Left Sided Heart Dysfunction in Sickle Cell Disease: Echocardiographic and Genetic Studies.
Authors: De Castro Laura M. , Jonassaint Jude C. , Telen Marilyn J. 
Published: April 2020

Abstract
The moderate to severe anemia associated with sickle cell disease (SCD) causes a high output state that can lead to cardiomyopathy, decompensation and left heart failure. While at least one report suggested that chronic high output and volume overload are relatively well tolerated in SCD, other studies have suggested that congestive heart failure and other cardiac abnormalities may occur in more than 50% of adults. The incidence of sudden death is also increased and may be as high as 40% in adults with SCD. Several types of left ventricular (LV) dysfunction are associated with sudden death in other populations, although an association of LV disease and sudden death in SCD has not been studied. For these reasons, and also based on the clinical observation that SCD patients frequently experience transient episodes of clinical congestive heart failure (especially when receiving intravenous fluids during vaso-occlusive episodes), we sought to document the frequency with which left-sided cardiac dysfunction existed in our patient population. We performed a retrospective review of resting echocardiograms to quantitate multiple parameters of cardiac function in patients either homozygous for hemoglobin S or with Sβ0 thalassemia. 116 patients had had at least one echocardiogram performed (55 females, mean age 37, range 13–71; 61 males, mean age 32, range 16–62). 31% of these patients (mean age 41) had left ventricular hypertrophy (LVH), defined as a left ventricular mass index ≥134 and ≥110 g/m2 for men and women, respectively, and 22% (mean age 35) had left ventricular enlargement. Of the 36 patients with LVH, 27 had mild LVH, and 9 had moderate-severe LVH. Presence and severity of LVH were significantly related to mean arterial blood pressure (p=0.004), even though most patients were not hypertensive. Mean arterial pressures were also related to posterior LV wall thickness (p&lt;0.0001), and baseline hemoglobin level was inversely associated with posterior wall thickness (p=0.0001). In addition, 53% had left atrial (LA) enlargement, 9% had mild-moderate aortic valve regurgitation, and 37% had mild-moderate mitral valve regurgitation (MR), with an additional 45% having trivial MR. Of all 116 patients studied, 61% (mean age 41, range 21–66) had pulmonary hypertension (pHTN), as indicated by a reported tricuspid regurgitant jet velocity of ≥2.5 m/s. In the patient group with LV enlargement, 75% of patients had pHTN, while of patients with LVH, 77% had pHTN. LA enlargement was also significantly more common in patients who had pHTN (p=0.002). While only 10% of patients had an ejection fraction below 55%, 37% (mean age 37) had fractional shortening (FS) less than 0.30. This suggests the presence of limited cardiac reserve in relatively young patients, as decreased FS is generally a finding that precedes a decrease in cardiac output. We have also begun to identify genetic polymorphisms that are associated with cardiac dysfunction. Two polymorphisms in the β2 adrenergic receptor gene were associated with either LA enlargement (rs1042713, p=0.02) and/or presence of LVH or LV enlargement (rs1042713, p=0.001; rs1042717, p=0.04). Polymorphisms of the adenylate cyclase 6 gene were also associated with LA enlargement (hcv1244841, p=0.02) and LV function as measured by FS (rs370070, p=0.01). In summary, these data demonstrate the significant prevalence of left-sided cardiac dysfunction in SCD. We hypothesize that these abnormalities contribute to progressive physical limitations, as well as sudden death. The pathophysiology of high output heart failure in this setting therefore merits considerable further study.