Millee Singh DO Non Invasive Cardiology First Coast Heart and Vascular Cardiac Sarcoidosis Millee Singh DO Non Invasive Cardiology First Coast Heart and Vascular

Introduction Multisystem granulomatous disease of unknown etiology characterized by non-caseating granulomas in involved organs The prevalence is 10-40/100,000 persons in the United States and Europe Increased prevalence in African- Americans compared to Caucasians with a ratio ranging from 17 : 1 Sekhri et al. Arch Med Sci 2011; 7, 4: 546-554

Introduction Sarcoidosis is more prevalent in women than in men Organs involved Include : Lymph nodes, skin, lung, central nervous system, and eye Cardiac involvement in sarcoidosis occurs in 20- 30% of patients in reported pathology series A review of 84 autopsy cases of pulmonary sarcoidosis and found myocardial granulomas in 27% of patients In Sarcoidosis, deaths from Cardiac sarcoid appear to have a regional connection : United States, 13 to 25% Japan, 47 to 85% Sekhri et al. Arch Med Sci 2011; 7, 4: 546-554

Introduction Genetic link: A Case Controlled Etiologic Sarcoidosis Study (ACCESS) concluded that first-degree relatives of patients with sarcoidosis had a relative risk of sarcoidosis that was five times that of control subjects

Pathophysiology Three aspects : Exposure to antigen Acquired cellular immunity directed against the antigen mediated through antigen presenting cells and antigen specific T lymphocytes Appearance of immune effector cells that promote a more nonspecific inflammatory response ALL LEADING TO GRANULOMA FORMATION AND PROGRESSION TO FIBROSIS OF TISSUE Sekhri et al. Arch Med Sci 2011; 7, 4: 546-554

Arch Med Sci 4, August / 2011

Pathology Characteristic lesion of sarcoidosis is a discrete, compact, noncaseating epitheloid cell granuloma Cardiac sarcoidosis is associated with noncaseating granulomas which may involve the left ventricular free wall, basal ventricular septum, right ventricle, papillary muscles, right atrium, and left atrium 3 successive histological stages: Edema Granulomatous infiltration Fibrosis leading to post- inflammatory scarring Roberts et al. ;Am J Med 1977; 63: 86-108

Pathology Pathological slides: Myocardium show the presence of numerous lymphocytes located at the border zones around the granulomas A dense band of fibroblasts, collagen fibers, and pro- teoglycans usually encase this aggregate of inflammatory cells

Clinical Presensation/Diagnosis Symptoms which include fever, fatigue, malaise, and weight loss can be very vague presentation overall When multi-systemic sarcoidosis has already been diagnosed – Cardiac diagnosis of symptoms are easier to diagnosed When cardiac dysfunction is the only manifestation of sarcoidosis, the diagnosis is frequently not entertained

Clinical Presentation/Diagnosis Sekhri et al. Arch Med Sci 2011; 7, 4: 546-554

Clinical Presentation/Diagnosis Early diagnosis and treatment is essential since treatment improves prognosis Serious cardiac dysfunction is detected in 5% to 10% of cases In a significant proportion of patients with cardiac sarcoidosis, the initial presentation is sudden death Sarcoid granulomas may serve as foci for abnormal automaticity or reentrant tachycardias Atrial arrhythmias are less common 15-17% of cases Result of atrial dilatation or pulmonary involvement rather than the result of atrial granulomas Fleming HA. Sarcoid heart disease. Br Heart J 1974; 36: 54-68.

Complete Heart Block Occurs in younger age in patients with sarcoidosis than in patients with complete heart block of other causes Rate of occurrence : Complete heart block - 23-30% Bundle branch block 12-32% Caused by the involvement of basal septum by scar tissue, granulomas, or involvement of the nodal artery causing ischemia in the conduction system Sarcoidosis pts who present with syncope/pre- syncope should be evaluated for CHB Yoshida et al. Am Heart J 1997; 134: 382-6.

Ventricular arrhythmias Sudden death caused by ventricular tachyarrhythmia's may account for 25-65% of deaths caused by cardiac sarcoidosis May be the initial presentation in 40% of patients with cardiac sarcoidosis Sekiguchi et al. I Sarcoidosis. Jpn Circ J 1980; 44: 249-63.

Congestive Heart Failure Accounts for 25% to 75% of cardiac deaths in patients with cardiac sarcoidosis Heart failure may be secondary to left- sided cardiac involvement with either systolic or diastolic dysfunction DDx: Idiopathic dilated cardiomyopathy (IDC) can be difficult to differentiate Sarcoidosis HF tend to have more progression to CHB then IDC Yazaki et al. Am J Cardiol 2001; 88: 1006-10.

Other Cardiac Manifestations Pericardial Effusions < 10 % of Cases- Small in size Valvular Involvement < 3 % , mostly Mitral Regurgitation noted Ventricular Aneurysms 10% of cases Anterior and septal segments Usually associated with steroid treatment for sarcoid rather than a direct cause Garrett et al; Am Heart J 1984; 107: 394 Pesola et a; Sarcoidosis 1987; 4: 42-4

Diagnosis Thorough clinical evaluation documenting a syndrome consistent with sarcoidosis AND Biopsy documentation of the presence of non- caseating granulomas Uemura et al. ;Am Heart J 1999; 138:299

Endomyocardial Biopsy “ Gold standard” Definite diagnosis of cardiac sarcoidosis can be made The sensitivity IS LOW-usually less than 20% Despite its low sensitivity, early myocardial biopsy can be considered when the diagnosis of cardiac sarcoidosis is still used Uemura et al. ;Am Heart J 1999; 138:299

DDX- Differential Diagnosis Connective tissue diseases Lyme disease Rheumatoid arthritis Dermatomyositis Cardiac amyloidosis alcohol related cardiomyopathy Sekhri et al. Arch Med Sci 2011; 7, 4: 546-554

Imaging Doppler echocardiography Radionuclide studies PET Abnormal septal thickening or thinning Dilatation of the left ventricle Systolic dysfunction of the left ventricle Radionuclide studies fibrogranulomatous lesions in the myocardium display segmental areas of decreased uptake in nuclear imaging PET 18F-Fluorodeoxyglucose (FDG) PET appears to detect active cardiac sarcoidosis with high sensitivity Non-specific for sarcoidosis, and uptake of 18F-FDG is seen in other inflammatory myocardial diseases Skold et al. J Intern Med 2002; 252: 465-71 .Haywood et al; J Natl Med Assoc 1983; 63: 478-82 Fields et al. ; South Med J 1990; 83: 339-42

Imaging- CMR Technique of choice in the evaluation of sarcoidosis zone of increased intramyocardial signal intensity More pronounced on T2 weighted images because of edema These images can be enhanced on gadolinium Focal myocardial thickening is often seen as a result of the edema Delayed enhanced MRI is considered a useful method for the early identification of cardiac sarcoidosis Tadamura et al. AJR Am J Roentgenol 2005; 185: 110-5.

Treatment and Prognosis Threshold for treatment is lower because of increased risk of sudden death Goal is to reduce inflammation Corticosteroids, the most common initial therapy Should be started in patients with a definite probability of cardiac sarcoidosis on different imaging studies, even with a negative myocardial biopsy Chiu et al. Am J Cardiol 2005; 95: 143-6.

Treatment Clinical Trials have suggested that Steroid treatments: (LVEF) > 55% may prevent LV remodeling and altered cardiac function Most benefited with LVEF < 54% who showed significant reduction in LV volumes and LVEF improvement LVEF < 30%, steroid therapy did not improve the LV volume or function Early/Middle stage disease, steroid therapy may be protective or therapeutic but may not be as effective in the late stages Chiu et al. Am J Cardiol 2005; 95: 143-6.

Other Treatment Options Methotrexate, azathioprine, or cyclophosphamide can be used as steroid sparing agents and in those whose disease is refractory to high-dose steroids Improvement in cardiac conduction abnormalities have been seen with the use of infliximab, a TNF alpha inhibitor Avoid using : Anti Arrhythmic drugs- Increased SCD Beta Blockers – Increased Heart Block ICD implantation in Cardiac sarcoid does have a lower threshold then other Heart Failure guidelines Baughman et al. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18:70-4 Lower et al . Am J Med Sci 1990; 299: 153-7 Baughman et al. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17: 60-6

Cardiac Transplantation Cardiac transplantation is reserved for end-stage disease unresponsive to medical therapy Major indications for cardiac transplantation : Resistant ventricular tachyarrhythmia Severe intractable heart failure ( Stage D) Valantine et al. J Heart Transplant 1987; 6: 244-50.

KEY POINTS Cardiac sarcoidosis may occur alone or alongside systemic sarcoidosis but is frequently clinically silent Diagnosis is still a major clinical challenges CMR and PET may be suggestive but are not diagnostic Endo-myocardial biopsy lacks sensitivity but still is “ Gold Standard” There is no clear-cut consensus on which diagnostic methodologies are best to evaluate disease presence and progression Suspect cardiac sarcoidosis in young adults with unexplained cardiac clinical manifestations , with a histologic (or clinical) diagnosis of extra-cardiac sarcoidosis, particularly in those who develop arrhythmias, conduction disease, or heart failure