The heart in sarcoidosis
Keywords: cardiac sarcoidosis, sarcoidosis cordis, sarcoid heart

# Overview
Pericarditis as a manifestation of sarcoidosis has been frequently described and necropsy studies have documented cardiac involvement in 27% of patients, but clinically significant pericarditis is uncommon. In addition, sarcoidosis has been rarely documented in children. The granulomatous infiltrative disease of the myocardium is often asymptomatic, but can cause arrhythmias, conduction disease and, rarely, otherwise unexplained congestive heart failure. Early diagnosis can be very important because it's generally believed aggressive steroid treatment may decrease mortality.  Granulomatous infiltration may be patchy, with a predilection toward involvement of the left ventricle, particularly the upper septal area. This distribution influences the likelihood of obtaining a diagnostic right sided endomyocardial biopsy. Use of gallium or thallium imaging may be helpful in determining the need for and duration of immunosuppressive therapy, but this approach has not been proved in any formal trial  . Sarcoid dilated cardiomyopathy may be difficult to distinguish from idiopathic cardiomyopathy or occasionally from giant cell myocarditis. Conduction disease is more common than pump dysfunction in patients with sarcoidosis. Biopsy may help distinguish sarcoidosis from idiopathic or giant cell myocarditis, but the diagnostic yield of endomyocardial biopsy is low. Active sarcoidosis is generally believed to be steroid responsive. However, myocardial involvement with sarcoid can result in large patches of fibrotic scar that may be arrhythmogenic but no longer respond to steroids. Scar is often significantly underestimated by imaging studies and biopsy. Pulmonary artery hypertension and cor pulmonale can occur in sarcoidosis, generally as a result of pulmonary fibrosis.Systemic vasculitis is an uncommon complication of sarcoidosis. Its prevalence remains unknown. Sarcoid vasculitis can affect small  to large caliber vessels, including the aorta. The latter presentation can be easily confused with Takayasu arteritis. African American patients appear predisposed to developing large vessel involvement.     

# Historical perspective
- In 1869 Jonathan Hutchinson described the first case of cutaneous sarcoid 
- In 1899 the disease was named by Boeck, a Norwegian dermatologist, who thought that the nodular skin lesions of epithelioid cells resemble sarcoma cells and descried them as sarcoid
- In 1929,  Bernstein was the first to recognize cardiac involvement in a patient with systemic sarcoidosis
- In 1952, Longcope and Freiman were the first to describe myocardial involvement in 20% of 92 necropsied cases of sarcoidosis
- The Japanese Ministry of Health and Welfare (JMH) published diagnostic guidelines for cardiac sarcoidosis  in 1993 and were updated in 2006. The guidelines require myocardial biopsy for histologic confirmation of cardiac involvement or clinical confirmation via a of major and minor criteria combination

# Pathophysiology
- The exact pathogenesis of cardiac sarcoidosis is not fully understood
- It is thought that antigens, non-self and self, trigger the helper inducer T cells primarily and  lead to the formation of granuloma lesions
- During the early stage of the disease, sarcoid infiltrates consist of:
Mononuclear phagocytes
CD4 positive T cells with a T helper type I response
Secret interleukin2 and interferon.
- Mononuclear phagocytes
- CD4 positive T cells with a T helper type I response
- Secret interleukin2 and interferon.
- During the late of the disease, the infiltrates shift to:
T helper type 2 response which has been demonstrated during the fibroproliferative phase of the granuloma
It is believed that it exerts antiinflammatory effects and result in tissue scarring
- T helper type 2 response which has been demonstrated during the fibroproliferative phase of the granuloma
- It is believed that it exerts antiinflammatory effects and result in tissue scarring
- High concentrations of interleukin6 can be found in the circulation at the onset of the disease and before the initiation of immunosuppressive therapy, but can't be found  thereafter
- Interleukin6 is believed to induce the proliferation of T cells and hence be involved in the maintenance of inflammation
- Genetic factors are also believed to have a role in the pathogenesis of cardiac sarcoidosis
HLADQB1*0601 has been reported to be positively associated with cardiac sarcoidosis
Potential markers that have been evaluated for an increased risk of sarcoidosis in general are:
ACE gene polymorphism and
Tumor necrosis factor  promoter gene polymorphism
- HLADQB1*0601 has been reported to be positively associated with cardiac sarcoidosis
- Potential markers that have been evaluated for an increased risk of sarcoidosis in general are:
ACE gene polymorphism and
Tumor necrosis factor  promoter gene polymorphism
- ACE gene polymorphism and
- Tumor necrosis factor  promoter gene polymorphism
- The heart has no portion that is immune to infiltration by sarcoid granulomas
- The most frequently involved heart portion is the myocardium. However, the granuloma can involve the pericardium and the endocardium.
- The predominant sites of myocardial involvement, in decreasing order of frequency, are:
The left ventricular free wall and papillary muscles
The basal aspect of the ventricular septum
The right ventricular free wall
The atrial walls
- The left ventricular free wall and papillary muscles
- The basal aspect of the ventricular septum
- The right ventricular free wall
- The atrial walls
- Microscopic appearance: samples of myocardium involved with sarcoidosis reveal the presence of:
Numerous lymphocytes located at the border zones around the granulomas
A dense band of fibroblasts, collagen fibers, and proteoglycans usually encase this aggregate of inflammatory cells 
- Numerous lymphocytes located at the border zones around the granulomas
- A dense band of fibroblasts, collagen fibers, and proteoglycans usually encase this aggregate of inflammatory cells 

# Differentiating Cardiac sarcoidosis from Other Diseases
Cardiac sarcoidosis must be differentiated from other diseases such as cardiac amyloidosis

# Epidemiology and Demographics
- Sarcoidosis granuloma formation involves most commonly the lungs
- 70% of sarcoidosis occurs in patients 25 to 60 years of age
- Sarcoidosis is rare in people 70 years of age
- The prevalence of sarcoidosis is about 4.7 to 64 in 100,000
- Sarcoidosis  highest rates are reported in northern Europeans and African Americans, mainly  in women
- Clinically manifest cardiac involvement occurs in about 5% of patients with sarcoidosis
- Studies say that cardiac sarcoidosis seems to be becoming more prevalent than before
- In Finland, the rate of sarcoidosis has increased more than 20-fold between 1988 and 2012 
- In the United States, the incidence of patients with sarcoidosis-induced cardiomyopathy who underwent transplantation increased from 0.1% (1994 to 1997) to 0.5% (2010 to 2014)
- In patients with clinically evident sarcoidosis, cardiac involvement has been reported in at least 2-7% of them
- Occult cardiac involvement has a much higher rate (> 20%)
- In the United States and United Kingdom, several necropsy series cited pathological evidence for cardiac involvement in 19.5 to 28% of sarcoid patients
- The incidence of cardiac sarcoidosis is higher in Japanese patients with sarcoidosis (5078% in necropsy studies)
- In Japan, cardiac involvement is the leading cause of death due to sarcoidosis, accounting for 77 to 85% of deaths
- In the United States, 13 to 50% of sarcoid deaths have been attributed to myocardial involvement

# Risk Factors
- There are no established risk factors for cardiac sarcoidosis
- Ethnicity: African Americans and people of European descent ,particularly Scandinavian.

# Screening
- There is insufficient evidence to recommend routine screening for cardiac sarcoidosis
- Patients with sarcoidosis can be screened for possible cardiac involvement by ECG, Holter monitoring, DE, and cardiac symptoms (i.e., palpitations, syncope, or presyncope). If symptoms or screening tests are with positive, patients can undergo MRI and PET scan.

# Natural History, Complications, and Prognosis
- Studies have concluded that survival in most patients with symptomatic cardiac sarcoidosis was limited to about two years
- later studies have concluded  better outcome where five year survival was 4060%

# Diagnosis
- The definitive diagnosis of isolated cardiac sarcoidosis is difficult.
- Noninvasive imaging should be added to the endomyocardial biopsy in order to diagnose and follow cardiac sarcoidosis
- Treatment of cardiac sarcoidosis  can be started even in the absence of histologic proof
- The diagnosis can be confirmed histologically by myocardial biopsy or clinically via a of major and minor criteria combination 
- Echocardiography
- CMR imaging
- Nuclear imaging
- Cardiac PET
- Hybrid imagingPET and CMR
- Coronary Angiography

## Cardiac MRI
Common MRI findings in patients with cardiac sarcoidosis include:
- Delayed enhancement, which may be either mid wall or transmural
- Nodular mid wall hyperintense foci on black blood T2-weighted imaging
- Areas of focal myocardial thickening.
- Disease may involve either the left or the right ventricle but more commonly involves the left ventricle.

# Treatment
- Corticosteroid treatment
- Antiarrhythmic treatment
- Pacemakers and defibrillators
- Cardiac transplantation