Abstract
This study examined the effects of hematopoietic cell transplantation (HCT) and associated preparative regimens on vascular structure and function. Measures of carotid artery stiffness as well as brachial artery endothelial-dependent-dilation were obtained in patients who had survived ≥2 yrs after HCT for hematologic malignancy and were diagnosed at <21 yrs. HCT (n=108) survivors were examined; 66 received TBI alone or with a low dose cranial radiation boost (TBI+/−LD-CRT), 19 received TBI plus high dose cranial radiation (TBI+HD-CRT), and 23 received a chemotherapy-only preparative regimen (CHEMO). Siblings (n=83) were invited to participate as controls. Although endothelial-dependent-dilation did not differ between siblings and HCT survivors, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance and diameter distensibility were greater in siblings than HCT survivors. Comparing the HCT preparative regimens, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, diameter distensibility, and incremental elastic modulus were significantly lower in TBI+HD-CRT compared to siblings or compared to TBI+/−LD-CRT and CHEMO treatment groups. Cross-sectional distensibility and diameter compliance were significantly lower in TBI+/−LD-CRT compared to siblings. TBI+/−LD-CRT and CHEMO groups did not differ from each other in these vascular measures. HCT preparative regimens containing TBI+HD-CRT radiation resulted in greater arterial decrements, indicating increased risk for cardiovascular disease.
Keywords: Ultrasound, Compliance, Distensibility, Endothelial Function, Cancer Survivors
INTRODUCTION
Although the incidence of cancer diagnoses in children has remained constant over the last few decades, survival has increased to a 5-year survival rate of 83% in 2003–20091. One of the main reasons for this improvement is major advances in treatment that were implemented during this period2,3. One such advance is the use of hematopoietic cell transplantation (HCT), which has been shown to be effective for several high risk and relapsed hematological malignancies. Over 80% of those who survive the first 2 years of HCT treatment are expected to be long-term survivors4,5. However, HCT survivors are at increased risk for a variety of chronic conditions and impairments involving virtually every organ system6. The risk of these complications isinfluenced by pre-transplantation treatment exposures and transplantation-related conditioning regimens and by development of post-transplantation graft-versus-host disease. To date, most studies examining cardiovascular risk in cancer survivors have focused on adult survivors of childhood cancer who have undergone chemotherapy and/or body irradiation7,8,9. Few if any studies have examined the effect on carotid vascular structure and function among childhood cancer survivors who underwent HCT and were conditioned with total body irradiation (TBI) and/or chemotherapy. Stiffening of arteries impairs the ability of the arterial system to handle the spontaneous elevation in blood pressure at systole, which leads to an increase in systolic blood pressure and left ventricular afterload with a subsequent increase in myocardium mass, as well as a decrease in diastolic blood pressure and diastolic coronary perfusion. Therefore, assessment of arterial compliance and distensibility of large conduit arteries such as the carotid artery is a technique widely used to assess vascular elasticity and arterial stiffness and overall vascular health10.
Therefore, this study’s primary objective was to evaluate measures of brachial and carotid artery structure and function in a relatively large population of young adult childhood cancer survivors, who received HCT as part of their treatment regimens when they were children, and to compare their results to a control group of healthy siblings.
MATERIALS AND METHODS
The study protocol was approved by the Institutional Review Board (IRB) and adhered to Health Insurance Portability and Accountability Act (HIPAA) guidelines. All subjects submitted written informed consent and assent (when appropriate) for study participation.
Study Population
HCT databases at the University of Minnesota and the Fred Hutchinson Cancer Research Center identified all HCT recipients who were transplanted for a hematologic malignancy between 1975 and 2008 and who had survived at least 2 years post-HCT. In addition, participants had to be less than age 22 years at diagnosis and at least 10 years old at the time of study entry in order to comply with the study procedures. In total 557 subjects were potentially eligible. Twenty-six of those were deemed ineligible due to active graft vs. host disease or disease status not in remission and 84 had previously been listed in the databases as known lost to follow-up, or had requested “Do Not Contact” research status, leaving an eligible population of 447 subjects. Eligible subjects were randomly ordered and recruited in sequential blocks of 20. If a sampled individual within a block declined to participate or could not be contacted after several attempts the next ordered individual in that block was approached for recruitment until study enrollment was completed, which occurred after attempted contact with the first 339 subjects. Of these 339 subjects, 60 refused participation, and we were unable to establish contact with 125 others after at least 3 attempts. Of the remaining 154 subjects who were recruited (overall participation rate of 45%, 72% of those who were successfully contacted), 3 were found to be ineligible at the time of study due to previously undiagnosed diabetes (n=1), severe hypertension (n=1), multiple medical issues (n=1) that all required immediate medical treatment so that they were unable to complete any study procedures. This left the final study population of 151 subjects. Due limitations in ultrasound imaging equipment and qualified sonographers only subjects (and their siblings) enrolled at the University of Minnesota were eligible to have vascular assessments performed; providing 108 cases with completed vascular assessments for inclusion in this analysis (Figure 1).
Figure 1.
CONSORT Diagram
All 108 patients received myeloablative preparative regimens. Details of TBI and cranial radiation doses are shown in Table 4. Sixty-six (61%) received TBI with or without low dose cranial radiation boost (n=8, LD-CRT) while 19 (18%) patients received TBI with high dose (HD) CRT given either before or concurrent with TBI in all cases. TBI was delivered in fractionated doses for all cases with the exception of 3 cases in the TBI + HD-CRT group and 10 cases in the TBI +/−LD-CRT group who received a single fraction TBI dose between 750–850 cGy. One additional patient in the TBI +/−LD-CRT group received 200cGy of single fraction TBI for an allogeneic HCT that followed a prior failed autologous HCT for Hodgkin Disease. Twenty-three (21%) patients received chemotherapy only, the majority of those busulfan based. Transplants were performed for acute lymphoblastic leukemia or non-Hodgkin lymphoma in 41 (38%) patients, acute or chronic myeloid leukemia or myelodysplastic syndrome in 57 (53%) patients, and for Hodgkin lymphoma in 10 (9%) patients.
Table 4.
Treatment and survival information
| Variable | TBI + HD-CRT | TBI +/− LD-CRT | CHEMO | P-value |
|---|---|---|---|---|
| N | 19 | 66 | 23 | - |
| Years Post-Transplant (Mean ± SE) | 15.71±1.78 | 14.58±0.93 | 13.69±1.11 | 0.67 |
| Types of BMT1, N (%) Allogeneic Autologous |
15 (79) 4 (21) |
58 (88) 8 (12) |
7 (30) 15 (70) |
<0.0001 |
| GVHD1, N (%) Yes No |
8 (42) 11 (58) |
34 (52) 32 (48) |
3 (13) 20 (87) |
0.0038 |
| TBI Dose2 Median (cGy) Range (cGy) |
1320 750–1375 |
1320 200–1375 |
na | 0.68 |
| Cranial Radiation2 Median Dose (cGy) Range (cGy) |
N=19 2340 1500–3600 |
N=8 600 300–600 |
na | <0.0001 |
CHEMO, chemotherapy only preparative regimen; HCT, survivors of hematopoietic stem cell transplantation; TBI + HD-CRT, total body irradiation plus high dose cranial; TBI +/− LD-CRT, total body irradiation plus no or low dose cranial radiation.
Both TBI groups are statistically significantly different from CHEMO group (p-value<0.05).
P-value is for Comparing TBI + HD –CRT with TBI =/- LD - CRT
P<0.05 vs. CHEMO. TBI, total body irradiation; HD-CRT, high dose cranial radiation; LD-CRT, low dose cranial radiation; GVHD, graft vs. host disease; cGy, centigray.
The control group consisted of eligible healthy siblings who were ≥10 years old at study entry and who had never had a malignancy or HCT. Based on a pre-determined frequency matched enrollment scheme, siblings were recruited with the intent to represent the age and sex distribution of HCT recipients. Selection of the sibling closest in age to the subject was preferred, although not required, and having a sibling was not a requirement for participation. Siblings were chosen as the control population to obtain greater similarity to HCT recipients in genetics, lifestyle, and environment/geographical trends. Due larger differences in age between sibling and the HCT survivor group and the sibling control group a sensitivity analysis was done to create a sibling control group that was closer in age to the HCT survivor group. To create the age appropriate sibling control group the HCT survivor group was divided by age into the 20th, 40th, 60th, 80th and > 80th percentiles. The sibling control group was than divided into 5 groups using the age quintiles computed in the HCT survivor group. Those siblings that fit into the HCT survivor age quintiles were than used as the sibling control (n=83).
Measurements
Anthropometric and Blood Pressure Assessments
Measurements for height and weight were taken at the start of the visit and the body mass index (BMI) was calculated as weight in kilograms (kg) divided by height in meters-squared (m2). Seated blood pressure was obtained in the right arm using an automatic blood pressure monitor (Model BP-8800C; Colin Press-Mate, San Antonio, TX, USA). Tanner stage was assigned according to pubic hair development in boys and breast and pubic hair development in girls.
Vascular Assessments
All vascular testing was performed following a 15 min rest period in a quiet, temperature-controlled environment (22–23°C) with the subject in the supine position. Artery images were measured using a conventional ultrasound scanner (Acuson, Sequoia 512, Siemens Medical Solutions USA, Inc., Mountain View, CA, USA) with a 15–8 MHz linear array probe. All images were digitized and stored on a personal computer for later off-line analysis of arterial compliance and distensibility. Electronic wall-tracking software was used for the analysis (Vascular Research Tools 5, Medical Imaging Application, LLC, Iowa City, IA, USA).
For imaging of the carotid artery the ultrasound transducer was held 1-cm proximal from the carotid bifurcation bulb, to measure the carotid intima-media thickness (cIMT) and to capture the left common carotid artery’s lumen diastolic and systolic diameters. Systolic and diastolic blood pressures were recorded with an automated blood pressure sphygmomanometer during the 10-sec carotid measurements. The ultrasound scanning system was interfaced with a standard personal computer equipped with a data acquisition card to obtain radio frequency ultrasound signals from the scanner. Images were collected at 20 frames per second for 10 seconds (200 frames) to ensure capture of the full arterial diameter change during a cardiac cycle. The mean diameter through the 10-second cycle was used to calculate measures of carotid vessel function. Briefly, the following formulas were used to measure carotid distensibility and compliance in the cross-sectional and longitudinal planes: Diameter distensibility (%) is defined as [(maxDiamM - minDiamM)/ minDiamM] × 100%; Cross-sectional distensibility ( %) is defined as [(π × (maxDiamM/2)2 − π × (minDiamM/2)2)/π × (minDiamM/2)2] × 100%; Diameter compliance ( mm/mmHg) is defined as [(maxDiamM - minDiamM)/ΔP]; Cross-sectional compliance ( mm2mmHg] is defined as [(π × (maxDiamM/2)2 − π × (minDiamM/2)2)/(ΔP)]; Incremental elastic modulus (mmHg) is defined as 3{1+[π × (maxDiamM/2)2/ π × (minDiamM/2)2}/cross-sectional compliance. Pulse pressure (ΔP) is calculated as the difference between systolic and diastolic pressures. In addition, maxDiamM denotes maximum diameter measurement, and minDiamM denotes minimum diameter measurement.
Following measures of carotid structure and function, flow-mediated endothelial-dependent dilation was assessed by imaging the left brachial artery at the distal third of the upper arm using techniques previously described by our laboratory and others11,12. A blood pressure cuff was inflated below the elbow to a pressure of 200 mmHg and maintained for 5 minutes to induce muscle ischemia. Brachial artery diameter was measured continuously for a three-minute period immediately after cuff release during reactive hyperemia to determine peak endothelial-dependent-dilation (the greatest percent change from resting baseline brachial artery diameter following reactive hyperemia during the 3 min collecting period). After a fifteen-minute rest, 0.3 mg sublingual nitroglycerin was administered and the diameter of the brachial artery was continuously measured for a 15 min period post nitroglycerin administration. Peak nitroglycerin- mediated endothelial-independent dilation was defined as the highest percent change from resting baseline brachial artery diameter following nitroglycerin administration. Reproducibility of the cIMT and endothelial-dependent-dilation techniques in healthy young adults in our laboratory shows a mean difference of 0.02±0.03 mm and 0.39±0.65% respectively for analysis separated by one week13.
All patients undergo standardized graft vs. host disease (GVHD) assessments and data reporting as part of the standardized process for data collection in the institutional Bone Marrow Transplant (BMT) database for both acute and chronic graft vs host disease. All case report forms are reviewed and evaluated by a single individual for confirmation of GVHD and scoring prior to database entry. Due to the potential impact on study outcomes from steroids and other GVHD therapies, no subjects with active GVHD requiring therapy were enrolled.
Statistical Analysis
Descriptive statistics are expressed as frequencies, percent or mean ± standard error (SE), as appropriate. For unadjusted comparisons among HCT groups but not controls, P-values are from a t-test or Fisher’s exact test; for unadjusted comparisons involving HCT groups and sibling controls, P-values are from generalized estimating equations with robust standard errors, accounting for clustering by sibship of cases and controls. Multivariable linear regression models were used to compare groups according to adjusted mean outcome measures, with adjustments for age, sex, race and Tanner stage unless noted otherwise. P-values and P-value thresholds are not adjusted for multiple comparisons. All analyses used the SAS system (v. 9.2; SAS Institute, Cary, NC).
RESULTS
Table 1 describes the study population’s demographic characteristics. There were no significant differences in race/ethnicity between the HCT survivors as a whole group and the sibling controls. Despite the frequency matching and the selection scheme for siblings, HCT survivors were slightly older compared to their sibling controls. However, the proportion of males to females as well as Tanner state was similar for the HCT survivors and sibling controls. The HCT survivor group was shorter in stature and had lower weight than the sibling control group, though BMI did not differ significantly between HCT survivors and sibling controls (Table 2). Although systolic blood pressure did not differ between the HCT survivors and the sibling controls, diastolic blood pressure was significantly higher in the HCT survivors (Table 2). The physical characteristics of the study population, divided according to treatment group, are described in Table 2. Patients who received TBI+/−LD-CRT or TBI+HD-CRT were significantly shorter and weighed less than the sibling controls. As a result, the TBI+/−LD-CRT group had BMI significantly lower than the sibling control group (Table 2). No differences in blood pressure were noted among the HCT treatment groups, except that the TBI+/−LD-CRT and TBI+HD-CRT group had diastolic blood pressure significantly higher than the sibling control group (Table 2).
Table 1.
Demographic characteristics between HCT survivor groups and sibling controls
| A | B | a | b | c | ||
|---|---|---|---|---|---|---|
| Siblings Mean ± SE | HCT Survivors Mean ± SE P-value* | TBI + HD- CRT Mean ± SE P-value* | TBI +/− LD- CRT Mean ± SE P- value* | CHEMO Mean ± SE P-value* | ||
| N | 83 | 108 | 19 | 66 | 23 | |
| Age (yrs) | 22.20±0.92 | 26.36±0.90 0.0002 | 25.19±1.63 0.11 | 26.33±1.28 0.0026 | 27.42±1.53 0.0028 | |
| Sex (male/female), (% male) | 45/38 (54%) | 66/42 (61%) 0.27 | 13/6 (68%) 0.25 | 42/24 (64%) 0.20 | 11/12 (48%) 0.69 | |
| Race/ethnicity, N (%) White Non- Hispanic Others White Hispanic Black Others |
75 (90) 8 (10) 1 (1) 1 (1) 6 (7) |
100 (93) 0.45 8 (7) 2 (2) 4 (4) 2(1) |
17 (89) 0.89 2 (11) 1 (5) 1 (5) 0 (0) |
63 (95) 0.17 3 (5) 0 (0) 2 (3) 1 (2) |
20 (87) 0.68 3 (13) 1 (4) 1 (4) 1 (4) |
|
| Tanner Stage 4–5, N (%) | 72 (90) | 87 (88) 0.64 | 16 (84) 0.46 | 51 (86) 0.50 | 20 (95) 0.45 |
Values presented are mean (±standard error) or N (%) where indicated. HCT, hematopoietic stem cell transplantation; TBI, total body irradiation, HD-CRT high dose cranial radiation; LD-CRT, low dose cranial radiation; CHEMO, chemotherapy only preparative regimen.
P-values reflect comparison of that treatment group vs. sibling control group.
Table 2.
Comparison body composition measures between HCT survivor groups and sibling controls
| A | B | a | b | c | ||
|---|---|---|---|---|---|---|
| Siblings Mean ± SE | HCT Survivors Mean ± SE P-value | TBI + HD- CRT Mean ± SE P- value | TBI +/− LD- CRT Mean ± SE P- value | CHEMO Mean ± SE P-value | ||
| N | 83 | 108 | 19 | 66 | 23 | |
| Height (cm) | 171.63±0.89 | 163.95±0.94 <0.0001 | 161.42± 1.96 <0.0001a | 162.26±1.12 <0.0001a | 170.98±1.78 0.72 | |
| Weight (kg) | 71.19±1.44 | 62.27±1.88 0.0002 | 58.79±3.96 0.0022a | 59.24±1.84 <0.0001a | 73.48±5.25 0.70 | |
| BMI (kg/m2) | 23.91±0.39 | 22.83±0.56 0.107 | 22.34±1.36 0.24a | 22.25±0.59 0.0165a | 24.77±1.50 0.59a | |
| SBP (mmHg) | 116.07±1.39 | 116.24±1.42 0.93 | 125.25±4.66 0.0626 | 113.59± 1.48 0.21a | 114.87±2.35 0.66a | |
| DBP (mmHg) | 61.77±1.00 | 66.70±1.11 0.0016 | 70.47±3.44 0.0169a | 65.88±1.26 0.0146a | 65.38±1.41 0.0523a |
HCT, survivors of hematopoietic stem cell transplantation; TBI + HD-CRT, total body irradiation plus high dose cranial; TBI +/− LD-CRT, total body irradiation plus no or low dose cranial radiation; CHEMO, chemotherapy only preparative regimen. All measures (mean ± standard error) are adjusted for age-at-study, sex, race, and Tanner score. P-values reflect that treatment group vs. sibling control group. If treatment groups do not share a letter within the same row they are significantly different (P<0.05).
Table 3 shows measures of carotid structure and function as well as brachial artery reactivity. Analyses of vascular measures were adjusted for age at study, sex, race, and Tanner score Although lumen diameter was significantly smaller in HCT survivors as a whole compared to sibling controls, cIMT did not differ significantly between HCT survivors and sibling controls. Also, cIMT did not differ significantly between the various HCT treatment groups. Carotid cross-sectional distensibility, carotid diameter compliance, and carotid diameter distensibility were significantly lower in HCT survivors than in sibling controls. The carotid cross-sectional distensibility, diameter compliance, diameter distensibility and incremental elastic modulus were significantly lower in the TBI+HD-CRT group compared to the sibling controls as well as the TBI+/−LD-CRT and CHEMO groups. Cross-sectional distensibility and diameter compliance were significantly lower in TBI compared to the sibling controls. The TBI+/−LD-CRT and CHEMO groups did not differ from each other in these vascular measures. Measures of brachial artery function (i.e., endothelial-dependent-dilation and endothelial-independent dilation) were corrected for brachial artery diameter; they did not differ significantly between HCT survivors as a whole and the sibling controls or between the three HCT survivor groups.
Table 3.
Comparison of brachial and carotid vascular measures between HCT survivor groups and sibling controls
| A | B | a | b | c | ||
|---|---|---|---|---|---|---|
| Siblings Mean ± SE | HCT Survivors Mean ± SE P- value | TBI + HD- CRT Mean ± SE P-value | TBI +/− LD- CRT Mean ± SE P-value | CHEMO Mean ± SE P-value | ||
| N | 83 | 108 | 19 | 66 | 23 | |
| Measures of Vascular Function | ||||||
| EDD (%) | 7.48±0.40 | 6.97±0.39 0.39 | 7.10±1.06 0.73 | 6.45±0.43 0.11 | 8.24±0.86 0.44 | |
| EID (%) | 24.34±0.67 | 23.46±0.60 0.34 | 23.38±1.30 0.50 | 23.74±0.86 0.62 | 22.79±0.89 0.14 | |
| CSC (mm2mmHg–1) |
0.51±0.02 | 0.46±0.02 0.0548 | 0.41±0.05 0.0613 | 0.47±0.02 0.17 | 0.49±0.04 0.70 | |
| cDC (mm/mmHg)x100 |
1.43±0.04 | 1.29±0.04 0.02 | 0.96±0.07 <0.0001 | 1.36±0.05a 0.36 | 1.40±0.09a 0.75 | |
| CSD (%) | 27.40±0.74 | 22.30±0.66 <0.0001 | 18.91±1.66 <0.0001 | 22.59±0.76a <0.0001 | 24.83±1.26a 0.0788 | |
| DD (%) | 12.81±0.33 | 10.54±0.29 <0.0001 | 8.99±0.75 <0.0001 | 10.68±0.34a <0.0001 | 11.69±0.56a 0.0867 | |
| IEM (mmHg) | 1166.0±57.5 | 1276.1±52.8 0.19 | 1745.5±172.3 0.0014 | 1187.8±50.0a 0.75 | 1076.4±83.1a 0.45 | |
| Measures of Vascular Structure | ||||||
| Brachial Diameter (mm) | 3.64±0.05 | 3.40±0.04 0.0003 | 3.34±0.11 0.0125 | 3.39±0.05 0.0005 | 3.49±0.09 0.14 | |
| cLD (mm) | 6.15±0.06 | 5.76±0.05 <0.0001 | 5.64±0.10 <0.0001 | 5.80±0.08 0.0002 | 5.75±0.08 <0.0001 | |
| cIMT (mm) | 0.46±0.005 | 0.47±0.006 0.18 | 0.50±0.025 0.095 | 0.47±0.007 0.28 | 0.45±0.015 0.61 | |
EDD, endothelial-dependent dilation; EID, endothelial-independent dilation; DD, diameter distensibility; CSD, cross-sectional distensibility; DC, diameter compliance; CSC, cross-sectional compliance; IEM, incremental elastic modulus; cLD, carotid luman diameter, cIMT, carotid intima-medial thickness; HCT, hematopoietic stem cell transplantation; TBI, total body irradiation, HD-CRT high dose cranial radiation; LD_CRT, low dose cranial radiation; CHEMO, chemotherapy only preparative regimen. All measures (mean ± standard error) except EDD, EID and cIMT are adjusted for age-at-study, sex, race, and Tanner score. EDD and EID are adjusted for age-at-study, sex, race, Tanner score and brachial artery diameter. cIMT is adjusted for age-at-study, sex, race, Tanner score and lumen diameter. P-values reflect comparison of that treatment group vs. sibling control group. If treatment groups do not share a letter within the same row they are significantly different (P<0.05).
Table 4 contains information regarding treatment and time since treatment. The three treatment groups did not differ significantly in years post-transplant. A greater percentage of the CHEMO group received autologous bone marrow transplant compared to the two other treatment groups. As a result, fewer subjects in the CHEMO group were at risk for GVHD compared to the other two groups and indeed fewer had any GVHD. When Table 3‘s comparisons were adjusted for GVHD as well as age-at-study, sex, race, Tanner score, the only notable change was that cIMT was significantly lower in the CHEMO group compared to the TBI+HD-CRT (adjusted average±standard error: 0.46±0.01 vs. 0.50±0.01 mm, P=0.05), though not different compared to the TBI+/−LD-CRT (0.047±0.01 mm, P=0.08) group. In addition, systolic blood pressure was significantly higher in the TBI + HD-CRT (123.36±4.56 mmHg) group compared to both the TBI+/−LD-CRT (111.71±1.48 mmHg, P<0.0001) and CHEMO (112.69±2.34 mmHg, P=0.006) groups. Diastolic blood pressure was also higher in the TBI+HD-CRT compared to TBI+/−LDCRT (68.73±3.45 vs. 64.09±1.25 mmHg, P=0.04) treatment group, but not different compared to the CHEMO (63.52±1.51 mmHg, P=0.065) treatment group.
DISCUSSION
Measures of vascular endothelial function, stiffness, and cIMT are important early markers of subclinical atherosclerosis and increased cardiovascular disease risk14,15,16,17. To our knowledge, this is the first study to examine the effect of HCT and associated pre-HCT conditioning regimens (chemotherapy alone or combined with total body irradiation, with or without additional central nervous system irradiation) on measures of vascular structure and function in childhood cancer survivors.
In the present study, HCT survivors as a whole displayed increased carotid artery stiffness compared to healthy sibling controls. This observation is consistent with the results of Vatanen et al18 and Turanlahti et al19, who both reported reduced carotid vascular function in HCT survivors. In the present study, HCT survivors who received both total body irradiation and central nervous system irradiation had significantly lower measures of carotid vascular function than HCT survivors who received the other two treatments. These results differ somewhat from those reported by Vatanen et al18, who did not find any difference in carotid vascular function between HCT survivors who received total body irradiation and HCT survivors who did not. One explanation for the differences between the present study and Vatanen et al18 may be the number of patients studied. Vatanen et al18 studied only 19 total HCT survivors, nine who did not receive total body irradiation while the other ten did. Also, none of the patients studied by Vatanen et al18 received central nervous system irradiation in conjunction with total body irradiation. It may be that additional radiation scatter field exposure received during central nervous system irradiation results in greater decrement in carotid vascular function. The finding that there was no difference in carotid vascular function between the total body irradiation and chemotherapy-only treatment groups would support the hypothesis that the addition of central nervous system irradiation results in further damage to the carotid artery.
Although we found significant differences in carotid vascular function between HCT survivors and healthy sibling controls, we did not find any structural differences as evidenced by the lack of significant differences in cIMT, whether examined in the entire cohort of HCT survivors or separated by treatment. These results are similar to a previous study by our group13 in childhood cancer survivors who survived ≥5 years after diagnosis of leukemia, lymphoma, a central nervous system tumor, or a sarcoma. In that study we observed lower carotid vascular function in survivors of leukemia compared to their sibling controls, but no difference in cIMT. Like the present study, Turanlahti et al19 also did not find any difference in cIMT between HCT survivors and healthy controls. It should be noted that Vatanen et al18 reported greater cIMT in HCT survivors than healthy controls, but when the HCT survivors were analyzed by treatment (i.e., those who received TBI and those who did not) no significant difference in cIMT was observed between these two HCT treatments and healthy controls.
Surprisingly, even though we observed significantly reduced carotid vascular function in the present study, we did not find reductions in brachial artery endothelial dependent- or independent-dilation in patients who had undergone HCT compared to healthy sibling controls. In our previous studies of childhood cancer survivors13,20 we observed significant decreases in both brachial artery endothelial-dependent dilation13,20 and brachial artery endothelial-independent dilation20. Those previous studies differed from the current study mainly in that no subjects in the previous studies underwent HCT. In the initial study20, we examined brachial artery function in young adult survivors of childhood acute lymphoblastic leukemia and observed that patients who received chemotherapy had significant reductions in both endothelial-dependent and -independent brachial dilation compared to healthy controls. Adding radiation to the chemotherapy regimen did not result in any further decrements in brachial artery endothelial-dependent or -independent brachial dilation. In the other study13, we examined brachial artery function in 319 childhood cancer survivors who survived for ≥5 years after diagnosis of leukemia, lymphomas, central nervous system tumors, or sarcomas. Endothelial-dependent dilation was significantly lower in leukemia survivors compared to healthy sibling controls, while there was no difference in endothelial-dependent dilation between central nervous system tumor and sarcoma survivors and healthy sibling controls. Endothelial-independent dilation did not differ significantly between healthy sibling controls and childhood cancer survivors as a whole or individual diagnosis groups. In this study13, all of the leukemia survivors had undergone chemotherapy but few received radiation (14%). Some survivors of central nervous system tumors (32%) and solid tumors (29%) also received radiation, but most of the irradiation was localized to the tumor site. However, in this study13 it is hard to attribute changes in vascular structure and function to one particular treatment exposure due to significant differences in the treatment protocols received. Two other studies18,19 have also reported no significant difference between HCT survivors and healthy controls in brachial artery endothelial-dependent dilation. As stated at a recent NIH consensus conference on the late effects of pediatric HCT treatments5, the degree of cellular damage that occurs in these patients is related to the health status of the pre-HCT recipient, presence of other co-morbidities, and baseline organ function of the recipient at the time of the HCT regimen. Other factors such as the intensity of conditioning regimen, infections, drug exposures and delayed immune intolerance also contribute to the end-organ fibrosis and dysfunction.
It should be noted that the present study has some limitations. The population was predominantly white non-Hispanic so the findings may not be generalizable to other racial/ethnic groups. There was a small age differences between the HCT survivors and their healthy sibling controls. However, the benefit of using siblings as controls is that the environment was the same for both individuals. The statistical analysis was performed controlling for differences between HCT survivors and healthy sibling controls, including gender and age differences. Finally, there are a number of multiple comparisons, which could have an effect on the final interpretation of the results.
In conclusion, the present study suggests that use of total body irradiation in the HCT regimen has an effect on measures of carotid stiffness. The addition of central nervous system irradiation to total body irradiation may contribute further dysfunction in the carotid arteries. Although it is important for clinicians to monitor cardiovascular health in all HCT survivors, the data from the present study suggest that HCT survivors who received TBI plus CRT might be at even greater risk for cardiovascular disease. These individuals may require an even higher degree of monitoring. The monitoring of HCT survivors’ cardiovascular health should include ultrasound imaging of the carotid artery. Measurement of carotid intima-media thickness is routine in most cardiovascular centers. However, as indicated by the results in the present study ultrasound imaging of the carotid artery should not only include measures of carotid intima-media thickness, but should also include measures of carotid function (i.e., compliance, distensibility, incremental elastic modulus, etc.). Although measures of carotid function have not been typically done in the past many new ultrasound scanners can automatically calculate these measures of carotid function. However, even if cardiovascular centers are using an older ultrasound scanner that does not have the necessary software these measures can be easily calculated using the formulas provided in this manuscript.
Highlights.
HCT survivors have decreased carotid function compared to healthy siblings
High dose irradiation resulted in lower carotid function in HCT survivors
Due to increased CVD risk HCT survivors should undergo CVD monitoring
ACKNOWLEDGEMENTS
This project is support by funding from the NIH (R01 CA113930 to J.S.; R01CA112530 to K.S.B.). General Clinical Research Center Program (M01-RR00400), National Center for Research Resources (1UL1-RR033183), the Clinical and Translational Science Institute at the University of Minnesota-Twin Cities (UL1TR000114). Statistical support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
- 1.Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, et al. (eds). SEER Cancer Statistics Review, 1975–2014, National Cancer Institute; Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, posted to the SEER web site, April 2017. [Google Scholar]
- 2.Gurney J, Bondy ML. Epidemiology of childhood cancer In: Pizzo PA, Poplack DG, editors. Principles and Practice of Pediatric Oncology (ed Fifth Edition). Philadelphia: Lippincott Williams & Wilkins; 2006. p 1–13. [Google Scholar]
- 3.Meadows AT. Pediatric cancer survivors: past history and future challenges. Curr Probl Cancer 2003;27(3):112–126. [DOI] [PubMed] [Google Scholar]
- 4.Bhatia S, Francisco L, Carter A, Sun CL, Baker KS, Gurney JG, et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors. Report from the Bone Marrow Transplant Survivor Study. Blood. 2007;110(10):3784–3792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nieder ML, McDonald GB, Kida A, Hingorani S, Armenian SH, Cooke KR, et al. NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: long term organ damage and dysfunction following pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17:1573–1584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Chow EJ, Anderson L, Baker KS, Bhatia S, Guilcher GMT, Huang JT, et al. Late effects surveillance recommendations among survivors of childhood hematopoietic cell transplantation: A children’s oncology group report. Biol Blood Marrow Transplant. 2016;22:782–795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Gurney JG, Ness KK, Sibley SD, O’Leary M, Dengel DR, et al. Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 2006;107(6):1303–1312. [DOI] [PubMed] [Google Scholar]
- 8.Oeffinger KC, Adams-Huet B, Victor RG, Church TS, Snell PG, Dunn AL, et al. Insulin Resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2009;27(22):3698–3704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.van Waas M, Neggers SJ, Pieters R, van den Heuvel-Eibrink MM. Components of the metabolic syndrome in 500 adult long-term survivors of childhood cancer. Ann Oncol 2010;21(5):1121–1126. Epub 2009 Oct 22. [DOI] [PubMed] [Google Scholar]
- 10.Marlatt KL, Kelly AS, Steinberger J, Dengel DR. The influence of gender on carotid artery compliance and distensibility in children and adults. J Clin Ultrasound 2013:41(6):340–346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Celermajer DS, Sorensen KE, , Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–1115. [DOI] [PubMed] [Google Scholar]
- 12.Williamson EB, Bronas UG, Dengel DR. Automated edge detection versus manual edge measurement in analysis of brachial artery reactivity: a comparison study. Ultrasound in Medicine and Biology 34;1499–1503, 2008. [DOI] [PubMed] [Google Scholar]
- 13.Dengel DR, Kelly AS, Zhang L, Hodges JS, Baker KS, Steinberger J: Signs of early sub-clinical atherosclerosis in childhood cancer survivors. Pediatric Blood & Cancer 2014;61:532–537. [DOI] [PubMed] [Google Scholar]
- 14.Dengel DR, Bronas UG. The role of endothelial dysfunction on development and progression of atherosclerosis and methods to assess vascular function and structure. Am J Life Med 2010;4(6):445–456. [Google Scholar]
- 15.Lemne C, Jogestrand T, de Faire U. Carotid intima-media thickness and plaque in borderline hypertension. Stroke 1995;26:34–39. [DOI] [PubMed] [Google Scholar]
- 16.O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr.. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14–22. [DOI] [PubMed] [Google Scholar]
- 17.Smith SC Jr, Greenland P, Grundy SM. AHA Conference Proceedings. Beyond secondary prevention: identifying the high-risk patient for primary prevention. Executive Summary. Circulation 2000;1001:111–116. [DOI] [PubMed] [Google Scholar]
- 18.Vatanen A, Sarkola T, Ojala TH, Turanlahti M, Jahnukainen T, Saarinen-Pihkala UM, et al. Radiotherapy-related arterial intima thickening and plaque formation in childhood cancer survivors detected with very-high resolution ultrasound during adulthood. Pediatr Blood Cancer 2015;62:2000–2006. [DOI] [PubMed] [Google Scholar]
- 19.Turanlahti MI, Taskinen M, Saarinen-Pihkala U, Jokinen EV. Time-related arterial changes after allogenic hematopoietic stem cell transplantation in children. Pediatr Res 2013;73(6):777–782. [DOI] [PubMed] [Google Scholar]
- 20.Dengel DR, Ness KK, Glasser SP, Williamson EB, Baker KS, Gurney JG. Endothelial function in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2008;30:20–25. [DOI] [PubMed] [Google Scholar]