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The assessment of LV size, systolic function, diastolic function, regional wall motion, and timing of mechanical activation remain diagnostically and prognostically important uses of radionuclide imaging. The exercise FPRNA LVEF has particularly greater prognostic value in patients with ischemic heart disease than many other clinical, noninvasive, and invasively derived variables.5–9 An exercise LVEF of 0.50 (50%) has been identified as the inflection point below which patients with CAD demonstrate a probability of cardiac death, which increases as the EF decreases.7 However, the direct applicability of these numerical data when the EF is obtained with other protocols or techniques, such as the more widely utilized ERNA technique, is uncertain.
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The evaluation of LV systolic function has become one of the most common applications of nuclear imaging, using FPRNA, planar ERNA, and, more recently, gated SPECT perfusion and SPECT ERNA. Each noninvasive imaging technique has unique strengths and limitations. Detection of regional global ventricular dysfunction can be performed with many noninvasive methods, but the nuclear imaging techniques are inherently quantitative, rather than relying on visual estimation of ventricular size and function. Factors to consider upon test selection include local expertise, local access, cost, and the need for reproducible quantitative measurements. The ability to distinguish systolic from diastolic dysfunction should also be considered. The RNA techniques can be used to compute quantitative estimates of LV, as well as RV EFs, and absolute volumes with geometric or count-based methods.
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FPRNA has some distinct advantages over ERNA. These include (1) the acquisition of data in <30 seconds; (2) the evaluation of RV function with less overlap of the activity from other chambers40; (3) the use of multiple radiopharmaceuticals, including bone, renal, and myocardial scintigraphic agents13; (4) a proven robust measurement of stress ventricular function at the true point of peak exercise5,7,9; and (5) the presence of a wealth of prognostic information available for management of patients with ischemic heart disease based on stratification by FPRNA exercise LVEFs.5,7,9 Despite these advantages, widespread use of FPRNA has been limited by the need for large-bore intravenous access, absence of significant tricuspid regurgitation,40 impeccable bolus technique,28 and a high-count rate-capable, often dedicated, gamma camera.16–18 Currently, ERNA use is far more widespread than FPRNA and allows for multiple views of imaging.
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In terms of feasibility, quantitation of LV chamber volume and EFs are obtainable in essentially 100% of patients. If venous access is poor, FPRNA cannot be performed, but ERNA requires no bolus, and therefore can be performed with a minimally sized intravenous catheter or direct venous punctures. If ERNA is difficult due to poor tagging of red cells (e.g., with heparin infusion), a Tc-99m–labeled perfusion agent may be employed for gated SPECT perfusion imaging. As noted earlier, the latter test has become the most commonly performed scintigraphic ejection EF, as a diagnostically and prognostically important addition to myocardial perfusion SPECT. The high degree of reproducibility in the EF makes RNA an ideal choice for the assessment of medical interventions on LV function, such as in oncology patients receiving chemotherapy. In particular, this is an ideal choice for serial imaging to assess for cardiotoxicity in patients receiving anthracycline-based drugs such as daunorubicin, discussed further below.
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Assessment of Systolic Function
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The assessment of systolic function is an important component of the initial evaluation of all patients with the clinical symptoms of right- or left-sided congestive heart failure (CHF), ischemic heart disease, and in patients who are undergoing potentially cardiotoxic treatments, such as doxorubicin. Systolic dysfunction is usually defined by the presence of an LVEF <50%, while a normal RVEF is 10 to 15 units lower than that of the LV. However, it should be recalled that the EF is an ejection phase index, which is dependent on loading conditions of the ventricle. Preload (i.e., fiber stretch) deficiency or inappropriate afterload (e.g., severe hypertension) may result in lowering of the EF in the absence of any real decrease in inotropic state or contractile reserve. Compensatory dilatation of the ventricle is present in most patients with systolic dysfunction. Assessment of ventricular volume indices has both diagnostic and therapeutic implications. The presence of ventricular enlargement in the absence of systolic dysfunction in the patient with clinical symptoms of heart failure raises the possibility of heart failure secondary to high-output states, such as anemia or valvular heart disease. For example, when systolic function deteriorates in the RV or LV, this is an indicator of the need to proceed with mitral or aortic (respectively) valvular replacement surgery.11,41 In the absence of dilatation or systolic dysfunction, heart failure symptoms suggest the presence of pulmonary disease (RV dysfunction), pericardial disease (biventricular dysfunction), or predominant diastolic dysfunction.
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Right ventricular function is less commonly assessed than LV function but can have diagnostic and prognostic implications in assessment of lung disease and lung transplantation patients, congestive heart failure, and assessment of arrhythmogenic RV dysplasia.39,42–45 FPRNA offers the most accurate scintigraphic assessment of RVEF, but again, is rarely performed these days.
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Assessment of Diastolic Function
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The presence and severity of diastolic dysfunction should be assessed in every patient presenting with evidence for heart failure, since it is the predominant abnormality in as many as 30% to 40% of such patients.46 Most often, this sways both the diagnostic considerations (e.g., hypertension, diabetes mellitus, hypertrophic myopathies, or myocardial infiltration) and the therapeutic options (e.g., antihypertensives and tight glucose control). This may indicate the need for further procedures, such as myocardial biopsy.
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In RNA studies, the rate of change (first derivative) of counts in diastole can be analyzed to calculate indices of diastolic filling, including the peak LV filling rate, time to peak filling, and atrial contribution to filling.47 In practice, Doppler blood flow velocity indices of transmitral flow are used much more commonly to assess LV diastolic filling parameters. For RNA, a peak diastolic filling rate of >2.5 end-diastolic volumes per second (EDV/s) is considered normal.47,48 Age- and gender-specific criteria for diagnosing LV diastolic dysfunction using Doppler blood flow velocity from transmitral flow based on large population studies have been defined that are applicable to clinical practice.49,50 However, large population-based criteria, adjusted for age and gender, for abnormal diastolic function have not yet been established for RNA.
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Assessment of Ventricular Dyssynchrony
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Recent advancements in the management of CHF include prevention of sudden death with implanted defibrillators and improvement of mechanical efficiency by synchronizing the timing of ventricular contraction. Ventricular dyssynchrony is typified by a wide QRS complex on electrocardiography, often with a left bundle branch block morphology,51 and is associated with a higher risk of sudden cardiac death.52 Various parameters have been looked at to help delineate which patients would be optimal candidates for cardiac resynchronization therapy, including LV dyssynchrony, scar burden, and site of late activation for placement of the LV lead.53
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Echocardiography has been highly touted as the method of choice for evaluation of ventricular dyssynchrony, but suffers from its two-dimensional nature, and lack of reproducibility.54 Recent data have indicated that gated SPECT perfusion55,56 and SPECT blood pool57 imaging can be utilized as three-dimensional methods that easily evaluate regional timing of myocardial contraction in an automated operator-independent fashion (Fig. 22-7). SPECT phase analysis has been shown to be reproducible, validated using commercially available software and has been validated again dyssynchrony parameters measured by tissue Doppler imaging and speckle tracking echocardiography.58–61 Phase analysis holds promise for improving the evaluation and selection of patients with CHF and QRS widening, but further randomized clinical trials are needed.
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Monitoring the Effects of Chemotherapy
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Monitoring for cardiotoxicity from chemotherapy is an important use of radionuclide angiography. The two main classes of chemotherapy that cause cardiac toxicity include anthracyclines and the newer tyrosine kinase inhibitors (TKIs).
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Anthracyclines include daunorubicin (the most commonly used) and various analogs of anthracyclines (including doxorubicin, epirubicin, idarubicin, mitoxantrone, and others).62 They cause myocardial necrosis due to free radical formation, characterized by myocellular vacuolization. Risk factors for the development of more rapid deterioration in LV function with anthracyclines include cumulative anthracycline dose, extremes of age, female gender, cardiovascular comorbidities, adjuvant chemotherapies, and adjuvant thoracic radiation therapy.63 Anthracyclines cause what is traditionally called type I cardiotoxicity, with irreversible injury from cardiomyocyte death.64 This results in progressive lowering of the LVEF as the cumulative dose of the agent increases and is clearly dose related.
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The tyrosine kinase inhibitors include trastuzumab, lapatinib, imatinib, sorafenib, and sunitinib, among others.65 They cause type 2 cardiotoxicity which is characterized by cardiomyocyte dysfunction, rather than cell death, which is felt to be reversible. For TKIs, the toxicity is not dose related and usually responds to standard medical treatment or discontinuation of drug.66 Risk factors for the development of trastuzumab-induced cardiotoxicity include previous or concurrent anthracycline use and older age.
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Noninvasive monitoring of LVEF during chemotherapy with anthracyclines or TKIs is recommended for the early assessment of cardiotoxicity; however there is no clear consensus on how to monitor. Both ECHO and ERNA techniques have been evaluated for chemotherapy monitoring. FPRNA has been found to be more sensitive than echocardiography for the detection of anthracycline-induced LV dysfunction,67 but is no longer readily available. ERNA is well established and is still commonly used. It has extensive data regarding its accuracy and reproducibility with long-term follow-up and is widely available.68 However, there are concerns about its cumulative radiation exposure. As such, echocardiography is used commonly these days, and certain protocols intersperse ECHO with RNA to provide reduced radiation and still have the improved accuracy of RNA. ECHO evaluation during chemotherapy should include assessment of LVEF (ideally by 3D echo, else by 2D echo using modified biplane Simpson's technique), assessment of wall motion score index, and global longitudinal strain.69 Other echocardiogram parameters being assessed for the early detection of cardiotoxicity include fractional shortening, and newer tissue Doppler and speckle tracking indices (strain).67 Although ECHO is used commonly these days, concerns do exist regarding the reproducibility of LVEF by ECHO. Regardless of which imaging technique is used, the LVEFs are likely not interchangeable, and it is recommended that a single technique be used in an individual patient for serial monitoring of LVEF.
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There are no definitive guidelines on the optimal timing and duration of cardiac monitoring for patients receiving anthracycline-based chemotherapy. All patients that are at high risk for cardiotoxicity should receive a baseline evaluation of LVEF. The newest guidelines by the European Society of Medical Oncology and the American Society of Echocardiography recommend: a baseline evaluation of LV function with ECHO and Troponin levels.69,70 For asymptomatic patients, serial evaluation should be considered at 6 months after completion of treatment, annually for 2 to 3 years thereafter, and then at 3- to 5-year intervals for life. High-risk patients may be monitored more frequently. Assessment of subclinical LV dysfunction should be considered with evaluation of global longitudinal strain on ECHO. American Society of Clinical Oncology (ASCO) guidelines include: (1) an evaluation of EF prior to each planned course of doxorubicin (per the labeling guidelines of the drug), (2) monitoring after a cumulative dose of 400 mg/m2 is reached, (3) repeated after 500 mg/m2 cumulative dose, and (4) thereafter after every 50 mg/m2 dose.71 Traditional ERNA assessment has included EF assessment at baseline, measurement at 250 to 300 mg/m2, at 450 mg/m2 and measurement before each dose above 450 mg/m2. If the baseline EF is >50%, then therapy should be discontinued once it decreases by >10% from baseline and LVEF is <50%. If EF is <50% at baseline, serial measurements should be obtained before each dose, with discontinuation of therapy once LVEF <30% or drops by >10%.72 It has been advocated that keeping a table of RNA/EF results along with cumulative doses may be helpful for proper monitoring.
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In general, if test results indicate deterioration in cardiac function associated with an anthracycline, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
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For tyrosine kinase inhibitors, especially trastuzumab, baseline cardiac function and troponin should be assessed prior to treatment.69,70 Optimal surveillance with these agents has also not been established, but higher-risk patients should be followed more closely. Both ERNA and ECHO are being used for monitoring of LV function. Serial assessment in an individual patient should be performed by a consistent method.