The apnea connection

PITTSBURGH—A recent study that explored the link between myocardial fibrosis and obstructive sleep apnea (OSA) could lead to more personalized therapies for cardiovascular disease. Yaron Fridman, the author of the study and cardiology fellow at the Heart and Vascular Institute of the University of Pittsburgh Medical Center, tells DDNews that his findings suggests that myocardial fibrosis could become a therapeutic target for patients with OSA.

“Cardiovascular magnetic resonance (CMR) measures of myocardial fibrosis may help us to identify those individuals with increased myocardial fibrosis and consequently at greatest risk for heart failure of death,” he says. “By developing medical therapies that are antifibrotic, we believe that targeting those individuals with increased myocardial fibrosis may improve cardiovascular outcomes. This technology allows us to precisely evaluate the nature of the myocardium in individual patients and personalize future antifibrotic therapies.”

Fridman’s study found that found that myocardial fibrosis correlated with adverse cardiovascular outcomes in patients with OSA who were referred for CMR. The study included 1,094 patients who had been referred for CMR because of known or suspected heart disease. Three hundred and twenty-four of these patients had OSA and 770 did not, while 16 healthy patients were included as a control group. Increased myocardial fibrosis was defined as an extracellular volume fraction (ECV) of 30 percent or greater.

“Since patients with cardiovascular disease are at two to three times higher risk of having OSA and OSA has been linked to myocardial fibrosis, we hypothesized that quantifying myocardial fibrosis in patients with OSA could aid in identifying those at increased risk of adverse cardiovascular outcomes,” Fridman says.

The high prevalence of pathological myocardial fibrosis in patients with OSA was the most striking finding of the study. Fridman tells DDNews there were several other aspects of the findings that surprised him, including the fact that an individual’s severity did not stratify the outcome and that patients with OSA who had higher myocardial fibrosis had significantly increased risk of adverse cardiovascular events in a dose-response relationship.

“Even after adjusting for clinically relevant variables, myocardial fibrosis improved stratification of cardiovascular risk in OSA, nearly doubling the risk of hospitalization for heart failure or death for every 5-percent increase in extracellular volume fraction,” says Fridman.

The prevalence of myocardial fibrosis in patients with suspected or known cardiovascular disease and OSA is unknown. Fridman tells DDNews that it is hypothesized that by causing chronic, intermittent hypoxia, OSA leads to increased sympathetic activity, endothelial dysfunction, systemic inflammation, oxidative stress and metabolic alterations, which ultimately promote myocardial fibrosis.

Fridman says his findings are particularly exciting because they identify a potential imaging biomarker for a pathological process occurring within the myocardium. He says that when there is myocardial fibrosis with abnormal extracellular matrix, the myocardium is less able to tolerate the vascular, ischaemic and hemodynamic insults seen in patients with OSA.

“CMR quantification of extracellular volume fraction now permits a noninvasive, histologically validated, method to quantify myocardial fibrosis,” he tells DDNews. “By using gadolinium, an extracellular contrast agent that passively equilibrates via diffusion throughout the extracellular space, the proportional uptake of gadolinium in the myocardium relative to plasma measures the extracellular volume fraction of the myocardium.”

In normal myocardium, the ECV is approximately 25 percent. In diseased and fibrotic myocardium, there is expansion of the extracellular matrix, causing the ECV to increase in proportion to disease severity. Fridman says that assessing ECV in patients referred for CMR has been shown to be an effective means of prognosis for adverse cardiovascular events.

“This is especially relevant since myocardial fibrosis is a reversible process,” says Fridman. “CMR quantification of myocardial fibrosis may present a unique opportunity for image-guided therapeutic intervention.”