- Email: [email protected]
Multimodality imaging in cardiac sarcoidosis: predicting treatment response
Author's Accepted Manuscript
Multimodality Imaging in Cardiac Sarcoidosis: Predicting Treatment Response Thomas C. Crawford MD
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)01011-5 http://dx.doi.org/10.1016/j.hrthm.2015.07.035 HRTHM6378
To appear in:
Heart Rhythm
Cite this article as: Thomas C. Crawford MD, Multimodality Imaging in Cardiac Sarcoidosis: Predicting Treatment Response, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2015.07.035 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Multimodality Imaging in Cardiac Sarcoidosis: Predicting Treatment Response
Thomas C. Crawford, MD
Division of Cardiovascular Medicine, Department of Internal Medicine and Frankel Cardiovascular Center, University of Michigan Health System, Ann Arbor, MI, USA
Address for correspondence: Thomas C. Crawford, MD University of Michigan Health System 1500 East Center Drive, SPC 5853 Ann Arbor, Michigan 48109-5853 Fax: (734) 936-7026 Email: [email protected] Word Count: 1,484 Keywords: cardiac sarcoidosis, cardiac magnetic resonance, positron emission tomography
Conflicts of Interest; Recipient of research support from Boston Scientific, BIOTRONIK, and Medtronic.
1
Sarcoidosis is a multisystem disorder of unclear etiology. Infectious, organic, and inorganic agents have been proposed as putative antigens, which in genetically susceptible individuals evoke an inflammatory cascade. Activation of CD4+ T cells leads to the production of various cytokines, which promote macrophage aggregation and the development of noncaseating granulomas. Granulomas are a tightly packed amalgamation of the macrophages, epithelioid cells, and multinucleated giant cells surrounded by an assortment of lymphocytes, monocytes, mast cells, and fibroblasts.
1
The histopathology of cardiac sarcoidosis (CS) spans
three successive stages: edema, granulomatous infiltration, and fibrosis with resultant scar formation, and may lead to a spectrum of manifestations with complete heart block (CHB), focal wall motion abnormality, aneurism, ventricular tachyarrhythmia, and heart failure. While the clinical course of sarcoidosis is highly variable, the natural history of the disorder may be affected especially if early immunosuppressant treatment is instituted.
2
The intensity and duration of the
regimen in part relies on the clinician’s ability to monitor disease activity. Positron emission tomography (PET) has emerged as a primary method to ascertain the inflammatory activity in CS. Up-regulation of glucose metabolism occurs at sites of macrophage-mediated inflammation.
After crossing the cell
membrane, 18F-fluorodeoxyglucose (18F-FDG), a glucose analogue, becomes trapped inside the macrophages, thus allowing for imaging of the hypermetabolic activity. A pattern of focal uptake (patchy with no background activity) and focal on diffuse uptake (intense patchy uptake with less intense diffuse uptake) have been considered indicative of active CS. In a recent study by Blankstein and colleagues 3
2
the presence of both perfusion defects and increased
18F-FDG
uptake conferred a
hazard ratio of 3.9 for adverse events, and remained significant after adjusting for left ventricular function and other clinical variables.
18F-FDG
PET has been used to
guide immunosuppressant management. 4 While
18F-FDG
PET reflects the level of metabolic activity, cardiac magnetic
resonance (CMR) imaging offers greater image resolution to aid in characterizing the myocardial tissue architecture. Increased cellular permeability, a hallmark of inflammation, is present during the early and intermediate phases of sarcoid infiltration and results in tissue edema, which can be seen as high intensity signal on T2-weighted images (T2-WI).
Late gadolinium enhancement (LGE), a more
established CMR technique in CS, shows as high intensity signal in T1-weighted inversion recovery following the administration of intravenous gadolinium. Gadolinium is an extracellular contrast agent that has a rapid washout from normal areas of myocardium. However, in patients with CS, the extracellular space, and thus the volume of distribution of gadolinium, is expanded in the presence of edema or scar, which results in a slower washout of the contrast and thus areas of T1 signal hyperenhancement. Due to its unique tissue characterization, cardiac magnetic resonance (CMR) imaging has improved both the diagnosis and prognostication in patients with sarcoidosis. In a cohort of patients with extracardiac sarcoidosis without overt cardiac involvement undergoing LGE-CMR, Patel et al. showed that twice as many patients were identified as having CS as by the application of the 1993 Japanese Ministry of Health and Welfare (JMHW) criteria. 5, 6 The study further demonstrated
3
that patients with LGE had a 9-fold higher rate of major adverse cardiac events and 11.5-fold higher rate of cardiac death compared to patients without LGE. In a cohort of 155 patients suspected of CS, Greulich and colleagues reported a hazard ratio of 31.6 for death, aborted sudden cardiac death, and appropriate implantable cardiac defibrillator (ICD) discharge.
7
No patient without LGE died or experienced any
events during follow-up of 2.6 years, even among those with the left ventricular enlargement and severely impaired left ventricular ejection fraction. In this issue of the Journal, Orii and colleagues 8 explore the utility of combining 18
F-FDG PET and CMR for predicting whether newly diagnosed CS patients with
complete heart block (CHB) will respond to corticosteroid treatment. The authors identified 32 patients meeting the modified JMHW diagnostic criteria.
9
Fifteen patients
had CHB; 17 patients without CHB served as controls. All patients underwent both
18
F-
FDG PET and CMR before the initiation of corticosteroids. The CHB group had higher 18
F-FDG uptake and increased T2-weigted signal in the interventricular septum, but not
more LGE than patients without CHB. All patients who recovered from CHB (6/10) had increased
18
F-FDG uptake, T2-weighted signal, and LGE at baseline. Among the 4
patients without recovery of conduction on ambulatory ECG at 12 weeks, 2 showed no abnormal
18
F-FDG uptake and 2 no increased T2-weighted signal, but all showed LGE.
The 2 non-responders with with baseline
18
18
F-FDG uptake had thinning of the septum. All 8 patients
F-FDG uptake showed reduced uptake on corticosteroid treatment.
Unfortunately, half of the initial responders re-developed CHB at a mean follow-up of 26±6 months. These findings offer an insight into the possible mechanism of heart block in
4
patients with CS. In sum, focal inflammation in the septum was significantly associated with CHB, while fibrosis and scarring were not. Preserved interventricular septal thickness was necessary for the response to corticosteroids. The study suggests that unlike in patients with CS and ventricular tachycardia (VT),10 inflammation-induced edema rather than fibrosis is primarily implicated in the pathophysiology of heart block. The study does have significant limitations, however. One major shortcoming, not uncommon in this field, is the lack of histopathological correlation in cardiac lesions through biopsy. This limitation is compensated in part by the 18FFDG PET data for all subjects. The second major limitation is the fact that the authors performed qualitative, not quantitative assessment of
18F-FDG
uptake, LGE, and high intensity
signal on T2-WI. Novel methods of quantification, using the volume of inflammation and integrated volume-intensity, have been developed to measure the absolute intensity of FDG uptake. 11 T2-WI also has significant limitations, as it is confounded by coil sensitivity issues among other factors. 12 An alternative approach to T2-WI is to directly quantify the T2 of the myocardium, using a technique called T2-mapping, which minimizes artifacts and removes dependency of image contrast on user defined parameters and subjective interpretation. Additionally, subtle T2 differences between tissues may be more easily detected on T2-mapping. PET and CMR allow us to visualize different aspects of CS, and as shown in this paper, may have a complementary role. Despite its limitations, the present study is a welcome addition to the CS literature, as it offers an insight into the enigmatic disease process in at least some patients with CS, and suggests a potential
5
approach ripe for investigation. While clinical factors such as CHB, ventricular arrhythmia, and left ventricular ejection fraction are often used to adjust therapy, 18F-FDG
PET and CMR offer another tool with which we can prognosticate and
monitor treatment efficacy. Multimodality imaging with
18F-FDG
PET and CMR
offers hope to better define the patient population most likely to benefit from the immunosuppressant therapy and to determine its optimal intensity and duration.
1.
Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med Nov 22 2007;357:2153-2165.
2.
Sadek MM, Yung D, Birnie DH, Beanlands RS, Nery PB. Corticosteroid therapy for cardiac sarcoidosis: a systematic review. Can J Cardiol Sep 2013;29:10341041.
3.
Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol Feb 4 2014;63:329-336.
4.
Mc Ardle BA, Leung E, Ohira H, Cocker MS, deKemp RA, DaSilva J, Birnie D, Beanlands RS, Nery PB. The role of F(18)-fluorodeoxyglucose positron emission tomography in guiding diagnosis and management in patients with known or suspected cardiac sarcoidosis. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology Apr 2013;20:297-306.
6
5.
Hiraga H, Hiroe, M, Iwai, K. Guideline for Diagnosis of Cardiac Sarcoidosis: Study Report on Diffuse Pulmonary Diseases The Japanese Ministry of Health and Welfare 199323-24.
6.
Patel MR, Cawley PJ, Heitner JF, Klem I, Parker MA, Jaroudi WA, Meine TJ, White JB, Elliott MD, Kim HW, Judd RM, Kim RJ. Detection of myocardial damage in patients with sarcoidosis. Circulation Nov 17 2009;120:19691977.
7.
Greulich S, Deluigi CC, Gloekler S, et al. CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis. JACC Cardiovasc Imaging Apr 2013;6:501-511.
8.
Orii M, Hirata K, Tanimoto T, Ota S, Shiono Y, Yamano T, Matsuo Y, Ino Y, Yamaguchi T, Kubo T, Tanaka A, Akasaka T. Comparison of cardiac MRI and F-FDG positron emission tomography manifestations and regional response to corticosteroid therapy in newly diagnosed cardiac sarcoidosis with complete heart block. Heart Rhythm Jun 22 2015.
9.
Diagnostic Standard and guidelines for sarcoidosis. Jpn J Sarcoidosis and Granulomatous Disorders 2007;27:89-102.
10.
Jefic D, Joel B, Good E, Morady F, Rosman H, Knight B, Bogun F. Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac sarcoidosis: report from a multicenter registry. Heart Rhythm Feb 2009;6:189-195.
11.
Cardiac Sarcoidosis: Key concepts in Pathogenesis, Disease Management, and Intersting Cases. Switzerland Springer; 2015.
7
12.
Abdel-Aty H, Simonetti O, Friedrich MG. T2-weighted cardiovascular magnetic resonance imaging. Journal of magnetic resonance imaging : JMRI Sep 2007;26:452-459.
8
Multimodality Imaging in Cardiac Sarcoidosis: Predicting Treatment Response Thomas C. Crawford MD
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)01011-5 http://dx.doi.org/10.1016/j.hrthm.2015.07.035 HRTHM6378
To appear in:
Heart Rhythm
Cite this article as: Thomas C. Crawford MD, Multimodality Imaging in Cardiac Sarcoidosis: Predicting Treatment Response, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2015.07.035 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Multimodality Imaging in Cardiac Sarcoidosis: Predicting Treatment Response
Thomas C. Crawford, MD
Division of Cardiovascular Medicine, Department of Internal Medicine and Frankel Cardiovascular Center, University of Michigan Health System, Ann Arbor, MI, USA
Address for correspondence: Thomas C. Crawford, MD University of Michigan Health System 1500 East Center Drive, SPC 5853 Ann Arbor, Michigan 48109-5853 Fax: (734) 936-7026 Email: [email protected] Word Count: 1,484 Keywords: cardiac sarcoidosis, cardiac magnetic resonance, positron emission tomography
Conflicts of Interest; Recipient of research support from Boston Scientific, BIOTRONIK, and Medtronic.
1
Sarcoidosis is a multisystem disorder of unclear etiology. Infectious, organic, and inorganic agents have been proposed as putative antigens, which in genetically susceptible individuals evoke an inflammatory cascade. Activation of CD4+ T cells leads to the production of various cytokines, which promote macrophage aggregation and the development of noncaseating granulomas. Granulomas are a tightly packed amalgamation of the macrophages, epithelioid cells, and multinucleated giant cells surrounded by an assortment of lymphocytes, monocytes, mast cells, and fibroblasts.
1
The histopathology of cardiac sarcoidosis (CS) spans
three successive stages: edema, granulomatous infiltration, and fibrosis with resultant scar formation, and may lead to a spectrum of manifestations with complete heart block (CHB), focal wall motion abnormality, aneurism, ventricular tachyarrhythmia, and heart failure. While the clinical course of sarcoidosis is highly variable, the natural history of the disorder may be affected especially if early immunosuppressant treatment is instituted.
2
The intensity and duration of the
regimen in part relies on the clinician’s ability to monitor disease activity. Positron emission tomography (PET) has emerged as a primary method to ascertain the inflammatory activity in CS. Up-regulation of glucose metabolism occurs at sites of macrophage-mediated inflammation.
After crossing the cell
membrane, 18F-fluorodeoxyglucose (18F-FDG), a glucose analogue, becomes trapped inside the macrophages, thus allowing for imaging of the hypermetabolic activity. A pattern of focal uptake (patchy with no background activity) and focal on diffuse uptake (intense patchy uptake with less intense diffuse uptake) have been considered indicative of active CS. In a recent study by Blankstein and colleagues 3
2
the presence of both perfusion defects and increased
18F-FDG
uptake conferred a
hazard ratio of 3.9 for adverse events, and remained significant after adjusting for left ventricular function and other clinical variables.
18F-FDG
PET has been used to
guide immunosuppressant management. 4 While
18F-FDG
PET reflects the level of metabolic activity, cardiac magnetic
resonance (CMR) imaging offers greater image resolution to aid in characterizing the myocardial tissue architecture. Increased cellular permeability, a hallmark of inflammation, is present during the early and intermediate phases of sarcoid infiltration and results in tissue edema, which can be seen as high intensity signal on T2-weighted images (T2-WI).
Late gadolinium enhancement (LGE), a more
established CMR technique in CS, shows as high intensity signal in T1-weighted inversion recovery following the administration of intravenous gadolinium. Gadolinium is an extracellular contrast agent that has a rapid washout from normal areas of myocardium. However, in patients with CS, the extracellular space, and thus the volume of distribution of gadolinium, is expanded in the presence of edema or scar, which results in a slower washout of the contrast and thus areas of T1 signal hyperenhancement. Due to its unique tissue characterization, cardiac magnetic resonance (CMR) imaging has improved both the diagnosis and prognostication in patients with sarcoidosis. In a cohort of patients with extracardiac sarcoidosis without overt cardiac involvement undergoing LGE-CMR, Patel et al. showed that twice as many patients were identified as having CS as by the application of the 1993 Japanese Ministry of Health and Welfare (JMHW) criteria. 5, 6 The study further demonstrated
3
that patients with LGE had a 9-fold higher rate of major adverse cardiac events and 11.5-fold higher rate of cardiac death compared to patients without LGE. In a cohort of 155 patients suspected of CS, Greulich and colleagues reported a hazard ratio of 31.6 for death, aborted sudden cardiac death, and appropriate implantable cardiac defibrillator (ICD) discharge.
7
No patient without LGE died or experienced any
events during follow-up of 2.6 years, even among those with the left ventricular enlargement and severely impaired left ventricular ejection fraction. In this issue of the Journal, Orii and colleagues 8 explore the utility of combining 18
F-FDG PET and CMR for predicting whether newly diagnosed CS patients with
complete heart block (CHB) will respond to corticosteroid treatment. The authors identified 32 patients meeting the modified JMHW diagnostic criteria.
9
Fifteen patients
had CHB; 17 patients without CHB served as controls. All patients underwent both
18
F-
FDG PET and CMR before the initiation of corticosteroids. The CHB group had higher 18
F-FDG uptake and increased T2-weigted signal in the interventricular septum, but not
more LGE than patients without CHB. All patients who recovered from CHB (6/10) had increased
18
F-FDG uptake, T2-weighted signal, and LGE at baseline. Among the 4
patients without recovery of conduction on ambulatory ECG at 12 weeks, 2 showed no abnormal
18
F-FDG uptake and 2 no increased T2-weighted signal, but all showed LGE.
The 2 non-responders with with baseline
18
18
F-FDG uptake had thinning of the septum. All 8 patients
F-FDG uptake showed reduced uptake on corticosteroid treatment.
Unfortunately, half of the initial responders re-developed CHB at a mean follow-up of 26±6 months. These findings offer an insight into the possible mechanism of heart block in
4
patients with CS. In sum, focal inflammation in the septum was significantly associated with CHB, while fibrosis and scarring were not. Preserved interventricular septal thickness was necessary for the response to corticosteroids. The study suggests that unlike in patients with CS and ventricular tachycardia (VT),10 inflammation-induced edema rather than fibrosis is primarily implicated in the pathophysiology of heart block. The study does have significant limitations, however. One major shortcoming, not uncommon in this field, is the lack of histopathological correlation in cardiac lesions through biopsy. This limitation is compensated in part by the 18FFDG PET data for all subjects. The second major limitation is the fact that the authors performed qualitative, not quantitative assessment of
18F-FDG
uptake, LGE, and high intensity
signal on T2-WI. Novel methods of quantification, using the volume of inflammation and integrated volume-intensity, have been developed to measure the absolute intensity of FDG uptake. 11 T2-WI also has significant limitations, as it is confounded by coil sensitivity issues among other factors. 12 An alternative approach to T2-WI is to directly quantify the T2 of the myocardium, using a technique called T2-mapping, which minimizes artifacts and removes dependency of image contrast on user defined parameters and subjective interpretation. Additionally, subtle T2 differences between tissues may be more easily detected on T2-mapping. PET and CMR allow us to visualize different aspects of CS, and as shown in this paper, may have a complementary role. Despite its limitations, the present study is a welcome addition to the CS literature, as it offers an insight into the enigmatic disease process in at least some patients with CS, and suggests a potential
5
approach ripe for investigation. While clinical factors such as CHB, ventricular arrhythmia, and left ventricular ejection fraction are often used to adjust therapy, 18F-FDG
PET and CMR offer another tool with which we can prognosticate and
monitor treatment efficacy. Multimodality imaging with
18F-FDG
PET and CMR
offers hope to better define the patient population most likely to benefit from the immunosuppressant therapy and to determine its optimal intensity and duration.
1.
Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med Nov 22 2007;357:2153-2165.
2.
Sadek MM, Yung D, Birnie DH, Beanlands RS, Nery PB. Corticosteroid therapy for cardiac sarcoidosis: a systematic review. Can J Cardiol Sep 2013;29:10341041.
3.
Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol Feb 4 2014;63:329-336.
4.
Mc Ardle BA, Leung E, Ohira H, Cocker MS, deKemp RA, DaSilva J, Birnie D, Beanlands RS, Nery PB. The role of F(18)-fluorodeoxyglucose positron emission tomography in guiding diagnosis and management in patients with known or suspected cardiac sarcoidosis. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology Apr 2013;20:297-306.
6
5.
Hiraga H, Hiroe, M, Iwai, K. Guideline for Diagnosis of Cardiac Sarcoidosis: Study Report on Diffuse Pulmonary Diseases The Japanese Ministry of Health and Welfare 199323-24.
6.
Patel MR, Cawley PJ, Heitner JF, Klem I, Parker MA, Jaroudi WA, Meine TJ, White JB, Elliott MD, Kim HW, Judd RM, Kim RJ. Detection of myocardial damage in patients with sarcoidosis. Circulation Nov 17 2009;120:19691977.
7.
Greulich S, Deluigi CC, Gloekler S, et al. CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis. JACC Cardiovasc Imaging Apr 2013;6:501-511.
8.
Orii M, Hirata K, Tanimoto T, Ota S, Shiono Y, Yamano T, Matsuo Y, Ino Y, Yamaguchi T, Kubo T, Tanaka A, Akasaka T. Comparison of cardiac MRI and F-FDG positron emission tomography manifestations and regional response to corticosteroid therapy in newly diagnosed cardiac sarcoidosis with complete heart block. Heart Rhythm Jun 22 2015.
9.
Diagnostic Standard and guidelines for sarcoidosis. Jpn J Sarcoidosis and Granulomatous Disorders 2007;27:89-102.
10.
Jefic D, Joel B, Good E, Morady F, Rosman H, Knight B, Bogun F. Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac sarcoidosis: report from a multicenter registry. Heart Rhythm Feb 2009;6:189-195.
11.
Cardiac Sarcoidosis: Key concepts in Pathogenesis, Disease Management, and Intersting Cases. Switzerland Springer; 2015.
7
12.
Abdel-Aty H, Simonetti O, Friedrich MG. T2-weighted cardiovascular magnetic resonance imaging. Journal of magnetic resonance imaging : JMRI Sep 2007;26:452-459.
8