New Developments / Technologies / Protocols in NC João V. Vitola, MD, PhD Cardiologist and Nuclear Medicine Physician Quanta Diagnostico Nuclear Curitiba - Brazil DISCLOSURES Honorarium Research / Advisor, Expert Services and Conferences in Nuclear Cardiology BMS, CVT, Astellas, Lantheus, PGx, IAEA Royalties Publications in Nuclear Cardiology Springer-Verlag Verlag-Nuclear Cardiology and Correlative Imaging: a teaching file, NY, 2004 Lippincott Williams & Wilkins, - Nuclear Medicine teaching File,, 2009
To be discussed New Gamma Cameras: CZT technology New Hybrid systems: SPECT/CT and PET/CT 64 slices New Perfusion Tracer for PET - BMS747158 New pharmacologic stressors the 2 min stress test: Regadenoson (FDA approved, n=784, USA, Brazil and Argentina) - bolus IV 400ug BMS068645 - Apadenoson - (PGx Health - Phase III, n = 753, USA and Brazil) bolus IV 100 or 150 ug
CZT Technology Ernest V. Garcia, PhD* Emory University School of Medicine Hi Joao, Please give my Cuban colleagues my best wishes for 2010! Ernie
Cadmium Zinc Telluride (CZT) - Direct Conversion Technology whose time has come Eliminates scintillation and photomultiplier tubes higher spatial resolution higher energy resolution smaller size Provides: improved image contrast improved multi-isotope imaging faster scanning / lower dose scans more flexibility in scanner design
Limitation of Conventional SPECT NaI(Tl) Crystal D e t e c t o r 1 Detector 2 Only a small portion of the NaI Crystal is used to view heart
Discovery NM 530c System Design Simultaneous Cardiac acquisition by all stationary detectors
Discovery NM 530c System Design 2. 4 6 m m 32 x 32 x 5 mm
Indirect vs. direct conversion Scintillator (e.g. NaI:Tl): 9000 photons @ 140 kev Indirect X-ray or γ-ray e e Light generation Light transport Q.E. 20%-80% Charge generation Charge transport X-ray or γ-ray Noise Direct h hh h h ee e ee + anode - cathode electronics Direct Conversion (CZT): 30,000 photons @ 140 kev CdZnTe Semiconductor Photosensor (PMT): 2000 photo-electrons Gain variation γ γ energy energy charge charge carriers carriers e e e e e e e e e e e e electronics Noise (APD/PD) Assuming no other sources of noise, Poisson statistics dictates energy resolution: γ γ energy energy light light photo-electrons photo-electrons
Energy Resolution CZT scintillator lightguide Energy Resolution for CZT is determined by: - crystal quality - incomplete charge collection PMT Energy resolution depends on - Light output of scintillator - Linearity & uniformity of scintillator - Uniformity of light collection - Quantum efficiency of PMT - Electronic noise Energy resolution can be improved by - Better scintillator - Better photosensor - Energy resolution can be improved by: - using perfect crystals - measuring and correction defects - compensating for incomplete charge collection: - using signal shape - using dual-sided readout: Anger 9.5% Alcyone 6.0% point sources in air 99m Tc: 140 kev 123 I: 159 kev 50 100 150 kev 200
Spatial Resolution scintillator lightguide Not to scale PMT CZT Resolution for PMT based system is determined by: - Thickness of crystal (light spreading) - Size of PMT - Light output of scintillator - Optimization of light spread function - Position estimation algorithm Spatial resolution can be improved by - Segmenting scintillator - Smaller (or multi-anode) photomultipliers Resolution for CZT based system is determined by: - anode pitch - charge spreading Spatial resolution can be improved (somewhat) by: - using a smaller pitch - using proportional readout - more electronic channels
Discovery NM 530c System Design Multiple-Pinhole Collimator Design Front Tungsten 5mm pinhole inserts provide high energy collimation (I-123) and limits Pb x-rays (Tl-201) Back Thick Pb septa prevents crosstalk between detectors
Discovery NM vs. Ventri Energy Resolution FWHM/Peak Central (mm) Resolution Tangential (mm) Radial (mm) Point Kcts/min Sensitivity Phantom Kcts/min DNM 530c 5.7% 4.8 3.35 5.25 688 573 Ventri 9.4% 10.9 7.5 10.9 99.2 150 Ratio 1.65 2.27 2.24 2.08 6.94 3.82 19 pinholes
Normal Example S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest
DNM 530c: Clinical Implications Fast 2-52 5 min acquisitions Increase patient throughput Increase protocol flexibility Increase patient comfort and convenience Decrease patient radiopharmaceutical dose Decrease patient motion Simultaneous dual isotope imaging (= 10 X sensitivity) Potential to improve CFR calculations Significantly improve I-123 I (MIBG, BMIPP, rotenone ) imaging Improve bad beat rejection and diastolic function measurement (due to list mode acquisition)
Multicenter Comparison between DNM530c & Standard Dual Detector Cameras: Objectives (n=161) To determine diagnostic agreement between the new Discovery NM 530c (DNM530c) and standard dual detector cameras (S-SPECT) SPECT) in patients with known or suspected CAD. The secondary goals included the strength of agreement on a per-vessel analysis, the image quality, and the correlation of automated rest and stress left ventricular ejection fractions (LVEF).
Patient Example: Normal (male 5 6 5 176 lbs) S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest
Patient Example: Reversible LAD and RCA defects (male 5 5 189 lbs) S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest
Abnormal Example S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest
Patient Example: Breast vs. Diaphragmatic Attenuation (female 5 3 5 206 lbs) S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest
Patient Example: Fixed defects S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest
Image Quality Rest S-SPECTSPECT (n=330) Rest DNM530c (n=330) Stress S-SPECTSPECT (n=330) Stress DNM530c (n=330) Excellent 232 (70.3%) 275 (83.3%) 224 (67.9%) 282 (85.5%) Adequate 94 (28.5%) 47 (14.2%) 105 (31.8%) 41 (12.4%) Suboptimal 4 (1.2%) 8 (2.4%) 1 (0.3%) 7 (2.1%) Esteves et al. J Nucl Cardiol 2009, 16:927-24.
Conclusions about CZT A novel solid-state state-detector dedicated cardiac camera (DNM530c) has been developed by GE Healthcare and tested in a multicenter study. DNM530c provides rest/stress Tc-99m tetrofosmin myocardial perfusion images comparable to S-SPECT S SPECT at significantly shorter acquisition times.
Hybrid Technology PET/CT and SPECT/CT and New Perfusion Agent for PET ATEN. CORRECTION CALCIUM SCORE ANATOMY 64 SLICES PERFUSION (Absolute) VIABILITY LV FUNCT (True Str) Vitola JV, Cerci J, Delbeke D. PET/CT em Cardiologia, Ed. Revinter, Rio de Janeiro, 2010 (in Press)
CLINICAL CASES
Routine Attenuation Correction SPECT/CT Potential artifacts
Routine Attenuation Correction PET/CT Potential artifacts
55 yo, Family Hx, No Known CAD, Atypical Pain
AVAILABILITY OF PET TECHNOLOGY 2009 MOST FOR ONCOLOGY USE 30 25 20 15 10 GE PH SI 5 0 2007 2009 GE - 29 PH 19 SIEMENS 24
Future Direction for Cardiac PET Ideal PET MPI Imaging Agent High cardiac uptake with minimal redistribution Near linear myocardial uptake vs. flow up to 5 ml/min/g or more (high first pass extraction fraction) High target to non-target ratio (vs. lung, liver, bowel) Usable for both exercise and pharmacologic stress Usable for quantitation of absolute myocardial flow Available as unit dose ( 18 F-labeled compound) Adapted from: Glover, D and Gropler, R., J. Nucl. Card 14:6 p765-8 Ver. 18Aug 09
New PET perfusion tracer labeled with F-18F Chemical Structure of BMS747158 Mitochondrial Complex 1 (MC-1) Inhibitor O N N C l O O 18 F 2-tert-Butyl-4-chloro-5-[4 [4-(2- (18F)fluoro-ethoxymethyl)-benzyloxy] benzyloxy]-2h-pyridazin-3-one Yu, et al., J Nucl Cardiol. 2007;14(6):789-98 Ver. 18Aug 09
First Pass Uptake in Isolated Rabbit Hearts 3 BMS747158 (n=4) 201 Tl (n=3) Uptake 2 1 99m Tc-sestamibi (n=3) * * 0 0 1 2 3 4 5 Coronary perfusion flow (ml/min/g) Yu, et al., J Nucl Cardiol. 2007;14(6):789-98 * Indicates p<0.05
Pre-Clinical Cardiac PET Imaging with BMS747158 Normal Rat Coronary ligation in Rat Normal primate Yu, M et al. J Nucl Cardiol 2007, 14(6):789-98 Ver. 18Aug 09
Phase 1 Studies of BMS747158 Study 101: Safety, dosimetry, and biodistribution. Single injection at rest. (n=13 healthy subjects) Study 102: Safety, dosimetry, and biodistribution. Separate day injection at rest and stress (12 subjects) Maddahi J, et al. JNM 2008 (abstract ) Ver. 18Aug 09
BMS747158 Phase 1 Safety Independent Data Monitoring Committee and a renowned electrophysiologist reviewed the entire safety data-set None of the AEs were considered serious or related to study drug No clinically significant changes in Physical and neurological exams (incl. EEG) Vital signs Clinical labs (incl. Cardiac enzymes) no safety concerns and no warnings in ECG data Individual subjects had non-consistent single time-point QT/QTc prolongation Maddahi J, et al. JNM 2008 (abstract ) Ver. 18Aug 09
21 min. 35 min. 165 min. 202 min. 21 min. 35 min. 165 min. 202 min. Exercise BMS747158 Adenosine Maddahi J, et al. JNM 2008; abstract
Summary and Conclusions Phase 1 BMS747158 Highest dose organ: Stress (pharmacologic and exercise): heart Rest: kidneys Dosimetry is within the clinically acceptable range No adverse events related to the tracer were noted Stress imaging is feasible with both treadmill exercise and pharmacologic vasodilation Myocardium is clearly visualized for several hours after rest and stress injection with good myocardial to background ratio Five minute gated acquisition - starting 2 minutes after injection - yields high quality images Maddahi J, et al. JNM 2009
BMS747158 Phase 2 Clinical Studies BMS747158-201 (first in patient) Cohort 1: develop a one-day rest/stress imaging protocol; safety Patients with reversible defects on SPECT Cohort 2: assess diagnostic efficacy compared to SPECT in detecting CAD; safety Patients classified as low, intermediate or high pre-test likelihood (ACC/AHA Guidelines for exercise testing) Ver. 18Aug 09
Study 201 - Patient 006-003 003 Stress BMS747158 SA Rest Stress Rest BMS747158 HLA BMS747158 VLA Stress Rest Stress Rest J. Maddahi, UCLA 39 Ver.18Aug 09
Phase III Ongoing discussion regarding protocol Compare MIBI SPECT vs 18 F BMS PET Latin American Patients first visit Brazil Feb / 2010 Goal to start second semester 2010
New Pharmacologic Stressors: A 2a N = 784 J Nucl Cardiol 2007; 14:645-58 Regadenoson (Lexiscan) FDA approved in April 2008
WHAT DO WE KNOW NOW? REGADENOSON = ADENOSINE IDENTIFY INDIVIDUALS WITH ISCHEMIA QUALITY OF IMAGES SOME POTENTIAL ADVANTAGES TO BE DISCUSSED
New Perspectives Bolus administration
Regadenoson-induced Blood Flow Time to 2.4-fold above baseline: 33 sec Duration at 2.5-fold above baseline: 2.3 min 3.5 Window for Tracer Uptake 3.0 400 mcg regadenoson APV ratio 2.5 2.0 1.5 1.0 0 2 4 6 8 10 Time (min) Lieu HD, et al. J Nucl Cardiol. 2007;14(4):514-520.
How do Patients Feel Compared to Adenosine?
84% equal or better
New Perspectives Bolus administration Standard dose
Standard dose 400 ug independent of body weight Rational Receptor binding = First pass phenomenon Initial experience - works regardless of body weight further evaluation desirable
New Perspectives Bolus administration Standard dose Selectivity and low to moderate receptor binding affinity
Selectivity Xu Circ 2000
Selectivity A 1 A 2B A 3 A 2A Undesirable effects (eg, AV block) Undesirable effects (eg, bronchospasm) Increase coronary blood flow
Selectivity Gao Journal of Pharm Exp Ther 2001
Selectivity A 1 A 2B A 3 A 2A Undesirable effects (eg, AV block) Undesirable effects (eg, bronchospasm) Increase coronary blood flow
Perspective to apply in COPD Various types of COPD patients Limited data still needs caution Further studies, larger experience is needed What is the literature showing?
New Perspectives Bolus administration Standard dose Selectivity and low to moderate receptor binding Special issues Potential to combine with exercise
Cortes Tomográficos-Referência Potential for on the fly protocol Eixo Curto Eixo Longo Vertical 30 secs from peak hyperemia Pts on meds Depressed chronotropic response Effects of Max Hyperemia on MPI Sensitivity? Eixo Longo Horizontal
Selective A 2A Adenosine Receptor Agonists NH 2 HO NH 2 N N N N O OH OH HO N O N NH HO N N H 2 N OH N N O N OH N N N N Binodenoson H 3 C O O H 3 C Apadenoson H N H N NH 2 N N N N O O OH OH Adenosine HO OH O Regadenoson CH 3 Zablocki J et al. Nucleosides Nucleotides Nucleic Acids. 2001;20:343-360. Gao Z et al. J Pharmacol Exp Ther. 2001;298:209-218.
Potential Apadenoson Protocol Fixed doses100 µg (< 100 kg) or 150 µg (> 100 kg) Bolus apadenoson Saline flush Inject tracer 0 1 2 Minutes Adapted from Hendel RC et al. Abstract presented during the 2005 Annual Scientific Sessions of the American Heart Association. Dallas, Texas.
Phase III Apadenoson Goal of 753 patients Compare adenosine to apodenoson (1:2) 75 US and 20 Brazil centers Goal to start second semester 2010
Selective A 2A Adenosine Receptor Agonists Conclusions Regadenoson is similar to adenosine to detect ischemia. Apadenoson will be tested in Phase III. Regadenoson has the advantage of bolus administration and less side effects than adenosine. Apadenoson also bolus. Potential for utilization in COPD patients. Potential for combination with exercise new protocols Regadenoson FDA approved in 2008. Will cost allow wide spread utilization?