- Miguel Chaput, MD, Massachusetts General Hospital, Boston, MA – Impact of Papillary Muscle Repositioning Therapy on Ventricular Remodeling in Ischemic Mitral Regurgitation – Read the abstract
- Josef Korinek, MD, Mayo Clinic, Rochester, MN – Association of Myocardial Functional Heterogeneity with Impairment of Energy Metabolism in Acute Ischemia for Estimation of Injury and Reperfusion Functional Recovery – Read the abstract
- Glen Miske, DO, University of Pittsburgh, Pittsburgh, PA – Quantitative Echocardiographic-Guided Lead Placement for Improved Response to Cardiac Resynchronization Therapy – Read the abstract
- Gila Perk, MD, NYU School of Medicine, New York, NY – Use of Echocardiography in the Evaluation of Chest Pain in the Emergency Department – Read the abstract
- Allen Borowski, RDCS, The Cleveland Clinic Foundation, Cleveland, OH – Tissue Doppler Assessment of Right Ventricular Performance in Acute Heart Failure (TARVA) Study – Read the abstract
- Sandra Witt, RDCS, FASE, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH – Utility of Ultrasound Biomicroscopy in Aortic Valve Development and Disease Progression – Read the abstract
- Pamela Douglas, MD, FASE, Duke University, Durham, NC – Differential Effects of Aerobic and Resistive Exercise on Diastolic Function – Read the abstract
- Colin Phoon, MD, FASE, NYU School of Medicine, New York, NY – In Vivo Imaging of the Evolution of Cardiac Malformations in the Mouse Embryo – Read the abstract
- Teresa Tsang, MD, Mayo Clinic, Rochester, MN – Echo-guided Intervention to Lower Stroke Risk: A Randomized Double Blind Pilot Study – Read the abstract
Miguel Chaput, MD
Massachusetts General Hospital, Boston, MA
Mitral regurgitation (MR) occurs in 25% of patients after myocardial infarction and doubles late mortality. Ventricular remodeling is thought to be partly responsible, but whether this process is driven by the infarction or by mitral regurgitation is debated.
Prior 3D echo work has established the fundamental role of mitral leaflet tethering by displaced papillary muscles (PMs) as the cause of ischemic MR, leading to a new procedure that realigns the PMs by external constraint from an adjustable epicardial patch. How this maneuver affects the progression of global LV remodeling remains to be determined.
The central hypothesis of this study is that PM repositioning in the context of ischemic MR not only reduces regurgitation but limits the progression of global ventricular remodeling in non-infarcted zones.
An infero-posterior myocardial infarction will be created in 18 sheep by ligation of two circumflex obtuse marginal coronary artery branches, previously shown to cause moderate ischemic MR over 8 weeks. Three groups (n=6 each) will then be created. A treatment group will have an inflatable epicardial patch placed over the infarct zone via thoracotomy. This patch will be inflated with saline under echo guidance to reposition the papillary muscle and abolish MR. One control group will undergo sham surgery at 8 weeks for epicardial 3D echo imaging, LV hemodynamics and biopsies. A second control group will be treated with prosthetic mitral valve replacement. All sheep will then be followed for an additional 12 weeks, followed by data acquisition. At all stages, biopsies will be taken from infarct, border, and non-infarcted zones. Comparing the groups treated by patching versus valve replacement will test whether patching reduces progressive LV remodeling to a greater extent than simply eliminating MR with a prosthesis. We will also test whether papillary muscle repositioning by patch placement remains effective over 3 months.
LV remodeling will be quantified at several levels: LV size and systolic function by 3D echo, regional strain by tissue Doppler, and elastance by sonomicrometry, to be correlated with tissue measures of calcium handling, and molecular markers of hypertrophy, apoptosis, and matrix turnover.
This project will highlight two roles of echocardiography: as a key technique for guiding cardiac interventions that are less invasive, and as a quantitative approach for studying ventricular remodeling and its consequences for mitral valve function. It will provide the applicant, a cardiac surgeon, an opportunity to develop a career involving echocardiographic research in the operating room.
Josef Korinek, MD
Mayo Clinic College of Medicine, Rochester, MN
Acute myocardial ischemia is primarily an energy-metabolic event where energy stores are depleted. Current echocardiographic segmental analyses of ischemic myocardium are limited to assessment of entire wall thickness. And yet, transmural functional heterogeneity and its changes during acute ischemia could provide insights into the stage of ischemia and severity of the energy-metabolic disorder and estimate post-reperfusion functional recovery. We propose to quantitatively characterize functional changes, measured selectively in subendocardial and subepicardial layers, without a stress test, in an experimental pig model of persisting acute ischemia due to left anterior descending coronary artery occlusion and link progression of these changes to the underlying alterations of energy metabolism and injury. We hypothesize that changes in subendocardial and subepicardial functional heterogeneity – as acute ischemia continues – correlate with a decrease in energetic turnover in these layers. We propose to test the hypothesis through the following 3 aims.
Aim 1: Measure subendocardial and subepicardial velocities and strains and compare their values to levels of high-energy phosphates at time points of acute persisting ischemia (30 pigs)
Here, we will selectively characterize the functional response of myocardial layers to progressive ischemia analyzed in subgroups of animals after 10, 30, 90, and 180 minutes of coronary occlusion and associate this response with decrease in levels of high-energy phosphates at those time intervals.
Aim 2: Quantitatively assess functional changes in subendocardial and subepicardial layers during the course of 1-hour reperfusion following a short-term (~10 minute) coronary occlusion (6 pigs)
Aim 3: Quantitatively assess functional changes in subendocardial and subepicardial layers during the course of 1-hour reperfusion following a long-term (~90 minute) coronary occlusion (6 pigs)
In these two aims, we study how layer-selective functional patterns of short-term and long-term acute ischemia reflect only partial (short-term ischemia) or essentially total (long-term ischemia) depletion of high-energy phosphates, and whether these patterns are sufficiently unique to predict post-reperfusion functional recovery without the need for a stress test. Data from 42 adult pigs obtained with state-of-the-art strain echocardiography and laboratory methods including high performance liquid chromatography will be used to accomplish these aims. The significance of the project is filling gaps in knowledge about the relationship between the changes in functional and energy-metabolic heterogeneity in acute progressive ischemia and in introducing novel concepts for analyses of the degree of injury in acute ischemia based on underlying energetic disorder and for prediction of postreperfusion functional recovery by resting echocardiography.
Cardiac resynchronization therapy (CRT) is a beneficial new therapy for heart failure patients with left ventricular (LV) dyssynchrony that improves symptoms, LV function, and survival. However, CRT trials using QRS duration as an inclusion criterion have shown heterogeneous responses with a subset of patients who are non-responders. Although several echo-Doppler techniques suggest that they may identify responders superior to QRS and also may play a role in directing LV lead placement, gaps in existing knowledge preclude clinical acceptance. Our group has developed novel quantitative approaches using tissue Doppler and speckle tracking to assess mechanical dyssynchrony. Our exciting preliminary data in 50 CRT patients suggest that we can quantify dyssynchrony and predict response. Furthermore, pilot data demonstrate our ability to localize the site of latest mechanical activation. We observed post hoc that patients with LV lead position concordant with latest mechanical activation site have greater increases in ejection fraction at chronic follow-up than other patients. Accordingly, the specific aims of this proposal are: 1) to test the hypothesis that the novel approaches using tissue Doppler longitudinal velocities combined with speckle tracking radial strain can quantify LV dyssynchrony and prospectively identify patients with a long-term favorable response to CRT 2) to test the hypothesis that echo-guided LV lead placement at site of latest mechanical activation will result in more favorable improvements in LV function and clinical outcome than routine LV lead placement. Approximately 70 patients (supported by power analysis) will be enrolled in a prospective, randomized, single-center trial. Tissue Doppler, speckle tracking and clinical evaluations will be performed prior to CRT. Patients with dyssynchrony defined as an opposing wall delay in longitudinal velocities > 65 ms, or septal to posterior wall delay > 130 ms by radial strain will be randomized to echo-guided LV lead placement vs. routine placement. Patients without dyssynchrony will have routine lead placement. Primary endpoints at 6 months are: 1) EF and 2) 6 min walk distance. Secondary endpoints are: 1) Combined HF hospitalization, death, cardiac transplantation, and ventricular assist device implant 2) LV end-systolic volume 3) Quality of life score. Data will be analyzed on an intent-to-treat basis. Statistical models will evaluate the predictive value of the echo-Doppler approach for identifying responders to CRT and the relationships between LV dyssynchrony, LV lead position and clinical outcome. This study has great promise to advance the role of echocardiography and the care of heart failure patients undergoing CRT.
Chest pain is one of the most common complaints that brings a patient to the emergency department (ED). The differential diagnosis of chest pain is broad and includes cardiac as well as non-cardiac diseases. One of the initial goals in the ED evaluation of a patient presenting with chest pain is to rapidly and accurately diagnose the presence or absence of acute coronary syndrome. The diagnostic accuracy of the initial routine evaluation is often limited and results in frequent admissions for patients presenting with chest pain for further diagnostic testing.
Echocardiography has a high sensitivity and specificity for the diagnosis of acute myocardial infarction. Tissue Doppler imaging with strain and strain rate (SR) measurement is a new echocardiographic technique, which enables accurate assessment of regional left ventricular systolic and diastolic function. Prior studies have shown that abnormal strain and SR are highly sensitive markers of ischemia. Acute ischemia induces early systolic thinning and a delay in the onset of systolic thickening, a progressive decrease in the rate and degree of maximal systolic thickening, and an abnormal ischemia-related thickening which occurs after aortic valve closure. A major obstacle to the routine use of echocardiography in the ED is the need for portable studies, using heavy, bulky portable echo machines. There are currently available portable hand-held echo machines (GE-Vivid I) that produce high quality images and offer an opportunity to incorporate echocardiography into routine practice in the ED.
Aims and Hypothesis
We will study the use of early, portable hand-held (GE-Vivid I) echocardiography, with detailed assessment of wall motion and left ventricular function by strain and strain rate measurements, for the evaluation of chest pain in the ED. We hypothesize that an early, portable echocardiogram with detailed left ventricular function assessment will be highly sensitive and specific for the diagnosis of myocardial ischemia, and will enable rapid triage of patients who present to the ED with chest pain.
We will study patients who present to the ED with a chief complaint of chest pain, who are admitted for a cardiac work up to rule out myocardial ischemia. We will perform a portable echocardiogram, using our hand-held Vivid I machine, within one to two hours after the patient has entered the ED. The echocardiogram results will be compared with the final clinical diagnosis the patient is given, and sensitivity and specificity for early diagnosis of ischemia will be calculated.
Allen Borowski, RDCS
The Cleveland Clinic Foundation, Cleveland, OH
Right ventricular (RV) function plays a key role in the outcome of heart failure patients, however the evaluation of RV function continues to be challenging due to image quality, ventricular geometry and lack of a gold standard. The primary purpose of this study is to examine the usefulness of 2D and 3D echocardiography in the intensive care unit in the evaluation of RV function, and the effects of pressure and volume changes on the RV as assessed by serial echocardiography. The proposed study would include 80 consecutive patients with acute decompensated heart failure (ADHF) admitted to the heart failure intensive care unit (H-22) for invasive hemodynamic monitoring by pulmonary artery catheter (PAC). Patients will be assessed at ICU admission, 24-48 hours after admission, and 7 days post discharge. At all three time points, 2-dimensional echocardiograms with color Doppler tissue echocardiography data (Vivid 7), 3-dimensional echocardiography data (Vivid 7, or Phillips ultrasound machine), and heart failure biomarkers will be collected. The hemodynamic data by PAC will be collected only at baseline and after 24-48h.
Sandra Witt, RDCS, FASE
Cincinnati’s Children’s Hospital Medical Center, Cincinnati, OH
Aortic valve disease is a major cause of morbidity and mortality in all age groups, with aortic valve replacement being the second most common cardiac operation. Aortic leaflet malformation, typically described as unicuspid, bicuspid or quadricuspid, as well as dysplastic tricuspid aortic valves are found in the majority of cases suggesting that aortic valve disease discovered later in life has its origins during intrauterine valve development. Aortic valvulogenesis is a complex process which includes extracellular matrix (ECM) remodeling which results in the development of normal, highly-organized and mature valve leaflets. Histological studies of bicuspid aortic valves explanted during surgical replacement were shown to have a disrupted ECM. Elastin is an abundant ECM protein that maintains structural integrity and is a primary component of both the semilunar and atrioventricular valves. Preliminary histological studies have shown that elastin haploinsufficiency in the mouse results in ECM disorganization and aortic valve malformation.
Genetic alterations in cardiovascular development and disease are most frequently performed in the mouse because its genome is extensively characterized and can be readily manipulated genetically. However, we still have a limited understanding how these manipulations affect the developing heart. Recently, improved high frequency mice echocardiography technology called ultrasound biomicroscopy, has become available allowing enhanced visualization and Doppler evaluation of cardiac structures not only in the juvenile and adult mouse, but also during embryonic development. This combination of a genetically manipulated mouse and advanced ultrasound technology provides the opportunity to evaluate valve development during the prenatal and postnatal period. Our proposal seeks to utilize ultrasound biomicroscopy in mice to obtain normal values and Doppler velocities in embryonic, juvenile and adult mice aortic valves. We will also study a mouse model of elastin haploinsufficiency to assess for abnormalities of the aortic valve during embryonic development and aging. Ultrasound biomicroscopy assessment will include two-dimensional measurement of the aortic annulus, classification of leaflet morphology, and Doppler assessment of the valve for stenosis and regurgitation. In addition to utilizing ultrasound biomicroscopy in evaluating aortic valves we hypothesize that elastin haploinsufficiency results in abnormalities in utero that produce morphological changes which promote aortic valve disease during the aging process when compared to control mice. This study will provide normative data of the aortic valve during embryonic, juvenile and adult development in the mouse which are currently lacking. In addition, it will enable us to more accurately understand the underlying developmental mechanisms for aortic valve disease.
Diastolic dysfunction frequently accompanies the systolic dysfunction caused by coronary artery disease or cardiomyopathy. It may also exist in isolation, as diastolic dysfunction is the primary cause of heart failure (HF) in patients with preserved systolic function. Further, age-related alterations in myocardial diastolic function are present in a significant percentage of apparently healthy individuals by age 50. While diastolic dysfunction contributes significantly to cardiovascular morbidity and mortality, there are few studies addressing the treatment of this common disorder, and no clearly established therapies for diastolic dysfunction.
Regular exercise is a promising therapy for modification of cardiovascular risk factors in healthy individuals and improves survival in those with symptomatic heart disease. However, its effects on diastolic function remain controversial and the appropriate dose and type of exercise needed to reverse the age or disease-related changes are unknown. Current recommendations for older individuals include both resistance and aerobic training. However, in many instances, including that of diastolic cardiac function, the two modalities have not been assessed side by side in the same population. This study aims to evaluate the differential effects of aerobic and resistance exercise training on diastolic performance measures, and thereby provide clinically useful data regarding the type of exercise that should be prescribed to improve diastolic function. We will also assess the ability of novel and sensitive techniques of measuring diastolic function (i.e. tissue Doppler, flow propagation and strain rate imaging) to identify subjects earlier in the spectrum of diastolic heart failure. Further, the ability of aerobic and resistance exercise to modulate cardiac diastolic function will be evaluated in the context of its effects on markers of metabolic and physiologic cardiovascular risk, thereby providing a “balanced” assessment of the impact of aerobic and resistance training on cardiovascular health.
To accomplish these aims this study will be conducted as a prospective ancillary study to the NHLBI-funded Peripheral Effects of Exercise on Cardiovascular Health (STRRIDE II). As such, it will take advantage of the STRRIDE II parent study infrastructure to conduct the proposed investigation in a highly cost effective fashion. Subject recruitment, exercise training and testing, muscle biopsies, body composition and metabolic measurements will all be performed as part of the parent study. As a result, the only costs incurred to complete this investigation will be related to obtaining and analyzing the echocardiographic images.
Congenital cardiac malformations are the most common birth defect, with a far higher prenatal incidence due to intrauterine loss. Most if not all defects are felt to result from cardiac development gone awry. Progress has been rapid in the elucidation of the developmental genetics underlying heart development. We know far less about how cardiovascular structures and functioning mature in the embryonic organism, particularly in the mouse, considered a model organism for mammalian development and therefore of human disease. One important biological problem is that of origin and evolution of cardiac malformations. Both genetic and epigenetic mechanisms serve to mold the developing cardiovascular system. Epigenetic mechanisms, however, remain little-understood; data on the evolution of structure-function relationships in abnormal cardiovascular development are scant, due largely to a dearth of phenotypic approaches. Histological analysis remains the mainstay of structural phenotyping, and techniques for functional analysis are nascent. It is clear that along with instrumentation, innovations in in vivo imaging approaches must be developed. Ultrasound has clearly emerged as the imaging/phenotyping approach of choice, and our laboratory has virtually defined the field of ultrasound phenotyping of the in vivo mouse embryo. The PI has pioneered a variety of ultrasound biomicroscopy (UBM)-Doppler approaches to study cardiovascular development in both normal and mutant mouse embryos, from the straight heart tube stage through septation. In addition to ongoing experiments at the forefront of cardiovascular functional imaging and intervention in the embryonic mouse, we will validate and establish approaches for non-invasive, in vivo structural phenotyping. In our first Specific Aim, we will test the accuracy of UBM in defining major categories of cardiac malformations in the in vivo mouse embryo. In various mouse models exhibiting a broad range of malformations, we will compare UBM diagnoses with the "gold standard" that is histological analysis, as well as India ink injections for definition of the outflow tracts. In our second Specific Aim and using the approaches developed in Specific Aim 1, we will determine patterns of evolution and progression of cardiac malformations longitudinally in several mouse models. Our broad, long-term objectives are to define cardiovascular structure-function relationships in the living mouse embryo, specifically in models of abnormal cardiovascular development that mimic human disease. With a better understanding of abnormal structural and functional development, treatment of congenital heart disease may eventually become possible as early as embryonic life, and may serve to reverse or even prevent abnormal developmental mechanisms.
Stroke is the leading cause of disability and the third leading cause of death in the United States. Yet, standardized primary prevention strategies are lacking. Our multidisciplinary team is committed to identifying low risk and cost-effective strategies for stroke risk reduction. We have previously demonstrated that left atrial (LA) is incremental to clinical risk profiling for risk stratification of first stroke. The larger the LA volume, the greater the risk of stroke. LA volume can be measured rapidly and accurately using a hand-held device at the point of care. We also have data on the modifiability of LA volume with pharmacotherapy. Large clinical trials have demonstrated that angiotensin receptor blocker (ARB) therapy can lower stroke risk, we believe that the use of hand-held echo for risk screening and guidance of therapy based on LA volume response to ARB may provide greater and more cost-effective stroke reduction.
In this study, we propose to assess the rate of LA volume change with valsartan using 2 strategies: echo-guided versus conventional management. We will assess whether the use of hand-held device to guide therapy intensity allows a greater LA volume reduction, and identify the characteristics of responders versus non-responders. We plan to recruit 150 older adults (age ≥65 years) with non-optimal blood pressure level by JNC VII criteria), plus at least one additional risk factor, from among the population of patients with scheduled outpatient visits for general medical examinations in the Department of Internal Medicine at Mayo Clinic, Rochester. Subjects who successfully complete the run-in phase (~15% attrition rate anticipated) will undergo LA volume assessment with a hand-held system. Participants will be randomized to one of two arms. For ARM 1, titration of valsartan from the initial 40 mg level to higher doses, as well as any adjustment of concomitant antihypertensive agents, will be based on LA volume assessments at baseline, 3, 6, and 9 month interim visits. For ARM 2, adjustment of valsartan and other medications will be left to each participant’s primary physician, without knowledge of the LA volume. LA volume will be reassessed at the 12 month close out visit. The changes in LA volume over time, including both rate and magnitude, will be analyzed.
The pilot study will provide important data for the design of a definitive trial to assess whether echo-guidance provides greater and more cost-effective reduction of stroke and stroke precursors.