ASE Funded Research – Project Summaries

ASE Funded Research – Project Summaries

2009 ASE Cardiovascular Sonographer Research Award RecipientEchocardiographic Assessment of Hypertrophic Cardiomyopathy Induced by Overexpression of C-Myc
Ann Liner, Brian Hoit, Mark Smith. University Hospitals of Cleveland, Cleveland, OH
Project summary: The objectives of these studies are to understand the role that cell cycle-related changes play in the development of cardiomyopathy and the ability of sophisticated echocardiographic measurements of myocardial motion to detect changes in ventricular function during that progression. To that end, we developed a conditional mouse model (MHC-MYC) that expresses the potent oncogene cell cycle-inducer, MYC, in a cardiomyocyte-specific manner. In our preliminary studies, MYC expression drives cardiomyocytes to enter the cell cycle, leads to pronounced hypertrophy and, ultimately, to death from heart failure. These findings led us to develop a novel “Cell Cycle Hypothesis” that predicts that cardiomyopathy, like cancer, is a disease of inappropriate cell cycle control. Importantly, early and transient MYC expression has been reported in various animal models of cardiomyopathy as well as in human disease; however, its functional role in pathogenesis is less clear. Importantly, MYC is potentially able to activate “pro-myopathic” pathways independent of cell cycle activation. Accordingly, the Specific Aims of this study are to examine the causal relationship between temporal expression patterns of MYC, hypertrophy, and heart failure (as determined echocardiographically and pathologically), and to use specific cell-cycle inhibitors to determine the effects of pharmacologic cell-cycle inhibition on these changes in MHC-MYC transgenic mice. In these aims, we will determine the ability of myocardial tissue motion, strain, and strain rate using velocity-vector imaging to provide insight into early and more subtle abnormalities of dysregulated myocardial function. The MHC-MYC mouse model provides an ideal tool to address these questions since the temporal expression of MYC (On & Off) can be easily regulated by doxycycline and cell cycle inhibition, and thus allow LV dysfunction to be titrated and assayed with sensitive measurements derived from velocity-vector imaging.
2009 ASE Echo Investigator Award RecipientDetermining the Genetics of Atherosclerosis Using a Vascular Ultrasound Phenotype
Jeanne DeCara, Roberto Lang, Carole Ober. University of Chicago Medical Center, Chicago, ILProject summary: The health and economic impact of atherosclerosis on US and worldwide populations is significant. Early identification and treatment of risk factors is imperative. Unlike traditional cardiac risk factors, genetic risk factors for atherosclerosis are not incorporated into commonly used risk assessment models. Instead, genetic risk is merely inferred from family history. In this proposal we will identify genetic risk factors for atherosclerosis. We will use an ultrasound-acquired measurement, carotid intima-media thickness, as marker of atherosclerosis. This marker is heritable, suggesting that atherosclerosis has a genetic component. We will perform our studies in the Hutterites, an inbred population living on communal farms in Minnesota. Their uniquely uniform environment minimizes the variation in environmental risk factors for atherosclerosis, likely making the effect of genetic variation in atherosclerotic risk more evident. Our ultimate goal is to identify novel genes that contribute to atherosclerosis and, in the future, incorporate these genetic factors into models of disease risk. To accomplish this, we request funds to increase our sample size of phenotyped individuals, which will provide additional power to detect atherosclerosis-susceptibility genes. To date, we have extensively defined cardiovascular traits for 460 Hutterites. If this proposal is funded, we will be able to collect, process, and analyze data from an additional 300 Hutterites during a multi-day research field trip to the Hutterite colonies in Minnesota in the summer of 2009. We are confident that this cumulative dataset will enable us to detect atherosclerosis-related genes in the Hutterites and set the stage to validate our findings in a non-Hutterite population.

2009 ASE Echo Investigator Award Recipient

Polymer Injection Therapy for Treatment of Ischemic Mitral Regurgitation
Judy Hung, Orhun Muratoglu, Gavin Braithwaite. Massachusetts General Hospital, Boston, MA

Project summary: This project examines the use of a biocompatible and biologically inert biomaterial (polyvinyl alcohol (PVA) polymer) for treatment of ischemic mitral regurgitation. Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction that doubles late mortality. The fundamental mechanism underlying ischemic mitral regurgitation is distortion of the damaged heart wall, which pulls on the mitral valve leaflets and restricts their ability to close. We plan to test PVA polymer application in an established ovine model of ischemic mitral regurgitation, examining both acute and chronic ischemic MR. The main objective of this proposal is to examine whether ischemic mitral regurgitation can be relieved by injection of a polymer (polyvinyl alcohol-PVA) that has been formulated specifically for this application, into the infarcted myocardium overlying the papillary muscles. Secondary objectives are to test the hypothesis that the polymer reduces MR by the following mechanisms: 1) by acting as a tissue strengthening and bulking agent to repositioning the papillary muscles and 2) injection of a polymer results in improved ventricular mechanics as reinforcement of the akinetic or dyskinetic myocardial wall, leads to improved regional and global mechanics of the remaining myocardium. The application of polymer therapy in order to reverse remodel the ventricle provides a unique opportunity to develop a less invasive and adjustable approach toward this important valvular disorder. Advances in polymer chemistry have led to a tremendous variety of polymers, that can be selected and modified based on their physical properties and suitability for use in biologic systems. Polyvinyl alcohol (PVA) polymer is highly water-soluble and elicits little or no host biological response when implanted in animals. For these reasons, PVA polymers are used in a variety of biomedical applications including drug delivery, cell encapsulation, artificial tears, contact lenses, and more recently as nerve cuffs. Furthermore, PVA polymer can be formulated in situ with physical properties that are adjustable and capable of withstanding the pulsatile loading conditions in the beating heart. PVA can be designed for injection into the myocardium with subsequent crosslinking once injected by modifying PVA concentrations and physical properties so that crosslinking occurs at or near body temperature. This project will highlight two roles of echocardiography: as a key participating technique for guiding new cardiac therapeutic interventions that are less invasive, such as PVA polymer injection into the beating heart; and as a quantitative approach for studying regional and global ventricular remodeling and its consequences for valvular function.
2008 ASE Career Development Award RecipientCombined Usefulness of Doppler Myocardial Imaging, Cardiac Biomarkers, and Cardiac Magnetic Resonance for Early Diagnosis of Cardiac Involvement and Risk Stratification in Patients with Systemic AL Amyloidosis
Diego Bellavia, Patricia Pellikka, Fletcher Miller, Angela Dispenzieri, Christopher Scott. Mayo Clinic, Rochester, MNProject summary: Background: 1) It is uncertain if the right ventricle is involved before the left ventricle in cardiac amyloidosis and whether right ventricular function assessment is useful for prognosis. 2) We demonstrated usefulness of Doppler myocardial imaging for early detection of cardiac amyloidosis in patients with primary (AL) amyloidosis. However, role of serial measurements during clinical follow-up to monitor myocardial function by time and to define risk, has yet to be determined. 3) Cardiac magnetic resonance (CMR) is useful to “phenotype” various forms of cardiomyopathy including cardiac amyloidosis. Sensitivity of CMR to depict subclinical early cardiac involvement, and its potential role, complementary to Doppler/speckle myocardial imaging requires clarification. 4) In the very last few years, a new, semi-automatic and faster approach for obtaining tissue velocity strain and strain rate information, based on myocardial “speckles”, have been implemented. Precision and accuracy of speckle myocardial imaging in relation with standard Doppler myocardial imaging has still to be proved. Primary Aims: 1) To test the usefulness of right ventricular function assessment by standard echocardiography and Doppler/speckle myocardial imaging for early diagnosis of cardiac amyloidosis and for risk stratification in patients with AL amyloidosis. 2) To test usefulness of serial Doppler/speckle myocardial imaging measurements for monitoring myocardial function during treatment. 3) To determine whether CMR is complementary to Doppler/speckle myocardial imaging information for early diagnosis and risk stratification. 4) To test precision and accuracy of 2-D strain and vector velocity imaging by comparison with Doppler myocardial imaging values. Methods: Echocardiographic images obtained in patients with a diagnosis of AL systemic amyloidosis at baseline (starting 1/2004) and every 6 months for 5 years (3/2009) will be used to assess longitudinal tissue velocity, strain and strain rate for the 16 left ventricular segments and for the basal, middle and apical right ventricular free wall segments. In addition, radial, circumferential, and twisting data by both Doppler and speckle myocardial imaging will be measured. Finally, enrolled patients will undergo a delayed contrast enhanced CMR and cardiac biomarkers will be collected, to test additional role of each in depicting early diagnosis of cardiac involvement and defining risk stratification in AL amyloidosis.

2008 ASE Career Development Award Recipient & 2009 Arthur E. Weyman Young Investigator’s Award Competition Finalist

Mitral Valve Leaflet Area Quantification: A 3D Echo-Histology Study of Mitral Valve Adaptation in Ischemic Mitral Regurgitation
Jacob Dal-Bianco1, Mark Handschumacher1, Elena Aikawa2, Robert Levine1. 1Massachusetts General Hospital, Boston, MA; 2Center for Molecular Imaging Research, MGH, Harvard Medical School, Boston, MA

Project summary: In patients with coronary heart disease and myocardial infarction (MI) or left ventricular (LV) dysfunction, mitral regurgitation (MR) is frequent and doubles mortality. Despite this, little is known about mitral valve (MV) leaflet tissue biology and its potential adaptation to altered ventricular size and function. Such understanding could lead to new therapies that stimulate endogenous repair pathways, including cellular activation and valve matrix production. The MV leaflets are normally prevented from prolapsing by chordae anchored to the LV walls by papillary muscles (PM). In ischemic MR (IMR), expansion of the LV chamber disturbs this finely balanced system: Systolic closure motion of the tethered MV leaflets is restricted, causing MR. A three-dimensional echocardiographic (3D Echo) technique developed by the sponsoring laboratory showed that MV leaflet area is increased in patients with IMR, but often not enough to ensure tight closure. It is unknown whether this MV leaflet area increase is the result of active adaptation with increased cell activation and matrix production, or only passive MV leaflet stretch. It is also unknown whether ischemic environment, the prerequisite for IMR, and local inflammatory cytokines released in LV dysfunction support or limit valve adaptation and repair attempts in a way that could provide a potential target for pharmacologic intervention. We will therefore address the following hypotheses in an experimental animal model that allows independent and controlled variation of leaflet tethering, ischemic environment, and MR flow: 1) MV tissue and biology adapt actively in IMR in a way that promotes adequate MV closure, including proliferation of activated mesenchymal cells capable of augmenting valve size and secreting matrix components; and 2) Ischemic environment and local inflammatory factors in LV dysfunction influence repair adaptation processes, largely in a limiting manner. These studies bridge 3D Echo quantification of MV leaflet area and MR with histologic and immunohistochemical exploration of mechanism. The anticipated findings will lead to a deeper understanding of MV tissue biology that can promote the development of new therapeutic strategies for MV disease.
2008 ASE Career Development Award RecipientMolecular Imaging of Stem Cell Therapy Using Targeting Contrast Ultrasound
Hiroko Fujii1, Jonathan Lindner2, Howard Leong-Poi1. 1St. Michael’s Hospital, Toronto, ON, Canada; 2Oregon Health & Science University, Portland, OR
Project summary: Studies to date have suggested beneficial effects of stem or progenitor cell administration to ischemic tissue. Despite these promising results, the biology of stem cells and the mechanisms underlying their beneficial effects remain poorly understood. A non-invasive technique capable of tracking intravascular cell engraftment with high resolution is lacking. The ability to monitor cell engraftment over time would be important in defining the role of vascular engraftment in the neovascularization response to cell-based therapies, and would allow the determination of the ideal strategy for cell therapy for therapeutic angiogenesis. Molecular Imaging: Non-invasive imaging techniques are being developed to detect and quantify processes that occur at the cellular or molecular level in vivo. These molecular imaging techniques are evolving rapidly in all imaging modalities, including ultrasound. Microbubble contrast agents can be targeted to intravascular processes, such inflammation, by conjugating specific ligands to their surface. Binding of targeted microbubbles in vivo would then allow their detection using ultrasound imaging. We have previously developed techniques for the molecular imaging of angiogenesis, using contrast-enhanced ultrasound (CEU) and microbubbles targeted to the cell-surface integrins expressed in neovessels. Using similar techniques, we have now developed a novel method of tracking the vascular engraftment of progenitor cells, using CEU and targeted microbubbles. Imaging Stem Cell Engraftment: We hypothesize that CEU molecular imaging with site-targeted microbubbles can be used to both spatially and temporally quantify intravascular cell engraftment into ischemic muscle and the subsequent angiogenic response. For our experiments, progenitor cells are transfected to express a specific surface marker that allows microbubble targeting using ligands attached to the bubble surface. Preliminary experiments have demonstrated the ability of our targeted microbubbles to track and image engrafted endothelial progenitor cells using an in vitro flow chamber model, and an in vivo implanted matrigel plug model. Using a rodent model of severe chronic ischemia, my present proposal aims to utilize CEU molecular imaging of cell engraftment and angiogenesis to determine 1) the direct contribution of vascular engraftment to changes in tissue perfusion in response to cell transplantation, 2) the optimal cell type to promote engraftment and neovascularization. Significance: The successful completion of these protocols will be an important step towards the development of an ultrasound imaging technique to spatially and temporally monitor stem cell therapy for chronic refractory ischemia, one which will help define the ideal strategy for stem cell-based therapy for therapeutic angiogenesis.
2008 ASE Career Development Award RecipientContrast Ultrasound for Quantification of Plaque Neovascularization: A New Method to Identify Vulnerable Plaque
Diego Moguillansky, Flordeliza Villanueva, Xucai Chen. University of Pittsburgh Medical Center, Pittsburgh, PAProject summary: The rupture of “vulnerable” atherosclerotic plaques which leads to acute coronary syndromes (ACS) is a major cause of morbidity and mortality. Catheter-based interventions to achieve acute reperfusion are a mainstay of therapy. Despite advances in acute reperfusion strategies once a plaque has become unstable, approaches to prospectively identify plaques which will become unstable in the future are poorly developed. Coronary angiography is poor in predicting which lesions will ultimately rupture, as evidenced by the fact that most ACS originate from angiographically non-occlusive lesions. Rupture-prone plaques manifest abnormal proliferation of adventitial vasa vasorum (VV), the microvessels that normally perfuse the blood vessel wall, and intraplaque neovascularization. These neovessels are leaky, leading to intraplaque hemorrhage. The lipid-rich membranes of extravasated erythrocytes add to the lipid content of the plaque, contributing to necrotic core expansion and plaque rupture. Hence, plaque neovascularization may be a marker of, as well as an etiologic factor in, the development of high risk atherosclerotic plaque. While the histologic components of high risk plaque have been characterized, methods for imaging them in vivo are lacking, thus constraining our ability to optimize therapies. This proposal approaches the general clinical problem of how to identify high risk atherosclerotic lesions. We address the overall hypothesis that VV density can be a clinical marker of cardiovascular risk by identifying specific plaques prone to instability and/or a general state of plaque “activation” requiring local or systemic therapies. Methods for in vivo detection of plaque neovascularization, however, are currently limited. Vascular contrast ultrasound (CUS) imaging has emerged as a possible approach to imaging VV. The ability of CUS, however, to quantify and serially follow VV density as plaques evolve, has not been firmly established. Further validation of this method is a pre-requisite to its clinical application for risk stratification. This proposal will use a cholesterol-fed rabbit model of atherosclerosis to test the hypothesis that contrast ultrasound can quantify VV. Our purpose is to develop and validate contrast ultrasound for the detection and quantification of VV, and ultimately to clinically translate this approach for diagnostic and therapeutic purposes. The Specific Aims of this proposal are to test the hypotheses that:

1. Contrast ultrasound (CUS) can quantify and serially track VV evolution during atherogenesis.
2. Molecular imaging of VV by targeted CUS will specifically delineate pathologic neovascularization.
3. Therapies to target angiogenesis can reverse or attenuate the progression of neovascularization, while decreasing plaque burden.2008 ASE Cardiovascular Sonographer Research Award RecipientThe Effect of Right Ventricular Pacing Site on Measures of Mechanical Ventricular Dyssynchrony
S. Michelle Bierig, Arthur Labovitz, Mark Richards. Saint Louis University, Saint Louis, MO

Project summary: Background: Reductions in right ventricular (RV) apical pacing have been shown to decrease atrial fibrillation (AF), heart failure (HF) symptoms, and mortality. This observation has prompted studies evaluating both alternative lead locations and the use of cardiac resynchronization therapy (CRT) to mitigate these effects. Although Doppler echocardiography has been utilized extensively to evaluate the effect of left ventricular lead location and stimulus timing, little data exists evaluating RV pacing locations. Echocardiographic measurements of dyssynchrony are a potentially powerful tool to evaluate the contribution of mechanical dyssynchrony (MD) to the deleterious effects of RV apical pacing. Furthermore, they can be utilized to determine whether alternative RV lead locations may alleviate MD created by pacing from the RV apex. Thus, this study is aimed at echocardiographically evaluating MD while pacing at various RV locations. Specific Aims: The specific aim of this study is to assess the degree of mechanical dyssynchrony (MD) induced by pacing from the apex and alternative locations in the RV of both structurally normal and abnormal hearts by:
1. Calculating the time difference of contraction using segmental tissue Doppler, tissue strain, and tissue displacement in 12 apical segments;
2. Evaluating three-dimensional dyssynchrony indices; and,
3. Determining which pacing location provides the most synchronous RV and LV contraction.
Methods: Patients with structurally normal hearts undergoing electrophysiology studies (EPS) and those with left ventricular dysfunction undergoing device (ICD) implantation will have baseline echocardiograms prior to procedures. During the procedure, a catheter will be used to anatomically map the RV. The RV will be paced in six different locations: RV apex (RVA), RV free wall (RVFW), RV septum with His capture (RVSH), RV septum without His capture (RVS), RV outflow tract (RVOTS) septal, and the RVOT free wall (RVOTFW). Echocardiographic measurements of dyssynchrony will be performed after two minutes of pacing at each site. Mechanical dyssynchrony measurements including tissue Doppler (TD), tissue strain (TS), and 3D volumetric dyssynchrony (3DVS) will be made. Concomitant measurements of cardiac output, ejection fraction, and patterns of mitral inflow will be made. Differences in these measures at different pacing locations will be quantitatively evaluated. Significance: The results of this study should help determine whether RV apical pacing induces a significant degree of MD in specific patient populations, and whether efforts to place RV pacing leads in new locations to decrease dyssynchrony and improve patient outcomes by utilizing cardiac ultrasound are justified.
2008 ASE Cardiovascular Sonographer Research Award RecipientPulmonary Response by Echocardiography: The PURE Study
Jose Daniel Rivera, Pamela Douglas, Victor Tapson, Zainab Samad. Duke University Medical Center, Durham, NCProject summary: Pulmonary arterial hypertension (PAH) is a progressive disease with poor long-term prognosis. Echocardiography is an inexpensive, non-invasive imaging technique that plays a vital role in the diagnosis and detection of PAH. However, the American Society of Echocardiography (ASE) reference values are limited to linear RV and RA measures for the right ventricle (RV), are based on a small sample size and, unlike LV/LA ranges, are not indexed to body size or sex. Of particular note is that right atrial area has no established reference limits despite studies showing a relationship to outcomes in patients with PAH. Our overall hypothesis is that improvement in the standardization and validation of echocardiographic RV/RA parameters will enhance the diagnosis and monitoring of patients with PAH. To this end, this project will address three specific aims:

i) Provide reference limits for common echocardiographic RA and RV and pulmonary hemodynamic parameters by sex and body size;
ii) Apply the variables from Aim 1 in a longitudinal study of PAH patients to determine which are most highly predictive of invasive hemodynamics and clinical outcomes;
iii) Based on the findings of Aims 1-2, a recommendation for standardization of echocardiographic assessment and analysis for patients with known or suspect PAH will be developed.
The study population will consist of 100 patients with known or suspected PAH, referred from the Duke Pulmonary Vascular Disease Center, and 120 age and sex matched healthy, normal controls. Patients enrolled in this study will receive prospective echocardiograms at three month intervals for up to nine months. PAH patients will undergo right heart catheterizations at initial enrollment and echocardiographic parameters will be validated against the invasive right heart measures. Clinical utility will be determined by correlations to responses to drug therapy, changes in symptoms, and/or catheterization hemodynamic measurements. The proposed PURE study is a sub-study of the NIH funded study entitled: Prospective validation of genomic signatures of chemosensitivity in NSCLC Standardize and validate the performance characteristics of the Affymetrix expression microarray platform for use in clinical decision making (Potti:1RO10CA131049-01). The goal of the parent study is to differentiate gene expression profiles in patients with idiopathic versus secondary PAH. As a result of this research, echocardiographic RV/RA and pulmonary hemodynamic parameters for the diagnosis and monitoring of patients with PAH will be improved through standardization, validation, and assessment of their clinical utility.2008 ASE Echo Investigator Award RecipientPreload Recruitable Stroke Work derived from Three Dimensional Echocardiographic Pressure: Volume Loop Analysis in Congenital and Pediatric Heart Disease
G. Hamilton Baker, Girish Shirali, Tim McQuinn, Michael Zile, Rickey Carter. Medical University of South Carolina, Charleston, SC

Project summary: Short term survival is no longer in doubt for most patients with congenital heart disease. Attention must now be directed towards protecting the health of growing myocardium presented with abnormal loading conditions in order to promote the best long term outcomes from catheter, surgical and pharmacologic interventions. To meet this goal, it becomes essential to accurately measure myocardial pump function, which has been out of the grasp of pediatric cardiologists. The clinical tools used in adult cardiology are often either not scaled to the size of the at-risk population (conductance catheters), are too invasive for parents to consent to, or are based on geometric/functional presumptions of the LV that have never been validated in the congenital heart disease population. In many respects the hearts of patients with congenital heart disease are fundamentally different – the active growth of the myocardium in infants and children, the abnormalities of loading and structure that result from congenital heart disease, and the goal of extending positive results throughout a normal 70 year lifespan are salient examples. It is therefore crucial to adapt the promise of 3D echocardiography to the measurement of ventricular function in this population. This research project proposes a new methodology for rapid, clinically feasible pressure•volume loop (PVL) analysis using 3D echocardiography. Research using PVL analysis has played a fundamental role in developing current concepts of cardiac pathophysiology and performance and 3D echo is a proven modality for clinical application. Most importantly, 3DE-PVL has the potential to become divorced from the geometric presumptions that invalidate most 2-D approaches in characterizing ventricular function of abnormal hearts. The ability to distinguish between altered ventricular loading conditions and impaired contractility would improve our ability to monitor patient status, determine effectiveness of drug therapy, and evaluate the benefits of surgical and catheter based interventions. The specific aims of this proposal are (1) to test the large-scale feasibility of a novel 3DE-PVL methodology, and (2) to assess myocardial contractility before and after percutaneous interventions using 3DE-PVL derived preload recruitable stroke work by both an invasive and non-invasive model. This methodology could provide clinical data not currently available concerning cardiac contractility and myocardial pump function. These indices could help to better identify, characterize, and serially follow myocardial pump dysfunction in these patients.
2008 ASE Echo Investigator Award RecipientComprehensive Evaluation of the Systemic Right Ventricle by Two-Dimensional Strain Echocardiography in Patients with D-Transposition of the Great Arteries: Impact on Outcomes
Randolph Martin, Andreas Kalogeropoulos, Wendy Book, Maria-Alexandra Pernetz, Michael McConnell, Vasliki Georgiopoulou, Stamatios Lerakis. Emory University Hospital, Atlanta, GA
Project summary: Surgical intervention, especially atrial switch repair, has substantially improved survival of patients with D-transposition of the great arteries (D-TGA), thus leading to a growing population of adult patients with systemic right ventricle (RV). Although the RV appears to tolerate functioning at systemic pressures in the short- to medium- term, >60% of D-TGA patients show moderate-to-severe RV dysfunction after 25 years of atrial switch. At present most patients with D-TGA are under 40 years of age. Since late survival after atrial switch shows an ongoing attrition rate, with the most frequent cause of death being systemic RV failure and sudden death, close follow-up of these patients is warranted. Despite its role in the prognosis of D-TGA, quantitative evaluation of systemic RV by echocardiography remains challenging because of complex geometry. This hampers our ability for early detection of RV dysfunction and reliable serial evaluation of the possible effects of medications and interventions. In addition, despite reports of successful application of cardiac resynchronization therapy (CRT) in D-TGA cases, the lack of a comprehensive means to evaluate dyssynchrony in the systemic RV prevents screening of D-TGA patients for CRT.
Two-dimensional strain (2DS) echocardiography (‘speckle tracking’) has been recently validated as a reliable method for myocardial deformation imaging, and has certain advantages in the evaluation of the systemic RV given the complex nature of this chamber. Indeed, our preliminary data in 27 D-TGA patients indicate that 2DS evaluation of the systemic RV is feasible and that global RV deformation parameters (strain, systolic and diastolic strain rate) have superior reproducibility and discriminative properties compared to conventional echocardiographic parameters. We also recently proposed a 2DS-based index of intra-ventricular dyssynchrony in the RV using a 6-segment model. In this proposal, we suggest the integration of 2Ds-derived global RV deformation parameters and dyssynchrony in the baseline echocardiographic evaluation of 50 patients with D-TGA. Since performance of the RV is key both to development of heart failure and arrhythmic events, we believe that objective measures of RV performance have the potential stratify risk among D-TGA patients. Based on recent literature data on the rate of hospitalizations, we anticipate that 1 year of follow up will provide the power to detect the effect of deformation parameters of outcomes, defined as hospitalization for cardiovascular causes, in this special population. We envision this project to lay the groundwork for wider application of 2DS echocardiography in the evaluation and follow-up of patients with D-TGA.
2007 ASE Career Development Award RecipientMechanisms of Diastolic Heart Failure after Myocardial Infarction: Relationship Between Extent of Myocardial Scarring, Infarct Location and Left Ventricular Relaxation and Stiffness
Benson Babu, Mario Garcia, Juan Badimon, Borja Ibanez, Juan Sanz. Mount Sinai Medical School, New York, NY
Project summary: Coronary artery disease is highly prevalent in patients with diastolic heart failure. Several functional and structural abnormalities, including abnormal calcium handling and ventricular remodeling have been implied in the pathophysiology of diastolic dysfunction in patients with coronary artery disease. Doppler echocardiography is the most useful clinical tool for the assessment of heart failure patients. However, the mechanisms by which ischemic injury leads to the development of Doppler echocardiographic abnormalities and their relation with the clinical presentation of heart failure are poorly understood. The objective of this proposal is to examine the relationship between the extent and location of ischemic injury and the development of left ventricular (LV) diastolic dysfunction. Acute myocardial infarction will be induced by either left anterior descending or circumflex coronary artery occlusion in 24 adult Yorkshire pigs. Doppler echocardiographic indices of diastolic function will be obtained and compared with the volume of myocardial scarring, as determined by gadolinium DTPA delayed enhanced (DE) cardiac magnetic resonance (CMR) and with the regional and global myocardial function. Our hypotheses are that: 1) LAD occlusion results in greater reduction of LV relaxation, compared to LCX occlusion, due to impairment of apical torsion and reduced apical suction; and 2) larger infarct size results in increased LV stiffness and development of Doppler restrictive filling.
2007 ASE Career Development Award RecipientCardiac Structure, Function, and Exercise Capacity in Competitive Athletes: A Prospective, Longitudinal Investigation of Endurance Athletes
Aaron Baggish1, Malissa Wood1, Michael Picard1, Adolph Hutter1, David Systrom1, James Januzzi1, Francis Wang2. 1Massachusetts General Hospital, Boston, MA; 2Harvard University Health Services, Cambridge, MA
Project summary: Observational reports of cardiovascular structure and function have demonstrated a high prevalence of adaptive abnormalities in athletic individuals. Referred to in aggregate as the “athlete’s heart”, these abnormalities include increased left ventricular wall thickness and cavity dimensions, increased left ventricular mass, increased left atrial volume, and altered diastolic function. Current characterization of cardiac structure and function in athletes relies largely on observational, cross-sectional data. Prospective and longitudinal studies examining the cardiovascular responses to sustained training are sparse and do not reflect recently developed echocardiographic techniques for the assessment of myocardial function. In addition, little is known about the relationship between cardiac measurements and exercise capacity both at baseline and following a period of sustained training. In an attempt to determine the impact of sustained training on cardiac structure and function and to examine the relationship between these parameters and exercise capacity, athletes partaking in competitive university sports will be studied and compared with age and gender matched controls. Athletes of both genders participating in endurance (isotonic cardiovascular stress) sports including rowing and long distance running will studied. Individuals will undergo focused medical and pre-participation training histories, standard 12-lead electrocardiography, echocardiographic examination, and cycle ergometry for the measurement of VO2max prior to the competitive season. Echocardiography will include measurement of standard two-dimensional variables, assessment of color-derived tissue Doppler indices, and calculation of both strain and strain rate. Detailed records of daily training volume, intensity, and sport specific performance results will be recorded. Finally athletes will undergo repeat electrocardiography, echocardiography, and VO2max testing at a pre-specified time to coincide with projected peak-season fitness (approximately 3 months of training). Data generated from the above protocol will allow for several important analyses. First, pre and post season electrocardiographic and echocardiographic parameters will be assessed for significant changes. Next, baseline measurement of cardiac structure and function will be compared to the results of VO2max testing to assess for significant correlations. Finally, pre and peak season cardiac measurements will be compared with VO2max data to identify an optimal non-invasive index for the serial assessment of exercise capacity. The potential applications of such findings are numerous.
2007 ASE Career Development Award RecipientEcho-Genomics: Identification of the Genetic Determinants of Left Ventricular Hypertrophy and its Pathophysiologic Consequences
Sanjiv Shah, Carole Ober, Roberto Lang. University of Chicago, Chicago, IL
Project summary: Increased left ventricular (LV) mass, measured with echocardiography, is a powerful predictor of adverse cardiovascular outcomes, including heart failure and death. Although we have some understanding of the genetic risk factors for left ventricular hypertrophy (LVH), prior studies have used imprecise electrocardiographic and M-mode echocardiographic data as measures of LV mass. Echocardiographic assessment of LVH and its consequences has advanced considerably with the advent of modalities such as real-time 3D echocardiography, tissue Doppler, and speckle tracking for strain and torsion analysis. With these advances in echocardiography, we now have the ability to provide comprehensive, sophisticated phenotypic measurements of LVH and its pathophysiologic consequences. Therefore, echocardiography is the optimal imaging tool for use in genetic studies of abnormal cardiovascular structure and function. Mirroring important advances in echocardiography, genomic science has also evolved remarkably. For the first time ever, we now have the ability to perform comprehensive genome-wide association studies that harness the power of analyzing nearly 500,000 different single nucleotide polymorphisms (SNPs) in order to determine which areas of the human genome give rise to the variation of traits measured with echocardiography such as LVH. We propose to utilize these rapid advances in echocardiography and genomics for a novel area of investigation: “Echo-Genomics”, by studying the genetic determinants of increased LV mass and its associated abnormalities in tissue velocity, strain, and torsion. Our hypothesis is that studying the genomics of LV mass will lead to the identification of novel genes and pathways across the entire human genome that predispose patients to LVH and its pathophysiologic consequences. We therefore propose the following specific aims:
1. Identify genes that influence echocardiography-derived LV mass by association mapping using the Affymetrix GeneChip Mapping 500K Array in the Hutterites, a communally-living, inbred, founder population in South Dakota.
2. Prospectively validate the association of genetic polymorphisms (identified in the Hutterites) with LV mass in the Chicago Echo-Genetics Study.
3. Test whether genetic polymorphisms identified in the Hutterites have an effect on tissue velocity, strain, and torsion in the Chicago Echo-Genetics Study.
The significance of our proposal is the ability to characterize the entire human genome though a genome-wide association study in order to determine how specific genes interact with each other to predispose to LVH, and then to test the effect of variation in these genes on sophisticated echocardiographic phenotypes in a large, outbred population.
2007 ASE Career Development Award RecipientEffect of Cardiac Resynchronization Therapy on Mitral Valve Geometry and LV Spatial Relationships
Jorge Solis-Martin, Judy Hung, Robert Levine, Mark Handschumacher. Massachusetts General Hospital, Boston, MAProject summary: This proposal aims to examine the effect of cardiac resynchronization therapy on mitral valve and annular geometry and left ventricular spatial relationships using 3D echocardiography as a physiologic tool. Cardiac resynchronization therapy (CRT) has emerged as an effective therapy for advanced heart failure in patients with systolic dysfunction and widened QRS duration, improving symptoms and decreasing mortality. CRT has been shown to reduce mitral regurgitation, however, the extent and mechanism of MR reduction is incompletely understood. The impact of cardiac resynchronization on the shape, size, and contraction pattern of the mitral annulus has not been determined, and could potentially be a strong modulator of MR severity. The central hypothesis of this study is that Cardiac Resynchronization Therapy results in favorable remodeling changes in mitral valve geometry and LV spatial relationships to restore normal mitral valve function and reduce mitral regurgitation. Specifically, CRT results in normalization of the saddle shape of the mitral annulus and mitral valve to left ventricle spatial relations resulting in reduction in leaflet tethering. These favorable remodeling changes result from decreases in LV volumes and improvements in LV contraction via increased LVEF and mechanical synchrony of contraction. This proposal aims to examine patients pre and post CRT (one, day, 3 months, 6 months and one year post CRT) to explore both acute and chronic remodeling effects CRT on mitral valve geometry and function. By better understanding the MV and LV remodeling changes that occur with CRT, this has the potential to better select patients who are more likely to benefit as well as lead to improvements in therapy for heart failure patients.

2007 ASE Career Development Award Recipient

Meta-Analysis Research Group in Echocardiography (MeRGE) Sub Analyses
Gillian Whalley1, Robert Doughty1, Allan Klein2. 1University of Auckland, Auckland, New Zealand; 2Cleveland Clinic Foundation, Cleveland, OH

Project summary: We have established an international collaboration (26 principle collaborators from 17 countries) to perform an individual patient meta-analysis evaluating the role of echocardiographic assessment of diastolic function in terms of prognosis in patients with heart failure (HF) and post acute myocardial infarction (AMI). We have merged data from 3540 HF and 3739 post AMI patients into what is essentially now two single, large patient cohorts. This has allowed us to study the independent predictors of outcome in these patients, with a particular emphasis on the relationship between severe diastolic dysfunction, in particular restrictive mitral filling (RFP), systolic function and all cause mortality. The main results of these analyses have been presented in abstract form at the World Congress of Cardiology (September 2006) and the American Heart Association (November 2006). Essentially, we have demonstrated that the presence of RFP is predictive of all-cause mortality in both patient cohorts and that this relationship is independent of systolic function and importantly RFP is a poor prognostic indicator at all levels of EF, including those with preserved systolic function.
We now propose to perform a number of hypothesis-driven sub-analyses which will provide further insight into what drives prognosis in these high risk patient groups. Several sub-analyses are able to be undertaken and these include, but are not restricted to, predicting HF admission, development of HF post AMI, other mitral filling patterns, the additive effect of left atrial size, and the presence of mitral regurgitation. We also propose to evaluate the clinical and echocardiographic factors that are associated with or predict the presence of RFP. The MeRGE collaboration will ultimately provide an excellent group of robust, unique papers that will help to direct the role of echocardiography for prognosis in these two high risk groups of patients. The diagnostic role of echocardiography has been well established for many years and the role of echocardiography in aiding prognosis and thus management is emerging as an important and clinically useful role for extending echocardiography practice.2007 ASE Cardiovascular Sonographer Research Award RecipientA Standardized Technician Facilitated Protocol for use in V-V Optimization of Biventricular Pacemakers for Cardiac Resynchronization Therapy
Samantha Buckley, Martin Goldman, W. Lane Duvall. Mount Sinai Medical Center, New York, NY

Project summary: Cardiac resynchronization in patients with symptomatic heart failure has shown to improve quality of life scores, NYHA functional class, exercise capacity, and ejection fraction as well as decrease left ventricular volume, mitral regurgitation, and reduce heart failure hospitalizations and all cause mortality. However, up to 25-30% of patients who receive cardiac resynchronization therapy (CRT) based on current guidelines fail to respond.1 Amelioration of heart failure by biventricular pacing is contingent on rectifying the electrical/mechanical dyssynchrony present in the diseased heart. Current echocardiographic dyssynchrony parameters, specifically M-mode, Doppler tissue, and strain are susceptible to variability because they evaluate only a small portion of the left ventricle and are prone to significant intra-patient variability. 3D echocardiography facilitates assessment of the entire left ventricle simultaneously and may overcome some of the limitations of other echocardiographic measurements. Because device implantation and its follow-up are costly, a formalized method of biventricular pacemaker optimization (V-V timing) using not only currently available methods of idealizing pacemaker settings, but also 3D measures of regional time-volume curves would be valuable. The changes in the measures of left ventricular dyssynchrony at various V-V timing settings during biventricular pacemaker optimization will be prospectively systematically recorded to determine which measurements of dyssynchrony correlate most strongly with short term echocardiographic defined response to cardiac resynchronization therapy (stroke volume and ejection fraction). We propose to establish a technician facilitated protocol to assess various pacemaker parameter settings to optimize CRT. We will establish and implement a protocol that incorporates current echo Doppler methods as well as 3D analysis to determine the appropriate pacing settings.
2007 ASE Cardiovascular Sonographer Research Award RecipientFunctional Measurements of Heart Failure and Clinical Outcomes after Cardiac Resynchronization Therapy: Correlation with Echocardiographic-derived Indices of Left Ventricular Function
Alan Waggoner, Victor Davila-Roman, Lisa de las Fuentes, Marye Gleva. Washington University School of Medicine, St. Louis, MO
Project summary: Patients with medically-refractory heart failure (HF) symptoms, left ventricular (LV) ejection fraction ≤ 35%, and an interventricular conduction delay (i.e., electrocardiographic QRS duration ≥ 130 ms), are now considered for cardiac resynchronization therapy (CRT). Functional measurements including the New York Heart Association (NYHA) classification, Minnesota Living with Heart Failure scores (i.e., QOL), and the 6-minute walk distance (6WT) are used to determine the severity of HF symptoms, identifying candidates for CRT, and to determine the clinical response after device implant. Although CRT improves functional measurements in 70-80% of HF patients, it is unclear whether these correlate with changes in echocardiographic measurements of LV volumes and systolic performance and/or predict clinical outcomes. Furthermore, the relationships between functional measurements and echocardiographic indices of LV diastolic function have not been studied in HF patients with severe LV systolic dysfunction. The hypothesis of this research proposal is that functional measurements of HF correlate with echocardiographic-determined indices of LV diastolic function prior to, and early after CRT, and this combined approach will predict clinical outcome events (i.e., hospital re-admission for heart failure exacerbation, cardiac-related death, or transplant) at long-term follow-up after CRT. The specific aims of this study are:
1. To determine whether functional measurements of HF severity correlate with echocardiographic indices of LV systolic and/or diastolic function.
2. To determine whether functional measurements of HF severity and/or echocardiographic indices of LV function, at baseline and at early follow-up, are predictive of clinical outcomes (i.e., re-hospitalization for HF and/or cardiac related death or transplant) at long-term follow-up after CRT.
The proposed research is a prospective study of HF patients that are evaluated by functional and echocardiographic measurements of LV systolic and diastolic function prior to CRT, at early follow-up (i.e., 4 month), and at intermediate follow-up (i.e, 12 months) after CRT to predict clinical outcomes. The primary end points (i.e., hospital re-admission for heart failure exacerbation, cardiac-related death, or transplant) will be assessed at each of these follow-up intervals and after 2 years of CRT for comparison to the functional and echocardiographic measurements. It is postulated that the echocardiographic indices will provide better prognostic value, compared to functional measurements of HF, to predict long-term clinical outcomes. Furthermore, the results of this study would support the necessity of performing echocardiography before and after CRT to identify Non-responders who may require additional intervention(s) to improve their clinical outcomes.
2007 ASE Echo Investigator Award RecipientCorrelation Between Changes in Functional Mitral Regurgitation and Diastolic Dysfunction and Changes in BNP Level and Wall Stress During Hospitalization for Heart Failure and their Significance in Predicting Outcome
Karthikeyan Ananthasubramaniam, Mohammed Abu-Mahfouz, Mohsin Alam, David Lanfear, James McCord, John Schairer. Henry Ford Hospital, Detroit, MI
Project summary: Acutely decompensated heart failure (HF) is a major public health problem with approximately one million hospitalizations per year. Though decompensated HF can be treated effectively with appropriate medical therapy, adverse future events remain significant. Identifying variables that characterize higher risk patients is desirable since it allows more intensive therapy and follow up for those patients. Systolic HF is usually associated with some degree of functional mitral regurgitation (FMR) and diastolic dysfunction (DD). Patients with HF and history of pulmonary edema show significant increase in FMR with exercise. Worsening FMR leads to increased pulmonary vascular pressure which may lead to acute dyspnea. Pharmacologic reduction in filling pressures and systemic vascular resistance leads to reduction in FMR. Significant FMR at rest and significant increase in FMR with exercise are both associated with increased mortality. DD is expected to improve with medical therapy during hospitalization as well. At time of discharge, DD with a restrictive filling is associated with increased mortality and HF readmissions while a pseudonormal pattern is associated with increased HF readmissions. FMR and DD are associated with increased BNP level. Elevated BNP level at time of discharge is a significant predictor of adverse events . BNP level correlates with reduced ejection fraction (EF) and elevated filling pressures. There is however significant variability in BNP level between patients with the same degree of left ventricular dysfunction and filling pressures. BNP release is stimulated by increased wall stress and its correlation with end-diastolic wall stress (EDWS) is robust (r=0.89) when compared to other parameters of HF like EF and filling pressures. This suggests EDWS may be an important prognostic factor in HF and may explain a portion of the variability in BNP levels. To our knowledge, the prognostic value of EDWS is not determined. This study will evaluate patients admitted with HF with depressed EF who receive standard therapy in a tertiary medical center. TTE with contrast will be performed at time of admission and discharge with evaluation of FMR, DD and EDWS at both times. BNP level will be determined at time of admission and discharge as well. Improvement in FMR and DD is expected to be associated with an improvement in EDWS and BNP level. Significant FMR, DD and EDWS at time of discharge and persistence of significant FMR and DD despite medical therapy during hospitalization are expected to identify a group of patients with poor outcome.
2007 ASE Echo Investigator Award RecipientReal-Time Three Dimensional Echocardiographic Quantification of Myocardial Perfusion
Victor Mor-Avi1, Enrico Caiani2, Patrick Coon1, Elizabeth Holper1, Roberto Lang1. 1University of Chicago, Chicago, IL; 2Politecnico di Milano, Milan, Italy
Project summary: With the recently developed improved contrast agents and contrast-targeted imaging techniques, the addition of perfusion imaging to the traditional assessment of left ventricular (LV) wall motion has been shown to improve the accuracy of echocardiographic diagnosis of ischemic heart disease. Our group has been actively involved in the development of quantitative methods for the evaluation of LV function and myocardial perfusion from 2D echocardiographic images. It is agreed however that the 2D nature of this methodology remains a stumbling block for the assessment of both perfusion and function, since it relies on partial information contained in specific cross-sectional planes. While the use of 3D reconstruction from multiple planes allowed more accurate assessment of LV function, this time-consuming and artifact-prone methodology is impractical for volumetric quantification of myocardial perfusion, which relies on 3D imaging of dynamic changes in myocardial contrast. The recently developed real-time 3D echocardiographic (RT3DE) technology obviates these limitations. Accordingly, we have focused our work on extending the quantitative tools we have previously applied to 2D images to RT3DE images. Our techniques for 3D assessment of global and regional LV function, based on the detection of endocardial surface, have since become standard and are available today as part of commercial imaging equipment. More recently, we have developed and tested in different animal models a technique for volumetric quantification of myocardial perfusion from contrast-enhanced RT3DE datasets based on analysis of myocardial contrast inflow. The feasibility of this approach was demonstrated in a small group of human subjects. This proposal is geared towards testing the clinical utility of RT3DE-based quantification of myocardial perfusion in a larger group of patients. Our specific aims are: (1) to establish normal values of volumetric measurements of myocardial perfusion at rest and during vasodilator stress testing, and (2) to validate volumetric perfusion measurements against quantitative coronary angiography reference, and (3) to test the feasibility of objective noninvasive RT3DE-based diagnosis of coronary artery disease and optimize this methodology by ROC analysis. The proposed studies will be carried out in three separate protocols designed to address these goals by studying 40 normal subjects and 90 patients with suspected coronary artery disease referred for coronary angiography. This study well matches our strengths and expertise, which empower us with the unique ability to achieve the to achieve the goals that need to be achieved for this technique to turn into an accurate and clinically useful diagnostic tool.