Project Summaries

ASE Funded Research – Project Summaries

2012 ASE Foundation Career Development Award Recipient
Determining Mechanisms of Right Ventricular Pacing-Induced Cardiac Dysfunction Using Speckle Tracking Strain Echocardiography and Impact on Therapy
Moha Ah, David Schwartzman, John Gorcsan. University of Pittsburgh, Pittsburgh, PA
Project summary: Right ventricular (RV) pacing is life-saving for patients suffering from complete atrioventricular (AV) block. Although many with normal left ventricular (LV) function tolerate chronic RV pacing well, an important subset, estimated to be 25-30%, have deterioration of ejection fraction (EF) and onset heart failure. These patients require an upgrade to cardiac resynchronization therapy (CRT). Importantly, a means to predict which patients will have deterioration of LV function has not been found. Accordingly, this proposal is to address two important aims: Specific Aim # 1 will test the hypothesis that a specific dyssynchronous activation pattern can be identified by speckle tracking strain in patients with RV pacing associated deterioration of LV function. Our compelling preliminary data on 27 patients using speckle tracking strain echocardiography has revealed a specific pattern of early apical septal mechanical activation, followed by basal delay early after RV pacing in pacemaker dependent patients who start with normal EF but have subsequent LV deterioration. In contrast, pacemaker patients who retain preserved EF have a uniform longitudinal strain pattern. Our hypothesis is that in patients whom the RV lead does not “plug in” to the native Purkinje system, a dyssynchronous mechanical activation pattern induces subsequent LV functional deterioration. We believe that RV paced patients with uniform electrical-mechanical activation without dyssynchrony have long term preservation of LV function. To support specific aim #1, 150 AV node ablation pacemaker-dependent patients will be analyzed by speckle tracking longitudinal strain from digital DICOM data (TomTec.Corp) to further define the incidence and specific characteristics of dyssynchrony patterns associated with deterioration of LVEF. Specific aim #2 is to test the hypothesis that induction of LV dysfunction and heart failure by RV pacing can be prevented by using a dyssynchronous strain mechanical activation pattern as a marker to identify which patients should have RV lead repositioned or CRT at the outset. This hypothesis will be objectively tested prospectively in 100 patients who will become pacemaker dependent with AV node ablation or complete heart block using two dimensional and three-dimensional speckle tracking strain (Toshiba, Corp). Acute dyssynchrony studies will be perfor in the electrophysiology laboratory with results compared to a matched control group of similar RV paced patients with 6 and 12 month follow-up clinical and EF data. This echocardiographic strain study has potential to directly influence patient care and improve human health by preventing deterioration of LV function and heart failure in pacemaker-dependent patients.
2012 ASE Foundation Career Development Award Recipient
Validation of Non-Invasive Indices of Contractility in Children
Shahryar M. Chowdhury, Girish Shirali, George Hamilton Baker, Paul Nietert, Anthony Hlavacek. Medical University of South Carolina, Charleston, SC
Project summary: Advances in ical and surgical therapy have advanced to the point where even children with the most severe heart disease are living well into middle age. Focus has shifted from preventing mortality to preserving myocardial function. In order to protect myocardial contractility from abnormal loads and morphological adaptations we must be able to accurately measure it. Measurement of myocardial function is currently done qualitatively or using measurements that have proven to be unreliable and load dependent. The gold-standard measurements of myocardial function are obtained through pressure-volume loop analysis. With the development of pediatric-sized conductance catheters we can now perform these analyses in children. The proposed study will compare non-invasive measures of function, such as those derived from non-invasive pressure-volume loop (PVL) analysis and 3D-speckle-tracking echocardiography, against the gold-standard measures of contractility.

Specific Aim # 1: Assess agreement and correlation of non-invasively derived indices of contractility against invasive measures of contractility obtained via conductance in children
Specific Aim # 2: Assess the application and provide reference values for these same non-invasive indices in a large cross-sectional pediatric/CHD population.

There will be two arms to this study, 1) validation arm and 2) outpatient arm. In the validation arm, patients with biventricular anatomy undergoing retrograde left heart catheterization in the pediatric catheterization laboratory will be enrolled prospectively to have PVL analysis of the left ventricle. Measures of correlation between invasive and non-invasive measures of contractility will then be calculated. We estimate 30 subjects in this arm with subgroup of 10 patients with left sided obstructive lesions. The second, outpatient arm of patients will be recruited prospectively from our pediatric cardiology outpatient clinic. All patients with a normal echocardiogram will be approached for enrollment. We expect to enroll a minimum of 200 patients into this arm. We will propose reference values based on these results and assess for inter- and intra-observer variability.

The ideal tool for measuring myocardial contractility in children would be non-invasive, quick, load independent, with low intra- and inter-observer variability, and be validated invasively in children against the gold standard. The indices examined in the proposed study have the potential to meet these criteria and could be moved from the laboratory to the bedside. Applying these newly validated measures could significantly advance our ability to understand the effects of pharmacologic, catheter, and surgical interventions on ventricular mechanics in pediatric cardiology.

2012 ASE Foundation Cardiovascular Sonographer Research Award Recipient
Myocardial Performance at Rest and During Exercise in Heart Failure with Preserved Ejection Fraction: Speckle Tracking Echocardiography – One piece of the puzzle.
Charlie E. Luoma1, Monique A. Freund1, Larry C. Casey1, Hector R. Villarraga2. 1Mayo Clinic Health System – Franciscan Healthcare, La Crosse, WI;2Mayo Clinic, Rochester, MN
Project summary: Background: Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases [1]. The hallmark limitation in this population is exercise intolerance [2-4], but the majority of clinical investigations are currently completed at rest. Moreover, exercise training has been shown to improve diastolic function in patients with HFpEF [5] while pharmacological therapy alone has not [6]. Further evaluation of patients with HFpEF during exercise will yield more insight into mechanisms of the condition as well as possible therapeutic strategies.

Speckle tracking echocardiography (STE) has the potential to identify myocardial mechanisms by which left ventricular (LV) function is impaired. Furthermore, STE may show by which mechanism LV function improves following exercise training [7]. Myocardial dysfunction in HFpEF involves both systolic and diastolic abnormalities [3, 7, 8]; therefore, this investigation will attempt to quantify contraction and relaxation changes at rest and during submaximal exercise using STE. Moreover, we will assess changes in strain (S) and strain rate (SR) following a structured clinical exercise program.
Methods: 25 Patients with stable HFpEF referred for a clinically indicated transthoracic echocardiogram and with optimized ical therapy will be compared to 25 healthy controls recruited from the community. A symptom limited cardiopulmonary exercise test (CPX) will be completed on an upright cycle ergometer (Corival, Medical Graphics) to determine aerobic capacity, oxygen-pulse slope, and ventilatory threshold. Subjects and controls will then complete CPX/echo at 25 watts and their personal ventilatory threshold while in the optimal ultrasound imaging position on a tilting table cycle ergometer (Ergoline 1200) to acquire STE, LV volumetrics, and diastolic function data with exercise. The maximal CPX and submaximal CPX/Echo will be repeated in the HFpEF group following 12 weeks of clinical exercise training (CET). All STE data will be analyzed offline using Syngo velocity vector imaging (VVI) software (Siemens Healthcare). Quality of life in the HFpEF group will be assessed pre and post training through use of the Minnesota Living with Heart Failure Questionaire (MLWHFQ).
2011 ASE Foundation Career Development Award Recipient
Comparison of Two Dimensional and Real-Time Three Dimensional Echocardiography with Cardiovascular Magnetic Resonance Imaging in Determining Predictors of Clinical Worsening in Patients with Pulmonary Arterial Hypertension
Benjamin Freed, Mardi Gomberg-Maitland, Victor Mor-Avi, Amit Patel, Roberto Lang. University of Chicago Medical Center, Chicago, IL
Project summary: Despite the advent of multiple new therapies in the last decade, approximately 15% of patients with pulmonary arterial hypertension (PAH) will die in one year. Contemporary prognostic scores, which include a variety of independent predictors of survival, attempt to risk stratify these patients so that the proper treatment can be given at the appropriate time. Since the right heart plays an integral part in the disease process of PAH, its structure and/or function may provide potential prognostic information. However, because the right heart is particularly challenging to assess with two-dimensional echocardiography (2DE), the only imaging parameter included in these scores is the presence of pericardial effusion.

In 2010, the American Society of Echocardiography (ASE) published guidelines for the optimal assessment of the right heart using a variety of 2DE parameters. While some of these parameters provide prognostic information in patients with PAH, there is no direct comparison between all recommended variables for assessing the right heart. Although real-time three dimensional echocardiography (RT3DE) and cardiovascular magnetic resonance (CMR) have proven to be more accurate and reproducible in measuring the right ventricle than 2DE, little data exists as to their role in predicting outcomes in patients with PAH. We, therefore, hypothesize that direct, three dimensional measurements of right ventricular size and function, such as those provided by RT3DE and CMR, will provide the most powerful independent imaging-based predictors of poor outcomes.

This study aims to test this hypothesis by prospectively enrolling patients with PAH to undergo 1) a comprehensive 2DE and RT3DE evaluation; 2) a CMR study; 3) laboratory tests including creatinine and NT-proBNP; and 4) a six minute walk test within a 24-hour time frame. Patients will be tracked monthly for the occurrence of the primary endpoint of time to clinical worsening (all-cause mortality, PAH-related hospitalization, and lung transplantation). The reproducibility and prognostic capability of all ASE-recommended 2DE parameters will be compared to those of RT3DE and CMR right ventricular measurements in order to determine which imaging modality is best at providing independent predictors of poor outcomes in this patient population. The significance of our study is that it provides a necessary step to showing that cardiovascular imaging provides important prognostic data in patients with PAH that will enhance the already established non-imaging data and help in improving patient outcomes.

2011 ASE Foundation Career Development Award Recipient
The use of strain techniques and 3D echocardiography in the diagnosis of subclinical cardiotoxicity in breast cancer patients following treatment with anthracycline and trastuzumab chemotherapy
Timothy Tan, Michael Picard, Marielle Scherrer-Crosbie. Massachusetts General Hospital, Boston, MA
Project summary: Left ventricular (LV) dysfunction is a major limitation of breast cancer treatments. Echocardiography is used to monitor cardiac function in chemotherapy-treated patients, however, conventional approaches currently used such as LV ejection fraction may not detect early LV dysfunction. Recently, myocardial strain and strain rate measured using tissue Doppler imaging (TDI) have been shown to be sensitive markers of LV function in cardiac pathologies. Strain rate in particular appears to accurately reflect myocardial contractility. The role of these parameters in the follow-up of patients treated by chemotherapy has not been investigated and will be explored in this research proposal.

Our group has validated 2D strain echocardiographic indices in an animal model of chemotherapy-induced cardiotoxicity. While 2D strain and strain rate assessments provide better sensitivities in the detection of subclinical LV dysfunction post chemotherapy compared to conventional echocardiographic techniques, it is still hampered by the limitations associated with imaging within a 2 dimensional plane. We propose that the utilization of 3D strain and strain rate assessments would significantly improve the sensitivities in the detection and assessment of subclinical cardiac dysfunction in individuals prior to and post chemotherapy.
We will study patients with HER2 positive breast cancer treated with anthracyclines and tratsuzumab. The first aim of this proposal is to detect subclinical LV dysfunction earlier than conventional parameters. The second aim is to identify patients at high-risk for heart failure prior to chemotherapy treatment.

We propose the following hypotheses: 1) Myocardial strain and strain rates will differ significantly pre and post treatment with chemotherapy. Myocardial deformation patterns are also likely to reach lower peak values or demonstrate significant changes following chemotherapy. 2) Myocardial strain and strain rates will be reduced in individuals with other pre-existent cardiac comorbidities which would place them at increased risk of developing cardiotoxicity if treated with known cardiotoxic chemotherapeutic agents such as anthracyclines or trastuzumab. Women who can be identified as being at high risk of cardiac toxicity, or who begin to show early signs of it, could be treated with alternative chemotherapy regimens and may benefit from increased cardiac monitoring or preventive cardiac treatments. The development and validation of 3D strain echocardiography protocol in this setting would provide us with an invaluable noninvasive diagnostic tool to allow us to characterize the patients most susceptible to developing chemotherapy-induced cardiotoxicity and to increase our understanding of heart failure associated with cancer treatment potentially helping to decrease its morbidity and mortality.

2010 ASE Foundation Career Development Award Recipient
Left Ventricular Torsion in the Healthy Heart and in Common Forms of Left Ventricular Hypertrophy: Defining Reference Values and the Response to Hemodynamic Stressors
Rory Weiner, Michael Picard, Aaron Baggish. Massachusetts General Hospital, Boston, MA

Project summary: Left ventricular (LV) rotation plays an important role in LV contraction and relaxation. This rotation occurs due to contraction of obliquely oriented myocardial fibers and is characterized by rotation of the LV apex and base in opposite directions.The net difference between this counter-directional rotation is left ventricular torsion (LVT). In addition to LVT, subsequent untwisting during early diastole is an important determinant of LV filling.

Magnetic resonance imaging (MRI) has been the traditional imaging modality used to measure LVT,although speckle tracking echocardiography (STE) has recently emerged as an attractive alternative. However, there is large variability in reported LVT values in subjects of similar age,which has limited the clinical application of this technology. There are several potential explanations for this variability, including variability due to technical / measurement factors or variability due to physiological factors.

Our group has recently developed novel techniques for the standardization of LVT and untwisting rate (UTR) imaging using STE and has begun to apply this to clinically relevant questions. In the current proposal we aim to apply these techniques to measure LVT and UTR in healthy individuals and in subjects with clinically relevant forms of left ventricular hypertrophy (LVH), including hypertrophic cardiomyopathy (HCM), hypertensive LVH, and exercise-induced LVH. Assessment of LVT and UTR will be perfor under resting conditions and during exposure to the cardinal hemodynamic stresses of volume (large volume normal saline infusion) and pressure (isometric hand grip testing).
We propose the following hypotheses: 1) LVT and UTR will differ significantly between healthy individuals and those with LVH; 2) LVT and UTR will differ significantly across the different etiologies of LVH; 3) LVT and UTR will both demonstrate significant load dependence and the magnitude of this load dependence will be a function of LV geometry. As such, the proposed work has the potential to advance the study of LVT and UTR by utilizing STE with torsion-specific imaging criteria to define reference values in healthy individuals as well as subjects with common clinical forms of LVH. Furthermore, assessment of changes in LVT and UTR with volume and pressure challenges will clarify the degree of load dependency of LV twist mechanics in these different subject populations. Results from this work will facilitate the clinical application of STE-derived LVT and UTR measurements.

2010 ASE Foundation Career Development Award Recipient

Analysis of Regional Myocardial Strain and Vortical Flow Dynamics as Predictors of Left Ventricular Remodeling after Infarction
Ben Lin, Albert Sinusas. Yale University, New Haven, CT

Project summary: Left ventricular (LV) remodeling after myocardial infarction (MI) is a leading cause of the development of chronic heart failure. Transmural myocardial injury is correlated with higher rates of pathologic LV remodeling than non-transmural injury. Echocardiographic myocardial strain and strain rate imaging have been used to determine the extent of MI, but there is limited information related to using these parameters to predict LV remodeling after acute MI.

Intracavitary vortical flow patterns have been shown to be altered in diseased hearts during LV filling and may be associated with decreased cardiac pumping efficiency. However, little is known about temporal changes in intracavitary flow patterns in relation to changes in regional myocardial strain or LV remodeling.

Using echocardiography in chronic canine models of transmural and non-transmural MIs, we propose studies with the following specific aims:

1. Test the hypotheses that early regional myocardial strain measurements after MI are related to infarct transmurality and are predictive of late LV remodeling. These hypotheses will be tested by comparing estimates of radial, circumferential and longitudinal strains from 2D speckle tracking with serial changes in LV geometry.
2. Test the hypotheses that intracavitary vortical flow patterns after MI are related to infarct transmurality and are predictive of late LV remodeling. We will compare 2D Doppler and contrast speckle tracking measurements of velocities and vorticity parameters (including circulation, sphericity index and vortex formation time) with serial changes in LV geometry.
3. Determine if combining measurements of regional myocardial strain and vortical flow dynamics after MI provides any incremental value in predicting LV remodeling.

Significance: These studies aim to determine the relevance of biomechanical parameters related to strain and blood flow for early prediction of the occurrence of pathologic LV remodeling.