**2. Cardiac sarcoidosis**

#### **2.1. Introduction**

Sarcoidosis is a multisystem disease characterized by noncaseating granulomas involving multiple organ systems. Cardiac involvement is relatively rare and ranges from 5 to 40%. Clinically, patients could have palpitations, atrioventricular block, syncope, shortness of breath, left ventricular dysfunction and sudden cardiac death. Early recognition and treatment is important since cardiac involvement portends a poor prognosis and is the second cause of death in patients with sarcoidosis [1].

#### **2.2. Epidemiology**

Sarcoidosis is common in Japan, Ireland, Scandanavia and the United States. Females are more commonly affected than males. In the United States, African Americans are more commonly affected and in general have more severe forms of the disease. The age adjusted annual incidence is highest for African American females in the age group of 30 to 39 years

and is at 107 per 100,000 [2]. Clinical cardiac involvement is reported to be 5%, while subclinical cardiac involvement detected by imaging studies is in the range of 30-40%, which matches autopsy series.

involvement can be subclinical without any apparent symptoms. Patients might have nonspecific symptoms like shortness of breath and fatigue. Palpitations are common and could be due to atrial tachycardia, atrial fibrillation, premature ventricular contractions, sustained and non-sustained ventricular tachycardia. Rarely patients could present with pericarditis and cardiac tamponade. The most common criteria used for diagnosing cardiac sarcoidosis is the 2006 revised guidelines of the Japanese Ministry of Health and Wellness [15]. Table 1 gives a

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Advanced atrioventricular block in young patients should prompt search for cardiac sarcoi‐ dosis especially in females [16]. Patients with extra-cardiac sarcoidosis and abnormalities in the electrocardiogram (ECG) should have at least an echocardiogram performed to look for left ventricular function, especially when symptoms suggestive of heart failure are present. However, the JMHW guidelines are not very sensitive and cardiac involvement could be present even in patients with normal electrocardiograms [17]. There is no consensus about the best way to screen patients with sarcoidosis for cardiac involvement. In a recent Delphi study on diagnosing cardiac sarcoidosis, a survey of a group of sarcoidosis experts from different subspecialties including pulmonologists, cardiologist and electrophysiologists showed a wide range of practices with most experts utilizing history, physical examination and ECG for screening. About 75% of experts would not do any further testing in the absence of symptoms or signs of cardiac involvement along with normal ECG. But when Cardiac sarcoidosis is suspected, most experts would perform ECG, TTE and cardiac MRI and 67% would order Holter monitor and cardiac fluorodeoxy-glucose (FDG) PET scan [18]. This reflects the wide range of clinical practice and the fact that sarcoidosis in general can mimic other diseases and could stay subclinical. However, it is clear from recent cardiac MRI studies that cardiac involvement can be present in patients with no cardiac symptoms and a normal ECG in 30% of patients with biopsy proven extracardiac sarcoidosis [17]. Smedema et al study suggests that the combination of ECG and MRI is the most cost effective for screening [14]. It is important to diagnose cardiac sarcoidosis, as patients with cardiac involvement die for heart failure or

Laboratory testing in sarcoidosis is non-specific. Patient can have anemia and some might have hypercalcemia due to activation of vitamin D by macrophages present in granulomas [19]. Elevated angiotensin converting enzyme levels were proposed initially as a diagnostic test and to follow treatment response. However, there is a wide range of normal in healthy subjects

The ECG has been used as a screening tool for cardiac involvement in patients with sarcoidosis. Abnormalities noted include right bundle branch block (RBBB), which can be seen in 20-25% of patients. Premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (NSVT) and sustained ventricular tachycardia (VT) could also occur. Inflammation and scar formation lead to slow conduction and reentry, which is the mechanism of VT in these patients

summary of these guidelines.

sudden cardiac death.

**2.6. Laboratory investigations**

and it is a poor therapeutic guide [20].

**2.7. Electrocardiography (ECG)**

#### **2.3. Environmental and genetic factors**

The etiology of sarcoidosis remains unknown. The presence of noncaseating granulomas in the lungs, skin and eyes and clustering of cases in certain occupations (navy personnel, firefighters at the world trade center) point to an immunological response to environmental agents or infectious exposure [3, 4]. Mycobacterial DNA and RNA have been found in sarcoid tissue using polymerase chain reaction, especially the DNA of the mycobacterium tuberculosis catalase-peroxidase (mKatG) gene [5].

There is familial clustering of the disease, and patients are more likely to have an affect‐ ed member but there is little concordance in organs involved. Class I HLA-B8 and Class II HLA-DRB1 and HLA-DQB1 alleles have been consistently associated with sarcoidosis [6, 7]. Genome-wide scans for loci associated with sarcoidosis showed the strongest signals in chromosomes 5p and 5q in African Americans [8]. The strongest signals in Germans were found in chromosome 6p, which helped identify the butyrophillin-like 2 (BTLN2) gene. This gene is a negative co-stimulatory molecule within the major histocompatibility complex region [9]. Chromosome 18q22 has a strong link to the presence of cardiac or renal sarcoidosis [10]. Likely there is an interaction between environmental exposure and certain susceptibility genes leading to the development of sarcoidosis. Further research is needed to clarify such interactions.

#### **2.4. Pathology**

The hallmark of sarcoidosis is the presence of noncaseating granulomas. These are compact collections of macrophages and epithelioid cells with minimal inflammation and multi‐ nucleated giant cells. Even though clinical involvement of the heart is reported to be 5%, autopsy series show cardiac involvement in 25 to 40% of patients [11, 12]. Several recent imaging studies show that delayed enhancement magnetic resonance imaging (DE MRI) in patients with histology proven extra-cardiac sarcoidosis could detect cardiac involvement even in patients with normal electrocardiograms, with cardiac involvement in these studies ranging from 26-32%, which matches autopsy series [13, 14]. The ventricles are common‐ ly affected, especially the left ventricular (LV) free wall, basal LV, inter-ventricular septum and conduction system. The heart could be involved among other systems, but isolated cardiac disease does occur. Endomyocardial biopsy has a low yield (~20%) given the patchy involvement of the heart muscle. However, it is still needed at times in diagnosis especial‐ ly when other diseases are suspected.

#### **2.5. Clinical features of cardiac sarcoidosis**

The heart could be the only organ affected or could be involved in combination with other systems. The degree of lung involvement does not predict cardiac involvement and cardiac involvement can be subclinical without any apparent symptoms. Patients might have nonspecific symptoms like shortness of breath and fatigue. Palpitations are common and could be due to atrial tachycardia, atrial fibrillation, premature ventricular contractions, sustained and non-sustained ventricular tachycardia. Rarely patients could present with pericarditis and cardiac tamponade. The most common criteria used for diagnosing cardiac sarcoidosis is the 2006 revised guidelines of the Japanese Ministry of Health and Wellness [15]. Table 1 gives a summary of these guidelines.

Advanced atrioventricular block in young patients should prompt search for cardiac sarcoi‐ dosis especially in females [16]. Patients with extra-cardiac sarcoidosis and abnormalities in the electrocardiogram (ECG) should have at least an echocardiogram performed to look for left ventricular function, especially when symptoms suggestive of heart failure are present. However, the JMHW guidelines are not very sensitive and cardiac involvement could be present even in patients with normal electrocardiograms [17]. There is no consensus about the best way to screen patients with sarcoidosis for cardiac involvement. In a recent Delphi study on diagnosing cardiac sarcoidosis, a survey of a group of sarcoidosis experts from different subspecialties including pulmonologists, cardiologist and electrophysiologists showed a wide range of practices with most experts utilizing history, physical examination and ECG for screening. About 75% of experts would not do any further testing in the absence of symptoms or signs of cardiac involvement along with normal ECG. But when Cardiac sarcoidosis is suspected, most experts would perform ECG, TTE and cardiac MRI and 67% would order Holter monitor and cardiac fluorodeoxy-glucose (FDG) PET scan [18]. This reflects the wide range of clinical practice and the fact that sarcoidosis in general can mimic other diseases and could stay subclinical. However, it is clear from recent cardiac MRI studies that cardiac involvement can be present in patients with no cardiac symptoms and a normal ECG in 30% of patients with biopsy proven extracardiac sarcoidosis [17]. Smedema et al study suggests that the combination of ECG and MRI is the most cost effective for screening [14]. It is important to diagnose cardiac sarcoidosis, as patients with cardiac involvement die for heart failure or sudden cardiac death.

#### **2.6. Laboratory investigations**

and is at 107 per 100,000 [2]. Clinical cardiac involvement is reported to be 5%, while subclinical cardiac involvement detected by imaging studies is in the range of 30-40%, which

The etiology of sarcoidosis remains unknown. The presence of noncaseating granulomas in the lungs, skin and eyes and clustering of cases in certain occupations (navy personnel, firefighters at the world trade center) point to an immunological response to environmental agents or infectious exposure [3, 4]. Mycobacterial DNA and RNA have been found in sarcoid tissue using polymerase chain reaction, especially the DNA of the mycobacterium tuberculosis

There is familial clustering of the disease, and patients are more likely to have an affect‐ ed member but there is little concordance in organs involved. Class I HLA-B8 and Class II HLA-DRB1 and HLA-DQB1 alleles have been consistently associated with sarcoidosis [6, 7]. Genome-wide scans for loci associated with sarcoidosis showed the strongest signals in chromosomes 5p and 5q in African Americans [8]. The strongest signals in Germans were found in chromosome 6p, which helped identify the butyrophillin-like 2 (BTLN2) gene. This gene is a negative co-stimulatory molecule within the major histocompatibility complex region [9]. Chromosome 18q22 has a strong link to the presence of cardiac or renal sarcoidosis [10]. Likely there is an interaction between environmental exposure and certain susceptibility genes leading to the development of sarcoidosis. Further research is needed

The hallmark of sarcoidosis is the presence of noncaseating granulomas. These are compact collections of macrophages and epithelioid cells with minimal inflammation and multi‐ nucleated giant cells. Even though clinical involvement of the heart is reported to be 5%, autopsy series show cardiac involvement in 25 to 40% of patients [11, 12]. Several recent imaging studies show that delayed enhancement magnetic resonance imaging (DE MRI) in patients with histology proven extra-cardiac sarcoidosis could detect cardiac involvement even in patients with normal electrocardiograms, with cardiac involvement in these studies ranging from 26-32%, which matches autopsy series [13, 14]. The ventricles are common‐ ly affected, especially the left ventricular (LV) free wall, basal LV, inter-ventricular septum and conduction system. The heart could be involved among other systems, but isolated cardiac disease does occur. Endomyocardial biopsy has a low yield (~20%) given the patchy involvement of the heart muscle. However, it is still needed at times in diagnosis especial‐

The heart could be the only organ affected or could be involved in combination with other systems. The degree of lung involvement does not predict cardiac involvement and cardiac

matches autopsy series.

134 Cardiomyopathies

**2.3. Environmental and genetic factors**

catalase-peroxidase (mKatG) gene [5].

to clarify such interactions.

ly when other diseases are suspected.

**2.5. Clinical features of cardiac sarcoidosis**

**2.4. Pathology**

Laboratory testing in sarcoidosis is non-specific. Patient can have anemia and some might have hypercalcemia due to activation of vitamin D by macrophages present in granulomas [19]. Elevated angiotensin converting enzyme levels were proposed initially as a diagnostic test and to follow treatment response. However, there is a wide range of normal in healthy subjects and it is a poor therapeutic guide [20].

#### **2.7. Electrocardiography (ECG)**

The ECG has been used as a screening tool for cardiac involvement in patients with sarcoidosis. Abnormalities noted include right bundle branch block (RBBB), which can be seen in 20-25% of patients. Premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (NSVT) and sustained ventricular tachycardia (VT) could also occur. Inflammation and scar formation lead to slow conduction and reentry, which is the mechanism of VT in these patients


systematic sarcoidosis with documented cardiomyopathy who underwent endomyocar‐ dial biopsy at John Hopkins, only 7 had noncasesating granulomas. If sarcoidosis is suspected, it is often recommended to obtain biopsy from other organs like the paratra‐ cheal lymphnodes, skin and even the liver. PET scanning could help detect disease activity

The main differential diagnosis to sarcoidosis histologically is giant cell myocarditis. In a series comparing 42 patients with cardiac sarcoidosis to 73 patients with giant cell myocarditis, nearly a third of the patients finally diagnosed with cardiac sarcoidosis had no extracardiac involve‐ ment. Underscoring the fact that isolated cardiac involvement does occur [24]. Table 2 lists the features that help differentiate cardiac sarcoidosis from giant cell myocarditis. Rarely, cardiac sarcoidosis could only be diagnosed at the time of heart transplantation, further scoring the

**Sarcoidosis Giant Cell Myocarditis**

Usually acute heart failure presentation

lymphocytic myocarditis

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and potential sites for biopsy [23].

difficulties of establishing the diagnosis [25].

**2.9. Imaging studies in cardiac sarcoidosis**

**Clinical Presentation**

*2.9.1. Chest x-ray*

*2.9.2. Echocardiography*

**African American race** 31% 4% **Syncope** 31% 5% **AV block** 50% 15%

duration

AV block or heart failure symptoms of > 9 weeks

**Table 2.** Clinical and Histological features comparing Sarcoidosis to Giant Cell Myocarditis.

**Histology** Granulomas and fibrosis Eosinophils, myocyte damage and foci of

Bilateral hilar lymphadenopathy is the most common finding on chest x-ray (CXR). However, bilateral hilar fullness could be also a sign of pulmonary dilatation secondary to cardiac involvement or pulmonary hypertension. Cardiomegaly is sometimes noted. When bilateral hilar lymphadenopathy is found and sarcoidosis is suspected, then high resolution computed

Transthoracic echocardiography (TTE) could be useful in detecting cardiac involvement in patients diagnosed with extracardiac sarcoidosis. Segmental wall motion abnormalities with thinning of the ventricular wall and LV dysfunction are common but non-specific findings. The presence of basal septal thinning in the LV should lead the clinician to consider sarcoidosis highly in the differential diagnoses especially in young patients with conduction abnormalities [26]. Aneurysms could be seen especially in the inferior wall. Regional hypertrophy could also

tomography scan is indicated to detect pulmonary parenchymal involvement [19].

**Table 1.** Modified Guidelines for the Diagnosis of Cardiac Sarcoidosis from the Japanese Ministry of Health and Wellness

[21]. Left bundle branch block and Q waves have been described [22]. Advanced atrioventric‐ ular block (AVB) and complete heart block could occur in up to 20-30% of patients due to the involvement of the basal LV septum as well as involvement of the AV nodal artery and they portend a poor prognosis [16]. In patients with symptomatic cardiac sarcoidosis, Shuller et al showed that fragmentation of the QRS occurs in up to 75% of patients and when combined with bundle branch block, has 90% sensitivity in detecting cardiac involvement, however, the study was limited to symptomatic patients [22]. Mehta et al showed that ECG sensitivity could be as low as 8%. Using 24 hours holter monitoring could help detect abnormalities including AV block, PVCs and NSVT and has more sensitivity compared to the 12 lead electrocardiogram (50% vs 8% respectively) [17].

#### **2.8. Endomyocardial biopsy**

The presence of noncaseating granulomas in endomyocardial biopsy is diagnostic of sarcoidosis. However, endomyocardial biopsy is not sensitive, since the disease is usually patchy and most commonly involves the left ventricle. Of the 28 patients with clinical systematic sarcoidosis with documented cardiomyopathy who underwent endomyocar‐ dial biopsy at John Hopkins, only 7 had noncasesating granulomas. If sarcoidosis is suspected, it is often recommended to obtain biopsy from other organs like the paratra‐ cheal lymphnodes, skin and even the liver. PET scanning could help detect disease activity and potential sites for biopsy [23].

The main differential diagnosis to sarcoidosis histologically is giant cell myocarditis. In a series comparing 42 patients with cardiac sarcoidosis to 73 patients with giant cell myocarditis, nearly a third of the patients finally diagnosed with cardiac sarcoidosis had no extracardiac involve‐ ment. Underscoring the fact that isolated cardiac involvement does occur [24]. Table 2 lists the features that help differentiate cardiac sarcoidosis from giant cell myocarditis. Rarely, cardiac sarcoidosis could only be diagnosed at the time of heart transplantation, further scoring the difficulties of establishing the diagnosis [25].


**Table 2.** Clinical and Histological features comparing Sarcoidosis to Giant Cell Myocarditis.

#### **2.9. Imaging studies in cardiac sarcoidosis**

#### *2.9.1. Chest x-ray*

[21]. Left bundle branch block and Q waves have been described [22]. Advanced atrioventric‐ ular block (AVB) and complete heart block could occur in up to 20-30% of patients due to the involvement of the basal LV septum as well as involvement of the AV nodal artery and they portend a poor prognosis [16]. In patients with symptomatic cardiac sarcoidosis, Shuller et al showed that fragmentation of the QRS occurs in up to 75% of patients and when combined with bundle branch block, has 90% sensitivity in detecting cardiac involvement, however, the study was limited to symptomatic patients [22]. Mehta et al showed that ECG sensitivity could be as low as 8%. Using 24 hours holter monitoring could help detect abnormalities including AV block, PVCs and NSVT and has more sensitivity compared to the 12 lead electrocardiogram

**Table 1.** Modified Guidelines for the Diagnosis of Cardiac Sarcoidosis from the Japanese Ministry of Health and

**Histologic diagnosis group Cardiac sarcoidosis is confirmed when endomyocardial biopsy specimens**

Clinical diagnosis group\* Cardiac sarcoidosis is diagnosed in the absence of an endomyocardial biopsy

diagnostic criteria has been satisfied:

2. Basal thinning of the ventricular septum 3. Positive cardiac gallium uptake 4. Left ventricular ejection fraction < 50%.

Major Criteria: 1. Advanced AV block

Minor Criteria:

scanning

endomyocardial biopsy.

**demonstrate noncaseating epithelioid granulomas.**

1. More than 2 of the 4 major diagnostic criteria are met OR

specimen or in the absence of typical granulomas on cardiac biopsy when extracardiac sarcoidosis has been proven and a combination of majore or minor

2. One of the 4 major criteria and 2 or more of the minor criteria are met.

1. Abnormal electrocardiogram findings including ventricular tachycardia, multifocal frequent premature ventricular contractions, complete right bundle

abnormalities, ventricular aneurysm or unexplained increase in wall thickness.

5. Interstitial fibrosis or monocyte infiltration greater than moderate grade by

4. Delayed godalinium enhancement of the myocardium on cardiac MRI

branch block, pathologic Q waves or abnormal axis deviation 2. Abnormal echocardiogram demonstrating regional wall motion

3. Perfusion defects detected by myocardial scintigraphy

The presence of noncaseating granulomas in endomyocardial biopsy is diagnostic of sarcoidosis. However, endomyocardial biopsy is not sensitive, since the disease is usually patchy and most commonly involves the left ventricle. Of the 28 patients with clinical

(50% vs 8% respectively) [17].

Wellness

136 Cardiomyopathies

**2.8. Endomyocardial biopsy**

Bilateral hilar lymphadenopathy is the most common finding on chest x-ray (CXR). However, bilateral hilar fullness could be also a sign of pulmonary dilatation secondary to cardiac involvement or pulmonary hypertension. Cardiomegaly is sometimes noted. When bilateral hilar lymphadenopathy is found and sarcoidosis is suspected, then high resolution computed tomography scan is indicated to detect pulmonary parenchymal involvement [19].

#### *2.9.2. Echocardiography*

Transthoracic echocardiography (TTE) could be useful in detecting cardiac involvement in patients diagnosed with extracardiac sarcoidosis. Segmental wall motion abnormalities with thinning of the ventricular wall and LV dysfunction are common but non-specific findings. The presence of basal septal thinning in the LV should lead the clinician to consider sarcoidosis highly in the differential diagnoses especially in young patients with conduction abnormalities [26]. Aneurysms could be seen especially in the inferior wall. Regional hypertrophy could also be found due to inflammation and edema. Right ventricular dysfunction is also seen and in later stages of pulmonary sarcoidosis, pulmonary hypertension and tricuspid regurgitation are seen. Mitral regurgitation and rarely pericardial effusion with tamponade physiology could be the first presentation in patients with sarcoidosis [27]. The sensitivity of TTE in detecting cardiac involvement in patients with extracardiac sarcoidosis is poor, and ranges from 14-25% [17, 28].

without DE MRI findings [13]. Furthermore, delayed enhancement correlated with disease duration, regional wall motion abnormalities, ventricular function, severity of mitral

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<sup>201</sup>Thallium has been used to detect cardiac involvement in patients with sarcoidosis. Segmen‐ tal areas of decreased perfusion at rest that improve with stress imaging (areas with reverse distribution) are seen in patients with cardiac sarcoidosis but are not necessarily specific, since they are also seen in other forms of cardiomyopathy. 201Thallium is more sensitive than 67Ga scanning in detecting cardiac sarcoidosis, but 67Ga is more specific for sarcoidosis since it accumulates in inflamed areas and could be used to predict response to therapy and follow disease activity [32]. 67Ga scanning has the advantage of detecting cardiac as well as extracar‐ diac sarcoidosis and could guide to areas that are more amenable to biopsy [33]. Both modal‐ ities suffer from poor spatial resolution and both are less sensitive than DE MRI in detecting cardiac sarcoidosis [13, 30]. 99mTc-sestamibi has been used in combination with 67Ga scanning and could help in showing that areas with increased67Ga uptake are due to cardiac as opposed

18- fluoro-2-deoxy-D-glucose PET scanning (18F-FDG PET) has been shown to be of great value in detecting cardiac involvement in patients with sarcoidosis. 18F-FDG PET is taken up by the macrophages, lymphocytes and epitheloid cells which are present in the granulomas and is helpful in detecting active inflammation and following response to corticosteroids treatment. In a series of 17 patients with biopsy proven extracardiac sarcoidosis, 18F-FDG PET was found to be the more sensitive in detecting cardiac involvement compared to both 201Thallium and 67Ga scintigraphy. While 67Ga scintigraphy was the least sensitive modality in detecting cardiac involvement, possibly because of it has a lower spatial resolution compared to 18F-FDG PET. Most of the abnormalities noted on 18F-FDG PET were found in the basal, mid anteroseptal and lateral walls and disappeared after treatment with corticosteroids [35]. In another study, PET and DE MRI were performed in patients with biopsy proven extracardiac sarcoidosis. In these series, 22 patients had both 18F-FDG PET and DE MRI performed. Of these, abnormalities in 18F-FDG PET were observed in 86% of the patients while MRI abnormalities were observed in 36% of the patients. It is possible that the apparent high sensitivity of 18F-FDG PET is due to its ability to detect active inflammation while DE MRI could only detect edema and scar and

Therapy for cardiac sarcoidosis aims at treating and preventing heart failure, treatment of conduction system disease and prevention of sudden cardiac death. It is important to recognize cardiac involvement in patients with sarcoidosis, since sudden cardiac death could be the first presentation and is the second leading cause of death in patients with

regurgitation and presence of ventricular tachycardia [31].

*2.9.4. Radionuclide scintigraphy*

to extracardiac involvement [34].

is unable to detect active inflammation [17].

**2.10. Therapy**

sarcoidosis [1].

#### *2.9.3. Magnetic Resonance Imaging (MRI)*

Cardiac MRI has emerged as a sensitive modality to detect clinical and subclinical cardiac sarcoidosis. It has great spatial resolution and can help detect disease activity, presence or absence of fibrosis, wall motion abnormalities, pericardial involvement as well as right ventricular involvement. Increased signal intensity on T2 weighted images signifies edema and inflammation. Focal myocardial thickening can also be due to edema. Delayed enhance‐ ment using godalinium is likely due to fibrosis. The basal and lateral LV walls are most commonly affected, especially the basal septum [29]. Delayed enhancement MRI is more sensitive than 201Thallium imaging and 67Ga imaging in detecting subclinical cardiac sarcoi‐ dosis. In a study of 10 patients by Tadamura et al, only 50% of patients with sarcoidosis exhibited abnormalities on 201Thallium imaging and only 20% had 67Ga uptake while a 100% of these patients had abnormalities detected by cardiac MRI [30]. Smedema et al studied 58 patients with biopsy proven extracardiac sarcoidosis using the JMHW 1993 criteria as gold standard. Other modalities studied included ECG, TTE, 201Thallium scintigrams and DE MRI. Cardiac MRI had a sensitivity of 78-100% and specificity of 64-89% in detecting cardiac involvement. Cardiac MRI was noted to detect cardiac involvement even in patients with normal ECG, Echocardiography and 201Thallium Scintigrams [14].

Mehta et al studied 62 patients with extracardiac sarcoidosis using a systematic approach including ECG, Holter monitoring, TTE, 18F-FDG PET scanning and cardiac MRI. The prevalence of cardiac sarcoidosis was 39%. The modified JMHW criteria had a sensitivity of 33% and specificity of 97%. Holter monitoring was superior of ECG in detecting conduction system abnormalities as well as other ventricular arrhythmias. In the 22 patients who had both cardiac MRI and 18F-FDG PET scans done, 32% had delayed enhancement and 5% had edema on T2 images while abnormalities on 18F-FDG PET scan was observed in 86% of the patients. Cardiac MRI and PET scans can be reasonably done in patients with suspected cardiac sarcoidosis and can detect subclinical involvement and are more sensitive than the JWHW criteria [17]. Patel et al studied 81 patients with biopsy proven extracar‐ diac sarcoidosis and used the JMHW modified criteria as well as DE MRI to look for cardiac involvement. The JMHW identified 10 patients (12%) with cardiac involvement while DE MRI identified cardiac involvement in 21 patients (26%), only 8 patients overlapped. The median extent of damage detected by DE MRI was 6.1% of the left ventricle. The basal and mid ventricular septum showed delayed enhancement in 76% of patients. Furthermore, of the 4 patients with positive endomyocardial biopsy, all the 4 patients (100%) had abnormal‐ ities detected by DE MRI, while only 2 patients (50%) met the diagnostic criteria of the JMHW. Patients with DE MRI had 11-fold increase risk of death compared to patients without DE MRI findings [13]. Furthermore, delayed enhancement correlated with disease duration, regional wall motion abnormalities, ventricular function, severity of mitral regurgitation and presence of ventricular tachycardia [31].

#### *2.9.4. Radionuclide scintigraphy*

be found due to inflammation and edema. Right ventricular dysfunction is also seen and in later stages of pulmonary sarcoidosis, pulmonary hypertension and tricuspid regurgitation are seen. Mitral regurgitation and rarely pericardial effusion with tamponade physiology could be the first presentation in patients with sarcoidosis [27]. The sensitivity of TTE in detecting cardiac involvement in patients with extracardiac sarcoidosis is poor, and ranges

Cardiac MRI has emerged as a sensitive modality to detect clinical and subclinical cardiac sarcoidosis. It has great spatial resolution and can help detect disease activity, presence or absence of fibrosis, wall motion abnormalities, pericardial involvement as well as right ventricular involvement. Increased signal intensity on T2 weighted images signifies edema and inflammation. Focal myocardial thickening can also be due to edema. Delayed enhance‐ ment using godalinium is likely due to fibrosis. The basal and lateral LV walls are most commonly affected, especially the basal septum [29]. Delayed enhancement MRI is more sensitive than 201Thallium imaging and 67Ga imaging in detecting subclinical cardiac sarcoi‐ dosis. In a study of 10 patients by Tadamura et al, only 50% of patients with sarcoidosis exhibited abnormalities on 201Thallium imaging and only 20% had 67Ga uptake while a 100% of these patients had abnormalities detected by cardiac MRI [30]. Smedema et al studied 58 patients with biopsy proven extracardiac sarcoidosis using the JMHW 1993 criteria as gold standard. Other modalities studied included ECG, TTE, 201Thallium scintigrams and DE MRI. Cardiac MRI had a sensitivity of 78-100% and specificity of 64-89% in detecting cardiac involvement. Cardiac MRI was noted to detect cardiac involvement even in patients with

Mehta et al studied 62 patients with extracardiac sarcoidosis using a systematic approach including ECG, Holter monitoring, TTE, 18F-FDG PET scanning and cardiac MRI. The prevalence of cardiac sarcoidosis was 39%. The modified JMHW criteria had a sensitivity of 33% and specificity of 97%. Holter monitoring was superior of ECG in detecting conduction system abnormalities as well as other ventricular arrhythmias. In the 22 patients who had both cardiac MRI and 18F-FDG PET scans done, 32% had delayed enhancement and 5% had edema on T2 images while abnormalities on 18F-FDG PET scan was observed in 86% of the patients. Cardiac MRI and PET scans can be reasonably done in patients with suspected cardiac sarcoidosis and can detect subclinical involvement and are more sensitive than the JWHW criteria [17]. Patel et al studied 81 patients with biopsy proven extracar‐ diac sarcoidosis and used the JMHW modified criteria as well as DE MRI to look for cardiac involvement. The JMHW identified 10 patients (12%) with cardiac involvement while DE MRI identified cardiac involvement in 21 patients (26%), only 8 patients overlapped. The median extent of damage detected by DE MRI was 6.1% of the left ventricle. The basal and mid ventricular septum showed delayed enhancement in 76% of patients. Furthermore, of the 4 patients with positive endomyocardial biopsy, all the 4 patients (100%) had abnormal‐ ities detected by DE MRI, while only 2 patients (50%) met the diagnostic criteria of the JMHW. Patients with DE MRI had 11-fold increase risk of death compared to patients

normal ECG, Echocardiography and 201Thallium Scintigrams [14].

from 14-25% [17, 28].

138 Cardiomyopathies

*2.9.3. Magnetic Resonance Imaging (MRI)*

<sup>201</sup>Thallium has been used to detect cardiac involvement in patients with sarcoidosis. Segmen‐ tal areas of decreased perfusion at rest that improve with stress imaging (areas with reverse distribution) are seen in patients with cardiac sarcoidosis but are not necessarily specific, since they are also seen in other forms of cardiomyopathy. 201Thallium is more sensitive than 67Ga scanning in detecting cardiac sarcoidosis, but 67Ga is more specific for sarcoidosis since it accumulates in inflamed areas and could be used to predict response to therapy and follow disease activity [32]. 67Ga scanning has the advantage of detecting cardiac as well as extracar‐ diac sarcoidosis and could guide to areas that are more amenable to biopsy [33]. Both modal‐ ities suffer from poor spatial resolution and both are less sensitive than DE MRI in detecting cardiac sarcoidosis [13, 30]. 99mTc-sestamibi has been used in combination with 67Ga scanning and could help in showing that areas with increased67Ga uptake are due to cardiac as opposed to extracardiac involvement [34].

18- fluoro-2-deoxy-D-glucose PET scanning (18F-FDG PET) has been shown to be of great value in detecting cardiac involvement in patients with sarcoidosis. 18F-FDG PET is taken up by the macrophages, lymphocytes and epitheloid cells which are present in the granulomas and is helpful in detecting active inflammation and following response to corticosteroids treatment. In a series of 17 patients with biopsy proven extracardiac sarcoidosis, 18F-FDG PET was found to be the more sensitive in detecting cardiac involvement compared to both 201Thallium and 67Ga scintigraphy. While 67Ga scintigraphy was the least sensitive modality in detecting cardiac involvement, possibly because of it has a lower spatial resolution compared to 18F-FDG PET. Most of the abnormalities noted on 18F-FDG PET were found in the basal, mid anteroseptal and lateral walls and disappeared after treatment with corticosteroids [35]. In another study, PET and DE MRI were performed in patients with biopsy proven extracardiac sarcoidosis. In these series, 22 patients had both 18F-FDG PET and DE MRI performed. Of these, abnormalities in 18F-FDG PET were observed in 86% of the patients while MRI abnormalities were observed in 36% of the patients. It is possible that the apparent high sensitivity of 18F-FDG PET is due to its ability to detect active inflammation while DE MRI could only detect edema and scar and is unable to detect active inflammation [17].

#### **2.10. Therapy**

Therapy for cardiac sarcoidosis aims at treating and preventing heart failure, treatment of conduction system disease and prevention of sudden cardiac death. It is important to recognize cardiac involvement in patients with sarcoidosis, since sudden cardiac death could be the first presentation and is the second leading cause of death in patients with sarcoidosis [1].

#### *2.10.1. Medical therapy*

Similar to other forms of cardiomyopathy, treatment with angiotensin converting enzyme inhibitors and angiotensin receptor blockers is important since they have anti-fibrotic prop‐ erties and have been shown to improve survival. β -blockers were also shown to improve survival in patients with heart failure. Since the initial cardiac lesions are due to granuloma formation which could progress with time to fibrosis, early recognition and initiation of corticosteroid treatment is important and could lead to improvement in LV function as well as achieve control of the arrhythmias [36]. In a Japanese retrospective study of 48 patients with cardiac sarcoidosis, only patients with pretreatment LVEF > 30% had improvement in their LV function with corticosteroid therapy, while those with pretreatment LVEF of < 30% showed little improvement [37]. The exact dose of corticosteroids and the duration of therapy are not well defined due to the absence of randomized controlled trials. In general, initial dose of 30 to 60 milligrams/day of prednisone is started for 8-12 weeks; with gradual taper to a daily dose of 5-10 mgs/day of prednisone over 6-12 months is recommended. Relapses could occur in up to 25% of patients [19, 38]. Use of Methotrexate, cyclosporine or hydroxychoroquine has been described and could be considered especially in patients with side effects to corticosteroids or who are not responding to therapy [38].

centers. In a retrospective study of patients with sarcoidosis who received ICD therapy, inappropriate shocks were low (13.3%) and appropriate shocks occurred in 37.8%, with an annual incidence of 15% per year. Most of the event occurred in the first 3 years post implan‐ tation [43]. In another study of 112 patients with cardiac sarcoidosis that had ICD implantation, 32% had appropriate ICD therapy and 14% had VT storm. Inappropriate therapies occurred in 11% of patients [44]. Depressed LVEF, Depressed RVEF and complete heart block were

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For patients who have frequent shocks due to ventricular tachycardia, catheter ablation could be used for treatment of these VTs. The mechanism of VT in patients with sarcoidosis is mostly due to reentry or triggered activity. Reentry is the most common mechanism and could be due to slow conduction from active inflammation or from scar formation. Most of these circuits are near the basal right ventricle near the tricuspid valve area and most patients have a dramatic

Some patients with cardiac sarcoidosis progress to advanced heart failure and might need heart transplantation. Patients with sarcoidosis have a good 1 and 5-year survival rates post transplantation [46]. Some of the patients were only diagnosed with cardiac sarcoidosis at the time of transplantation, underscoring the difficulties clinicians face in establishing the

Arrhythmogenic right ventricular Dysplasia/ Cardiomyopathy (ARVD/C) is an inherited myopathy characterized by fibrofatty infiltration of the right ventricular (RV) wall, with left ventricular involvement over time in some patients [47, 48]. Males are more commonly affected than females. The true prevalence of the disease is unknown, but familial involvement is seen in up to 50%, which means screening family members is essential. The overall incidence is thought to be 1:1000 to 1:5000, with certain regions in Greece and Italy having increased

There is no clear environmental cause of ARVD/C, and the etiology is not fully understood. Family members of patients with ARVD/ C are affected in 30-50% of the time, and the disease has autosomal dominant inheritance with variable penetrance. Several genetic loci have been identified, and mostly are mutations in cardiac desmosomes. Desmosomes are membrane structures composed of plasma cell membrane proteins that are responsible for force trans‐ mission between the cells. Abnormal function of these structures leads to cell detachment, death and inflammatory reaction leading to fibrosis and fatty infiltration. The most common mutation involves the PKP2 gene, encoding the plakophilin 2. Other desomsomal mutations

decrease in the VT burden or complete elimination of the VTs following ablation [45].

**3. Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy**

important predictors of appropriate ICD therapies [44].

diagnosis of cardiac sarcoidosis [25].

prevalence compared to the rest of the world [49].

**3.2. Environmental and genetic factors**

**(ARVD/C)**

**3.1. Epidemiology**

#### *2.10.2. Device based therapy and the role of electrophysiology study*

Patients presenting with heart block due to cardiac sarcoidosis could see improvement with corticosteroids therapy [36]. However, permanent pacemaker implantation is recommended even if there is a transient improvement in heart block with corticosteroids therapy [39]. Patients with depressed LVEF < 35%who do not improve with steroid therapy and patients who present with VT or survive cardiac arrest should undergo defibrillator (ICD) implantation [39]. Some experts advocate ICD implantation in patients with AVB due to cardiac sarcoidosis with extensive cardiac involvement on imaging studies even if the LVEF is still preserved [40]. The 2008 guidelines for device based therapy recommend consideration for defibrillator implantation to be based on LV function, presence of spontaneous or induced ventricular tachycardia, heart failure status and syncope. Patients with depressed LVEF < 35%, NYHA Class II-IV heart failure and wide QRS of > 120 milliseconds are candidates for biventricular defibrillator implantation (BiV ICD) [39].

For patients with LVEF of 35-55%, programmed electrical stimulation (PES) could help in the risk stratification of these patients. In a study by Mehta et al, PES helped identify patients at risk of ventricular arrhythmias and only 1 of the 68 patients with negative PES died over 5 yrs [41]. In another series by Aizer et al, PES was predictive of arrhythmic events and ICD therapy; however 2 of the 20 patients with negative PES died or had spontaneous sustained VT during follow up [42]. Currently, PES is used for risk stratification, but the negative predictive value of programmed electrical stimulation needs further study and the clinician needs to utilize knowledge of the published literature as well as clinical judgment when considering ICD therapy for primary prevention of SCD in sarcoidosis patients with LVEF of 35-55%.

There are no randomized trials for the prevention of sudden cardiac death in patients with cardiac sarcoidosis, and most of the efficacy is obtained from the experience of tertiary care centers. In a retrospective study of patients with sarcoidosis who received ICD therapy, inappropriate shocks were low (13.3%) and appropriate shocks occurred in 37.8%, with an annual incidence of 15% per year. Most of the event occurred in the first 3 years post implan‐ tation [43]. In another study of 112 patients with cardiac sarcoidosis that had ICD implantation, 32% had appropriate ICD therapy and 14% had VT storm. Inappropriate therapies occurred in 11% of patients [44]. Depressed LVEF, Depressed RVEF and complete heart block were important predictors of appropriate ICD therapies [44].

For patients who have frequent shocks due to ventricular tachycardia, catheter ablation could be used for treatment of these VTs. The mechanism of VT in patients with sarcoidosis is mostly due to reentry or triggered activity. Reentry is the most common mechanism and could be due to slow conduction from active inflammation or from scar formation. Most of these circuits are near the basal right ventricle near the tricuspid valve area and most patients have a dramatic decrease in the VT burden or complete elimination of the VTs following ablation [45].

Some patients with cardiac sarcoidosis progress to advanced heart failure and might need heart transplantation. Patients with sarcoidosis have a good 1 and 5-year survival rates post transplantation [46]. Some of the patients were only diagnosed with cardiac sarcoidosis at the time of transplantation, underscoring the difficulties clinicians face in establishing the diagnosis of cardiac sarcoidosis [25].
