Cardiovascular Manifestations of Sickle Cell Disease

Nadjib Hammoudi; François Lionnet; Alban Redheuil; Gilles Montalescot


Eur Heart J. 2020;41(13):1365-1373. 

In This Article

Maladaptive Cardiac Remodelling

During the course of the disease, several mechanisms can lead to maladaptive cardiac remodelling and HF (Figure 2).

Figure 2.

Pathophysiological model of high-output heart failure in sickle cell disease. LV, left ventricle.

Chronic Volume Overload

As described in valvular heart disease such as mitral regurgitation, volume overload induces morphological cardiac remodelling and can be well tolerated for a long time.[23] However, chronic volume overload may cause progressive myocardial damages leading to exercise intolerance and HF.[23] In experimental models, iron deficiency anaemia induces LV dilation and hypertrophy together with increased cardiac angiogenesis as an adaptive mechanism. However, long-term severe anaemia leads to cardiac fibrosis, LV dysfunction, and congestion.[24] Compared to iron deficiency anaemia, SCD patients have a disproportional cardiac remodelling related to their haemoglobin level.[16,17,25] This could be partly explained by less efficient peripheral oxygen delivery due to abnormal haemoglobin nature and red blood cells rheology.[26]

Microvascular Dysfunction

Besides anaemia, microvascular dysfunction related to repeated vaso-occlusive events and nitrite oxide scavenging resulting from chronic intravascular haemolysis[25,27] can contribute to cardiac functional alteration in SCD. Consistently, a much more pronounced cardiac involvement was observed in a mice model of homozygous SCD as compared to animals with non-haemolytic anaemia (i.e. iron deficiency). The animals mimicking SCD progressively develop LVDD associated with diffuse myocardial fibrosis and features of chronic ischaemia at histopathology.[25] In humans, a correlation between haemolysis biomarkers, cardiac output, and LV remodelling was reported in several investigations,[12,15,28] and cardiac magnetic resonance (CMR) studies have confirmed an alteration of myocardial perfusion reserve suggesting abnormal microcirculation in SCD patients (Table 1).[29,30]

Focal myocardial fibrosis could be identified in up to a quarter of SCD patients, while myocardial infarct scars are rarely observed (Table 1 and Figure 3).[30] Using recent T1 mapping technique to investigate a small cohort of homozygous patients, a significant increase of extracellular volume fraction suggesting diffuse myocardial fibrosis was identified in all individuals.[31]

Figure 3.

Cardiac magnetic resonance in sickle cell disease. Steady state free precession cine imaging allows to visualize regional wall motion and precisely measure left ventricular volumes and mass using left ventricular endocardial (red) and epicardial (green) contours in (A) four-chamber and (B) short-axis views. T2* mapping image from multi-echo GRE sequence in short axis allowing the quantification of myocardial iron content (C). Small myocardial infarct seen as focal subendocardial late gadolinium enhancement localized in a mid-ventricular segment of the left ventricular lateral wall on a short-axis T1-weighted inversion recovery image acquired 10 min after contrast injection (D, arrow).

Iron Overload

Although iron cardiomyopathy is a leading cause of death in patients with thalassaemia major,[32] this complication appears to be uncommon in SCD patients, who generally require fewer transfusions. Moreover, the high level of effective erythropoiesis and chronic inflammation could mitigate iron overload in SCD.[33] Accordingly, recent CMR studies have found a very low prevalence of cardiac iron deposition, ranging from 0% to 3% (Table 1).[32,33]

Systemic Arterial Hypertension and Kidney Failure

There is a growing body of evidence showing that SCD subjects with systemic arterial hypertension face increased risk of stroke, LVDD, and early mortality.[19,30,36] Considering that SCD patients have generally lower blood pressure than reported normal values,[18,19] a mild increase in blood pressure (>130/80 mmHg) could reflect an alteration of systemic microcirculation.

Kidney failure is a common finding in patients with SCD affecting about one-third of adults, this complication is associated with higher mortality.[3,37] Renal dysfunction is linked to cardiac involvement and both organs damage shared common mechanisms[38] as chronic haemolysis and repeated sickling episodes promote microvascular alteration.[37,38] Chronic kidney failure, in a vicious circle, can lead to progressive myocardial and vascular damages. Therefore, further aggravating SCD-related cardiac remodelling and dysfunction.[39]