Negative studies shape the state of sickle trait.

Currently in the United States, people with SCT may be identified through mandated state newborn screening programs or athletic association screening. However, despite widespread screening recommendations, clear guidelines regarding follow-up, counseling, and management of individualswithSCTdonot exist secondary to a paucity of data fromwell-designed studies. This research void in SCT is particularly evident in cardiovascular and exercise-related outcomes, where SCT has been the subject of rampant speculation. In extreme conditions such as military training and high-intensity sports, SCT has been linked to an increased relative, but very small, absolute risk of sudden death. This has led to the hypothesis that SCT may be associated with impaired exercise tolerance and adverse cardiac events in the general population.Usingmeasures of cardiac fitness and heart failure (HF) from large population-based cohorts, the 2 studies in this issue add important and rigorous data to this understudied area. To explore whether racial disparities in cardiopulmonary fitness are associated with SCT, Liem and colleagues examined changes in fitness in 1995 African Americans (136 with SCT) followed over 25 years in the Coronary Artery Risk Development inYoungAdults cohort.They found that baseline fitness and changes in fitness over time were no different for individuals with SCT compared with those without the trait. They also found no association of SCT with hypertension, diabetes, and metabolic syndrome. Bello and colleagues performed a meta-analysis of 4 different population-based cohorts and similarly found no association between SCT and the risk of incident HFin15 364AfricanAmericans (1211withSCT). Additionally, they found no difference in left ventricular size, wall thickness, or systolic function between those with SCT and those without. SCT has long been considered a clinically benign recessive traitwith the exception of the rare reported complications of extreme exertionrelated sudden death and renal medullary carcinoma. However, recent studies, using similarly large cohorts as in the Liem and Bello studies, have shown an increased risk of chronic kidney disease and venous thromboembolism among African Americans with SCT. In addition, a recent study found an association of SCT with exertional rhabdomyolysis, but no demonstrated increased risk of sudden death in a contemporary military cohort followed after the institution of universal precautions. Unlike in sickle cell disease (SCD), erythrocyte sickling and hemolysis do not normally occur in individuals with SCT. However, red cell changes have been documented in SCT in the context of severedehydration, lowoxygen tension, or exercise that mimic those observed in SCD. Increased whole-blood viscosity, erythrocyte stiffness, and overt sickling have all been demonstrated to occur in individuals with SCT in the setting of stress. Although these alterations in erythrocyte rheology and activity offer a biologically plausible mechanism for the development of end-organ damage, it is important tonote that, in starkcontrast to SCD, clinically relevant red cell changes in SCT likely only occur in local areas with extreme conditions, such as in the hypoxic environment of the renalmedulla orwithin anaerobicmuscle tissue during strenuous exercise. For this reason, chronic arterial complications would not be expected in individuals with SCT. The absence of an association between SCT and cardiovascular fitness or HF in the investigations by Liem et al and Bello et al is, therefore, not surprising but is nonetheless exceedingly valuable. That these studies are negative only increases their importance for themedical community and the 300million peopleworldwidewithSCT.We can now offer some reassurance that carrying SCT does not increase the risk of HF and the development of factors known to increase the risk of cardiovascular disease. Conflict-of-interest disclosure: R.P.N. is funded by the National Institutes of Health, National Heart, Lung, Blood Institute grant K08HL12510. S.L. has no competing financial interests. n