Author + information
- Received May 13, 2014
- Revision received November 2, 2014
- Accepted November 4, 2014
- Published online February 17, 2015.
- John D. Groarke, MBBCh, MPH∗,†,‡,
- Varsha K. Tanguturi, MD∗,
- Jon Hainer, BS†,
- Josh Klein, BA†,
- Javid J. Moslehi, MD∗,‡,
- Andrea Ng, MD§,
- Daniel E. Forman, MD∗,†,
- Marcelo F. Di Carli, MD∗,† and
- Anju Nohria, MD∗,‡∗ ()
- ∗Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- †Noninvasive Cardiovascular Imaging Program, Department of Medicine (Cardiovascular Division) and Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts
- ‡Cardio-Oncology Program, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts
- §Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Anju Nohria, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115-6110.
Background Hodgkin lymphoma (HL) survivors treated with thoracic radiation therapy (RT) have impaired exercise tolerance and increased cardiovascular mortality.
Objectives The purpose of this study was to evaluate the prevalence of autonomic dysfunction and its implications on exercise capacity and mortality in long-term survivors of HL.
Methods Exercise parameters in 263 HL survivors referred for exercise treadmill testing at a median interval of 19 years after RT were compared with 526 age-, sex-, and cardiovascular risk score–matched control subjects. Within the RT cohort, the presence of autonomic dysfunction, defined by an elevated resting heart rate (HR) (≥80 beats/min) and abnormal heart rate recovery (HRR) at 1 min (≤12 beats/min if active cool-down, or ≤18 beats/min if passive recovery), was correlated with exercise capacity and all-cause mortality over a median follow-up of 3 years.
Results RT was associated with elevated resting HR and abnormal HRR after adjusting for age, sex, cardiovascular risk factors, medications, and indication for exercise treadmill testing: odds ratio: 3.96 (95% confidence interval [CI]: 2.52 to 6.23) and odds ratio: 5.32 (95% CI: 2.94 to 9.65), respectively. Prevalence of autonomic dysfunction increased with radiation dose and time from RT. Both elevated resting HR and abnormal HRR were associated with reduced exercise capacity in RT patients. Abnormal HRR was also associated with increased all-cause mortality (age-adjusted hazard ratio: 4.60 [95% CI: 1.62 to 13.02]).
Conclusions Thoracic RT is associated with autonomic dysfunction, as measured by elevated resting HR and abnormal HRR. These abnormalities are associated with impaired exercise tolerance, and abnormal HRR predicts increased all-cause mortality in RT patients.
- abnormal heart rate recovery
- cardiac autonomic dysfunction
- elevated resting heart rate
- Hodgkin lymphoma
- radiation therapy
Thoracic radiation therapy (RT) is associated with increased cardiovascular morbidity and mortality (1–3). In particular, delayed cardiotoxicity is seen in long-term survivors of Hodgkin lymphoma (HL) treated with high-dose (36 to 45 Gy) extended-field or mantle radiation (4,5). Although radiation-related injuries to the coronary arteries, valves, myocardium, and pericardium are well described, autonomic injury has been suggested (6) but not accurately quantified in HL survivors. Furthermore, whether autonomic dysfunction contributes to impaired exercise tolerance and prognosis in HL survivors is unknown.
Elevated resting heart rate (HR) and abnormal heart rate recovery (HRR) after exercise are established markers of autonomic dysfunction (7) that are associated with cardiovascular morbidity and mortality (8) and with all-cause mortality in many patient populations (9–13). We examined the prevalence and functional and prognostic significance of elevated resting HR and abnormal HRR in HL survivors treated with RT and referred for exercise treadmill testing (ETT).
We identified 498 survivors of HL among 25,059 consecutive patients undergoing ETT at the study institution between January 2003 and October 2013. Medical record review confirmed whether HL patients received thoracic RT before ETT. Patients undergoing exercise protocols other than the standard Bruce protocol and those in atrial fibrillation or paced rhythms at or during ETT were excluded to yield 263 patients in the radiation cohort. For every RT patient, 2 patients matched by age, sex, and Morise clinical risk score were identified from the ETT database to yield 526 control subjects (Online Figure 1). The Morise score considers age, sex, symptoms, tobacco use, hyperlipidemia, diabetes mellitus, hypertension, estrogen status, body mass index, and family history of coronary artery disease to assess the pretest probability of coronary artery disease (14). Similar exclusion criteria were applied to control patients. The Partners Healthcare Institutional Review Board approved this study.
Risk factor assessment
Demographic factors, symptoms, cardiovascular risk factors, and medications were determined at the time of ETT by use of structured patient interviews and medical chart review. Ischemic heart disease (IHD) was defined as any history of myocardial infarction, coronary revascularization, or angiographic coronary artery disease. Congestive heart failure was defined as any documented history of heart failure, cardiomyopathy, or loop diuretic use at the time of ETT. Hyperlipidemia included any history of hyperlipidemia or statin use at the time of ETT. Diabetes was defined as any documented history of diabetes or current use of insulin or oral hypoglycemic agents. Ongoing or prior tobacco use defined a positive smoking history.
Age at HL diagnosis, year of RT, interval from RT to ETT, radiation field, and anthracycline exposure were determined from medical chart review. The dose of thoracic RT was available for 183 of 263 (69.6%) patients.
All patients underwent ETT according to the standard Bruce protocol (15) without interruption of baseline cardiac medications. HR on the 12-lead electrocardiogram and manually measured blood pressure (BP) were recorded at rest in the supine position, after each 3-min stage of exercise, at maximum exercise, and at 1, 3, and 5 min in recovery. Exercise was continued until one or more of the following endpoints was reached: exhaustion, symptom limitation, ≥85% of age-predicted maximal HR (APMHR), ≥10 mm Hg decline in systolic BP from baseline, sustained ventricular tachycardia, ST-segment depression ≥3 mm measured at 80 ms after the J-junction, or ST-segment elevation ≥1 mm. ETTs performed as part of stress myocardial perfusion imaging involved a 1-min active cool-down at 1.5 miles/h recovery protocol, whereas ETTs performed alone or during stress echocardiography involved passive recovery in the supine position. ETTs were performed, analyzed, and reported according to international standards (16) with the use of a computerized database.
Echocardiographic assessment of left ventricular diastolic function
One hundred fifty-four of 263 (58.6%) RT patients had necessary images acquired at resting transthoracic echocardiograms performed 0.6 (interquartile range [IQR]: 5.5 to 0.5) days before the index ETT to allow retrospective quantification of the following parameters: peak early diastolic tissue velocity (E′) measured from the septal and lateral mitral annulus, mitral inflow Doppler E- and A-wave velocities, E/A ratio, and E-wave deceleration time. Left atrial volume was assessed by use of the biplane area-length method at end systole from apical 2- and 4-chamber views and indexed to body surface area (17). These data were used in exploratory subgroup analyses to evaluate the association of primary endpoints with diastolic function.
Primary endpoints included elevated resting HR and abnormal HRR at 1 min.
Secondary endpoints included other exercise parameters with prognostic significance in non-HL populations. These were: 1) workload in metabolic equivalents (METs); 2) percentage of APMHR achieved; 3) rate-pressure product; 4) abnormal systolic BP response to exercise; 5) Duke treadmill score; 6) chronotropic incompetence; and 7) reserve pulse pressure. The individual endpoints are defined in Table 1.
Follow-up and all-cause mortality
All-cause mortality was assessed for the RT cohort through the use of the Social Security Death Index in January 2014. The median follow-up period was 3.0 (IQR: 1.5 to 4.6) years after the index ETT.
Continuous, normally distributed variables are presented as mean ± SD and compared by use of the Student t test. Continuous, non-normal data are presented as median with interquartile range and compared by use of the Wilcoxon rank-sum test. Categorical variables are presented as percentages and compared by use of the Fisher exact test. HR and systolic BP measured at rest, at 3-minute intervals during exercise, and in recovery were compared between cohorts by use of separate Student t tests without adjustments for repeated measures. Study endpoints were dichotomized as normal or abnormal on the basis of the definitions in Table 1. Logistic regression was used to examine the relationship between RT and individual endpoints. Multivariable logistic regression was used to control for aggregate confounding by age, sex, cardiovascular risk factors, medications, indication for ETT referral, exercise performance, and anthracycline exposure. The effects of radiation dose, interval from RT, radiation field, and anthracycline exposure on the association of primary endpoints with RT were explored in subgroup analyses. Univariable linear regression was used to assess the relationship between continuous exercise HR and BP parameters and RT. Multiple linear regression was used to control for potential confounders. Multivariable logistic regression was used to assess the relationship between the primary endpoints and exercise performance in RT patients.
Cox proportional hazards regression models were used to estimate the risk of all-cause mortality associated with primary and secondary endpoints in RT patients. The assumption of proportional hazards was assessed on the basis of Martingale residuals. Group survival rates were compared by use of the log-rank test. To assess for bias introduced by IHD or the use of atrioventricular nodal (AVN)-blocking agents on the association between abnormal HRR and all-cause death, analyses were repeated, censoring all patients with a history of IHD or AVN-blocking medications, respectively.
All statistical analyses were performed with the use of SAS version 9.3 (SAS Institute, Cary, North Carolina). To adjust for multiple testing, a Bonferroni-adjusted p value of <0.025 was considered statistically significant.
Baseline characteristics are shown in Table 2. RT patients were leaner and had a higher prevalence of IHD, hyperlipidemia, and statin use compared with that in control subjects. RT patients received radiation at a mean age of 30.0 ± 12.4 years and underwent ETT at a median interval of 19 years (interquartile range [IQR]: 12 to 26 years) after treatment. The median radiation dose was 38 Gy (IQR: 36 to 40 Gy), and 46% received concomitant anthracycline chemotherapy. The neck was included in the radiation field for 220 of 263 (83.7%) patients and excluded in 18 (6.8%) patients treated with mediastinal RT only. Neck radiation could not be confirmed for the remaining 25 (9.5%) patients who received involved field RT.
Electrocardiographic changes with exercise testing
Control patients more frequently underwent ETT for evaluation of chest pain or arrhythmias, whereas the majority of RT patients (71.1%) were referred for indications other than symptom evaluation, including elective post-radiation cardiovascular screening (Online Table 1). Despite differences in referral indications, RT patients were more likely to have positive ETTs (17.9% vs. 7.4%, p < 0.0001), and a greater proportion had moderate or high-risk Duke treadmill scores compared with control subjects (19.4% vs. 12.6%, p = 0.01) (Online Table 1).
RT patients had a significantly higher resting HR than did matched control subjects (78 ± 12 beats/min vs. 68 ± 12 beats/min, p < 0.0001) (Table 3). The resting HR distribution for each cohort is shown in Figure 1A⇓. Crude and adjusted odds ratios (OR) for the association between RT and elevated resting HR are presented in Table 4. These associations remained significant after excluding patients with a history of IHD (Online Table 2). Stratified analyses demonstrated effect modification of this association by sex: RT was associated with a crude OR for elevated resting HR of 6.22 (95% confidence interval [CI]: 4.00 to 9.67; p < 0.0001) for women and 1.90 (95% CI: 1.10 to 3.27; p = 0.02) for men. Although there were no significant differences in the median dose of RT or interval from RT to ETT between men and women, women were significantly younger than men at the time of RT (28 ± 11 years vs. 32 ± 14 years; p = 0.006).
RT patients had a greater frequency of abnormal HRR than did matched control subjects (31.9% vs. 9.3%, p < 0.0001) (Table 3). The HRR distributions for each cohort are presented in Figure 1B. The crude and adjusted ORs for the association between RT and abnormal HRR are presented in Table 4 and remained significant after excluding patients with a history of IHD (Online Table 2). There was no evidence of effect modification by sex in stratified analyses.
Although there were no differences in exercise duration, METs, or percentage of APMHR achieved between the 2 cohorts, the rate-pressure product at peak exercise was significantly lower among RT patients (25,065 ± 5,459 vs. 26,411 ± 5,794; p = 0.002) (Online Table 1). Importantly, in RT patients, exercise duration was significantly reduced among those with an elevated resting HR (9.2 ± 2.9 min vs. 10.7 ± 3.1 min; p < 0.0001) and those with abnormal HRR (8.3 ± 3.1 min vs. 10.6 ± 2.9 min; p < 0.0001). Elevated resting HR and abnormal HRR were associated with a 1.1 ± 0.3–min (p = 0.001) and a 1.0 ± 0.4–min (p = 0.006) reduction in exercise duration, respectively, after adjusting for age, sex, cardiovascular risk factors, medications, indication for ETT, and ETT result. In similar adjusted analyses, elevated resting HR and abnormal HRR were associated with a 1.1 ± 0.4 (p = 0.002) and a 1.0 ± 0.4 (p = 0.007) reduction in METs achieved among RT patients, respectively.
Heart rate response to exercise
Although mean HR at rest and at stages 1 through 3 of exercise was greater in the RT cohort compared with that in control subjects, there was no difference in the peak HR achieved (Figure 2A). Although, HR reserve was significantly lower in the RT cohort, the prevalence of chronotropic incompetence was similar between cohorts (Table 3).
Blood pressure response to exercise
Resting systolic and diastolic BP were similar between RT and control patients: 121 ± 16 mm Hg versus 124 ± 17 mm Hg (p = 0.07) and 75 ± 9 mm Hg versus 76 ± 10 mm Hg (p = 0.10), respectively. However, the systolic BP response at all stages of exercise was blunted in RT patients compared with that in control subjects (Figure 2B). Furthermore, RT patients were more likely to have an abnormal systolic BP response to exercise and abnormal reserve pulse pressure compared with that in control subjects (Table 3). Crude and adjusted ORs for the association between RT and key exercise parameters for all patients (n = 789) and for those without a history of IHD (n = 696) are presented in Table 4 and Online Table 2, respectively.
Left ventricular diastolic function
Left ventricular diastolic echocardiographic parameters and indexed left atrial volumes compared among RT patients with normal versus elevated resting HR and with normal versus abnormal HRR are presented in Online Table 3. Absolute E/E′ ratios were significantly higher among RT patients with abnormal HRR compared with those with normal HRR: lateral E/E′ 10.08 (IQR: 7.05 to 12.52) versus 6.98 (IQR: 5.96 to 9.03), p = 0.002, and septal E/E′ 11.80 (IQR: 9.47 to 16.69) versus 9.25 (IQR: 7.68 to 12.19), p < 0.001. No such differences in E/E′ ratios were identified within RT patients with or without an elevated resting HR.
Variation in primary endpoints with interval from RT, dose of radiation, radiation field, and anthracycline exposure
RT patients were divided into tertiles on the basis of interval from RT to ETT. Frequency of elevated resting HR and abnormal HRR increased with time from RT (Figure 3). Every 5-year increase in interval from RT was associated with a 1.0 ± 0.4 beats/min (p = 0.01) increase in resting HR and a 1.5 ± 0.4 beats/min (p < 0.0001) decline in HRR after adjusting for age, sex, body mass index, diabetes, IHD, congestive heart failure, AVN-blocking agents, result of ETT, and exercise time.
Radiation dose was available for 69.6% of the RT cohort; the median dose of 38 Gy was used to dichotomize patients into low-dose (n = 91, dose = 36 Gy [IQR: 31 to 36 Gy] and high-dose cohorts (n = 92, dose = 40 Gy [IQR: 40 to 42 Gy]). Prevalence of elevated resting HR did not differ between high- and low-dose patients (56.7% vs. 43.3%, p = 0.10), even after adjusting for age, sex, and AVN-blocking agents (OR: 1.74; 95% CI: 0.90 to 3.37; p = 0.10). However, the prevalence of abnormal HRR was significantly higher in the high-dose group (46.7% vs. 14.3%, p < 0.0001), even after adjusting for age, sex, and AVN-blocking agents (OR: 4.02; 95% CI: 1.90 to 8.47; p = 0.0003).
Prior neck radiation was associated with an increased likelihood of both elevated resting HR and abnormal HRR compared with patients treated with mediastinal radiation alone (OR: 4.04; 95% CI: 1.24 to 15.64; p = 0.01 and OR: 9.71; 95% CI: 1.26 to 74.37; p = 0.008, respectively).
There was no significant independent association between anthracycline exposure and elevated resting HR or abnormal HRR in adjusted analyses.
All-cause mortality and survival analyses
Nineteen of 263 (7.2%) RT patients died over a median follow-up of 3.0 (IQR: 1.5 to 4.6) years. Elevated resting HR was not associated with mortality in this group. However, abnormal HRR was associated with an increased risk of death: unadjusted hazard ratio = 5.50 (95% CI: 1.97 to 15.36; p = 0.001) (Figure 4, Online Figure 2). Age- and sex-adjusted hazard ratios for this association were 4.60 (95% CI: 1.62 to 13.02; p = 0.0005) and 6.24 (95% CI: 2.20 to 17.70; p = 0.0002), respectively. Unadjusted, age-adjusted, and sex-adjusted hazard ratios for the secondary endpoints are presented in Online Figure 2.
After excluding patients with IHD (n = 41, 15.6%), 11 of 222 (5.0%) RT patients died over a median follow-up of 3.0 (IQR: 1.6 to 4.6) years. Abnormal HRR remained significantly associated with mortality in this IHD-naive cohort (hazard ratio: 6.32; 95% CI: 1.67 to 23.91; p = 0.007). Similarly, after excluding patients receiving AVN-blocking agents (n = 73, 27.8%), 9 of 190 (4.7%) patients died over a median period of 3.0 years (IQR: 1.6 to 4.7 years), and abnormal HRR remained significantly associated with mortality (hazard ratio: 9.06; 95% CI: 1.85 to 44.43]; p = 0.007). Furthermore, abnormal HRR predicted mortality after adjusting for left ventricular ejection fraction among 226 RT patients with echocardiographic data available (hazard ratio: 12.31; 95% CI: 2.76 to 54.80; p = 0.001).
HL survivors treated with thoracic RT are at increased risk for cardiovascular morbidity and mortality (2,18). Although the risk of premature IHD, valvular disease, and myopericardial disease is clearly recognized, autonomic dysfunction has not been well described in these patients. To our knowledge, this is the first study to demonstrate that RT is associated with an elevated resting HR and abnormal HRR compared with that in matched control subjects in a large cohort of HL survivors. Autonomic dysfunction increases with time from RT and is independent of other cardiac risk factors and established cardiovascular disease. Survivors of RT with an elevated resting HR or abnormal HRR have reduced exercise capacity on ETT. Furthermore, abnormal HRR predicts all-cause mortality, which suggests that autonomic dysfunction may contribute to the adverse outcomes seen in HL survivors of RT (Central Illustration).
The autonomic nervous system regulates the hemodynamic response to exercise (19,20). Parasympathetic tone predominates in the resting state. Hemodynamic compensation during initial exercise is mediated by parasympathetic withdrawal, followed by sympathetic activation as exercise progresses. Prompt restoration of parasympathetic tone after cessation of exercise and subsequent adrenergic withdrawal mediate HRR (21). Autonomic dysfunction is characterized by attenuated parasympathetic and increased sympathetic activity. In this study, HL survivors had a higher prevalence of autonomic dysfunction, as evidenced by a higher resting HR and abnormal HRR compared with that in radiation-naive control subjects. Moreover, RT patients had a blunted systolic BP response to exercise, a potential further indication of autonomic abnormalities. These findings agree with a prior study of 48 childhood HL survivors showing an elevated resting HR on ambulatory Holter monitoring and a blunted HR or BP response to exercise (6). We demonstrated progressive autonomic dysfunction with increasing interval from RT. Additionally, higher doses of RT predisposed to abnormal HRR. These observations suggest possible dose-related radiation-mediated injury of the autonomic nervous system, with a progressive and late manifestation over time. Given the increased prevalence of elevated resting HR and abnormal HRR in patients with neck radiation, it is likely that injury at the level of the vagus nerve/carotid sinus is the dominant contributor to the observed autonomic dysfunction. However, given the small number of patients who received mediastinal RT alone (n = 18), we are cautious to avoid conclusive statements regarding the mechanism of injury. Furthermore, the interval from RT to ETT was much longer in patients with neck exposure: 21 years (IQR: 15 to 28 years) versus 10 years (IQR: 8 to 11 years), p < 0.0001. This difference reflects recent changes in HL treatment practices to limit unnecessary radiation exposure and may confound the observed differences between patients with and those without neck RT.
In childhood HL survivors, elevated resting HR is associated with self-reported exercise limitation on quality-of-life questionnaires (6). Although there were no differences in overall exercise capacity between RT patients and control subjects, elevated resting HR and abnormal HRR were associated with impaired exercise performance within RT patients. These data provide novel evidence that autonomic dysfunction might contribute to objective functional limitation in RT survivors. Additionally, we cannot exclude the possibility that diastolic dysfunction, as suggested by our limited echocardiographic analyses, might have also contributed to the impaired exercise performance seen in patients with autonomic abnormalities. Others have previously shown an association between autonomic abnormalities and diastolic dysfunction (22). Although the mechanisms remain poorly understood, autonomic influences on myocardial calcium handling might adversely influence left ventricular relaxation (23) and exercise tolerance in RT patients.
Autonomic dysfunction is associated with increased mortality in patients with coronary artery disease and congestive heart failure and in asymptomatic patients at risk for cardiovascular disease (10,11,24–26). In this study, abnormal HRR was associated with a 5-fold-higher age-adjusted risk of death among RT patients. Although we failed to demonstrate an association between elevated resting HR and mortality, other studies have shown that an elevated resting HR is an independent predictor of sudden (10), cardiovascular (13), and all-cause (10,12) death in nonradiation patients. Limited sample size and short follow-up duration probably prevented us from detecting an association between elevated resting HR and mortality. We also evaluated other established exercise parameters known to predict adverse outcomes in nonradiation cohorts. Exercise time, failure to achieve ≥85% APMHR, Duke treadmill score, chronotropic incompetence, abnormal systolic BP response, and abnormal pulse pressure reserve were each predictive of all-cause mortality in RT patients. These findings validate the prognostic utility of ETT in this patient population.
The retrospective nature of this study poses several inherent limitations. We cannot exclude selection bias in both the RT and control patients referred for ETT. However, this is the largest study to date that evaluates hemodynamic responses to exercise after thoracic RT and thus provides novel information regarding autonomic abnormalities in these patients. The recovery protocol varied according to whether ETT was performed in isolation or as part of a stress imaging study; however, the definitions of HRR applied were test-specific to account for this variability. We were also unable to assess other validated measures of autonomic dysfunction such as HR variability (27). Our ability to detect differences in exercise tolerance of RT and control patients was limited, given that physical exhaustion was not the exercise endpoint for all patients. However, similar exercise performance in the RT and exercise cohorts suggests that exercise conditioning was comparable between groups. Furthermore, we were able to demonstrate reduced exercise performance in RT patients with evidence of autonomic dysfunction. We were unable to detect a dose-response relationship between RT and elevated resting HR, given the narrow range of radiation doses observed in this study (IQR: 36 to 40 Gy). In addition, data on thoracic radiation dose were available for only 69.6% of patients, given the long interval from RT to ETT and/or off-site treatment in some cases with the associated challenges in medical record retrieval. Echocardiographic data were not available for all patients, which limited our ability to fully quantify the contribution of diastolic function to the abnormal functional capacity noted in this study. All-cause mortality was assessed through the use of the Social Security Death Index, which has inherent limitations. The low number of deaths during the limited follow-up in the RT cohort restricted the number of confounders that could be controlled for simultaneously in survival analyses and limited meaningful evaluation of causes of death. Regardless, we were able to demonstrate the prognostic significance of abnormal HRR after controlling for age, sex, IHD, left ventricular ejection fraction, and AVN-blocking agents, individually.
These findings have important clinical implications for the evaluation and management of HL survivors treated with thoracic RT. First, it is important for clinicians to appreciate the increased prevalence of autonomic dysfunction in this patient population. Second, these abnormalities may contribute to the reduced exercise tolerance experienced by these patients (28,29). Third, abnormal HRR after thoracic RT identifies patients at increased risk of all-cause mortality who may warrant further evaluation. Last, the potential benefit of interventions that modulate adrenergic tone such as beta-blockers, angiotensin-converting enzyme inhibitors, and structured exercise training should be evaluated in future clinical trials (30). Although we do not necessarily endorse routine exercise testing, as currently recommended in a consensus statement (39), attention to abnormalities in autonomic function may allow clinicians to identify higher-risk patients even in the absence of overt cardiovascular symptoms.
Survivors of HL treated with thoracic RT demonstrate higher resting HR and an increased propensity for abnormal HRR compared with that in age-matched, sex-matched, and clinical risk score–matched control subjects. These observations suggest that sympathovagal imbalance may be secondary to radiation-mediated injury of the autonomic nervous system. Furthermore, objective exercise capacity is reduced in the presence of autonomic dysfunction, and abnormal HRR predicts increased all-cause mortality among RT patients. Further studies are required to evaluate therapeutic interventions that modulate this sympathovagal imbalance.
COMPETENCY IN MEDICAL KNOWLEDGE: Survivors of mantle and mediastinal radiation therapy for Hodgkin lymphoma have a higher prevalence of elevated resting heart rate (HR) and abnormal HR recovery after exercise compared with a control group of individuals who have not undergone radiation therapy. These variables are associated with diminished exercise capacity, and abnormal HR recovery is associated with increased mortality among radiation therapy survivors.
TRANSLATIONAL OUTLOOK: Further studies are needed to evaluate the impact on clinical outcomes of therapeutic interventions that affect autonomic mechanisms and HR responses in survivors of mediastinal and mantle radiation therapy.
For supplementary tables and figures, please see the online version of this article.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- age-predicted maximal heart rate
- atrioventricular node
- blood pressure
- exercise treadmill test
- Hodgkin lymphoma
- heart rate
- heart rate recovery
- ischemic heart disease
- metabolic equivalents
- radiation therapy
- Received May 13, 2014.
- Revision received November 2, 2014.
- Accepted November 4, 2014.
- American College of Cardiology Foundation
- Gustavsson A.,
- Eskilsson J.,
- Landberg T.,
- et al.
- Jaworski C.,
- Mariani J.A.,
- Wheeler G.,
- Kaye D.M.
- Adams M.J.,
- Lipsitz S.R.,
- Colan S.D.,
- et al.
- Lauer M.S.
- Gibbons R.J.,
- Balady G.J.,
- Beasley J.W.,
- et al.
- Lang R.M.,
- Bierig M.,
- Devereux R.B.,
- et al.
- Lahiri M.K.,
- Kannankeril P.J.,
- Goldberger J.J.
- Mora S.,
- Redberg R.F.,
- Sharrett A.R.,
- Blumenthal R.S.
- Nolan J.,
- Batin P.D.,
- Andrews R.,
- et al.
- La Rovere M.T.,
- Bigger J.T. Jr..,
- Marcus F.I.,
- et al.
- ↵(1996) Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93:1043–1065.
- Villani F.,
- Busia A.,
- Villani M.,
- et al.
- Busia A.,
- Laffranchi A.,
- Viviani S.,
- et al.
- Vivekananthan D.P.,
- Blackstone E.H.,
- Pothier C.E.,
- Lauer M.S.
- Watanabe J.,
- Thamilarasan M.,
- Blackstone E.H.,
- et al.
- Tanaka H.,
- Monahan K.D.,
- Seals D.R.
- Olivotto I.,
- Maron B.J.,
- Montereggi A.,
- et al.
- Shaw L.J.,
- Peterson E.D.,
- Shaw L.K.,
- et al.
- Brubaker P.H.,
- Kitzman D.W.
- Thomas D.,
- Al-Mallah M.,
- Govindarajulu U.,
- et al.
- Lancellotti P.,
- Nkomo V.T.,
- Badano L.P.,
- et al.