875
Atrioventricular Block as the Initial Manifestation of Cardiac Sarcoidosis in Middle-Aged Adults PABLO B. NERY, M.D.,∗ ROB S. BEANLANDS, M.D.,∗ GIRISH M. NAIR, M.B.B.S.,∗ MARTIN GREEN, M.D.,∗ JIM YANG, B.Sc.,∗ BRIAN A. MCARDLE, M.D.,∗ DARRYL DAVIS, M.D.,∗ HIROSHI OHIRA, M.D.,∗ MICHAEL H. GOLLOB, M.D.,∗ EUGENE LEUNG, M.D.,† JEFF S. HEALEY, M.D.,‡ and DAVID H. BIRNIE, M.B.Ch.B., M.D.∗ From the ∗ Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada; †Division of Nuclear Medicine, Department of Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, Canada; and ‡Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
Cardiac Sarcoidosis Presenting as Atrioventricular Block. Introduction:
Atrioventricular block (AVB) can be caused by several conditions, including cardiac sarcoidosis (CS). The prevalence of CS causing this presentation in a North American population has not been investigated and was the purpose of this study. Methods: We prospectively evaluated patients aged 18–60 years presenting with unexplained 2nd or 3rd degree AVB and no previous history of sarcoidosis in any organ. All patients had fluorodeoxyglucosepositron emission tomography (FDG-PET) scans for the evaluation of CS. Japanese Ministry of Health Welfare (JMHW) criteria and biopsy results were used to confirm the diagnosis of CS. Subjects with advanced imaging suggestive of CS were investigated for extracardiac involvement. Patients were followed for major adverse cardiac events. Results: Thirty-two patients presenting with unexplained AVB underwent cardiac and whole body FDGPET for the investigation of CS from February 2010 to June 2013. Mean age was 52.8 ± 6.2 years, and 20 were male. CS was diagnosed in 11/32 (34%) subjects and 11/11 were subsequently diagnosed with extra-CS. Average follow-up was 21 ± 9 months. Adverse events were observed in 3 subjects with CS but none in subjects with idiopathic AVB. All 3 patients presented with heart failure, 2 also had recurrent VT resulting in ICD shocks. Conclusions: In this prospective study of consecutive patients aged ࣘ60 years presenting with unexplained AVB, we found that 11/32 (34%) had previously undiagnosed CS. Among patients with CS, 3/11 had adverse clinical outcomes compared with 0/21 (P = 0.011). Our data suggest that all patients aged ࣘ60 years with unexplained AVB should be investigated for CS. Moreover, patients diagnosed with CS should be closely followed. (J Cardiovasc Electrophysiol, Vol. 25, pp. 875-881, August 2014) cardiac sarcoidosis, atrioventricular block, pacing, middle-aged, prevalence, outcomes, ventricular tachycardia, implantable cardioverter defibrillator Introduction Atrioventricular block (AVB) can result from a variety of pathologic conditions affecting the conduction system. This project was supported in part by the Cardiac Care Network of Ontario. D. H. Birnie is a career investigator supported by the Heart and Stroke Foundation of Ontario. R. S. Beanlands serves as consultant to GE Healthcare and Jubilant Draximage. Other authors: No disclosures. R. S. Beanlands is a career investigator supported by the Heart and Stroke Foundation of Ontario and Tier 1 Research Chair supported by the University of Ottawa. Address for correspondence: Pablo B. Nery, M.D., Arrhythmia Service, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Room H1285, Ottawa, Canada K1Y4W7; E-mail: [email protected] Manuscript received 18 January 2014; Revised manuscript received 16 February 2014; Accepted for publication 27 February 2014. doi: 10.1111/jce.12401
These include infiltrative, infectious or autoimmune processes, coronary artery disease, degenerative, metabolic, neuromuscular disorders, inherited syndromes, and idiopathic conduction system disease.1 Sarcoidosis is a granulomatous disease of unknown etiology and can first present with AVB.2 Noncaseating granulomas are the typical pathological finding and most commonly affect the lungs and mediastinal lymphnodes but may involve other organs, including the heart. Current data suggests genetic susceptibility to an immunological response to an antigenic trigger with human leukocyte antigen predisposition.3,4 Clinical manifestations of cardiac sarcoidosis (CS) are dependent on the location, extent, and disease activity. CS may result in AVB, ventricular tachycardia (VT), heart failure (HF), and sudden cardiac death.5-9 Conduction abnormalities occur due to involvement of the basal interventricular septum and may result in bundle branch block or AVB of any degree.10-15 Limited data are available on the incidence, clinical characteristics, and outcomes of AVB caused by CS; no prospective studies have been published to date. In this prospective study, we sought to systematically investigate for CS and describe the outcomes in young and middle-aged
876
Journal of Cardiovascular Electrophysiology
Vol. 25, No. 8, August 2014
2nd degree or 3rd degree AV block of unknown etiology in middle-aged adults (age ≤ 60y)
Advanced Cardiac Imaging 1. FDG-PET ± 2. CMR
1. FDG-PET suggestive of sarcoidosis* 2. CMR suggestive of sarcoidosis*
One or more of 1-2
Yes
No
CT Chest
Idiopathic AVB
Biopsy Extra-cardiac if feasible, otherwise guided EMB to confirm diagnosis
CS diagnosed based on JMHW criteria
* Cardiac or extra-cardiac sarcoidosis. JMHW = Japanese Ministry of Health and Welfare; FDG PET = Fluorodeoxyglucose Positron Emission Tomography; CT = computed tomography.
individuals (ࣘ60 years) presenting with 2nd or 3rd AVB of unknown cause. Methods Patient Population In this prospective cohort study, patients aged 18–60 years presenting with new onset 2nd degree (Mobitz II) or 3rd degree AVB of unknown cause were systematically investigated for CS. Subjects with history of a condition known to cause AVB (e.g., acute myocardial infarction, aortic valve surgery, infectious endocarditis, autoimmune disease, congenital heart disease, and cardiac transplantation), or diagnosis of Lyme disease were excluded. A preexisting history of sarcoidosis in any organ was an exclusion criterion. The remaining patients were classified as having unexplained AVB and thus, enrolled in the study.
Figure 1. Screening algorithm for investigation of cardiac sarcoidosis in subjects aged ࣘ60 years presenting with 2nd degree (Mobitz II) and/or 3rd degree atrioventricular block of unknown origin. A preexisting history of sarcoidosis in any organ was an exclusion criterion. AV = atrioventricular; CS = cardiac sarcoidosis; CMR = cardiac magnetic resonance; EMB = endomyocardial biopsy; FDGPET = fluorodeoxyglucose positron emission tomography.
All patients were assessed for CS with cardiac and whole body F-18 fluorodeoxyglucose-positron emission tomography (FDG-PET).16 A subset of patients also underwent cardiac magnetic resonance (CMR) imaging with delayed gadolinium enhancement. All patients had transthoracic 2dimensional echocardiogram and a chest X-ray (CXR). Subjects in whom FDG-PET or CMR was suggestive of sarcoidosis were further evaluated with high resolution chest CT scan. Whole body FDG-PET imaging and CT chest results were assessed for the presence of extra-CS and to select appropriate sites for biopsy. Histological diagnosis was confirmed through tissue biopsy. If feasible, lymphnode, lung, or skin biopsies were attempted before endomyocardial biopsy (EMB). EMB was performed with 3-dimensional electroanatomic bipolar voltage mapping (CARTOTM , Biosense Webster Inc., Diamond Bar, CA, USA) guidance.17 A cardiac pathologist with expertise in the diagnosis of CS verified samples for the presence of noncaseating granulomas. CS
Nery et al. Cardiac Sarcoidosis Presenting as Atrioventricular Block
18F-FDG
A
B
PET/CT
Cardiac PET Short Axis
877
Horizontal Long Axis
Vertical Long Axis
82Rb
18F-FDG
was diagnosed based on Japanese Ministry of Health Welfare (JMHW) criteria.18 Patients underwent cardiac device implantation and corticosteroid therapy at the discretion of the treating physician. The study’s investigation algorithm is shown in Figure 1.
TABLE 1 Demographic and Baseline Characteristics of Patients Presenting with Atrioventricular Block of Unknown Etiology Variable
Study Outcomes Major adverse cardiac events (MACE) were predefined as 1 or more of sustained VT, appropriate implantable cardioverter-defibrillator (ICD) shocks, hospitalization for decompensated HF, heart transplant/left ventricular assist device insertion, or death. Safety outcomes associated with corticosteroid or immunosuppressive therapy was followed throughout the study. Also, the status of AV conduction was evaluated 6 months after presentation and at the longest follow-up visit. Atrioventricular conduction was compared to the initial presentation and classified as (a) unchanged, (b) improved by 1 degree, or (c) improved from 3rd degree to either 1st degree AVB or normal AV conduction. Electrocardiographic Analysis Twelve-lead ECGs were analyzed in all patients presenting with 3rd degree AVB. The objective was to compare the escape rhythms. Data Analysis Descriptive statistics are presented as the number (percent) for categorical variables and mean (± standard deviation [SD]) or median (25th–75th percentile) for continuous variables. The differences between patient group characteristics were assessed using the Mann–Whitney U-test and Fisher’s exact tests. The survival curves were analyzed and plotted by the Kaplan–Meier method. All tests were 2-tailed, with P ࣘ 0.05 considered to be statistically significant. All analyses were performed using SAS software version 9.0 (SAS Institute Inc., Cary, NC, USA).
Figure 2. Fusion PET/CT images from a 48-year-old male presenting with 3rd degree atrioventricular block. A: Transaxial slices of cardiac fasting FDG-PET images demonstrating focal uptake in the interventricular septum (red arrow) and RV free wall (white arrow). B: 82Rubidium PET/CT showing normal perfusion at rest (top). FDG-PET/CT revealed focal FDG uptake in the basal to mid segments of the septum (red arrow) and RV free wall (white arrow; bottom). For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
Age on presentation, years (mean ± SD) Male gender, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Coronary artery disease, n (%) Both 2nd and 3rd degree AVB, n (%) 3rd degree AVB only, n (%) 2nd degree AVB only, n (%) Abnormal LVEF on presentation, n (%) Abnormal RV function, n (%) Troponin elevated on presentation, n (%)†
Cardiac Sarcoidosis (n=11)
Idiopathic AVB (n=21)
P
53.4 ± 5.1
52.5 ± 6.9
0.969
8 (73) 4 (36) 1 (9) 0 (0)
12 (57) 8 (38) 7 (33) 1 (5)
0.465 1.000 0.209 1.000
4 (36)
8 (38)
0.770
5 (45)
11 (52)
2 (18)
2 (10)
2 (18)
3 (16)
1.000
0 (0)
1 (5)
1.000
3 (38)
6 (33)
1.000
† Troponin (TnI) available in 8/11 CS and 18/21 idiopathic AVB patients, percentages were only calculated on the TnI available samples. AVB = atrioventricular block; LVEF = left ventricular ejection fraction on presentation; RV = right ventricular.
Ethics The study protocol was approved by the institutional ethics review board. All patients signed written informed consent. Results Patients Thirty-two patients met inclusion criteria and were investigated for CS with cardiac and whole body FDG-PET
8 had therapy initiated >6 months after diagnosis. AVB = atrioventricular block; LVEF = left ventricular ejection fraction; LFN = lymph nodes; MACE = major adverse cardiac event.
† LVEF/TnI assessed on presentation with atrioventricular block. ‡ Steroid therapy refers to corticosteroid therapy. Subjects 1, 2, and
2nd and 3rd degree AVB Mediastinal, hilar, and retrocrural LFN 3rd degree AVB Pulmonary, mediastinal LFN 2nd and 3rd degree AVB Mediastinal and hilar LFN 58 47 49 9 10 11
M M M
Caucasian Mild global LV hypokinesis / 47 Caucasian Normal / 60 Caucasian Normal / 55
Atrioventricular Block as the Initial Manifestation of Cardiac Sarcoidosis in Middle-Aged Adults PABLO B. NERY, M.D.,∗ ROB S. BEANLANDS, M.D.,∗ GIRISH M. NAIR, M.B.B.S.,∗ MARTIN GREEN, M.D.,∗ JIM YANG, B.Sc.,∗ BRIAN A. MCARDLE, M.D.,∗ DARRYL DAVIS, M.D.,∗ HIROSHI OHIRA, M.D.,∗ MICHAEL H. GOLLOB, M.D.,∗ EUGENE LEUNG, M.D.,† JEFF S. HEALEY, M.D.,‡ and DAVID H. BIRNIE, M.B.Ch.B., M.D.∗ From the ∗ Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada; †Division of Nuclear Medicine, Department of Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, Canada; and ‡Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
Cardiac Sarcoidosis Presenting as Atrioventricular Block. Introduction:
Atrioventricular block (AVB) can be caused by several conditions, including cardiac sarcoidosis (CS). The prevalence of CS causing this presentation in a North American population has not been investigated and was the purpose of this study. Methods: We prospectively evaluated patients aged 18–60 years presenting with unexplained 2nd or 3rd degree AVB and no previous history of sarcoidosis in any organ. All patients had fluorodeoxyglucosepositron emission tomography (FDG-PET) scans for the evaluation of CS. Japanese Ministry of Health Welfare (JMHW) criteria and biopsy results were used to confirm the diagnosis of CS. Subjects with advanced imaging suggestive of CS were investigated for extracardiac involvement. Patients were followed for major adverse cardiac events. Results: Thirty-two patients presenting with unexplained AVB underwent cardiac and whole body FDGPET for the investigation of CS from February 2010 to June 2013. Mean age was 52.8 ± 6.2 years, and 20 were male. CS was diagnosed in 11/32 (34%) subjects and 11/11 were subsequently diagnosed with extra-CS. Average follow-up was 21 ± 9 months. Adverse events were observed in 3 subjects with CS but none in subjects with idiopathic AVB. All 3 patients presented with heart failure, 2 also had recurrent VT resulting in ICD shocks. Conclusions: In this prospective study of consecutive patients aged ࣘ60 years presenting with unexplained AVB, we found that 11/32 (34%) had previously undiagnosed CS. Among patients with CS, 3/11 had adverse clinical outcomes compared with 0/21 (P = 0.011). Our data suggest that all patients aged ࣘ60 years with unexplained AVB should be investigated for CS. Moreover, patients diagnosed with CS should be closely followed. (J Cardiovasc Electrophysiol, Vol. 25, pp. 875-881, August 2014) cardiac sarcoidosis, atrioventricular block, pacing, middle-aged, prevalence, outcomes, ventricular tachycardia, implantable cardioverter defibrillator Introduction Atrioventricular block (AVB) can result from a variety of pathologic conditions affecting the conduction system. This project was supported in part by the Cardiac Care Network of Ontario. D. H. Birnie is a career investigator supported by the Heart and Stroke Foundation of Ontario. R. S. Beanlands serves as consultant to GE Healthcare and Jubilant Draximage. Other authors: No disclosures. R. S. Beanlands is a career investigator supported by the Heart and Stroke Foundation of Ontario and Tier 1 Research Chair supported by the University of Ottawa. Address for correspondence: Pablo B. Nery, M.D., Arrhythmia Service, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin Street, Room H1285, Ottawa, Canada K1Y4W7; E-mail: [email protected] Manuscript received 18 January 2014; Revised manuscript received 16 February 2014; Accepted for publication 27 February 2014. doi: 10.1111/jce.12401
These include infiltrative, infectious or autoimmune processes, coronary artery disease, degenerative, metabolic, neuromuscular disorders, inherited syndromes, and idiopathic conduction system disease.1 Sarcoidosis is a granulomatous disease of unknown etiology and can first present with AVB.2 Noncaseating granulomas are the typical pathological finding and most commonly affect the lungs and mediastinal lymphnodes but may involve other organs, including the heart. Current data suggests genetic susceptibility to an immunological response to an antigenic trigger with human leukocyte antigen predisposition.3,4 Clinical manifestations of cardiac sarcoidosis (CS) are dependent on the location, extent, and disease activity. CS may result in AVB, ventricular tachycardia (VT), heart failure (HF), and sudden cardiac death.5-9 Conduction abnormalities occur due to involvement of the basal interventricular septum and may result in bundle branch block or AVB of any degree.10-15 Limited data are available on the incidence, clinical characteristics, and outcomes of AVB caused by CS; no prospective studies have been published to date. In this prospective study, we sought to systematically investigate for CS and describe the outcomes in young and middle-aged
876
Journal of Cardiovascular Electrophysiology
Vol. 25, No. 8, August 2014
2nd degree or 3rd degree AV block of unknown etiology in middle-aged adults (age ≤ 60y)
Advanced Cardiac Imaging 1. FDG-PET ± 2. CMR
1. FDG-PET suggestive of sarcoidosis* 2. CMR suggestive of sarcoidosis*
One or more of 1-2
Yes
No
CT Chest
Idiopathic AVB
Biopsy Extra-cardiac if feasible, otherwise guided EMB to confirm diagnosis
CS diagnosed based on JMHW criteria
* Cardiac or extra-cardiac sarcoidosis. JMHW = Japanese Ministry of Health and Welfare; FDG PET = Fluorodeoxyglucose Positron Emission Tomography; CT = computed tomography.
individuals (ࣘ60 years) presenting with 2nd or 3rd AVB of unknown cause. Methods Patient Population In this prospective cohort study, patients aged 18–60 years presenting with new onset 2nd degree (Mobitz II) or 3rd degree AVB of unknown cause were systematically investigated for CS. Subjects with history of a condition known to cause AVB (e.g., acute myocardial infarction, aortic valve surgery, infectious endocarditis, autoimmune disease, congenital heart disease, and cardiac transplantation), or diagnosis of Lyme disease were excluded. A preexisting history of sarcoidosis in any organ was an exclusion criterion. The remaining patients were classified as having unexplained AVB and thus, enrolled in the study.
Figure 1. Screening algorithm for investigation of cardiac sarcoidosis in subjects aged ࣘ60 years presenting with 2nd degree (Mobitz II) and/or 3rd degree atrioventricular block of unknown origin. A preexisting history of sarcoidosis in any organ was an exclusion criterion. AV = atrioventricular; CS = cardiac sarcoidosis; CMR = cardiac magnetic resonance; EMB = endomyocardial biopsy; FDGPET = fluorodeoxyglucose positron emission tomography.
All patients were assessed for CS with cardiac and whole body F-18 fluorodeoxyglucose-positron emission tomography (FDG-PET).16 A subset of patients also underwent cardiac magnetic resonance (CMR) imaging with delayed gadolinium enhancement. All patients had transthoracic 2dimensional echocardiogram and a chest X-ray (CXR). Subjects in whom FDG-PET or CMR was suggestive of sarcoidosis were further evaluated with high resolution chest CT scan. Whole body FDG-PET imaging and CT chest results were assessed for the presence of extra-CS and to select appropriate sites for biopsy. Histological diagnosis was confirmed through tissue biopsy. If feasible, lymphnode, lung, or skin biopsies were attempted before endomyocardial biopsy (EMB). EMB was performed with 3-dimensional electroanatomic bipolar voltage mapping (CARTOTM , Biosense Webster Inc., Diamond Bar, CA, USA) guidance.17 A cardiac pathologist with expertise in the diagnosis of CS verified samples for the presence of noncaseating granulomas. CS
Nery et al. Cardiac Sarcoidosis Presenting as Atrioventricular Block
18F-FDG
A
B
PET/CT
Cardiac PET Short Axis
877
Horizontal Long Axis
Vertical Long Axis
82Rb
18F-FDG
was diagnosed based on Japanese Ministry of Health Welfare (JMHW) criteria.18 Patients underwent cardiac device implantation and corticosteroid therapy at the discretion of the treating physician. The study’s investigation algorithm is shown in Figure 1.
TABLE 1 Demographic and Baseline Characteristics of Patients Presenting with Atrioventricular Block of Unknown Etiology Variable
Study Outcomes Major adverse cardiac events (MACE) were predefined as 1 or more of sustained VT, appropriate implantable cardioverter-defibrillator (ICD) shocks, hospitalization for decompensated HF, heart transplant/left ventricular assist device insertion, or death. Safety outcomes associated with corticosteroid or immunosuppressive therapy was followed throughout the study. Also, the status of AV conduction was evaluated 6 months after presentation and at the longest follow-up visit. Atrioventricular conduction was compared to the initial presentation and classified as (a) unchanged, (b) improved by 1 degree, or (c) improved from 3rd degree to either 1st degree AVB or normal AV conduction. Electrocardiographic Analysis Twelve-lead ECGs were analyzed in all patients presenting with 3rd degree AVB. The objective was to compare the escape rhythms. Data Analysis Descriptive statistics are presented as the number (percent) for categorical variables and mean (± standard deviation [SD]) or median (25th–75th percentile) for continuous variables. The differences between patient group characteristics were assessed using the Mann–Whitney U-test and Fisher’s exact tests. The survival curves were analyzed and plotted by the Kaplan–Meier method. All tests were 2-tailed, with P ࣘ 0.05 considered to be statistically significant. All analyses were performed using SAS software version 9.0 (SAS Institute Inc., Cary, NC, USA).
Figure 2. Fusion PET/CT images from a 48-year-old male presenting with 3rd degree atrioventricular block. A: Transaxial slices of cardiac fasting FDG-PET images demonstrating focal uptake in the interventricular septum (red arrow) and RV free wall (white arrow). B: 82Rubidium PET/CT showing normal perfusion at rest (top). FDG-PET/CT revealed focal FDG uptake in the basal to mid segments of the septum (red arrow) and RV free wall (white arrow; bottom). For a high quality, full color version of this figure, please see Journal of Cardiovascular Electrophysiology’s website: www.wileyonlinelibrary.com/journal/jce
Age on presentation, years (mean ± SD) Male gender, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Coronary artery disease, n (%) Both 2nd and 3rd degree AVB, n (%) 3rd degree AVB only, n (%) 2nd degree AVB only, n (%) Abnormal LVEF on presentation, n (%) Abnormal RV function, n (%) Troponin elevated on presentation, n (%)†
Cardiac Sarcoidosis (n=11)
Idiopathic AVB (n=21)
P
53.4 ± 5.1
52.5 ± 6.9
0.969
8 (73) 4 (36) 1 (9) 0 (0)
12 (57) 8 (38) 7 (33) 1 (5)
0.465 1.000 0.209 1.000
4 (36)
8 (38)
0.770
5 (45)
11 (52)
2 (18)
2 (10)
2 (18)
3 (16)
1.000
0 (0)
1 (5)
1.000
3 (38)
6 (33)
1.000
† Troponin (TnI) available in 8/11 CS and 18/21 idiopathic AVB patients, percentages were only calculated on the TnI available samples. AVB = atrioventricular block; LVEF = left ventricular ejection fraction on presentation; RV = right ventricular.
Ethics The study protocol was approved by the institutional ethics review board. All patients signed written informed consent. Results Patients Thirty-two patients met inclusion criteria and were investigated for CS with cardiac and whole body FDG-PET
8 had therapy initiated >6 months after diagnosis. AVB = atrioventricular block; LVEF = left ventricular ejection fraction; LFN = lymph nodes; MACE = major adverse cardiac event.
† LVEF/TnI assessed on presentation with atrioventricular block. ‡ Steroid therapy refers to corticosteroid therapy. Subjects 1, 2, and
2nd and 3rd degree AVB Mediastinal, hilar, and retrocrural LFN 3rd degree AVB Pulmonary, mediastinal LFN 2nd and 3rd degree AVB Mediastinal and hilar LFN 58 47 49 9 10 11
M M M
Caucasian Mild global LV hypokinesis / 47 Caucasian Normal / 60 Caucasian Normal / 55
