For years, clinicians and scientists have seen the frequency of heart attacks increase during flu season. However, little clinical evidence exists to explain the fatal phenomenon.
Now, researchers at Mount Sinai Hospital have had a breakthrough that alludes to the underlying mechanisms of the situation. They recently identified a cellular mechanism that acts as the “Trojan horse” of the immune system during influenza infection—becoming infected in the lung, trafficking the virus to the heart and disseminating it to cardiomyocytes. This now-revealed process links infections from influenza A viruses to cardiovascular disease, providing critical insights on how influenza can damage the heart and increase the risk of a heart attack or other major cardiovascular event.
For the new study, published in Immunity, the Mount Sinai team studied autopsies of 35 hospitalized patients who died of influenza and found that more than 85 percent had at least one significant cardiovascular comorbidity, such as hypertension. Additionally, the majority of the patients had multiple comorbidities, including atherosclerosis and cardiac fibrosis.
In these cases, the research data pointed to a novel subset of white blood cells—known as pro-dendritic cell 3—that becomes infected in the lung and, after traveling to the heart, produces large amounts of type 1 interferon. Essentially, pro-dendritic cell 3 does the opposite of its normal function—instead of clearing the influenza virus from the heart, it triggers the death of cardiomyocytes.
In a proof-of-concept study for a possible treatment, the Mount Sinai researchers directly injected a modified mRNA therapeutic that modulates the type 1 interferon signaling pathway. They saw reduced levels of cardiac damage, as evidenced by lower troponin, and improved cardiac function, as measured by higher left ventricular ejection fraction.
Although the proof-of-concept was a success, the team is now investigating a systemic delivery method of the modified RNA therapeutic to the heart’s muscle cells, instead of direct injection. Additional work is focused on the pro-dendritic cell 3 itself: why is it so susceptible to influenza and how could its protective capacity be fully harnessed to potentially minimize heart damage exacerbated by cardiovascular disease?
Influenza A viruses are responsible for an estimated 1 billion infections globally each year, ranging from seasonal flu outbreaks locally to pandemics globally.
“Pathogens are constantly emerging and evolving, which means our strategies to combat them must evolve as well,” said senior author of the study Filip Swirski, director of the Cardiovascular Research Institute at the Icahn School of Medicine at Mount Sinai. “Better understanding of influenza pathogenesis and immune pathways that are activated throughout the body will help fuel the next stage of advanced care.”