Nov. 20, 2015
With advancements in cardiac surgical techniques, an increasing number of patients with a single ventricle are surviving to adulthood. Ventricular dysfunction is one of the frequent consequences of palliative surgical procedures as these individuals age, and assessment of ventricular dysfunction in these complex patients is challenging.
"Functionally, single ventricles have unique anatomy and physiologic stresses that cannot be compared to any biventricular circulation owing to a combination of increased volume and pressure load," says Muhammad (Yasir) Y. Qureshi, M.B.B.S., a pediatric cardiologist at Mayo Clinic in Rochester, Minnesota. "In addition, many of these patients undergo several staged surgical procedures that may further injure the myocardium. Therefore, it is not surprising that ultimately myocardial dysfunction develops in many of these patients."
Categorizing the single ventricle as a morphologically left or right structure is an inadequate classification because of variations between disease entities. For example, in both tricuspid atresia and double inlet left ventricle, the single ventricle is a morphologic left ventricle; however, these ventricles are very different anatomically. Double inlet left ventricle is characterized by two inlets and excessive papillary muscle and chordal tissue, whereas these are not seen in tricuspid atresia. Additionally, there are individual variations in both anatomy and physiology.
The unique features of a single ventricle make assessment of ventricular function a challenge. Currently, the predominant imaging modality in clinical practice is echocardiography supplemented by magnetic resonance imaging (MRI). In general, the goals of imaging in patients with a single ventricle are to assess patency of pulmonary or systemic pathways, valve competency, and ventricular function. Each imaging modality has its own pros and cons in achieving these goals.
Echocardiography is readily available and usually does not require sedation, even in pediatric patients. However, it is limited by availability of acoustic windows. The echocardiographic quantification of ventricular function can be challenging, and there are no guidelines or recommendations for quantifying function in a single ventricle by echocardiography.
The most commonly used method of assessing function in these patients is a visual estimate or qualitative assessment of ejection fraction. Multiple views of a single ventricle are obtained in both short axis and long axis to estimate ejection fraction. The accuracy and precision of this method improve with experience but remain suboptimal in day-to-day assessment of individual patients. Better quantification tools are needed for more objective evaluations.
Because of the unique anatomy of single ventricles, the echocardiographic parameters that use geometric assumptions in quantification of ventricular function (such as biplane method to measure ejection fraction) cannot be used.
Apical echocardiographic views before and after intramyocardial injection of umbilical cord blood-derived stem cells
Apical echocardiographic views performed before (top panels) and three months after (bottom panels) intramyocardial injection of umbilical cord blood-derived stem cells. Images show improvement in right ventricular function, with an increase in the ejection fraction from 30-35 percent to 50 percent. FAC, fractional area change; EF, estimated ejection fraction.
Fractional area change has been shown to have good correlation with pressure-volume loop-derived indices of ventricular function. The fractional area change can be measured in both morphologic left and right single ventricles.
The biggest limitation of fractional area change is the interobserver variability. Myocardial performance index can be calculated by spectral Doppler imaging, as well as by tissue Doppler. Significantly higher values in single ventricles versus normal controls have been seen in various studies, which point toward reduced ventricular function even in patients generally considered to have normal function.
Studies in tissue Doppler imaging have shown reduced peak systolic, peak early diastolic and peak late diastolic annular velocities in all patients with a single ventricle. However, these measures do not correlate well with MRI-derived ejection fraction.
Deformation imaging offers an alternative strategy for assessment of function in a single ventricle. Universally, all patients with a single ventricle show reduced longitudinal strain and strain rate. For example, at birth, longitudinal strain in neonates with hypoplastic left heart syndrome (HLHS) is more negative than that in normal neonates, which means the ventricular function is better in HLHS at birth. But after the first surgery, the longitudinal strain becomes less negative, suggesting reduced systolic function. It improves somewhat after the second and third stages of palliative repairs, but never becomes normal.
The circumferential strain also remains abnormal in these patients. Three-dimensional echocardiography is an additional modality that can help in assessing ventricular function in patients with a single ventricle. This method may offer less inter- and intraobserver variability, but its utility is limited by the need for breath holds, which cannot be performed in small children without general anesthesia.
Magnetic resonance imaging
Cardiac MRI can be extremely useful in evaluating ventricular function, vascular anatomy and flow quantification. Ventricular function is assessed by volumetric methods in MRI. A stack of cine images is obtained in axial or short-axis planes, and the endocardial borders are traced in end systole and end diastole to generate end-diastolic and end-systolic volumes. This allows calculation of stroke volume and ejection fraction.
Magnetic resonance angiogram in patient with hypoplastic left heart syndrome
Magnetic resonance angiogram in a patient with hypoplastic left heart syndrome who has undergone Norwood, Glenn and Fontan procedures. This 3-D reconstructed image shows severe dilation of neoaortic (native pulmonary) root and single right ventricle. Norwood anastomosis between native aortic and neoaortic roots to create neoaorta can be appreciated.
This technique is considered to be the best method and standard reference for assessing ventricular function; however, it is influenced by the operator variability. Vascular anatomy can be seen very well by cardiac MRI, with or without contrast. Flow quantification is one of the major strengths of cardiac MRI. An imaging plane can be set up across any blood vessel in the body, and the blood volume going across that plane can be calculated. This method allows calculation of stroke volume, cardiac output, pulmonary flow, differential flow to branch pulmonary arteries, and also flows in superior and inferior venae cavae. This can also be a useful tool in quantifying valve regurgitation.
The limitations of cardiac MRI include limited availability, susceptibility artifacts from metallic hardware, need for anesthesia in pediatric patients and operator variability.
Current research studies for imaging of a single ventricle
The Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome is dedicated to advancements in diagnostic and therapeutic sciences to help patients with HLHS as well as those with other congenital heart diseases, especially single ventricle physiology.
Under the umbrella of this program, specialists at Mayo Clinic in Rochester, Minnesota, are trying to develop better imaging strategies that can be used to quantify and predict ventricular dysfunction in these patients earlier in the disease course.
In an ongoing prospective study at Mayo Clinic, participating patients with HLHS have transthoracic echocardiography and cardiac MRI. "Preliminary data suggest that echocardiographically derived fractional area change and longitudinal strain are the best parameters to assess function in these patients with a single ventricle, as these two parameters correlate very well with MRI-derived ejection fraction," says Dr. Qureshi.
Newer imaging parameters to better quantify and predict ventricular function are also being developed. A prospective observational study of patients with HLHS following stage II surgical palliation is also underway. The goal of this study is to document the natural history of post-surgical HLHS patients who have undergone standard of care procedures with protocol-specific follow-up over a course of six months.
Clinical trials of cell-based therapies in single ventricle disorders
The goal of ongoing research is to develop regenerative strategies to strengthen the myocardium of the single ventricle after the initial palliative surgical procedures. As part of the Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome, physicians and scientists at Mayo Clinic are running clinical trials of cell-based therapies in patients with a single ventricle.
The advancements in imaging strategies are much needed for better patient selection and recognition of the early changes in ventricular function with these therapies. Current phase 1 clinical trials are focusing on evaluating the safety and feasibility of using mononuclear cells derived from autologous umbilical cord blood or bone marrow.
Autologous mononuclear cells injected in the right ventricular myocardium
In an ongoing clinical trial, autologous mononuclear cells derived from umbilical cord blood are injected in the right ventricular myocardium at the time of stage II surgical palliation in patients with hypoplastic left heart syndrome.
After baseline imaging and clinical evaluations of the enrolled patients, the cells are delivered to the myocardium either by direct intramyocardial injection at the time of planned surgery or by coronary artery catheterization. The patients are then followed clinically with repetitive cardiac imaging for six months.
The initial case report, published in The Journal of Thoracic and Cardiovascular Surgery in 2015, highlights the promise of cell-based therapies in patients with a single ventricle. This report described a patient with HLHS and reduced ventricular function (fractional area change, 18 percent; estimated ejection fraction, 30 to 35 percent) who had remarkable improvement of ventricular function (fractional area change, 47 percent; estimated ejection fraction, 50 percent) three months after cell therapy.
All of these efforts are with the goal of preventing heart failure in patients with a single ventricle.
For more information
Mayo Clinic. Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome imaging and outcome research.
Clinical trials: Hypoplastic left heart syndrome. Mayo Clinic.
Burkhart HM, et al. Regenerative therapy for hypoplastic left heart syndrome: First report of intraoperative intramyocardial injection of autologous umbilical-cord blood-derived cells. The Journal of Thoracic and Cardiovascular Surgery. 2015;149:e35.