Sickle cell disease: at the crossroads of pulmonary hypertension and diastolic heart failure

Abstract

Sickle cell disease (SCD) is caused by a single point mutation in the gene that codes for beta globin synthesis, causing haemoglobin polymerisation, red blood cell stiffening and haemolysis under low oxygen and pH conditions. Downstream effects include widespread vasculopathy due to recurring vaso-occlusive events and haemolytic anaemia, affecting all organ systems. Cardiopulmonary complications are the leading cause of death in patients with SCD, primarily resulting from diastolic heart failure (HF) and/or pulmonary hypertension (PH). HF in SCD often features biventricular cardiac hypertrophy and left ventricular (LV) diastolic dysfunction. Among HF cases in the general population, approximately half occur with preserved ejection fraction (HFpEF). The insidious evolution of HFpEF differs from the relatively acute evolution of HF with reduced ejection fraction. The PH of SCD has diverse origins, which can be pulmonary arterial (precapillary), pulmonary venous (postcapillary) or pulmonary thromboembolic. It is also appreciated that patients with SCD can develop both precapillary and postcapillary PH, with elevations in LV diastolic pressures, as well as elevations in transpulmonary pressure gradient and pulmonary vascular resistance. Regardless of the cause of PH in SCD, its presence significantly reduces functional capacity and increases mortality. PH that occurs in the presence of HFpEF is usually of postcapillary origin. This review aims to assemble what has been learnt from clinical and animal studies about the manifestation of PH-HFpEF in SCD, specifically the contributions of LV diastolic dysfunction and myocardial fibrosis, in an attempt to gain an understanding of its evolution.

Biomarkers of clinical severity in treated and untreated sickle cell disease: a comparison by genotypes of a single center cohort and African Americans in the NHANES study

“…Our study showed a markedly lower percent predicted of FEV1 and FVC in severe but not mild SCD genotypes compared to matched NHANES controls. Risk for developing pulmonary hypertension in SCD correlates with steady‐state severity of haemolysis and anaemia 18,30 . Whereas our study demonstrated a difference in haemolysis markers between the severe and mild genotype groups, it failed to show a difference in the TRV, a noninvasive marker of systolic pulmonary artery pressure 31–33 .…”

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

“…Although platelets and red blood cells display important roles in pulmonary hypertension associated with hypoxic, thromboembolic or hematologic diseases [ 176 , 177 , 178 ], their contribution to PH pathophysiology remains poorly understood. Both cell types may interfere with disease progression and RV dysfunction because they impair pulmonary hemodynamics and promote cardiovascular remodeling [ 179 ].…”

Chronic organ injuries in children with sickle cell disease

“…26 Prevalence in adults with SCD ranges from 10% to 33% when measured by right heart catheterization (RHC) or echocardiography, respectively. 24 Pulmonary artery systolic pressure (PASP) is assessed on echocardiography by the quantification of the tricuspid regurgitant jet velocity (TRV) using the modified Bernoulli equation. Raised TRV was shown to be a risk factor for death in adults.…”