This transcript has been edited for clarity.
Hello, my name is Farooq Sheikh. I am the medical director of the Advanced Heart Failure Program at MedStar Heart and Vascular Institute in Washington, DC. It is my pleasure to provide commentary on the topic of Cardiac Sarcoidosis: Making the Diagnosis.
Cardiac sarcoidosis is an infiltrative heart disease owing to granulomatous inflammation, which may present with conduction disease, such as high-grade atrioventricular (AV) block, ventricular arrhythmias, and ventricular dysfunction, resulting in cardiomyopathy and heart failure.
This disease mimics other forms of heart disease with very nonspecific symptoms, such as palpitations, chest pain, and shortness of breath. The only definitive way to make the diagnosis is through histologic proof of granulomatous inflammation, but this is challenging given the patchy nature of disease and the limited utility of endomyocardial biopsy.
Given the risks associated with cardiac sarcoidosis, it behooves us to try to make the diagnosis as soon as possible to avoid adverse cardiovascular events. The problem is that making the diagnosis is challenging. It requires a high degree of suspicion with the pursuit of a comprehensive diagnostic strategy that includes advanced cardiac imaging, a multidisciplinary team, and the exclusion of other diseases that may be phenotypically similar to cardiac sarcoidosis.
We will explore the detective work necessary to cinch the diagnosis. Let's first review some basic principles related to sarcoidosis and cardiac sarcoidosis.
Suspecting Cardiac Sarcoidosis: What Are the Red Flags?
First, sarcoidosis may be best described as an immunologic response to an antigenic trigger in a susceptible host — this is genetically susceptible. It is currently believed that environmental trigger results in antigenic exposure, resulting in immune system dysregulation involving T-cells, cytokines, and eventual activation of macrophages, resulting in granulomatous inflammation.
It is notable that this is a worldwide disease whose incidence and prevalence vary based on geography, race, and sex. There are estimates of prevalence between 14-100 per 100,000 individuals, with higher prevalence and incidence in individuals of self-described black background, particularly women.
The cardiac phenotype, meaning heart failure versus ventricular arrhythmias, can also differ based on race and sex. But it is notable that patients with systemic sarcoidosis are at increased risk for ventricular arrhythmias, atrial arrhythmias, the development of heart failure, and sadly, the risk of sudden cardiac death.
The first step is to suspect the disease in order to make the diagnosis. There are classic presentations, including unexplained heart failure and cardiomyopathy; ventricular arrhythmias, including premature ventricular contractions; [and] abnormal echocardiographic features, such as regional wall motion abnormalities, wall thinning, and ventricular aneurysms, in patients who have no coronary artery disease.
A particular red flag sign is an individual with high-grade AV block under the age of 60 who presents with symptoms associated with this conduction disease. Cardiac sarcoidosis may also be considered in patients who present with chest pain, who have abnormal myocardial perfusion imaging, where coronary artery disease assessment is negative.
It is noteworthy that a number of patients with cardiac sarcoidosis present with their first manifestation being myocardial involvement. If you do a thorough whole-body assessment for organ involvement, particularly with the use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, the majority of these patients will be found to have multisystem disease.
It has been described and is known that isolated cardiac sarcoidosis can exist, and this is a disease with a more fulminant presentation associated with ventricular arrhythmias. It is important that we exclude diseases that mimic this form of inflammatory heart disease, most notably, patients with coronary artery disease, inflammatory heart diseases other than cardiac sarcoidosis, and patients with genetic or inherited cardiomyopathies.
Imaging Tools and Diagnostic Insights
What about the diagnostic tools that we use? Electrocardiogram (ECG) and echocardiogram are the cornerstone initial diagnostic tools, but they are neither sensitive nor specific for making the diagnosis. In patients with systemic sarcoidosis, you might find AV block, you might find bundle branch blocks, both left and right, as well as conduction disease, premature ventricular complexes, and nonsustained ventricular tachycardia.
Echocardiogram can reveal left and/or right ventricular (LV/RV) systolic dysfunction with a low ejection fraction. You might find regional wall motion abnormalities not explained by coronary artery disease, ventricular aneurysms, as well as basal septal wall thinning in patients who have no known coronary artery disease.
Neither ECG nor echocardiogram are sensitive or specific enough to make the diagnosis. This is why the cornerstone diagnostic tools are cardiac MRI and FDG- PET imaging. We use cardiac MRI to identify disease because of the ability to use a contrast agent known as gadolinium — which in patients with cardiac sarcoidosis, unfortunately, hangs up in the heart, resulting in the characteristic feature known as late gadolinium enhancement, which has been associated as a marker for cardiac sarcoidosis.
Gadolinium is an extracellular contrast agent injected in the venous blood pool, which in normal myocardium, goes into the blood pool, through the heart, and then leaves the heart, leaving no trace behind where the MRI shows the heart to be black and the blood pool to be white. In patients with fibrosis and inflammation in diseases such as cardiac sarcoidosis, gadolinium gets hung up in the heart, resulting in late gadolinium enhancement.
It is not the presence of late gadolinium enhancement that cinches the diagnosis of cardiac sarcoidosis but rather the pattern in which you might find it. It’s typically multifocal, patchy in nature, and there have been some wonderful papers highlighting typical patterns that have been correlated with histologic evidence of disease. Right ventricular involvement or biventricular involvement, particularly multifocal, where the base to the mid-septum of the left ventricle extending in the right ventricle is a classic feature.
This is a highly sensitive and specific tool with [> 80%] sensitivity and specificity based on published data as well as meta-analysis, including the reality that the absence of LGE speaks strongly against the diagnosis of cardiac sarcoidosis. What is also nice about this is it allows us to look for other types of disease that may mimic cardiac sarcoidosis, such as arrhythmogenic RV cardiomyopathy, other forms of inflammatory heart disease, and ischemic heart disease.
FDG-PET uses the radionuclide fluorodeoxyglucose (FDG), a glucose analog, which is used by inflammatory cells, such as macrophages and lymphocytes, in areas where glucose metabolism is revved up or hypermetabolic, particularly in areas of granulomatous inflammation, and can be seen in all forms of inflammatory heart disease.
In order for us to identify these areas, we must, at first, shift the normal metabolism of the body, particularly the heart, by starving the heart and the body of carbohydrates. We do this by shifting our diet from one of carbohydrates to fat — a high-fat diet for at least 24 up to 72 hours, which suppresses the use of glucose within the myocytes, shifting it to fatty acids, which then allows us to inject FDG in the venous blood pool to identify these areas of hypermetabolic inflammatory state.
The classic features of cardiac sarcoidosis include multifocal uptake, particularly associated with areas where the resting perfusion is abnormal, classically described as a metabolic perfusion mismatch. A negative PET scan in sarcoidosis can be seen and is classically associated with clinically quiescent or metabolically quiescent disease, otherwise known as “burned-out” disease. You should not just assume, particularly in the face of a positive MRI, that a negative PET scan means the patient does not have cardiac sarcoidosis. It is important to consider these tests, not as positive or negative, but rather looking at the patterns of uptake, both in MRI and PET, to be able to increase or decrease your suspicion of the disease.
What about endomyocardial biopsy? Unfortunately, endomyocardial biopsy is positive only 20%-30% of the time in patients with cardiac sarcoidosis, meaning that we do not exclude the diagnosis with a negative biopsy. We might increase our yield with voltage-gated mapping, but that yield is no better than 50%, or the flip of a coin, so endomyocardial biopsy is not a typical tool used to make the diagnosis given the lack of sensitivity and specificity.
On the other hand, we might look at FDG-PET imaging, given the fact that we are able to get images of the whole body, and harness or utilize mediastinal lymph nodes to make the diagnosis through transbronchial biopsy, which is of great yield and a particular benefit of FDG-PET imaging.
I'm asked frequently by clinicians whether cardiac MRI or PET scans should be the diagnostic tool used. The answer is they are complementary tools that we should be using in all our patients to make this diagnosis.
Making the Diagnosis: Key Insights
Finally, I will conclude with key points and practical tips. One, making the diagnosis of cardiac sarcoidosis requires a high grade of clinical suspicion, with red-flag clinical scenarios including high-grade AV block in a younger patient, typically under the age of 60; unexplained ventricular arrhythmias, cardiomyopathy, or heart failure; and abnormal echocardiographic features that cannot be explained by coronary artery disease, such as regional wall thinning or abnormalities, as well as ventricular aneurysms.
Cardiac MRI and FDG-PET imaging are essential in the diagnostic evaluation, allowing us to increase or decrease our suspicion for the disease. Unfortunately, the only way to truly make the diagnosis is to find histologic evidence of granulomatous inflammation. It is important to note that FDG-PET imaging allows us to look at the entire body to assess for total body organ involvement.
There are diagnostic criteria from the Heart Rhythm Society, the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG), and the Japanese Circulation Society, and I encourage you to review them to increase your suspicion of the disease all the way from definite cardiac sarcoidosis, where there is evidence of granulomatous inflammation within the heart, to low probability or possible disease.
A multidisciplinary team approach is essential, and clinicians must be rigorous in excluding alternative diagnoses that mimic this disease, such as ischemic heart disease and inherited genetic cardiomyopathies.
Thank you for joining me today.
COMMENTARY
Cardiac Sarcoidosis: Diagnostic Tips for Clinicians
DISCLOSURES
| December 17, 2024Editorial Collaboration
&
This transcript has been edited for clarity.
Hello, my name is Farooq Sheikh. I am the medical director of the Advanced Heart Failure Program at MedStar Heart and Vascular Institute in Washington, DC. It is my pleasure to provide commentary on the topic of Cardiac Sarcoidosis: Making the Diagnosis.
Cardiac sarcoidosis is an infiltrative heart disease owing to granulomatous inflammation, which may present with conduction disease, such as high-grade atrioventricular (AV) block, ventricular arrhythmias, and ventricular dysfunction, resulting in cardiomyopathy and heart failure.
This disease mimics other forms of heart disease with very nonspecific symptoms, such as palpitations, chest pain, and shortness of breath. The only definitive way to make the diagnosis is through histologic proof of granulomatous inflammation, but this is challenging given the patchy nature of disease and the limited utility of endomyocardial biopsy.
Given the risks associated with cardiac sarcoidosis, it behooves us to try to make the diagnosis as soon as possible to avoid adverse cardiovascular events. The problem is that making the diagnosis is challenging. It requires a high degree of suspicion with the pursuit of a comprehensive diagnostic strategy that includes advanced cardiac imaging, a multidisciplinary team, and the exclusion of other diseases that may be phenotypically similar to cardiac sarcoidosis.
We will explore the detective work necessary to cinch the diagnosis. Let's first review some basic principles related to sarcoidosis and cardiac sarcoidosis.
Suspecting Cardiac Sarcoidosis: What Are the Red Flags?
First, sarcoidosis may be best described as an immunologic response to an antigenic trigger in a susceptible host — this is genetically susceptible. It is currently believed that environmental trigger results in antigenic exposure, resulting in immune system dysregulation involving T-cells, cytokines, and eventual activation of macrophages, resulting in granulomatous inflammation.
It is notable that this is a worldwide disease whose incidence and prevalence vary based on geography, race, and sex. There are estimates of prevalence between 14-100 per 100,000 individuals, with higher prevalence and incidence in individuals of self-described black background, particularly women.
The cardiac phenotype, meaning heart failure versus ventricular arrhythmias, can also differ based on race and sex. But it is notable that patients with systemic sarcoidosis are at increased risk for ventricular arrhythmias, atrial arrhythmias, the development of heart failure, and sadly, the risk of sudden cardiac death.
The first step is to suspect the disease in order to make the diagnosis. There are classic presentations, including unexplained heart failure and cardiomyopathy; ventricular arrhythmias, including premature ventricular contractions; [and] abnormal echocardiographic features, such as regional wall motion abnormalities, wall thinning, and ventricular aneurysms, in patients who have no coronary artery disease.
A particular red flag sign is an individual with high-grade AV block under the age of 60 who presents with symptoms associated with this conduction disease. Cardiac sarcoidosis may also be considered in patients who present with chest pain, who have abnormal myocardial perfusion imaging, where coronary artery disease assessment is negative.
It is noteworthy that a number of patients with cardiac sarcoidosis present with their first manifestation being myocardial involvement. If you do a thorough whole-body assessment for organ involvement, particularly with the use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, the majority of these patients will be found to have multisystem disease.
It has been described and is known that isolated cardiac sarcoidosis can exist, and this is a disease with a more fulminant presentation associated with ventricular arrhythmias. It is important that we exclude diseases that mimic this form of inflammatory heart disease, most notably, patients with coronary artery disease, inflammatory heart diseases other than cardiac sarcoidosis, and patients with genetic or inherited cardiomyopathies.
Imaging Tools and Diagnostic Insights
What about the diagnostic tools that we use? Electrocardiogram (ECG) and echocardiogram are the cornerstone initial diagnostic tools, but they are neither sensitive nor specific for making the diagnosis. In patients with systemic sarcoidosis, you might find AV block, you might find bundle branch blocks, both left and right, as well as conduction disease, premature ventricular complexes, and nonsustained ventricular tachycardia.
Echocardiogram can reveal left and/or right ventricular (LV/RV) systolic dysfunction with a low ejection fraction. You might find regional wall motion abnormalities not explained by coronary artery disease, ventricular aneurysms, as well as basal septal wall thinning in patients who have no known coronary artery disease.
Neither ECG nor echocardiogram are sensitive or specific enough to make the diagnosis. This is why the cornerstone diagnostic tools are cardiac MRI and FDG- PET imaging. We use cardiac MRI to identify disease because of the ability to use a contrast agent known as gadolinium — which in patients with cardiac sarcoidosis, unfortunately, hangs up in the heart, resulting in the characteristic feature known as late gadolinium enhancement, which has been associated as a marker for cardiac sarcoidosis.
Gadolinium is an extracellular contrast agent injected in the venous blood pool, which in normal myocardium, goes into the blood pool, through the heart, and then leaves the heart, leaving no trace behind where the MRI shows the heart to be black and the blood pool to be white. In patients with fibrosis and inflammation in diseases such as cardiac sarcoidosis, gadolinium gets hung up in the heart, resulting in late gadolinium enhancement.
It is not the presence of late gadolinium enhancement that cinches the diagnosis of cardiac sarcoidosis but rather the pattern in which you might find it. It’s typically multifocal, patchy in nature, and there have been some wonderful papers highlighting typical patterns that have been correlated with histologic evidence of disease. Right ventricular involvement or biventricular involvement, particularly multifocal, where the base to the mid-septum of the left ventricle extending in the right ventricle is a classic feature.
This is a highly sensitive and specific tool with [> 80%] sensitivity and specificity based on published data as well as meta-analysis, including the reality that the absence of LGE speaks strongly against the diagnosis of cardiac sarcoidosis. What is also nice about this is it allows us to look for other types of disease that may mimic cardiac sarcoidosis, such as arrhythmogenic RV cardiomyopathy, other forms of inflammatory heart disease, and ischemic heart disease.
FDG-PET uses the radionuclide fluorodeoxyglucose (FDG), a glucose analog, which is used by inflammatory cells, such as macrophages and lymphocytes, in areas where glucose metabolism is revved up or hypermetabolic, particularly in areas of granulomatous inflammation, and can be seen in all forms of inflammatory heart disease.
In order for us to identify these areas, we must, at first, shift the normal metabolism of the body, particularly the heart, by starving the heart and the body of carbohydrates. We do this by shifting our diet from one of carbohydrates to fat — a high-fat diet for at least 24 up to 72 hours, which suppresses the use of glucose within the myocytes, shifting it to fatty acids, which then allows us to inject FDG in the venous blood pool to identify these areas of hypermetabolic inflammatory state.
The classic features of cardiac sarcoidosis include multifocal uptake, particularly associated with areas where the resting perfusion is abnormal, classically described as a metabolic perfusion mismatch. A negative PET scan in sarcoidosis can be seen and is classically associated with clinically quiescent or metabolically quiescent disease, otherwise known as “burned-out” disease. You should not just assume, particularly in the face of a positive MRI, that a negative PET scan means the patient does not have cardiac sarcoidosis. It is important to consider these tests, not as positive or negative, but rather looking at the patterns of uptake, both in MRI and PET, to be able to increase or decrease your suspicion of the disease.
What about endomyocardial biopsy? Unfortunately, endomyocardial biopsy is positive only 20%-30% of the time in patients with cardiac sarcoidosis, meaning that we do not exclude the diagnosis with a negative biopsy. We might increase our yield with voltage-gated mapping, but that yield is no better than 50%, or the flip of a coin, so endomyocardial biopsy is not a typical tool used to make the diagnosis given the lack of sensitivity and specificity.
On the other hand, we might look at FDG-PET imaging, given the fact that we are able to get images of the whole body, and harness or utilize mediastinal lymph nodes to make the diagnosis through transbronchial biopsy, which is of great yield and a particular benefit of FDG-PET imaging.
I'm asked frequently by clinicians whether cardiac MRI or PET scans should be the diagnostic tool used. The answer is they are complementary tools that we should be using in all our patients to make this diagnosis.
Making the Diagnosis: Key Insights
Finally, I will conclude with key points and practical tips. One, making the diagnosis of cardiac sarcoidosis requires a high grade of clinical suspicion, with red-flag clinical scenarios including high-grade AV block in a younger patient, typically under the age of 60; unexplained ventricular arrhythmias, cardiomyopathy, or heart failure; and abnormal echocardiographic features that cannot be explained by coronary artery disease, such as regional wall thinning or abnormalities, as well as ventricular aneurysms.
Cardiac MRI and FDG-PET imaging are essential in the diagnostic evaluation, allowing us to increase or decrease our suspicion for the disease. Unfortunately, the only way to truly make the diagnosis is to find histologic evidence of granulomatous inflammation. It is important to note that FDG-PET imaging allows us to look at the entire body to assess for total body organ involvement.
There are diagnostic criteria from the Heart Rhythm Society, the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG), and the Japanese Circulation Society, and I encourage you to review them to increase your suspicion of the disease all the way from definite cardiac sarcoidosis, where there is evidence of granulomatous inflammation within the heart, to low probability or possible disease.
A multidisciplinary team approach is essential, and clinicians must be rigorous in excluding alternative diagnoses that mimic this disease, such as ischemic heart disease and inherited genetic cardiomyopathies.
Thank you for joining me today.
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