Identifying Causes of Cardiomyopathy in Patients With Sickle Cell Anemia

Author’s Perspective

Lead author Omar Niss, MD: “Diffuse myocardial fibrosis is a common finding and a newly recognized mechanism of heart disease in sickle cell anemia (SCA). Myocardial fibrosis is associated with worse cardiac outcomes in other diseases, including increased risk for heart failure, dysrhythmia, and sudden death. The severity and extent of diffuse myocardial fibrosis in SCA and its association with diastolic dysfunction – a known risk factor for mortality in SCA – suggest that diffuse myocardial fibrosis can also be associated with poor outcomes in SCA. Understanding the pathways that cause myocardial fibrosis and eventually preventing or therapeutically targeting fibrosis may be beneficial in ameliorating cardiac disease in SCA.”

Cardiac disease is a leading cause of mortality and morbidity in patients with sickle cell anemia (SCA). Mouse studies have revealed that diastolic dysfunction is associated with microscopic myocardial fibrosis, abnormal electrophysiology, and transcriptome changes; however, these associations are untested in humans.

In a prospective, longitudinal cardiac magnetic resonance imaging (CMR) study published in Blood, Omar Niss, MD, of the Division of Hematology at the Cincinnati Children’s Hospital Medical Center, and co-authors found that diffuse myocardial fibrosis is a common feature in patients with SCA that “appears to predate the development of diastolic dysfunction.”

The study enrolled 25 patients (median age = 19 years; range = 6-61 years; 56% female) between 2014 and 2015. Patients were included if they could undergo CMR and echocardiography without sedation and were excluded if they were receiving chronic transfusion therapy, had ventricular septal defect, or had an estimated glomerular filtration rate of <60 mL/min/1.73 m2.

Researchers assessed extracellular volume fraction (ECV) via pre- and post-gadolinium T1 measurements of blood and myocardium as a measure of myocardial fibrosis, and they assessed diastolic function via echocardiography. Patients’ T1 and ECV results were compared with a control cohort of 16 healthy individuals without SCA who had normal values (median age = 15.2 years; range not provided).

ECV was “markedly increased” in the study patients compared with controls (0.44±0.08 vs. 0.26±0.02; p<0.0001), “indicating the presence of diffuse myocardial fibrosis,” the authors wrote. T1 values were also significantly increased in the study patients compared with controls (1,008±67 vs. 942±25 ms; p<0.001) which also indicates fibrosis.

Seventeen patients (71%) had diastolic abnormalities, seven of whom (29%) met the definition of diastolic dysfunction (per guidelines from the American Society of Echocardiography), according to the authors. Compared with patients with normal diastolic function, those with diastolic dysfunction had:

  • higher ECV (0.37±0.04 vs. 0.49±0.07; p=0.01)
  • higher N-terminal pro-brain natriuretic peptide (NT-proBNP; 33±33 vs. 191±261 pg/mL; p=0.04)
  • lower hemoglobin (10.9±1.4 vs. 8.4±0.3 g/dL; p=0.004)

Patients with the highest ECV values (≥0.40) were more likely to have left ventricular diastolic dysfunction (p=0.003) and increased left atrial volume (57±11 vs. 46±12 mL/m2; p=0.04), compared with those with ECV <0.40. Higher ECV values also correlated with lower hemoglobin levels (p=0.02) and higher NT-proBNP levels (p=0.04).

More severe anemia also was associated with myocardial fibrosis (higher ECV [p=0.03] and higher native T1 [p=0.003]).

The researchers did not observe an association between ECV and systolic blood pressure (p=0.24), diastolic blood pressure (p=0.17), baseline heart rate (p=0.84), baseline oxygen saturation (p=0.89), or pulse pressure (p=0.27). Patient sex also did not affect ECV measurements (p=0.17).

No deaths were reported during the study.

The study is limited by its small patient population. Larger studies are needed to confirm any associations. “In addition, the metric used to express diffuse myocardial fibrosis in our study (ECV) represents an average value for diffuse fibrosis in the whole myocardium; therefore, it does not inform about regional variations if present,” Dr. Niss told ASH Clinical News.

The authors also could not determine the exact cause of ECV elevation in a subset of young SCA patients, but they proposed that “SCA-related tissue injury causing inflammation and edema are possible early factors that contribute to increased ECV in some individuals that eventually culminate in tissue fibrosis.”

The authors noted that their institution is conducting a longitudinal study to evaluate the progress of diffuse myocardial fibrosis in SCA.

Source: Niss O, Fleck R, Makue F, et al. Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia. Blood. 2017 May 15. [Epub ahead of print]

Disclosures: The authors report no relevant financial disclosures.