Association Between Hematologic Response and Change in Health-Related Quality of Life Among Patients with Light-Chain (AL) Amyloidosis.

Purpose: The purpose of this secondary data analysis was to examine the association between hematologic response and health-related quality of life (HRQoL) among patients with light-chain (AL) amyloidosis. Patients and Methods: Data for this secondary analysis were collected through a non-interventional, longitudinal, online self-report survey of patients with AL amyloidosis. Patients completed an initial online survey, with follow-up surveys administered 1, 6, 12, 18, and 24 months after completion of the initial survey. The online survey included an assessment of patients' most recent self-reported hematologic response status. Eight domains and 2 summary components of HRQoL were evaluated with the SF-36v2® Health Survey. A series of logistic regression models were used to examine the association between self-reported hematologic response at 24 months (dichotomized as new or maintained complete hematologic response; less than a complete response) and change in HRQoL from baseline to 24 months (dichotomized as meaningful worsening; improvement or preservation). Results: For all measured domains of HRQoL except physical functioning, there was no statistically significant relationship between meaningful worsening in HRQoL and hematologic response status at 24 months. Patients without a complete hematologic response had an odds of experiencing meaningful worsening of HRQoL that was similar to that of patients with a complete hematologic response. Conclusion: Among patients with AL amyloidosis, change in HRQoL was generally not associated with hematologic response. Achieving a complete hematologic response does not necessarily mean that a patient will experience increased or stable HRQoL. When defining treatment success, it is important to recognize that clinical markers such as hematologic response may not fully encapsulate the patient experience.

Safety and Tolerability of the Potassium Binder Patiromer From a Global Pharmacovigilance Database Collected Over 4 Years Compared with Data from the Clinical Trial Program.

INTRODUCTION: The availability of the sodium-free potassium binder patiromer opens new opportunities for hyperkalemia management. OBJECTIVE: Our objective was to compare data from a 4-year global pharmacovigilance database of adverse events (AEs) reported in patients prescribed patiromer in clinical practice compared with data obtained from the clinical trial program. METHODS: Postmarketing safety data regarding patiromer (Veltassa®; Vifor Pharma, Inc.), collected and recorded in the company's global pharmacovigilance database, were analyzed for the period from January 2016 through September 2019. These data were both solicited (i.e., via an organized data-collection method such as a patient-support program) and unsolicited (i.e., voluntarily reported by healthcare professionals, consumers, and competent authorities worldwide). The cumulative annualized mortality rate (events per 100 patient-years [PYs]) for the pharmacovigilance database analysis period were compared with the rate obtained in the longest patiromer clinical trial to date (up to 52 weeks of treatment). For individual AEs, reporting rates (% of events/100 PYs) for events collected in the global pharmacovigilance database were compared with the frequencies (% of patients with event/patients exposed) of events collected in the clinical trial program (N = 666). RESULTS: Over 4 years, the global pharmacovigilance database contained an estimated 45,000 PYs of exposure (17,823 individual case reports and 38,109 AEs), with most cases (95%) from the USA; > 85% of cases utilized 8.4 g/day. In total, 1214 deaths were reported, with a cumulative annualized mortality rate of 2.69/100 PYs (vs. 5.70 deaths/100 PYs in the 52-week clinical trial). Global pharmacovigilance reporting rates for the two most common AEs, constipation and diarrhea, were 6.90 and 3.48%, respectively. Respective frequencies were 7.2 and 4.8% in the clinical trial program. The pharmacovigilance reporting rate for AEs of decreased blood potassium was 0.45%; serum potassium < 3.5 mmol/L was reported in 4.7% of patients in the clinical trial program. For hypomagnesemia or decreased blood magnesium, reporting rates in the postmarketing setting were 0.02 and 0.16%, respectively, and they were observed in 5.3 and 0.8% of patients, respectively, in the clinical trial program. CONCLUSIONS: Global pharmacovigilance data over 4 years confirmed that the tolerability and safety of patiromer in clinical practice is predictable and consistent with clinical trial data, with no evidence of any new safety signals to date.

Muscle tension in generalized anxiety disorder: a critical review of the literature.

BACKGROUND: Generalized anxiety disorder (GAD) is a prevalent, disabling, and often chronic disorder. With a typical recovery rate of only about 40% with current psychological treatments a better understanding of potential psychophysiological mechanisms is vital. METHODS: Since the most discriminative somatic symptom of GAD compared to other anxiety disorders is muscle tension this review qualitatively examines the literature on muscle tension as it relates to GAD and muscle relaxation therapy for GAD patients. RESULTS: Muscle tension in GAD is poorly understood. Experimental studies refute the often-assumed direct relationship between anxiety and muscle tension. However, muscle relaxation therapies have been as effective as cognitive interventions directly addressing the defining symptom worry. CONCLUSIONS: Muscle tension in its objective and subjective representations may play a role in GAD through various pathways that are testable. Future research needs to better examine the different aspects and functions of muscle tension in GAD.

Real-World Evaluation of Patiromer for the Treatment of Hyperkalemia in Hemodialysis Patients.

INTRODUCTION: Patiromer is a potassium (K+) binding polymer indicated for treating hyperkalemia. Among patients receiving chronic hemodialysis (HD), this study aimed to identify patient characteristics associated with patiromer initiation, describe patiromer utilization, and analyze serum K+ pre- and post-patiromer initiation. METHODS: In a retrospective cohort study, using electronic health record data from a large dialysis provider in the United States (study period: December 21, 2015, to December 20, 2016), HD patients were included who had a medication order for patiromer, sodium polystyrene sulfonate (SPS), or laboratory evidence of hyperkalemia (no K+ binder [NoKb] cohort). The index date was the first order for patiromer/SPS, or the first K+ ≥5.0 mEq/l (NoKb cohort), respectively. Using multivariable logistic regression, we identified patient characteristics associated with patiromer initiation. We evaluated patiromer utilization using Kaplan-Meier methodology and proportion of days covered. Serum K+ concentrations were assessed pre- versus post-patiromer initiation. RESULTS: Study cohorts included 527 (patiromer), 852 (SPS), and 8747 (NoKb) HD patients. Median follow-up was 141 days. Patiromer initiators were 2.6 times more likely to have had multiple prior episodes of hyperkalemia (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.8-3.7). Most (61%) commenced patiromer on 8.4 g once daily; 60% of patients' first patiromer order remained open after 180 days. Statistically significant reductions in K+, averaging approximately -0.5 mEq/l, were observed post-patiromer initiation (48% pre-patiromer vs. 22% post-patiromer had K+ ≥6.0 mEq/l [P < 0.001]). CONCLUSION: Patiromer initiators receiving chronic hemodialysis had comparatively more severe, uncontrolled baseline hyperkalemia. Medication order data show long-term patiromer use was associated with significantly reduced K+.

Circadian affective, cardiopulmonary, and cortisol variability in depressed and nondepressed individuals at risk for cardiovascular disease.

Depression is a risk factor for cardiovascular disease (CVD) perhaps mediated by hypothalamic-pituitary-adrenal (HPA) axis or vagal dysregulation. We investigated circadian mood variation and HPA-axis and autonomic function in older (55 years) depressed and nondepressed volunteers at risk for CVD by assessing diurnal positive and negative affect (PA, NA), cortisol, and cardiopulmonary variables in 46 moderately depressed and 19 nondepressed volunteers with elevated CVD risk. Participants sat quietly for 5-min periods (10:00, 12:00, 14:00, 17:00, 19:00, and 21:00), and then completed an electronic diary assessing PA and NA. Traditional and respiration-controlled heart rate variability (HRV) variables were computed for these periods as an index of vagal activity. Salivary cortisols were collected at waking, waking+30min, 12:00, 17:00, and 21:00h. Cortisol peaked in the early morning after waking, and gradually declined over the day, but did not differ between groups. PA was lower and NA was higher in the depressed group throughout the day. HRV did not differ between groups. Negative emotions were inversely related to respiratory sinus arrhythmia in nondepressed participants. We conclude that moderately depressed patients do not show abnormal HPA-axis function. Diurnal PA and NA distinguish depressed from nondepressed individuals at risk for CVD, while measures of vagal regulation, even when controlled for physical activity and respiratory confounds, do not. Diurnal mood variations of older individuals at risk for CVD differ from those reported for other groups and daily fluctuations in NA are not related to cardiac autonomic control in depressed individuals.

Sympathetic activation in broadly defined generalized anxiety disorder.

The definition of generalized anxiety disorder (GAD) has been narrowed in successive editions of DSM by emphasizing intrusive worry and deemphasizing somatic symptoms of hyperarousal. We tried to determine the clinical characteristics of more broadly defined chronically anxious patients, and whether they would show physiological signs of sympathetic activation. A group whose chief complaint was frequent, unpleasant tension over at least the last six weeks for which they desired treatment, was compared with a group who described themselves as calm. Participants were assessed with structured interviews and questionnaires. Finger skin conductance, motor activity, and ambient temperature were measured for 24h. Results show that during waking and in bed at night, runs of continuous minute-by-minute skin conductance level (SCL) declines were skewed towards being shorter in the tense group than in the calm group. In addition, during waking, distributions of minute SCLs were skewed towards higher levels in the tense group, although overall mean SCL did not differ. Thus, the tense group showed a failure to periodically reduce sympathetic tone, presumably a corollary of failure to relax. We conclude that broader GAD criteria include a substantial number of chronically anxious and hyperaroused patients who do not fall within standard criteria. Such patients deserve attention by clinicians and researchers.

The effects of cognitive behavior therapy on depression in older patients with cardiovascular risk.

This study examined the effect of a cognitive behavior therapy (CBT) therapy intervention designed to reduce depression in older patients with elevated cardiovascular disease (CVD) risk. Forty-eight depressed patients with elevated CVD were randomized to a 16-week individual CBT intervention (n = 23) or a wait-list control (WLC) group (n = 25). Pre- and post-treatment measures of depression were obtained during office visits, and measures of positive and negative affect were obtained during laboratory psychological stress testing and at five points during the day. At post-treatment, the CBT subjects were significantly less depressed than WLC subjects on the Hamilton Depression Inventory (F = 52.8, P<.001, ES = 1.85) and the Beck Depression Inventory (F = 17.1, P = <.001, ES = 0.85). Fifty-seven percent (13/23) of subjects in the CBT treatment were considered to be in remission (on the basis of a clinical interview) at post compared to only 4% (1/25) in the WLC (chi(2) = 9.0, P =.003). Treatment subjects reported significantly less stress on the Perceived Stress Scale (F = 23.2, P<.001). CBT significantly improved mean positive affect during the day (F = 12.7, P =.0001) but there were no significant differences in mean negative affect (F = 1.8, P =.19). CBT significantly reduced negative affect (F = 7.1, P =.01) during psychological stress testing but did not affect positive affect. CBT is an effective treatment for reducing depression and increasing positive affect in patients at risk for CVD, but the results vary by time of measurement and measurement setting.

Psychophysiological reactions to two levels of voluntary hyperventilation in panic disorder.

Panic disorder (PD) patients usually react with more self-reported distress to voluntary hyperventilation (HV) than do comparison groups. Less consistently PD patients manifest physiological differences such as more irregular breathing and slower normalization of lowered end-tidal pCO(2) after HV. To test whether physiological differences before, during, or after HV would be more evident after more intense HV, we designed a study in which 16 PD patients and 16 non-anxious controls hyperventilated for 3 min to 25 mmHg, and another 19 PD patients and another 17 controls to 20 mmHg. Patients reacted to HV to 20 mmHg but not to 25 mmHg with more self-reported symptoms than controls. However, at neither HV intensity were previous findings of irregular breathing and slow normalization of pCO(2) replicated. In general, differences between patients and controls in response to HV were in the cognitive-language rather than in the physiological realm.

Exploring Emotion-Regulation and Autonomic Physiology in Metastatic Breast Cancer Patients: Repression, Suppression, and Restraint of Hostility.

We examined relationships between three emotion-regulation constructs and autonomic physiology in metastatic breast cancer patients (N = 31). Autonomic measures are not often studied in breast cancer patients and may provide evidence of an increase in allostatic load. Patients included participated as part of a larger clinical trial of supportive-expressive group therapy. Systolic and diastolic blood pressure and heart rate were assessed at a semi-annual follow-up. We averaged 3 resting assessments and used measures of Repression, Suppression, Restraint of Hostility, and Body Mass Index as predictors of autonomic response. We found that higher repression was significantly associated with higher diastolic blood pressure, while higher restraint of hostility was significantly associated with higher systolic blood pressure. A repressive emotion regulation style may be a risk factor for higher sympathetic activation possibly increasing allostatic load, while restraint of hostility may be a protective factor for women with metastatic breast cancer.

Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors.

INTRODUCTION: Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. METHODS: Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. RESULTS: Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. CONCLUSIONS: Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.

Muscle relaxation therapy for anxiety disorders: it works but how?

Muscle relaxation therapy (MRT) has continued to play an important role in the modern treatment of anxiety disorders. Abbreviations of the original progressive MRT protocol [Jacobson, E. (1938). Progressive relaxation (2nd ed.). Chicago: University of Chicago Press] have been found to be effective in panic disorder (PD) and generalized anxiety disorder (GAD). This review describes the most common MRT techniques, summarizes recent evidence of their effectiveness in treating anxiety, and explains their rationale and physiological basis. We conclude that although GAD and PD patients may exhibit elevated muscle tension and abnormal autonomic and respiratory measures during laboratory baseline assessments, the available evidence does not allow us to conclude that physiological activation decreases over the course of MRT in GAD and PD patients, even when patients report becoming less anxious. Better-designed studies will be required to identify the mechanisms of MRT and to advance clinical practice.

Depression and stress reactivity in metastatic breast cancer.

OBJECTIVE: Cancer-related distress due to the psychological and physical challenges of metastatic breast cancer (MBC) may result in symptoms of depression, which negatively affects quality and may influence quantity of life. This study investigated how depression affects MBC stress reactivity, including autonomic (ANS) and hypothalamic-pituitary-adrenal (HPA) axis function. METHOD: Forty-five nondepressed and 45 depressed patients with MBC underwent a modified Trier Social Stress Test (TSST) while affect, cardiovascular, respiratory, and cortisol responses were measured. RESULTS: At study entry, depressed compared with nondepressed patients had significantly lower log cortisol waking rise levels (p = .005) but no other HPA differences. Positive affect (p = .025) and high-frequency heart-rate variability (lnHF) (p = .002) were significantly lower at TSST baseline in depressed patients. In response to the TSST, depressed patients reported significantly lower positive (p = .050) and greater negative affect (p = .037) and had significantly reduced lnHF (p = .031). In secondary analyses, at TSST baseline both low-frequency (lnLF) (p = .002) and very-low-frequency (lnVLF) (p = .0001) heart rate variability were significantly lower in the depressed group. In secondary analyses during the TSST, those who were depressed had significantly lower lnVLF (p = .008) and did not increase aortic impedance reactivity as much as did the nondepressed during the stressor (p = .005). CONCLUSION: Depression in patients with MBC was associated with alterations in autonomic regulation, particularly reductions in respiratory sinus arrhythmia, a measure of cardiac vagal control, at baseline and during the TSST. In addition, depression was associated with blunted HPA response to awakening. Both MBC groups had relative cortisol hyporesponsiveness to acute stress.

Psychophysiological and cortisol responses to psychological stress in depressed and nondepressed older men and women with elevated cardiovascular disease risk.

OBJECTIVE: The objective of this study was to compare psychophysiological and cortisol reactions to psychological stress in older depressed and nondepressed patients at risk for cardiovascular disease (CVD). METHODS: Forty-eight depressed participants and 20 controls with elevated cardiovascular risk factors underwent a psychological stress test during which cardiovascular variables were measured. Salivary cortisol was collected after each test segment. Traditional (e.g., lipids) and atypical (e.g., C-reactive protein) CVD risk factors were also obtained. RESULTS: At baseline, the groups did not differ on lipid levels, flow-mediated vasodilation, body mass index, or asymmetric dimethylarginine. However, the depressed patients had significantly higher C-reactive protein levels. Contrary to our hypothesis, there were no differences in baseline cortisol levels or diurnal cortisol slopes, but depressed patients showed significantly lower cortisol levels during the stress test (p = .03) and less cortisol response to stress. Compared with nondepressed subjects, depressed subjects also showed lower levels of respiratory sinus arrhythmia (RSA(TF)) during the stress test (p = .02). CONCLUSIONS: In this sample, older depressed subjects with elevated risk for CVD exhibited a hypocortisol response to acute stress. This impaired cortisol response might contribute to chronic inflammation (as reflected in the elevated C-reactive proteins in depressed patients) and in other ways increase CVD risk. The reduced RSA(TF) activity may also increase CVD risk in depressed patients through impaired autonomic nervous system response to cardiophysiological demands.

Do unexpected panic attacks occur spontaneously?

BACKGROUND: Spontaneous or unexpected panic attacks, per definition, occur "out of the blue," in the absence of cues or triggers. Accordingly, physiological arousal or instability should occur at the onset of, or during, the attack, but not preceding it. To test this hypothesis, we examined if points of significant autonomic changes preceded the onset of spontaneous panic attacks. METHODS: Forty-three panic disorder patients underwent repeated 24-hour ambulatory monitoring. Thirteen natural panic attacks were recorded during 1960 hours of monitoring. Minute-by-minute epochs beginning 60 minutes before and continuing to 10 minutes after the onset of individual attacks were examined for respiration, heart rate, and skin conductance level. Measures were controlled for physical activity and vocalization and compared with time matched control periods within the same person. RESULTS: Significant patterns of instability across a number of autonomic and respiratory variables were detected as early as 47 minutes before panic onset. The final minutes before onset were dominated by respiratory changes, with significant decreases in tidal volume followed by abrupt carbon dioxide partial pressure increases. Panic attack onset was characterized by heart rate and tidal volume increases and a drop in carbon dioxide partial pressure. Symptom report was consistent with these changes. Skin conductance levels were generally elevated in the hour before, and during, the attacks. Changes in the matched control periods were largely absent. CONCLUSIONS: Significant autonomic irregularities preceded the onset of attacks that were reported as abrupt and unexpected. The findings invite reconsideration of the current diagnostic distinction between uncued and cued panic attacks.

Change point analysis for longitudinal physiological data: detection of cardio-respiratory changes preceding panic attacks.

Statistical methods for detecting changes in longitudinal time series of psychophysiological data are limited. ANOVA and mixed models are not designed to detect the existence, timing, or duration of unknown changes in such data. Change point (CP) analysis was developed to detect distinct changes in time series data. Preliminary reports using CP analysis for fMRI data are promising. Here, we illustrate the application of CP analysis for detecting discrete changes in ambulatory, peripheral physiological data leading up to naturally occurring panic attacks (PAs). The CP method was successful in detecting cardio-respiratory changes that preceded the onset of reported PAs. Furthermore, the changes were unique to the pre-PA period, and were not detected in matched non-PA control periods. The efficacy of our CP method was further validated by detecting patterns of change that were consistent with prominent respiratory theories of panic positing a relation between aberrant respiration and panic etiology.

Does improving mood in depressed patients alter factors that may affect cardiovascular disease risk?

To determine if improvement in mood would ameliorate autonomic dysregulation, HPA dysfunction, typical risk factors and C-reactive protein in depressed patients with elevated cardiovascular disease risk (CVD), 48 depressed participants with elevated cardiovascular risk factors were randomized to a cognitive behavioral intervention (CBT) or a waiting list control (WLC) condition. Twenty non-depressed age and risk-matched controls were also recruited. Traditional risk factors (e.g., lipids, blood pressure) and C-reactive protein were assessed pre- and post-treatment six months later. Subjects also underwent a psychophysiological stress test while cardiovascular physiology was measured. Salivary cortisol was measured during the day and during the psychological stress test. At post-treatment, the CBT subjects were significantly less depressed than WLC subjects. There was no significant difference in change scores on any of the traditional risk factors or C-reactive protein, cortisol measures, or cardiovascular physiology, except for triglyceride levels and heart rate, which were significantly lower in treatment compared to control subjects. The normal controls exhibited no change in the variables measured during the same time. A significant improvement in mood may have little impact on most traditional or atypical risk factors, cortisol or cardiophysiology.

The psychophysiology of generalized anxiety disorder: 2. Effects of applied relaxation.

Muscle relaxation therapy assumes that generalized anxiety disorder (GAD) patients lack the ability to relax but can learn this in therapy. We tested this by randomizing 49 GAD patients to 12 weeks of Applied Relaxation (AR) or waiting. Before, during, and after treatment participants underwent relaxation tests. Before treatment, GAD patients were more worried than healthy controls (n=21) and had higher heart rates and lower end-tidal pCO2, but not higher muscle tension (A. Conrad, L. Isaac, & W.T. Roth, 2008). AR resulted in greater symptomatic improvement than waiting. However, 28% of the AR group dropped out of treatment and some patients relapsed at the 6-week follow-up. There was little evidence that AR participants learned to relax in therapy or that a reduction in anxiety was associated with a decrease in activation. We conclude that the clinical effects of AR in improving GAD symptoms are moderate at most and cannot be attributed to reducing muscle tension or autonomic activation.

The psychophysiology of generalized anxiety disorder: 1. Pretreatment characteristics.

Generalized anxiety disorder (GAD) patients have been reported to have more muscle tension than controls, which has provided a rationale for treating them with muscle relaxation therapies (MRT). We tested this rationale by comparing 49 GAD patients with 21 controls. Participants underwent 5-min relaxation tests, during which they either just sat quietly (QS) or sat quietly and tried to relax (R). GAD patients reported themselves to be more worried during the assessment than the controls, had higher heart rates and lower end-tidal pCO2, but not higher muscle tension as measured by multiple EMGs. QS and R did not differ on most psychological and physiological measures, indicating that intention to relax did not affect speed of relaxation. In the GAD group, self-reported anxiety was not associated with electromyographic or autonomic measures. We conclude that GAD is not necessarily characterized by chronic muscle tension, and that this rationale for MRT should be reconsidered.

Vagal regulation, cortisol, and sleep disruption in women with metastatic breast cancer.

STUDY OBJECTIVES: To determine the relationship between hypothalamic pituitary axis (HPA) dysregulation, vagal functioning, and sleep problems in women with metastatic breast cancer. DESIGN: Sleep was assessed by means of questionnaires and wrist actigraphy for 3 consecutive nights. The ambulatory, diurnal variation in salivary cortisol levels was measured at 5 time points over 2 days. Vagal regulation was assessed via respiratory sinus arrhythmia (RSA(TF)) during the Trier Social Stress Task. PARTICIPANTS: Ninety-nine women (54.6 +/- 9.62 years) with metastatic breast cancer. RESULTS: Longer nocturnal wake episodes (r = 0.21, p = 0.04, N=91) were associated with a flatter diurnal cortisol slope. Sleep disruption was also associated with diminished RSA(TF). Higher RSA baseline scores were significantly correlated with higher sleep efficiency (r = 0.39, p = 0.001, N=68) and correspondingly lower levels of interrupted sleep (waking after sleep onset, WASO; r = -0.38, p = 0.002, N=68), lower average length of nocturnal wake episodes (r = -0.43, p < 0.001, N=68), and a lower self-reported number of hours of sleep during a typical night (r = -0.27, p = 0.02, N=72). Higher RSA AUC was significantly related to higher sleep efficiency (r = 0.45, p < 0.001, N=64), and a correspondingly lower number of wake episodes (r = -0.27, p = 0.04, N=64), lower WASO (r = -0.40, p = 0.001, N=64), and with lower average length of nocturnal wake episodes (r = -0.41, p = 0.001, N=64). While demographics, disease severity, and psychological variables all explained some portion of the development of sleep disruption, 4 of the 6 sleep parameters examined (sleep efficiency, WASO, mean number of waking episodes, average length of waking episode) were best explained by RSA. CONCLUSIONS: These data provide preliminary evidence for an association between disrupted nocturnal sleep and reduced RSA the subsequent day, confirming an association between disrupted nocturnal sleep and flattened diurnal cortisol rhythm in women with metastatic breast cancer. They suggest that the stress-buffering effects of sleep may be associated with improved parasympathetic tone and normalized cortisol patterns during the day.