether this impacts the accuracy of qualitative and quantitative MCE for diagnosis of CAD. MCE was performed in the LAD territory of 83 patients undergoing angiography for assessment of chest pain. Of these 28 patients had significant LAD stenosis (8 with DM) and 55 had no CAD (19 with DM). The presence of DM had no impact on qualitative interpretation, however quantitative MBF reserve was reduced in DM patients without CAD, significantly reducing test specificity, indicating caution should be exercised when using standardized cut offs for pure quantitative MCE to diagnose CAD in patients with DM The next chapter involves the application of quantitative tools to resting echocardiography. Clinical evaluation of reperfusion of the infarct related artery (IRA) following thrombolysis for ST segment elevation myocardial infarction (STEMI) is unreliable. Chapter 8 investigates the utility of resting quantitative MCE for prediction of angiographic flow in the IRA in 34 patients with STEMI going for angiography. In patients with STEMI, quantitatively derived myocardial blood flow was significantly lower in territories subtended by an artery with impaired (TIMI 0 to 2) flow than those territories supplied by a reperfused artery with TIMI 3 flow. A receiver-operator characteristic curve derived cut-off Q value of <11.3, representing impaired myocardial flow, was 73% sensitive and 67% specific for TIMI <3 flow at angiography, which was superior to standard clinical parameters. We concluded that quantitative MCE can predict impaired flow in patients with acute STEMI. Chapter 9 further explores the use of quantitative myocardial contrast echocardiography and other quantitative modalities for determination of myocardial function. The pathogenesis of the cardiac dysfunction in patients with DM and no CAD is controversial, but micro-vascular disease is suggested as a significant contributor. Patients with diabetes, normal left ventricular ejection fraction and no demonstrable myocardial ischemia have been demonstrated to have sub clinical LV dysfunction manifest as abnormal strain rate imaging (SRI) parameters. In Chapter 9 we examined the relationship between myocardial flow and function in type II diabetes. Stress MCE and resting SRI were performed in 48 patients (22 with type II diabetes mellitus and 26 controls), all with normal LV systolic function and no obstructive coronary disease by quantitative coronary angiography. The mean strain, SR and MBF reserve were all significantly lower in the diabetic group compared with controls, with diabetes the only independent predictor of each parameter. No correlation was demonstrated between MBF and SR (r=-0.10, p=0.54), or MBF and strain (r=-0.20, p=0.20) indicating that whilst micro-angiopathy and dysfunction coexist microvascular disease does not appear to be the predominant causative factor in this disease. In conclusion we have demonstrated the use of microbubble contrast agents with echocardiography enables accurate estimation of ventricular volumes and ejection fraction, with contrast enhanced 3-D echocardiography appearing superior to standard 3-D and contrast enhanced 2-D images. We have demonstrated the incremental benefit for diagnosis of CAD of adding contrast for LVO and perfusion to stress echocardiographic studies, and furthermore demonstrated that quantitative MCE is a tool with potential utility for diagnosis of CAD, as well as for recognition of infarct related artery flow in the setting of acute ST elevation myocardial infarction. Finally we were able to use quantitative MCE and also techniques for quantification of myocardial function to gain insight into the influence of diabetes on the microcirculation as well as the development of diabetes related myocardial dysfunction.

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