Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia

Abstract

Sickle cell anemia (SCA)-related cardiomyopathy is characterized by diastolic dysfunction and hyperdynamic features. Diastolic dysfunction portends early mortality in SCA. Diastolic dysfunction is associated with microscopic myocardial fibrosis in SCA mice, but the cause of diastolic dysfunction in humans with SCA is unknown. We used cardiac magnetic resonance measurements of extracellular volume fraction (ECV) to discover and quantify diffuse myocardial fibrosis in 25 individuals with SCA (mean age, 23 ± 13 years) and determine the association between diffuse myocardial fibrosis and diastolic dysfunction. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and diastolic function was assessed by echocardiography. ECV was markedly increased in all participants compared with controls (0.44 ± 0.08 vs 0.26 ± 0.02, P < .0001), indicating the presence of diffuse myocardial fibrosis. Seventeen patients (71%) had diastolic abnormalities, and 7 patients (29%) met the definition of diastolic dysfunction. Participants with diastolic dysfunction had higher ECV (0.49 ± 0.07 vs 0.37 ± 0.04, P = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, P = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, P = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction (P = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m², P = .04) compared with those with ECV <0.4. ECV correlated with hemoglobin (r = -0.46, P = .03) and NT-proBNP (r = 0.62, P = .001). In conclusion, diffuse myocardial fibrosis, determined by ECV, is a common and previously underappreciated feature of SCA that is associated with diastolic dysfunction, anemia, and high NT-proBNP. Diffuse myocardial fibrosis is a novel mechanism that appears to underlie diastolic dysfunction in SCA.

Figure 1.

Study design. Scheme of study enrollment, grouping, and final evaluable participants.

Figure 2.

Increased myocardial extracellular volume fraction and native T1 in sickle cell anemia. Scatterplots showing increased (A) ECV and (B) native T1 in SCA compared with normal controls. Dotted lines represent the reported lower and upper normal limits. (C) Bar graph demonstrating the mean ECV values in previously published studies of fibrotic heart diseases (shown in green),^- in comparison with normal controls (shown in blue) and SCA patients in this study (shown in red). Dashed line represents the upper limit of normal. CMP, cardiomyopathy; MI, myocardial infarction; TM, thalassemia major (+iron, indicates presence of myocardial iron overload).

Figure 3.

Associations among ECV, diastolic dysfunction, and markers of restrictive physiology. Box-and-whisker plots showing differences in (A) ECV, (B) hemoglobin, (C) LAVi, (D) LVEF, and (E) NT-proBNP between participants with diastolic dysfunction and normal diastolic function (normal). (F) Difference in TRV between participants with diastolic dysfunction and normal diastolic function. Participants >21 years are shown in green. P value for the difference in the overall group is shown in black, and P value for the difference among participants >21 years is shown in green. Each box in panels A-F extends from the 25th to 75th percentile, and the line in the box is plotted at the median while the whiskers extend from the smallest to the largest value. (G-I) Linear regression of ECV and (G) lateral E/e′ ratio, (H) tricuspid E/A ratio, and (I) log-NT-proBNP.