Diastology || Evaluation of Diastolic Function by Radionuclide Techniques

99 MANUEL D. CERQUEIRA, MD INTRODUCTION PATHOPHYSIOLOGY Basic Principles of Radionuclide Assessment of Diastolic Function Equilibrium Radionuclide Angiocardiography Methods in Diastolic Assessment First Pass Radionuclide Angiography CLINICAL RELEVANCE Coronary Artery Disease Heart Failure Hypertrophic Cardiomyopathy Hypertension Aging LIMITATIONS FUTURE RESEARCH Evaluation of Diastolic Function by Radionuclide Techniques 105 INTRODUCTION For over 30 years, in the diagnosis and management of patients with known or suspected heart disease, nuclear cardiology proce- dures have made extensive use of radioactive tracers that can be injected as a bolus and tracked during fi rst pass through the vas- cular system, attached to red blood cells and in equilibrium within the vascular space or as myocardial perfusion tracers that defi ne the endocardial borders of the left ventricle.1 First pass radio- nuclide angiography (FPRNA) and equilibrium radionuclide angiocardiography (ERNA) have been the most commonly used techniques capable of assessing global and regional systolic and diastolic function at rest and following supine or upright exercise. Th ey were used extensively in the 1970s and 1980s. Th e advan- tages of these modalities over other cardiac tests available at that time included counts based on true three-dimensional measure- ments (independent of geometric assumptions), high accuracy, reproducibility, and absolute quantitation. However, such accu- rate measurements of diastolic function were diffi cult to perform using the standard methods of acquisition, and processing in clinical practice and eff orts to achieve greater accuracy and repro- ducibility were time consuming, computer intensive, and not practical in most clinical settings.2 Echocardiography provides similar information on diastolic function and is portable and highly fl exible, which off ers practical advantages. In addition, echocardiography provides assessment of valves, wall thickness, left ventricular (LV) mass, chamber pressures, fl ow dynamics, and the integrity of the pericardium from the same study, which makes it much more valuable for patient evaluation and management. For these reasons, echocardiography has been the most practical method for the assessment of diastolic function. Due to practical and economic factors, FPRNA and ERNA techniques are rarely performed in general clinical practice, and even less for evaluation of diastolic function. However, many of the concepts and methods developed for diastolic function analysis for FPRNA and ERNA in the 70s and 80s may be applicable today to the information available from the 8 million radionuclide myocardial perfusion imag- ing studies performed annually in the United States. Early radionuclide perfusion imaging did not allow the assessment of systolic or diastolic ventricular function. In the mid-1990s, several methods for assessment of systolic ventricular function using 8 time frames in the heart cycle were developed, and recently this technique has been modifi ed to allow greater temporal sampling through 16 time frames, which can be used for the evaluation of diastolic function.3,4 Th is may provide incremental Ch009-X3754.indd 105 1/16/2008 2:37:03 PM Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques106 information to the assessment of perfusion and systolic function. In some circumstances, diastolic dysfunction may identify pre- clinical abnormalities in the absence of alterations of systolic function. Given the current limited utilization of FPRNA and ERNA for assessment of diastolic function, this review will focus on the concepts and methods that have been found to be useful in the past and will then look at the opportunities for obtaining diastolic information from radionuclide myocardial perfusion studies that are currently being performed in such large numbers. PATHOPHYSIOLOGY Basic Principles of Radionuclide Assessment of Diastolic Function All radionuclide approaches for assessing systolic and diastolic LV function require the generation of a curve plotting the changes in radioactivity, which is proportional to changes in LV volume over time, as shown in Figure 9-1. From this time-activity curve (TAC), the fi rst derivative, which measures the change in volume over time, is derived and used to calculate the most rapid changes in ejection and fi lling and the time when the maximal rate occurs. Th e typical ranges of normal values for these diastolic parameters in humans are shown in Box 9-1.5 Th e left side of the curve prior to end systole (ES) in Figure 9-1 provides information on the systolic function of the ventricle as expressed by the rate of ejection, measured as end diastolic volumes per second (EDV/sec), and the time at which this peak ejection occurs, expressed as time to peak fi lling rate (TPFR). For ventricles with muscle damage or infi ltration, pericardial abnor- malities, or ischemia, the rate of emptying is decreased and there is prolongation of the time when the peak emptying rate is achieved. Diastole is represented to the right of end systole in Figure 9-1 and is a much more complicated process, which con- sists of four distinct phases: 1. Isovolumic relaxation 2. Peak fi lling rate (PFR) 3. Diastasis 4. Atrial systole Isovolumic relaxation starts at end systole, is an energy- dependent process, has a short duration (usually 2.5 end diastolic volumes/ second) 2. Time to peak fi lling rate (TPFR) ( Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 107 Equilibrium Radionuclide Angiocardiography Methods in Diastolic Assessment Data Acquisition Important variables for performing diastolic function analysis using ERNA are listed in Box 9-2. Technetium (Tc)-99m pertech- netate is the radioisotope of choice and is attached to the patient’s own red blood cells using one of three possible labeling methods, which vary in the time to perform labeling, expense, and labeling effi ciency.1 Both planar and single photon emission computed tomography (SPECT) methods of acquisition are available, but nearly all studies are performed using planar techniques, with the patient positioned in the left anterior oblique (LAO) view, which allows the best separation of the right and left ventricles for inde- pendent and accurate volume measurements in each chamber.8,9 An example of a typical LAO view is shown in Figure 9-3. Th e labeled red blood cells circulate in the vascular space, and the patient’s electrocardiographic (ECG) signal is used to set the timing for acquisition of each heart beat at individual time points, which may vary from 10 to 150 msec, depending on heart rate and the preset parameters. Information for each time point for each beat (usually >400 beats are acquired) is summed so that the fi nal TAC is an average rather than information from a single beat or a small number of beats, as is provided by other modalities. For this reason, this technique may be more representative of overall function than are other methods, due to the large number of beats averaged. Unlike systolic function analysis, where changes in heart rate and arrhythmias have relatively little infl uence on the time to end systole and EF, diastolic parameters are markedly aff ected by heart rate variability during acquisition and processing. To avoid volume and fi lling inconsistencies due to heart rate variability and arrhyth- mias from such a large number of beats, the R-R interval is sampled prior to acquisition and the parameters set up to reject individual beats that vary by ±10% of the mean R-R. Since the beat following a rejected beat has a longer fi lling period and will add variability to the measurements due to diff erences in end diastolic volume and EF, it is also rejected. Th ere are three computer methods used to acquire ERNA studies: frame, list, and buff ered beat acquisition. Frame mode is the simplest method. It samples the R-R interval prior to acquisi- tion, determines the number of time frames for each beat, and puts data into the appropriate time frame in real time for each beat using the set parameters until a new ECG gating signal identifi es the beginning of a new contraction. Once a beat has been added to the particular time bin, it cannot be removed. If there is an early beat, a new ECG trigger resets the acquisition so that the time bins toward the end of the heart cycle will have fewer beats contributing counts. Th e TAC generated from this method of acquisition suff ers from count dropoff in the terminal frame(s) due to heart rate variability; and although accurate for EF mea- surements, these curves cannot be analyzed for diastolic parame- ters using harmonic analysis. Although this is not the best method, it is universally used because of its simplicity and the small storage size of the retained data. List mode acquisition is the best method. It retains the X,Y spatial distribution of the radiotracer for every millisecond of acquisition, along with the ECG trigger signal so that the data set Time (msec) V ol um e E D V /s ec ED PER ES IR PFR Diastasis ED Atrial systole Normal Abnormal Diastolic function Figure 9-2 Schematic of normal and abnormal diastolic function time- activity curves. The blue line shows that PFR has a fl atter slope and is shifted to the right, indicating a delay in fi lling in comparison with the normal curve. ED, end diastole; EDV, end diastolic volume; PER, peak ejec- tion rate; ES, end systole; IR, isovolumic relaxation; PFR, peak fi lling rate. Box 9-2 Basics of Equilibrium Radionuclide Angiocardiography (ERNA) Acquisition for Diastolic Function Analysis 1. 20–30 millicuries Tc-99m labeled red blood cells 2. Labeling methods a. In vivo: fastest and least expensive but lowest binding effi ciency b. Modifi ed in vivo/in vitro: compromise with good labeling effi ciency c. In vitro: longest time and expense but best labeling effi ciency 3. Planar or single photon emission computed tomography (SPECT) 4. Positioning: Best septal separation, left anterior oblique (LAO) 5. Arrhythmia rejection: ±10% of mean R-R interval and drop postpremature beat 6. Temporal resolution: Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques108 can be reformatted into any timing interval and use the appropri- ate arrhythmia rejection during postprocessing. It provides maximal fl exibility relative to heart rate variability, but unfortu- nately at the expense of prolonged processing time and massive data storage. Th is technique was used exclusively for all studies performed by the group at the U.S. National Institutes of Health.10 A hybrid method, the buff ered beat approach, is an attempt to provide realistic fl exibility for heart rate variability while keeping data size to a manageable limit. It uses a temporary memory buff er to examine each beat and the ECG gating signal with regard to the set baseline parameters and makes an instant deci- sion to keep or reject the beat.6,7 An additional feature of this method is a forward-backward curve generation technique to avoid discontinuities or count dropoff in the last several frames, which precludes harmonic analysis of the TAC. Data Analysis For analysis of diastolic indices, there needs to be adequate tem- poral sampling of LV volume to capture the fi ne detail required to detect minor or subtle alterations in diastolic fi lling. Th e actual sampling interval will vary with heart rate. To achieve a temporal resolution under 50 msec usually requires 16–32 frames per heart cycle with frame mode or buff ered beat. At slow heart rates, more frames are required than at faster heart rates. Th e processed images are fi ltered to reduce statistical noise, the edges of the left ventricle are defi ned using manual or automated edge detection software, and background subtraction is performed. Th e radioac- tive counts within these boundaries represent the total volume in the ventricle and are used to produce a TAC. A TAC from a frame mode of 16 time intervals acquired from a clinical study is shown in Figure 9-4. All the fi ne detail shown schematically in Figure 9-1 is retained in this curve, which does not have any dropoff in counts in the terminal frames that may be seen in the presence of even minor sinus arrhythmias but is much more pronounced in the presence of atrial or ventricular arrhythmias. Figure 9-5 is from a study with 32 frame intervals. In comparison with the 16-frame study shown in Figure 9-4, the higher temporal resolution results in even more detail during the diastolic fi lling period. Once the TAC has been generated, there are two general methods of diastolic function analysis: digital fi ltering and math- ematical curve fi tting.10 With digital fi ltering or harmonic analy- sis, three to fi ve harmonics are applied to smooth noise in the TAC, and the fi rst derivative is taken to defi ne the point at which the greatest change in volume is present; this change and the time at which it occurs represents the PFR and TPFR. An example is shown in Figure 9-6. An absolute requirement for harmonic analysis is that the EDV from the TAC start and end at the same volume point. Figure 9-7 shows an example of count dropoff due to arrhythmias in a study acquired by frame mode. In the presence of count dropoff , error is introduced into the derived values from harmonic analysis. Discontinuity occurs in the terminal frames with frame mode acquisition, and for this reason, list or buff ered beat acquisition with forward and backward reconstruction of the TAC is required to use harmonic methods of analysis. Diastolic function values derived using a mathematical curve fi tting technique generally take the available data and apply a third-order polynomial equation to derive PFR and TPFR from the slope changes in the TAC. Th is method is less susceptible to discontinuities in the TAC. Th e basic concepts of diastolic function analysis for ERNA were developed and performed in the late 1970s and early 1980s, when the technical requirements were recognized and observed. Currently, most software packages on nuclear cardiology worksta- tions are capable of generating diastolic function values from any 70000 60000 50000 40000 30000 20000 10000 0 0 55045035025015050 C ou nt ( co un t) Time (msec) Figure 9-4 A 16 time interval frame mode time-activity curve from the study in Figure 9-3. The individual time points and triangles and the fi tted curve are shown. All the fi ne diastolic detail shown in the schematics for Figures 9-1 and 9-2 can be seen in this curve, even though the 16 time intervals provide less temporal sampling than a 24- or 32-frame study. A 20000 15000 10000 5000 0 0 1100900700500300100 C ou nt ( co un t) Time (msec)B Figure 9-5 An equilibrium radionuclide angiocardiogram, shown in rep- resentative end diastole and end systole for the actual study and with the 32 time frame derived curve. With 32 frames, fi ner detail can be seen for all four phases of diastole. Ch009-X3754.indd 108 1/16/2008 2:37:05 PM Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 109 TAC obtained from ERNA or ECG gated SPECT studies. A typical print-out of results is shown in the right-hand panel of Figure 9-5. Unfortunately, details such as the accuracy of the ECG gating mechanism, the presence or absence of count dropoff in the terminal frames, information density, and temporal resolu- tion are ignored. Th ese systems are capable of generating values for diastolic function indices but are not used clinically. First Pass Radionuclide Angiography Data Acquisition A method for diastolic radionuclide analysis involves FPRNA. At one time this technique was being performed with equal frequency to myocardial perfusion imaging and ERNA for detection of coro- nary artery disease (CAD) and systolic function assessment. Today it is rarely performed. First pass techniques for assessment of diastolic function require administration of a compact intrave- nous (IV) bolus of radioactivity and use of a very high temporal resolution and high count rate camera system to follow the radio- activity as it traverses the right and left ventricles. Serial gated images at 25–50 msec of temporal resolution are acquired, and the resultant TACs allow systolic and diastolic function analysis of the right and left ventricles at rest or following exercise or pharmaco- logic stress. Th ere was a dramatic decline in the use of this tech- nique in the 1980s and 1990s due to a lack of high count rate multicrystal camera systems, which are optimal for the technique. Performing FPRNA studies with a conventional single crystal gamma camera system is not optimal due to the low count rate. Th e basic requirements for performing studies are shown in Box 9-3 and will be discussed in the following section. Any Tc-99m radiolabeled compound can be used for bolus administration. When assessment is to be made at rest and fol- lowing stress on one day, an agent that is cleared by the kidneys (Tc-99m DMSO or DTPA) can be given fi rst, followed by an agent that is cleared by the liver (Tc-99m sulfur colloid) or a heart perfusion tracer (Tc-99m tetrofosmin or sestamibi), so that there is no interference during the second study from the initial dose. Th e total dose administered can be lower when a multicrystal camera is used, but with a single crystal camera that is not capable of high count rates, 25–30 millicuries are required. Th e total dose must be given as a tight IV bolus over 2 or 3 seconds, which requires at least an 18-gauge IV in the antecubital fossa or the external jugular. If such venous access is not available, the study should not be attempted. 0 8.00e4 EDC (count) ESC (count) TES (msec) TPE (msec) PER(/SV) (%/sec) TPE/T (%) 1/3EF(/SV) (%) 1/3ER(/SV) (%/sec) TPF (msec) PFR(/SV) (%/sec) TPF/TF (%) 1/3FF(/SV) (%) 1/3FR(/SV) (%/sec) 1/2FF(/SV) (%) 64162 36386 202 92 718.8 15.5 31.7 471.4 94 637.2 24.0 59.8 460.2 11.2 ED PER ES PFR6.00e4 4.00e4 2.00e4 –8.00e4 –6.00e4 –4.00e4 –2.00e4 0 55050045040035030025020015010050 (d v/ dt � 1 0) : (c ou nt ) Time (msec) FITTING RESULTS Item Value 30000 15000 20000 25000 10000 5000 0 0 800700600500400300200100 C ou nt s Time (msec) Figure 9-6 The graph shows the third harmonic fi tted curve superimposed by the fi rst derivative curve with the peak ejection rate and peak fi lling rate. To the right is the print-out of all the variables that can be derived from the data. ED, end diastole; PER, peak ejection rate; ES, end systole; PFR, peak fi lling rate. Figure 9-7 Time-activity curve from a 32-frame study showing terminal frame dropoff in the last two frames due to an arrhythmia. Box 9-3 Basics of First Pass Radionuclide Angiography (FPRNA) Acquisition for Diastolic Function Analysis 1. Radiopharmaceutical a. 10–30 millicuries of Tc-99m sulfur colloid, DTPA b. Bolus injection of Tc-99m sestamibi or tetrofosmin in conjunction with perfusion, given rapidly in small volume c. Total dose injected adjusted for count rate capabilities of camera 2. Injection site a. Antecubital vein or external jugular with minimum of 18-gauge IV cannula 3. Camera types a. Multicrystal preferred due to high count rates b. Single crystal must be capable of 150,000 counts/sec 4. Temporal resolution: Usually 25 msec 5. Acquire images in anterior position Ch009-X3754.indd 109 1/16/2008 2:37:06 PM Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques110 Anterior images are acquired with the patient supine or upright with the chest directly on the camera head. Exercise is best per- formed on a bicycle, which allows the chest to be relatively station- ary and the images free of motion artifacts. Studies have been acquired during treadmill exercise, but this requires placement of external radioactive markers that can be used to correct for motion. Since only eight to ten beats can be used to analyze right ventricular (RV) or LV function without having bolus overlap in the chambers, heart rate variability or arrhythmias will further limit the number of beats that can be processed and will result in sampling bias or overlap of tracer activity in more than one chamber. Th ese sampling limitations may result in poor study quality and limit the conclusions that can be reached. Echocar- diography, computed tomography (CT) ventriculography, and cardiac magnetic resonance have similar sampling limitations. ERNA, which averages more than 400 beats, provides a more robust assessment of overall function. Depending on the count rate capabilities, diastolic and systolic parameters can be acquired from a single beat, or beats can be summed using ECG gating to give higher information density and allow better edge detection. Conventional gamma camera acquisition provides low counts and generally requires gating and summing of multiple beats for accu- rate results. Data Analysis From a single beat or summed beats, the data are Fourier fi ltered using a third- to fi fth-order harmonic with appropriate back- ground subtraction, and the fi rst derivative of the resultant TAC is used to measure fi lling rates and the time to peak fi lling. Th is technique remains the most accurate for assessment of RV func- tion and for the detection of pulmonary hypertension. CLINICAL RELEVANCE Radionuclide methods for diastolic function analysis have been performed predominantly on a research basis in specifi c patient populations and are not used on a day-to-day basis in general clinical cardiology practice. Th is is due, in part, to the lack of appropriate equipment, diffi culty in accurately performing the measurements, and variability in the measurements due to factors other than cardiac pathology, such as age-related changes and the eff ects of medications. Th is variability makes it diffi cult to measure diastolic parameters in a given patient and meaningfully apply the values for purposes of diagnosis, management, or monitoring of therapy. Is the abnormal value due to the patient’s age, systolic function, myocardial stiff ness, ischemia, or other variables? Even with all of these limitations, the technique has been useful in certain disease states and clinical scenarios, as listed in Box 9-4. Th ese will be discussed in detail. Coronary Artery Disease Diagnosis Although CAD diagnosis using radionuclide methods is usually performed by measuring myocardial perfusion or changes in sys- tolic function at baseline and following stress, analysis of diastolic function alone or in conjunction with these other measures pro- vides an accurate diagnosis5 based on the induction of LV isch- emia, which causes a transient increase in myocardial “stiff ness” and a decrease in relaxation refl ected in a decreased PFR and an increased TPFR. Th ese are usually measurements of global changes, but regional analysis can also be performed in an attempt to increase sensitivity by measuring the small changes that may not be detected by a global fi lling value or time.11 Using ERNA, Bonow et al. found a very high percentage of abnormal diastolic function in the resting state in patients with documented CAD.12 In 231 patients with chronic CAD, PFR and TPFR were abnormal in 91%, in 85% of those without Q waves, and in 82% of patients with normal resting LV EFs, no resting regional wall motion abnormalities, and no Q waves. Th ese fi ndings suggest a high rate of abnormalities in patients with CAD at rest independent of LV systolic function or previous myocardial infarction. Using FPRNA, Reduto et al. performed rest and bicycle exercise measurements of PFR and of PFR in the fi rst third of diastole in 32 normal and 68 CAD patients.13 In comparison with normals, patients with CAD had a lower PFR overall and a lower PFR in the fi rst third of diastole during exer- cise. Although the CAD patients also had an abnormal EF response to exercise, diastolic parameters were more sensitive for detection of disease. It has also been shown among patients with CAD and with normal LV systolic function at rest that impaired LV fi lling and regional asynchrony predict a greater degree of exercise-induced ischemia, suggesting a greater extent of jeopar- dized myocardium.14,15 Despite the documented effi cacy of diastolic function analysis for CAD diagnosis, it is not being used in the practice of cardiol- ogy today due to the limitations previously listed. With the potential for deriving similar information from 16-frame ECG gated perfusion studies, the technique may provide ancillary information beyond perfusion that may have a role for diagnosis and monitoring. Th is needs to be validated. Monitoring Treatment of Coronary Artery Disease Once a diagnosis of CAD has been made, diastolic function anal- ysis has also been used to document the response to treatment. Bonow et al. documented improvement in abnormal diastolic function following revascularization.16 Again, diastolic abnor- malities were present in the resting state and did not require stress to provoke dysfunction. In a study of only 25 patients with single- vessel CAD, all had abnormal resting diastolic dysfunction despite normal systolic function. With exercise, 23 of the 25 developed a drop in EF, indicating the development of ischemia. Following percutaneous transluminal coronary angioplasty, resting diastolic function normalized in all patients; and with exercise, EF Box 9-4 Clinical Patient Populations Evaluated Using Radionuclide Diastolic Function Analysis 1. Coronary artery disease (CAD) a. Diagnosis of CAD b. Monitoring therapy 2. Heart failure a. Normal systolic function b. Abnormal systolic function 3. Hypertrophic cardiomyopathy 4. Hypertension 5. Aging Ch009-X3754.indd 110 1/16/2008 2:37:06 PM Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 111 increased. Th ese fi ndings suggest that resting diastolic dysfunc- tion is a very sensitive indicator of signifi cant CAD, even in the absence of systolic abnormalities, and that following successful revascularization, resting diastolic dysfunction improves. Heart Failure Normal Systolic Function Patients with clinical symptoms of congestive heart failure gener- ally have abnormal systolic function, but as many as 30% to 40% of these patients may have normal systolic function and their symptoms are on the basis of diastolic dysfunction.17,18 Common causes of diastolic dysfunction include increased resistance to ventricular infl ow caused by constrictive and restrictive pericar- dial disease, hypertrophy, scarring due to infarction, and volume overloading. Two other causes include impaired myocardial relax- ation due to ischemia or cardiomyopathies and increased resis- tance to atrial emptying in patients with mitral stenosis. Although radionuclide methods may be useful for detection of diastolic abnormalities in these groups, the information provided is less useful than that provided by echocardiography, which should be the fi rst diagnostic test performed. Soufer was able to show in 58 patients with congestive heart failure and normal systolic function that 38% had a reduction in PFR below 2.5 EDV/sec, and an additional 24% had probable diastolic dysfunction with values of 2.5–3.0 EDV/sec. Th e etiol- ogy was CAD and hypertension in the majority of patients. Abnormal Systolic Function Although it has been shown using ECG techniques that patients with heart failure and abnormal systolic function also have diastolic abnormalities, radionuclide methods have not been in- vestigated in this population.19,20 In these patients, diagnostic abnormalities were associated with worse symptoms and increased event rate. Due to complex hemodynamics, neurohumoral factors, arrhythmias, and medications, the values for diastolic indices are diffi cult to measure and interpret. For these reasons, radionuclide methods have limited application. Hypertrophic Cardiomyopathy Patients with HCM have been extensively evaluated in terms of diagnosis and management using radionuclide techniques because of the interest and expertise of the group at the National Insti- tutes of Health.21–26 Th e major abnormalities in HCM patients include prolonged isovolumic relaxation caused by myocardial ischemia and intracellular calcium overloading, as well as delayed rapid ventricular fi lling and a greater dependence on the atrial contribution to fi lling. In addition to documenting these abnor- malities, radionuclide techniques have been used to monitor the eff ects of treatment. Th e calcium blockers verapamil and nifedip- ine have been shown to improve LV relaxation and fi lling with IV administration and with long-term oral administration. In addi- tion to improving hemodynamic parameters, there are also clinical improvements in exercise tolerance and heart failure symp- toms.21,22 It was shown that the early and late improvement in symptoms with verapamil was related to the extent of improve- ment in diastolic fi lling. Th ese fi ndings also explain why HCM patients can go into severe heart failure when they are not in sinus rhythm and lose atrial contraction, which makes a larger than normal contribution to ventricular fi lling in these abnormal ventricles. However, at this stage of our understanding of the etiology and management of HCM, it is accepted that diastolic dysfunction is present and that there is no need to document its existence inde- pendently of the results available from echocardiography, which is an essential test in HCM. Hypertension In the presence of hypertension, there are alterations in diastolic function independent of alterations in systolic function or the presence of CAD that can be measured by radionuclide methods.27,28 Cuocolo et al. evaluated 41 essential hypertensive patients without CAD at rest and with exercise by ERNA.27 With exercise, 22 patients had an appropriate increase in EF and 19 had a drop in EF. In the patients with a drop in EF, resting PFR and TPFR were reduced. Th is suggests that resting diastolic function detects early changes in myocardial function at rest in patients with essential hypertension that predict an abnormal response during stress. Th ese changes were not directly related to previously identifi ed modifi ers of diastolic parameters such as age, heart rate, and the extent and severity of hypertension. Abnor- malities were directly related to myocardial mass. Th e acute eff ects of verapamil on diastolic function in hyper- tensive patients have also been studied in the cardiac catheteriza- tion laboratory. Patients had resting diastolic abnormalities that improved with the acute administration of verapamil.29 Th ese studies suggest that diastolic function analysis may be used for preclinical detection of myocardial dysfunction in patients with hypertension. Aging Th ere are age-related changes in ventricular relaxation and fi lling that are independent of the increasing prevalence of hypertension, CAD, increased LV mass, and altered response to catecholamines and that suggest that there are primary eff ects of aging on dia- stolic function.7,30,31 It has been documented by many methods that with increasing age, there is a decrease in PFR and TPFR and an increase in the atrial component of diastole. Th e etiology of these changes is multifactorial but may be reversed, in part, through exercise training and with the use of calcium blockers.7,30 It is also possible that fi brosis or protein deposition within the myocardium may mediate the abnormalities.32 Documentation of these abnormalities is most useful when diastolic radionuclide parameters are being used to diagnose ischemia, in order not to confuse age-related changes with the presence of CAD. Adjusting for age is critical. LIMITATIONS Despite the extensive literature on the use of radionuclide methods for analysis of diastolic function, the technique is not being used in clinical settings due to several factors. Th ese include the lack of clinical utilization of these techniques for diagnosis of CAD and systolic function and the absence of special gamma cameras that optimize performance of the measurements. Such measure- ments were diffi cult to perform using the standard methods of acquisition and processing in clinical practice, and eff orts to achieve greater accuracy and reproducibility were time consum- Ch009-X3754.indd 111 1/16/2008 2:37:07 PM Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques112 ing, computer intensive, and not practical in most clinical set- tings.2 In addition, techniques such as echocardiography and cardiovascular magnetic resonance provide similar information on diastolic function and much more information on heart valves, wall thickness, LV mass, chamber pressures, fl ow dynamics, and the integrity of the pericardium. Th is additional information makes these techniques much more valuable for patient evalua- tion and management. Other studies have brought into question the value of measur- ing relaxation rates and time intervals. Studies have shown that despite the improvement in these parameters with the use of calcium channel blockers, there may be an increase in LV end diastolic pressure as well as an overall prolongation of the time constant of relaxation.2 FUTURE RESEARCH Given the widespread use of ECG gated SPECT perfusion imaging and the relative lack of utilization of ERNA and FPRNA, the ability to assess diastolic function analysis from perfusion data would allow screening of diastolic dysfunction in a larger patient population during the assessment for obstructive CAD. In order to correctly perform diastolic function analysis from gated SPECT perfusion images, there are limitations to overcome. Th ese include the low temporal resolution, failure to perform optimal arrhyth- mia rejection, and poor edge detection due to the low information density contained in the perfusion data. Despite these limitations, there are several groups that have shown the feasibility of such an approach.3,9,33–36 Unlike ERNA and FPRNA, in which the injected radioactivity remains in the intravascular space, Tc-99m perfusion agents are cleared by the liver and empty into the gastrointestinal tract. Th is means that a smaller percentage of the injected dose is actually in the myocardium when imaging is performed and that the counts are low, mandating that the time intervals for each beat be rela- tively long to achieve adequate information density in each frame. Increasing the imaging time will improve counts but decrease quality, as patients are likely to move. Most studies are acquired for 8 time frames. If the heart rate is 60 beats/minute, each time frame will be 125 msec, which does not allow suffi cient temporal resolution to adequately separate out the various components of diastole. If 16 frames are used, each frame will have a temporal resolution of 63 msec and half the counts, but adequate edge defi nition can still be performed.3 Th e other problem that requires resolution is getting a TAC without terminal frame count dropout. Currently, arrhythmia rejection for ECG gated perfusion SPECT uses ±50% of the mean R-R interval to avoid compromising the perfusion study, which would either drop beats and lower total counts or prolong the acquisition time to achieve adequate counts. Some of the newer camera/workstation systems allow multiple acquisition windows so that arrhythmia rejection can be performed on one set of data while a separate window can be used for the perfusion data without arrhythmia rejection. Additional time is not added to the acquisition. If arrhythmias are present, the ECG gated data set will still be compromised, and quality control needs to be performed. Th e fi nal hurdle is getting appropriate edge defi nition from the available algorithms to accurately track the endocardial borders of the ventricle. Existing software packages have been shown to handle the lower counts in 16-frame acquisition.3 Defi nition of the mitral valve plane at the base of the heart is also diffi cult, as the transition from the left atrium, which has little uptake, to the myocardium in the area of the valves and membranous septum is diffi cult to identify. Failure to clearly delineate this separation will result in error in the volume of the cavity and the resul- tant TAC. Using this approach in ECG gated SPECT studies, normal value ranges were developed for PFR (2.62 ± 0.46 and −2 SD 216.7 msec) in 90 patients without CAD or hypertension. PFR had signifi cant correlations with age, EDV, and EF, but TPFR did not. Th is sug- gests that TPFR may be a more robust measurement by this technique, as it is independent of these other factors that infl u- ence PFR. Th ese normal ranges were then applied to a validation set of patients and showed similar results. From the combined populations, normal threshold values for PFR of greater than 1.70 EDV/sec and for TPFR under 208 msec were established.3 Th ese results need to be validated in a larger population. R E F E R E N C E S 1. Cerqueira M: Nuclear Cardiology. Boston, Blackwell Scientifi c, 1994. 2. Arrighi JA, Soufer R: Left ventricular diastolic function: Physiology, methods of assessment, and clinical signifi cance. J Nucl Cardiol 1995;2: 525–543. 3. Akincioglu C, Berman DS, Nishina H, et al: Assessment of diastolic func- tion using 16-frame 99mTc-sestamibi gated myocardial perfusion SPECT: Normal values. J Nucl Med 2005;46:1102–1108. 4. Germano G, Kiat H, Kavanagh PB, et al: Automatic quantifi cation of ejec- tion fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;36:2138–2147. 5. Bonow RO: Radionuclide angiographic evaluation of left ventricular dia- stolic function. Circulation 1991;84:I208–I215. 6. Johannessen KA, Cerqueira M, Veith RC, Stratton JR: Th e relation between radionuclide angiography and Doppler echocardiography during contractile changes with infusions of epinephrine. Int J Cardiol 1991;33: 149–157. 7. Levy WC, Cerqueira MD, Abrass IB, et al: Endurance exercise training augments diastolic fi lling at rest and during exercise in healthy young and older men. Circulation 1993;88:116–126. 8. Updated imaging guidelines for nuclear cardiology procedures, part 1. J Nucl Cardiol 2001;8:G5–G58. 9. Higuchi T, Taki J, Nakajima K, et al: Left ventricular ejection and fi lling rate measurement based on the automatic edge detection method of ECG-gated blood pool single-photon emission tomography. Ann Nucl Med 2004;18:507–511. 10. Bacharach SL, Green MV, Borer JS: Instrumentation and data processing in cardiovascular nuclear medicine: Evaluation of ventricular function. Semin Nucl Med 1979;9:257–274. 11. Bonow RO, Vitale DF, Bacharach SL, et al: Asynchronous left ventricular regional function and impaired global diastolic fi lling in patients with coro- nary artery disease: Reversal after coronary angioplasty. Circulation 1985;71:297–307. 12. Bonow RO, Bacharach SL, Green MV, et al: Impaired left ventricular dia- stolic fi lling in patients with coronary artery disease: Assessment with radio- nuclide angiography. Circulation 1981;64:315–323. 13. Reduto LA, Wickemeyer WJ, Young JB, et al: Left ventricular diastolic performance at rest and during exercise in patients with coronary artery disease. Assessment with fi rst-pass radionuclide angiography. Circulation 1981;63:1228–1237. 14. Perrone-Filardi P, Bacharach SL, Dilsizian V, Bonow RO: Eff ects of regional systolic asynchrony on left ventricular global diastolic function in patients with coronary artery disease. J Am Coll Cardiol 1992;19:739– 744. 15. Perrone-Filardi P, Bacharach SL, Dilsizian V, Bonow RO: Impaired left ventricular fi lling and regional diastolic asynchrony at rest in coronary artery disease and relation to exercise-induced myocardial ischemia. Am J Cardiol 1991;67:356–360. Ch009-X3754.indd 112 1/16/2008 2:37:07 PM Chapter 9 • Evaluation of Diastolic Function by Radionuclide Techniques 113 16. Bonow RO, Kent KM, Rosing DR, et al: Improved left ventricular diastolic fi lling in patients with coronary artery disease after percutaneous trans- luminal coronary angioplasty. Circulation 1982;66:1159–1167. 17. Soufer R, Wohlgelernter D, Vita NA, et al: Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985;55: 1032–1036. 18. Watanabe J, Levine MJ, Bellotto F, et al: Eff ects of coronary venous pressure on left ventricular diastolic distensibility. Circ Res 1990;67:923–932. 19. Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779. 20. Shen WF, Tribouilloy C, Rey JL, et al: Prognostic signifi cance of Doppler- derived left ventricular diastolic fi lling variables in dilated cardiomyopathy. Am Heart J 1992;124:1524–1533. 21. Bonow RO, Dilsizian V, Rosing DR, et al: Verapamil-induced improvement in left ventricular diastolic fi lling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term eff ects. Circula- tion 1985;72:853–864. 22. Bonow RO, Rosing DR, Bacharach SL, et al: Eff ects of verapamil on left ventricular systolic function and diastolic fi lling in patients with hypertro- phic cardiomyopathy. Circulation 1981;64:787–796. 23. Bonow RO, Vitale DF, Maron BJ, et al: Regional left ventricular asynchrony and impaired global left ventricular fi lling in hypertrophic cardiomyopathy: Eff ect of verapamil. J Am Coll Cardiol 1987;9:1108–1116. 24. Cannon RO 3rd, Rosing DR, Maron BJ, et al: Myocardial ischemia in patients with hypertrophic cardiomyopathy: Contribution of inadequate vasodilator reserve and elevated left ventricular fi lling pressures. Circulation 1985;71:234–243. 25. Maron BJ, Bonow RO, Cannon RO 3rd, et al: Hypertrophic cardiomyopa- thy. Interrelations of clinical manifestations, pathophysiology, and therapy (2). N Engl J Med 1987;316:844–852. 26. Maron BJ, Spirito P, Green KJ, et al: Noninvasive assessment of left ven- tricular diastolic function by pulsed Doppler echocardiography in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:733– 742. 27. Cuocolo A, Sax FL, Brush JE, et al: Left ventricular hypertrophy and impaired diastolic fi lling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990;81:978–986. 28. Inouye I, Massie B, Loge D, et al: Abnormal left ventricular fi lling: An early fi nding in mild to moderate systemic hypertension. Am J Cardiol 1984;53:120–126. 29. Brush JE Jr, Udelson JE, Bacharach SL, et al: Comparative eff ects of vera- pamil and nitroprusside on left ventricular function in patients with hyper- tension. J Am Coll Cardiol 1989;14:515–522. 30. Arrighi JA, Dilsizian V, Perrone-Filardi P, et al: Improvement of the age- related impairment in left ventricular diastolic fi lling with verapamil in the normal human heart. Circulation 1994;90:213–219. 31. Bonow RO, Vitale DF, Bacharach SL, et al: Eff ects of aging on asynchronous left ventricular regional function and global ventricular fi lling in normal human subjects. J Am Coll Cardiol 1988;11:50–58. 32. Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic cardiomyopa- thy of the elderly. N Engl J Med 1985;312:277–283. 33. Kikkawa M, Nakamura T, Sakamoto K, et al: Assessment of left ventricular diastolic function from quantitative electrocardiographic-gated 99mTc- tetrofosmin myocardial SPET. Eur J Nucl Med 2001;28:593–601. 34. Kumita S, Cho K, Nakajo H, et al: Assessment of left ventricular diastolic function with electrocardiography-gated myocardial perfusion SPECT: Comparison with multigated equilibrium radionuclide angiography. J Nucl Cardiol 2001;8:568–574. 35. Higuchi T, Nakajima K, Taki J, et al: Assessment of left ventricular systolic and diastolic function based on the edge detection method with myocardial ECG-gated SPET. Eur J Nucl Med 2001;28:1512–1516. 36. Sakamoto K, Nakamura T, Zen K, et al: Identifi cation of exercise-induced left ventricular systolic and diastolic dysfunction using gated SPECT in patients with coronary artery disease. J Nucl Cardiol 2004;11:152– 158. Ch009-X3754.indd 113 1/16/2008 2:37:07 PM