Clinical Nuclear Cardiology: State of the Art and Future Directions E-Book

Barry L. Zaret, George A. Beller

• Publisher: Mosby
• Year: 2010
• ISBN:
  9780323085724
• Edition: 4
• Topic: Medicine
• Subtopic: Cardiology

Clinical Nuclear Cardiology—now in its fourth edition—covers the tremendous clinical growth in this field, focusing on new instrumentation and techniques. Drs. Barry L. Zaret and George A Beller address the latest developments in technology, radiopharmaceuticals, molecular imaging, and perfusion imaging. Thoroughly revised to include 20 new chapters—Digital/Fast SPECT, Imaging in Revascularized Patients, and more—this new edition provides state-of-the-art guidance on key areas and hot topics with stunning visuals. Online access to the fully searchable text at expertconsult.com includes highly illustrated case studies that let you see the problem using a variety of imaging modalities. In other words, this is an invaluable resource no clinician or researcher in nuclear cardiology should be without.

• Features an editorial and contributing team of worldwide leaders in nuclear cardiology to provide you with current and authoritative guidance.
• Includes a section focusing on acute coronary syndromes to provide you with practical management tools for these conditions.
• Presents a full-color design that allows color images to be integrated throughout the text.

• Includes access to the fully searchable contents of the book online at expertconsult.com, along with highly illustrated case studies that let you see the problem using a variety of imaging modalities.
• Features 20 new chapters including Cellular Mechanisms of Tracer Uptake and Clearance; Attenuation/Scatter Corrections: Clinical Aspects; Hybrid Imaging; Digital/Fast SPECT; Imaging in Revascularized Patients; and more.
• Focuses on perfusion imaging in a section dedicated to this hot topic so you get all the information you need to stay current.

Section 1

Radiopharmaceuticals/Tracer Kinetics

Chapter 1 Overview of Tracer Kinetics and Cellular Mechanisms of Uptake

Denny D. Watson, David K. Glover

INTRODUCTION

The kinetics of tracer transport provides a skeletal framework that supports the body of clinical imaging using radionuclide tracers. This underlying framework provides an essential basis for understanding and clinical interpretation of tracers, including the sensitivity of different tracers to indicate reduction of coronary flow reserve, the use and limitations of redistribution and reinjection, and the applications of tracers for indication of myocardial viability and prediction of recovery of myocardial contractile function.

Tracer transport kinetics are most compactly and simply understood in terms of “models.” A model is a mathematical function that defines a relationship. An example would be the curve that relates tracer uptake as a function of myocardial blood flow. There are certain basic relationships that govern the extraction, washout, and recirculation of tracers. These basic generic relationships facilitate the understanding of many different tracers used in various ways.

As an introduction to perfusion tracers, the first part of this chapter will review the basic properties and cellular uptake mechanisms of a few of the single-photon emission computed tomography (SPECT) myocardial perfusion agents. Next, we will present the “bare bones” of tracer extraction, retention, and recirculation. We will employ a common solute absorption model to help understand the relationship of tracer extraction to capillary perfusion and use a simplified compartmental exchange model to help understand tracer redistribution. Comparing model predictions to experimental data will add some fascinating light to the mechanism of myocardial vasoregulation. Following this introduction, and in the light of our improved understanding of tracer kinetics, we will discuss specific clinical applications of the tracers commonly used for myocardial imaging.

CELLULAR UPTAKE OF MYOCARDIAL PERFUSION AGENTS

Before delving into a modeling approach to better understand the complex behavior of a myocardial perfusion imaging agent after intravenous injection, we will briefly review the physical and/or chemical properties of a few classes of these agents that play a role in their cellular uptake in the myocardium.

Thallium-201

Thallium-201 (²⁰¹Tl) is a radioactive potassium analog. The initial myocardial uptake of ²⁰¹Tl is dependent upon myocardial blood flow and its first-pass extraction fraction, which is approximately 85% under resting flow conditions.^1,2 At higher flow rates, such as those obtained during pharmacologic vasodilation, the extraction of ²⁰¹Tl is not linear with respect to flow.³ The plateau in extraction results in an underestimation of the true maximal flow. This phenomenon is true of all diffusible flow tracers and will be discussed in detail in the next section of this chapter.

The intracellular uptake of ²⁰¹Tl predominantly involves active exchange across the sarcolemmal membrane of the myocytes via the Na⁺/K⁺ adenosine triphosphate (ATP) transport system.⁴ Because this system is energy dependent, thallium transport can only occur in viable myocardium. Once inside the myocyte, ²⁰¹Tl is not bound intracellularly and can diffuse back out into the circulation. As will be discussed in detail later, these uptake and redistribution kinetic properties form the basis of clinical assessment of myocardial perfusion and viability using ²⁰¹Tl. Although the introduction of ²⁰¹Tl in the mid-1970s represented a major advance in nuclear cardiology, its physical properties are not ideal for gamma camera imaging. The low-energy 69- to 80-keV x-ray photopeak can result in attenuation artifacts and the relatively long 73-hour half-life limits the maximal dose that can be safely administered.

Monovalent Cationic Technetium-99m-Labeled Tracers

Technetium-99m (^99mTc) is a generator-produced isotope that is readily available and has a number of advantages over ²⁰¹Tl for gamma camera imaging. The higher-energy 140-keV principle photopeak is ideal for detection using standard collimated gamma cameras with less attenuation, and its short 6-hour half-life allows for a higher administered dose yielding improved count statistics.

Over the years, there have been a number of ^99mTc-labeled myocardial perfusion imaging agents that have been investigated as replacements for ²⁰¹Tl. The most successful ones to date are the lipophilic monovalent cationic agents, ^99mTc-sestamibi (sestamibi, Cardiolite) and ^99mTc-tetrofosmin (tetrofosmin, Myoview), that are now widely used for clinical studies. Following an intravenous injection, the first-pass extraction fractions of sestamibi and tetrofosmin are approximately 65% and 54%, respectively, under basal resting flow conditions.^5,6 Because of their lower extraction fractions compared with ²⁰¹Tl, the plateau in tracer uptake observed during hyperemia occurs at lower flow rates. The effect of this “roll-off” in extraction at lower flow rates is to diminish the relative difference in tracer activities between high-flow regions and those myocardial regions subtended by a coronary stenosis, making it more difficult to detect milder stenoses.

Although these agents are members of two distinct chemical classes of compounds, isonitriles and diphosphines, respectively, they share several common properties. Unlike ²⁰¹Tl, which utilizes a specific membrane-active transporter, these tracers are passively drawn across the sarcolemmal and mitochondrial membranes along a large electronegative transmembrane potential gradient, owing to their lipophilicity and positive charge.⁷ Once inside the mitochondria, these cationic tracers are tightly bound by the potential gradient such that there is a very slow net efflux resulting in prolonged myocardial retention times. Although ATP is not directly required for the intracellular sequestration of cationic tracers, as it is for ²⁰¹Tl, the influx and retention of these tracers are energy dependent because the presence of a normal electronegative transmembrane gradient is required. With irreversible injury, the mitochondrial and sarcolemmal membranes are depolarized, and the uptake of these cationic tracers is impaired.⁸ Accordingly, like ²⁰¹Tl, the cationic ^99mTc-labeled agents can be used to assess myocardial viability.

In addition to the lower plateau in extraction mentioned, another disadvantage to both sestamibi and tetrofosmin is the problem of photon scatter from the adjacent liver that can interfere with the interpretation of myocardial perfusion defects, particularly in the inferior left ventricular wall. Accordingly, there has been renewed interest in recent years to design improved cationic ^99mTc-labeled tracers that exhibit more rapid liver clearance. ^99mTc-(N)(PNP5)(DBODC5)⁺ (DBODC5) is a lipophilic nitride that is rapidly taken up and retained by the myocardium in a manner that is mechanistically similar to sestamibi and tetrofosmin. However, studies in both rats and dogs demonstrated that DBODC5 cleared more rapidly from the liver than either of these other cationic tracers, with virtually no liver activity observed after only 1 hour.^9,10 The first-pass extraction fraction of DBODC5 is intermediate to that of sestamibi and tetrofosmin.¹⁰ Although there is no improvement in the ability of DBODC5 to track myocardial blood flow at hyperemic flow rates, its more favorable biodistribution properties offer a potential advantage that warrants further investigation.

Another new lipophilic cationic tracer with improved biodistribution and very rapid liver clearance is ^99mTc-[N(MPO)(PNP5)]⁺ (MPO). The myocardial uptake of MPO in Sprague Dawley rats was reported to be between that of sestamibi and DBODC5 over 2 hours.¹¹ Interestingly, the heart-liver ratio of MPO at 30 minutes after injection was more than twice that of DBODC5 and approximately 4 times higher tha...