San Antonio (TX), Bolton (MA)
Medical imaging has always been an important part of clinical trials. Echocardiography, which uses sound waves to create moving real-time images of cardiac structure and function, provides an excellent noninvasive method to evaluate the impact of therapeutics on cardiac morphology. Sound waves are at no risk to the study subject and echocardiographic machines are very portable. Given the affordability of this technology, echocardiograms are performed worldwide allowing for a broad population that can be studied. Obtained images can be rapidly delivered over the internet for remote post-processing and interpretation which makes this technology ideal for standardized interpretations from a core laboratory.
Clinical trials have used the data collected from echocardiographic studies to evaluate cardiac chamber size, cardiac function, valvular function, cardiac mass, and as a surrogate marker of cardiovascular prognosis. Adverse cardiac remodeling, progressive reductions in ejection fractions, or changes in diastolic function or mass have been linked to major adverse cardiovascular events (i.e. stroke, myocardial infarction, heart failure, death). By using cardiac dimensions obtained by echocardiography as surrogates for clinical endpoints one can draw a conclusion to a trial prior to the onset of negative cardiac symptoms. Conversely, positive remodeling and improvement in left ventricular ejection fraction have been used to demonstrate success of therapeutic interventions. The sensitivity of echocardiography to obtain dimensions down to the millimeter allows for a reduced trial sample size. Subtle changes of measurements over time can point to improved or worsening clinical outcomes if study subjects were followed out to clinical endpoints.
In clinical practice echocardiography is used to obtain ventricular dimensions and volumes on every patient studied. These values are used to determine the consequences of valvular heart disease, myocardial infarctions, cardiomyopathies, and congenital heart disease. The values obtained are also used to derive a calculated ejection fraction which aids in determination of prognosis for each patient and treatment course. Left ventricular mass is used to differentiate different etiologies of myocardial hypertrophy especially when indexed to body surface area. Serial evaluations of these dimensions aids in changes from therapeutic interventions (i.e. medical and surgical therapies) and the lack of changes in dimensions can imply the lack of response to certain therapies.
Standardized methods for measuring chamber dimensions are essential to reduce both intra and inter-observer variability. Considering variations in cardiac dimensions due to body size, all cardiac dimensions should be indexed to the individual subject’s body surface area. Left ventricular dimensions should be measured with 2D echo (as opposed to M-mode) using the parasternal long axis view. Left ventricular volumes are measured using a modified Simpson’s biplane method using the apical 2 and 4 chamber views. These volumes are then used to calculate left ventricular ejection fraction. Left ventricular mass can be calculated from left ventricular dimensions taken from parasternal long axis or apical views if endocardial borders are well seen. Typical dimensional measurements include the following: left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic volume index (LVESVI), left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF).
Doppler echocardiography allows for functional assessment of the heart. Analyzing the shifts in emitted frequencies, the velocity of moving structures can be determined. Doppler echocardiography is utilized to determine severity of valvular lesions (stenosis and/or regurgitation) as well as disease states which may affect myocardial contractility or relaxation. Doppler is also frequently used to assess for pericardial involvement of disease.
More advanced echocardiography capitalizes on subtle differences in tissue density to assess relative changes in myocardial contractility. This technique, commonly known as ‘speckle tracking’, is used to reveal previously hidden areas of myocardial infarct or ischemia. The utilization of speckle tracking in the setting of stress testing also improves both sensitivity and specificity for the identification of obstructive coronary artery disease. The post processing of this data can be time consuming although newer software is being developed to automate much of the work.
The dependency of sound transmission to create interpretable images has its limitations. Sound must be able to travel to the heart and back to the receiver in order to be processed. Structures which can affect the quality of the image commonly include adipose tissue, bones (i.e. ribs), air filled pulmonary tissue, calcified vascular plaques, and implantable structures such as pacemaker wires or mechanical heart valves. Some of these limitations can be overcome through patient positioning, probe selection and positioning, and echocardiographic contrast. Contrast agents are FDA approved intravascular drugs which are specially designed to resonate and amplify transmitted ultrasound that is being emitted from the probe. They allow for significantly improved intravascular border definition and have been shown to increase the accuracy of 2-D echo measurements. These contrast agents can also augment Doppler signals therefore providing a clear assessment of blood velocities.
Transthoracic echocardiography provides a complete assessment of left ventricular function and dimensions. Measurements of left ventricular dimensions by echocardiography have been shown to closely correlate with cardiac MRI and are only limited by patient parameters and acoustic windows. Doppler echocardiography and speckle tracking add extra elements to the complete evaluation of cardiac function and are typically used even in day-to-day clinical use. Echocardiographic contrast can be safely used in most patients and has been shown to significantly augment the accuracy of intracardiac measurements both with 2D and Doppler technology.
Echocardiography is a worldwide available technology that is safe to use repeatedly on study subjects. Serial measurements over time can be obtained in order to measure the effect a therapeutic may have over days, months to years later. Using echocardiography as a surrogate endpoint has been shown to limit study size and enrollment when compared to using other cardiovascular outcomes such as stroke or death. There are many advantages to data collection via echocardiography and it is no surprise that many well accepted published clinical trials depend on echocardiography as a pillar to support or refute the tested hypothesis.
About the Author
Dr. Steel completed his Advanced Cardiac Imaging Fellowship at the Brigham and Women’s Hospital at Harvard Medical School in 2007. Prior to that, Dr. Steel completed his Cardiovascular Disease fellowship at the Wilford Hall Medical Center at Lackland Air Force Base. Graduating from Kirksville Medical School in 1999, Dr. Steel has continued to advance his knowledge in his respective field. As a leading physician in San Antonio, Dr. Steel has held numerous academic appointments. He has been invited to speak both internationally and nationally on cardiac imaging and has published extensively within this field. Dr. Steel is board certified/Level III trained in Echo, Cardiac CT, MRI, and Nuclear Cardiology.
About Intrinsic Imaging LLC
Located in Bolton, Massachusetts and San Antonio, Texas, Intrinsic Imaging is an FDA audited, ISO 9001:2008 and ISO 13485:2003 certified, GAMP® 5 compliant medical imaging core lab specializing in providing imaging core lab services for clinical trials. Its comprehensive medical imaging core lab services include, but are not limited to, expert radiologist consultation, protocol and charter development, site qualification, training and management, as well as image acquisition, processing and detailed radiologic analysis.
Intrinsic Imaging has more than sixty full-time, board-certified diagnostic radiologists on staff that have sub-specialization in all therapeutic areas including, but not limited to, Cardiovascular, Central Nervous System, Gastrointestinal & Genitourinary, Medical Device, Musculoskeletal and Oncology.