Pediatr Blood Cancer 2015;62:1832–1837

Arterial Stiffness in Childhood Cancer Survivors Julie I. Krystal, MD,1* Marina Reppucci, BA,2 Theresa Mayr, RN,1 Jonathan D. Fish, MD,1* and Christine Sethna, MD3 Background. Cardiovascular disease is prevalent among childhood cancer survivors (CCS). Arterial stiffness measured by pulse wave velocity (PWV) may be predictive of cardiovascular morbidity. Increased PWV has been seen in adults following chemotherapy. Purpose. To evaluate PWV in a cohort of CCS and healthy controls. Patients and Methods. All participants were >6 years old. CCS were >12 months off-therapy and free of cardiac disease, diabetes, and kidney dysfunction. Height, weight, blood pressure (BP), medications, cancer diagnosis, age at diagnosis, time off therapy, chemotherapy, and radiation exposures were recorded. PWV was measured on all participants. Results. Sixty-eight CCS (mean 17.3  6 years, 52.9% male), and 51 controls (mean 18.4 5.5 years, 37.3% male) were evaluated. Among CCS, 34% had lymphoma, 44% leukemia, and 22% solid tumors, and 49% were exposed to radiation. CCS were off

therapy 7 4.2 years. Both groups were statistically similar in age, BMI, and BP. CCS 18 years old had significantly higher PWV compared to controls 18 years old (6.37  0.89 vs. 5.76  0.88 m/sec, P ¼ 0.012). The relationship persisted in a regression model adjusted for age, sex, and BMI z-score (b ¼ 0.52, 95%CI 0.051–0.979, P ¼ 0.03). Seventy percent of CCS 18 had elevated PWV compared to established norms. Radiation therapy, anthracycline dose, and chemotherapy exposures were not predictive of increased PWV in CCS. Conclusions. CCS 18 demonstrated prematurely elevated PVW. Further studies are needed to determine the predictive value of PWV in this population and its utility as a screening modality. Pediatr Blood Cancer 2015;62:1832–1837. # 2015 Wiley Periodicals, Inc.

Key words: cardiotoxicity; late-effects of chemotherapy; pulse wave velocity

INTRODUCTION Cardiovascular disease is a major contributor to morbidity and mortality in the childhood cancer survivor (CCS) population, with cardiovascular disease ranking as a leading cause of death in CCS after secondary neoplasms and cancer recurrence.[1] CCS are at increased risk for congestive heart failure, coronary artery disease, valvular disease, and cerebrovascular accidents, and these occur earlier in CCS than in the general population.[2–5] Anthracycline exposure is toxic to cardiac myocytes, resulting in an increased risk of developing a cardiomyopathy that persists years following treatment.[6–13] Similarly, radiation damages the capillary endothelial cells, which leads to ischemia and ultimately myocardial cell death.[9] Heart failure, arrhythmia, valvular disease, myocardial fibrosis, and coronary artery disease all can occur following radiation.[6,12] Despite the substantial morbidity associated with cardiovascular disease among CCS, it remains difficult to predict when or in whom such complications will occur.[14,15] Although the risk to CCS is well documented, evidence supporting screening modalities for early detection is lacking. The Children’s Oncology Group’s screening guidelines suggest echocardiogram evaluation for patients exposed to anthracyclines or certain radiation fields,[16] but recent data have shown that even “low-risk” anthracycline doses of 6 years old, CCS were >12 months off of therapy, and CCS were free of diabetes, kidney disease, pulmonary disease, or cardiac dysfunction. Organ dysfunction was excluded by having a normal HbA1C within the previous 5 years, normal glomerular filtration rate (eGFR) for age, normal respiratory exam, and a normal echocardiogram within the previous 5 years. Patients who did not have a recent blood work or echocardiogram at the time of study entry were enrolled and retained as long as they had the studies performed within the following month. Controls were screened for diabetes, kidney, pulmonary, or cardiac disease by review of their medical chart, and were excluded for any such diagnoses. Height, weight, blood pressure (BP), and medications were recorded on all participants. Original cancer diagnosis, age at diagnosis, time off therapy, chemotherapy, and radiation exposures were collected for CCS. Regular medications were not held prior to testing, nor was caffeine withheld. Subjects were in a nonfasting state at the time of testing. This study was approved by the Institutional Review Board Abbreviations: BP, blood pressure; BMI, body mass index; DE, doxorubicin-equivalents; GFR, glomerular filtration rat 1 Division of Pediatric Hematology-Oncology, Cohen Children’s Medical Center, New Hyde Park, New York 11040; 2Hofstra Northshore-LIJ School of Medicine, Hempstead, New York; 3Division of Pediatric Nephrology, Cohen Children’s Medical Center, New Hyde Park, New York

Jonathan D. Fish and Christine Sethna contributed equally to this work and share last authorship. Conflict of interest: Nothing to declare. 

Correspondence to: Julie I. Krystal and Jonathan D. Fish, Cohen Children’s Medical Center, 269-01 76th Avenue, Suite 255, New Hyde Park, NY 11040. E-mail: [email protected]; [email protected] Received 18 February 2015; Accepted 16 March 2015

Arterial Stiffness in Childhood Cancer Survivors and the Cancer Services Scientific Review Committee of the North Shore-LIJ Health System and all participants provided written, witnessed informed consent.

Pulse Wave Velocity PWV is a simple, non-invasive measure of arterial stiffness utilizing applanation tonometry to analyze wave forms. PWV increases with increasing arterial stiffness. PWV is expressed as a change in distance over change in time (V¼DD/DT) in meters per seconds (m/sec).[24] Distance is measured at two sites along a single vessel or at two separate sites in the arterial tree. The SphygmoCor device, produced by AtCor Medical (West Ryde, Australia) derives a measure of arterial stiffness from peripherally acquired waveforms using tonometry simultaneously with an electrocardiogram (EKG). Cartoid–femoral PWV was used in this study. EKG leads were applied to the right arm, left arm, and left leg. The distance from the sternal notch to the carotid pulse (proximal distance), and from the sternal notch to the umbilicus and then to the femoral pulse (distal distance) were measured and entered into the SphygmoCor, along with the subject’s height, weight, and BP. The tonometry probe was applied to the carotid pulse and then femoral pulse, capturing approximately 10 sec of data, respectively. When possible, subjects had two PWV measurements. If the two measurements differed by >0.5 m/sec, a third measurement was taken. When multiple PWV measurements were recorded, the mean was used.

Statistical Analysis Descriptive analyses included means, standard deviation (SD), and distributions of categorical variables. Blood pressure index was calculated by dividing the BP of the subject by the age, sex, and height specific 95th percentiles for systolic and diastolic BP.[25] For adult

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participants, BP was indexed to systolic 140 mmHg and diastolic 90 mmHg.[26] A blood pressure index 1 indicated the presence of hypertension. Body mass index (BMI) was calculated using the measured height and weight. BMI was defined as weight/height2, expressed as kg/m2, and age- and sex-specific Z-scores (standard deviation scores) for height, weight, and BMI were calculated.[27] Demographic and clinical variables were compared between the CCS and control groups using the two sample t-test or x2 test, as appropriate. Differences in PWV were examined by multiple linear regression analysis adjusted for age, sex, and BMI z-score (variables chosen a priori). Correlations between PWV and clinical measures were evaluated by Pearson correlation analysis. Risk factors for higher PWV were examined in the CCS group only using multiple linear regression analysis. Potential risk factors included chemotherapy and radiation exposures, age, time off therapy, blood pressure, blood pressure index, BMI, BMI z-score, serum creatinine, and GFR. Analysis of variance (ANOVA) was used to examine the association between PWV and diagnosis. Diagnoses included Hodgkin disease (n ¼ 17), non-Hodgkin lymphoma (n ¼ 6), lymphoid leukemia (n ¼ 28), myeloid leukemia (n ¼ 2), and solid tumors (n ¼ 15).

RESULTS Between February and November 2014, 73 CCS were enrolled. Of these, five experienced device malfunction or did not wish to complete the study, leaving 68 CCS who underwent data analysis. Between February 2014 and February 2015, 51 control subjects were enrolled, all of whom completed the study. All PWV measurements on CCS were taken by three investigators, who’s calculated inter-rater reliability correlation coefficient was 0.94. CCS and controls were statistically similar in age, sex, and BP although the CCS had significantly lower BMI Z-scores than controls (Table I). More CCS were using medications than controls, with the most frequent medication being vitamins or supplements,

TABLE I. Participant Demographics

Age, years Sex, N BMI, kg/m2 BMI z-score Systolic blood pressure, mm Hg SBP index Diastolic blood pressure, mm Hg DBP index Medication usage, N/% Medications used, N Propecia Synthroid Oral contraceptive pills Antihistamine Psychiatric medications (ADHD, depression) Albuterol/asthma meds Hormone replacement Vitamins/supplements Other Pulse wave velocity (m/sec)

CCS (n ¼ 68)

Controls (n ¼ 51)

P-value

17.3  6.0 36 M, 32 F 23.4  5.4 ()0.17  0.1 114.3  11.3 0.88  0.08 72.2  8.5 0.86  0.1 25 (36.8%)

18.5  5.5 19 M, 32 F 23.7  3.2 0.46  1.02 114  18.8 .87  0.14 69.4  9.5 0.82  0.11 3 (5.8%)

NS NS NS

Arterial stiffness in childhood cancer survivors.

Cardiovascular disease is prevalent among childhood cancer survivors (CCS). Arterial stiffness measured by pulse wave velocity (PWV) may be predictive...
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