Left Ventricular Diastolic Dysfunction in Youth with Sickle Cell Disease: Evaluating Genotypic Differences and Effects of Hydroxyurea

Q: What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Sickle cell disease (n=196). Intervention: Hydroxyurea vs. No hydroxyurea. Primary outcome: Left ventricular diastolic dysfunction (defined as a diastolic aggregate score >= 2 of 5 echocardiographic parameters) (OR 1.01, 95% CI 0.55, 1.87, p=>0.9).

Q: What does this research mean for the field?

Hydroxyurea therapy is associated with significantly lower odds of left ventricular diastolic dysfunction in youth with the HgbSS genotype of sickle cell disease. Novelty: ClaimNovelty.CONTRADICTORY. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

Chukwuemeka Igwe; Isaac S. Kistler; Christopher Schmitt; Chance Alvarado; Susan Elizabeth Creary; Megan E. Gunsaulus; Amulya Buddhavarapu; Kan N. Hor; Hannah Jacobs

doi:10.1007/s00246-026-04534-3

November 3, 2026Pediatric CardiologyOpen Access

Left Ventricular Diastolic Dysfunction in Youth with Sickle Cell Disease: Evaluating Genotypic Differences and Effects of Hydroxyurea

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Key result

Hydroxyurea use was associated with lower age-adjusted odds of left ventricular diastolic dysfunction in youth with HgbSS sickle cell disease (OR 0.22, p=0.004), but not across all genotypes (OR 1.01).

Why the study?

Diastolic dysfunction is common in sickle cell disease and impacts morbidity and mortality, prompting an evaluation of whether diastolic dysfunction rates differ by genotype and hydroxyurea use among youths.

Does hydroxyurea use reduce the odds of left ventricular diastolic dysfunction in youth with sickle cell disease across different genotypes?

Key Points

To evaluate whether rates of left ventricular diastolic dysfunction differ by sickle cell disease genotype and hydroxyurea use among children and young adults.
Retrospective study of 196 youths with sickle cell disease (aged 7 to 22 years; median age 17.6 years) who received an echocardiogram, including 102 (52%) on hydroxyurea and 94 not on hydroxyurea.
Defined diastolic dysfunction as a diastolic aggregate score ≥ 2 of 5 echocardiographic parameters (mitral valve E/A ratio < 0.8 or > 2, septal E’ < 7 cm/s, lateral E’ < 10 cm/s, average E/e’ > 10, and left atrium to aortic root ratio > 1.3:1).
Evaluated associations between diastolic dysfunction and hydroxyurea use by genotype using multivariable logistic regression models adjusted for age.
Left ventricular diastolic dysfunction was identified in 39% of the overall cohort, occurring in 36% (37/102) of youths on hydroxyurea compared to 41% not on hydroxyurea.
Among youths with the HgbSS genotype, hydroxyurea use was associated with significantly lower age-adjusted odds of diastolic dysfunction compared to no hydroxyurea (OR 0.22, 95% CI [0.07, 0.59], p = 0.004).

Study Design

Type

Cross-Sectional (n=196)

Multicenter

No

Structured PICO

Does hydroxyurea use reduce the odds of left ventricular diastolic dysfunction in youth with sickle cell disease across different genotypes?

P

Population

196 youths aged 7 to 22 years (median age 17.6 years, 50.5% female, 97.4% Black/African American) with sickle cell disease (54% HgbSS, 33% HgbSC) who underwent an echocardiogram, with a median hydroxyurea treatment duration of 5.2 years.

E

Exposure

Hydroxyurea therapy (n=102) for a median duration of 5.2 years (IQR 2.5, 9.5).

C

Comparator

No hydroxyurea therapy (n=94) and no other disease-modifying therapies, chronic transfusions, or stem cell transplant.

O

Outcome

Left ventricular diastolic dysfunction (LV DD), defined as an echocardiographic diastolic aggregate score ≥ 2 of 5 parameters: mitral valve (MV) E/A ratio < 0.8 or > 2, MV septal E' < 7 cm/s, MV lateral E' < 10 cm/s, MV E/e' average > 10, and left atrial to aortic root (LA:Ao) ratio > 1.3:1.surrogate

Main Result

Odds Ratio: 1.01 (95% CI 0.55–1.87)

Absolute Event Rate: 36.3% vs 41.5%

p-value: p=>0.9

Longer-term hydroxyurea therapy (median 5.2 years) is associated with significantly lower odds of left ventricular diastolic dysfunction in youths with the HgbSS sickle cell genotype, supporting its cardioprotective role in this population.

Limitations

Single-center retrospective study with potential for selection bias (echocardiograms after 2020 were obtained only for clinical symptoms rather than routine screening)
Limited sample size due to rarity of the disease and exclusion of patients receiving chronic transfusions or stem cell transplantation
Challenges in defining pediatric diastolic dysfunction using normative Z-scores because over 50% of the sample was >= 18 years old
Inability to perform left atrial strain or trace left atrial indexed volume for all patients due to inaccessible older archived images
Inability to determine patient adherence to hydroxyurea therapy
Cross-sectional design limits the ability to assess longitudinal improvement over time from baseline
Single-center retrospective study design
Left atrial dilation used to assess diastolic dysfunction can be confounded by chronic anemia alone in the SCD population
Small sample size of patients with the HgbSC genotype on hydroxyurea (n=14)
Potential selection bias in the HgbSC group, as echocardiograms and hydroxyurea may have been preferentially utilized in those with a more severe phenotype

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

May support hydroxyurea in HgbSS youth; leaves open genotype-specific effects and need for prospective trials.

Abstract

Sickle cell disease (SCD) encompasses a spectrum of genotypes, most commonly Hemoglobin (Hgb)SS and HgbSC. Diastolic dysfunction (DD) is common in SCD and impacts morbidity and mortality. We sought to evaluate if the rates of DD differed by SCD genotype and by hydroxyurea (HU) use among youths. This was a retrospective study of patients with HgbSS and HgbSC who received an echocardiogram, stratifying genotype and HU use. DD was assessed using mitral valve (MV) E/A ratio < 0.8 or > 2, septal E’ < 7 cm/s, lateral E’ <10 cm/s, E/e’ Average > 10; and LA: Aortic root (LA: Ao) ratio > 1.3:1. DD was defined as a diastolic aggregate score ≥ 2 of 5. Multivariable regression models adjusted for age were used to estimate the associations of DD with HU use by genotype. 39% of youth with SCD who had an echocardiogram had DD. DD rates were lower in those on HU ( n = 102, 36%) vs. those not on HU ( n = 94, 41%). Adjusting for age, youths with HgbSS on HU had lower odds of DD compared to those not on HU, OR 0.22 [95% CI (0.07, 0.59), p = 0.004]. Conversely, youth with HgbSC on HU had slightly increased odds of DD compared to those not on HU, OR 1.36 [95% CI (0.35, 4.98) p = 0.6]. In contrast to previous studies suggesting HU has no impact in reducing DD over time, our study showed DD was less common among patients with HgbSS on HU. Larger, prospective, multi-center studies are needed to assess longitudinal improvement of DD from baseline for SCD patients on HU.

Discussion

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Cite This Study

Igwe et al. (2026) conducted a cross-sectional in Sickle cell disease (n=196). Hydroxyurea vs. No hydroxyurea was evaluated on Left ventricular diastolic dysfunction (defined as a diastolic aggregate score >= 2 of 5 echocardiographic parameters) (OR 1.01, 95% CI 0.55, 1.87, p=>0.9). Hydroxyurea use was associated with lower age-adjusted odds of left ventricular diastolic dysfunction in youth with HgbSS sickle cell disease (OR 0.22, p=0.004), but not across all genotypes (OR 1.01).

synapsesocial.com/papers/6aebc8cf3e63ca1b6c315ef1 https://doi.org/10.1007/s00246-026-04534-3

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Left Ventricular Diastolic Dysfunction in Youth with Sickle Cell Disease: Evaluating Genotypic Differences and Effects of Hydroxyurea

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Left Ventricular Diastolic Dysfunction in Youth with Sickle Cell Disease: Evaluating Genotypic Differences and Effects of Hydroxyurea

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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