Author + information
- Received November 30, 2017
- Revision received February 14, 2018
- Accepted March 8, 2018
- Published online August 6, 2018.
- Jennifer Liu, MDa,∗ (, )@JLiu_MSKCardOnc,
- Jose Banchs, MDb,
- Negareh Mousavi, MDc,
- Juan Carlos Plana, MDd,
- Marielle Scherrer-Crosbie, MD, PhDe,
- Paaladinesh Thavendiranathan, MDf and
- Ana Barac, MD, PhDg,∗∗ (, )@AnaBaracCardio
- aCardiology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, New York
- bDivision of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- cDivision of Cardiology, McGill University Health Center, Montreal, Quebec, Canada
- dDivision of Cardiology, Texas Heart Institute Baylor St. Luke’s Medical Center, Houston, Texas
- eDivision of Cardiology, The Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
- fDivision of Cardiology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- gMedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC
Early recognition of cancer therapy–related cardiac dysfunction (CTRCD) provides an opportunity to mitigate cardiac injury and risk of developing late cardiac events. Echocardiography serves as the cornerstone in the detection and surveillance of CTRCD in patients during and after cancer therapy. Guidelines from professional societies and regulatory agencies have been published on approaches to surveillance, diagnosis, and treatment of CTRCD, although adoption as standard of care remains limited given the lack of evidence on the prognostic value of asymptomatic left ventricular (LV) dysfunction in the oncology population. The frequency of cardiac monitoring and the appropriateness of the Food and Drug Administration (FDA)–recommended cardiac monitoring schedule in all patients receiving trastuzumab for breast cancer has been challenged. Interruption versus continuation of oncological therapy in the setting of asymptomatic LV dysfunction remains a clinical conundrum given the uncertain balance of the risk of cardiac dysfunction and benefit of oncology efficacy. Despite their limitations, echocardiographic measures of LV function continue to play a pivotal role in clinical decision making, with global longitudinal strain emerging as a promising tool in informing and facilitating the selection of cancer treatment and optimizing cardiovascular outcomes. This review highlights the key recommendations of the existing guidelines and discusses recent developments in cardio-oncology imaging practices with the aim of providing practical guidance on the role and use of echocardiography in challenging clinical cases in cardio-oncology.
Advances in cancer treatment have resulted in significant improvement in cancer-specific survival. With prolonged survival, cancer survivors are increasingly subject to late cardiovascular disease related to cancer therapies compounded by the development or progression of age-related cardiovascular risk factors. Consequently, higher cardiovascular disease is observed among subgroups of cancer survivors (1,2), potentially attenuating the survival gains from advances in oncological treatment.
Early recognition of cancer therapy–related cardiac dysfunction (CTRCD) provides an opportunity to mitigate cardiac injury and risk of developing late cardiac events (3). Current approaches for evaluating and managing CTRCD aim to prevent, recognize, and mitigate adverse cardiovascular effects and at the same time minimize interference with optimal anticancer regimens. In current cardio-oncology practice, echocardiography serves as a cornerstone in the detection and surveillance of CTRCD and is the most widely used technique in clinical practice because of its availability, feasibility, and cost-effectiveness. There are a number of published studies that have used echocardiography in the diagnosis, prevention, and risk stratification of CTRCD in patients during and after cancer therapy (Online Tables 1 to 4). The purpose of this review is to summarize recent developments in cardio-oncology imaging practices and present practical guidance on the use of echocardiography in the screening, diagnosis, and treatment of CTRCD.
Evolving Definition of CTRCD
The overarching concept of CTRCD includes heterogeneous effects that different categories of cancer therapies can exert on the cardiovascular system, from apoptosis and necrosis of myocardial cells to microvascular and macrovascular effects such as ischemia and promotion of inflammation and fibrosis (4). The revolution in personalized cancer therapeutics, often targeting molecular pathways with essential roles in cardiomyocyte or vascular homeostasis, has greatly increased interest in cardiovascular injury while providing unprecedented insights into cardiovascular biology. A recent review provides a detailed description of the wide spectrum of cardiotoxicity profiles associated with chemotherapeutic agents and the mechanisms of their actions (5). Clinical application of this new knowledge, particularly with respect to awareness and detection of CTRCD, has also made advances in the past decade; however, significant gaps remain in our understanding of the cardiovascular pathophysiology of a growing number of cancer therapies, and the translation of this to clinical practice, as well as optimal approaches to cardiovascular monitoring and treatment, continues to be examined.
Reflecting the diversity of cancer regimens and therapeutic agents, definitions of CTRCD vary widely depending on the specific cancer treatment modality and agent used, as well as the clinical setting in which they are observed and approved for use. In adults, the U.S. Food and Drug Administration (FDA) defines doxorubicin-related deterioration in cardiac function as a 10% decline in left ventricular ejection fraction (LVEF) to below the lower level of normal, or an absolute LVEF of 45%, or a 20% decline in LVEF at any point. In pediatric patients, the definition is a drop in fractional shortening by an absolute value of >10% or below 29% and a decline in LVEF of 10% or an LVEF below 55% (6). For trastuzumab, a monoclonal antibody that was first used in conjunction with doxorubicin in the treatment of metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer, LVEF monitoring is recommended, with toxicity defined by an absolute LVEF decline of ≥16% from pre-treatment values or an LVEF decline of ≥10% from pre-treatment values to below the institutional lower level of normal (7). For the newer HER2-targeted antibody pertuzumab, an LVEF decline to 40% or an LVEF of 40% to 45% with ≥10% decrease from pre-treatment values is considered indicative of cardiac injury (8). The differences in FDA definitions of cardiac toxicity for each of the agents are largely explained by the different cardiac toxicity criteria that evolved over time or were used in the clinical trials of these agents. The favorable outcome of many women despite asymptomatic falls in ejection fraction (EF) into the midrange, coupled with the recognized efficacy of HER2-targeted agents, has led to less stringent stopping criteria for the newly approved pertuzumab (8), which points to the challenges of creating a single definition of cardiac toxicity across oncology treatments. The American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) consensus statement published in 2014 defined CTRCD as a decline in LVEF of >10 percentage points to an absolute value of <53% (9). This definition largely follows the FDA trastuzumab recommendation with the exception of the updated low-normal LVEF limit of 53%, which was based on the revised standards for echocardiographic chamber quantification (9). The definition of CTRCD from trastuzumab and anthracycline trials cannot be simply extrapolated to guide evaluation of the cardiovascular toxicity of other cancer therapies, which could be acting through different mechanisms, be given for different pathological process, or be given as part of a distinct multimodality oncology regimen.
Current Clinical Practice Statements and Guidelines for Monitoring and Therapeutic Interventions
In 2014, the ASE/EACVI published the first document providing clinicians with guidance as to how to image the cancer patient before, during, and after contemporary cancer therapy (9). Since then, other organizations (American Society of Clinical Oncology [ASCO], European Society of Cardiology, and National Comprehensive Cancer Network) have published standards and position papers that include recommendations on the imaging evaluation of this important cohort of patients (10–12). With the recognition that the ASE/EACVI and the ASCO documents target different audiences (cardiovascular imagers and oncologists, respectively), this section aims to reconcile and put in perspective the most important recommendations for clinical practice (Online Table 5).
Which patients are at increased risk for cardiac dysfunction related to cancer treatment?
The ASCO clinical guideline on prevention and monitoring of cardiac dysfunction in survivors of adult cancer recognizes categories of patients at risk for left ventricular (LV) dysfunction based on prior exposure (10). These categories include high-dose anthracycline (e.g., doxorubicin >250 mg/m2), high-dose radiation therapy (>30 Gy), or low-dose anthracycline (<250 mg/m2) in combination with lower-dose radiation therapy (<30 Gy) (10). The document is particularly helpful in raising concern for patients not recognized before, such as patients receiving lower-dose anthracycline (<250 mg/m2) or trastuzumab alone but in the presence of cardiovascular risk factors. The presence of more than 2 cardiovascular risk factors, age ≥60 years, and compromised or low-normal cardiac function at baseline (LVEF of 50% to 54%, previous myocardial infarction, or moderate valvular heart disease) are all recognized as markers of elevated risk for cardiac toxicity. The ASCO guideline does not address the risk of cardiac dysfunction with other cancer therapeutic agents, given the very limited and mostly short-term cardiovascular data in clinical trials.
What are the evaluation and prevention strategies prior to cardiotoxic cancer treatment?
The ASCO and ASE/EACVI documents agree on avoidance and minimization of use of cardiotoxic therapies whenever an established alternative that will not compromise cancer-specific outcomes is available. In addition, a comprehensive cardiovascular assessment, including screening for cardiovascular risk factors, and an echocardiogram are recommended before their initiation (9,10).
Given the lack of recommendations concerning the cardiovascular risk of other treatments (beyond anthracyclines and trastuzumab), oncology providers might be unlikely to obtain baseline cardiovascular imaging or echocardiograms for patients receiving other therapies. Recent reports indicate that impaired or even a low-normal LVEF at baseline carries an increased risk of cardiac events in patients treated with anthracyclines (13). From epidemiological studies in the general population, the probability that an asymptomatic patient has an abnormal LVEF is 6% in men and 0.8% in women, although the risk increases with age (14). As such, the ASE/EACVI document recommends the inclusion of LVEF and global longitudinal strain (GLS) assessment before the initiation of treatment in all patients for whom therapy is planned that has been associated with LV dysfunction and heart failure (HF), to identify potential baseline cardiomyopathy or other markers of risk that might compromise oncology outcomes by increasing cardiovascular risk (9).
What are the cardiovascular monitoring and surveillance strategies during cancer treatment?
Echocardiography is recommended as a surveillance strategy in all asymptomatic patients at increased cardiovascular risk; however, the ASE/EACVI and ASCO documents differ with regard to frequency of cardiac imaging, reflecting the lack of studies comparing the efficacy of one cardiac surveillance timing to another (9,10). In clinical practice, repeated imaging, often every 3 months during treatment with any of the HER2-targeted therapies (trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine]), has been recommended by the FDA, although with different rates of adoption (15). Recently, the frequency of monitoring of trastuzumab has been challenged, in particular with patients at low cardiovascular risk, in whom the risk of holding or stopping cancer therapy on the basis of asymptomatic LVEF decline might outweigh the benefit of screening (16). The yield of finding abnormalities among truly asymptomatic patients is relatively low. It is not clear how many patients would have to be studied before abnormalities were detected, what easily defined clinical characteristics can be used to identify patients with a higher likelihood of actionable abnormalities, and finally what evidence exists that these findings can be used to favorably influence patient outcomes. At present, routine imaging assessment of asymptomatic patients remains part of the FDA package inserts for HER2-targeted therapies and patients receiving high doses of anthracyclines. Ongoing clinical trials investigating imaging-based intervention and outcomes in these patients have the potential to modify clinical practice. For all other cancer therapies, diligent clinical assessment, based on the pathophysiology of cardiac toxicity with follow-up testing dictated by patient risk profile and clinical suspicion, is likely the best practice approach for cardiac monitoring of patients during cancer therapy.
What are the cardiovascular prevention and intervention strategies during cancer treatment?
During cancer treatment, primary prevention strategies (in patients with high risk who have normal LVEF) and secondary prevention strategies (in patients with reduced LVEF) need to be considered, in addition to decisions about continuation or modification of cancer treatment itself. In patients receiving high doses of anthracyclines, infusion of dexrazoxane or liposomal preparations have been shown to reduce the risk of LV dysfunction in randomized clinical trials; however, their use in clinical practice remains limited (10). Although a number of smaller studies have investigated the role of neurohormonal antagonists and statins, at present there are no data to support their routine use for primary prevention in all patients undergoing treatment with anthracyclines or HER2-targeted agents. The ongoing PREVENT (Preventing Anthracycline Cardiovascular Toxicity With Statins) (17) and STOP-CA (Statins to Prevent the Cardiotoxicity From Anthracyclines) trials (18), with randomization to placebo or atorvastatin, in patients for whom treatment of either breast cancer or lymphoma was planned with low-dose doxorubicin (240 to 300 mg/m2) will increase our knowledge in this area. The SUCCOUR (Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcome) study is an ongoing multicenter, randomized, controlled trial that addresses the impact of strain-guided cardioprotective therapy on mitigating LVEF reduction in patients at risk of cardiotoxicity during cancer therapy (19).
Cardiac imaging has been important in the design of prevention trials, although changes in LV volumes and function as the most common primary endpoint have been increasingly questioned (20,21). This is particularly relevant in patients receiving HER2-targeted therapies, for whom primary prevention studies were designed within current FDA recommendations to hold or stop therapy with predetermined LVEF changes suggestive of CTRCD (21,22). Recently, with evidence of continued long-term benefit of trastuzumab on cancer recurrence and survival in patients with HER2-positive breast cancer, there have been increasing calls for the examination of clinical HF outcomes and revision of current cardiovascular surveillance practices (16). The long-term follow-up data now available from 2 large adjuvant trastuzumab trials demonstrate the low risk of symptomatic HF in patients treated with trastuzumab and anthracyclines, which raises the question of whether asymptomatic LVEF declines predict adverse HF outcomes in this population (13,23). Accordingly, the ASCO guideline does not provide a recommendation regarding continuation or discontinuation of therapy but rather focuses on informed decision making by an oncologist, achieved in collaboration with a cardiologist, considering the overall risk and benefits (10).
The ongoing SAFE-HEaRt (Cardiac Safety of HER2 Targeted Therapy in Patients With HER2-Positive Breast Cancer and Reduced Left Ventricular Function) study is testing the hypothesis that HER2-targeted therapies can be safely continued or initiated in patients with mild LV dysfunction, defined as LVEF 40% to 49%, with concurrent treatment with beta-blockers or angiotensin-signaling inhibitors as tolerated (24). If proven safe, this approach will provide a path for consideration of HER2-targeted therapy in patients with abnormal LV function and will create a platform for future studies investigating cancer-specific and cardiovascular outcomes.
What are the screening and imaging strategies post cancer treatment?
Even though relatively large studies have reported the prognostic value of LVEF post anthracyclines in predicting cardiac events in patients treated with anthracyclines (3,13), there is no consensus with regard to follow-up imaging during survivorship. The ASE/EACVI expert consensus recommends one echocardiographic follow-up 6 months after completion of either anthracycline or trastuzumab therapy (9), whereas the more recent European Society of Cardiology position statement includes consideration of follow-up surveillance echocardiography at 1 and 5 years after completion of treatment in patients who received high-dose anthracycline therapy or who developed LV dysfunction during treatment (11). The timing of imaging remains arbitrary, which reflects the lack of prospective studies demonstrating improved outcomes with population screening and treatment of individuals with asymptomatic LV dysfunction. Although traditional oncology clinical practice did not include any routine cardiac imaging after treatment, the ASCO guideline recommends consideration of a single echocardiogram between 6 and 12 months after completion of treatment in individuals considered to be at high risk for cardiac dysfunction (10). At present, the long-term risk of new LV dysfunction after exposure to cancer therapy (anthracycline/HER2 or other), as well as the risk of symptomatic HF in patients with asymptomatic LVEF decline (stage B HF), remains unknown. Future studies are needed to determine the cost-effectiveness of screening techniques and of imaging-guided pharmacological and other treatment interventions.
Echocardiographic phenotyping of CTRCD
LVEF by 2-dimensional (2D) echocardiography has been the most widely used parameter to evaluate cardiac function in patients during and after potentially cardiotoxic therapy. Thus, most definitions of CTRCD are based on a quantitative measure of LVEF decline from pre-treatment values (25). A recent report showed that among survivors of breast cancer, early changes in LV mechanics and ventricular-arterial coupling by 2D echocardiography were associated with LVEF changes and HF symptoms 1 to 2 years after initiation of anthracycline or trastuzumab therapy, providing further insight into cancer therapy–induced myocardial dysfunction (26). The utility of these measures as efficacy biomarkers of potential strategies to mitigate LV dysfunction requires further investigation. Abnormalities in diastolic function can occur in patients undergoing cancer therapy, and changes in diastolic indices such as mitral E velocity, E/A ratio, pulmonary venous flow, isovolumic relaxation time, and tissue Doppler velocities have been described as occurring as early as a few hours after the administration of chemotherapy (27). However, longitudinal changes in diastolic function have not been consistently predictive of LVEF decline or HF symptoms, which raises questions about their prognostic value. Importantly, changes in loading conditions associated with chemotherapy, such as diarrhea, vomiting, and poor intake, need to be considered, because they can influence LV volumes and function measurements (28). Subclinical impairment of right ventricular function can also occur after radiotherapy or chemotherapy in long-term survivors of childhood cancer, although further studies are needed to establish its prognostic role (29).
Detection of subclinical LV dysfunction using speckle tracking myocardial strain
There has been significant interest in early detection of CTRCD as an opportunity to prevent or reverse progression of cardiotoxicity with prompt initiation of HF therapies (3). Although LVEF is recognized as a strong predictor of cardiac outcomes in the general population, it lacks sensitivity for the detection of subclinical changes in cardiac function caused by early myocyte damage (30). The parameters of myocardial deformation (strain and strain rate) have emerged as more sensitive markers for earlier detection of subtle changes in myocardial function. Although early interest in tissue Doppler-based deformation existed, technical challenges related to image quality and measurement limited its clinical feasibility. Speckle tracking–based deformation analysis has become the clinical standard. Among the myocardial deformation indices, GLS emerged as a highly reproducible and accurate measure of myocardial mechanics and has therefore evolved as clinically useful and feasible. The use of circumferential and rotational strain remains primarily in the research setting, although emerging data have shown that global circumferential strain can also be predictive of cardiotoxicity (26). There is a growing body of evidence demonstrating the value of GLS in detecting subclinical myocardial dysfunction and prognosticating subsequent LV dysfunction in patients during and after cancer therapy (31). On the basis of the results of published studies, the ASE/EACVI consensus statement defined a relative percentage decrease in GLS of >15% from baseline as clinically meaningful evidence of subclinical LV dysfunction. It is, however, important to consider the use of the same vendor for deformation measurements in longitudinal follow-up given potential intervendor variability in strain measurements.
Accuracy and reproducibility of EF measurement: Role of 3-dimensional EF and GLS to minimize variability and improve risk prediction
Because detection of CTRCD depends on reliable identification of change in LVEF, it is important that the techniques used are accurate and have low intrinsic temporal variability. The superior accuracy of 3-dimensional LVEF compared with cardiac magnetic resonance imaging (MRI) and its lower observer variability have been demonstrated in multiple studies. Among available echocardiographic techniques, 3-dimensional LVEF using semiautomated contouring was shown to have the lowest temporal variability, with a conservative estimate at 5.6% in a cohort of women followed up during treatment for breast cancer (32). Numerous articles have demonstrated superiority of GLS to 2D EF with regard to reproducibility, correlation with MRI-determined EF, and prediction of overall outcome in the general population (33,34). Given the uncertainty and margins of error in calculating 2D EF, GLS has been shown to provide additional risk prediction, which appears particularly useful in patients with EF in the low-normal to mildly impaired range (35). Whether GLS can provide incremental prognostic prediction in patients with other ranges of EF needs further investigation. Furthermore, trials such as SUCCOUR will shed light on the impact on outcomes of the adjudication of stage B HF using GLS, with its subsequent initiation of pharmacotherapy.
Role of cardiac MRI
Cardiac MRI has not been used routinely in patients receiving cancer therapy, likely for historical reasons, lack of its use in oncology trials, its limited availability in community centers, and cost concerns. However, because of its precision and the high reproducibility of LVEF measurements, recent randomized clinical trials investigating cardiotoxicity prevention strategies have relied on cardiac MRI parameters of LV remodeling or quantitative LVEF assessment as primary outcomes (21,22). In the clinical setting of diagnosis and treatment of CTRCD, cardiac MRI is mostly used for LVEF assessment in the situation of abnormal findings or poor-quality data from other imaging modalities. Research interest in the use of cardiac MRI is growing, with a focus on ventricular remodeling during cancer therapy and identification of pathophysiological changes within the myocardium (e.g., edema and fibrosis) as potential tools for risk stratification (36).
A Practical Approach to Diagnostic and Management Strategies
Despite their limitations, echocardiographic measures of LV function continue to play a pivotal role in clinical decision making, with GLS emerging as a promising tool to inform and facilitate the selection of cancer treatment and to optimize cardiovascular outcomes during and after cancer therapy in the current cardio-oncology practice (Central Illustration). Echocardiography is useful to guide management in clinical scenarios along the spectrum of CTRCD throughout the cancer treatment continuum (Figure 1).
Normal LVEF and decline in GLS
It is recommended that patients receiving anthracyclines or HER2-targeted therapies (such as trastuzumab, pertuzumab, and T-DM1) undergo an echocardiogram both before initiation of therapy and during treatment. Development of LV dysfunction compromises drug delivery in these patients, and changes in GLS have been shown to predict LV dysfunction. Clinically significant changes in GLS during treatment should warrant closer surveillance for signs and symptoms of cardiac dysfunction. The role of GLS in identifying patients who might benefit from the use of beta-blockers to prevent LVEF decline is being investigated in the SUCCOUR trial (19). There is no evidence that changes in strain should prompt changes in oncology treatment at this time.
Asymptomatic decline in LVEF during HER2-targeted treatment
Current FDA recommendations support holding trastuzumab treatment in patients who develop LV dysfunction. We believe that treatment with beta-blockers or renin-angiotensin system inhibitors should be considered, although strong evidence for their use in patients with asymptomatic LVEF decline (stage B HF not due to myocardial ischemia) is missing. Recent primary prevention studies in women with breast cancer have demonstrated safety and attenuation in LVEF decline with candesartan (21) and bisoprolol (22) in patients with breast cancer treated with anthracyclines or trastuzumab. The safety of continuing HER2 therapies with concomitant HF medications in patients with mild LV dysfunction is being prospectively investigated in the SAFE-HEaRt trial (24), and until the data from SAFE-HEaRt and other similar studies become available, treatment decisions should be individualized on a case-by-case basis, weighing the risk/benefit ratio of cancer treatment and cardiac dysfunction and its overall impact on outcome.
Symptoms of HF and reduced LVEF
Symptoms of HF with reduced LVEF in patients receiving cancer therapy require treatment and evaluation of all causes of HF (37), as well as interdisciplinary discussion about possible causative cancer agent adverse effects. Many cancer therapeutic agents, including those that do not require routine LVEF monitoring, can lead to HF with reduced LVEF. Early recognition and treatment in accordance with guideline-directed medical care are critically important, as is an individualized approach to cancer treatment choice in consultation with a cardio-oncology expert. Potentially cardiotoxic therapies should be avoided in patients with HF symptoms.
The field of imaging in cardio-oncology is evolving to identify test modalities and practice algorithms with the goal to inform and facilitate clinical decision making based on the benefit of oncology efficacy versus the risk of cardiac dysfunction. Although this paper focused on imaging, progress has also been made to determine blood-based biomarkers that are sensitive in the early detection of CTRCD. Advanced imaging modalities such as myocardial strain imaging offer an opportunity to complement LVEF and other biomarkers to improve detection of cardiotoxicity and mitigate the cardiovascular mortality and morbidity related to cancer treatment while achieving better overall survival in patients with cancer. Prospective research is much needed to validate the diagnostic and prognostic utility of monitoring strategies, determine the optimal timing and frequency of testing, and assess the prognostic significance of imaging-guided interventions.
The authors thank Dr. Richard Steingart for his review and comments on the manuscript.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- American Society of Clinical Oncology
- American Society of Echocardiography
- cancer therapy–related cardiac dysfunction
- European Association of Cardiovascular Imaging
- ejection fraction
- Food and Drug Administration
- global longitudinal strain
- human epidermal growth factor receptor 2
- heart failure
- left ventricular
- left ventricular ejection fraction
- magnetic resonance imaging
- Received November 30, 2017.
- Revision received February 14, 2018.
- Accepted March 8, 2018.
- 2018 American College of Cardiology Foundation
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- Central Illustration
- Evolving Definition of CTRCD
- Current Clinical Practice Statements and Guidelines for Monitoring and Therapeutic Interventions
- Echocardiographic Evaluation
- A Practical Approach to Diagnostic and Management Strategies
- Conclusions/Future Directions