Rapid cardiovascular aging following allogeneic hematopoietic cell transplantation for hematological malignancy

Abstract

IntroductionAllogeneic hematopoietic cell transplantation (allo-HCT) offers a potential cure for high-risk hematological malignancy; however, long-term survivors experience increased cardiovascular morbidity and mortality. It is unclear how allo-HCT impacts cardiovascular function in the short-term. Thus, this 3-month prospective study sought to evaluate the short-term cardiovascular impact of allo-HCT in hematological cancer patients, compared to an age-matched non-cancer control group.MethodsBefore and ~3-months following allo-HCT, 17 hematological cancer patients (45 ± 18 years) underwent cardiopulmonary exercise testing to quantify peak oxygen uptake (VO2peak)—a measure of integrative cardiovascular function. Then, to determine the degree to which changes in VO2peak are mediated by cardiac vs. non-cardiac factors, participants underwent exercise cardiac MRI (cardiac reserve), resting echocardiography (left-ventricular ejection fraction [LVEF], global longitudinal strain [GLS]), dual-energy x-ray absorptiometry (lean [LM] and fat mass [FM]), blood pressure (BP) assessment, hemoglobin sampling, and arteriovenous oxygen difference (a-vO2diff) estimation via the Fick equation. Twelve controls (43 ± 13 years) underwent identical testing at equivalent baseline and 3-month time intervals.ResultsSignificant group-by-time interactions were observed for absolute VO2peak (p = 0.006), bodyweight-indexed VO2peak (p = 0.015), LM (p = 0.001) and cardiac reserve (p = 0.019), which were driven by 26, 24, 6, and 26% reductions in the allo-HCT group (all p ≤ 0.001), respectively, as no significant changes were observed in the age-matched control group. No significant group-by-time interactions were observed for LVEF, GLS, FM, hemoglobin, BP or a-vO2diff, though a-vO2diff declined 12% in allo-HCT (p = 0.028).ConclusionIn summary, allo-HCT severely impairs VO2peak, reflecting central and peripheral dysfunction. These results indicate allo-HCT rapidly accelerates cardiovascular aging and reinforces the need for early preventive cardiovascular intervention in this high-risk group.

Reduced cardiovascular reserve capacity in long-term allogeneic stem cell transplant survivors

“…Therefore, with the 7.8 ml kg −1 min −1 deficit in O 2peak observed among the survivors in our study it is not unexpected that this population are burdened by markedly elevated rates of overt CVD, and premature cardiovascular and all-cause mortality. Our results are consistent with Armenian et al 21 who found O 2peak to be 22% below predicted values at a median of 9.8 years post-SCT, but intriguingly, are in contrast to the degree of O 2 peak impairment observed among short, and very long-term survivors 13 , 22 . Indeed, O 2peak has been shown to be 49% below predicted among early survivors (~ 3 months post-SCT) 13 and 11% below predicted among very long-term survivors of allo-SCT (median 17 years [range 6–26] post-SCT) 22 .…”

“…Our results are consistent with Armenian et al 21 who found O 2peak to be 22% below predicted values at a median of 9.8 years post-SCT, but intriguingly, are in contrast to the degree of O 2 peak impairment observed among short, and very long-term survivors 13 , 22 . Indeed, O 2peak has been shown to be 49% below predicted among early survivors (~ 3 months post-SCT) 13 and 11% below predicted among very long-term survivors of allo-SCT (median 17 years [range 6–26] post-SCT) 22 . It may therefore be reasonable to speculate that allo-SCT-induced impairments in O 2peak ‘recover’ to some degree over time.…”

“…Resting Cardiac Function. Resting cardiac function (left-ventricular ejection fraction [LVEF], and global longitudinal strain [GLS]) was evaluated via echocardiogram (Vivid E95, GE Vingmed, Horten, Norway) as previously described 13 , with images saved in a digital format for offline analysis (Echopac v13.0.00, GE, Norway).…”

“…On the other hand, this highlights an important window of opportunity to detect and address dysfunction at a subclinical stage of disease when targeted interventions may be efficacious. We have recently documented subclinical impairments in cardiac function and skeletal muscle oxygenation as early as 3 months following allo-SCT 13 . However, there is little information regarding subclinical cardiovascular dysfunction among long-term survivors, and so it is unclear whether these immediate impairments are transient or sustained.…”

“…In the two studies that have sought to characterise ˙O 2peak in allo-SCT survivors, significant impairment has been observed 21 , 22 . However, in this population, investigations into the key organ systems underpinning impaired O 2peak (1) produced conflicting results, and (2) were limited to standard-of-care resting measures of cardiac (i.e., echocardiography) and pulmonary (e.g., spirometry) function which are likely to miss subtle impairments that, in the case of the heart, could be unmasked during exercise (i.e., exercise cardiovascular magnetic resonance imaging [ExCMR]) 13 , 20 , 23 , 24 . Further, the potential contribution of vascular, skeletal muscle and body composition metrics to poor O 2peak is yet to be elucidated among long-term allo-SCT survivors.…”