Autonomic Dysfunction in Early Breast Cancer
Autonomic Dysfunction in Early Breast Cancer
Autonomic dysfunction represents a loss of normal autonomic control of the cardiovascular system associated with both sympathetic nervous system overdrive and reduced efficacy of the parasympathetic nervous system. Autonomic dysfunction is a strong predictor of future coronary heart disease, vascular disease, and sudden cardiac death. In the current review, we will discuss the clinical importance of autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review the effects of antineoplastic therapy on autonomic function, as well as discuss secondary exposures, such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness, which may negatively impact autonomic function in breast cancer patients. Lastly, we review potential strategies to improve autonomic function in this population. The perspective can help guide new therapeutic interventions to promote longevity and cardiovascular health among breast cancer survivors.
Because of significant improvements in early detection and adjuvant therapy, early breast cancer patients are now expected to live long enough to be at risk for competing causes of death. Cardiovascular disease (CVD) is rapidly becoming the predominant cause of mortality in breast cancer survivors older than 60 years. The magnitude of this problem is likely to increase with the aging of the US population, improvements in breast cancer–specific survival, and the continued use of antineoplastic agents with cardiovascular toxicities. Thus, given the nearly 3 million breast cancer survivors in the United States, the number of women at excess risk for CVD is likely to increase dramatically over the next 2 decades, requiring specific strategies to predict and mitigate these risks.
Adjuvant therapies used in the current treatment of early breast cancer are associated with unique and varying degrees of direct (eg, cardiac dysfunction) as well as indirect (eg, unfavorable CVD risk factors) sequential and progressive cardiovascular insults. In current oncology practice, the "cardiovascular" impact of cytotoxic therapies is evaluated solely by changes in resting left ventricular ejection fraction (LVEF). However, LVEF is load, rate, and contractility dependent; and acute declines in myocardial function can be initially compensated for to maintain cardiac output. Thus, left ventricular dysfunction is a late marker, only becoming evident after significant myocardial damage has already occurred. Therefore, alternative tools are required to identify patients at high risk for adverse cardiovascular impacts before significant damage develops.
The term autonomic dysfunction describes a loss of normal autonomic regulation of the cardiovascular system associated with both excessive sympathetic nervous system (SNS) activation and a reduced ability of the parasympatheic nervous system (PNS) to deactivate appropriately. Autonomic dysfunction can result in increased heart rate, atrioventricular node conduction, and left ventricular contractility. The autonomic nervous system also regulates various hormonal systems including the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system (RAAS), and the endocannabinoid system. Thus, autonomic dysfunction may also promote oxidative stress, reduce vasodilation, increase chronic inflammation, and accelerate atherosclerosis progression leading to CVD. Clinically, the onset and progression of autonomic dysfunction can manifest through chronically elevated heart rates and a loss of normal heart rate variability (HRV), which becomes both a marker of increased risk and, through decreased cardiac resilience, a mediator of adverse cardiovascular consequences.
The current review will highlight the emerging data on autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review current methods for assessing cardiac autonomic function and the effects of antineoplastic therapy on autonomic function. We will also discuss secondary exposures—such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness—that occur in breast cancer patients and may adversely impact autonomic function. Finally, potential strategies to prevent and/or mitigate autonomic dysfunction will be discussed. Ultimately, this review sets the stage for future studies to unravel potential interventions via the autonomic pathway to prevent competing risk of CVD among breast cancer patients.
Healthy autonomic function is the capacity of the autonomic nervous system to deliver appropriate stimulatory and inhibitory signals through sympathetic and parasympathetic pathways. The interplay between sympathetic and parasympathetic inputs is vital for the regulation of cardiac output via changes in heart rate, electrical conduction, left ventricular contractility, vascular tone, and blood pressure.
Changes in cardiac autonomic function can be tracked by several techniques (Table I). The simplest measure of cardiac autonomic status is resting heart rate. Greater autonomic dysfunction is associated with increasing resting heart rates over time. A more robust measure of autonomic function is HRV, which is measured using continuous heart rate monitoring. Heart rate variability is a set of parameters that reflects interval fluctuations between sequential beats of the heart. Measures derived from interval differences between successive beats reflect parasympathetically modulated changes in heart rate. Other HRV measures reflect the combined signaling of the 2 arms of the autonomic nervous system and reflect both intrinsic (eg, baroreflex, renin-angiotensin, sleep cycles, circadian) and extrinsic (activity, rest) rhythms. In general, decreased or decreasing HRV would be a signal for worse cardiac autonomic dysfunction. However, a higher, but more disorganized, HRV pattern, detectable by certain "nonlinear" HRV measures, also reflects greater cardiac autonomic dysfunction. Ideally, HRV is measured using a 24-hour ambulatory monitoring that can capture both daytime heart rate patterns and heart rate patterns during sleep, providing insights into circadian rhythm, sleep quality, and possible sleep-disordered breathing or periodic limb movements, all of which affect cardiac autonomic functioning. However, significant clinical information can be obtained from shorter recordings performed, perhaps, at the time of clinical visits and in association with standard "bedside autonomic tests."
Heart rate recovery (HRR) and chronotropic competence, assessed after submaximal or maximal exercise stress testing, also reflect the health of cardiac autonomic regulation. Traditionally, HRR is measured as the difference in heart rate assessed at peak exercise and 1-minute postexercise. A reduction of <12 beat/min or the 10th percentile within the first minute reflects inadequate reactivation of the parasympathetic nervous system poststress. Chronotropic competence describes the ability of the heart to adjust its intrinsic rate appropriately for the level of cardiovascular demand during exercise testing. Chronotropic competence is commonly determined from measurement of heart rate reserve (difference between heart rate at peak exercise compared with rest) or achievement of age-predicted maximal heart rate.
The importance of autonomic dysfunction as a marker of CVD risk was first demonstrated in a series of studies of canines subjected to transient ischemia in the post–myocardial infarction (MI) setting. In these studies, the presence of parasympathetic activity (or lack of sympathetic activation) was associated with a lower incidence of sudden cardiac death. A subsequent study in humans demonstrated that decreased HRV and an impaired baroreceptor reflex were prognostic of cardiac death independent of baseline LVEF among post-MI patients. After 21 months of follow-up, impaired 24-hour HRV was associated with a 3-fold higher risk of cardiac mortality in men and women (hazard ratio, 2.8; 95% CI, 1.2–6.2) compared with individuals with normal HRV measures. Cole et al extended these findings by showing that HRR after exercise testing was strongly predictive of all-cause mortality after multivariable adjustment (hazard ratio, 2.0; 95% CI, 1.5–2.7) among individuals referred for exercise testing. This has been corroborated by others and found to be independent of angiographic severity and cardiac function. Importantly, more recent studies suggest that resting heart rate, the simplest measure of autonomic functioning, is also a powerful predictor of future CVD events and survival. Cooney et al found that, among 10,519 men and 11,334 women followed in a Finnish population-based study, a 15-beat increase in resting heart rate was associated with a 24% and 32% increase in future cardiovascular death in men and women, respectively. Moreover, in a 2012 study of 112,680 men and women pooled from 12 cohort studies, higher resting heart rate (≥80 beat/min compared with <65 beat/min) was associated with an increased risk of both CVD events (hazard ratio, 1.44; 95% CI, 1.29–1.60) and all-cause mortality (hazard ratio, 1.54; 1.43–1.66).
Relationships between autonomic dysfunction and cardiovascular risk have also been demonstrated in studies specifically focused on women. Mora et al investigated the clinical value of HRR independently and in combination with exercise capacity in predicting 20-year CVD mortality. Women with HRR and exercise capacity values less than the median had nearly a 4-fold higher risk of CVD death after adjustment for traditional CVD risk factors (hazard ratio, 3.5; 95% CI, 1.6–7.9) compared with women with values greater than the median. More recently, Gulati et al found that achieving 1 standard deviation (1-SD) less than age-predicted peak heart rate during exercise testing was the strongest predictor of adverse outcomes (hazard ratio, 3.5; 95% CI, 2.9–4.2) in asymptomatic women over 15.9 ± 2.2 years. Taken together, these studies indicate that autonomic dysfunction is also a strong predictor of both short-term and long-term CVD mortality in women.
Multiple pathways between anthracycline-based therapy and cardiotoxicity have been delineated. Although less well elucidated, several lines of evidence suggest that anthracyclines act directly on adrenergic nerve tissue to alter autonomic function. In animal models of heart failure, left ventricular dysfunction often presents with enhanced sympathetic activity as evidenced by elevated circulating concentrations of norepinephrine. Local activation of adrenergic receptors and subsequent depletion of myocardial norepinephrine occur as heart failure ensues. Thus, elevated circulating levels of norepinephrine and depletion of myocardial norepinephrine are characteristic of sympathetic hyperactivity during acute injury. Previous studies among patients exposed to anthracyclines have also demonstrated high circulating levels of norepinephrine as well as reductions in cardiac autonomic function (ie, impaired HRV from short-term recordings) before left ventricular dysfunction. Studies using radiolabeled metaiodobenzylguanidine scintigraphy to capture myocardial norepinephrine uptake have also demonstrated decreases in norepinephrine uptake with increasing anthracycline exposure. Importantly, alterations in circulating and cardiac neuronal norepinephrine concentrations occurred before left ventricular dysfunction and were dose dependent, substantiating the hypothesis that anthracyclines impact norepinephrine turnover both locally and systemically to impact autonomic signaling before clinically evident heart failure. These data support the hypothesis that cardiac autonomic regulation is altered with anthracycline-based therapy and should be detectable before the onset of LV dysfunction.
Several small clinical studies support the hypothesis that anthracycline therapy is associated with autonomic dysfunction in women with breast cancer. In a study of 47 breast cancer patients with an average follow-up of 3 years post–chemoendocrine adjuvant therapy, our group found that resting heart rate was significantly elevated in patients compared with age-matched controls (91 ± 15 vs 76 ± 8 beat/min, respectively; P = 0.004) despite normal LVEF (>50%). In a second study, we demonstrated that 50% of breast cancer patients previously treated with anthracycline-trastuzumab–containing chemotherapy for HER2-positive operable breast cancer presented with sinus tachycardia (resting HR >110 beat/min) compared with 0% age-matched controls. Finally, in examining resting heart rate across the breast cancer continuum, we showed that mean resting heart rate was 74 ± 10 beat/min in breast cancer patients before adjuvant therapy compared with 91 ± 17, 89 ± 16, and 92 ± 17 beat/min in patients during adjuvant therapy, in patients after adjuvant therapy, or in those with metastatic disease, respectively.
Although studies from other groups have shown similar results, the exact time course of autonomic dysfunction following anthracycline exposure is unclear, likely because of small sample sizes, diverse measures of autonomic function, and lack of long-term follow-up. Further work is needed to determine whether anthracycline exposure alone or in combination with radiation therapy and/or other cytoxic agents has additive adverse effects on autonomic function. Importantly, recent data suggest that thoracic radiation exposure is associated with a higher risk of autonomic dysfunction and subsequent all-cause mortality among Hodgkin lymphoma survivors. Studies are lacking on the question of whether radiation for the treatment of breast cancer independently impacts autonomic function, although there is compelling evidence for the development of ischemic heart disease and myocardial fibrosis among women after radiotherapy. Lastly, cyclophosphamide and taxanes are commonly used in combination with anthracyclines as first-line therapy for breast cancer. Two small studies have demonstrated no effect of taxanes by themselves on HRV or blood pressure control. Cyclophosphamide commonly causes nausea and vomiting, which are mediated by the autonomic nervous system and are generally associated with other symptoms of autonomic activation; however, susceptibility to nausea and fatigue during treatment has also been associated with pretreatment differences in psychological factors. Further studies are required to assess whether this relationship of psychological factors and symptoms impacts objective measures of cardiac autonomic functioning and subsequent levels or autonomic dysfunction.
The Figure outlines the potential mechanisms associated with both autonomic dysfunction and increased CVD risk in breast cancer patients. In addition to anthracyclines and other therapies such as radiation treatment, psychosocial stress, sleep disturbances, weight gain/metabolic dysregulation, and low cardiorespiratory fitness can be present in breast cancer patients, both at the time of diagnosis and as a consequence of diagnosis and treatment. Each of these potentially modifiable risk factors can result in even greater autonomic dysfunction and potentially higher CVD risk. A discussion of each of these factors will be presented below.
(Enlarge Image)
Figure.
Potential mechanisms associated with both autonomic dysfunction and increased CVD risk in breast cancer patients. Breast cancer diagnosis is associated with therapy-induced cardiovascular injury and lifestyle perturbations leading to increased activation of the SNS and decreased activation of the parasympathetic nervous system. In turn, this autonomic imbalance triggers the hypothalamic-pituitary-adrenal axis, the RAAS, and the endocannabinoid system, leading to oxidative stress, reduced vasodilation, inflammation, and atherosclerosis progression that promotes CVD. PNS, Parasympathetic nervous system; HPA, hypothalamic-pituitary-adrenal.
Psychosocial Stress. Growing epidemiologic evidence supports a link between psychological stress and CVD, with autonomic dysfunction as one of the proposed pathophysiologic mechanisms. Psychological stress results in a perception of chronic threat and an upregulation of the sympathetic-adrenal-medullary axis and release of catecholamines (norepinephrine and epinephrine), prompting chronically heightened cardiovascular responses. The downstream effects of chronic psychological stress include fatigue and depression, which can exacerbate key factors involved in SNS activity. For example, in the postadjuvant setting, breast cancer patients who report chronic fatigue have significantly higher norepinephrine levels and lower HRV compared with less fatigued counterparts (P = 0.02). Importantly, >30% of breast cancer survivors have cancer-related fatigue. Moreover, breast cancer patients with depression are more likely to exhibit autonomic dysfunction compared with their counterparts without depression. Depression is also highly prevalent at 1 year postdiagnosis (50%) and remains elevated up to 5 years. Taken together, psychological stress leading to fatigue and depression is common in the breast cancer setting; and each shares common pathways implicated in the development of autonomic dysfunction.
Circadian Sleep. Basal heart rate and HRV are, in part, regulated by central and cardiomyocyte circadian clocks. The master circadian pacemaker, located within the hypothalamic suprachiasmatic nuclei, directly regulates heart rate via neural and neuroendocrine pathways or indirectly through the sleep/wake cycle. Circadian rhythms are integral in the sleep/wake cycle, hormonal secretions, as well as other physiological processes and coordinate with peripheral clocks found in tissues such as liver, adipose, and heart.
Sympathetic and parasympathetic activities vary with sleep/wake cycles. Heart rate is lowest during deep non–rapid eye movement sleep compared with wakefulness. During rapid eye movement sleep, sympathetic nerve activity and subsequent blood pressure and heart rate are reported to be similar to waking hours. Disturbances in sleep/wake potentially influence sympathetic activity and timing, previously linked to increased cardiovascular risks. In a study of 52,610 men and women followed for a mean of 11.4 years, insomnia symptoms were associated with a graded increase in risk of acute MI. For example, in adjusted models, individuals with insomnia symptoms had a 2-fold greater risk of MI compared with those with no symptoms (hazard ratio, 2.1; 95% CI, 1.1–4.0). In addition, difficulty maintaining sleep every night (HR, 1.5; 95% CI, 1.2–1.9) and a feeling of nonrestorative sleep more than once a week (HR, 1.4; 95% CI, 1.1–1.8) were associated with significant MI risk after adjustment for potential confounders compared with those with no sleep problems.
Importantly, sleep/wake cycles are commonly disturbed in cancer patients. More severe sleep disorders occur at a frequency 2 to 3 times greater than that of the general population. In a recent study by Savard et al, 962 patients with nonmetastatic cancer in the perioperative phase (T1) were studied and followed for 18 months. At T1, 31% had insomnia symptoms, defined as a complaint of sleep difficulties and need for hypnotic medication 1 to 2 nights per week, whereas 28% had more severe insomnia syndrome. In that study, breast cancer patients had the highest rates of insomnia (42%-69%) and insomnia syndrome (25%-36%). Over an 18-month period, rates of insomnia decreased significantly across all types of cancers, although they remained higher than that in the general population. Importantly, sleep remained significantly impaired and persisted throughout treatment. These results highlight the prevalence of severe forms of insomnia before, during, and beyond active treatment in breast cancer, which can subsequently influence sympathetic activity and autonomic timing, linked to increased cardiovascular risks.
Weight Gain/Metabolic Derangements. Previous studies support a strong correlation between weight change and autonomic functioning. For example, weight gain of 10% above baseline body weight has been shown to be associated with sympathetic activation. Conversely, corresponding weight loss of approximately 4 kg has been shown to be associated with enhancement in parasympathetic activity as well as improvements in HRR. Prior work has linked chronic sympathetic activation as a potential mechanism between weight gain and CVD risk.
Importantly, breast cancer patients are more likely to gain weight, experience changes in visceral adiposity, and report other features of the metabolic syndrome compared with healthy women. Breast cancer patients commonly gain an average of 3 to 6 lb over the course of treatment.Sarcopenic obesity, defined as increased fat mass with concomitant skeletal muscle loss, can occur as a result of weight gain in breast cancer patients. Skeletal muscle changes related to sarcopenia may contribute to an unfavorable metabolic milieu leading to greater sympathetic activation. Moreover, skeletal muscle abnormalities can cause metabolic distress during exercise and disturb normal patterns of cardiorespiratory control. Muscle metabolites evoked during exercise can stimulate a muscle reflex leading to elevated heart rate, blood pressure, and enhanced muscle sympathetic nerve activity, which, when chronically stimulated, can adversely impact LV function. Delineating whether these potential mechanisms link fat distribution, autonomic control, and CVD risk in breast cancer patients will require future studies.
Cardiorespiratory Fitness. Cardiorespiratory fitness, defined as the efficiency of O2 transport and utilization, is a robust marker of CVD mortality risk. One proposed mechanism for CV protection associated with fitness is through an autonomic pathway. Indeed, multiple studies have shown a strong relationship between cardiorespiratory fitness and autonomic control, with a reported correlation coefficient of 0.53 between HRV and Vo2max (mL·kg·min). Direct correlations between cardiorespiratory fitness and autonomic function are less well delineated in the breast cancer literature. We have demonstrated lower cardiorespiratory fitness levels among breast cancer patients compared with age-matched controls, with lower fitness sustained at 7 years posttreatment. Similarly, we have shown significant differences in resting heart rate and chronotropic competence (peak heart rate − resting heart rate) as a function of the timing of adjuvant therapy and stage of disease (P <0.001). However, to date, no study has determined the relationship between loss of cardiorespiratory fitness and impairment in autonomic function in a breast cancer population or assessed longitudinal patterns of change. It will be important to elucidate the relative contribution of cardiorespiratory fitness to autonomic dysfunction or vice versa to tailor treatment therapies that might help minimize this adverse cycle.
Exercise training is an attractive intervention to improve autonomic dysfunction due to the ability of exercise to simultaneously impact cardiopulmonary and skeletal muscle O2 consumption, which are both important regulators of sympathetic activity. In a recent study of individuals in a cardiac rehabilitation program participating in aerobic training 3 times a week for 30 to 50 minutes, patients with abnormal autonomic function at baseline (defined as impaired HRR) who normalized HRR with exercise had a significant survival benefit. In addition to aerobic training, resistance training has been shown to maintain lean muscle mass, improve O2 transport from circulation to muscle mitochondria, and increase the oxidative capacity of the muscle, which may be important in preserving normal skeletal muscle SNS activity. Overall, prior work suggests that exercise training can shift the autonomic balance and modify survival among those post-MI.
We have shown that exercise training is a safe and feasible intervention in the oncology setting. Moreover, there are emerging data that exercise training has positive effects on autonomic function among cancer patients. One recent study in cancer patients demonstrated improvement in heart rate response during submaximal exercise testing among individuals who were randomized to combination aerobic/resistance training compared with controls (mean change, 4.3 beat/min [95% CI, 2.9–5.7]; P < 0.001). In a study of cancer patients in both the acute treatment phase and posttreatment phase, Niederer et al found that participation in a 16-week, moderate-intensity exercise intervention improved cardiac autonomic regulation, particularly HRV. Among breast cancer patients, our group has also recently completed a study showing improvements in Vo2peak as well as a mitigating effect on change in resting heart rate after endurance exercise 3 times a week for 12 weeks. Independent of changes in VO2peak, there are robust data on the impact of exercise training on improvement of quality of life and reduction of cancer-related fatigue in this population.
Exercise training in breast cancer patients has also been associated with improved sleep, although there is controversy on type and timing of exercise to facilitate sleep. The importance of adequate sleep is often overlooked. In a recent study, sleep quality, as measured objectively using actigraphy, was a predictor of survival in patients with advanced breast cancer. Untreated sleep disorders can significantly add to the downward spiral of exhaustion, weight gain, and psychological distress in cancer patients; in these cases, referral to sleep medicine specialists for sleep studies is recommended. The efficacy of sleep interventions, such as cognitive behavior therapy, to alter sleep patterns have been substantiated. Also efficacious in this context is yoga therapy which also has been shown to have a positive impact on sleep patterns in breast cancer patients.
Beyond exercise training and sleep-related interventions, initial studies of pharmacologic therapies directed toward increasing HRV and normalizing autonomic dysfunction have been shown to mitigate the negative effects of chemotherapy on cardiac function among cancer patients. For example, β-blockade has been shown to offset anthracycline-induced cardiomyopathy among cancer patients, as well as reduce the incidence of heart failure. Although no direct relationship between β-blockade and autonomic dysfunction has been elucidated, β-blockers are protective in cardiac failure by preventing the deleterious link between chronically enhanced sympathetic activity and cardiac failure. A similar argument could be made for drugs that inhibit RAAS—a key pathway involved in autonomic function. Several prior studies have demonstrated the cardioprotective effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients undergoing chemotherapy. Moreover, spironolactone, an aldosterone antagonist, has been shown to reduce early morning increases in heart rate in patients with known heart failure and has a favorable response on HRV in patients with ischemic heart failure. In a recent study of 83 breast cancer patients, 25 mg of spironolactone daily during anthracycline treatment mitigated a decrease in LVEF. Lastly, statins have shown benefit for the prevention of anthracycline-based cardiotoxicity in a small single-center study. In the breast cancer literature, continuous statin use has been shown to decrease incident heart failure hospitalization among those receiving anthracyclines. Although these data are promising, each of the proposed medically targeted regimens requires large clinical trials to support standard use of these medications in the breast cancer population to prevent autonomic dysfunction leading to CVD.
Lastly, a stronger research focus on psychosocial stress among breast cancer patients and posttreatment survivors is needed. The diagnosis of cancer per se is a major trauma, and a significant number of patients (estimated at 5%-10%) still meet criteria for posttraumatic stress disorder 5 years after diagnosis. Systematic screening for psychosocial stress, particularly adverse childhood experiences,before a breast cancer diagnosis as well as during and after treatment and development of appropriate therapies could mitigate development of CVD associated with chronic overstimulation of SNS and/or loss of the restorative function of the PNS. Having a way for patients to access professional and knowledgeable support for acute exacerbations of symptoms of distress during treatment may reduce panic and promote better navigation of this difficult period both psychologically and physiologically. Moreover, the effect of expanding access to stress-reducing interventions such as yoga, mindfulness mediation, music therapy, and other integrative or complementary therapies that support the ability to return to a relaxed state and a greater sense of efficacy should be studied as a way to reduce psychosocial stress, reduce symptoms, and support improved cardiac autonomic functioning among breast cancer patients.
In summary, emerging evidence shows that key factors in cardiac autonomic function, heart rate, and HRV predict functioning and survival among patients with metastatic and recurrent breast cancer. There is a need to extend these findings to earlier-stage breast cancers as well as to perform studies on a larger scale. Data on whether restoration in autonomic functioning, using nonpharmacologic or pharmacologic interventions, reduces CVD risk breast cancer patients undergoing adjuvant chemotherapy will be of key importance. Other major gaps in the current knowledge include (1) dose, type, and time course of chemotherapy associated with autonomic dysfunction; (2) etiology and prevalence of psychological stress and sleep disorders among breast cancer patients and their impact on cardiac function; (3) mechanistic links between sympathetic activity and metabolic derangements in breast cancer patients; and (4) the effectiveness of exercise interventions, sleep interventions, and medical therapies to improve autonomic function in breast cancer patients. Taken together, more robust data in these areas will allow clinicians to pinpoint the timing of autonomic function insult as well as determine the most effective intervention to offset this impact (Table II; proposed studies). Given the enhanced mobile technology that allows for minute-to-minute capture of heart rate, physical activity, sleep and robust measures of autonomic functioning, as well as measures of mood states, the future looks promising to address this knowledge gap. Ultimately, this line of research will enhance understanding of autonomic dysfunction in the pathogenesis of CVD in breast cancer and provide insight into potential pathways to intervene to promote longevity and cardiovascular health.
Autonomic dysfunction represents a loss of normal autonomic control of the cardiovascular system associated with both sympathetic nervous system overdrive and reduced efficacy of the parasympathetic nervous system. Autonomic dysfunction is a strong predictor of future coronary heart disease, vascular disease, and sudden cardiac death. In the current review, we will discuss the clinical importance of autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review the effects of antineoplastic therapy on autonomic function, as well as discuss secondary exposures, such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness, which may negatively impact autonomic function in breast cancer patients. Lastly, we review potential strategies to improve autonomic function in this population. The perspective can help guide new therapeutic interventions to promote longevity and cardiovascular health among breast cancer survivors.
Because of significant improvements in early detection and adjuvant therapy, early breast cancer patients are now expected to live long enough to be at risk for competing causes of death. Cardiovascular disease (CVD) is rapidly becoming the predominant cause of mortality in breast cancer survivors older than 60 years. The magnitude of this problem is likely to increase with the aging of the US population, improvements in breast cancer–specific survival, and the continued use of antineoplastic agents with cardiovascular toxicities. Thus, given the nearly 3 million breast cancer survivors in the United States, the number of women at excess risk for CVD is likely to increase dramatically over the next 2 decades, requiring specific strategies to predict and mitigate these risks.
Adjuvant therapies used in the current treatment of early breast cancer are associated with unique and varying degrees of direct (eg, cardiac dysfunction) as well as indirect (eg, unfavorable CVD risk factors) sequential and progressive cardiovascular insults. In current oncology practice, the "cardiovascular" impact of cytotoxic therapies is evaluated solely by changes in resting left ventricular ejection fraction (LVEF). However, LVEF is load, rate, and contractility dependent; and acute declines in myocardial function can be initially compensated for to maintain cardiac output. Thus, left ventricular dysfunction is a late marker, only becoming evident after significant myocardial damage has already occurred. Therefore, alternative tools are required to identify patients at high risk for adverse cardiovascular impacts before significant damage develops.
The term autonomic dysfunction describes a loss of normal autonomic regulation of the cardiovascular system associated with both excessive sympathetic nervous system (SNS) activation and a reduced ability of the parasympatheic nervous system (PNS) to deactivate appropriately. Autonomic dysfunction can result in increased heart rate, atrioventricular node conduction, and left ventricular contractility. The autonomic nervous system also regulates various hormonal systems including the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system (RAAS), and the endocannabinoid system. Thus, autonomic dysfunction may also promote oxidative stress, reduce vasodilation, increase chronic inflammation, and accelerate atherosclerosis progression leading to CVD. Clinically, the onset and progression of autonomic dysfunction can manifest through chronically elevated heart rates and a loss of normal heart rate variability (HRV), which becomes both a marker of increased risk and, through decreased cardiac resilience, a mediator of adverse cardiovascular consequences.
The current review will highlight the emerging data on autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review current methods for assessing cardiac autonomic function and the effects of antineoplastic therapy on autonomic function. We will also discuss secondary exposures—such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness—that occur in breast cancer patients and may adversely impact autonomic function. Finally, potential strategies to prevent and/or mitigate autonomic dysfunction will be discussed. Ultimately, this review sets the stage for future studies to unravel potential interventions via the autonomic pathway to prevent competing risk of CVD among breast cancer patients.
Measures of Cardiac Autonomic Function
Healthy autonomic function is the capacity of the autonomic nervous system to deliver appropriate stimulatory and inhibitory signals through sympathetic and parasympathetic pathways. The interplay between sympathetic and parasympathetic inputs is vital for the regulation of cardiac output via changes in heart rate, electrical conduction, left ventricular contractility, vascular tone, and blood pressure.
Changes in cardiac autonomic function can be tracked by several techniques (Table I). The simplest measure of cardiac autonomic status is resting heart rate. Greater autonomic dysfunction is associated with increasing resting heart rates over time. A more robust measure of autonomic function is HRV, which is measured using continuous heart rate monitoring. Heart rate variability is a set of parameters that reflects interval fluctuations between sequential beats of the heart. Measures derived from interval differences between successive beats reflect parasympathetically modulated changes in heart rate. Other HRV measures reflect the combined signaling of the 2 arms of the autonomic nervous system and reflect both intrinsic (eg, baroreflex, renin-angiotensin, sleep cycles, circadian) and extrinsic (activity, rest) rhythms. In general, decreased or decreasing HRV would be a signal for worse cardiac autonomic dysfunction. However, a higher, but more disorganized, HRV pattern, detectable by certain "nonlinear" HRV measures, also reflects greater cardiac autonomic dysfunction. Ideally, HRV is measured using a 24-hour ambulatory monitoring that can capture both daytime heart rate patterns and heart rate patterns during sleep, providing insights into circadian rhythm, sleep quality, and possible sleep-disordered breathing or periodic limb movements, all of which affect cardiac autonomic functioning. However, significant clinical information can be obtained from shorter recordings performed, perhaps, at the time of clinical visits and in association with standard "bedside autonomic tests."
Heart rate recovery (HRR) and chronotropic competence, assessed after submaximal or maximal exercise stress testing, also reflect the health of cardiac autonomic regulation. Traditionally, HRR is measured as the difference in heart rate assessed at peak exercise and 1-minute postexercise. A reduction of <12 beat/min or the 10th percentile within the first minute reflects inadequate reactivation of the parasympathetic nervous system poststress. Chronotropic competence describes the ability of the heart to adjust its intrinsic rate appropriately for the level of cardiovascular demand during exercise testing. Chronotropic competence is commonly determined from measurement of heart rate reserve (difference between heart rate at peak exercise compared with rest) or achievement of age-predicted maximal heart rate.
Autonomic Dysfunction is a Prognostic Marker of Short-term and Long-term CVD Risk
The importance of autonomic dysfunction as a marker of CVD risk was first demonstrated in a series of studies of canines subjected to transient ischemia in the post–myocardial infarction (MI) setting. In these studies, the presence of parasympathetic activity (or lack of sympathetic activation) was associated with a lower incidence of sudden cardiac death. A subsequent study in humans demonstrated that decreased HRV and an impaired baroreceptor reflex were prognostic of cardiac death independent of baseline LVEF among post-MI patients. After 21 months of follow-up, impaired 24-hour HRV was associated with a 3-fold higher risk of cardiac mortality in men and women (hazard ratio, 2.8; 95% CI, 1.2–6.2) compared with individuals with normal HRV measures. Cole et al extended these findings by showing that HRR after exercise testing was strongly predictive of all-cause mortality after multivariable adjustment (hazard ratio, 2.0; 95% CI, 1.5–2.7) among individuals referred for exercise testing. This has been corroborated by others and found to be independent of angiographic severity and cardiac function. Importantly, more recent studies suggest that resting heart rate, the simplest measure of autonomic functioning, is also a powerful predictor of future CVD events and survival. Cooney et al found that, among 10,519 men and 11,334 women followed in a Finnish population-based study, a 15-beat increase in resting heart rate was associated with a 24% and 32% increase in future cardiovascular death in men and women, respectively. Moreover, in a 2012 study of 112,680 men and women pooled from 12 cohort studies, higher resting heart rate (≥80 beat/min compared with <65 beat/min) was associated with an increased risk of both CVD events (hazard ratio, 1.44; 95% CI, 1.29–1.60) and all-cause mortality (hazard ratio, 1.54; 1.43–1.66).
Relationships between autonomic dysfunction and cardiovascular risk have also been demonstrated in studies specifically focused on women. Mora et al investigated the clinical value of HRR independently and in combination with exercise capacity in predicting 20-year CVD mortality. Women with HRR and exercise capacity values less than the median had nearly a 4-fold higher risk of CVD death after adjustment for traditional CVD risk factors (hazard ratio, 3.5; 95% CI, 1.6–7.9) compared with women with values greater than the median. More recently, Gulati et al found that achieving 1 standard deviation (1-SD) less than age-predicted peak heart rate during exercise testing was the strongest predictor of adverse outcomes (hazard ratio, 3.5; 95% CI, 2.9–4.2) in asymptomatic women over 15.9 ± 2.2 years. Taken together, these studies indicate that autonomic dysfunction is also a strong predictor of both short-term and long-term CVD mortality in women.
Antineoplastic Exposure and Autonomic Dysfunction in Breast Cancer Patients
Multiple pathways between anthracycline-based therapy and cardiotoxicity have been delineated. Although less well elucidated, several lines of evidence suggest that anthracyclines act directly on adrenergic nerve tissue to alter autonomic function. In animal models of heart failure, left ventricular dysfunction often presents with enhanced sympathetic activity as evidenced by elevated circulating concentrations of norepinephrine. Local activation of adrenergic receptors and subsequent depletion of myocardial norepinephrine occur as heart failure ensues. Thus, elevated circulating levels of norepinephrine and depletion of myocardial norepinephrine are characteristic of sympathetic hyperactivity during acute injury. Previous studies among patients exposed to anthracyclines have also demonstrated high circulating levels of norepinephrine as well as reductions in cardiac autonomic function (ie, impaired HRV from short-term recordings) before left ventricular dysfunction. Studies using radiolabeled metaiodobenzylguanidine scintigraphy to capture myocardial norepinephrine uptake have also demonstrated decreases in norepinephrine uptake with increasing anthracycline exposure. Importantly, alterations in circulating and cardiac neuronal norepinephrine concentrations occurred before left ventricular dysfunction and were dose dependent, substantiating the hypothesis that anthracyclines impact norepinephrine turnover both locally and systemically to impact autonomic signaling before clinically evident heart failure. These data support the hypothesis that cardiac autonomic regulation is altered with anthracycline-based therapy and should be detectable before the onset of LV dysfunction.
Several small clinical studies support the hypothesis that anthracycline therapy is associated with autonomic dysfunction in women with breast cancer. In a study of 47 breast cancer patients with an average follow-up of 3 years post–chemoendocrine adjuvant therapy, our group found that resting heart rate was significantly elevated in patients compared with age-matched controls (91 ± 15 vs 76 ± 8 beat/min, respectively; P = 0.004) despite normal LVEF (>50%). In a second study, we demonstrated that 50% of breast cancer patients previously treated with anthracycline-trastuzumab–containing chemotherapy for HER2-positive operable breast cancer presented with sinus tachycardia (resting HR >110 beat/min) compared with 0% age-matched controls. Finally, in examining resting heart rate across the breast cancer continuum, we showed that mean resting heart rate was 74 ± 10 beat/min in breast cancer patients before adjuvant therapy compared with 91 ± 17, 89 ± 16, and 92 ± 17 beat/min in patients during adjuvant therapy, in patients after adjuvant therapy, or in those with metastatic disease, respectively.
Although studies from other groups have shown similar results, the exact time course of autonomic dysfunction following anthracycline exposure is unclear, likely because of small sample sizes, diverse measures of autonomic function, and lack of long-term follow-up. Further work is needed to determine whether anthracycline exposure alone or in combination with radiation therapy and/or other cytoxic agents has additive adverse effects on autonomic function. Importantly, recent data suggest that thoracic radiation exposure is associated with a higher risk of autonomic dysfunction and subsequent all-cause mortality among Hodgkin lymphoma survivors. Studies are lacking on the question of whether radiation for the treatment of breast cancer independently impacts autonomic function, although there is compelling evidence for the development of ischemic heart disease and myocardial fibrosis among women after radiotherapy. Lastly, cyclophosphamide and taxanes are commonly used in combination with anthracyclines as first-line therapy for breast cancer. Two small studies have demonstrated no effect of taxanes by themselves on HRV or blood pressure control. Cyclophosphamide commonly causes nausea and vomiting, which are mediated by the autonomic nervous system and are generally associated with other symptoms of autonomic activation; however, susceptibility to nausea and fatigue during treatment has also been associated with pretreatment differences in psychological factors. Further studies are required to assess whether this relationship of psychological factors and symptoms impacts objective measures of cardiac autonomic functioning and subsequent levels or autonomic dysfunction.
Additional Mechanisms Leading to Autonomic Dysfunction in Breast Cancer
The Figure outlines the potential mechanisms associated with both autonomic dysfunction and increased CVD risk in breast cancer patients. In addition to anthracyclines and other therapies such as radiation treatment, psychosocial stress, sleep disturbances, weight gain/metabolic dysregulation, and low cardiorespiratory fitness can be present in breast cancer patients, both at the time of diagnosis and as a consequence of diagnosis and treatment. Each of these potentially modifiable risk factors can result in even greater autonomic dysfunction and potentially higher CVD risk. A discussion of each of these factors will be presented below.
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Figure.
Potential mechanisms associated with both autonomic dysfunction and increased CVD risk in breast cancer patients. Breast cancer diagnosis is associated with therapy-induced cardiovascular injury and lifestyle perturbations leading to increased activation of the SNS and decreased activation of the parasympathetic nervous system. In turn, this autonomic imbalance triggers the hypothalamic-pituitary-adrenal axis, the RAAS, and the endocannabinoid system, leading to oxidative stress, reduced vasodilation, inflammation, and atherosclerosis progression that promotes CVD. PNS, Parasympathetic nervous system; HPA, hypothalamic-pituitary-adrenal.
Psychosocial Stress. Growing epidemiologic evidence supports a link between psychological stress and CVD, with autonomic dysfunction as one of the proposed pathophysiologic mechanisms. Psychological stress results in a perception of chronic threat and an upregulation of the sympathetic-adrenal-medullary axis and release of catecholamines (norepinephrine and epinephrine), prompting chronically heightened cardiovascular responses. The downstream effects of chronic psychological stress include fatigue and depression, which can exacerbate key factors involved in SNS activity. For example, in the postadjuvant setting, breast cancer patients who report chronic fatigue have significantly higher norepinephrine levels and lower HRV compared with less fatigued counterparts (P = 0.02). Importantly, >30% of breast cancer survivors have cancer-related fatigue. Moreover, breast cancer patients with depression are more likely to exhibit autonomic dysfunction compared with their counterparts without depression. Depression is also highly prevalent at 1 year postdiagnosis (50%) and remains elevated up to 5 years. Taken together, psychological stress leading to fatigue and depression is common in the breast cancer setting; and each shares common pathways implicated in the development of autonomic dysfunction.
Circadian Sleep. Basal heart rate and HRV are, in part, regulated by central and cardiomyocyte circadian clocks. The master circadian pacemaker, located within the hypothalamic suprachiasmatic nuclei, directly regulates heart rate via neural and neuroendocrine pathways or indirectly through the sleep/wake cycle. Circadian rhythms are integral in the sleep/wake cycle, hormonal secretions, as well as other physiological processes and coordinate with peripheral clocks found in tissues such as liver, adipose, and heart.
Sympathetic and parasympathetic activities vary with sleep/wake cycles. Heart rate is lowest during deep non–rapid eye movement sleep compared with wakefulness. During rapid eye movement sleep, sympathetic nerve activity and subsequent blood pressure and heart rate are reported to be similar to waking hours. Disturbances in sleep/wake potentially influence sympathetic activity and timing, previously linked to increased cardiovascular risks. In a study of 52,610 men and women followed for a mean of 11.4 years, insomnia symptoms were associated with a graded increase in risk of acute MI. For example, in adjusted models, individuals with insomnia symptoms had a 2-fold greater risk of MI compared with those with no symptoms (hazard ratio, 2.1; 95% CI, 1.1–4.0). In addition, difficulty maintaining sleep every night (HR, 1.5; 95% CI, 1.2–1.9) and a feeling of nonrestorative sleep more than once a week (HR, 1.4; 95% CI, 1.1–1.8) were associated with significant MI risk after adjustment for potential confounders compared with those with no sleep problems.
Importantly, sleep/wake cycles are commonly disturbed in cancer patients. More severe sleep disorders occur at a frequency 2 to 3 times greater than that of the general population. In a recent study by Savard et al, 962 patients with nonmetastatic cancer in the perioperative phase (T1) were studied and followed for 18 months. At T1, 31% had insomnia symptoms, defined as a complaint of sleep difficulties and need for hypnotic medication 1 to 2 nights per week, whereas 28% had more severe insomnia syndrome. In that study, breast cancer patients had the highest rates of insomnia (42%-69%) and insomnia syndrome (25%-36%). Over an 18-month period, rates of insomnia decreased significantly across all types of cancers, although they remained higher than that in the general population. Importantly, sleep remained significantly impaired and persisted throughout treatment. These results highlight the prevalence of severe forms of insomnia before, during, and beyond active treatment in breast cancer, which can subsequently influence sympathetic activity and autonomic timing, linked to increased cardiovascular risks.
Weight Gain/Metabolic Derangements. Previous studies support a strong correlation between weight change and autonomic functioning. For example, weight gain of 10% above baseline body weight has been shown to be associated with sympathetic activation. Conversely, corresponding weight loss of approximately 4 kg has been shown to be associated with enhancement in parasympathetic activity as well as improvements in HRR. Prior work has linked chronic sympathetic activation as a potential mechanism between weight gain and CVD risk.
Importantly, breast cancer patients are more likely to gain weight, experience changes in visceral adiposity, and report other features of the metabolic syndrome compared with healthy women. Breast cancer patients commonly gain an average of 3 to 6 lb over the course of treatment.Sarcopenic obesity, defined as increased fat mass with concomitant skeletal muscle loss, can occur as a result of weight gain in breast cancer patients. Skeletal muscle changes related to sarcopenia may contribute to an unfavorable metabolic milieu leading to greater sympathetic activation. Moreover, skeletal muscle abnormalities can cause metabolic distress during exercise and disturb normal patterns of cardiorespiratory control. Muscle metabolites evoked during exercise can stimulate a muscle reflex leading to elevated heart rate, blood pressure, and enhanced muscle sympathetic nerve activity, which, when chronically stimulated, can adversely impact LV function. Delineating whether these potential mechanisms link fat distribution, autonomic control, and CVD risk in breast cancer patients will require future studies.
Cardiorespiratory Fitness. Cardiorespiratory fitness, defined as the efficiency of O2 transport and utilization, is a robust marker of CVD mortality risk. One proposed mechanism for CV protection associated with fitness is through an autonomic pathway. Indeed, multiple studies have shown a strong relationship between cardiorespiratory fitness and autonomic control, with a reported correlation coefficient of 0.53 between HRV and Vo2max (mL·kg·min). Direct correlations between cardiorespiratory fitness and autonomic function are less well delineated in the breast cancer literature. We have demonstrated lower cardiorespiratory fitness levels among breast cancer patients compared with age-matched controls, with lower fitness sustained at 7 years posttreatment. Similarly, we have shown significant differences in resting heart rate and chronotropic competence (peak heart rate − resting heart rate) as a function of the timing of adjuvant therapy and stage of disease (P <0.001). However, to date, no study has determined the relationship between loss of cardiorespiratory fitness and impairment in autonomic function in a breast cancer population or assessed longitudinal patterns of change. It will be important to elucidate the relative contribution of cardiorespiratory fitness to autonomic dysfunction or vice versa to tailor treatment therapies that might help minimize this adverse cycle.
Strategies to Improve Autonomic Function
Exercise training is an attractive intervention to improve autonomic dysfunction due to the ability of exercise to simultaneously impact cardiopulmonary and skeletal muscle O2 consumption, which are both important regulators of sympathetic activity. In a recent study of individuals in a cardiac rehabilitation program participating in aerobic training 3 times a week for 30 to 50 minutes, patients with abnormal autonomic function at baseline (defined as impaired HRR) who normalized HRR with exercise had a significant survival benefit. In addition to aerobic training, resistance training has been shown to maintain lean muscle mass, improve O2 transport from circulation to muscle mitochondria, and increase the oxidative capacity of the muscle, which may be important in preserving normal skeletal muscle SNS activity. Overall, prior work suggests that exercise training can shift the autonomic balance and modify survival among those post-MI.
We have shown that exercise training is a safe and feasible intervention in the oncology setting. Moreover, there are emerging data that exercise training has positive effects on autonomic function among cancer patients. One recent study in cancer patients demonstrated improvement in heart rate response during submaximal exercise testing among individuals who were randomized to combination aerobic/resistance training compared with controls (mean change, 4.3 beat/min [95% CI, 2.9–5.7]; P < 0.001). In a study of cancer patients in both the acute treatment phase and posttreatment phase, Niederer et al found that participation in a 16-week, moderate-intensity exercise intervention improved cardiac autonomic regulation, particularly HRV. Among breast cancer patients, our group has also recently completed a study showing improvements in Vo2peak as well as a mitigating effect on change in resting heart rate after endurance exercise 3 times a week for 12 weeks. Independent of changes in VO2peak, there are robust data on the impact of exercise training on improvement of quality of life and reduction of cancer-related fatigue in this population.
Exercise training in breast cancer patients has also been associated with improved sleep, although there is controversy on type and timing of exercise to facilitate sleep. The importance of adequate sleep is often overlooked. In a recent study, sleep quality, as measured objectively using actigraphy, was a predictor of survival in patients with advanced breast cancer. Untreated sleep disorders can significantly add to the downward spiral of exhaustion, weight gain, and psychological distress in cancer patients; in these cases, referral to sleep medicine specialists for sleep studies is recommended. The efficacy of sleep interventions, such as cognitive behavior therapy, to alter sleep patterns have been substantiated. Also efficacious in this context is yoga therapy which also has been shown to have a positive impact on sleep patterns in breast cancer patients.
Beyond exercise training and sleep-related interventions, initial studies of pharmacologic therapies directed toward increasing HRV and normalizing autonomic dysfunction have been shown to mitigate the negative effects of chemotherapy on cardiac function among cancer patients. For example, β-blockade has been shown to offset anthracycline-induced cardiomyopathy among cancer patients, as well as reduce the incidence of heart failure. Although no direct relationship between β-blockade and autonomic dysfunction has been elucidated, β-blockers are protective in cardiac failure by preventing the deleterious link between chronically enhanced sympathetic activity and cardiac failure. A similar argument could be made for drugs that inhibit RAAS—a key pathway involved in autonomic function. Several prior studies have demonstrated the cardioprotective effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients undergoing chemotherapy. Moreover, spironolactone, an aldosterone antagonist, has been shown to reduce early morning increases in heart rate in patients with known heart failure and has a favorable response on HRV in patients with ischemic heart failure. In a recent study of 83 breast cancer patients, 25 mg of spironolactone daily during anthracycline treatment mitigated a decrease in LVEF. Lastly, statins have shown benefit for the prevention of anthracycline-based cardiotoxicity in a small single-center study. In the breast cancer literature, continuous statin use has been shown to decrease incident heart failure hospitalization among those receiving anthracyclines. Although these data are promising, each of the proposed medically targeted regimens requires large clinical trials to support standard use of these medications in the breast cancer population to prevent autonomic dysfunction leading to CVD.
Lastly, a stronger research focus on psychosocial stress among breast cancer patients and posttreatment survivors is needed. The diagnosis of cancer per se is a major trauma, and a significant number of patients (estimated at 5%-10%) still meet criteria for posttraumatic stress disorder 5 years after diagnosis. Systematic screening for psychosocial stress, particularly adverse childhood experiences,before a breast cancer diagnosis as well as during and after treatment and development of appropriate therapies could mitigate development of CVD associated with chronic overstimulation of SNS and/or loss of the restorative function of the PNS. Having a way for patients to access professional and knowledgeable support for acute exacerbations of symptoms of distress during treatment may reduce panic and promote better navigation of this difficult period both psychologically and physiologically. Moreover, the effect of expanding access to stress-reducing interventions such as yoga, mindfulness mediation, music therapy, and other integrative or complementary therapies that support the ability to return to a relaxed state and a greater sense of efficacy should be studied as a way to reduce psychosocial stress, reduce symptoms, and support improved cardiac autonomic functioning among breast cancer patients.
In summary, emerging evidence shows that key factors in cardiac autonomic function, heart rate, and HRV predict functioning and survival among patients with metastatic and recurrent breast cancer. There is a need to extend these findings to earlier-stage breast cancers as well as to perform studies on a larger scale. Data on whether restoration in autonomic functioning, using nonpharmacologic or pharmacologic interventions, reduces CVD risk breast cancer patients undergoing adjuvant chemotherapy will be of key importance. Other major gaps in the current knowledge include (1) dose, type, and time course of chemotherapy associated with autonomic dysfunction; (2) etiology and prevalence of psychological stress and sleep disorders among breast cancer patients and their impact on cardiac function; (3) mechanistic links between sympathetic activity and metabolic derangements in breast cancer patients; and (4) the effectiveness of exercise interventions, sleep interventions, and medical therapies to improve autonomic function in breast cancer patients. Taken together, more robust data in these areas will allow clinicians to pinpoint the timing of autonomic function insult as well as determine the most effective intervention to offset this impact (Table II; proposed studies). Given the enhanced mobile technology that allows for minute-to-minute capture of heart rate, physical activity, sleep and robust measures of autonomic functioning, as well as measures of mood states, the future looks promising to address this knowledge gap. Ultimately, this line of research will enhance understanding of autonomic dysfunction in the pathogenesis of CVD in breast cancer and provide insight into potential pathways to intervene to promote longevity and cardiovascular health.