Cardiovascular Manifestations of Sickle Cell Disease

Nadjib Hammoudi; François Lionnet; Alban Redheuil; Gilles Montalescot

Disclosures

Eur Heart J. 2020;41(13):1365-1373. 

In This Article

Left Ventricular Dysfunction

Clinical Presentation

Exercise intolerance, dyspnoea, and fatigue are the most frequent tell-tale symptoms of SCD-associated HF. These symptoms are not specific and could be related to multiple other causes including chronic anaemia. As observed in other aetiologies of high-output HF, SCD mainly leads to right-sided HF signs with increased jugular venous pressure, tender hepatomegaly, and peripheral oedema.[20,47] In one American cohort study, 11% of the patients had congestive HF,[5] however, contemporary data about the prevalence of this complication in SCD are still limited.

Several conditions increasing volume overload and systemic metabolic demand can promote cardiac decompensation in SCD. In particular, a close monitoring is required during pregnancy.[2]

Electrocardiogram

LV hypertrophy is the most frequently observed electrocardiographic abnormality in SCD patients.[48,49] Prolonged QTc involves around one-third of patients and has been attributed to myocardial alteration,[25,50] but it remains incompletely understood.[50] The possible association of prolonged QTc with mortality is still discussed.[5,50]

Palpitations, affecting from 15% to 37% of SCD patients,[48,49] can be partially explained by hyperdynamic state. Atrial fibrillation is relatively uncommon; and the prevalence of this arrhythmia was 2% in a large cohort of adult patients.[5] In a small study conducted more than 35 years ago, the risk of arrhythmia was increased during vaso-occlusive crises.[48]

Brain Natriuretic Peptides

An increased N-terminal pro-brain natriuretic peptide (NT-proBNP) level identifies a subgroup of SCD patients with increased risk of death.[51] High NT-proBNP shall lead to careful phenotyping looking for other evidence of LV dysfunction and alternative diagnosis such as pulmonary embolism or pre-capillary PH. Similar to patients with HF and preserved ejection fraction, a normal NT-proBNP level does not exclude HF at an early stage.[52]

Left Ventricular Systolic Dysfunction

A meta-analysis of 19 controlled case studies has shown similar LV ejection fraction (LVEF) in homozygous S patients compared to healthy controls.[53] Accordingly, the prevalence of an LVEF <50% is low, ranging from 0% to 2.5% in ultrasound cohorts studies[9,12] and 0% to 4% in smaller CMR studies[30–32] (Table 1 and Supplementary material online, Table S2). In most of the cases, the LVEF is mildly reduced, a value <35% is found in only 0.5% of patients.[28]

Considering the low prevalence of LV systolic alteration in SCD, a low LVEF should orient to an alternative explanation such an inherited cardiomyopathy or any toxic abuse including alcohol.[39] CMR imaging should be encouraged.

Left Ventricular Diastolic Dysfunction

LVDD is commonly reported and is linked to premature death in SCD patients.[36] In ultrasound studies, the prevalence varies widely with the characteristics of the studied patients and on the criteria used to define LV functional alteration (Supplementary material online, Table S2). For instance, some studies included only children while others included only adults or both. In addition, some authors have investigated patients in stable conditions, while other groups have also included patients who were evaluated at the time of vaso-occlusive crises.

Echocardiography is the most widely used method to evaluate LV diastolic function in clinical practice. The diagnosis algorithm of LVDD has been recently updated and is based on the analysis of four parameters including left atrial size, peak TRV, mitral inflow, and tissue Doppler analysis of mitral annulus motion.[54] These guidelines, which are mainly based on expert consensus with low prospective evidence,[55] have not been specifically evaluated in SCD patients in whom chronic high-output state complicates the ultrasound approach of LV diastole. Moreover, it is well established that the evaluation of diastolic function is more challenging in subjects with preserved LVEF,[54,56] which is the case in the majority of SCD patients.

It has been widely reported in the general population that left atrial enlargement was linked to LV diastolic function.[54] However, in SCD subjects the magnitude of left atrial remodelling due to volume overload could overshadow the additional contribution of increased LV filling pressures and left atrial size does not appear as the best index of chronic LVDD.[22,30] Accordingly, in a cohort of 127 adults with homozygous SCD, it has been shown that the left atrium was markedly enlarged; however, left atrial size was not related to LV diastolic function but to the severity and duration of SCD.[22]

Peak TRV as an index of systolic pulmonary pressure is also included in the diagnosis algorithm of LVDD.[54] However, an elevated TRV does not necessarily mirror pulmonary venous hypertension, it could also be related to high cardiac output or to pre-capillary PH.[21] This parameter should be interpreted with caution when used in assessing LV diastolic function.

Even though, the ratio of early diastolic transmitral velocity to tissue velocity (E/e') for estimation of LV filling pressure was not validated against invasive haemodynamic in SCD, this index was independently associated with poor exercise capacity in a large cohort of patients.[57] Moreover, using mitral inflow profile and E/e' ratio to categorize LV diastolic function (Supplementary material online, Table S3 and Figure 4), LVDD was associated with mortality in another study.[36] Waiting for further evidences, we think that this latter algorithm, which was specifically evaluated in SCD patients against prognosis, is probably the most appropriate approach of LV diastolic function in this population. Using this method, an LVDD is diagnosed in 15–20% of adult SCD patients.[22,36]

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