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As advancements in care improve longevity in patients with congenital heart disease (CHD), it is crucial to further characterize this rapidly growing adult population. It is also essential that equitable care is offered across demographic groups. Hospitalizations for adults with CHD in the National Inpatient Sample were identified to describe trends in overall and cause-specific rates of admission per 1,000 adults with CHD from 2000 to 2018. Primary admission causes were then analyzed and stratified by race. An aggregate rate of left-ventricular assist device placements and heart transplants was calculated for each group and trended over the years. A total of 1,562,001 weighted hospitalizations were identified. Overall, annual rates of hospital admissions increased from 39 per 1,000 adults with CHD in 2000 to 74 per 1,000 in 2018, as did rates of cardiovascular admissions (16 of 1,000 to 34 of 1,000, p0.001 for both). Transient ischemic attack/stroke (2.5 of 1,000 to 10.7 of 1,000), coronary artery disease (4.1 of 1,000 to 5.6 of 1,000), arrhythmias (2.8 of 1,000 to 4.6 of 1,000), and heart failure (2.8 of 1,000 to 5.0 of 1,000) were the most common cardiovascular primary causes of admission (other than CHD itself), and each significantly increased over time (p0.001 for each). Mean age at all-cause and primary heart failure hospitalization increased for all races but remained 7 to 9 years younger for Black and Hispanic adults than White adults. In conclusion, hospitalization rates of adults with CHD in the United States increased from 2000 to 2018, largely driven by an increase in adults ≥55 years. Although the age at hospitalization increased overall, Black and Hispanic patients were substantially younger at presentation for advanced heart failure. Anticoagulation guidelines in this population may need revisiting as transient ischemic attack/stroke hospitalizations were frequent.

Immunoglobulin light chain (AL) amyloidosis is a disorder of clonal plasma cells characterized by deposition of amyloid fibrils in a variety of tissues, leading to end-organ injury. Renal or cardiac involvement is most common, though any organ outside the central nervous system can develop amyloid deposition, and symptomatic presentations may consequently vary. The variability and subtlety of initial clinical presentations may contribute to delayed diagnoses, and organ involvement is often quite advanced and symptomatic by the time a diagnosis is established. Additionally, while organ function can improve with plasma-cell-directed therapy, such improvement lags behind hematologic response. Consequently, highly effective supportive care, including symptom management, is essential to improve quality of life and to maximize both tolerance of therapy and likelihood of survival. Considering the systemic nature of the disease, close collaboration between clinicians is essential for effective management.

Background While guidelines suggest intravenous (IV) iron to improve functional status and quality of life (QoL) in patients with NYHA class II-III heart failure (HF), continuous flow left ventricular assist device (CF-LVAD) recipients were not included in early IV iron studies. Our study compared outcomes between patients who did and did not receive IV iron during the index admission following Abbott HeartMate III™ (HM 3) CF-LVAD placement. Methods Thirty-three adult patients with a HM3 placed at our institution who received early post-operative IV iron (n = 20) or no IV iron replacement (n = 13) were compared. The co-primary outcomes were mean change in quality of life (by the Minnesota Living with Heart Failure Questionnaire [MLHFQ]) and 6-minute walk distance (6MWD) from baseline to first >90 day clinic follow-up. Results At first clinic follow-up there was no significant difference between the IV iron and no-IV iron groups in MLHFQ (−27 ± 38 vs −21 ± 41, P = .8822) or 6MWD (360 ± 740 vs 786 ± 722, P = .208). Conclusion Patients receiving IV iron during index admission following HM3 implantation did not experience an improvement in quality of life or functional capacity when compared to those who did not receive IV iron.

Coronavirus disease 2019 (COVID-19) is characterized by heterogeneity in susceptibility to the disease and severity of illness. Understanding inter-individual variation has important implications for not only allocation of resources but also targeting patients for escalation of care, inclusion in clinical trials, and individualized medical therapy including vaccination. In addition to geographic location and social vulnerability, there are clear biological differences such as age, sex, race, presence of comorbidities, underlying genetic variation, and differential immune response that contribute to variability in disease manifestation. These differences may have implications for precision medicine. Specific examples include the observation that androgens regulate the expression of the enzyme transmembrane protease, serine 2 which facilitates severe acute respiratory syndrome coronavirus 2 viral entry into the cell; therefore, androgen deprivation therapy is being explored as a treatment option in males infected with COVID-19. An immunophenotyping study of COVID-19 patients has shown that a subset develop T cytopenia which has prompted a clinical trial that is testing the efficacy of interleukin-7 in these patients. Predicting which COVID-19 patients will develop progressive disease that will require hospitalization has important implications for clinical trials that target outpatients. Enrollment of patients at low risk for progression of disease and hospitalization would likely not result in such therapy demonstrating efficacy. There are efforts to use artificial intelligence to integrate digital data from smartwatch applications or digital monitoring systems and biological data to enable identification of the high risk COVID-19 patient. The ultimate goal of precision medicine using such modern technology is to recognize individual differences to improve health for all.

Background: In United States (US) emergency departments (ED), ~80% of patients presenting with exacerbation of heart failure (HF) symptoms are admitted to the hospital. However, some patients are at low-risk of adverse outcomes and might be effectively managed as outpatients. While ED HF risk prediction tools guide admission or discharge decisions, they have not been compared, are not routinely used in EDs, and do not include patient-reported outcomes that may be associated with prognosis. Objective: To assess the feasibility of collecting variables for three published ED-based HF risk prediction tools (table) and the capacity to collect participant-reported outcomes. Methods: We screened a convenience sample of patients age ≥20 years with symptoms of HF (e.g. shortness of breath, edema) receiving care in a US ED. We collected information from medical records, and administered a questionnaire to collect patient-reported outcomes and a 3-minute walking test. We developed a safety protocol to identify participants ineligible for the walking test. Results: We screened 66 patients and consented 31 (47%) participants. The average age was 61 years, 6 (19.4%) were female and 28 (90.3%) were admitted. We completed all the questionnaires with an average time of 31 minutes. For the walking test, 15 were ineligible per the safety protocol, 6 completed the test, and 10 did not consent. For the three HF tools, we collected an average of 93.4% of the variables needed per participant (range across tools 91.4%-97.7%; Table). The main missing variables were BMI on ED arrival (n=23) and troponin (due to hemolyzed values, n=5). Conclusion: We obtained complete data for the participant questionnaires, yet there were missing values for variables needed for the HF tools. The Emergency Heart Failure Mortality Risk Grade tool had the most complete data. If a research or clinical study plans to use these tools, the study protocol should include BMI and troponin measurements and consider alternative strategies to collect data, such as by self-report.

One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The “omics”—genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics— of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.

This review summarizes contemporary desensitization strategies for patients awaiting cardiac transplantation in an era when specific management is still somewhat controversial.The number of sensitized patients awaiting heart transplantation is rising. Clinical assessment of antibody levels is mostly focused on human leukocyte antigen (HLA) antibodies. Sensitization to HLA antigens increases the risk of antibody medicated rejection and cardiac allograft vasculopathy after transplant, thus translates to reduced access to compatible donors and increased wait time to transplant. Desensitization therapy is commonly considered in listed patients with cPRA more than 50%, to either decrease the amount of circulating anti-HLA antibodies, reduce the antibody production, or a combination of both. Despite promising results on specific therapies (e.g., plasmapheresis, intravenous immunoglobulin, rituximab, bortezomib), there is a significant gap in knowledge on desensitization therapies in heart transplantation. Most data are from small observational studies and extrapolated from nonheart solid organ transplants.Management of the sensitized patient awaiting heart transplant is individualized. Desensitization can facilitate negative cross-match and successful transplantation, but is associated with significant cost and potential adverse effects. The long-term outcomes of desensitization therapy remain to be determined, further emphasizing the importance of personalizing the treatment approach to each patient.

Sympathovagal imbalance contributes to progressive worsening of heart failure (HF) and is associated with untoward clinical outcomes. Based on compelling pre-clinical studies that supported the role of autonomic modulation in HF models, a series of clinical studies were initiated using spinal cord stimulation, vagus nerve stimulation, and baroreceptor activation therapy in patients with HF with a reduced ejection fraction. Whereas the phase II studies with baroreceptor activation therapy remain encouraging, the larger clinical studies with spinal cord stimulation and vagus nerve stimulation have yielded disappointing results. Here we will focus on the pre-clinical studies that supported the role of neuromodulation in the failing heart, as well provide a critical review of the recent clinical trials that have sought to modulate autonomic tone in HF patients. This review will conclude with an analysis of some of the difficulties in translating device-based modulation of the autonomic nervous system from pre-clinical models into successful clinical trials, as well as provide suggestions for how to move the field of neuromodulation forward.

OBJECTIVE Obesity affects adults with congenital heart disease (CHD). The effect of an increased body mass index (BMI) with respect to morbidity and mortality has not been evaluated in adults with complex CHD. Our objective was to evaluate the effects of increased BMI on heart failure and mortality in univentricular patients who had undergone Fontan palliation. METHODS A query of Fontan patients' first appointments at the Washington University Center for Adults with CHD between 2007 and 2014 yielded 79 patients. BMI status as normal (

Left Ventricular Assist Device (LVAD) therapy use is increasing rapidly in advanced heart failure (HF). Little data exists on the application of this therapy in patients with advanced HF due to hypertrophic cardiomyopathy (HCM). Altered ventricular geometry, thickened septum and reduced LV end-diastolic diameter (LVEDD) in HCM may lead to increased suction events, arrhythmias and inflow cannula malfunction. We hypothesized that patients with end stage HCM benefit from LVAD therapy and have a similar rate of complications to those with ischemic or dilated CM. Between 2009 and 2014, 5 patients with end stage HCM (HCM and EF

Sympathovagal imbalance contributes to progressive worsening of heart failure and is associated with untoward clinical outcomes. Here we review the role of the autonomic nervous system in modulating the cardiovascular system, as well as the role of dysregulation of the autonomic nervous system in the pathogenesis of heart failure. We also discuss the experimental basis, rationale, and outcomes of ongoing clinical trials of using five different approaches to modulate the autonomic system in heart failure, including vagus nerve stimulation, spinal cord stimulation, renal denervation, baroreceptor activation therapy, and left cardiac sympathetic denervation. These approaches represent an exciting new era for the treatment of patients with heart failure.

Background Heart failure (HF) remains one of the leading causes of hospital admissions, representing annual healthcare costs exceeding $30 billion in the United States. In an effort to reduce hospitalizations and transition to a value-based care model, Medicare's Hospital Readmission Reduction Program penalizes hospitals that have above average 30 day readmission rates, withholding 3% of all Medicare reimbursement for these hospitals. While the national average for HF readmissions is currently at 22%, the 30 day readmission rate for HF at the University of North Carolina (UNC) is 23.9%. Fiscal incentives to reduce the burden of hospital admissions have fueled interest in ambulatory strategies that can better manage HF, including clinic-based administration of IV diuretics. Methods The aim of this study was to assess the impact of an outpatient diuresis clinic on HF hospitalizations and resultant cost savings. The clinic is staffed by an advanced practice provider and a registered nurse with cardiologist oversight. There is also multidisciplinary support by pharmacy, nutrition, and social work. Data were collected retrospectively from 445 patient encounters between August 2017 and February 2019. Primary endpoints included observation stays, inpatient hospitalizations, and cost to payers. Results As of February 2019, 162 unique patients had been treated in the diuresis clinic, totaling 445 encounters. Based on our FY2016 data, 90% of patients presenting to the emergency department with a diagnosis of HF are admitted for either an observation or inpatient stay. For patients admitted to UNC who require less than a 48 hour hospitalization, the total cost to payers was approximately $3.5 million. These 445 encounters would have resulted in a total payer cost of $1,184,145 for observation stays and $4,040,155 for inpatient admissions (less than 48 hours). In comparison, the cost to payer for each diuresis clinic visit is $276, resulting in a total cost of $122,820. In addition, assuming that each outpatient diuresis encounter substitutes for at least a 36 hour hospital stay (median length of stay in observation unit), this would, at minimum, result in 668 hospital bed days saved. Though transient electrolyte abnormalities and rare but reversible episodes of acute kidney injury were noted during clinic visits, there were no significant adverse events requiring hospitalizations during the study period. Conclusions For stable patients with decompensated heart failure, the outpatient IV diuresis clinic is a patient-centered, safe, and cost savings alternative to hospital admission.

Heart failure with preserved ejection fraction can present with clinical and imaging findings suggestive of an infiltrative cardiomyopathy. In some cases, endomyocardial biopsy is required for definitive diagnosis. A 64 year old male with a history of bariatric surgery with jejunoileal bypass

Neuropeptide Y (NPY) is a cotransmitter with norepinephrine (NE) and ATP in sympathetic nerves. There is evidence for increased activity of the sympathetic nervous system and the renin-angiotensin system (RAS), as well as a role for NPY in the development of hypertension in experimental animal models and in humans. Angiotensin II (ANG II) is known to facilitate sympathetic neurotransmission, an effect greater in spontaneously hypertensive rats (SHR) than normotensive Wistar-Kyoto (WKY) rats. A newly discovered product of the RAS is angiotensin-(1–7) [ANG-(1–7)]. There is evidence suggesting that ANG-(1–7) opposes the actions of ANG II, resulting in hypotensive effects. The objective of this study was to investigate the role of ANG-(1–7) on the nerve-stimulated overflow of NE and NPY from the mesenteric arterial bed of SHR and the mechanisms involved in mediating any effects produced. ANG-(1–7) (0.001, 0.01, 0.1 μM) decreased nerve-stimulated NE and NPY overflow, as well as perfusion pressure in preparations obtained from SHR. This effect was greater in preparations of SHR than WKY controls. In addition, ANG-(1–7) decreased NE overflow to a greater extent than NPY overflow. Administration of the Mas receptor antagonist, d-Ala7 ANG-(1–7), attenuated the decrease in both NE and NPY overflow due to ANG-(1–7) administration. However, the angiotensin type 2 receptor antagonist, PD-123391, attenuated the effect of ANG-(1–7) on NE overflow without affecting the decrease in NPY overflow. Moreover, in the presence of NG-nitro-l-arginine methyl ester, ANG-(1–7) decreased NPY overflow, but not NE overflow. ANG-(1–7) decreases the nerve-stimulated overflow of NE and NPY in preparations of SHR, whereas ANG II enhances it. Therefore, ANG-(1–7) may counteract the effects of ANG II by acting on ANG type 2 and Mas receptors.

The sympathetic nervous system and renin-angiotensin system are both thought to contribute to the development and maintenance of hypertension in experimental models such as the spontaneously hypertensive rat (SHR). We demonstrated that periarterial nerve stimulation (NS) increased the perfusion pressure (PP) and neuropeptide Y (NPY) overflow from perfused mesenteric arterial beds of SHRs at 4–6, 10–12, and 18–20 wk of age, which correspond to prehypertensive, developing hypertensive, and maintained hypertensive stages, respectively, in the SHR. NS also increased PP and NPY overflow from mesenteric beds of Wistar-Kyoto (WKY) normotensive rats. NS-induced increases in PP and NPY were greater in vessels obtained from SHRs of all three ages compared with WKY rats. ANG II produced a greater increase in PP in preparations taken from SHRs than WKY rats. ANG II also resulted in a greater increase in basal NPY overflow from 10- to 12-wk-old and 18- to 20-wk-old SHRs than age-matched WKY rats. ANG II enhanced the NS-induced overflow of NPY from SHR preparations more than WKY controls at all ages studied. The enhancement of NS-induced NPY overflow by ANG II was blocked by the AT1 receptor antagonist EMD-66684 and the angiotensin type 2 receptor antagonist PD-123319. In contrast, ANG II greatly enhanced norepinephrine overflow in the presence of PD-123319. Both captopril and EMD-66684 decreased neurotransmitter overflow from SHR mesenteric beds; therefore, we conclude that an endogenous renin-angiotensin system is active in this preparation. It is concluded that the ANG II-induced enhancement of sympathetic nerve stimulation may contribute to the development and maintenance of hypertension in the SHR.

Obesity affects adults with congenital heart disease (CHD). The effect of an increased body mass index (BMI) with respect to morbidity and mortality has not been evaluated in adults with complex CHD. Our objective was to evaluate the effects of increased BMI on heart failure and mortality in univentricular patients who had undergone Fontan palliation.A query of Fontan patients' first appointments at the Washington University Center for Adults with CHD between 2007 and 2014 yielded 79 patients. BMI status as normal (25 kg/m(2) ), overweight (≥25,30 kg/m(2) ), and obese (≥30 kg/m(2) ) was established at the patient's first appointment. We analyzed demographics, diuretic requirements, New York Heart Association (NYHA) class, and laboratory values using Student's two-sample t-test and Fisher's exact test. Mortality was assessed via survival curves, and hazard ratios were compiled with proportional hazard modeling.The recent average BMI was significantly greater in patients with NYHA classes II-IV (29.3 ± 9 kg/m(2) ) compared with asymptomatic patients (24.8 ± 5.1 kg/m(2) , P = .006). Additionally, the average BMI of patients with a high diuretic requirement (≥40 mg/day IV furosemide equivalent) was obese, at 32.15 ± 9.1 kg/m(2) , compared with 25.91 ± 7.3 kg/m(2) for those on no or lower doses of diuretics (P = .009). Eighteen of the 79 patients met an endpoint of death, hospice placement, or cardiac transplant by the study conclusion. Kaplan-Meier analysis from time of first appointment until recent follow-up revealed a significant association between time to combined endpoint and BMI class. Cox proportional hazard modeling with age adjustment yielded a hazard ratio of 3.2 (95% CI 1.096-9.379) for obesity upon first presentation to an adult CHD clinic.In patients with univentricular hearts and Fontan palliation, obesity is associated with symptomatic heart failure and mortality.

The entrainment of some circadian rhythms in rodents and humans to the environmental light-dark cycle deteriorates during aging. Recent evidence suggests that the time-keeping ability of the circadian pacemaker maintains its endogenous period in both hamsters and humans. This suggests that any changes in the coupling between environmental cues and the circadian pacemaker are not due to changes in “clock speed,” but rather due to a weakened coupling between the afferent systems relaying environmental information and the circadian pacemaker located in the suprachiasmatic nucleus. The suprachiasmatic nucleus receives serotonergic input from the raphe nuclei, and serotonergic 5HT1A,7 agonists have been reported to lose their circadian phase-adjusting efficacy during aging in hamsters. In the present study, the authors report the effects of a novel serotonergic agonist BMY 7378 on light-induced phase advances during aging in the hamster. The present report demonstrates that BMY 7378 is a highly efficacious chronobiotic that more than doubles the magnitude of light-induced phase shifts in hamster wheel-running activity rhythms. Light-induced phase advances in hamster wheel-running activity of at least 6 h following a single systemic dose of BMY 7378 are routinely observed. Furthermore, BMY 7378 potentiation of phase shifts is maintained in old hamsters, suggesting that BMY 7378 has a different site of activity than previously reported 5HT1A,7 agonists that have a diminished effect on circadian phase during aging.

The hamster suprachiasmatic nucleus (SCN) is innervated by a dense plexus of enkephalin-containing axons originating from cells in the intergeniculate leaflet (IGL) of the thalamus. However, the distribution of opioid receptors within the hamster SCN has not been reported. Opioid receptors consist of three primary subtypes: mu, delta and kappa opioid receptors. Enkephalins have the highest affinity for delta opioid receptors. Therefore, in the present study, we examined the distribution of delta opioid receptor immunoreactivity in the hamster SCN and the IGL of the thalamus. Coronal sections of the hamster hypothalamus inclusive of the SCN or thalamic regions containing the IGL were prepared at specific times of the day and labeled with anti-delta opioid receptor polyclonal antisera using standard immunohistochemical techniques. delta opioid receptors were heavily distributed within rostral-caudal regions of the SCN, with the densest labeling located in the ventral and medial regions of the mid-SCN. Similar patterns of labeling were observed for tissue prepared during mid-day or mid-night times. In contrast, delta opioid receptor immunoreactivity only sparsely labeled cells in the IGL. Cellular staining in all regions appeared as dark punctate labeling surrounding cells, indicative of terminal boutons. Therefore, it is suggested that delta opioid receptors are located presynaptically on axon terminals within the hamster SCN and IGL. These results suggest that delta opioid receptors may play a role in modulating circadian rhythms generated within the SCN, possibly by regulating transmitter release within the nucleus.

Work from our laboratory has established that angiotensin II (Ang II) produces a greater enhancement of the nerve stimulation (NS)-induced release (overflow) of both norepinephrine (NE) and neuropeptide Y (NPY) and a greater increase in perfusion pressure of the mesenteric arterial bed obtained from the spontaneously hypertensive rat (SHR) compared to age-matched Wistar-Kyoto (WKY) or Sprague-Dawley rats. The enhancement of NS-induced NPY release was blocked by the AT1 receptor antagonist EMD 66684 and the AT2 receptor antagonist PD 123319. Both captopril and EMD 66684 decreased NPY and NE overflow from SHR mesenteric beds, suggesting an endogenous renin-angiotensin system (RAS) is active in the mesenteric artery. We also observed that the recently discovered new arm of the RAS, namely, angiotensin (1-7) (Ang-(1-7)), attenuated the NS-induced increase in NE and NPY release and the accompanied increased perfusion pressure. These inhibitory effects were greater in blood vessels obtained from SHR compared to WKY. We suggest that inhibition of sympathetic neurotransmission contributes to the mechanism(s) by which Ang-(1-7) acts to inhibit the vasoconstrictor effect of Ang II. Administration of the MAS receptor antagonist D-Ala(7)Ang-(1-7) attenuated the decrease in both NE and NPY release due to Ang-(1-7) administration. The AT2 receptor antagonist PD 123391 attenuated the effect of Ang-(1-7) on NE release without affecting the decrease in NPY release. We observed a shift in the balance between Ang II and Ang-(1-7) levels in the SHR with an increase in Ang II and a decrease in Ang-(1-7) in the blood and mesenteric artery. This appears to be due to an increase in angiotensin-converting enzyme (ACE) in the mesenteric artery of the SHR.

Work from our laboratory has established that angiotensin II (Ang II) produces a greater enhancement of the nerve stimulation (NS)-induced release (overflow) of both norepinephrine (NE) and neuropeptide Y (NPY) and a greater increase in perfusion pressure of the mesenteric arterial bed obtained from the spontaneously hypertensive rat (SHR) compared to age-matched Wistar–Kyoto (WKY) or Sprague–Dawley rats. The enhancement of NS-induced NPY release was blocked by the AT1 receptor antagonist EMD 66684 and the AT2 receptor antagonist PD 123319. Both captopril and EMD 66684 decreased NPY and NE overflow from SHR mesenteric beds, suggesting an endogenous renin–angiotensin system (RAS) is active in the mesenteric artery. We also observed that the recently discovered new arm of the RAS, namely, angiotensin (1–7) (Ang-(1–7)), attenuated the NS-induced increase in NE and NPY release and the accompanied increased perfusion pressure. These inhibitory effects were greater in blood vessels obtained from SHR compared to WKY. We suggest that inhibition of sympathetic neurotransmission contributes to the mechanism(s) by which Ang-(1–7) acts to inhibit the vasoconstrictor effect of Ang II. Administration of the MAS receptor antagonist D-Ala7Ang-(1–7) attenuated the decrease in both NE and NPY release due to Ang-(1–7) administration. The AT2 receptor antagonist PD 123391 attenuated the effect of Ang-(1–7) on NE release without affecting the decrease in NPY release. We observed a shift in the balance between Ang II and Ang-(1–7) levels in the SHR with an increase in Ang II and a decrease in Ang-(1–7) in the blood and mesenteric artery. This appears to be due to an increase in angiotensin-converting enzyme (ACE) in the mesenteric artery of the SHR.

Coronary vasospasm may result in myocardial infarct (MI), ventricular arrhythmia and cardiac arrest. Survivors of cardiac arrest from this condition are at increased risk for recurrent spasm, ventricular arrhythmias and sudden cardiac death (SCD), despite normal cardiac function and medical

The phase of the circadian pacemaker in hamsters can be shifted by the application of certain non-photic stimuli late in the subjective day. A projection from the intergeniculate leaflet of the thalamus to the circadian pacemaker in the suprachiasmatic nucleus is believed to mediate some types of non-photic phase-shifting stimuli. In hamsters, this projection is immunoreactive to both Neuropeptide Y and enkephalin. Previous work in other laboratories has shown that Neuropeptide Y administration is capable of phase shifting circadian rhythms without the application of light. The present study was undertaken to determine if enkephalinergic compounds likewise have the ability to non-photically phase shift hamster activity rhythms. Hamsters were maintained under conditions of constant darkness and circadian wheel running activity was recorded. Agonists and antagonists selective for kappa, mu, and delta opioid receptors were systemically applied without light to hamsters at circadian times 8 and 10 to determine if they were able to elicit phase shifts in wheel running activity rhythms. Of the compounds tested, only the delta opioid agonist BW373U86 significantly affected circadian phase. BW373U86 phase advanced hamster wheel running activity rhythms by approximately 45 min, although total activity levels following drug application were not significantly affected. Changes in the amount of wheel running activity were detected after administration of some mu and kappa opioids, although the circadian phase was not altered. These results indicate that enkephalin-mimetic delta opioid agonists are capable of producing non-photic phase shifts in hamster activity rhythms, and that opioids can independently affect circadian phase and activity levels in hamsters.

Non-photic stimuli administered to hamsters during the subjective day can cause phase advances in circadian wheel running activity. It is believed that afferent projections from the intergeniculate leaflet of the thalamus to circadian pacemaker cells within the suprachiasmatic nucleus mediate the phase shifting effects of some non-photic stimuli. In hamsters, many of the intergeniculate leaflet afferents contain enkephalin, yet the role of opioids in producing non-photic phase shifts in hamsters has not been reported. In the present study, we show that SNC 80, an agonist for the delta opioid receptor subtype, will phase advance hamster wheel running activity rhythms when administered late in the subjective day. These results indicate that opioids may be involved in modulating the circadian pacemaker in hamsters.