Cardiovascular abnormalities in sickle cell disease

Abstract

Sickle cell disease is characterized by recurrent episodes of ischemia-reperfusion injury to multiple vital organ systems and a chronic hemolytic anemia, both contributing to progressive organ dysfunction. The introduction of treatments that induce protective fetal hemoglobin and reduce infectious complications has greatly prolonged survival. However, with increased longevity, cardiovascular complications are increasingly evident, with the notable development of a progressive proliferative systemic vasculopathy, pulmonary hypertension (PH), and left ventricular diastolic dysfunction. Pulmonary hypertension is reported in autopsy studies, and numerous clinical studies have shown that increased pulmonary pressures are an important risk marker for mortality in these patients. In epidemiological studies, the development of PH is associated with intravascular hemolysis, cutaneous leg ulceration, renal insufficiency, iron overload, and liver dysfunction. Chronic anemia in sickle cell disease results in cardiac chamber dilation and a compensatory increase in left ventricular mass. This is often accompanied by left ventricular diastolic dysfunction that has also been a strong independent predictor of mortality in patients with sickle cell disease. Both PH and diastolic dysfunction are associated with marked abnormalities in exercise capacity in these patients. Sudden death is an increasingly recognized problem, and further cardiac investigations are necessary to recognize and treat high-risk patients.

Figure 1. Mechanisms of hemolytic anemia in reducing NO bioavailability and association with vasculopathic sub-phenotypes of sickle cell disease

Hemolysis releases cell-free plasma hemoglobin and arginase 1 into plasma, which catabolize NO and L-arginine. Activation of vascular oxidases, such as xanthine oxidase, NADPH oxidase and uncoupled eNOS, generate superoxide which scavenges NO. Hemolytic anemia and reduced NO bioavailability are associated with vasculopathic clinical complications in SCD patients.

Figure 2. Mechanisms of pulmonary hypertension in SCD patients

A pulmonary vessel with severe intimal and smooth muscle proliferation is shown from a 35 year old patient with SCD who died suddenly with known PAH. Mechanisms that contribute to the development of PH identified in animal and human studies are summarized.

Figure 3. Sensitivity and specificity analysis of diastolic dysfunction measures in SCD patients

Receiver operating characteristic curve for tissue Doppler lateral E/e′ ratio to predict a pulmonary capillary wedge pressure>15mmHg by cardiac catheterization within 72 hours in SCD patients.

Figure 4. This echocardiographic image (apical 4-chamber view) from a SCD patient admitted with acute chest syndrome shows a dilated, dysfunctional right ventricle

A movie image of this patient’s echocardiogram is available on-line.