Abstract
We present an illustrative educational case series focused on the use of nuclear imaging in the diagnosis and follow-up of cardiac inflammation. (Level of Difficulty: Intermediate.)
Key Words: cardiac magnetic resonance, cardiomyopathy, nuclear medicine, echocardiography, positron emission tomography
Abbreviations and Acronyms: FDG, 18F-fluorodeoxyglucose; ICD, implanted cardioverter-defibrillator; LVEF, left ventricular ejection fraction; PET/CT, positron emission tomography/computed tomography; Rb82, rubidium-82
Graphical abstract
Nuclear imaging is invaluable not only for the assessment of coronary artery disease and myocardial viability, but also for the noninvasive diagnosis of infectious, inflammatory, and infiltrative cardiovascular disorders.1 Position emission tomography/computed tomography (PET/CT) accomplishes this via detection of radiopharmaceutical avidity in tissues and precise quantification of their local concentration. The most common radiotracer used for detection of inflammation, 18F-fluorodeoxyglucose (FDG), accumulates proportionally to the degree of cellular glucose metabolism, which is increased in metabolically active white blood cells in sarcoidosis, endocarditis, myocarditis, and pericarditis.2 Anatomic and morphologic information derived from combination with CT further improves localization, extent, and characterization of lesions detected. Imaging with rubidium-82 (Rb82) offers insight into myocardial perfusion, and may demonstrate scarred myocardium late in the inflammatory process. Unlike imaging for hibernating myocardium, imaging for cardiac inflammation requires preinjection patient preparation intended to suppress normal glucose uptake in cardiac myocytes, which would otherwise overshadow inflammatory foci. We present selected cases illustrating the multimodality assessment of myocardial inflammation.
Learning Objectives
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To accurately assess the burden of cardiac inflammation with the use of 18F-fluorodeoxyglucose PET
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To synthesize a patient’s clinical presentation with multimodality imaging findings in the diagnosis of cardiac inflammation
Case 1
A 60-year-old woman with a long history of complete heart block status-post implantation of a dual chamber permanent pacemaker presented for evaluation of worsening dyspnea. Electrocardiography showed an atrial and ventricular sequentially paced rhythm (Figure 1). Echocardiography demonstrated a drop in left ventricular ejection fraction (LVEF) from 55% previously to 25% (Supplemental Video 1, Supplemental Video 2, Supplemental Video 3, Supplemental Video 4). LVEF did not improve despite treatment with guideline-directed medical therapy including sacubitril/valsartan and metoprolol. Coronary angiography revealed nonobstructive atherosclerosis. She had a greater than 90% right ventricular pacing burden on device interrogation and therefore was referred to an electrophysiologist for consideration of cardiac resynchronization therapy. However, in light of the young age of onset of complete heart block, chest CT was done to investigate for intrathoracic evidence of sarcoidosis. This revealed scattered nonspecific pulmonary nodules (Supplemental Figure 1). This finding raised the possibility of pulmonary sarcoidosis with cardiac involvement, so resting perfusion and metabolic PET/CT was ordered.
Figure 1.
Case 1: Electrocardiography
Electrocardiogram demonstrating atrial and ventricular sequential pacing.
Patient preparation and imaging protocoling were conducted according to the American Society of Nuclear Cardiology guidelines.1 In brief, the patient was advised to follow a ketogenic diet. Fifteen minutes before injection of 9.8 mCi FDG she received an injection of 50 U/kg heparin intravenously. Resting Rb82 perfusion images after injection of 34.7 mCi Rb82 revealed multiple scattered resting perfusion defects (Figure 2). FDG uptake localized to these perfusion defects accounting for inflammation in approximately 20% of the myocardium, including uptake in the right ventricular free wall. In summary, her extracardiac findings of pulmonary nodules, evidence of premature conduction disease, and evidence of inflammation on cardiac PET/CT findings satisfied the Heart Rhythm Society and Japanese Ministry of Health criteria for systemic sarcoid with cardiac involvement.3,4 She underwent device upgrade with implantation of a cardiac resynchronization therapy defibrillator. In addition to her heart failure medication she was prescribed a steroid taper, methotrexate, and prophylactic trimethoprim/sulfamethoxazole. With these measures she improved clinically. Repeated echocardiography remained stable with no change in LVEF (Video 5).
Figure 2.
Case 1: Positron Emission Tomography
Rubidium-82 (Rb82) and 18F-fluorodeoxyglucose (FDG) images demonstrating active cardiac inflammation. Short-axis (SA), horizontal long-axis (HLA), and vertical long-axis (VLA) images shown. Resting Rb82 images reveal multiple scattered perfusion defects involving the mid-anterior wall, basal and mid-inferolateral wall extending into the basal and mid-inferior wall, and lateral apex. FDG images demonstrate tracer uptake in the corresponding segments, as well as uptake in the right ventricular free wall and the basal anterior segment. (Bottom left) Polar maps. (Bottom right) Representative co-localized computed tomographic and nuclear images. The correlation between Rb82 perfusion defects and FDG uptake in the absence of ischemic disease is suggestive of active inflammation. ANT = anterior; INF = inferior; LAT =lateral; SEP = septal.
Case 2
A 41-year-old man presented to the emergency department with generalized malaise. He was found to be hypotensive, and electrocardiography revealed ventricular tachycardia (Figure 3). Acute kidney and liver injury were evident on laboratory investigation. Despite cardioversion he remained hypotensive, so he was transferred to the cardiac intensive care unit for management of shock. Echocardiography revealed an LVEF of 20% (Supplemental Video 6, Supplemental Video 7, Supplemental Video 8, Supplemental Video 9). Coronary angiography revealed nonobstructive coronary disease (images not shown). The patient underwent cardiac magnetic resonance imaging once stabilized in the intensive care unit, which re-demonstrated reduced ventricular systolic function and showed patchy delayed gadolinium enhancement consistent with nonischemic cardiomyopathy (Figure 4). The patient then underwent resting perfusion and metabolic PET/CT to evaluate for active inflammation.
Figure 3.
Case 2: Electrocardiography
Electrocardiogram demonstrating sustained ventricular tachycardia.
Figure 4.
Case 2: Cardiac Magnetic Resonance Imaging
Delayed gadolinium-enhancement cardiac magnetic resonance imaging sequence in the short-axis view at the mid-ventricular cavity. There is patchy late enhancement in the subepicardial inferoseptum and the subendocardial lateral wall in a noncoronary distribution (arrows), suggestive of an infiltrative cardiomyopathy. T2-STIR imaging did not reveal evidence of myocardial edema. IR = inversion recovery sequence.
Resting perfusion images after injection of 30 mCi Rb82 showed focal defects in the anterior and inferior walls (Figure 5). FDG images after injection of 11 mCi FDG demonstrated patchy uptake in the entire anterior wall, anterior septum, inferior wall, mid-inferoseptal segment, and basal inferoseptal segment; this pattern of uptake matched the perfusion defects seen on perfusion images. In addition, whole-body FDG PET revealed FDG-avid portal adenopathy (Figure 6); a biopsy via esophagogastroduodenoscopy of a lymph node in the gastrohepatic ligament revealed noncaseating granulomas consistent with sarcoidosis. The patient was started on carvedilol, hydralazine, isosorbide dinitrate, prednisone, trimethoprim-sulfamethoxazole for prophylaxis, and valsartan. An implanted cardioverter-defibrillator (ICD) was placed for secondary prevention of ventricular tachycardia.
Figure 5.
Case 2: Cardiac Positron Emission Tomography
Resting Rb82 and FDG demonstrating active cardiac inflammation. Polar maps shown on the bottom left and fusion images with FDG and low-dose computed tomography (CT) on the bottom right. Rb82 imaging demonstrates perfusion defects in the anterior wall extending from the anterior periapical segment to the base, as well as in the basal and mid inferoseptal segments. FDG uptake in these segments represents active inflammation. Abbreviations as in Figure 2.
Figure 6.
Case 2: Whole-Body PET
Whole-Body FDG PET/CT images revealing a focus of increased uptake in a periportal lymph node (arrow), suggesting extracardiac involvement of the inflammatory process. Abbreviations as in Figures 2 and 5.
Despite treatment, the patient suffered appropriate ICD discharges requiring initiation of amiodarone, and repeated imaging showed a worsening burden of inflammation. Immunosuppression was intensified with the addition of methotrexate. His renal function had improved and he was changed from valsartan to sacubitril/valsartan with discontinuation of hydralazine and isosorbide. Four months later, repeated PET was done with injection of 30 mCi Rb82 and 12.4 mCi FDG (Figure 7). This revealed a large perfusion defect in the anterior wall and basal inferoseptum with no residual active inflammation; FDG uptake was limited to the cardiac blood pool. Repeated echocardiography showed a modest improvement in LVEF to 29%. Immunosuppression was weaned over the course of 6 months and the patient has remained stable.
Figure 7.
Case 2: Repeated PET
Follow-Up Rb82 and FDG PET on a patient undergoing treatment for cardiac sarcoidosis. Previous study is shown in Figure 6. There are persistent resting perfusion defects in the anterior wall and basal inferoseptum. However, FDG PET demonstrates uptake in the cardiac blood pool but no uptake in the myocardium. FDG co-localization with low-dose CT, shown in the bottom 3 images, corroborates blood pool uptake and absent myocardial uptake. Normalization of the tracer counts to background renders the blood pool signal similar in intensity to the signal from liver uptake. Abbreviations as in Figures 2, 5, and 6.
Case 3
A 58-year-old woman who had undergone ICD placement for aborted sudden cardiac arrest of unknown etiology presented to the hospital with appropriate ICD discharges. Electrocardiography showed sinus bradycardia with first-degree atrioventricular block (Figure 8). Echocardiography showed preserved biventricular systolic function with normal chamber dimensions (Supplemental Video 9, Supplemental Video 10, Supplemental Video 11, Supplemental Video 12, Supplemental Video 13, Supplemental Video 14). There was moderate posterior mitral valve leaflet prolapse with moderate anteriorly directed mitral regurgitation. Cardiac magnetic resonance imaging confirmed bi-leaflet prolapse and moderate mitral regurgitation, and showed mitral annular disjunction with associated transmural delayed enhancement in the basal to mid-inferolateral wall (Figure 9, Video 15). Cardiac catheterization revealed unremarkable coronary arteries (Videos 16 and 17). Resting perfusion and metabolic cardiac PET/CT was done to rule out an inflammatory etiology of her ventricular tachycardia.
Figure 8.
Case 3: Electrocardiography
Electrocardiogram demonstrating sinus bradycardia with prolonged atrioventricular conduction.
Figure 9.
Case 3: Cardiac Magnetic Resonance Imaging
Delayed gadolinium-enhancement cardiac magnetic resonance images in the short-axis view at the left ventricular base (left) and in the 3-chamber view (right). There is delayed enhancement in the basal inferolateral wall (arrows). In the absence of coronary disease, this is suggestive of inflammation progressing to fibrosis.
The patient underwent rest Rb82 imaging with 30 mCi RB82 as well as FDG imaging with 9 mCi FDG (Figure 10). There was evidence of a small perfusion defect in the basal inferolateral wall. This region exhibited focal FDG uptake consistent with active inflammation. The patient was diagnosed with malignant mitral valve prolapse. The patient was treated with amiodarone and metoprolol. Follow-up was scheduled at discharge.
Figure 10.
Case 3: PET
Resting Rb82 and FDG PET in a patient with mitral valve prolapse and mitral annular dysjunction. Resting perfusion shows a small inferolateral segment perfusion defect. FDG localizes to this region as well, suggesting inflammation. Coronary angiography was normal (Videos 16 and 17). Polar maps and fusion images with CT are shown at the bottom. Abbreviations as in Figures 2, 5, and 6.
Discussion
Ultimately, no single imaging modality is infallible in the diagnosis of cardiac inflammation. The clinical presentation of the patient must be foremost in the minds of the providers ordering and interpreting tests in pursuit of these elusive diagnoses. Even with modern optimization protocols, pathologic studies demonstrate that sarcoidosis remains frequently misdiagnosed.5 PET/CT with FDG is a crucial tool used to assess myocardial inflammation. As new tracers and imaging techniques emerge and improve, safe noninvasive diagnosis of cardiac inflammation will become more accurate and reproducible. These tools must be evaluated in longitudinal trials and registries for their diagnostic and therapeutic implications.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For a supplemental figure, please see the online version of this paper.
Appendix
Parasternal long-axis echocardiography clip showing a severely dilated left ventricle with severely reduced systolic function.
Parasternal short-axis echocardiography clip at the level of the mitral valve with color Doppler re-demonstrating a severely dilated left ventricle with severely reduced systolic function and mild secondary mitral regurgitation.
Apical 4-chamber echocardiography clip showing a severely dilated left ventricle with severely reduced systolic function. The right ventricle is mildly dilated with mildly reduced systolic function.
Apical 2-chamber echocardiography clip showing a severely dilated left ventricle with severely reduced systolic function.
Transthoracic echocardiography clip in the parasternal long-axis view demonstrating stability of left ventricular function on serial echocardiography compared with Video 1.
Parasternal long-axis echocardiography clip showing a mildly dilated left ventricle with severely reduced systolic function.
Parasternal short-axis echocardiography clip at the level of the mitral valve leaflet tips showing a mildly dilated left ventricle with severely reduced systolic function.
Apical 4-chamber echocardiography clip showing symmetric 4-chamber dilation and severely reduced systolic function.
Apical 2-chamber echocardiography clip showing severely reduced left ventricular systolic function.
Parasternal long-axis echocardiography clip showing severe prolapse of the posterior leaflet of the mitral valve along with mitral annular disjunction.
Parasternal long-axis echocardiography clip with color Doppler showing moderate late systolic mitral regurgitation, severe prolapse of the posterior leaflet of the mitral valve, and mitral annular disjunction.
Parasternal short-axis echocardiography clip with color Doppler at the level of the mitral valve leaflet tips showing moderate late systolic mitral regurgitation.
Apical 4-chamber echocardiography clip with color Doppler showing moderate late systolic mitral regurgitation due to severe posterior leaflet prolapse.
Apical 2-chamber echocardiography clip showing normal chamber dimensions and function in a patient with severe posterior leaflet mitral valve prolapse.
Turbo field echo cardiac magnetic resonance cine image in the 3-chamber view demonstrating bi-leaflet mitral valve prolapse, a late systolic jet of mitral regurgitation, and mitral annular disjunction.
Left anterior oblique cranial projection of coronary angiography with injection of the right coronary artery demonstrating no significant epicardial atherosclerotic disease.
Right anterior oblique cranial projection of coronary angiography with injection of the left main coronary artery demonstrating no significant epicardial atherosclerotic disease.
References
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Associated Data
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Supplementary Materials
Parasternal long-axis echocardiography clip showing a severely dilated left ventricle with severely reduced systolic function.
Parasternal short-axis echocardiography clip at the level of the mitral valve with color Doppler re-demonstrating a severely dilated left ventricle with severely reduced systolic function and mild secondary mitral regurgitation.
Apical 4-chamber echocardiography clip showing a severely dilated left ventricle with severely reduced systolic function. The right ventricle is mildly dilated with mildly reduced systolic function.
Apical 2-chamber echocardiography clip showing a severely dilated left ventricle with severely reduced systolic function.
Transthoracic echocardiography clip in the parasternal long-axis view demonstrating stability of left ventricular function on serial echocardiography compared with Video 1.
Parasternal long-axis echocardiography clip showing a mildly dilated left ventricle with severely reduced systolic function.
Parasternal short-axis echocardiography clip at the level of the mitral valve leaflet tips showing a mildly dilated left ventricle with severely reduced systolic function.
Apical 4-chamber echocardiography clip showing symmetric 4-chamber dilation and severely reduced systolic function.
Apical 2-chamber echocardiography clip showing severely reduced left ventricular systolic function.
Parasternal long-axis echocardiography clip showing severe prolapse of the posterior leaflet of the mitral valve along with mitral annular disjunction.
Parasternal long-axis echocardiography clip with color Doppler showing moderate late systolic mitral regurgitation, severe prolapse of the posterior leaflet of the mitral valve, and mitral annular disjunction.
Parasternal short-axis echocardiography clip with color Doppler at the level of the mitral valve leaflet tips showing moderate late systolic mitral regurgitation.
Apical 4-chamber echocardiography clip with color Doppler showing moderate late systolic mitral regurgitation due to severe posterior leaflet prolapse.
Apical 2-chamber echocardiography clip showing normal chamber dimensions and function in a patient with severe posterior leaflet mitral valve prolapse.
Turbo field echo cardiac magnetic resonance cine image in the 3-chamber view demonstrating bi-leaflet mitral valve prolapse, a late systolic jet of mitral regurgitation, and mitral annular disjunction.
Left anterior oblique cranial projection of coronary angiography with injection of the right coronary artery demonstrating no significant epicardial atherosclerotic disease.
Right anterior oblique cranial projection of coronary angiography with injection of the left main coronary artery demonstrating no significant epicardial atherosclerotic disease.