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CARDIA Study: Sickle Cell Trait Is Not Independently Associated With Cardiovascular Disease Risk

December 30, 2021

Despite concerns that sickle cell trait (SCT) is associated with poor cardiopulmonary fitness and certain cardiovascular risk factors, the relationship between SCT and fitness has not been extensively examined. In a report published in Blood, Robert I. Liem, MD, MS, and authors analyzed data from the 25-year, longitudinal CARDIA (Coronary Artery Risk Development in Young Adults) study to determine if patients with SCT were at an increased risk for adverse cardiovascular outcomes, such as sudden death during strenuous physical activity or the development of cardiovascular disease (CVD), compared with those without SCT.

Dr. Liem, from the Department of Hematology, Oncology & Stem Cell Transplantation at Ann & Robert H. Lurie Children's Hospital of Chicago, and authors found that SCT carrier status was not associated with baseline or long-term changes in cardiopulmonary fitness.

Combined with results from a recent population study of African-American active-duty soldiers in the U.S. Army, which found that SCT was not associated with a higher overall risk of death (but was associated with a higher risk of exertional rhabdomyolysis), these findings support the idea that SCT status is not a risk for adverse cardiovascular outcomes.

"Having SCT alone does not affect one's overall fitness level or one's risk of developing risk factors for heart disease," Dr. Liem told ASH Clinical News. "However, it doesn't mean that individuals with SCT will not have lower fitness or will not develop those complications for all of the usual reasons that people without SCT do."

CARDIA included 5,115 patients (age range = 18-30 years) who were enrolled from four U.S. cities (Birmingham, Alabama; Oakland, California; Chicago, Illinois; and Minneapolis, Minnesota) between 1985 and 1986; patients were followed for 25 years, with seven examinations over the course of the follow-up period (at years 2, 5, 7, 10, 15, 20, and 25).

Dr. Liem and authors restricted their analysis to the 1,995 African-American patients enrolled in CARDIA who had SCT genotype information and fitness data available at baseline. Patients with sickle cell disease, those who underwent bariatric surgery, and those with missing baseline covariates were excluded.

Seven percent of these patients had confirmed SCT – a prevalence rate similar to the estimated carrier rate in the United States, the authors noted. Mean patient age was 24.8 years for those with SCT and 24.3 years for those without SCT. Baseline characteristics were similar between patients with and without SCT, with a similar prevalence of hypertension, diabetes, and metabolic syndrome among both cohorts. However, diastolic blood pressure (BP) was slightly higher in those with SCT compared with those without SCT (71 vs. 69 mm Hg; p=0.02).

The authors used a graded, symptom-limited maximal treadmill test (Balke protocol, which included 9 stages of increasing difficulty defined by treadmill speed and incline) during the year 7 and year 20 exams to assess fitness. Seated BP, cholesterol, height, weight, waist circumference, and physical activity were also assessed after a 12-hour fast. Demographic information, physical activity, and medication use were recorded via an interview-administered questionnaire.

No significant differences were observed in baseline fitness parameters (including mean duration of exercise, maximum heart rate achieved, and heart rate at 2 minutes of recovery), even after adjusting for sex, baseline age, body mass index, and physical activity, the authors noted. Long-term follow-up also showed no significant difference in annual change in graded exercise performance between patients with and without SCT status.

Those with and without SCT had a similar risk of developing the following cardiovascular risk factors during the 25-year, follow-up period:

  • hypertension (defined as systolic BP ≥140 mm Hg, diastolic BP ≥90 mm Hg, or those who were taking antihypertensive medication; p=0.19)
  • diabetes (defined as fasting glucose ≥126 mg/dL, glycated hemoglobin >6.5 percent, post-load glucose ≥200 mg/dL, or those who were taking diabetes medication; p=0.08)
  • metabolic syndrome (defined as presence of diabetes or hypertension, increased waist circumference, triglycerides ≥150 mg/dL or those who were taking cholesterol medication; p=0.15)

See TABLE for more detailed results about the risks of developing incident CVD risk factors in each study cohort.

"Our findings suggest that SCT status alone probably does not explain the racial disparities in fitness observed between African Americans and non−African Americans, given that we found no difference in fitness by SCT status," the authors wrote.

Dr. Liem noted that the study is limited by its retrospective design and small sample size. Because the CARDIA study was not powered to test the hypothesis by Dr. Liem and authors, sample-size limitations could explain the analysis' null findings.

CARDIA also did not allow for direct measurement of peak oxygen consumption during exercise (considered the reference standard for fitness), meaning that the authors could not determine if there were differences in the actual physiologic responses to exercise between those with and without SCT, according to Dr. Liem. Further studies are warranted to examine the potential differences in the physiologic response to exercise in the SCT population.


Liem RI, Chan C, Vu THT, et al. Longitudinal association among sickle cell trait, fitness, and cardiovascular disease risk factors in African Americans in CARDIA. Blood. 2016 November 16. [Epub ahead of print]

TABLE. SCT and Incident CVD Risk Factors Over 25 Years
  Hazard Ratio (HR)
Incident hypertension
   No SCT 682/1,482


   SCT 56/108



(95% CI 0.91-1.65)

Incident diabetes
   No SCT 262/1,519


   SCT 26/112



(95% CI 0.96-2.27)

Incident metabolic syndrome
   No SCT 596/1,502


   SCT 49/109



(95% CI 0.92-1.74)

SCT = sickle cell trait; CVD = cardiovascular disease


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