Assessment of late-term progression of cardiac allograft vasculopathy in patients with orthotopic heart transplantation using quantitative cardiac 82Rb PET.

The risk stratification and long-term survival of patients with orthotopic heart transplantation (OHT) is impacted by the complication of cardiac allograft vasculopathy (CAV). This study evaluates changes in myocardial blood flow (MBF) and myocardial coronary flow reserve (CFR) in a group of long-term OHT patients using quantitative cardiac 82Rb-positron emission tomography (PET). Twenty patients (7 females and 13 males, mean age = 72.7 ± 12.2 years with CAV and 62.9 ± 7.2 years without CAV and post-OHT mean time = 13.9 years), were evaluated retrospectively using dynamic cardiac 82Rb-PET at rest and regadenoson-induced stress. The patients also underwent selective coronary angiography (SCA) for diagnosis and risk stratification. CAV was diagnosed based on SCA findings and maximal intimal thickness greater than 0.5 mm, as defined by International Society of Heart and Lung Transplantation (ISHLT). Global and regional MBFs were estimated in three vascular territories using the standard 1-tissue compartment model for dynamic 82Rb-PET. The myocardial CFR was also calculated as the ratio of peak stress MBF to rest MBF. Among twenty patients, seven had CAV in, at least, one major coronary artery (ISHLT CAV grade 1 or higher) while 13 patients did not have CAV (NonCAV). Mean rate-pressure products (RPP) at rest were significantly elevated in CAV patients compared to those without CAV (P = 0.002) but it was insignificant at stress (P = NS). There was no significant difference in the stress MBFs between CAV and NonCAV patients (P = NS). However, the difference in RPP-normalized stress MBFs was significant (P = 0.045), while RPP-normalized MBFs at rest was not significant (P = NS). Both CFR and RPP-normalized CFR were significantly lower in CAV compared to NonCAV patients (P < 0.001). There were significant correlations between MBFs and RPPs at rest for both CAV (ρ = 0.764, P = 0.047) and NonCAV patients (ρ = 0.641, P = 0.017), while there were no correlations at stress for CAV (ρ = 0.232, P = NS) and NonCAV patients (ρ = 0.068, P = NS). This study indicates that the resting MBF is higher in late-term post-OHT patients. The high resting MBF and reduced CFR suggest an unprecedented demand of blood flow and blunted response to stress due to impaired vasodilatory capacity that is exacerbated by the presence of CAV.

A combined static-dynamic single-dose imaging protocol to compare quantitative dynamic SPECT with static conventional SPECT.

BACKGROUND: SPECT myocardial perfusion imaging (MPI) is a clinical mainstay that is typically performed with static imaging protocols and visually or semi-quantitatively assessed for perfusion defects based upon the relative intensity of myocardial regions. Dynamic cardiac SPECT presents a new imaging technique based on time-varying information of radiotracer distribution, which permits the evaluation of regional myocardial blood flow (MBF) and coronary flow reserve (CFR). In this work, a preliminary feasibility study was conducted in a small patient sample designed to implement a unique combined static-dynamic single-dose one-day visit imaging protocol to compare quantitative dynamic SPECT with static conventional SPECT for improving the diagnosis of coronary artery disease (CAD). METHODS: Fifteen patients (11 males, four females, mean age 71 ± 9 years) were enrolled for a combined dynamic and static SPECT (Infinia Hawkeye 4, GE Healthcare) imaging protocol with a single dose of 99mTc-tetrofosmin administered at rest and a single dose administered at stress in a one-day visit. Out of 15 patients, eleven had selective coronary angiography (SCA), 8 within 6 months and the rest within 24 months of SPECT imaging, without intervening symptoms or interventions. The extent and severity of perfusion defects in each myocardial region was graded visually. Dynamically acquired data were also used to estimate the MBF and CFR. Both visually graded images and estimated CFR were tested against SCA as a reference to evaluate the validity of the methods. RESULTS: Overall, conventional static SPECT was normal in ten patients and abnormal in five patients, dynamic SPECT was normal in 12 patients and abnormal in three patients, and CFR from dynamic SPECT was normal in nine patients and abnormal in six patients. Among those 11 patients with SCA, conventional SPECT was normal in 5, 3 with documented CAD on SCA with an overall accuracy of 64%, sensitivity of 40% and specificity of 83%. Dynamic SPECT image analysis also produced a similar accuracy, sensitivity, and specificity. CFR was normal in 6, each with CAD on SCA with an overall accuracy of 91%, sensitivity of 80%, and specificity of 100%. The mean CFR was significantly lower for SCA detected abnormal than for normal patients (3.86±1.06 vs 1.94±0. 0.67, P < 0.001). CONCLUSIONS: The visually assessed image findings in static and dynamic SPECT are subjective, and may not reflect direct physiologic measures of coronary lesion based on SCA. The CFR measured with dynamic SPECT is fully objective, with better sensitivity and specificity, available only with the data generated from the dynamic SPECT method.

Noninvasive PET quantitative myocardial blood flow with regadenoson for assessing cardiac allograft vasculopathy in orthotopic heart transplantation patients.

BACKGROUND: Risk stratification and early detection of cardiac allograft vasculopathy (CAV) is essential in orthotopic heart transplantation (OHT) patients. This study assesses the changes in myocardial blood flow (MBF) noninvasively in OHT patients using quantitative cardiac PET with regadenoson. METHODS: Twelve patients (Group 1) (8 males, 4 females, mean age 55 ± 7 years) with no history of post OHT myocardial ischemia were enrolled 5.4 ± 2.0 years after OHT. Fifteen patients (Group 2) (9 males, 6 females, mean age 71 ± 9 years) with intermediate pretest probability but not documented evidence for coronary artery disease (CAD) were also included to serve as control. Global and regional MBFs were assessed using dynamic 13N-NH3 PET at rest and during regadenoson-induced hyperemia. The coronary flow reserve (CFR) was also calculated as the ratio of hyperemic to resting MBF. RESULTS: Mean regadenoson-induced rate-pressure products were similar in both groups, while there was an increase in resting rate-pressure product in Group 1 patients. Both mean and median values of resting MBF were higher in Group 1 than Group 2 patients (1.33 ± 0.31 and 1.01 ± 0.21 mL/min/g for Groups 1 and 2, respectively, P < .001), while mean hyperemic MBF values were similar in both Groups (2.68 ± 0.84 and 2.64 ± 0.94 mL/min/g, P = NS) but median hyperemic MBF values were lower in Group 1 than Group 2 patients (2.0 vs. 2.60 mL/min/g, P = .018). Both mean and median CFR values demonstrated a significant reduction for Group 1 compared to Group 2 patients (2.07 ± 0.74 vs 2.63 ± 0.48, P = .025). CONCLUSIONS: This study suggests that the MBF in OHT patients may be abnormal at resting state with diminished CFR. This hints that the epicardial and microvascular coronary subsystem may be exacerbated after OHT leading to the gradual progression of CAV.

Measurement of absolute myocardial blood flow in humans using dynamic cardiac SPECT and 99mTc-tetrofosmin: Method and validation.

BACKGROUND: The objective of this study was to measure myocardial blood flow (MBF) in humans using 99mTc-tetrofosmin and dynamic single-photon emission computed tomography (SPECT). METHODS: Dynamic SPECT using 99mTc-tetrofosmin and dynamic positron emission tomography (PET) was performed on a group of 16 patients. The SPECT data were reconstructed using a 4D-spatiotemporal iterative reconstruction method. The data corresponding to 9 patients were used to determine the flow-extraction curve for 99mTc-tefrofosmin while data from the remaining 7 patients were used for method validation. The nonlinear tracer correction parameters A and B for 99mTc-tefrofosmin were estimated for the 9 patients by fitting the flow-extraction curve [Formula: see text] for K 1 values estimated with 99mTc-tefrofosmin using SPECT and MBF values estimated with 13N-NH3 using PET. These parameters were then used to calculate MBF and coronary flow reserve (CFR) in three coronary territories (LAD, RCA, and LCX) using SPECT for an independent cohort of 7 patients. The results were then compared with that estimated with 13N-NH3 PET. The flow-dependent permeability surface-area product (PS) for 99mTc-tefrofosmin was also estimated. RESULTS: The estimated flow-extraction parameters for 99mTc-tefrofosmin were found to be A = 0.91 ± 0.11, B = 0.34 ± 0.20 (R 2 = 0.49). The range of MBF in LAD, RCA, and LCX was 0.44-3.81 mL/min/g. The MBF between PET and SPECT in the group of independent cohort of 7 patients showed statistically significant correlation, r = 0.71 (P < .001). However, the corresponding CFR correlation was moderate r = 0.39 yet statistically significant (P = .037). The PS for 99mTc-tefrofosmin was (0.019 ± 0.10)*MBF + (0.32 ± 0.16). CONCLUSIONS: Dynamic cardiac SPECT using 99mTc-tetrofosmin and a clinical two-headed SPECT/CT scanner can be a useful tool for estimation of MBF.

Utility of Equilibrium Radionuclide Angiogram-Derived Measures of Dyssynchrony to Predict Outcomes in Heart Failure Patients Undergoing Cardiac Resynchronization Therapy.

We evaluated a novel scintigraphic method using new parameters of mechanical left ventricular (LV) dyssynchrony and correlated it with clinical outcomes in heart failure patients with reduced ejection fraction receiving cardiac resynchronization therapy (CRT). METHODS: Sixty-six advanced heart failure patients referred for CRT with an LV ejection fraction (EF) of < 35% and QRS ≥ 120 ms were studied. We performed equilibrium radionuclide angiography (ERNA) before and 6 mo after CRT. We assessed ventricular dyssynchrony with parameters derived from the first harmonic phase (Ø) analysis of the ERNA time-activity curve and evaluated change in these parameters after 6 mo of CRT. These parameters include novel indices of synchrony (S), a measure of intraventricular contraction order, and entropy (E), a measure of intraventricular contraction disorder, and interventricular synchrony (IVS), a measure of synchronous biventricular function. RESULTS: Forty-seven (71%) patients improved clinically (responders) at 6 mo after CRT whereas 19 (28.8%) showed no change in New York Heart Association class or worsened (nonresponders). The post-CRT changes in QRS duration (P = 0.006), echocardiographic (P = 0.03) and ERNA LVEF (P = 0.0007), LVS (P = 0.004), LVE (P = 0.006), LV standard deviation of ventricular phase (LVSDØ) (P = 0.004), and IVS (P = 0.05) were significantly different between responders and nonresponders. Sixty-two percent of responders had either an LVS < 0.84 or an IVS ≥ 18.8° as opposed to only 16% of nonresponders (P = 0.001). Twenty-nine of 32 (91%) patients with either of these measures responded to CRT (P < 0.01). CONCLUSION: LVS and IVS are novel measures of LV dyssynchrony derived from ERNA planar analysis. A baseline value of LVS < 0.84 or IVS ≥ 18.8° predicts a positive response to CRT.

Image reconstruction in higher dimensions: myocardial perfusion imaging of tracer dynamics with cardiac motion due to deformation and respiration.

Myocardial perfusion imaging (MPI) using slow rotating large field of view cameras requires spatiotemporal reconstruction of dynamically acquired data to capture the time variation of the radiotracer concentration. In vivo, MPI contains additional degrees of freedom involving unavoidable motion of the heart due to quasiperiodic beating and the effects of respiration, which can severely degrade the quality of the images. This work develops a technique for a single photon emission computed tomography (SPECT) that reconstructs the distribution of the radiotracer concentration in the myocardium using a tensor product of different sets of basis functions that approximately describe the spatiotemporal variation of the radiotracer concentration and the motion of the heart. In this study the temporal B-spline basis functions are chosen to reflect the dynamics of the radiotracer, while the intrinsic deformation and the extrinsic motion of the heart are described by a product of a discrete set of Gaussian basis functions. Reconstruction results are presented showing the dynamics of the tracer in the myocardium as it deforms due to cardiac beating, and is displaced due to respiratory motion. These results are compared with the conventional 4D-spatiotemporal reconstruction method that models only the temporal changes of the tracer activity. The higher dimensional reconstruction method proposed here improves bias, yet the signal-to-noise ratio (SNR) decreases slightly due to redistribution of the counts over the cardiac-respiratory gates. Additionally, there is a trade-off between the number of gates and the number of projections per gate to achieve high contrast images.

Comparison of radionuclide angiographic synchrony analysis to echocardiography and magnetic resonance imaging for the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable arrhythmia syndrome entailing a high risk of sudden cardiac death. Discernment from benign arrhythmia disorders, particularly right ventricular outflow tract ventricular tachycardia (RVOT VT), may be challenging, providing an impetus to explore alternative modalities that may facilitate evaluation of patients with suspected ARVC. OBJECTIVE: We evaluated the role of equilibrium radionuclide angiography (ERNA) as a diagnostic tool for ARVC. METHODS: ERNA measures of ventricular synchrony-synchrony (S) and entropy (E)-were examined in patients with ARVC (n = 16), those with RVOT VT (n = 13), and healthy controls (n = 49). The sensitivity and specificity of ERNA parameters for ARVC diagnosis were compared with those of echocardiography (ECHO) and cardiovascular magnetic resonance (CMR). RESULTS: ERNA right ventricular synchrony parameters in patients with ARVC (S = 0.91 ± 0.07; E = 0.61 ± 0.1) differed significantly from those in patients with RVOT VT (S = 0.99 ± 0.01 [P = .0015]; E = 0.46 ± 0.05 [P < .001]) and healthy controls (S = 0.97 ± 0.02 [P = .003]; E = 0.48 ± 0.07 [P = .001]). The sensitivity of ERNA synchrony parameters for ARVC diagnosis (81%) was higher than that for ECHO (38%; P = .033) and similar to that for CMR (69%; P = .162), while specificity was lower for ERNA (89%) than that for ECHO and CMR (both 100%; P = .008). CONCLUSION: ERNA right ventricular synchrony parameters can distinguish patients with ARVC from controls with structurally normal hearts, and its performance is comparable to that of ECHO and CMR for ARVC diagnosis. These findings suggest that ERNA may serve as a valuable imaging tool in the diagnostic evaluation of patients with suspected ARVC.

Quantitative Signature of Coronary Steal in a Patient with Occluded Coronary Arteries Supported by Collateral Circulation Using Dynamic SPECT.

Coronary steal (CS) is a physiological process that induces absolute decrease in blood flow in collateralized myocardium compared to resting flow during coronary vasodilation due to redistribution of blood away from collateral-dependent myocardium. Although, CS has been well known for decades, there are very few noninvasive perfusion studies in humans that quantitatively predict the existence of CS. In this study, we show that the quantitative measurement of absolute value of regional myocardial blood flow (MBF) and coronary flow reserve (CFR) using dynamic single photon emitted computed tomography (SPECT) can help estimate the presence of CS in myocardium with obstructed coronary artery and collateral circulation.

Current methods of pharmacologic stress testing and the potential advantages of new agents.

This article presents the exciting advances made and ongoing in the area of pharmacologic cardiac stress testing. In particular, new A(2A)-specific receptor agonists work like adenosine but promise the delivery of uncomplicated vasodilator stress testing or the diagnosis and prognosis of coronary disease. These agents, although not perfect, do likely present a level of protection against the complications of bronchospasm and heart block. Phase III studies have shown that these agents promise a reduced symptom intensity and greater patient tolerance. One of these agents, regadenoson, is now Food and Drug Administration approved and will be delivered as the same single-dose bolus in all patients, regardless of weight, greatly simplifying the method and increasing its acceptability. Most widely applied with myocardial perfusion SPECT, these agents will find application with PET myocardial perfusion studies and likely MRI studies. Because of their effect on coronary supply rather than demand, they will not be applied with stress echocardiography. Before considering these agents, we will consider the principles and methods of stress testing, and particularly pharmacologic stress testing. The learning objectives of this article are to familiarize the reader with the methods and choices in stress testing for coronary disease diagnosis and prognosis, to present the advantages and disadvantages of pharmacologic stress testing, to review current pharmacologic stress-testing methods and their specific combination with imaging methods, to present the chemistry and effects of the new A(2a)-specific receptor agonists and their advantages compared with existing nonspecific agents, and to help the reader better understand the clinical role of the A(2a)-specific receptor agonists and their application.

Age-related decrease in cardiopulmonary adrenergic neuronal function in children as assessed by I-123 metaiodobenzylguanidine imaging.

BACKGROUND: Radioiodinated metaiodobenzylguanidine (MIBG) imaging has been used to evaluate adrenergic nerve activity in different organs. Cardiac and pulmonary MIBG uptake is important in predicting the prognosis of certain cardiopulmonary diseases. It has been reported that cardiac MIBG uptake decreases with age and is significantly lower in the elderly. However, there has been no systemic study on age-related changes in cardiac and pulmonary MIBG uptake in children. This study was undertaken to determine the changes in MIBG uptake in the developing heart and lung in children and adolescents. METHODS AND RESULTS: MIBG scans of 44 children (16 female and 28 male; age range, 2 months to 19 years) without abnormal uptake were selected from a large pool of patients with whole-body MIBG imaging performed for evaluation of neuroblastoma. All of the selected subjects had a normal physiologic distribution of MIBG and no history of heart or lung diseases. The patients were divided into 4 groups by age: group 1, 0 to 24 months; group 2, 25 to 48 months; group 3, 49 to 72 months; and group 4, 73 months or greater. Cardiac and pulmonary MIBG uptake values (expressed as heart-to-mediastinum [H/M] ratio and lung-to-mediastinum [L/M] ratio, respectively) were determined and compared among the 4 groups. H/M and L/M ratios were noted to decrease with age. The mean H/M and L/M ratios were in group 1, 4.13 +/- 0.66 and 1.53 +/- 0.18, respectively; in group 2, 3.46 +/- 0.71 and 1.26 +/- 0.18, respectively; in group 3, 3.19 +/- 0.94 and 1.13 +/- 0.17, respectively; and in group 4, 2.84 +/- 0.48 and 1.14 +/- 0.14, respectively. There was a significant inverse correlation between H/M ratio and age (r = 0.711, P < .001) as well as between L/M ratio and age (r = 0.718, P < .001). CONCLUSION: Cardiac and pulmonary MIBG uptake is inversely related to age in children.

A unique method by which to quantitate synchrony with equilibrium radionuclide angiography.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves symptoms and the survival rate in patients with advanced heart failure by improving synchrony. However, CRT is not always successful, is costly, and is applied without individualization. There is no specific measure of synchrony. The goal of this study was to analyze new quantitative parameters of synchrony and compare them with established measures. METHODS AND RESULTS: Equilibrium radionuclide angiography, phase angle (Ø), and amplitude quantitate regional contraction timing and magnitude and are the basis for new synchrony (S) and entropy (E) parameters. S is the vector sum of all amplitudes based on the angular distribution of Ø divided by the scalar sum of the length of all vectors. Complete S equals 1, and its absence equals 0. E measures the disorder in the region of interest, is 1 with random contraction and 0 with full synchrony, and differentiates among differing contraction patterns. Left ventricular S and E were measured in 22 normal equilibrium radionuclide angiography studies, where regions of interest were drawn from the left ventricle, left atrium, and background to analyze model ventricles with normal wall motion (N), ventricles with aneurysm (An), ventricles with severe diffuse dysfunction (Diff), and ventricles with severe regional dysfunction (Reg). The new S and E parameters were highly reproducible and well differentiated among N, An, Diff, and Reg, which were not separated by SD Ø (SD of ventricular phase), which has gained popularity as a measure of synchrony. CONCLUSION: Unique scintigraphic parameters for the evaluation of ventricular synchrony were derived, and their added value was determine compared with established measures. Indications for pacemaker therapy now include the treatment of severe congestive heart failure (CHF). Atrial triggered biventricular pacemakers reduce CHF symptoms and prolong life in patients with cardiomyopathy, severe CHF, left ventricular (LV) ejection fraction (EF) lower than 35%, and QRS greater than 120 milliseconds. Such pacing, or cardiac resynchronization therapy (CRT), seeks to reduce the heterogeneity and increase the synchrony of ventricular activation, conduction, and contraction. CRT has improved hemodynamics, increased exercise tolerance, reduced symptoms and the need for hospitalization, reversed ventricular remodeling, and reduced the all-cause mortality rate in CHF. However, CRT is costly, fails to improve symptoms or activity level in more than 30% of patients, and is applied blindly without individualization or consideration of lead placement sight. A variety of echocardiographic methods have sought to measure synchrony and its serial changes with CRT. A recent study presented evidence of the poor reproducibility of several widely applied echocardiographic measurements by which to determine ventricular synchrony. Magnetic resonance imaging has excellent resolution of regional wall motion and has been applied to assess ventricular synchrony and its response to pacing therapy. However, these methods are complex and are not well established or widely available, and magnetic resonance imaging has not been widely applied after pacing. An accurate and reproducible method is needed by which to objectively measure regional ventricular synchrony. Phase image analysis, a functional method based on the first Fourier harmonic fit of the gated blood pool time versus radioactivity curve, generates the parameters of amplitude (A), which parallels the extent of regional ventricular contraction or stroke volume, and phase angle (Ø), which represents the timing of regional contraction. It was applied early with demonstrated reproducibility to show the linkage between electrical and mechanical dyssynchrony and to characterize the contraction pattern in heart failure and its alteration with CRT. The SD of ventricular Ø, applied as a marker of synchrony, has been shown to demonstrate the beneficial effects of biventricular pacing, and its strong prognostic value has been shown in patients with congestive cardiomyopathy and CHF, superior to LVEF. The SD Ø may not be optimal for synchrony evaluation. We sought improved, more sensitive parameters to better differentiate synchrony among the spectrum of possible patterns of dyssynergy. We derived, initially evaluated, and here present new synchrony (S) and entropy (E) parameters, based on the phase method, to quantitate regional and global ventricular synchrony and applied them in simulation and clinical protocols.

Unique contraction pattern in patients after coronary bypass graft surgery by gated SPECT myocardial perfusion imaging.

PURPOSE: Although left ventricular systolic function seems to be accurately represented on gated SPECT myocardial perfusion imaging, specific patterns of wall motion (WM) and thickening after coronary bypass graft surgery (CABG), demonstrated by other imaging methods, have not been characterized for gated SPECT myocardial perfusion imaging. METHODS: Gated SPECT myocardial perfusion imaging was studied in 30 consecutive patients after CABG (group 1) and 40 non-CABG patients-30 with normal stress perfusion studies (group 2) and 10 with known previous anterior wall infarction (group 3). Two expert readers evaluated epicardial and endocardial systolic WM. Regional WM and the thickening percentage were obtained using CEQUAL 20 segment bull's eye analysis and compiled into regional values. RESULTS: Qualitatively, the post-CABG patients had hypokinetic septum, a hyperdynamic lateral wall, and preservation of anterior WM. In 25 of 30 (83.3%) patients, an anterior systolic epicardial "swing" was evident and was different from the inward endocardial and epicardial motion seen in groups 2 and 3. Septal WM was decreased in group 1 compared with group 2 (2.9 vs. 6.0 mm, < 0.001), with no significant difference in septal thickening. This was not different from the reduced septal motion seen in group 3 (4.1 mm), which was accompanied by both reduced thickening and abnormalities of anterior WM. Lateral WM was increased in group 1 compared with group 2 (9.9 vs. 8.2, < 0.001), with no significant difference in lateral wall thickening (34.6% vs. 39%). CONCLUSIONS: There is a characteristic contraction pattern on gated SPECT myocardial perfusion imaging in post-CABG patients distinguished by apparent septal hypokinesis with preservation of septal wall thickening, apparent increase in endocardial lateral WM, and an anterior epicardial "swing," different from the contraction pattern seen in normal patients and those with previous anterior wall infarction. The related perfusion pattern aids in evaluation of the mechanism of these findings.