Brigham researchers are tackling long COVID from every angle, addressing critical questions about how the condition affects such wide-ranging aspects of health and laying the groundwork for preventing and treating symptoms. This story is part of a new, special series about collaborative research efforts underway across Mass General Brigham.

Masanori Aikawa

Acute infection with COVID-19 can damage the heart, causing arrhythmia, myocarditis, heart failure and more. While long-term cardiovascular outcomes for patients who have had COVID-19 are still being studied, there is already evidence that infection may have lingering effects on the heart — part of the constellation of symptoms that make up long COVID. Long COVID goes by many names and its definition continues to evolve, but generally refers to signs, symptoms and conditions that continue or develop after initial COVID-19 or SARS-CoV-2 infection.

In a study that followed more than 150,000 individuals with COVID-19, researchers at Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care System found that beyond the first 30 days of infection, individuals who had COVID-19 were at increased risk for a span of cardiovascular diseases. The risk was elevated even among participants who had not been hospitalized during the acute phase of infection.

Spurred by these observations, Masanori Aikawa, MD, PhD, director of the Center for Interdisciplinary Cardiovascular Science (CICS), and his co-investigators at the Brigham and Massachusetts General Hospital are working to characterize vascular long COVID-19. The team is led by Aikawa and co-principal investigators Bruce Levy, MD, of the Brigham’s Pulmonary Division, and Antonis Armoundas, PhD, of MGH’s Cardiovascular Research Center. Together, they will use machine learning to analyze clinical information from electronic health records and biospecimens to characterize patients who have vascular complications after acute COVID-19 infection (known as post-acute sequelae of COVID, or PASC).

“Despite the high clinical burden, our knowledge of the clinical course and mechanisms of vascular PASC remains limited,” said Aikawa. “Our goals are to gain insight into why these sequalae occur and find biomarkers associated with them. If we can identify potential mediators, those might provide us with therapeutic targets to prevent the onset of vascular long COVID.”

Searching for Clues

Biomarkers — telltale molecules that may correlate with or be part of the chain of events leading to disease — can serve as critical tools for both prediction and drug development. But to find them, Aikawa and his colleagues needed to look in vascular tissue, which can only come from deceased donors.

“We heavily rely on technologies like artificial intelligence for understanding complex human diseases, but without histology and pathology — without the precious tissue that can only come from deceased donors — we would not be able to find the answers,” said Aikawa.

This is why Aikawa and colleagues from the CICS are working closely with the RECOVER Autopsy Cohort Central Biorepository, a national initiative to collect tissue samples from deceased donors. Local efforts are being led by James R. Stone, MD, PhD, of the Department of Pathology at Mass General, and Robert Padera, MD, PhD, of the Department of Pathology at the Brigham, who are enrolling participants and collecting samples from autopsies. Stone works with patients and their families to explain how donors can help shed light on many aspects of long COVID.

“It’s extremely delicate to approach a family about participating in a research project like this one,” said Stone. “But it’s also so important. We talk to family members about the positive impact that a donor can have in helping us understand long COVID and solving its many mysteries. In some cases, we’ve had families who have initially declined a routine autopsy, but, when we talk with them about the context of this study, they’ve said yes.”

An Eye Toward Clinical Impact

As part of the RECOVER Autopsy Cohort, seven sites across the country intend to perform 700 autopsies, cumulatively, in the four years of the study. Stone’s team has had a high rate of success — since the work began last year, MGH has had highest percentage enrollment of any site in the country based on their target enrollment, with 40 percent of their target already enrolled.

Aikawa’s team aims to get as much information as possible from the samples provided by the Autopsy Cohort. They will compare biospecimens from long COVID patients experiencing vascular symptoms with samples from patients with vascular symptoms who did not have COVID-19. Integrating many types of data, the team will use proteomics and single cell RNA-sequencing to identify key molecules unique to vascular PASC. The samples will include aorta and coronary arteries from the RECOVER Autopsy Cohort.

“I’m proud of our highly innovative team and that we are working across disciplines to apply the most advanced technologies and computational methods to try to produce a clinical impact for patients with COVID,” said Aikawa. “The samples collected through the RECOVER Autopsy Cohort’s efforts, combined with our multidisciplinary approach, may help us gain insights that otherwise would have never been possible.”

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