A Timely Addition: Cardiac Sarcoidosis Guidance

Sarcoidosis is a systemic granulomatous inflammatory disease which most commonly affects the lungs (~90% of cases) with the heart involved in over 25% of cases, however clinically apparent cardiac sarcoidosis occurs in as few as 5%¹. Evidence suggests that sarcoidosis is more prevalent in Black Americans in the United States, and in females, also more common in those of Northern European or Japanese descent, though remains an underrecognized cause of cardiomyopathy². Presentation of cardiac disease can range from acute focal granulomatous inflammation which may relapse and remit leading to myocardial fibrosis and scar, culminating in restrictive or dilated cardiomyopathy and end stage heart failure in a proportion of patients, while others will not experience any significant clinical sequelae. Cardiac involvement typically presents as heart failure, conduction abnormalities or ventricular arrhythmias/sudden cardiac death. It is responsible for 25% of deaths in patients with sarcoidosis in the United States and up to 85% in Japan. The etiology of sarcoidosis is unclear, thought to be triggered by an environmental exposure in a genetically susceptible individual. This leads to a hyperpolarized T-helper cell immune response with formation of noncaseating granulomas and impaired regulatory T-cell response.³ The balance between these two entities is thought to be the underpinning of disease activity.⁴ Definitive diagnosis of sarcoidosis relies on a tissue biopsy showing noncaseating granulomas, however, given the patchy nature of disease endomyocardial biopsy is only 20% sensitive, though can rise to 50% with electroanatomic mapping guidance⁵. In the absence of biopsy positive diagnosis, we rely on multimodal imaging and expert interpretation within a multidisciplinary forum. Unfortunately, such resources are not widely available and limited to larger academic centers, therein contributing to the challenges in accurate and timely diagnosis of this disease and the underscoring need for comprehensive guidelines.

This AHA Scientific Statement outlines the diagnosis and management of cardiac sarcoidosis, incorporating and building upon prior guidelines from the Heart Rhythm Society, WASOG and Japanese Circulation Society^6-8. It begins by highlighting the clinical manifestations and ‘red flags' which should prompt evaluation for cardiac sarcoidosis. Electrocardiography (ECG) and echocardiography are useful modalities in screening for cardiac sarcoidosis, particularly when there is confirmed extracardiac disease though are neither sensitive nor specific enough for definitive diagnosis. Indeed, patients with cardiac sarcoidosis may have both a normal ECG and echocardiogram. Advanced imaging techniques including cardiac magnetic resonance imaging (CMR) and fluorine-18 fluorodeoxyglucose (FDG)- positron emission tomography (PET) are imperative diagnostic tools. CMR using gadolinium contrast identifies areas of inflammation and fibrosis resulting from granulomatous infiltration of the myocardium with high sensitivity and specificity. Late gadolinium enhancement (LGE) is also a prognostic indicator for mortality, appropriate ICD therapy, and ventricular arrhythmias⁹. FDG-PET is more accurate than current CMR for detecting inflammation and assessing response to therapy. It also has prognostic value for death or ventricular tachycardia¹⁰. Areas of FDG uptake identify regions of increased metabolic activity (inflammation) within the myocardium. While multifocal FDG uptake in the presence of co-localized resting perfusion defects is characteristic, this is not specific for cardiac sarcoidosis and can be seen in other inflammatory diseases of the heart and hibernating myocardium. Despite a preponderance for the basal septum and inferior wall of the left ventricle, there is no particular pattern of FDG uptake or LGE that is pathognomonic for cardiac sarcoidosis. As such, this Statement, in alignment with prior guidelines, recommends evaluation for other possible causes of imaging findings when there is diagnostic uncertainty. Centered around these multimodal imaging techniques, this AHA Scientific Statement proposes a diagnostic and evaluation algorithm, which integrates both expert consensus of the writing group and prior diagnostic guidelines^6,8. Given the inherent diagnostic uncertainty in cardiac sarcoidosis, particularly in the absence of a positive biopsy, a highlight of this algorithm is categorizing the likelihood of cardiac sarcoidosis into definite, highly probable, probable, and possible/low probability. This helps to weigh the risk/benefit of initiation of immunosuppression based on strength of clinical suspicion.

This AHA publication is the first Scientific Statement to provide a suggested approach to the treatment of cardiac sarcoidosis. Treatment should always be initiated in those who are symptomatic with definite or highly probable cardiac sarcoidosis. However, consideration should be given to the risk/benefit ratio of immunosuppression in those with probable cardiac sarcoidosis and treatment should generally be avoided in the low probability group. Corticosteroids are the mainstay of therapy in cardiac sarcoidosis, generally first-line treatment. They have been shown to improve conduction disease, though the effect on mortality is less well delineated¹¹. While historically, higher doses of corticosteroids have been utilized, data now show that initial doses no higher than 30-40mg of prednisone daily are generally sufficient to suppress myocardial inflammation. The addition of a steroid sparing agent can be considered in patients who are intolerant of moderate or higher doses of corticosteroids, or who have a severe initial presentation such as cardiogenic shock, ventricular arrhythmias, or high-grade conduction block. Tumor necrosis factor-alpha inhibitors can be considered in those who have ongoing or progressive inflammation despite optimization of first- and second-line therapies. Historically, these agents have been used with extreme caution in heart failure due to the risk of causing an exacerbation, however, data from the cardiac sarcoidosis population suggest that they may be useful in targeting inflammation without the aforementioned risk.

Given the myocardial dysfunction that often accompanies cardiac sarcoidosis, with a subset progressing to end stage heart failure, this statement also briefly outlines the use of advanced heart failure therapies. It outlines sarcoidosis-specific considerations which should not be overlooked during evaluation. Durable left ventricular assist devices should be used with caution in those with a high burden of ventricular arrhythmias or significant RV dysfunction. In addition, the continuation of immunosuppression post operatively may cause complications and worsen comorbidities. In these settings, heart transplantation should be considered.

This AHA Scientific Statement also outlines management of cardiac sarcoidosis associated conduction system abnormalities and arrhythmias, highlighting the use of cardiovascular implantable electronic devices in this group. Although standard ACC/AHA guidelines should be adhered to for those with a left ventricular ejection fraction (LVEF) ≤ 35%, those with an EF in the 36-50% range are at increased risk of sudden cardiac death. Furthermore, as highlighted in the HRS consensus document, those with a right ventricular EF < 40%, LGE on CMR, indication for permanent pacing or those who have inducible ventricular arrhythmias at electrophysiology study should be considered for implantable cardioverter defibrillator therapy.⁶ This document concludes by highlighting the necessity of a multidisciplinary care approach given the systemic nature of this disease.

 In conclusion, the AHA Scientific Statement on the Diagnosis and Management of Cardiac Sarcoidosis is a much-needed addition to the literature. Given the dearth of data driven evidence, lack of randomized clinical trials, and absence of accepted diagnostic guidelines in cardiac sarcoidosis, the clinical guidance offered by this AHA statement is timely. This Statement will inform clinicians on the recommended diagnostic approach, therapeutic treatment options and possible complications of this rare disease, with the goal of ultimately enhancing outcomes.