Cardiac QTc Interval Characteristics and Behavior in 995 Consecutive Hematopoietic Cell Transplantation Patients At a Single Institution

The cardiac QT interval (QT) has gained deserved scrutiny among electrophysiologists. Reflecting the duration of the ventricular myocardial depolarization/repolarization cycle, the QT depends upon ion exchange across cardiomyocyte membranes. Ion flux perturbations (due to abnormalities of membrane-bound ion channel number, structure or function) can predispose to QT prolongation that, in turn, is associated with linearly increasing risks of ventricular tachy-arrhythmias and sudden death. As both polypharmacy and dys-electrolytemia have been reported to affect QT, we studied the interval's behavior in the potentially at-risk population of children and adults undergoing hematopoietic cell transplantation (HCT).

We retrospectively reviewed over 2600 cardiologist-evaluated electrocardiograms (ECG) and transplant-related data for 995 consecutive children and adults undergoing HCT between 2006 and 2010, inclusive. Patients underwent routine pre-HCT ECG screening; repeat studies were obtained for various clinical indications. Corrected QT intervals (QTc) were noted; any study demonstrating non-sinus rhythm was disregarded. Multivariate regression models tested the association between QTc and other patient or transplant-related covariates (including age, gender, primary diagnosis, intensity of conditioning, and donor relatedness/graft-versus host disease prophylaxis for allograft recipients); reference groups representing fixed covariate characteristics were defined among the cohort for comparison. Student's t-test was used to determine the significance of aggregate intra-patient change in QTc from pre- to post-HCT.

Pre-HCT: 952 patients had an evaluable pre-HCT maximum QTc observed at a median Day −22. Median QTc was 428 ms (range, 330 to 569; interquartile range [IQR], 409 to 447). Statistically significant QTc variability with age was observed and reflected widely accepted age-dependent phenomena in the population-at-large. Factors predicting shorter QTc included male gender (-11 ms compared to reference group [CRG], p < 0.01) and inherited metabolic disorder (IMD) as HCT indication (-10 ms CRG, p = 0.03). Factors predicting longer QTc were myeloproliferative disorder (+22 ms CRG, p = 0.01) and acute myeloid leukemia (+7 ms CRG, p = 0.02) as HCT indications.

Post-HCT: 578 patients had an evaluable post-HCT maximum QTc observed at a median Day +69. Median QTc was 454 ms (range, 367 to 619; IQR, 433 to 476). Age was not significantly predictive of maximum QTc post-HCT. Factors predicting shorter QTc were male gender (-7 ms CRG, p = 0.05) and no exposure to mycophenolate mofetil (MMF) for graft-versus-host disease (GvHD) prophylaxis (-11 ms CRG; p = 0.05). Patients diagnosed with acute lymphoblastic leukemia (ALL) demonstrated longer QTc (+17 ms CRG, p = 0.03).

δQTc: 559 patients had at least one evaluable pre- and one evaluable post-HCT ECG. The median δQTc (defined per patient as [mean post-HCT QTc] - [mean pre-HCT QTc]) was 15.7 ms (range, −72 to 142; IQR, −2 to 32). A highly significant difference between post-HCT and pre-HCT QTc per patient was observed in this cohort (p < 0.01).

Very Long QTc: 92 (15%) males demonstrated QTc ≥ 480 ms and 39 (10%) females demonstrated QTc ≥ 500 ms on any ECG. Of patients with ≥ 2 evaluable ECGs, 306 (50%) demonstrated prolongation ≥ 40 ms. Factors significantly predicting extreme prolongation included age < 1 year (+39 ms CRG, p < 0.01) and diagnosis of ALL (+15 ms CRG, p = 0.04); a trend toward more extreme prolongation was seen in patients with myelodysplastic syndrome (+14 ms CRG, p = 0.05). The factor protecting from extreme QTc prolongation was treatment with a related allograft (-9 ms CRG, p = 0.03); trends toward less extreme prolongation were also seen in autologous HCT and those not receiving MMF for GvHD prophylaxis.

Prolonged QTc is associated with life-threatening ventricular tachy-arrhythmias. This retrospective analysis of a large, diverse HCT cohort shows statistically significant prolongation during transplantation. Too, we identify sub-populations demonstrating very-long QTc and/or experiencing marked QT prolongation during HCT. Further analysis regarding pharmacologic, electrolytic and HCT-related predictors as well as outcomes for the cohort is underway.

No relevant conflicts of interest to declare.