Sympathetic neural responses to sleep disorders and insufficiencies

Short sleep duration and poor sleep quality are associated with cardiovascular risk, and sympathetic nervous system (SNS) dysfunction appears to be a key contributor. The present review will characterize sympathetic function across several sleep disorders and insufficiencies in humans, including sleep deprivation, insomnia, narcolepsy, and obstructive sleep apnea (OSA). We will focus on direct assessments of sympathetic activation (e.g., plasma norepinephrine and muscle sympathetic nerve activity), but include heart rate variability (HRV) when direct assessments are lacking. The review also emphasizes sex as a key biological variable. Experimental models of total sleep deprivation and sleep restriction are converging to support epidemiological studies reporting an association between short sleep duration and hypertension, especially in women. A systemic increase of SNS activity via plasma norepinephrine is present with insomnia, and has also been confirmed with direct, regionally-specific evidence from microneurographic studies. Narcolepsy is characterized by autonomic dysfunction via both HRV and microneurographic studies, but with opposing conclusions regarding SNS activation. Robust sympathoexcitation is well documented in OSA, and is related to baroreflex and chemoreflex dysfunction. Treatment of OSA with continuous positive airway pressure results in sympathoinhibition. In summary, sleep disorders and insufficiencies are often characterized by sympathoexcitation and/or sympathetic/baroreflex dysfunction, with several studies suggesting women may be at heightened risk.

Effects of Fatty Acid Amide Hydroxylase Inhibitor URB597 on the Catecholaminergic Activity of the Adrenal Medulla in Stressed Male and Female Rats

<b><i>Introduction:</i></b> The present study examined the effects of fatty acid amide hydrolase inhibitor URB597 on the level of plasma catecholamine and their content, synthesis, and degradation in the adrenal medulla of male and female rats subjected to chronic unpredictable stress (CUS). <b><i>Material and Methods:</i></b> Male and female Wistar rats were exposed to the 6 weeks of CUS and treated intraperitoneally with either 0.3 mg/kg/day of URB597 or vehicle in the last 2 weeks of stress protocol. Catecholamines’ plasma levels and catecholamines’ levels in adrenal medulla were examined using Elabscience ELISA kits. Western blot analysis was used to detect the protein in the medulla. <b><i>Results:</i></b> The results of our experiment showed that adrenal weights and catecholamine of unstressed control were higher in females and that CUS induced further enlargement of adrenal glands and catecholamine content and its synthesis compared to male rats. CUS caused an increase of plasma norepinephrine and depletion of norepinephrine content as well as unchanged synthesis and degradation of catecholamine in the adrenal medulla of male rats. URB597 reduced enlarged adrenals and catecholamine content and its synthesis in stressed female rats. URB597 reduces increased plasma norepinephrine and restores its content in the adrenal medulla, unchanging the expression of enzyme synthesis, while reduced protein levels of monoamine oxidase A in male rats are exposed to CUS. <b><i>Discussion:</i></b> Our results support the role of endocannabinoids as an antistress mechanism that inhibits elevated adrenomedullary activation and promotes its recovery to baseline in both male and female stressed rats.

Standardized Autonomic Testing in Patients With Probable Radiation-Induced Afferent Baroreflex Failure

Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF. We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0–10) was 7 (interquartile range, 6–7). Cardiovascular adrenergic impairment was seen in 85 patients (94.4%), increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 seconds), and orthostatic hypotension in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722–1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.

Analytic and Integrative Framework for Understanding Human Sympathetic Arterial Baroreflex Function: Equilibrium Diagram of Arterial Pressure and Plasma Norepinephrine Level

BackgroundThe sympathetic arterial baroreflex is a closed-loop feedback system for stabilizing arterial pressure (AP). Identification of unique functions of the closed system in humans is a challenge. Here we propose an analytic and integrative framework for identifying a static operating point and open-loop gain to characterize sympathetic arterial baroreflex in humans.Methods and ResultsAn equilibrium diagram with two crossing functions of mechanoneural (MN) and neuromechanical (NM) arcs was analyzed during graded tilt maneuvers in seven healthy subjects. AP and plasma norepinephrine level (PNE), as a surrogate for sympathetic nerve activity, and were recorded after vagal modulation of heart function was blocked by atropine. The MN-arc curve was described as a locus of operating points during –7, 0, 15, and 60° head-up tilting (HUT) on a PNE-AP plane. The NM-arc curve was drawn as a line between operating points before and after ganglionic blockade (trimethaphan, 0.1 mg⋅ml–1⋅kg–1) during 0° or 15° HUT. Gain values were estimated from the slopes of these functional curves. Finally, an open-loop gain, which is a most important index for performance of arterial baroreflex, was given by a product of the gain values of MN (GMN) and NM arcs (GNM). Gain values of MN was 8.92 ± 3.07 pg⋅ml−1⋅mmHg−1; and GNM at 0° and 15° HUT were 0.61 ± 0.08 and 0.36 ± 0.05 mmHg⋅ml⋅pg–1, respectively. A postural change from supine to 15° HUT significantly reduced the open-loop gain from 5.62 ± 0.98 to 3.75 ± 0.62. The effects of HUT on the NM arc and open-loop gain seemed to be similar to those of blood loss observed in our previous animal studies.ConclusionAn equilibrium-diagram analysis contributes to a quantitative and integrative understanding of function of human sympathetic arterial baroreflex.

Effects of Experimental Sleep Restriction on Ambulatory and Sleep Blood Pressure in Healthy Young Adults: A Randomized Crossover Study

Although insufficient sleep is associated with increased cardiovascular risk, evidence of a causal relationship is lacking. We investigated the effects of prolonged sleep restriction on 24-hour ambulatory blood pressure (BP) and other cardiovascular measures in 20 healthy young participants (aged 23.4±4.8 years, 9 females), who underwent a randomized, controlled, crossover, 16-day inpatient study consisting of 4 days of acclimation, 9 days of sleep restriction (4 hours of sleep/night) or control sleep (9 hours), and 3 days of recovery. Subjects consumed a weight maintenance diet with controlled nutrient composition throughout. A 24-hour BP (primary outcome) and cardiovascular biomarkers were measured repeatedly. Polysomnographic monitoring was continuous. Comparing sleep restriction versus control sleep, 24-hour mean BP was higher (adjusted mean difference, day 12: 2.1 mm Hg [95% CI, 0.6–3.6], corrected P =0.016), endothelial function was attenuated ( P <0.001), and plasma norepinephrine increased ( P =0.011). Despite increased deep sleep, BP was elevated while asleep during sleep restriction and recovery. Post hoc analysis revealed that 24-hour BP, wakefulness, and sleep BP increased during experimental and recovery phases of sleep restriction only in women, in whom 24-hour and sleep systolic BP increased by 8.0 (5.1–10.8) and 11.3 (5.9–16.7) mm Hg, respectively (both P <0.001). Shortened sleep causes persistent elevation in 24-hour and sleep-time BP. Pressor effects are evident despite closely controlled food intake and weight, suggesting that they are primarily driven by the shortened sleep duration. BP increases are especially striking and sustained in women, possibly suggesting lack of adaptation to sleep loss and thus greater vulnerability to its adverse cardiovascular effects.

Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension

We previously reported that the norepinephrine transporter inhibitor, atomoxetine, improved standing blood pressure and lightheadedness in patients with neurogenic orthostatic hypotension (nOH). The purpose of the present study was to determine the predictors of the pressor response to atomoxetine. Patients with nOH who participated in the clinical trials ( https://www.clinicaltrials.gov ; Unique identifiers: NCT00223691 and NCT01316666) were included in this retrospective analysis. All subjects underwent autonomic function testing, plasma norepinephrine, systolic, diastolic blood pressure, and symptoms assessments, whereas seated and standing, before, and 60 minutes after a single dose of atomoxetine 18 mg. A subset of 25 patients underwent iodine-123–labeled metaiodobenzylguanidine scanning to estimate the degree of cardiac sympathetic denervation. A total of 99 subjects with nOH (67±9 years old, 40 women) participated in the study, 35 with multiple system atrophy, 52 with pure autonomic failure, and 12 with Parkinson disease. The average orthostatic decrease in their systolic blood pressure/diastolic blood pressure was −52±26/−22±15 mm Hg. Supine plasma norepinephrine levels predicted the standing systolic blood pressure (adjusted R 2 was 0.12, F [3,80]=4.66, P =0.007) and diastolic blood pressure (adjusted R 2 was 0.18, F [3, 80]=7.04, P =0.001) in response to atomoxetine. The increase in systolic blood pressure after atomoxetine was associated with the decrease in nOH-related symptoms ( R 2 =0.14, F [1,44]=8.16 P =0.007). In conclusion, plasma norepinephrine was modestly associated with the pressor response to atomoxetine in patients with nOH. Additionally, the improvement in nOH-related symptoms was associated with the increase in the pressor response to atomoxetine.

Correlation between plasma catecholamines, weight, and diabetes in pheochromocytoma and paraganglioma

Context Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes. Objective The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1C (HA1C). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control. Design A retrospective cohort study was performed (1999–2020). Wilcoxon rank-sum tests compared non-parametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HA1C. The median study duration was 54.2 months (IQR: 19.0–95.1). Setting Tertiary academic hospital. Patients 360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR: 45–67) and 56.4% (N=203) were female. Main outcome measures The primary and secondary outcomes were weight and HA1C, respectively. Results On multivariable MEM, norepinephrine (p&lt;0.0005) negatively correlated with weight when all catecholamines and their derivatives were tried in the model, and normetanephrine (p&lt;0.0005) correlated when only metanephrines were included. In the surgical cohort (N=272), normetanephrine decreased postoperatively and was inversely associated with weight (p&lt;0.0005). Elevated norepinephrine or normetanephrine at the study termination, indicative of metastatic and/or recurrent disease (MRD), correlated with weight loss. Norepinephrine and normetanephrine (p&lt;0.0005) directly correlated with HA1C. Conclusion Plasma norepinephrine and its metabolite directly correlate with HA1C and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HA1C despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.

A Unique Presentation of a Paraganglioma and Its Consequences

Introduction: Paragangliomas (PGL) are extremely rare tumors arising from extra-adrenal neural crest cells with an incidence of 0.8 per 100,000 person-years. Sympathetic chain PGLs usually arise in the abdomen, with about 75% of them arising intra-abdominally [2]. On CT or MRI, PGLs are usually have homogenous enhancement or central areas of low attenuation. The consequences of PGLs are many, and one complication that is rarely noted is glycemic disturbances with catecholamine excess. Here, we present a case of a radiographically unique appearing PGL that resulted in dramatic improvement of diabetes after resection. Case: 41 year old male with a past medical history of diabetes, CKD and developmental delay presented with hyperglycemia. Patient’s home regimen of Glargine 15 units qHS and Humalog 5 units TID AC had run out a few days prior. Patient had Hemoglobin A1c of 11.8% mg/dL and a C-peptide of 0.4 ng/ml. Endocrine was initially consulted for glucose management. Hospital course was complicated by abdominal pain and CT imaging showed low attenuation splenic masses, retroperitoneal lymphadenopathy and a large, necrotic appearing mesenteric mass consistent with lymphoma. MRI reaffirmed mass with peripheral enhancement and central necrosis consistent with neoplasm. Patient underwent biopsy of lymphadenopathy, which came back benign and then went for biopsy of mass. As the needle entered the mass, the patient became acutely hypertensive and tachycardic. He received phentolamine with good response and labs were drawn for catecholamine producing tumor. Plasma norepinephrine level was 6048 pg/ml and a chromogranin level of 4788 ng/ml. An MIBG scan revealed focal uptake at the lesion without evidence of metastasis. In the subsequent weeks, he was alpha- and then beta-blocked and underwent resection of mass that was complicated by transient hypotension and hypoglycemia. Eventually, patient’s blood pressure was controlled and insulin requirements dropped precipitously to just requiring 4 units of glargine by discharge. Discussion: This patient had a mass on CT scan that appeared to be consistent with lymphoma as opposed to PGL that led to biopsy and subsequent catecholamine crisis. Fortunately, this was controlled and subsequent resection led to improvement in the patient’s glycemic control. It has been thought that glucose intolerance in PGL patients is due to impaired insulin release through desensitization of the beta-adrenergic receptor. Furthermore, Catecholamines, as counter-regulatory hormones, have been well documented to raise blood sugar on this basis as well. Fortunately for our patient, he survived an initial biopsy and post-operatively, was able to actually have an improvement in his glycemic control. It also is a reminder to always do a screen for PGL before doing a needle biopsy of a compatible abdominal mass.

Attenuated β-adrenergic response in calcium/calmodulin-dependent protein kinase IV-knockout mice

In the present study, we examined the importance of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) in the regulation of cardiac function using genetically modified CaMKIV-null mice. RT-PCR analysis revealed decreased expression of voltage-dependent calcium channels in the cardiac myocytes of CaMKIV-null mice compared with wild-type mice. CaMKIV-null mice showed shortened QT time on electrocardiograms. Pharmacological analysis revealed decreased responsiveness to the β-adrenergic blocker propranolol in CaMKIV-null mice, whereas the plasma norepinephrine level was not affected. CaMKIV-null mice showed decreased baroreflex on electrocardiograms. Heart rate variability analysis showed unstable R-R intervals, a decreased low frequency power/high frequency power (LF/HF) ratio, and increased standard deviation of the normal to normal R-R intervals (SDNN) in CaMKIV-null mice, suggesting decreased responsiveness to β-adrenergic stimulation in CaMKIV-null mice. Atrial contraction analysis and cardiac action potential recording showed a decreased response to the β-adrenoceptor agonist isoproterenol in CaMKIV-null mice. Furthermore, fluorescence imaging in a CRE-hrGFP assay revealed a decreased response to isoproterenol in CaMKIV-null cardiac myocytes. Taken together, our data strongly suggest a significant effect of CaMKIV gene ablation on cardiac β-adrenergic signal transduction.