July 18, 2024 | Most of the time, sarcoidosis appears in the lungs and lymph nodes, but the heart is impacted in a smaller number of patients. Known as cardiac sarcoidosis (CS), this rare condition can lead to serious complications like arrhythmia or heart failure. Recently, Diagnostics World covered efforts to improve diagnostic and treatment options for sarcoidosis. Here, we explore new and emerging research focused on CS in particular.
One of the main challenges of CS is that it is underdiagnosed, according to Daniela Cihakova, a professor in the Department of Pathology and an associate director of the Diagnostic Immunology Lab at Johns Hopkins University. And while reported CS makes up only a small fraction of all diagnosed cases of sarcoidosis, it is a big contributor to sarcoidosis-related deaths. Considering that many CS cases are first diagnosed during an autopsy, there is a clear need for improvement. “We are really lacking biomarkers,” she said.
There is a relative lack of research showing differences between CS and the most common form of sarcoidosis, Cihakova explained, which is located in the lungs. Her lab has taken an initial step forward by analyzing publicly available data sets from the heart and lungs in an effort to identify relevant biomarkers that could help distinguish these different forms of the disease. Their work has previously revealed that endothelial cells—the cells that line blood vessels—of CS hearts “significantly upregulate formation of new blood vessels, a process known as neovascularization, relative to control endothelial cells.”
More recently, a grant from the Foundation for Sarcoidosis Research will enable her group to “use the novel 3D multi-omic pathology to determine unique properties of vasculature surrounding cardiac sarcoidosis granulomas and find new potential biomarker targets and histological criteria for cardiac sarcoidosis diagnosis,” according to a news release.
Pursuing New Biomarker Targets and Diagnosis Criteria
Cihakova and her colleagues have begun work on this grant-funded project. In collaboration with Nisha Gilotra, a cardiologist and sarcoidosis specialist at Johns Hopkins, her team has gained access to the tissue of patients with CS.
Oftentimes, CS patients need to undergo transplantation, Cihakova explained, and when the old heart with sarcoidosis is removed, it becomes possible to reconstruct the organ. They are essentially “trying to see what the tissue that has granulomas looks like on a molecular basis compared to the tissue that doesn’t have granulomas,” she said. Then, the big question is whether some of these markers can be used as targets for future therapies.
A method called CODA was initially developed by Ashley Kiemen, a computer scientist at Johns Hopkins, to perform 3D histological reconstruction of large tissues. By adapting this approach, the researchers can now analyze cardiac diseases and map microanatomy in 3D. “She applied it for us on tumors,” Cihakova said, “but when we saw it, we were very intrigued, and we wanted to apply it to the heart.”
Abdel Daoud, a computer scientist in the Cihakova lab, did just that, enabling the 3D imaging of a whole mouse heart and the imaging of human cardiac tissue with diseases including sarcoidosis. Using CODA, the researchers can perform 3D histological reconstruction of tissue pieces gathered from CS hearts and examine granulomas in 3D.
“The idea is we take these pieces from patients, and we do serial sectioning of them, and then we can essentially consolidate them back into 3D space,” Daoud told Diagnostics World. “It’s a really powerful tool because not only can we get the microanatomy at the scale of micrometers, but we can also detect single cells, so it’s really a single-cell multi-omic approach.”
The process involves taking a one-centimeter cube of human heart sarcoidosis and using CODA to conduct imaging to show anatomical structures. They can also harness AI to annotate the vasculature surrounding granulomas and detect the 3D distribution of different immune cells, like macrophages and T cells, inside of the granulomas.
Their preliminary results have demonstrated that vasculature is far more dense near granulomas than apparently normal cardiac tissue. This supports the notion that neovascularization may be a pathological feature of CS, with potential implications for both diagnosis and treatment.
The integration of spatial transcriptomics enables the researchers to figure out how granulomas are distinct, on a molecular level, from apparently healthy tissue surrounding the granulomas. This would be clinically relevant, according to the researchers, because many heart biopsies miss granulomas, which must be observed to confirm a CS diagnosis.
Cihakova said that in addition to this recent grant award, her team’s work has received support from the Global Autoimmune Institute, a private foundation supporting autoimmune disease research. She pointed out that funding of this nature makes a difference for new teams entering this field of study.
She also emphasized the importance of collaboration. “What allows us to do this research is our cooperation with the clinicians,” Cihakova said, noting that their current work with human heart tissue hinges on collaboration from Gilotra, the cardiac sarcoidosis specialist.
Looking ahead, Cihakova hopes to expand their work in this field of research with a comparison of heart and lung sarcoidosis in 3D.
Grant support from the Foundation for Sarcoidosis Research will also enable Senthil Selvaraj, an assistant professor of medicine at Duke University, to pursue improved specificity of CS diagnosis.
The aim, according to Selvaraj, is to accomplish this with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) using a novel strategy that incorporates combined SGLT1/2 inhibition with sotagliflozin.
Researchers at Aichi Medical University, Fujita Health University School of Medical Science, and Tajimi City Hospital in Japan have also recently studied the utilization of FDG-PET for CS diagnosis.
In a paper published in Scientific Reports (DOI: 10.1038/s41598-024-58475-z), they noted that the limitations of endomyocardial biopsy can lead to undiagnosed patients with pacemaker implants. In their paper, the researchers detailed findings that support a new guideline for CS.
According to the study authors, “the new guideline using FDG-PET/CT enabled the definitive diagnosis of CS, including iCS,” and led to more than two times the number of CS diagnoses compared to conventional criteria.
Prognosis Differences Between iCS and sCS
In some cases, called isolated CS (iCS), this disease affects only the heart as opposed to systemic CS (sCS), which affects multiple organs. Previous studies have revealed that patients diagnosed with iCS have a worse prognosis than patients with sCS.
To learn more about why the prognosis seems to be worse when sarcoidosis is confined to the heart alone, a group of researchers led by Daichi Maeda of Juntendo University Graduate School of Medicine in Japan compared the prognosis and clinical characteristics of nearly 500 patients with either iCS or sCS and ran statistical analyses.
Their findings, published in the European Journal of Heart Failure (DOI: 10.1002/ejhf.3056), indicated that patients with iCS were more likely to have a history of heart-related issues like atrial fibrillation, heart failure, or lower ventricular ejection fraction than patients with sCS.
Once the researchers adjusted for these confounding factors, the discrepancy disappeared. In other words, the poor prognosis of iCS patients might just relate to the patient’s poor health condition.
“Our findings suggest that the conditions at the time of diagnosis determine a patient’s prognosis rather than whether they have iCS or sCS,” Maeda said, so early detection of iCS is crucial. “We hope that our current study facilitates the development of an early diagnostic tool for CS, and that researchers around the world engage in studies on CS.”
Study Focuses on Disparities Among Patients with CS
Other researchers, meanwhile, are exploring disease disparities. A group of researchers spanning the UK, US, Pakistan, and the African country of Mauritius have taken a closer look at racial disparities among US patients with CS.
The disease is often associated with arrhythmias and conduction abnormalities, and the study aimed to examine disparities in arrhythmia frequency and related co-morbidities. Nearly 8,000 patients with CS were included in the study.
The findings, published in Current Problems in Cardiology (DOI: 10.1016/j.cpcardiol.2024.102450), showed that White patients were at a higher risk of developing arrhythmias and conduction disorders compared to African Americans. However, African Americans had a higher incidence of cardiogenic shock, acute kidney injury, and death.
In Search of the Optimal Therapeutic Approach
According to a group of Norwegian researchers, the diagnosis of CS can be challenging. “Without appropriate clinical suspicion and diagnostic workup, the disease can often go unrecognized,” they explained in a study published in the International Journal of Cardiology (DOI: 10.1016/j.ijcard.2024.131809).
On the other hand, advances in imaging, especially the use of cardiac magnetic resonance imaging (CMR) and FDG-PET, have both “simplified and improved the diagnostic process,” they explained. “As a result, more patients are diagnosed at an earlier stage, and long-term survival appears to have improved.”
Although immunosuppressive treatment is generally recommended for “clinically manifest, metabolically active CS, to reduce inflammation and prevent myocardial complications,” there is a scarcity of studies focused on immunosuppressive therapy, and the studies that have been conducted are “usually limited by size and retrospective design.”
As a result, they say the evidence-based guidelines for CS are currently lacking in terms of the use of second- and third-line agents and the duration of treatment, in addition to surveillance and prognostic factors. To learn more, they analyzed the clinical presentation, diagnostics, treatment, monitoring, and outcomes of 52 patients with CS.
Immunosuppressive treatment was delivered to 49 of the 52 patients for a median of 43 months, and the addition of second and third-line agents played a significant role in the overall course of the treatment regimen. Roughly 7 in 10 were treated with second-line (methotrexate, azathioprine, mycophenolate mofetil) and 1 in 4 with third-line (rituximab, infliximab) agents.
According to their findings, all patients survived during a median follow-up of 44 months. However, just 1 in 5 achieved complete remission, and the risk of major cardiovascular events (MACE) was substantial during the first year following CS diagnosis.
The researchers indicated that advanced cardiac imaging was essential for initial diagnosis and for treatment monitoring. They also concluded that “long-term immunosuppression including a liberal use of non-steroidal agents” appeared to be a crucial aspect of treating CS. However, they see a need for more research, and for prospective randomized studies in particular, to help arrive at the optimal form of treatment for CS patients.
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.