August 31, 2017
3 min read

Diffuse myocardial fibrosis may predict diastolic dysfunction in sickle cell anemia

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Omar Niss

Diffuse myocardial fibrosis, a common feature in sickle cell anemia, predicted the development of diastolic dysfunction, according to an observational study published in Blood.

Even in the absence of focal fibrosis, extracellular volume fraction appeared markedly increased in all study participants, including young children.

“Cardiac disease is a major cause of morbidity and mortality in adults with sickle cell disease,” Omar Niss, MD, assistant professor of pediatric oncology at Cincinnati Children’s Hospital Medical Center, told HemOnc Today. “However, the cause of diastolic dysfunction in humans with sickle cell disease is not known.”

Diastolic dysfunction, pulmonary hypertension and increased N-terminal pro-brain natriuretic peptide — a marker of myocardial wall stress and cardiac dysfunction — all are associated with early mortality in sickle cell anemia.

To test their hypothesis that diffuse myocardial fibrosis underlies the diastolic dysfunction of sickle cell anemia-related cardiomyopathy, researchers measured the presence and extent of diffuse myocardial fibrosis in 25 patients (median age, 19 years; 56% female) with sickle cell anemia.

“We previously found that mice with sickle cell disease develop patchy myocardial fibrosis, but we did not know if similar pathology exists in humans,” Niss said.

Investigators defined the relationship between extracellular volume fraction (ECV) and diastolic dysfunction. They also monitored study participants for adverse events.

ECV appeared markedly increased in all patients with sickle cell anemia compared with controls (0.44 ± 0.88 vs. 0.26 ± 0.02; P < .001), indicating the presence of diffuse myocardial fibrosis. Additionally, patients with sickle cell anemia demonstrated significantly increased native T1 values (1008 ms ± 67 vs. 942 ± 25 ms, P < .001), which also correlate with collagen volume fraction.

Participants with higher ECV ( 0.40) had higher native T1 values (P = .005), lower hemoglobin (P = .02) and, higher left ventricle stroke volume index (P = .04). They also appeared more likely to have left ventricle diastolic dysfunction (P = .03).

These data demonstrate that myocardial fibrosis, left ventricle diastolic dysfunction, and severe anemia are concordant with sickle cell anemia.

Most participants (68%) had left atrial enlargement and ventricular enlargement (left ventricle, 72%; right ventricle, 56%), and 76% of participants had increased cardiac index due to chronic anemia.

“We found that diffuse myocardial fibrosis is common in individuals with sickle cell disease and strongly correlates with diastolic dysfunction,” Niss said. “The severity of diffuse myocardial fibrosis in sickle cell anemia exceeds most other forms of cardiomyopathies. Diffuse myocardial fibrosis is a novel mechanism underlying diastolic dysfunction and the cardiomyopathy of sickle cell anemia.”


One participant reported a grade 2 reaction (nausea, vomiting) to contrast administration. Three participants with a history of recurrent vaso-occlusive episodes experienced painful events 3 to 24 days after cardiac magnetic resonance that resolved without sequelae.

Niss and colleagues determined ECV was significantly associated with acute transfusions, but not with the number of painful events or acute chest syndrome. Researchers observed no association between ECV and systolic blood pressure, diastolic blood pressure, baseline heart rate, baseline oxygen saturation, or pulse pressure. Results showed no significant differences in EVC measurements between males and females.

“Myocardial fibrosis is associated with worse cardiac outcome in other diseases and predisposes to heart failure and arrhythmias,” Niss said. “The severity of diffuse myocardial fibrosis in sickle cell disease and its association with diastolic dysfunction, a known risk factors for mortality in sickle cell disease, suggest that diffuse myocardial fibrosis can also be associated with poor outcomes in sickle cell disease.”

Researchers acknowledged limitations of their study, including their difficulty classifying diastolic dysfunction in children. Eight of 10 participants with inconclusive classification were aged younger than 21 years.

“Because of the relatively small sample size, our study was not powered to identify correlates of diffuse myocardial fibrosis,” Niss said. “Larger studies are needed to better assess the association between diffuse myocardial fibrosis and different clinical outcomes in patients with sickle cell anemia.”

In two separate studies, researchers at Cincinnati Children’s Hospital Medical Center are investigating the specific pathways that lead to diffuse myocardial fibrosis in patients with sickle cell anemia, along with available therapies such as hydroxyurea and transfusions.

“Identifying the specific mechanisms behind fibrosis can lead to targeted therapies to reverse or stop the progression of myocardial fibrosis,” Niss said. – by Chuck Gormley

For more information: Omar Niss , MD, can be reached at

Disclosures: The NIH-NHLBI Excellence in Hemoglobinopathy Research Award program supported the study. The researchers report no relevant financial disclosures.