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PGMJ Online First, published on June 30, 2015 as 10.1136/postgradmedj-2014-133219 Review
Cardiac sarcoidosis: diagnosis and management S W Dubrey,1 R Sharma,2 R Underwood,3 T Mittal3 1
Department of Cardiology, Hillingdon Hospital, Uxbridge, UK 2 Department of Cardiology, The Royal Brompton Hospital, London, UK 3 Department of Radiology, Harefield Hospital, Harefield, UK Correspondence to Dr Simon W Dubrey, Department of Cardiology, Hillingdon Hospital, Pield Heath Road, Uxbridge UB8 3NN, UK; [email protected] Received 20 December 2014 Revised 11 June 2015 Accepted 12 June 2015
ABSTRACT Cardiac sarcoidosis is one of the most serious and unpredictable aspects of this disease state. Heart involvement frequently presents with arrhythmias or conduction disease, although myocardial infiltration resulting in congestive heart failure may also occur. The prognosis in cardiac sarcoidosis is highly variable, which relates to the heterogeneous nature of heart involvement and marked differences between racial groups. Electrocardiography and echocardiography often provide the first clue to the diagnosis, but advanced imaging studies using positron emission tomography and MRI, in combination with nuclear isotope perfusion scanning are now essential to the diagnosis and management of this condition. The identification of clinically occult cardiac sarcoidosis and the management of isolated and/or asymptomatic heart involvement remain both challenging and contentious. Corticosteroids remain the first treatment choice with the later substitution of immunosuppressive and steroid-sparing therapies. Heart transplantation is an unusual outcome, but when performed, the results are comparable or better than heart transplantation for other disease states. We review the epidemiology, developments in diagnostic techniques and the management of cardiac sarcoidosis.
INTRODUCTION Sarcoidosis is a relatively uncommon multisystem inflammatory granulomatous disease, in which, cardiac involvement can result in life-threatening events as a first presentation. The diagnosis and long-term management of heart involvement remain controversial,1 with international guidelines recently updated.2 In the past, a patient suffering a cardiac death from sarcoidosis was most likely to be the result of a fatal arrhythmic event. The use of pacemakers and/or defibrillators has meant that progressive cardiac failure is now a more frequent cause. Two of the most contentious issues include ‘isolated’ cardiac sarcoidosis and ‘asymptomatic’ cardiac involvement, which continue to frustrate clinician’s attempts to diagnose and manage these scenarios.
EPIDEMIOLOGY
To cite: Dubrey SW, Sharma R, Underwood R, et al. Postgrad Med J Published Online First: [please include Day Month Year] doi:10.1136/ postgradmedj-2014-133219
Around 2%–5% of patients with sarcoidosis show clinical evidence of cardiac involvement,3 4 representing one of the least common manifestations of sarcoidosis. Autopsy studies indicate a considerably greater prevalence of 27%.5 Cardiac sarcoid has been found in people of all ethnic groups. Autopsy studies show a prevalence in Japanese patients of 21%–58%,6–8 while in the USA and Western countries, the prevalence is between 13% and 25%.5 9–11 In contrast, a prevalence of only 0.7% is described for Korean patients.12 The prognosis in different ethnic groups
with cardiac sarcoidosis is also highly variable. In Japanese patients, the 5-year survival rate ranges between 60% and 90%,13 accounting for as many as 85% of sarcoidosis-related deaths.14 15 In the USA, cardiac involvement accounts for 13%–25% of sarcoidosis-related deaths.5 16 Racial groups with a high prevalence for heart involvement tend to show clear female predominance,6 17 although equal gender distribution11 or a male predominance has been described.18 It should be stated that the high prevalence of cardiac sarcoidosis in Japan has resulted in a considerable literature concerning Japanese patients with cardiac sarcoidosis, which may not be applicable across all races.
Genetics and cardiac sarcoidosis Familial clustering19 20 and racial phenotypes18 21 22 indicate a strong genetic element in sarcoidosis.23 Class II human leucocyte antigen (HLA) links with individual phenotypes further support a genetic association.24 Extrapulmonary involvement occurs in combination with the alleles (DRB1*04/*15),22 and an occupational exposure to insecticides is reported for HLA DRB1*1101 and cardiac sarcoidosis.25 Japanese women with cardiac sarcoidosis show an association with HLA DQB*0601,26 and with the allele Tumour Necrosis Factor (TNF)A2.27 There may also be a link between ACE gene polymorphisms and a risk of developing sarcoidosis.28 In addition, a high prevalence of cardiac-related mortality29 is seen in Japanese patients with two distinct genotypes; tumour necrosis factor-α2 and HLA DQB1*0601.26 27 Ultimately, the genetics of cardiac sarcoidosis is complex in terms of contributing to the susceptibility and severity of heart involvement, with more definitive factors yet to be identified.30 31
CLINICAL EXPRESSION Cardiac involvement can be difficult to diagnose, even among subjects known to have sarcoidosis,30 and may present in many different ways (box 1), including sudden death, or it may be asymptomatic. Symptoms will depend on the underlying cardiac pathology, duration of disease and ethnicity, but include dyspnoea, cough, syncope, palpitations, chest pain and peripheral oedema. Systemic features, including fever, fatigue, anorexia, arthralgia, ophthalmic issues, neurological sequelae and night sweats can support the diagnosis. Additionally, occupational, environmental and family history32–35 is useful. Heart involvement may present with serious and life-threatening arrhythmias, including ventricular tachycardia (VT), non-sustained ventricular fibrillation or heart block.9 14 36 Complete AV block is described in 23%–30% of patients with clinically
Dubrey SW, et al. Postgrad Med J 2015;0:1–11. doi:10.1136/postgradmedj-2014-133219
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://pmj.bmj.com/ on July 2, 2015 - Published by group.bmj.com
Review DIAGNOSTIC TESTS Box 1 Differential diagnoses for cardiac sarcoidosis 1. 2. 3.
Ischaemic heart disease Idiopathic dilated cardiomyopathy Lyme disease ( particularly when presenting with heart block) 4. Infiltrative cardiomyopathies (eg, amyloid heart disease) 5. Giant cell myocarditis 6. Lymphocytic myocarditis 7. Connective tissue disease 8. Vasculitis ( particularly Takayasu arteritis) 9. Arrhythmogenic right ventricular cardiomyopathy 10. Wegener’s granulomatosis 11. Other infective causes of cardiomyopathy (eg, dengue fever, Chagas disease, syphilis, fungal infections and tuberculosis)
evident cardiac involvement,9 possibly explained by a predilection for the basal portion of the interventricular septum and proximity to the conduction system.37 Nery et al38 described 32 middle-aged patients with AV block, 11 (34%) of whom were identified as having underlying cardiac sarcoidosis. Less commonly, patients develop structural and mechanical myocardial dysfunction. Patients may present with breathlessness from congestive heart failure,7 9 10 or pulmonary hypertension.37 39 Ventricular aneurysms, while not unique to sarcoidosis, are considered a ‘hallmark’ feature, with additional concern that long-term steroid use might contribute to aneurysm development.9 Papillary muscle involvement can lead to valve dysfunction (most commonly the mitral valve) and subsequent ventricular failure,10 although direct valvular involvement occurs in less than 3% of cases.40 The development of pulmonary hypertension is multifactorial,39 being predominantly related to pulmonary sarcoidosis causing cor pulmonale, with contributions from left ventricular dysfunction, mitral incompetence and pulmonary vasculopathy.20 Pericardial involvement is less common,41 with small pericardial effusions reported in 19% of echocardiograms,42 and rarely progressing to tamponade.
Sarcoidosis is often suspected from an incidental chest radiograph, characteristically showing bilateral hilar and right paratracheal lymphadenopathy, with or without pulmonary parenchymal involvement (figure 1). Further clues include an elevated serum calcium (10% of cases) and hypercalciuria (30%–40% of cases).43 44 Both occur as a result of dysregulation of vitamin D metabolism.44 Serum ACE (SACE) is frequently elevated during active disease, but is non-specific, being elevated in other granulomatous diseases. Although SACE levels are unreliable diagnostically,45 46 levels are sometimes used to follow treatment responses.47 An excess of immunoglobulin (hypergammaglobulinaemia) may occur due to a recognised B-cell ‘proliferation’,48 and routine bloods may indicate elevated inflammatory markers. The Kveim test is not used in the UK, the reagent being unavailable since 1996. Despite a lack of Food and Drug Administration (FDA) approval and the risk of transmitting sarcoidosis or an infective agent, some units still employ this test. In patients with known sarcoidosis, detecting cardiac involvement usually starts with electrical recordings (ECG and Holter monitoring) and echocardiographic studies. Advanced imaging studies (MRI and positron emission tomography (PET)) follow, which also permit monitoring of disease progression and ‘activity’.
Electrocardiography ECGs are non-specific as a stand-alone investigation,49 but an abnormality (bundle branch block, ventricular ectopy, seconddegree and third-degree AV block) and cardiac symptoms (ie, palpitations, syncope) appear predictive of a later diagnosis of cardiac sarcoidosis.18 Less commonly, ECG features may include a pseudoinfarction pattern, prolonged QT interval, sinus node dysfunction and prominent U waves.50 51 Most experts (87%) would use electrocardiography to screen for cardiac involvement,29 and the majority would perform no further testing in the absence of cardiac symptoms and a normal ECG.1 The role of signal-averaged electrocardiography and related in-depth ECG analyses, including QRS fragmentation and microvolt T-wave alternans, remains contentious.1 2 51 52 However, most experts agree that they would not use signal-averaged ECGs in their assessment of suspected cardiac sarcoidosis.1
Holter monitor electrocardiography Many clinicians use Holter ECG recordings to detect and monitor cardiac sarcoidosis. In a 2012 report, around one-third of experts (39%) supported Holter monitoring within routine screening and two-thirds (64%) in cases of suspected heart involvement.1 A 2014 consensus statement indicated that a higher proportion (71%) of experts would select Holter monitoring in screening for cardiac involvement.2 Using Holter recording, a Japanese study proposed that more than 100 ventricular ectopic beats/day had a sensitivity of 67% and specificity of 62% in detecting heart involvement.53
Electrophysiological testing
Figure 1 Chest radiograph showing characteristic hilar and right paratracheal lymphadenopathy. 2
Electrophysiological (EP) testing using programmed electrical stimulation can be used to risk-stratify patients with cardiac sarcoid for the occurrence of significant rhythm disturbance. EP testing also allows a means to treating (catheter ablation) such dysrhythmias once mapped. Around 39% of sarcoidosis experts would refer patients for such an evaluation and only marginally more (42%) when active arrhythmias have already been identified.1 The data to support EP testing in assessing asymptomatic Dubrey SW, et al. Postgrad Med J 2015;0:1–11. doi:10.1136/postgradmedj-2014-133219
Downloaded from http://pmj.bmj.com/ on July 2, 2015 - Published by group.bmj.com
Review patients, with occult cardiac involvement, for implantation defibrillator therapy is limited.52 The drawbacks to using EP testing routinely is that it is time consuming, expensive, not always successful and not without risk to the patient.
Echocardiography Echocardiographic appearances are variable, with interventricular thinning a feature of cardiac sarcoidosis.5 9 40 54–57 Thickening of the interventricular septum is less common,37 49 and might indicate an early prefibrotic stage, associated with inflammation, oedema and granuloma formation.58 When the ventricles appear thinned, there may be regional wall motion abnormalities, aneurysmal distortion and/or global dysfunction. A Korean report looking at ‘characteristic features’ (interventricular basal wall thinning and localised aneurysms) in patients with sarcoidosis, and either a pacemaker or implantable cardioverter defibrillator (ICD), found surprisingly low numbers with these features.12 Of 1357 patients, only 21 exhibited suggestive findings; of which, 1.2% (14 of 1184) were in the pacemaker group, and 4% (7 of 173) were in the defibrillator group. Less commonly, increased myocardial echogenicity occurs, a feature consistent with infiltration. Diastolic dysfunction is seen with initial interstitial inflammation when systolic function may still be normal.59 Subsequent injury and fibrosis can then progress to systolic abnormalities.56 60
Box 2 Guidelines for diagnosing cardiac sarcoidosis (from the Japanese Ministry of Health and Welfare) 1. Histological diagnosis group Cardiac sarcoidosis is confirmed when myocardial biopsy specimens demonstrate non-caseating epithelioid granuloma with histological or clinical diagnosis of extracardiac sarcoidosis 2. Clinical diagnosis group Although myocardial biopsy specimens do not demonstrate non-caseating epithelioid granuloma, extracardiac sarcoidosis is diagnosed histologically or clinically and satisfies the following conditions and more than one in six basic diagnostic criteria ▸ More than 2 of 4 major criteria are satisfied ▸ 1 in 4 major criteria and more than 2 in 5 minor criteria are satisfied Major criteria A. Advanced atrioventricular block B. Basal thinning of the interventricular septum C. Positive cardiac gallium 67 uptake D. Depressed ejection fraction of the left ventricle (
PGMJ Online First, published on June 30, 2015 as 10.1136/postgradmedj-2014-133219 Review
Cardiac sarcoidosis: diagnosis and management S W Dubrey,1 R Sharma,2 R Underwood,3 T Mittal3 1
Department of Cardiology, Hillingdon Hospital, Uxbridge, UK 2 Department of Cardiology, The Royal Brompton Hospital, London, UK 3 Department of Radiology, Harefield Hospital, Harefield, UK Correspondence to Dr Simon W Dubrey, Department of Cardiology, Hillingdon Hospital, Pield Heath Road, Uxbridge UB8 3NN, UK; [email protected] Received 20 December 2014 Revised 11 June 2015 Accepted 12 June 2015
ABSTRACT Cardiac sarcoidosis is one of the most serious and unpredictable aspects of this disease state. Heart involvement frequently presents with arrhythmias or conduction disease, although myocardial infiltration resulting in congestive heart failure may also occur. The prognosis in cardiac sarcoidosis is highly variable, which relates to the heterogeneous nature of heart involvement and marked differences between racial groups. Electrocardiography and echocardiography often provide the first clue to the diagnosis, but advanced imaging studies using positron emission tomography and MRI, in combination with nuclear isotope perfusion scanning are now essential to the diagnosis and management of this condition. The identification of clinically occult cardiac sarcoidosis and the management of isolated and/or asymptomatic heart involvement remain both challenging and contentious. Corticosteroids remain the first treatment choice with the later substitution of immunosuppressive and steroid-sparing therapies. Heart transplantation is an unusual outcome, but when performed, the results are comparable or better than heart transplantation for other disease states. We review the epidemiology, developments in diagnostic techniques and the management of cardiac sarcoidosis.
INTRODUCTION Sarcoidosis is a relatively uncommon multisystem inflammatory granulomatous disease, in which, cardiac involvement can result in life-threatening events as a first presentation. The diagnosis and long-term management of heart involvement remain controversial,1 with international guidelines recently updated.2 In the past, a patient suffering a cardiac death from sarcoidosis was most likely to be the result of a fatal arrhythmic event. The use of pacemakers and/or defibrillators has meant that progressive cardiac failure is now a more frequent cause. Two of the most contentious issues include ‘isolated’ cardiac sarcoidosis and ‘asymptomatic’ cardiac involvement, which continue to frustrate clinician’s attempts to diagnose and manage these scenarios.
EPIDEMIOLOGY
To cite: Dubrey SW, Sharma R, Underwood R, et al. Postgrad Med J Published Online First: [please include Day Month Year] doi:10.1136/ postgradmedj-2014-133219
Around 2%–5% of patients with sarcoidosis show clinical evidence of cardiac involvement,3 4 representing one of the least common manifestations of sarcoidosis. Autopsy studies indicate a considerably greater prevalence of 27%.5 Cardiac sarcoid has been found in people of all ethnic groups. Autopsy studies show a prevalence in Japanese patients of 21%–58%,6–8 while in the USA and Western countries, the prevalence is between 13% and 25%.5 9–11 In contrast, a prevalence of only 0.7% is described for Korean patients.12 The prognosis in different ethnic groups
with cardiac sarcoidosis is also highly variable. In Japanese patients, the 5-year survival rate ranges between 60% and 90%,13 accounting for as many as 85% of sarcoidosis-related deaths.14 15 In the USA, cardiac involvement accounts for 13%–25% of sarcoidosis-related deaths.5 16 Racial groups with a high prevalence for heart involvement tend to show clear female predominance,6 17 although equal gender distribution11 or a male predominance has been described.18 It should be stated that the high prevalence of cardiac sarcoidosis in Japan has resulted in a considerable literature concerning Japanese patients with cardiac sarcoidosis, which may not be applicable across all races.
Genetics and cardiac sarcoidosis Familial clustering19 20 and racial phenotypes18 21 22 indicate a strong genetic element in sarcoidosis.23 Class II human leucocyte antigen (HLA) links with individual phenotypes further support a genetic association.24 Extrapulmonary involvement occurs in combination with the alleles (DRB1*04/*15),22 and an occupational exposure to insecticides is reported for HLA DRB1*1101 and cardiac sarcoidosis.25 Japanese women with cardiac sarcoidosis show an association with HLA DQB*0601,26 and with the allele Tumour Necrosis Factor (TNF)A2.27 There may also be a link between ACE gene polymorphisms and a risk of developing sarcoidosis.28 In addition, a high prevalence of cardiac-related mortality29 is seen in Japanese patients with two distinct genotypes; tumour necrosis factor-α2 and HLA DQB1*0601.26 27 Ultimately, the genetics of cardiac sarcoidosis is complex in terms of contributing to the susceptibility and severity of heart involvement, with more definitive factors yet to be identified.30 31
CLINICAL EXPRESSION Cardiac involvement can be difficult to diagnose, even among subjects known to have sarcoidosis,30 and may present in many different ways (box 1), including sudden death, or it may be asymptomatic. Symptoms will depend on the underlying cardiac pathology, duration of disease and ethnicity, but include dyspnoea, cough, syncope, palpitations, chest pain and peripheral oedema. Systemic features, including fever, fatigue, anorexia, arthralgia, ophthalmic issues, neurological sequelae and night sweats can support the diagnosis. Additionally, occupational, environmental and family history32–35 is useful. Heart involvement may present with serious and life-threatening arrhythmias, including ventricular tachycardia (VT), non-sustained ventricular fibrillation or heart block.9 14 36 Complete AV block is described in 23%–30% of patients with clinically
Dubrey SW, et al. Postgrad Med J 2015;0:1–11. doi:10.1136/postgradmedj-2014-133219
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://pmj.bmj.com/ on July 2, 2015 - Published by group.bmj.com
Review DIAGNOSTIC TESTS Box 1 Differential diagnoses for cardiac sarcoidosis 1. 2. 3.
Ischaemic heart disease Idiopathic dilated cardiomyopathy Lyme disease ( particularly when presenting with heart block) 4. Infiltrative cardiomyopathies (eg, amyloid heart disease) 5. Giant cell myocarditis 6. Lymphocytic myocarditis 7. Connective tissue disease 8. Vasculitis ( particularly Takayasu arteritis) 9. Arrhythmogenic right ventricular cardiomyopathy 10. Wegener’s granulomatosis 11. Other infective causes of cardiomyopathy (eg, dengue fever, Chagas disease, syphilis, fungal infections and tuberculosis)
evident cardiac involvement,9 possibly explained by a predilection for the basal portion of the interventricular septum and proximity to the conduction system.37 Nery et al38 described 32 middle-aged patients with AV block, 11 (34%) of whom were identified as having underlying cardiac sarcoidosis. Less commonly, patients develop structural and mechanical myocardial dysfunction. Patients may present with breathlessness from congestive heart failure,7 9 10 or pulmonary hypertension.37 39 Ventricular aneurysms, while not unique to sarcoidosis, are considered a ‘hallmark’ feature, with additional concern that long-term steroid use might contribute to aneurysm development.9 Papillary muscle involvement can lead to valve dysfunction (most commonly the mitral valve) and subsequent ventricular failure,10 although direct valvular involvement occurs in less than 3% of cases.40 The development of pulmonary hypertension is multifactorial,39 being predominantly related to pulmonary sarcoidosis causing cor pulmonale, with contributions from left ventricular dysfunction, mitral incompetence and pulmonary vasculopathy.20 Pericardial involvement is less common,41 with small pericardial effusions reported in 19% of echocardiograms,42 and rarely progressing to tamponade.
Sarcoidosis is often suspected from an incidental chest radiograph, characteristically showing bilateral hilar and right paratracheal lymphadenopathy, with or without pulmonary parenchymal involvement (figure 1). Further clues include an elevated serum calcium (10% of cases) and hypercalciuria (30%–40% of cases).43 44 Both occur as a result of dysregulation of vitamin D metabolism.44 Serum ACE (SACE) is frequently elevated during active disease, but is non-specific, being elevated in other granulomatous diseases. Although SACE levels are unreliable diagnostically,45 46 levels are sometimes used to follow treatment responses.47 An excess of immunoglobulin (hypergammaglobulinaemia) may occur due to a recognised B-cell ‘proliferation’,48 and routine bloods may indicate elevated inflammatory markers. The Kveim test is not used in the UK, the reagent being unavailable since 1996. Despite a lack of Food and Drug Administration (FDA) approval and the risk of transmitting sarcoidosis or an infective agent, some units still employ this test. In patients with known sarcoidosis, detecting cardiac involvement usually starts with electrical recordings (ECG and Holter monitoring) and echocardiographic studies. Advanced imaging studies (MRI and positron emission tomography (PET)) follow, which also permit monitoring of disease progression and ‘activity’.
Electrocardiography ECGs are non-specific as a stand-alone investigation,49 but an abnormality (bundle branch block, ventricular ectopy, seconddegree and third-degree AV block) and cardiac symptoms (ie, palpitations, syncope) appear predictive of a later diagnosis of cardiac sarcoidosis.18 Less commonly, ECG features may include a pseudoinfarction pattern, prolonged QT interval, sinus node dysfunction and prominent U waves.50 51 Most experts (87%) would use electrocardiography to screen for cardiac involvement,29 and the majority would perform no further testing in the absence of cardiac symptoms and a normal ECG.1 The role of signal-averaged electrocardiography and related in-depth ECG analyses, including QRS fragmentation and microvolt T-wave alternans, remains contentious.1 2 51 52 However, most experts agree that they would not use signal-averaged ECGs in their assessment of suspected cardiac sarcoidosis.1
Holter monitor electrocardiography Many clinicians use Holter ECG recordings to detect and monitor cardiac sarcoidosis. In a 2012 report, around one-third of experts (39%) supported Holter monitoring within routine screening and two-thirds (64%) in cases of suspected heart involvement.1 A 2014 consensus statement indicated that a higher proportion (71%) of experts would select Holter monitoring in screening for cardiac involvement.2 Using Holter recording, a Japanese study proposed that more than 100 ventricular ectopic beats/day had a sensitivity of 67% and specificity of 62% in detecting heart involvement.53
Electrophysiological testing
Figure 1 Chest radiograph showing characteristic hilar and right paratracheal lymphadenopathy. 2
Electrophysiological (EP) testing using programmed electrical stimulation can be used to risk-stratify patients with cardiac sarcoid for the occurrence of significant rhythm disturbance. EP testing also allows a means to treating (catheter ablation) such dysrhythmias once mapped. Around 39% of sarcoidosis experts would refer patients for such an evaluation and only marginally more (42%) when active arrhythmias have already been identified.1 The data to support EP testing in assessing asymptomatic Dubrey SW, et al. Postgrad Med J 2015;0:1–11. doi:10.1136/postgradmedj-2014-133219
Downloaded from http://pmj.bmj.com/ on July 2, 2015 - Published by group.bmj.com
Review patients, with occult cardiac involvement, for implantation defibrillator therapy is limited.52 The drawbacks to using EP testing routinely is that it is time consuming, expensive, not always successful and not without risk to the patient.
Echocardiography Echocardiographic appearances are variable, with interventricular thinning a feature of cardiac sarcoidosis.5 9 40 54–57 Thickening of the interventricular septum is less common,37 49 and might indicate an early prefibrotic stage, associated with inflammation, oedema and granuloma formation.58 When the ventricles appear thinned, there may be regional wall motion abnormalities, aneurysmal distortion and/or global dysfunction. A Korean report looking at ‘characteristic features’ (interventricular basal wall thinning and localised aneurysms) in patients with sarcoidosis, and either a pacemaker or implantable cardioverter defibrillator (ICD), found surprisingly low numbers with these features.12 Of 1357 patients, only 21 exhibited suggestive findings; of which, 1.2% (14 of 1184) were in the pacemaker group, and 4% (7 of 173) were in the defibrillator group. Less commonly, increased myocardial echogenicity occurs, a feature consistent with infiltration. Diastolic dysfunction is seen with initial interstitial inflammation when systolic function may still be normal.59 Subsequent injury and fibrosis can then progress to systolic abnormalities.56 60
Box 2 Guidelines for diagnosing cardiac sarcoidosis (from the Japanese Ministry of Health and Welfare) 1. Histological diagnosis group Cardiac sarcoidosis is confirmed when myocardial biopsy specimens demonstrate non-caseating epithelioid granuloma with histological or clinical diagnosis of extracardiac sarcoidosis 2. Clinical diagnosis group Although myocardial biopsy specimens do not demonstrate non-caseating epithelioid granuloma, extracardiac sarcoidosis is diagnosed histologically or clinically and satisfies the following conditions and more than one in six basic diagnostic criteria ▸ More than 2 of 4 major criteria are satisfied ▸ 1 in 4 major criteria and more than 2 in 5 minor criteria are satisfied Major criteria A. Advanced atrioventricular block B. Basal thinning of the interventricular septum C. Positive cardiac gallium 67 uptake D. Depressed ejection fraction of the left ventricle (
