Clinical application of PET in Cardiology

Dr. Raghu Kishore Galla

A positron emission tomography (PET) is anuclear medical imaging technique whichproduces a three dimensional image offunctional processes in the body.

• PET is a non-invasive, diagnostic imagingtechnique for measuring the metabolicactivity of cells in the human body.

• It was developed in the mid 1970s and it wasthe first scanning method to give functionalinformation about the brain.

A brief history of the positron & PET

• Existence first postulated in 1928 by Paul Dirac.

• First observed in 1932 by Carl D. Anderson, who gave thepositron its name.

• The concept of emission and transmission tomographywas introduced by David E. Kuhal and Roy Edwards in thelate 1950s at the university of Pennsylvania.

• In the 1970s, Tatsuo Ido at the Brookhaven Nationallaboratory was the first to describe the synthesis of 18-FFDG, the most commonly used PET scanning isotopecarrier.

What is a Positron….

• A Positron is an anti-matter electron, it is identicalin mass but has an apposite charge of +1.

• Positron can come from different number ofsources, but for PET they are produced by nucleardecay.

• Nuclear decay is basically when unstable nucleiare produced in a cyclotron by bombarding thetarget material with protons, and as a result aneutron is released.

18-O + proton => 18-F + neutron

• In PET the target material is chosen so that theproduct of the bombardment decays to a more stablestate isotope by emitting a positron, for instance 18-Fhas too many protons, so one of these protons decaysinto a neutron emitting in the process a positron an aneutrino.

proton (+1 charge) => neutron (0 charge) + positron(+1 charge) + neutrino (0 charge)

• Positron begins its activity in colliding with otherparticles and gradually losing its kinetic energy andthus slowing down.

Annihilation of a positron and electron…

• The positron will encounter an electron andcompletely annihilate each other resulting inconverting all their masses into energy. This is theresult of two photons, or gamma rays.

• Because of conservation of energy and momentum,each photon has energy of 511keV and head in analmost 180 degrees from each other.

• 511keV is the ideal rest state annihilation value.

How it works…

• A short lived radioactive tracer isotope, is injected in tothe living subject (usually in to blood circulation) . Thetracer is chemically incorporated in to a biologicallyactive molecule.

• There is a waiting period while the active moleculebecomes concentrated in tissues of interest.

• As the radioisotope undergoes positron emission decay(also known as positive beta decay), it emits a positron,an antiparticle of the electron with opposite charge.

• After traveling up to a few millimeters the positronencounter an electron.

• The encounter annihilates them both, producing a pairof (gamma) photon moving in opposite directions.

• These are detected when they reach scintillator in thescanning device creating a burst of light which isdetected by photomultiplier tubes.

● The spatial resolution of reconstructed clinical PETimages is currently in the range of 4 to 7 mm.

● readily available correction algorithms for photonattenuation, scatter, and random events.

IMPROVEMENTS….

● New detector material

● 3 dimensional detectors

● Better software

● Increase in spatial information and signal noise ratio.

PET in cardiology

● First positron emission tomography (PET) scanner in 1975

● Use in research in

- myocardial blood flow regulation

- myocardial substrate metabolism

- cardiac autonomic innervation

In Cardiology, PET has become the 'gold standard' for

• - Non-invasive evaluation of stunned (ischemic)myocardium

- Differentiation of ischemic heart muscle frominfracted myocardium

- Absolute quantification of myocardial blood flow

- Determining the candidates most suitable forcoronary bypass

PROPERTIES OF SELECTED PET TRACERS

TRACERS OF MYOCARDIAL PERFUSION

• Tracers that are only partially extracted by the myocardium

- Rb 82 chloride

- N 13 ammonia

• Tracers that are freely diffusible

- O 15 water

Rubidium 82 PET MPI

• Rb 82 is a monovalent cation with a ultra short half life of75 seconds

• Can be done without a onsite cyclotron

• Serial evaluations of regional myocardial perfusion can bemade at intervals as short as 5 mins

• First pass extraction at rest is 50-60% via Na-K ATPasepump similar to Thallium 201 and less than N 13

• Uptake is a function of both blood flow and myocardial cellintegrity

• Usually performed before and after the vasodilatorstress.

• Infarcted myocardium doesn’t retain IV administered Rb82.

• Washes of rapidly from damaged myocardial cellsfallowing the initial uptake phase.

• Despite of short half life modern PET gamma camerasare able to obtain good quality of images.

• Displayed using polar maps utilizing the bulls eyeapproach with the apex located at the center and thebase at the rim.

• 3D displays of Rb82 activity are more quantitativewith respect to polar maps.

• The sensitivity and specificity of PET MPI is superiorto other non invasive tests.

• In addition to four studies directly comparing 342patients undergoing SPECT with Thallium 201 and RB82 PET, numerous studies of PET MPI found excellentsensitivity of 92% and a specificity of 90%.

• Though all patients of intermediate probability ofCAD can undergo PET MPI, its is preferable to SPECTMPI in patients with attenuation problems like…

- obese patients

- women

- breast implants or left mastectomy

- chest deformity

- left pleural or pericardial effusion

N13 Ammonia or O15 water PET MPI

• Widely used for the last 2 decades

• Has 10 mins half life

• Needs a onsite cyclotron

• Takes 100-120 mins for the procedure

• Both rest and stress images can be gated

• Good quality of gated & ungated images

• Cumbersome and time taking

• Some normal volunteers show mild defect in lateral wall of LV in N13 ammonia retention

Stress 18 FDG PET MPI

• Direct imaging using FDG radionucleotide duringexercise or pharmacological stress and rest.

• The differential uptake of glucose in ischemic and nonischemic myocardium can help in development of “hotspots” of imaging agent for myocardial ischemia.

• Longer half life allows single dose on a daily basis.

• 18F would allow assessment of perfusion duringtreadmill test rather than vasodilator stress alone

Intense F18 FDG uptake in the lateral wall of the myocardium in the stressischemia which is showing as a fixed defect in the regular stress and restmyocardial perfusion imaging

Intense F-18 FDG uptake in inferior and lateral walls with a small fixed defect in regular stress and rest myocardial perfusion imaging

• Under fasting conditions the normal myocardium primarilyutilizes fatty acids while glucose utilization and thus FDGuptake is minimal.

• The ischemic myocardium has enhanced glucose metabolism,markedly takes up FDG which is displayed on PET images ashotspot.

• Under the fasting conditions there is heterogeneousdistribution of FDG into normal myocardium showing higherFDG uptake in lateral wall than in septum.

• For these reasons FDG PET under fasting conditions is notbeen recommended for clinical viability assessment.

• Most commonly used protocol

– Oral loading of 50-70gms of glucose stimulatinginsulin secretion and increasing FDG uptakeinto normal myocardium to near maximal

• Euglycemic insulin clamping is an alternativetechnique and is more complex but guaranteesmore stable and controlled metabolic conditions

• FDG uptake into normal and ischemic but viablemyocardium is enhanced and negative FDG uptakeis considered to indicate scar tissue

Hibernating myocardium

• Demonstrate increased FDG uptake in the fastingstate unlike the surrounding normal myocardium

• But in post-prandial state it demonstrates FDGuptake

• Therefore, either preserved or even enhancedFDG uptake in dysfunctional myocardial regionsrepresent presence of myocardial viability by thehelp of most popular criteria of flow metabolismmismatch

Stunned myocardium

• Regional dysfunction due to stunned myocardiummay be manifested by normal/enhanced/reducedglucose utilization using FDG and flow images

• Only criteria to diagnose stunned myocardium ispresence of regional myocardial wall motionabnormalities

• Perfusion – Metabolism match indicates myocardialscar.

Cardiac PET: Myocardial Perfusion Imaging- Appropriate Use Criteria

1. Detection of CAD in the symptomatic patient:

– a. Evaluation of Ischemic Equivalent (Non-Acute)

– b. Acute Chest Pain

– c. Acute chest pain (rest imaging only)

2. Detection of CAD/Risk Assessment without Ischemic Equivalent

– a. Asymptomatic- High CHD Risk (ATP III Risk Criteria)

– b. New-Onset or Newly diagnosed Heart Failure with LV Systolic Dysfunction without Ischemic Equivalent

– c. Ventricular Tachycardia

– d. Syncope with Intermediate or High CHD risk (ATP III Risk Criteria)

– e. Troponin elevation without additional evidence of acute coronary syndrome

3.Risk Assessment with prior test results and/or knownchronic stable CAD– a. Equivocal, borderline or discordant stress testing where

obstructive CAD remains a concern

– b. New or worsening symptoms- Abnormal coronaryangiography OR abnormal prior stress imaging study

– c. Coronary stenosis or anatomic abnormality of uncertainsignificance. Asymptomatic, High CHD risk, Agatston scorebetween 100-400

– e. Asymptomatic, Agatston score greater than 400

– f. Asymptomatic, Intermediate-Risk Duke Treadmill Score

– g. Asymptomatic, High-Risk Duke Treadmill Score

Cardiac PET: Myocardial Perfusion Imaging- Appropriate Use Criteria

• 4. Risk Assessment: Preoperative Evaluation for Non-CardiacSurgery without Active Cardiac Conditions– a. Intermediate-Risk Surgery– b. Vascular Surgery

• 5. Risk Assessment: Within 3 months of an Acute Coronary Syndrome– a. STEMI– b. UA/NSTEMI

• 6. Risk Assessment: Post Revascularization (PCI or CABG)– a. Symptomatic– b. Asymptomatic- Incomplete Revascularization or greater

than or equal to 5 years post CABG

Cardiac PET: Myocardial Perfusion Imaging- Appropriate Use Criteria

Cardiac PET: Myocardial Perfusion Imaging- Appropriate Use Criteria

• 7. Assessment of Viability/Ischemia

– a. Ischemic Cardiomyopathy

– b. Assessment of Viability for patient eligible forrevascularization

• 8. Evaluation of Left Ventricular Function

– a. In absence of recent reliable diagnosticinformation from another imaging modality

– b. Baseline and serial measures after keytherapeutic milestones or evidence of toxicity frompotentially cardiotoxic therapy

Metabolic tracers

• Flourine-18 FDG

– Deoxy glucose is an analogue of glucose can be labelledwith F-18 a cyclotron produced radionuclide to form F-18FDG reflects the overall myocardial utilization ofglucose

• C-11 Palmitate

– Palmitate, a naturally occurring fatty acid labeled withcyclotron produced radionuclide C-11, uptake andclearance of which reflects myocardial utilization of fattyacids

• C-11 Acetate

Cardiac PET: Myocardial Viability – Appropriate Use Criteria

• The applications for Cardiac Viability Imaging with FDG PET are:

1. The identification of patients with partial loss of heartmuscle movement or hibernating myocardium is importantin selecting candidates with compromised ventricularfunction to determine appropriateness forrevascularization.

2. Distinguish between dysfunctional but viablemyocardial tissue and scar tissue in order to affectmanagement decisions in patients with ischemiccardiomyopathy and left ventricular dysfunction.

Flow quantification by PET

• It is helpful in patients suffering from

– Severe CAD having balanced ischemia

– Subclinical CAD (micro vascular dysfunction)

– Monitoring response to therapy

(progression or regression of CAD)

• PET quantification of perfusion reserve by use ofRb82 net retention may suggest a greater extent ofdisease than the other standard approaches of MPI

Flow quantification by PET

Computation of myocardial blood flow with Rubidium82 and comparison to N13 Ammonia

Computation of myocardial blood flow with Rubidium82 and comparison to N13 Ammonia

Hybrid PET-CT

● Combines CT-derived morphologic information withPET-derived functional information

● Schenker et al. measured myocardial perfusion andcoronary calcium in a single cardiac PET-CT study in695 patients

● They observed an increasing prevalence of abnormalPET with increasing coronary calcium scores

Novel myocardial perfusion tracer

• PET perfusion tracers have half-lives that are very short. Thislimits their applicability for exercise stress

• Flurpiridaz F-18

– New PET-MPI radiopharmaceutical

– In phase III clinical trial

– Binds to mitochondrial complex with high affinity

– Has an extraction ratio of >90%

– Has a long half life 110min

• Can be used during exercise stress testing unlike othertraditional PET tracers

Molecular imaging

● Cardiovascular molecular imaging is a rapidlyemerging discipline that aims toward visualizationof specific molecular targets that precedechanges in morphology, physiology, and function.

● Examples are the use of neuronal imaging toidentify subjects at risk for ventricular arrhythmia

● Great potential to facilitate discovery anddevelopment of novel therapies

Takayasu arteritis

• 18F-fluorodeoxyglucose positron emission tomography(18F-FDG-PET) allow diagnosis of TA earlier in the diseasecourse than standard angiography.

• Gold standard for knowing the extent of involvement andthe activity of the inflammation

• provide a means for monitoring disease activity.

• Early detection of relapse in patients receivingimmunosuppressive therapy

PET in Takayasu arteritis

MYOCARDITIS

• Cardiac FDG PET/CT with Very High Fat Low CarbohydrateProtein Preferred diet is shown to be an excellent modality indiagnosing inflammatory myocarditis.

• Combined positron emission tomography (PET) and CT maydepict inflammatory processes before structural changes occur.

• unmatched in patient with ICD devices where MRI could not bedone.

• In the era of practice of evidence based medicine this has beenshown to be very promising investigation to show the treatmentresponse.

FDG-PET in the trans axial plane shows moderate FDG uptake (arrows) involving mainly the right heart

Other applications of PET-MPI

• FDG PET – sarcoidosis

– Acute Vs Chronic

– Disease activity

– Follow-up

– Recurrence

• Sympathetic innervations

– C11 Hydroxyephedrine

– F18 Fluorobenzyl guanidine

– Provides high resolution imaging of regional analysis of cardiac innervation

Bengel, F. M. et al. J Am Coll Cardiol 2009;54:1-15

Translational Molecular Cardiac PET Imaging

• F-18 FDG is an excellent probe to target macrophageinfiltration as a marker of plaque inflammation

• F18 NaF targets active microcalcifications in theatherosclerotic plaques and highest uptake was observedin the culprit lesion

• F18 GalactoRGD targets both macrophages and intraplaque neovasculature that may directly involved in thedegradation of protective fibrous cap of atheroscleroticplaques

• FDG PET-CT can reliably detect cardiac prosthetic valveinfection very early

Other applications of PET-MPI

18F-NaF – Microvascular calcification

PET-CT – prosthetic valve infection

Prognostic Value

● Greatest value of perfusion imaging isconsidered to be its potential to predictadverse cardiac events

● Useful as a gatekeeper for invasive procedures

● In one study, 685 patients were scanned withdipyridamole 82Rb PET and follow-up wasobtained over a mean of 41 months

● The annual mortality rate for a normal scan was0.9%; it was 4.3% for an abnormal scan

PET Vs SPECT

• PET has a better resolution and clarity of imaging

• Slightly higher sensitivity and specificity

• Costlier than SPECT

• Needs a onsite cyclotron

• Advantage in patients with attenuation artifacts

• Absolute myocardial blood flow quantification ispossible with PET

DSE SPECT PET CMR

Subjective Objective Objective Subjective

Cannot quantifyRelative

quantitation of myocardial flow

Absolute quantitation of flow

Cannot quantify

No radiation Radiation Radiation No radiation

Lower cost, easy availability

Most commonly used

Requires cyclotron, not readily available

Upcoming

Poor image in COPD and obesity

Study protocol extends one or two

days, artifacts.

Gold Standard for viability assessment,

Least artifacts.

Not possible ifpacemaker, motion

artifacts.

Radiation exposure

● Radiation exposure from cardiac imaging procedures hasincreasingly become a matter of discussion

● The effective dose from a PET scan is modest and dependson the activity of the injected FDG (18F-Fluorodeoxyglucose) and is typically 8 mSv for adults using 400MBq and is the same whether a part of the body or thewhole body is imaged

● PET provide less radiation burden to the patient whencompared with SPECT

● Doses with PET seem to be lower for staff

Cost-effectiveness considerations

● The costs of a single test are high

● But the costs and risk of avoidable surgical orinterventional treatment may be even higher

● Avoidance of an unnecessary bypass operation, oreven of an unnecessary cardiac transplantation

● May justify conducting numerous non invasive tests

Summary

● Cardiac PET is a powerful, quantitative, noninvasive imaging technique that is increasinglypenetrating the clinical arena.

● Best used for clinical assessment of myocardialperfusion and viability

● Novel isotopes will improve the accuracy andfeasibility of PET MPI with increasing itsapplications in the newer horizons of cardiologylike molecular imaging.

THANK U