- Benson A. Babu, MD, Mount Sinai Medical School, New York, NY – Mechanisms of Diastolic Heart Failure after Myocardial Infarction: Relationship Between Extent of Myocardial Scarring, Infarct Location and Left Ventricular Relaxation and Stiffness – Read the abstract
- Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, MA – Cardiac Structure, Function, and Exercise Capacity in Competitive Athletes: A Prospective, Longitudinal Investigation of Endurance Athletes – Read the abstract
- Sanjiv J. Shah, MD, University of Chicago, Chicago, IL – Echo-Genomics: Identification of the Genetic Determinants of Left Ventricular Hypertrophy and its Pathophysiologic Consequences – Read the abstract
- Jorge Solis-Martin, MD, Massachusetts General Hospital, Boston, MA – Effect of Cardiac Resynchronization Therapy on Mitral Valve Geometry and LV Spatial Relationships – Read the abstract
- Gillian A. Whalley, PhD, University of Auckland, Auckland, New Zealand – Meta-Analysis Research Group in Echocardiography (MeRGE) Sub Analyses – Read the abstract
- Samantha J. Buckley, BS, RDCS, Mount Sinai Medical Center, New York, NY – A Standardized Technician Facilitated Protocol for use in V-V Optimization of Biventricular Pacemakers for Cardiac Resynchronization Therapy – Read the abstract
- Alan D. Waggoner, MHS, RDCS, Washington University School of Medicine, St. Louis, MO – Functional Measurements of Heart Failure and Clinical Outcomes after Cardiac Resynchronization Therapy: Correlation with Echocardiographic-derived Indices of Left Ventricular Function – Read the abstract
- Karthikeyan Ananthasubramaniam, MD, FASE, Henry Ford Hospital, Detroit, MI – Correlation 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 – Read the abstract
- Victor Mor-Avi, PhD, University of Chicago, Chicago, IL – Real-Time Three Dimensional Echocardiographic Quantification of Myocardial Perfusion – Read the abstract
Benson A. Babu, MD
Mount Sinai Medical School, New York, NY
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.
Aaron L. Baggish, MD
Massachusetts General Hospital, Boston, MA
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.
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.
Jorge Solis-Martin, MD
Massachusetts General Hospital, Boston, MA
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.
Gillian A. Whalley, PhD
University of Auckland, Auckland, New Zealand
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.
Samantha J. Buckley, BS, RDCS
Mount Sinai Medical Center, New York, NY
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.
Alan D. Waggoner, MHS, RDCS
Washington University School of Medicine, St. Louis, MO
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.
Karthikeyan Ananthasubramaniam, MD, FASE
Henry Ford Hospital, Detroit, MI
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.
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 goals that need to be achieved for this technique to turn into an accurate and clinically useful diagnostic tool.