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.
- Heart failure with preserved ejection fraction
- secondary pulmonary hypertension
- primary pulmonary hypertension
- myocardial disease basic science
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Correction notice Since this article was first published online, the middle initials of all authors have been added to their names.
Contributors All authors contributed to the manuscript draft, revisions and approval of the final version.
Funding This work was supported, in whole or in part, by the Institute for Transfusion Medicine (Vitalant) and National Institutes of Health Grants: R25 HL128640-03 (KW); R01 HL098032, R01 HL125886-01 and P01HL103455, T32 HL007563 (MG) and R01 HL133864, R01 HL128304 and AHA Established Investigator Award (AS).
Competing interests AS receives research support from Bayer Pharmaceuticals. MG is listed as a coinventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases and on provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning; the former has been licensed by United Therapeutics and the latter by Globin Solutions, Inc. MG is a coinvestigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with SCD.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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