RadiopharmaceuticalsFor Nuclear Cardiology

Studies

Mark Soffing, PharmD, MBA, MS, RPh, BCNPmarksoffing@gmail.com

ObjectivesUnderstand basics and advantages of myocardial imagingDescribe isotopes and radiopharmaceuticals available in cardiac imagingDescribe methods of pharmacological stressReview some technical aspects of protocols

Kit PreparationAseptic technique ALWAYS

alcohol swabs, fresh syringes & saline vialsAssay the Tc99m activity

Do not exceed package insert recommendations

Add the Tc99m activitySufficient volume to dissolve contents of vial

Agitate gently and let standAdjust concentration by adding saline

Radiochemical Purity

Related to bonding of isotope to reagentFor Tc99m, it represents the reduction of

TcO4+7 to TcO4

+4and bonding of TcO4+4 to

carrier. Verification by means of chromatography

methods generally designed around the physical properties of both the radio-pharmaceutical and impurities that form.

For Tc99m, there may be bound Tc99m, or free and hydrolyzed/reduced impurities.

Sestamibi QC ProcedureEthanol:Top: Tagged radiopharmaceutical Bottom: Free Tc-99m, hydrolyzed reduced Tc-99m % tagged Tc-99m = (top counts)/(bottom counts + top counts) x 100

Heart Functions as a Pump Heart pumps blood around the vascular system in two circuits (right atrium pumps blood to the lung in the pulmonary circulation, and the left atrium pumps blood to the whole body in the systemic circulation)Main parameter for function is the Cardiac Output (Index) l/min (/m2)Each beat the ventricle pumps a volume of blood called the stroke volume (EDV-ESV)Ejection fraction: % of blood expelled by the ventricle in each beat EDV-ESV

EDV

Evaluation of Cardiac Function

Non-invasive tests:– Exercise physiology– Echocardiography (very beneficial for

measuring the ejection fraction)– GBPS, First pass studies, Gated

SPECTInvasive– Cardiac catheterization (angiopathy)

Radiopharmaceuticals In Nuclear Cardiac Imaging Procedures

Myocardial perfusionSPECT PETThallium-201 Rubidium-82Tc-99m Sestamibi N-13 ammoniaTc-99m Tetrofosmin

Cardiac function- Tc-99m Pertechnetate

Myocardial metabolism- F-18 Deoxyglucose

Regulatory “Food For Thought:

Pharmaceutical Outsourcing and JCAHO

RadioNuclide Cardiac Angiography (RNCA)

Multi-Gated Cardiac Blood Pool Imaging (MUGA)

Dynamic imaging of the cardiac blood pool (cavity) to evaluate ventricular size, wall motion and ejection fractionAccurate and reproducible measurement of LVEF (left ventricular ejection fraction) most suitable for follow up (after chemotherapy, MI) Can be done with exercise/stress in the study of patients with CAD (coronary artery disease)

Gated Blood Pool IndicationsPatients with coronary artery disease (rest and exercise):– EF response to exercise– Induced wall motion abnormalities– Prognosis post-MI (EF, ventricular

aneurysm)– Pre and post bypass surgery

Patients receiving anthracyclinechemotherapy (Adriamycin) to monitor cardiac toxicity because adriamycin is cardio-toxicPresurgical evaluation

Scintigraphic TechniqueRadiopharmaceuticals: Blood pool agents– 99mTc RBC: usually in vivo labeling, in vitro,

or modified in vivo/vitro give better labelingPertechnetate enters RBCs, reduced by intra-cellular stannous ion, and bound to hemoglobinInstrumentation:– Scintillation camera with on-line acquisition– ECG monitor (trigger)

The patient is given 99mTc and monitored with a gamma camera which is connected to ECG monitor.

Regulatory “Food For Thought:

Re-Infusion of Blood Products and DOH

MUGA Analysis

Qualitative:– Size and configuration of cardiac

chambers: dilatation, thick wall, etc– Regional wall motion: normal, hypokinetic

(decreased movement), akinetic (no movement),dyskinetic (movement in the opposite direction)

Quantitative:– LVEF, regional EF, stroke volume– Diastolic function: LV filling rate and time to

peak filling rate– RVEF: problem with reproducibility– Phase analysis

Infarct-Avid Imaging Pathophysiology

Necrotic tissue accumulates in phosphate compounds (bone imaging agents) due to presence of calcium deposits.

This finding is useful for the diagnosis of atypical cases of myocardial infarction in which clinical, biochemical and electrocardiographic data are inconclusive.

99mTc Pyrophosphate ScanNormal: no uptake in the heart (grade 0)Diagnostic value– Acute myocardial infarction with atypical

presentation and lab findings– Right (and left) ventricular infarction– Peri-operative infarction (CABG)

99mTc PYP, 25 mCi - given intravenouslyImage (planar & SPECT) at 3-4 hrRepeat after 3 hr if necessary

Myocardial Perfusion Study

Assess coronary blood flow

Demonstrate blood perfusing the LV myocardium

Performed at rest & stress

Software allows gating for EF

3D reconstruction of heart

Patient PreparationContinue taking cardiac meds when evaluating effectiveness of therapyAny stress procedure– NPO at least 4, preferably 12 hours – off beta-blocker medications

Chemical stress procedure– off caffeine and asthma medications for

adenosine/persantine chemical stressAny rest procedure– requires no patient prep

Hemodynamically & clinically stable at least 48 hours

Thallous Cloride

Thallium-201 is a potassium analog which can be detected by single photon emission computed tomography (SPECT)Uptake by myocardial cells depends on an active transport process requiring intact sarcolemmal membranes and adequate ATP storesImages are obtained at rest and 4 hours laterIn normal myocardium, intial uptake is high but decreases rapidly within hours

Technetium Tc-99m Sestamibi Technetium Tc-99m Tetrofosmin

Lipophilic cationic compounds– Methoxy isobutyl isonitrile – Ethoxyethyl phosphino ethane

Uptake across myocardial membranes is passive and requires presence of intact electrochemical membrane gradients– Binds to a low molecular weight protein

fraction in the cytosol complex There is limited redistribution after initial uptake which would appear to limit its usefulness in determining viability

Myocardial Resting DoseSelect agents for myocardium viability.Second reinjection may be needed. IV administrationTc-99m sestamibi adult doses 8-30 mCiTc-99m tetrofosmin adult doses 8-30 mCiTl-201 chloride adult doses 2-5 mCiTl-201 chloride redistributes 3-4 hours after injection.

Indications

Detection and evaluation of CAD (coronary artery disease)Coronary bypass surgery or angioplastyDetection of viable tissue (Tl-201) Evaluation of MI, chest pain, SOB, family history of heart disease.Evaluation of blood work indicators ie: elevated creatine phosphokinase, troponin etc.

Myocardial Stress Dose

Tc-99m sestamibi Tc99m tetrofosmin = 20-30 mciTl-201 chloride 3-5 mciIV administration. Must have patent line.Myocardial localization same as resting.

Indications

Same as resting protocals.Contraindications :– Chest pain– Discontinue chemical

stressors: CaffeinePersantineViagra

Contraindications

High blood pressureNot comfortable weaned from nitroglycerinAllergies to chemicals (stress pharmaceuticals)Lung conditions (asthmatic reaction to persantine or adenosine) dobutamineused in these cases.

Adenosine & DipyridamolePharmacologic Effect

Immediate with AdenosineDelayed with Dipyridamole (Converted to Adenosine; Peak reached after stopped)

Absolute Contraindications Asthmatics with persistent wheezing2nd or 3rd degree AV block, sick sinus node (Unless pt has functioning pacemaker)Systolic BP < 90 mm HgDipyridamole use < 24hrs; Xanthines <12hrs

Pharmacologic Stress - Adenosine

STARTINFUSION

END INFUSION

END INFUSION

START INFUSION

Adenosine Adenosine

1 2 3 4 5 6

Recommended Adult Dose: 140ug/kg/min x 6 mins

Hemodynamic EffectsModest increase in heart rateModest decrease in systolic & diastolic

Perfusion Radiopharmaceutical

Pharmacologic Stress- Dipyridamole

STARTINFUSION

END INFUSION

Dipyridamole Dipyridamole

1 2 3 4 5 6

Recommended Adult Dose: .142mg/kg/min x4 mins* No Added Benefit above 60 mg TOTAL Infusion

Hemodynamic EffectsModest increase in heart rateModest decrease in systolic & diastolic

7 111098 12

INJECTPERFUSION

AGENTOR OR

DobutaminePharmacologic Effect

Stimulates sympathetic nervous system β1 receptors and used when adenosine & dipyridamole contra-indicated

Contraindications Recent MI or unstable anginaCritical aortic stenosis, dissection or aneurysmAtrial tachyarrhythmiaPrior history of ventricular tachycardiaUncontrolled hypertension

Pharmacologic Stress- Dobutamine

END INFUSION

Dobutamine Dobutamine

3 4 5 6 5 6

Recommended Adult Dose: 5-10ug/kg/min x3 mins* Increase at 3 min intervals to 20, 30, 40

Hemodynamic EffectsModest increase in heart rate (Beta blockers limit effect)Modest decrease in systolic & diastolic

7 111098 12

to20

ug/kg/min

to40

ug/kg/min

to30

ug/kg/minINJECT

PerfusionAgt

STARTINFUSION

@ 5ug/kg/min

to10

ug/kg/min

1 2 13

Regulatory “Food For Thought:

Compounding Medications and JCAHO

Regadenoson

Lexiscan is simple, single unit dose injection standardized for all patients, regardless of weight8 out of 10 now use this agent

Cardiac PET Imaging

Perfusion studies– Rest-stress perfusion imaging– Detection of coronary artery disease

and assessing the progression of coronary artery disease

Viability studies– Perfusion-metabolism imaging– Identification of tissue that may recover

contractile function following revascularization techniques

Nitrogen-13 Ammonia

PET Perfusion Agent Cyclotron ProducedSynthesis < 30 minsHalf-life = 10 minsApproved by CMS

Shallow metal half-cyclinders, later called “dees” after their shape, serve as electrodesCharged particles injected into the gap near the center are pulled by the potential into the electrode AThe magnetic field, perpendicular to the plane of the cylinders, bends them in a semicircle back into the gapIn the meantime the electric field has reversed and can pull them into electrode B, emerging again in step with the electric field, eventually spiraling out to the edgeEach passage through the gap boosts the particles to higher energies.

Regulatory “Food For Thought:

PET Drugs and FDA

CardioGen-82® (Sr 82 / Rb 82 Generator)

PET Perfusion AgentNo cyclotron requiredHalf life = 75 secsLong-lived Sr85 contaminantDistinguish normal from abnormal myocardium in suspected MI

Infusion System Schema

Regulatory “Food For Thought:

Generator Breakthrough and FDA

F-18 FlurpiridazLonger half-life of F-18 vs N-13 Ammonia and Rb-82 would permit commercial distributionEliminates need for on-site medical cyclotron or costly generator infusion systemPhase III efforts demonstrated better target to background resolution vsAmmonia, over-reporting findingsTherefore, required increase in cohort

Representative Normal F18Flurpiridaz

J Am Coll Cardiol Img. 2012;5(12):1269-1284. doi:10.1016/j.jcmg.2012.10.006

A) Consecutive tomograms of paired stress (top row) and rest (bottom row) images show normal distribution of the radiotracer in all myocardial regions

Representative Abnormal F18Flurpiridaz

J Am Coll Cardiol Img. 2012;5(12):1269-1284. doi:10.1016/j.jcmg.2012.10.006

(B) Paired stress (top row) and rest (bottom row) images show extensive reversible regional perfusion defects in all 3 coronary artery vascular territories associated with transient ischemic cavity dilation.

Myocardial Viability ImagingMechanism of Uptake & Metabolism

Myocardial cells continuously utilize chemicals (K+ analogs & nitrates) and substrates (free fatty acids & glucose) to meet energy needs

Impact on Patient ManagementEarly referral to revascularization improves– Survival– Left Ventricular function– Heart failure symptoms & exercise capacity

Reduces readmissions for CHF

Cardiac Viability (Done only at rest)

Tl-201 SPECT studyFDG PET study

Ant

Inf

LatSep

Ant

Inf

Apex

Apex

Sep Lat

Preparation for FDG StudyNon-Diabetic Patients

NPO for six hoursOral ( Glucola ) or IV glucose loading

Diabetic PatientsOral glucose leads to sub-optimal imagesModified Protocol for IV glucose loading– Fasting BG < 125 mg/dL, give 25g 50% dextrose– Fasting BG 125-225, give 13g 50% dextrose– Fasting BG >225, give regular insulin

• # units = (BG – 50) / 25• Inject FDG if BG < 150mg/dL

Perfusion & Metabolism Patterns

Perfusion

GlucoseMetabolism

Normal Non-Viable Viable

Paradigm Shift in Markers?Stenosis-----------Ischemia---------Necrosis1980’s: Myocyte Necrosis1990’s: Cardiac Myocyte Necrosis2000’s: Ischemia and Vessel Inflammation

1. Dx prior to cell death2. Better outcomes3. Efficient resource use4. Risk stratification in the ED without need for

cardiologists/radiologists

New Biochemical MarkersHeart Type Fatty-Acid Binding Protein (H-FABP)CholineSerum Amyloid AMalondialdehyde-modified LDLGlutathione Peroxidase 1Monocyte Chemoattractant Protein 1 (MCP-1)Ischemia Modified Albumin (IMA) Myeloperoxidase (MPO) CD 40 Ligand C-Reactive Protein (CRP) Pregnancy-Associated Plasma Protein A (PAPP-A)Placenta-derived Growth Factor (PDGF)

Let’s Review…

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http://imaging.onlinejacc.org/article.aspx?articleid=1476546

Dilsizian V, Taillefer R. Journey in Evolution of Nuclear Cardiology: Will There Be Another Quantum Leap With the F-18–Labeled Myocardial Perfusion Tracers?. J Am Coll CardiolImg. 2012;5(12):1269-1284.