Heart Rate Recovery Is Impaired After Maximal Exercise Challenge in Pediatric Sickle Cell Anemia

Abstract ³²²⁰

Slow heart rate recovery (HRR) after exercise, particularly at 1 and 2 minutes during recovery, is a strong indicator of autonomic nervous system (ANS) imbalance and represents an important risk factor for increased cardiovascular morbidity and mortality in the general population. Recent evidence suggests cardiovascular ANS dysfunction and vagal tone impairment also exist in individuals with sickle cell anemia (SCA). Despite the known impact of disease burden on exercise capacity and overall fitness in SCA, post-exercise HRR has not previously been studied in this population. The objective of this study was to examine HRR in the post-exercise recovery phase following maximal exercise testing in a cohort of children and young adults with SCA. Methods We prospectively performed maximal cardiopulmonary exercise testing using a ramp, cycle ergometry protocol in 60 subjects with SCA (hemoglobin SS and S-β⁰ thalassemia) and 20 controls without SCA or sickle cell trait matched for race and gender. Data from standard 12-lead electrocardiography (ECG) was assessed during a 10-minute recovery phase, and HR and corrected QT (QTc) interval measured from tracings obtained at 1-minute intervals. A single investigator performed all measurements manually using leads II, V5, and V6. Final values were averaged from 3 independent measurements. The difference between maximal HR and both HR at 1-minute (ΔHR_1min) and 2-minute (ΔHR_2min) recovery was our primary outcome. Between-group differences were compared using Mann-Whitney U testing (IBM, SPSS V20). The relationship between ΔHR_1min and exercise parameters was examined using Spearman's rank correlation coefficient. Results Post-exercise ECG data from 58 subjects with SCA (median age 15.5 years) and 20 controls without SCA (median age 12 years) were interpretable for this analysis. A total of 30/58 (52%) and 22/58 (38%) subjects were male and on hydroxyurea, respectively. There was no significant difference in median baseline HR or QTc interval in subjects versus controls. Median peak HR was also not significantly different in the 2 groups. When compared to controls, subjects with SCA demonstrated significantly lower HR reserve (100 vs. 111 bpm, p = 0.005), representing the difference between peak and baseline HR. Impaired HRR, defined by slower declines in HR during recovery, was also evident among subjects with SCA following maximal exercise challenge. Although the absolute HR measured at each minute of recovery did not differ significantly in the 2 groups, subjects demonstrated significantly smaller median ΔHR_1min (21 vs. 33 bpm, p < 0.0001) and ΔHR_2min (39 vs. 51 bpm, p = 0.003), even after adjustment for age between groups. Significantly smaller ΔHR values were also noted in subjects at each minute up to 8 minutes throughout recovery. When compared to subjects not on hydroxyurea, subjects on treatment had significantly greater median ΔHR_1min (25 vs. 19 bpm, p = 0.037) but similar ΔHR_2min. In subjects with SCA, ΔHR_1min correlated inversely with age (−0.41, p = 0.001) and directly with peak oxygen consumption (peak VO₂) (0.30, p = 0.03) and oxygen delivery (ΔVO₂/Δwork rate) (0.46, p < 0.0001), but not with baseline QTc interval or hemoglobin. Through mono-exponential curve fitting, we found that the time constant associated with HR decline over the first 5 minutes of recovery was greater in subjects with SCA versus controls (T = 128 sec, 95% CI [123, 134] versus 104 sec, 95% [97, 110]). Conclusions Compared to controls without SCA, children and young adults with SCA demonstrate impaired HRR following maximal cardiopulmonary exercise testing, as evidenced by smaller decrements in HR at 1 and 2 minutes during recovery and exponential time constants that indicate a longer period of time over which HR declines. Slower HRR is also associated with decreased fitness and measures of oxygen delivery during exercise testing in subjects with SCA. Although the mechanisms are not well understood, prolonged HRR in this population may in part be explained by ANS imbalance, suggesting either inadequate sympathetic withdrawal or suboptimal parasympathetic reactivation in the post-exercise period. Future studies should focus on delineating the role of the ANS in post-exercise HRR and assessing the prognostic potential of this marker as it relates to disease severity and outcomes in SCA.