- Diego Bellavia, MD, Mayo Clinic, Rochester, MN – “Combined 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” – Read the abstract
- Jacob P. Dal-Bianco, MD, Massachusetts General Hospital, Boston, MA – “Mitral Valve Leaflet Area Quantification: A 3D Echo – Histology Study of Mitral Valve Adaptation in Ischemic Mitral Regurgitation” – Read the abstract
- Hiroko Fujii, MD, St. Michael's Hospital, Toronto, ON, Canada – “Molecular Imaging of Stem Cell Therapy Using Targeted Contrast Ultrasound” – Read the abstract
- Diego Moguillansky, MD, University of Pittsburgh Medical Center, Pittsburgh, PA – “Contrast Ultrasound for Quantification of Plaque Neovascularization: A New Method to Identify Vulnerable Plaque” – Read the abstract
- Serena Michelle Bierig, MPH, RDCS, FASE, Saint Louis University, Saint Louis, MO – “The Effect of Right Ventricular Pacing Site on Measures of Mechanical Ventricular Dyssynchrony” – Read the abstract
- Jose Daniel Rivera, RCS, Duke University Medical Center, Durham, NC – “Pulmonary Response by Echocardiography: The PURE Study” – Read the abstract
- G. Hamilton Baker, MD, Medical University of South Carolina, Charleston, SC – “Preload Recruitable Stroke Work derived from Three Dimensional Echocardiographic Pressure: Volume Loop Analysis in Congenital and Pediatric Heart Disease” – Read the abstract
- Randolph P. Martin, MD, FASE, Emory University Hospital, Atlanta, GA – “Comprehensive Evaluation of the Systemic Right Ventricle by Two-Dimensional Strain Echocardiography in Patients with D-Transposition of the Great Arteries: Impact on Outcomes” – Read the abstract
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.
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.
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.
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 anin 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.
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.
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.
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.
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.
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.