Sickle cell anemia (SCA) is a multisystemic disease characterized by acute episodes of pain and progressive lesions of target organs. It is one of the most common and most severe monogenic disorders in the world. In Brazil, it is estimated that 3500 children are born with sickle cell anemia each year, that is 1:1000 live births, and is thus a serious public health problem.1 Cardiovascular disease is a frequent clinical manifestation of people with sickle cell anemia.

Eccentric left ventricular hypertrophy (LVH), dilation of the chambers, biventricular dysfunction, pulmonary hypertension and myocardial ischemia are the principal findings.2–5 Patients with SCA frequently have severe anemia that results in increased cardiac output with minimal or no increase in cardiac frequency thereby causing dilatation of the left ventricle6 correlated to the hemoglobin (Hb) level.7,8 The dilated left ventricle adapts to the chronic volume overload by hypertrophy, thickening the heart muscle and stretching the myofibrils of the muscle. Hypertrophy allows the left ventricle to adapt to the chronic volume overload, initially preserving diastolic compliance and maintaining the filling pressure at normal levels.9 The literature shows that LVH is a common condition in sickle cell anemia after the second decade of life.10 Diagnosed by transthoracic Doppler echocardiography, the prevalence of LVH varies between 13 and 86%.7,10–14 In chronic cases, LVH presents with diastolic3,15,16 and systolic dysfunction.3,15

Given the high morbimortality, the present article aimed to estimate the frequency of LVH in children, adolescents and young adults with sickle cell anemia and determine variables associated to this condition.

The results were analyzed using the Statistical Package for the Social Sciences for Windows version 17.0 (SPSS, Chicago IL). Categorical variables were analyzed using the chi-squared distribution or Fisher's exact test. The Student's t-test or Mann–Whitney test were used to compare numerical variables between the groups. A logistical regression model was used to evaluate the protective effect of hydroxyurea after the elimination of possible confusing variables. The level of significance was set for p-values <0.05.

One hundred and nine patients with SCA were studied; 56 (51.4%) were male. SCA was diagnosed at a mean age of 69.28±46.09 months and LVH was present in 41 (37.6%) patients. The mean age, and the proportions of Hb S and Hb F were similar between patients with or without LVH. The main complications resulting from SCA were acute chest syndrome (69.2%), cholelithiasis (34%), stroke (15.1%) and leg ulcers (15.1%). Patients presented on average 0.84±1.31 episodes of hospitalization/year and 0.66±1.13 pain crises that required hospitalization/year and received 1.22±2.32 units of packed red blood cells/year; there were no significant differences in respect to these variables between the two groups. Hydroxyurea was continuously used by 17.6% of the 109 patients, 7.5% in the group with LVH and 24.2% in the group without LVH (p-value=0.02). The duration of hydroxyurea use was similar between the two groups (Table 1).

Patients with LVH presented greater LVDD, LVSD, end diastolic thickness of the IVS, end-diastolic thickness of the LVPW and larger diameters of the aortic root and of the left atria. End-diastolic volume, ejection fraction and the systolic shortening fraction were similar between the two groups (Table 2).

The group with LVH presented lower Hb levels (7.65±1.39g/dL vs. 8.46±1.70g/dL; p-value=0.01), hematocrit concentrations (21.94±3.41% vs. 25.26±5.49%; p-value=0.001), reticulocyte index (1.23±0.75 vs. 1.97±1.52; p-value=0.02) and a higher 24-h albumin:creatinine ratio in urine (97.92±217.83mg/dL vs. 27.60±43.51mg/dL; p-value=0.01). Hemolysis markers (lactate dehydrogenase, indirect bilirubin and ferritin) and creatinine clearance were statistically similar in both groups (Table 3). The logistic regression model did not confirm any protective effect of hydroxyurea in this sample.

LVH was present in 37.6% of the patients included in the study. There was no difference between groups with respect to clinical, demographic or pathological aspects, with a possible exception for the use of hydroxyurea. Patients with LVH had a larger left atria index for body surface and lower hemoglobin and hematocrit levels, and reticulocyte index and higher 24-h albumin:creatinine ratio in urine. Markers of hemolysis (lactic dehydrogenase, indirect bilirubin and ferritin) and creatinine clearance were uniformly high in both groups. Using echocardiography, previous studies have shown that LVH is a common condition of SCA adults8,9 with a prevalence that ranges between 13 and 86%, a variation related to the different criteria used in the studies.7,10–14 Anatomopathological studies show frequencies for LVH of 20–100% in SCA patients.21 Sickle cell disease patients have higher rates of left ventricular mass when compared to Hb S heterozygotes, patients with iron deficiency anemia and healthy patients.2,8

In this study, no significant difference was identified between the groups with respect to age and age at diagnosis. Several authors have shown that LVH is directly related to the age3,7,8,15 whereas another study10 showed that LVH is much more common in young people. Moreover, other authors did not find any difference in age among patients with or without hypertrophy.12 There was no statistical difference regarding the percentage of Hb S and Hb F at diagnosis between the groups in this study. A previous study showed a directly proportional relationship between left ventricular mass and Hb S levels,7 but not with Hb F.11,22

The continued use of hydroxyurea was a protector against LVH in the bivariate analysis, but the logistic regression model did not confirm this finding, which may be related to the sample size. There is no reference in previous studies regarding association between LVH and leg ulcers, cholelithiasis, stroke, priapism or acute chest syndrome. Although statistically similar between groups, the numerical difference can be considered, as these were the most common morbidities in patients without LVH, perhaps because of a ‘shield’ effect given by a possible higher frequency of blood transfusions. Likewise, patients with histories of stroke, priapism and acute chest syndrome constitute the group with classical indication for the use of hydroxyurea, which also contributes to increased levels of hemoglobin and a proportionate decrease in Hb S, previously demonstrated as being directly related to increases in left ventricular mass in SCA patients. The left atrium, a potential marker of diastolic dysfunction, was significantly larger in patients with LVH, a result consistent with previous studies.13,14 Systolic pulmonary artery pressure was similar between the groups in this study, thereby disagreeing with the literature.14,23

LVH is inversely related to the hemoglobin concentration, which is consistent with previous studies.7,8,12 The reticulocyte index, lower in patients with LVH, may signal bone marrow exhaustion. Markers of hemolysis (lactic dehydrogenase, indirect bilirubin and ferritin) and creatinine clearance were uniformly high in both groups, possibly due to the predominant haplotype in Brazil, Bantu, which is associated with the most severe disease.24 Previous studies showed that patients who more often received red blood cell transfusions had lower left ventricular masses,12,25 similar to data found in the present study, in which numerical, albeit non-significant, differences were observed. LVH was not associated to ferritin levels, similar to a previous study.12 In one study patients with LVH had a higher mean 24-h albumin:creatinine ratio in urine, with similar glomerular filtration rates between the two groups.12 Patients were described as chronically anemic, with established renal impairment, dilation of the left ventricle and LVH in another study,26 reinforcing the difference found in the albumin:creatinine ratio, although there was no relation to the glomerular filtration rate. This is possibly due to the state of hyperfiltration, characteristic of early renal injury in SCA patients. In one study cardiac remodeling was prevented with the use of enalapril in nine SCA patients.27 Although the association of increased left ventricular mass and diastolic dysfunction is related to hypertension in the general population, in SCA patients this association is due to a combination of compensatory hypertrophy of the left ventricle, secondary anemia and left ventricular dilatation along with systemic vasculopathy. Direct myocardial injury and microvascular disease by iron deposition have been postulated as possible etiologies for cardiac abnormalities.17 The dilated left ventricle allows an adaptation to chronic volume overload, initially preserving diastolic compliance and maintaining filling pressures normal.28 Chronic LVH evolves to left ventricular diastolic3,15,17 and systolic dysfunction3,15 and has been described as a cause of sudden death in SCA patients.10

This study presents limitations. The criteria used to define LVH are designed for more ethnically homogeneous populations. Moreover, arterial blood pressures were not evaluated. The low number of patients using hydroxyurea may have interfered in the adequate analysis of a possible protective role.

Young SCA patients in this study had a high prevalence of LVH (37.6%); this was associated with lower hemoglobin and hematocrit levels and reticulocyte index and a higher albumin:creatinine ratio.

The authors declare no conflicts of interest.