Cardiac amyloidosis, sarcoidosis, and cardiovascular infections are major causes of morbidity and mortality. Early diagnosis and timely application of specific therapy are critical to improve clinical outcomes.^1,2 Echocardiography, cardiac magnetic resonance imaging (CMR), and cardiac CT can detect increased wall thickness, expanded extracellular volume, diffuse late gadolinium enhancement, wall motion abnormalities, fibrosis, vegetations, and abscesses resulting from cardiac amyloidosis, sarcoidosis, or infection. However, by the time the above cardiac structural changes are evident, the disease is at a fairly advanced stage. Moreover, some of these changes are nonspecific and may represent sequelae of other forms of heart diseases and are not disease specific. Radionuclide imaging methods are evolving as specific disease markers in amyloidosis, sarcoidosis, and infection imaging.

Introduction

Cardiac amyloidosis is a subset of systemic amyloidosis, which is caused by deposition of insoluble nonbranching protein aggregates of amyloid fibrils in the extracellular space of the myocardium. This results in left ventricular thickening and heart failure. Heart failure is a frequent cause of death in these patients. Two major forms of systemic amyloidosis have cardiac involvement^3,4: (1) Light chain amyloidosis (AL) where amyloid fibrils are formed from immunoglobulin light chains produced by clonal population of plasma cells and (2) Transthyretin amyloidosis (ATTR) where misfolded monomers or dimers from either mutant or wild type TTR deposit as fibrils in the myocardium. The mutant type (ATTRm) is an autosomal dominant disorder while the wild type disease (ATTRwt) is associated with aging (senile systemic amyloidosis). Some of the ATTRm diseases have predominant cardiomyopathic manifestations while others have coexistent or predominant neuropathy, including carpal tunnel syndrome and/or autonomic neuropathy along with cardiomyopathy. ATTRwt may be significantly underdiagnosed clinically, as a recent autopsy study showed a prevalence of up to 30% of myocardial amyloid deposits in individuals over 75 years with heart failure and preserved ejection fraction.⁵

Distinction between the two types of cardiac amyloidosis is critical as the treatment and prognosis are vastly different. For AL amyloidosis, chemotherapy is used to inhibit the plasma cell dyscrasia which results in the abnormal light-chain production. Overall mortality as well as treatment-related mortality for AL patients is markedly increased in individuals with cardiac involvement, therefore demonstrating cardiac involvement can guide treatment in these patients. AL cardiac amyloidosis can be rapidly progressive (median survival, if untreated, is <12 months after heart failure onset).³ On the other hand, median survival after heart failure onset is better for ATTR patients (median survival 75 months)⁴ and within this subset, individuals with ATTRwt do better than those with ATTRm. In recent years, new therapies for ATTR have emerged including drugs that inhibit TTR synthesis, stabilize TTR, or degrade proteins.⁶ Hence, there is an urgent need to image and quantify myocardial amyloid burden for early diagnosis and for assessment of response to therapy with these new therapies.

Imaging with echocardiography and CMR typically raises the suspicion of cardiac amyloidosis in individuals with heart failure.⁷ However, imaging features on structural imaging, though highly suggestive, may not be definitively diagnostic for cardiac amyloidosis. Importantly, no specific imaging feature on echocardiography or CMR can distinguish AL from ATTR amyloidosis.⁷ Several radiotracers have been used for imaging cardiac amyloidosis including bone imaging compounds, ¹²³I metaiodobenzylguanidine (mIBG, to image myocardial denervation in familial amyloidosis), and amyloid binding agents (¹²³I-serum amyloid p-component SAP, ¹⁸F-florbetapir, flutemetamol, florbetaben, ¹¹C-Pittsburgh B compound).⁷ In this chapter, we will focus on ^99mTc bone imaging compounds, which are widely used clinically and are highly sensitive and specific for imaging cardiac ATTR amyloidosis.

Indications

Diagnosis

Radionuclide imaging plays an important role in noninvasive diagnosis of cardiac ATTR amyloidosis. ^99mTc-pyrophosphate (PYP) and ^99mTc-3,3-diphosphono-1,2-propranodicarboxylic acid (DPD) are two radiopharmaceuticals that are used for imaging cardiac amyloidosis. In a recent multicenter study, ^99mTc-PYP has been shown to identify ATTR amyloidosis with 97% sensitivity and 100% specificity.^{8–10 99m}Tc-DPD, available in Europe but not approved for clinical use in the United States, has a specificity of 88% and a sensitivity of 100%.^10–12

Several other amyloid binding radiotracers, in particular PET agents that have been used for beta-amyloid imaging in the brain (¹¹C Pittsburgh B-compound,^{13,14 18}F-florbetapir,^{15,16 18}F-flutemetamol, and ¹⁸F-florbetaben¹⁷) are being investigated for cardiac amyloid imaging.

¹²³I-MIBG had been used for the diagnosis of early myocardial denervation in ATTRm.^18–21 mIBG imaging is discussed in Chapter 23.

Echocardiography and CMR have well-established roles in the diagnosis and follow-up of cardiac amyloidosis and a proposed algorithm incorporating radionuclide imaging is shown in Figure 24-1.

In patients with CHF and unexplained left ventricular thickening with suspected cardiac amyloidosis who either have echo findings that are classic for cardiac amyloid and no evidence of plasma cell dyscrasia or patients with suggestive but not classical echo findings and a negative cardiac MRI (or cannot get an MRI) without plasma cell dyscrasia, ^99mTcPYP/DPD scan can be performed to assess for ATTR amyloidosis. Patients with familial ATTR and suspected cardiac amyloidosis can also be evaluated with ^99mTcPYP/DPD scan. Patients with a typical echocardiographic appearance and strongly positive (grade 2 or 3 myocardial radiotracer uptake ≥ rib uptake) ^99mTcPYP/DPD scan can be considered to have ATTR amyloidosis (Fig. 24-2). In these patients, biopsy is not necessary, but may be performed for typing of amyloid. A negative scan, however, does not exclude AL amyloidosis and further evaluation is necessary.⁷ In these patients, bone marrow, fat pad, or endomyocardial biopsy can be performed to confirm the diagnosis of AL. Early studies of cardiac PET imaging for amyloidosis such as with ¹⁸F-florbetapir show potential for detection of AL cardiac amyloidosis. However, this is not yet currently in routine clinical use.

Response to Therapy

Currently, response to therapy for cardiac ATTR is mainly monitored using echocardiography and CMR. However, they are limited due to the temporal delay in detection of change in myocardial wall thickness. Extracellular volume fraction on CMR is emerging as a novel and quantitative marker to diagnose changes in cardiac amyloidosis burden. SPECT/CT with ^99mTcPYP/DPD has the potential to provide quantitative imaging for monitoring response. Results to date, with planar imaging, however, have been disappointing.²² However, it is unclear whether the therapy was not successful or the imaging technique was limited at detecting changes. Amyloid imaging using PET amyloid tracers is inherently quantitative and offers the promise to detect changes in amyloid burden following response to therapy.²³

Prognosis

For patients with ATTRm, it has been shown that the heart-to-whole body ratio (>7.5) combined with LV wall thickness (>12 mm) was associated with the highest rate of major adverse cardiovascular events (defined as cardiovascular death, hospitalization or stroke).¹² A heart-to-contralateral lung ratio of ≥1.6 on planar ^99mTc-PYP scan is associated with worse survival.⁹ Among individuals with V30M mutation ATTRm a heart to mediastinal (H/M) ratio of <1.6 on late ¹²³I-mIBG imaging was associated with a significantly worse 5-year mortality (42% vs. 7% for H/M ratio of <1.6 and ≥1.6, respectively, p < 0.001).

Imaging Technique

Protocol

^99mTc-PYP/DPD

The standard dose for ^99mTc-PYP/DPD is 20 to 25 mCi injected intravenously. No special patient preparation is required and imaging is performed at 1 to 2.5 hours after radiotracer injection. Protocol options include: (1) whole-body or planar cardiac with chest/cardiac SPECT if planar is abnormal and (2) planar and chest/cardiac SPECT or (3) chest/cardiac SPECT-only images. SPECT-only imaging is adequate and provides quickest imaging times. Images are reconstructed with standard ^99mTc protocols and displayed in standard short-axis, vertical long-axis, and horizontal long-axis views.

Image Interpretation ^99mTc-PYP

Qualitative

Images are evaluated qualitatively with regard to uptake in the myocardium when compared to bone (ribs) as follows:

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  Negative/grade 0: no uptake

  
  
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  Mild/grade 1: less than rib uptake

  
  
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  Moderate/grade 2: equal to rib uptake

  
  
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  Severe/grade 3: greater than rib uptake

Grade 2 or greater is considered positive for ATTR amyloidosis.²⁴

Quantitative Analysis

Regions of interest over the heart and in the contralateral lung can be used to assess heart-to-contralateral-lung ratio.⁶ The heart-to-contralateral-lung ratio is derived by drawing a region of interest (ROI) over the heart and copying it over to the right chest. Visual uptake in the heart is compared to visual radiotracer uptake in the ribs on planar images and preferably on SPECT images.

Other Findings

Normal physiologic distribution of ^99mTc-PYP/DPD is similar to a standard nuclear medicine bone scan with uptake in the osseous structures and excretion in the genitourinary system.

Pitfalls

A potential pitfall is myocardial blood pool uptake in early images or in individuals with renal dysfunction. Myocardial radiotracer uptake in ATTR amyloidosis is usually clear-cut with excellent contrast between myocardium and blood pool, if there is any question on early images, more delayed images can be obtained to increase the contrast between the myocardium and the blood pool.

Reporting

Report should contain the presence and degree of myocardial uptake, as well as other incidental findings on whole-body imaging and SPECT/CT, if performed. If qualitative analysis is requested, the heart-to-contralateral-lung ratio on planar imaging can be reported as well. Readers are referred to American Society of Nuclear Cardiology (ASNC) practice points on ^99mTc-PYP imaging for more details.²⁵

Conclusion/Future Directions

Radionuclide imaging of cardiac ATTR amyloidosis with ^99mTc-PYP/DPD is easy to perform with essentially no contraindications. Image analysis is relatively straightforward and nuclear imaging can provide important adjunct diagnostic and prognostic information to echocardiography and CMR. ¹²³I-mIBG imaging can be useful to identify myocardial denervation and stratify risk of adverse clinical outcomes in individuals with ATTRm. Amyloid-binding PET radiotracers that are approved for beta-amyloid brain imaging are currently under investigation and show promise, particularly for quantitation and for characterization of the AL subtype of amyloidosis.

Positron emission tomography (PET) with ¹⁸F-2-fluoro-2-deoxy glucose (¹⁸F-FDG) is emerging as a robust technique for early diagnosis of focal myocardial inflammation and infection, particularly prosthetic material infection. ¹⁸F-FDG is a cyclotron-produced glucose analog with a half-life of 110 minutes. Due to its long half-life, ¹⁸F-FDG can be shipped as unit doses to sites without a cyclotron on-site. ¹⁸F-FDG is a surrogate marker for cellular glucose uptake. Tissue hypoxia is a potent stimulus for increased glucose utilization by the cardiomyocytes. High glycolytic activity from infiltrates of active inflammatory cells also increases glucose utilization in inflammation and infection. GLUT1 synthesis and cell membrane expression of GLUT1 receptors are upregulated in activated macrophages facilitate increased glucose utilization.²⁶ In addition, circulating cytokines and growth factors are thought to increase the affinity of glucose transporters for ¹⁸F-FDG.²⁷ Once transported into the cells through GLUT1, GLUT3, and GLUT4 receptors,^{28 18}F-FDG is phosphorylated by hexokinase to ¹⁸F-FDG-6-phosphate which is not metabolized any further. The trapped ¹⁸F-FDG-6-phosphate within the cell²⁸ provides the imaging signal for metabolically active inflamed tissues. This chapter will focus on imaging of cardiac sarcoidosis and cardiovascular prosthetic infection using ¹⁸F-FDG PET. (See Chapter 3 for further review of FDG.)

¹⁸F-FDG PET/CT Imaging of Cardiac Sarcoidosis

Introduction

Sarcoidosis is an idiopathic, multisystem inflammatory disorder characterized by accumulation of noncaseating granulomas. These organized collections of macrophages, epithelioid cells, and lymphocytes are formed in response to inciting antigens and can eventually lead to organ damage. Both cardiac and neurologic sarcoidosis can occur in isolation without involvement of other organs.²⁹

Cardiac sarcoidosis can involve virtually any part of the heart from endocardium to pericardium and both ventricles and atria.³⁰ The myocardium is most frequently affected, in particular, the left ventricular free wall at the base of the heart, followed by the basal interventricular septum.³¹ Clinical manifestations range from arrhythmias to congestive heart failure to sudden death. Cardiac involvement represents the cause of death in up to 25% of fatal sarcoidosis in the United States. Early diagnosis is important as these complications are potentially preventable with early treatment. Until recently cardiac sarcoidosis was diagnosed using the criteria proposed by the Japanese Ministry of Health and Welfare, that included a histological diagnosis by endomyocardial biopsy or a clinical diagnosis by extracardiac biopsy-proven sarcoidosis in conjunction with major and minor criteria including findings on ECG, echocardiography, myocardial perfusion imaging with ²⁰¹thallium, ^99mtechnetium, ⁶⁷gallium, and CMR (Table 24-1). ¹⁸F-FDG PET/CT, though not included in the Japanese criteria, plays a major role in the contemporary diagnosis and management of cardiac sarcoidosis.³²

Indications for ¹⁸F-FDG PET/CT

Diagnosis of Cardiac Sarcoidosis

The most definitive diagnosis of cardiac sarcoidosis, currently, is based on a positive endomyocardial biopsy. Endomyocardial biopsy is usually a blind procedure with several small samples taken from the right ventricular aspect of the interventricular septum (usual location). As sarcoidosis is a focal disease, endomyocardial biopsy is more prone to sampling error. In sarcoidosis, different parts of the myocardium may harbor granulomas in different stages of inflammation, fibrosis, or an admixture of inflammation and fibrosis. As only a minute portion of the myocardium from the interventricular septum is sampled randomly, assessment of disease activity in the whole heart is limited. ¹⁸F-FDG-PET/CT overcomes these limitations. Inflammation is assessed in the entire heart. Furthermore, as shown in Table 24-2, an abnormal ¹⁸F-FDG PET/CT clinches a diagnosis of cardiac sarcoidosis, without an endomyocardial biopsy, in individuals with a histological proof of extracardiac sarcoidosis and abnormal cardiac symptoms, examination findings, ECG findings, or LVEF <50%.³³

Despite these advantages, when cardiac sarcoidosis is suspected, a CMR study is generally considered before ¹⁸F-FDG PET/CT due to its high negative predictive value to exclude sarcoidosis⁷ and the absence of ionizing radiation. ¹⁸F-FDG PET/CT may be considered as the initial test, if CMR is contraindicated (ferromagnetic devices, glomerular filtration rate, GFR <30 mL/min), or if CMR is abnormal and a confirmation of active inflammation may change clinical management or if clinical suspicion of cardiac sarcoidosis remains high despite a normal CMR.³² The sensitivity and specificity of ¹⁸F-FDG PET for the diagnosis of cardiac sarcoidosis are summarized in Table 24-3.³⁴ Figure 24-3 outlines a proposed algorithm for CMR and ¹⁸F-FDG PET/CT to diagnose cardiac sarcoidosis.