Elevated Plasma Norepinephrine Research Articles

8358 A Diagnostic Challenge: Occult Paraganglioma Misdiagnosed as Pheochromocytoma Leading to Unnecessary Adrenalectomy

Abstract Disclosure: A.R. Kasireddy: None. S. Alshami: None. S. Gummalla: None. C. Balasubramaniapandian: None. J.A. Henske: None. A. Albashaireh: None. Background: Pheochromocytomas and paragangliomas are rare neuroendocrine tumors. Catecholamine-secreting paragangliomas, like pheochromocytomas, can present with hypertension, sweating and episodic headaches. Thoughtful consideration must be given to distinguish between the two and potentially avoid a critical misdiagnosis. Case: A 61-year-old woman with hypertension and diabetes presented for evaluation of glomus jugulare discovered on CT of the head during evaluation of worsening hearing loss and tinnitus. She reported a longstanding history of episodic headaches, palpitations, anxiety spells and excessive sweating with more recent onset of ear fullness. When symptoms first presented, she had a left adrenalectomy 3 years prior. CT abdomen at that time showed 1.8 x 2.2 cm left adrenal nodule with a density of 12.2 HU and early contrast washout. Plasma metanephrines were normal but normetanephrines were elevated at 5.1 nmol/L (nl: less than 0.9 nmol/L). 24-hour urine metanephrines were normal but normetanephrines were elevated to 892mcg/24h (nl: 122-676 mcg/24h). MIBG scan was done and showed increased activity in the left adrenal nodule. Decision was made to proceed with left adrenalectomy. Surgical pathology was benign. Present evaluation after discovery of the glomus tumour with worsening symptoms showed normal plasma metanephrines, elevated plasma normetanephrines at 1529.9 pg/ml (0- 285.2 pg/ml), elevated plasma norepinephrine at 3280 pg/ml (0-874 pg/ml), with normal dopamine and epinephrine levels. CT head showed a 3 x 2.7 x 2.1 cm lytic destructive mass within the petrous temporal bone at the left skull base containing multiple internal calcifications. Given the lab and imaging findings, paraganglioma was diagnosed. Genetic testing revealed SDHB mutation. Neurosurgery consultants determined that the tumour was not amenable to resection. She was treated with radiation therapy, alpha blockade, and close blood pressure monitoring. Discussion: This case highlights the importance of reviewing the degree of hormonal elevations as well as the pattern of elevation to obtain a correct diagnosis. Paragangliomas commonly secrete normetanephrines rather than metanephrines and are often not immediately localized. Understanding the most likely genetic mutations when a paraganglioma is suspected can direct appropriate choice of radionuclide scanning agents. In this case, an earlier diagnostic scan may have prevented unnecessary adrenalectomy and facilitated earlier discovery of the paraganglioma. Presentation: 6/2/2024

Abstract 14993: Empagliflozin Exerts a Sympathoinhibitory Effect and Ameliorates Cardiorenal Injuries in a Rat Model of Hypertensive Heart Failure

Background: SGLT2 inhibitors may have protective effects on cardiac and renal injuries; however, their mechanisms remain unclear. Sympathetic activation has a crucial role in cardio/renal injuries. This study aimed to investigate whether empagliflozin can inhibit cardio/renal injuries through sympathoinhibition in a rat model of hypertensive heart failure. Methods: Male Dahl salt-sensitive rats were divided into low-salt (LS) and high-salt (HS) diet groups from 6 weeks of age. The rats in HS group were assigned to vehicle (HS-VEH) or empagliflozin (HS-EMPA) treatment group at 8 weeks. The effect of empagliflozin on central sympathetic regulation and cardio/renal injuries was assessed at 12 weeks (pre-heart failure phase), while its protective effect on heart failure was evaluated at 15 weeks in another cohort. Results: At 12 weeks , systolic blood pressure was similarly elevated in HS-VEH and HS-EMPA. Plasma norepinephrine levels were increased in HS-VEH compared to LS, and were suppressed in HS-EMPA, which was consistent with the neuronal activity of pre-sympathetic neurons in the brain. Increased left ventricular (LV) weight/body weight, plasma creatinine levels, renal fibrosis, and glomerular sclerosis in HS-VEH were attenuated in HS-EMPA. At 15 weeks , the high salt-induced blood pressure elevation was similar between HS-VEH and HS-EMPA. Although LV hypertrophy did not significantly differ, both decreased echocardiographic LV fractional shortening and increased lung weight observed in HS-VEH were attenuated in HS-EMPA. Elevated plasma creatinine and norepinephrine levels in HS-VEH were also attenuated in HS-EMPA. Conclusion: Empagliflozin inhibits sympathoexcitation and ameliorates cardio/renal injuries without lowering blood pressure in the hypertensive heart failure model. This sympathoinhibitory effect of empagliflozin observed in the pre-heart failure phase might contribute to the attenuation of heart failure progression.

Sympathoinhibitory electroacupuncture (EA) interacts positively with anti-inflammatory EA alleviating blood pressure in hypertensive rats.

Elevated sympathetic activity and chronic inflammation are known contributory factors observed in hypertension. We have observed that sympathoinhibitory electroacupuncture (SI-EA) at acupoints ST36-37 alleviates sympathetic activity and hypertension. Additionally, EA at acupoints SP6-7 exerts anti-inflammatory (AI-EA) effects. However, it is not known whether simultaneous stimulation of this combination of acupoints attenuates or enhances individual effects. A 2 × 2 factorial design was used to test the hypothesis that combining SI-EA and AI-EA (cEA) leads to greater reduction of hypertension by decreasing sympathetic activity and inflammation in hypertensive rats than either set of acupoints alone. Dahl salt-sensitive hypertensive (DSSH) rats were treated with four EA regimens including cEA, SI-EA, AI-EA, and sham-EA twice weekly for five weeks. A group of normotensive (NTN) rats served as control. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were measured non-invasively by tail-cuff. Plasma norepinephrine (NE), high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) concentrations were determined with ELISA at the completion of treatments. DSSH rats on high salt diet progressively developed moderate hypertension within five weeks. DSSH rats treated with sham-EA showed continuous increase in SBP and DBP and elevations in plasma NE, hs-CRP, and IL-6 levels relative to NTN control. Both SI-EA and cEA decreased SBP and DBP, and had corresponding changes in biomarkers (NE, hs-CRP, and IL-6) compared with sham-EA. AI-EA prevented SBP and DBP elevation and decreased IL-6 and hs-CRP relative to sham-EA. Importantly in DSSH rats that received repetitive cEA treatment, SI-EA interacted positively with AI-EA leading to greater reduction of SBP, DBP, NE, hs-CRP, and IL-6 than SI-EA or AI-EA alone. These data suggest that by targeting both elevated sympathetic activity and chronic inflammation, cEA regimen results in a greater reduction of BP effects in treating hypertension compared to using individual SI-EA or AI-EA alone.

Imaging and pathologic correlation of composite pheochromocytoma-ganglioneuroma.

A 50-year-old man consulted our institution for headaches and uncontrolled high blood pressure. Laboratory work-up and endocrine evaluation were consistent with pheochromocytoma with elevated plasma free metanephrine, free normetanephrine, plasma epinephrine, norepinephrine, total catecholamines, and 24-hour urine fractionated metanephrines, normetanephrines and total metanephrines levels. CT showed a contrast-enhancing 11.5 × 12.4 × 8.8 cm right adrenal complex cystic mass (Fig. 1A). Subsequent 68Ga-DOTATATE PET/CT confirmed the large right adrenal lesion with prominent tracer avidity (Fig. 1B). Surgical resection and pathology (Figs. 1C and 2) reached the diagnosis of composite pheochromocytoma-ganglioneuroma (CPG). The patient’s symptoms resolved after surgery. Genetic testing was normal. CPG, a rare tumor of mostly third-to-fifth decade of life with no gender preference, contains both pheochromocytoma (PC) and ganglioneuroma (GN) neoplastic components. CPG features symptoms of catecholamine overproduction: headache, palpitations, hypertension, and diaphoresis, and abdominal pain and watery diarrhea from excess VIP production by ganglioneuroma cells. CPG is indistinguishable from PC by clinical presentation, imaging features and biomarkers. Most CPG patients present with elevated catecholamines (1,2). CPG appears on CT as a well-circumscribed, heterogeneous or cystic adrenal mass with contrast enhancement. 68Ga-DOTATATE PET/CT may be an effective functional imaging modality for the detection and post-surgical monitoring of CPG based on its PC component (2). Diagnosis is histological with the identification of admixed regions of usually dominant PC and GN. PC cells stain positively for synaptophysin, GN cells with NeuN and Schwann cells with S-100. BRAF and HRAS mutations are frequently associated with CPG (3). CPG resection proceeds like PC surgery with preoperative adrenergic blockade, increased oral hydration and salt supplementation. The overall risk of malignancy associated with CPG is notably lower than with pure PC. Symptoms usually resolved upon CPG surgical resection, as seen in our case. One-out-of-eight treated patients may develop recurrence within 15 months (1).

Brain fog in neuropathic postural tachycardia syndrome may be associated with autonomic hyperarousal and improves after water drinking.

BackgroundBrain fog is a common and highly disturbing symptom for patients with neuropathic postural tachycardia syndrome (POTS). Cognitive deficits have been measured exclusively in the upright body position and mainly comprised impairments of higher cognitive functions. The cause of brain fog is still unclear today. This study aimed to investigate whether increased autonomic activation might be an underlying mechanism for the occurrence of brain fog in neuropathic POTS. We therefore investigated cognitive function in patients with neuropathic POTS and a healthy control group depending on body position and in relation to catecholamine release as a sensitive indicator of acute stress. The second aim was to test the effect of water intake on cardiovascular regulation, orthostatic symptoms, cognitive function and catecholamine release.MethodsThirteen patients with neuropathic POTS and 15 healthy control subjects were included. All participants completed a total of four rounds of cognitive testing: two before and two after the intake of 500 ml still water, each first in the supine position and then during head-up tilt. At the end of each cognitive test, a blood sample was collected for determination of plasma catecholamines. After each head-up tilt phase participants were asked to rate their current symptoms on a visual analogue scale.ResultsWorking memory performance in the upright body position was impaired in patients, which was associated with self-reported symptom severity. Patients had elevated plasma norepinephrine independent of body position and water intake that increased excessively in the upright body position. The excessive increase of plasma norepinephrine was related to heart rate and symptom severity. Water intake in patients decreased norepinephrine concentrations and heart rate, and improved symptoms as well as cognitive performance.ConclusionBrain fog and symptom severity in neuropathic POTS are paralleled by an excessive norepinephrine secretion. Bolus water drinking down-regulates norepinephrine secretion and improves general symptom severity including brain fog.

Olfactory Receptor78 Participates in Carotid Body‐Dependent Sympathetic Activation and Hypertension in Murine Models of Obstructive Sleep Apnea

Olfactory receptor (Olfr) 78 participates in carotid body (CB) activation by acute hypoxia. We examined the role of Olfr78 in CB‐dependent sympathetic activation and hypertension in: 1) mice treated with chronic intermittent hypoxia (CIH) patterned after blood O2 profiles during obstructive sleep apnea (OSA) and 2) heme oxygenase‐2 (HO‐2) null mice, which exhibit OSA. CIH treated wild type (WT) mice showed: enhanced CB sensory nerve response to hypoxia and sensory long‐term facilitation (sLTF), hypertension, activation of the sympathetic nervous system as evidenced by spectral analysis of inter‐beat interval as well as elevated plasma nor‐epinephrine (NE) levels. All these responses were absent in Olfr78 null mice. HO‐2 null mice showed spontaneous apneas with an apnea index (AI) of 58±1.2 apneas/hour compared to AI of 8±0.8 apneas/hour in WT mice. CBs of HO‐2 null mice showed enhanced CB response to hypoxia and sLTF as well as elevated plasma NE levels and hypertension. The magnitude of hypertension correlated to AI in HO‐2 null mice (P<0.01). In striking contrast, HO‐2/Olfr78 double null mice showed stable breathing with an AI of 12±1.3 apneas/hour. HO‐2/Olfr78 double null mice showed absence of augmented CB response to hypoxia, sLTF, elevated plasma NE levels and hypertension. These results demonstrate that Olfr78 participates in CB activation and ensuing sympathetic nerve excitation and hypertension in two mouse models of OSA.

Absence of Erythropoietin and Cardio‐respiratory Responses to Hypobaric Hypoxia in Olfactory Receptor 78 Null mice

Hypobaric hypoxia (HH) evokes a series of physiological adaptations, including carotid body (CB)–dependent ventilatory acclimatization to hypoxia (VAH), elevated blood pressure (BP), and stimulation of erythropoietin (Epo) gene in the kidney. Olfactory receptor 78 (Olfr78) is a G‐protein coupled receptor that has been implicated in CB response to acute hypoxia. Given that both CB and kidney express Olfr78, we tested the hypothesis that Olfr78 plays a role in the cardio‐respiratory and renal Epo gene responses to HH. Studies were performed on wild type (WT) and Olfr78 null mice reared in room air (control) or exposed to 18h of HH (0.4 atmospheres). HH treated WT exhibited: 1) VAH manifested as increased baseline breathing, and enhanced hypoxic ventilatory response (HVR; 12% O2); 2) elevated BP and plasma norepinephrine levels; and 3) increased baseline CB sensory nerve activity and augmented CB sensory nerve response to subsequent acute hypoxia‐ all these responses to HH are either markedly attenuated or absent in Olfr78 null mice. WT mice responded to HH with activation of the renal Epo gene expression and elevated plasma Epo levels, and these effects were attenuated or absent in Olfr78 null mice. The attenuated Epo activation by HH was accompanied with markedly reduced hypoxia‐inducible factor (HIF)‐2α protein and reduced activation of HIF‐2 target gene Sod‐1 in Olfr78 null mice, suggesting impaired transcriptional activation of HIF‐2 contributes to attenuated Epo responses to HH. These results suggest a role for Olfr78 in physiological adaptations to HH experienced at high altitude

Inflammatory phenotype and T‐cell mitochondrial reactive oxygen species in young adults with major depressive disorder

BackgroundMajor depressive disorder (MDD) is prevalent in young adults and projected to rise further with the COVID pandemic. Notably, MDD is associated with an increased risk of cardiovascular disease (CVD) and mortality. Although the mechanisms are unclear, evidence supports chronic systemic inflammation as a major contributor to CVD risk in older adults with MDD. However, whether an inflammatory phenotype is present in young adults with MDD prior to the onset of CVD and other comorbidities is equivocal. Recent work has implicated the sympathetic nervous system and specifically norepinephrine as a potent driver of inflammation via stimulating an increase in T‐cell mitochondrial reactive oxygen species (T‐cell mitoROS). Given previous findings of elevated plasma norepinephrine and inflammation in MDD, the purpose of this study was to examine the potential for a T‐cell mitoROS pro‐inflammatory pathway in young otherwise healthy adults with MDD. We hypothesized that young adults with MDD but otherwise free of clinical disease would have augmented circulating pro‐inflammatory cytokines and T‐cell mitoROS compared to young healthy adults without MDD (HA).MethodsAll participants underwent a structured diagnostic neuropsychiatric interview to determine the presence or absence of MDD based on the DSM‐5 diagnostic criteria for MDD. Systemic pro and anti‐inflammatory cytokines and T‐cell mitoROS were measured in 14 healthy young adults with MDD of mild‐to‐moderate severity (non‐medicated; age: 23±2 years) and 11 HA (age: 22±1 years). Serum cytokines were detected using LEGENDplex Human Essential Immune Response panel and assessed by flow cytometry. Seven serum cytokines related to the norepinephrine‐T‐cell mitoROS‐inflammation pathway were measured. Immune cells were isolated from whole blood by red blood cell lysis. T‐cell mitoROS was measured by labeling with antibodies against CD3+ (total T cells) and mitoROS targeted fluorogenic dye (MitoSoxRED) and assessed by flow cytometry. All data are expressed as mean ± SE.ResultsFor pro‐inflammatory cytokines, there were no differences between MDD and HA for IL‐6 (41±18 pg/mL; 92± 66 pg/mL, P=0.66), IL‐17A (7±3 pg/mL; 17±8 pg/mL, P=0.13), TNF‐α (19±9 pg/mL; 36±18 pg/mL, P=0.20), IFNγ (120±70 pg/mL; 201±137 pg/mL, P=0.34) or IL‐2 (5±2 pg/mL; 13±6 pg/mL, P=0.25), respectively. Likewise, no differences were found in anti‐inflammatory cytokines between MDD and HA for IL‐10 (18±9 pg/mL; 78±57 pg/mL, P=0.19) or IL‐4 (33±15 pg/mL; 95±46 pg/mL, P=0.13), respectively. In contrast, T‐cell mitoROS was significantly elevated in MDD (34402±13353 a.u) compared to HA (6258±2942 a.u, P<0.05).ConclusionThese preliminary findings suggest T‐cell mitoROS but not circulating cytokine profiles are different between young adults with and without MDD. Thus, an elevated T‐cell mitoROS may represent an early marker of immune system alterations and inflammation in MDD.

Depression of Non-Neuronal Cholinergic System May Play a Role in Co-Occurrence of Subjective Daytime Sleepiness and Hypertension in Patients with Obstructive Sleep Apnea Syndrome.

PurposeSimultaneous occurrence of hypertension and excessive daytime sleepiness (EDS) is very common in obstructive sleep apnea syndrome (OSAS), although no study has specifically addressed this issue. The present study explored the risk factors for co-occurrence of OSAS-related EDS and hypertension.Patients and MethodsA total of 161 OSAS patients were studied after undergoing an eight-hour in-laboratory polysomnography for one night. The OSAS severity assessment depends on the number of breathing disturbances per hour of sleep. EDS was defined using the Epworth Sleepiness Scale (ESS) scores of ≥13. Hypertension was defined according to direct cuff blood pressure (BP) measurements. Beat-to-beat R-R interval data were incorporated in polysomnography for heart rate variability analysis. The low-frequency/high-frequency band ratio was used to reflect sympathovagal balance. The study participants were divided into four groups based on the presence of EDS and/or hypertension: EDS with hypertension (n = 53), EDS without hypertension (n = 27), no EDS with hypertension (n = 38), and no EDS or hypertension (n = 43). Clinical, polysomnographic and heart rate data were compared and studied among the four groups. Plasma acetylcholine (ACh) levels were assessed to explore the effects of the non-neuronal cholinergic system and the co-occurrence of EDS and hypertension.ResultsPatients with EDS and hypertension had more severe OSAS severity indices compared to control patients. Increased cardiac sympathovagal imbalance and nocturnal hypoxemia regulated the presence of EDS and hypertension. Further plasma biomarker analysis revealed that both ESS scores and BP levels were associated with significantly elevated plasma norepinephrine, interleukin-6 and superoxide dismutase levels and significantly decreased ACh levels. Logistic regression analyses showed that ACh was the only factor significantly associated with co-occurrence of EDS and hypertension after controlling for confounders using odds ratio of 0.932, with a 95% confidence interval of 0.868 to 1.000 (P = 0.049).ConclusionThe results suggested that OSAS coupled with both EDS and hypertension is a more severe phenotype of the respiratory disorder. The presence of EDS and hypertension was accompanied by sympathovagal imbalance, and co-occurrence of these two conditions may be related to decreased plasma ACh levels.

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.

Abstract P210: Central Blockade Of Tumor Necrosis Factor-Á-Converting Enzyme (tace) Ameliorates Neuroinflammation, Sympathetic Excitation And Cardiac Dysfunction In Heart Failure Rat

TACE is a key metalloprotease involved in ectodomain shedding of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-α. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to the sympathetic excitation in heart failure (HF). Additionally, the upregulated TGF-α in the PVN transactivates the epidermal growth factor receptor (EGFR) to activate extracellular signal-regulated kinase (ERK) 1/2 in HF. Here we sought to determine whether central inhibition of TACE attenuates neuroinflammation and prevents the progress of HF. Male rats underwent coronary artery ligation to induce HF or sham surgery (Sham). These rats were treated with bilateral PVN microinjection of a TACE siRNA or control siRNA while some rats received a 4-week intracerebroventricular (ICV) infusion of TACE inhibitor TAPI-0 or vehicle. Compared with Sham rats, HF rats treated with control siRNA, had higher (*P<0.05) levels of TNF-α (7.88±1.32* vs 2.77±0.98 pg/mL) and TGF-α (28.27±2.76* vs 11.62±2.48 pg/mL) in cerebrospinal fluid, and increased mRNA expression of TACE (2.53±0.30* vs 1.04±0.12), TNF-α (3.43±0.55* vs 1.03±0.11), TNF-α receptor 1 (2.32±0.27* vs 1.07±0.19), cyclooxygenase-2 (2.96±0.31* vs 1.10±0.19) and TGF-α (2.68±0.41* vs 1.06±0.14) in the PVN, but these levels were markedly reduced (39-54%*) in TACE siRNA-treated HF rats. Compared with control HF rats, HF rats treated with TACE siRNA had reduced expression of phosphorylated (p-) NF-κB p65 (1.27±0.14 vs 0.84±0.07*), p-EGFR (0.52±0.05 vs 0.37±0.04*) and p-ERK1/2 (1.06±0.10 vs 0.62±0.09*) in the PVN. Moreover, the elevated plasma norepinephrine levels, lung/body weight, heart/body weight and left ventricular (LV) end-diastolic pressure along with decreased LV dP/dt max in HF rats-treated with control siRNA were significantly attenuated in HF rats treated with TACE siRNA. Treatments with TACE siRNA in the PVN also improved the indicators of cardiac hypertrophy and fibrosis of HF. ICV infusion of TAPI-0 had the similar effects with PVN TACE siRNA on these variables in HF. These data indicate that central interventions suppressing TACE activity ameliorate neuroinflammation, sympathetic activation and cardiac dysfunction in HF.

Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome

BackgroundHigh sodium intake is recommended for the treatment of postural tachycardia syndrome (POTS) to counteract the hypovolemia and elevated plasma norepinephrine that contribute to excessive orthostatic tachycardia, but evidence of its efficacy is not available. ObjectivesThis study tested whether a high sodium (HS) diet reduces orthostatic tachycardia (Δ heart rate) and upright heart rate compared with a low sodium (LS) diet in POTS patients, and secondarily its effect on plasma volume (PV) and plasma norepinephrine. MethodsA total of 14 POTS patients and 13 healthy control subjects (HC), age 23 to 49 years, were enrolled in a crossover study with 6 days of LS (10 mEq sodium/day) or HS (300 mEq sodium/day) diet. Supine and standing heart rate, blood pressure, serum aldosterone, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine were measured. ResultsIn POTS, the HS diet reduced upright heart rate and Δ heart rate compared with the LS diet. Total blood volume and PV increased, and standing norepinephrine decreased with the HS compared with the LS diet. However, upright heart rate, Δ heart rate, and upright norepinephrine remained higher in POTS than in HC on the HS diet (median 117 beats/min [interquartile range: 98 to 121 beats/min], 46 beats/min [interquartile range: 32 to 55 beats/min], and 753 pg/ml [interquartile range: 498 to 919 pg/ml] in POTS vs. 85 beats/min [interquartile range: 77 to 95 beats/min], 19 beats/min [interquartile range: 11 to 32 beats/min], and 387 pg/ml [interquartile range: 312 to 433 pg/ml] in HC, respectively), despite no difference in the measured PV. ConclusionsIn POTS patients, high dietary sodium intake compared with low dietary sodium intake increases plasma volume, lowers standing plasma norepinephrine, and decreases Δ heart rate. (Dietary Salt in Postural Tachycardia Syndrome; NCT01547117)

Limited reliability of heart rate as a sympathetic marker in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by a pronounced sympathetic overactivity as documented by the marked increase in muscle sympathetic nerve traffic (MSNA) and in plasma norepinephrine reported in this condition. Whether and to what extent in CKD heart rate (HR) reflects the adrenergic overdrive remains undefined. It is also undefined the relative validity of the different adrenergic markers in reflecting renal dysfunction. In 82 CKD patients, aged 58.4 ± 1.1 years (mean ± SEM), we measured resting clinic blood pressure, HR (EKG), venous NE (HPLC) and MSNA (microneurography). The same measurements were made in 24 age-matched healthy controls. HR was significantly greater in CKD than in controls (74.0 ± 1.1 versus 68.2 ± 1.8 bpm, P < 0.02) and significantly directly related to the elevated plasma norepinephrine and MSNA values (r = 0.22 and 0.39, P < 0.05 and <0.0003, respectively). Both MSNA and plasma norepinephrine were significantly and inversely related to the estimated glomerular filtration rate. The correlation did not achieve statistical significance for HR. Similar results were obtained examining the relationships with left ventricular mass index. Our data show that in CKD not only peripheral but also cardiac sympathetic drive is markedly enhanced and HR can be regarded as a marker of the adrenergic overdrive characterizing this condition. The reliability of HR as sympathetic marker appears to be limited, however, this variable being unable to closely reflect, at variance from MSNA and plasma norepinephrine, the interindividual differences in renal dysfunction and the accompanying structural cardiovascular alterations.

Abstract 13438: The Role and Mechanism of Chronic Beta3-Adrenergic Receptor Blockade on the Progression of Heart Failure in a Rat Model

Background: The negative inotrope and up-regulation of β 3 -adrenergic receptors (AR) in human and animal failing hearts suggest a direct and contributing role of cardiac β 3 -AR activation on the progression of congestive heart failure (CHF). However, its precise role is still being debated. We hypothesize that up-regulation of cardiac β 3 -AR is detrimental and chronic β 3 -AR blockade may prevent CHF-caused intrinsic defects of left ventricular (LV) myocyte force-generating capacity and relaxation and improve β-AR regulation, thereby limiting the progression of CHF. Methods: We compared the alterations of LV and myocyte functional responses and [Ca 2+ ] i transient ([Ca 2+ ] iT ) in SD rats divided into 3 groups (8/group): 1) CHF 3 months after isoproterenol (ISO) (170 mg/kg, sq, for 2 days); 2) ISO/β 3 -ANT , 2 months after receiving ISO, a selective β 3 -AR antagonist (ANT), L-748,337, was initiated (10 -7 M/kg/day, sq. by mini-pump) and was given for 1 month; and 3) Sham controls . Results: Compared with controls, the animals that received ISO treatment had CHF onset at 1 month and progressed to severe HF at 3 months after ISO. Plasma norepinephrine (NE) (1295 vs 259 pg/ml) increased 5-fold; whereas, stroke volume (SV) (39 vs 91 μl) and ejection fraction (EF) (39 vs 62%) significantly decreased, and LV end-diastolic pressure (P ED ) (13.9 vs 6.0 mmHg) was doubled. These changes were paralleled with about 50% reductions in cell contraction (dL/dt max , 93 vs 186 μm/s) and relaxation (dR/dt max , 96 vs 159 μm/s) associated with a significant decrease in the peak systolic [Ca 2+ ] iT , (0.17 vs 0.26). In addition, superfusion of ISO (10 -8 M) caused much less increases in dL/dt max (39 vs 68%), dR/dt max (23 vs 54%), and [Ca 2+ ] IT (14 vs 28%). Treatment with β 3 -ANT increased SV (89 μl) and EF (60%), decreased P ED more than 90% from ISO-treated values, and corrected the elevation of plasma NE (301 pg/ml), dL/dt max (184 μm/s), dR/dt max (152 μm/s), and [Ca 2+ ] iT (0.24). ISO-induced increase in dL/dt max and [Ca 2+ ] iT also returned close to control levels. Conclusion: Chronic β 3 -ANT treatment after CHF significantly improves LV and myocyte contractile function and [Ca 2+ ] i regulation and limits the development of CHF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of CHF.

Chronically elevated norepinephrine concentrations lower glucose uptake in fetal sheep.

Fetal conditions associated with placental insufficiency and intrauterine growth restriction (IUGR) chronically elevate plasma norepinephrine (NE) concentrations. Our objective was to evaluate the effects of chronically elevated NE on insulin-stimulated glucose metabolism in normally grown, non-IUGR fetal sheep, which are independent of other IUGR-related reductions in nutrients and oxygen availability. After surgical placement of catheters, near-term fetuses received either a saline (control) or NE intravenous infusion with controlled euglycemia. In NE fetuses, plasma NE concentrations were 5.5-fold greater than controls, and fetal euglycemia was maintained with a maternal insulin infusion. Insulin secretion was blunted in NE fetuses during an intravenous glucose tolerance test. Weight-specific fluxes for glucose were measured during a euinsulinemic-euglycemic clamp (EEC) and a hyperinsulinemic-euglycemic clamp (HEC). Plasma glucose and insulin concentrations were not different between groups within each clamp, but insulin concentrations increased 10-fold between the EEC and the HEC. During the EEC, rates of glucose uptake (umbilical uptake + exogenous infusion) and glucose utilization were 47% and 35% lower (P < 0.05) in NE fetuses compared with controls. During the HEC, rates of glucose uptake were 28% lower (P < 0.05) in NE fetuses than controls. Glucose production was undetectable in either group, and glucose oxidation was unaffected by the NE infusion. These findings indicate that chronic exposure to high plasma NE concentrations lowers rates of net glucose uptake in the fetus without affecting glucose oxidation rates or initiating endogenous glucose production. Lower fetal glucose uptake was independent of insulin, which indicates insulin resistance as a consequence of chronically elevated NE.

Noradrenergic uptake in the liver on 123 I-mIBG imaging: Influence of heart failure and diabetes.

Imaging noradrenergic uptake in the liver with norepinephrine analog 123 I-meta-iodobenzylguanidine (mIBG) was explored in normal controls and patients with heart failure (HF). A total of 961 HF (343 with diabetes mellitus [DM]) and 94 control subjects underwent anterior planar mIBG images including upper abdomen at 15min (early) and 3h 50min (late) post-injection. Decay-corrected liver activity normalized to injected activity and body surface area (counts/pixel [cpp]/MBq/m2 ) was compared in three groups: HF with DM; HF without DM; and controls. Associations with plasma norepinephrine, liver function tests, and level of cardiac innervation were explored. In controls, liver mIBG activity decreased over time (early: 2.78 vs late: 2.43cpp/MBq/m2 , P<0.0001); in HF subjects, activity increased during this interval (HF without DM: 2.85 vs 2.93 [P=0.005]; HF with DM: 2.37 vs 2.43 [P=0.054]). Early liver activity was lower in HF with DM subjects than in the other groups (P<0.001); late liver activity was higher in HF without DM than in the other two groups (P<0.01). Subjects with elevated plasma norepinephrine (>520pg/mL) or ≥1 abnormal liver function test had lower early and late liver activity. In subjects with preserved cardiac mIBG uptake, HF subjects had higher and control subjects lower liver activity than comparable subjects with decreased cardiac innervation. In HF subjects, liver mIBG activity increased over time, reversing the normal washout pattern, suggesting a compensatory change in sympathetic nerve function. DM, abnormal liver function tests, and decreased cardiac innervation were associated with decreased liver mIBG uptake in HF.

SUN-908 Mediastinal Paraganglioma: A Rare Presentation of a Rare Tumor

BACKGROUNDParagangliomas (PPGL’s) are extra-adrenal chromaffin-cell originating tumors that arise from the para-aortic ganglia and are exceptionally rare making up only 1% of the mediastinal tumors. They are slowly growing and highly vascular tumors associated with high morbidity and mortality due to proximity and invasion into the heart, great vessels. The majority of them are asymptomatic and hence discovered incidentally. Surgical resection remains the standard of care with good long term survival. We describe a case of a young male with middle mediastinal PPGL who remained asymptomatic despite large functional tumor.CLINICAL CASEA 38-year old Arab male with no previous smoking history was referred to our hospital for evaluation of mediastinal mass that was incidentally noted on an echocardiogram done 1 year ago in his home country when he presented with intermittent exertional shortness of breath for 10 years. The workup done there with CT chest revealed a large mediastinal mass measuring 10.4×8.8×8.6 cm extending into ascending aorta, right pulmonary artery, right superior pulmonary vein, right and left atria as well as the main bronchi bilaterally invading the superior vena cava. However, he had no further treatment until he was seen 1 year later in the US at another institution where biochemical testing showed elevated plasma norepinephrine of 2697 (70-750 pg/ml, supine), dopamine 7667 (<30 pg/ml). 24hr-urine studies showed elevated normetanephrine of 3418 (111-419 mcg/24hr), metanephrine 3488 (200-614 mcg/24hr), and Homovanillic acid (HVA) 51.5 (<0.8 mg/24hr). He underwent endobronchial ultrasound with mediastinal tissue biopsy of the mass that revealed pheochromocytoma. The patient was subsequently referred for cardiovascular intervention at our hospital and endocrinology was consulted for pre-operative preparation. One week before surgery, he was started on doxazosin 2mg daily followed 3 days later by propranolol 10 mg twice daily and recommend high salt and fluid intake. The patient underwent surgical resection of the mass and pathology showed mediastinal PPGL. The postoperative course was complicated by bradycardia with the placement of a permanent pacemaker. He recovered well after surgery with the resolution of symptoms and a significant decline in catecholamines to urine normetanephrine of 385 mcg/24hr and metanephrine 497 mcg/24hrs. There was no evidence of metastatic or residual disease on follow-up CT chest 5 months later.CONCLUSIONThere are limited case reports of PPGL in the middle mediastinum. This case highlights that mediastinal PPGL’s can remain clinically silent for many years prior to the presentation which can lead to delayed diagnosis, yet a strong collaborative team approach between oncology, cardiovascular surgery and endocrinology can confer favorable clinical outcome.

Gene expression profiles T helper cell chemokines, cytokines and transcription factors in the genital tract of a stress mouse model during Chlamydia muridarum infection

A stress mouse model established in our laboratory showed that prolonged exposure of mice to cold water-induced stress results in elevated plasma norepinephrine levels, increased intensity of Chlamydia muridarum genital infection, and decreased functions of the immune system. The current study was designed to test whether Active Hexose Correlated Compound (AHCC) modulates the gene expression profiles of chemokines associated with either Thelper 1 (Th1) or Th2 in the stress model. We hypothesized that oral administration of AHCC feeding up-regulates the gene expression profiles of Th1 chemokines and Th1 transcription factors and increases the secretion of cytokines in Th cells and lysates of the genital tract. During the stressing period of 21 days, we mice either 300 mg/kg of AHCC or PBS per day using a gavage feeding technique. We used real PCR to determine gene expression of chemokines favoring Th1 or Th2 chemokines and cytokines. We used ELISA to assess cytokine production in the genital tract lysates. Oral administration of AHCC to stressed mice resulted in the up-regulation of Th1 chemokines. The level of mRNA fold-changes of CXCL10 (+2.2 fold), CXCL9 (+1.8 fold), and CCL5 (+2.fold) was observed. Moreover, AHCC feeding resulted in a significant increase in productions of interleukin-1b, and interleukin 10(IL-10) in the genital tract of stressed mice. However, the production of TNF-a and IL-6 were undetectable by ELISA. Although further study is needed, preliminary data suggest that AHCC feeding favors the production of protective cytokines in our stress mouse model. (Supported by NIH Grant P20GM103434 to the West Virginia IDeA Network for Biomedical Research Excellence and NIH Grant P20GM103434 awarded to Bluefield State College).

A 3-day dietary manipulation affects muscle glycogen and results in modifications of carbohydrate and fat metabolism during exercise when hyperglycaemic

The effect of hyperglycaemia on exercise with low and elevated muscle glycogen on glucose utilization (GUR), carbohydrate and fat oxidation, hormonal and metabolite responses, as well as rating of perceived exertion (RPE) were explored. Five healthy trained males were exercised for 90min at 70% V̇O2max in two trials, while glucose was infused intravenously at rates to "clamp" blood glucose at 12mM. On one occasion, participants were 'loaded' with carbohydrate (CHO-L), whilst on a separate occasion, participants were glycogen depleted (CHO-D). Prior exercise and dietary manipulations produced the 'loaded' and 'depleted' states. The CHO-L and CHO-D conditions resulted in muscle glycogen concentrations of 377 and 159mmol/g dw, respectively. Hyperglycaemia elevated plasma insulin concentrations with higher levels for CHO-L than for CHO-D (P < 0.01). Conversely, CHO-D elevated plasma adrenaline and noradrenaline higher than CHO-L (P < 0.05). Plasma fat metabolites (NEFA, β-hydroxybutyrate, and glycerol) were higher under CHO-D than CHO-L (P < 0.01). The resultant was that the rates of total carbohydrate and fat oxidation were elevated and depressed for loaded CHO-L vs CHO-D respectively (P < 0.01), although no difference was found for GUR (P > 0.05). The RPE over the exercise period was higher for CHO-D than CHO-L (P < 0.05). Hyperglycaemia during exercise, when muscle glycogen is reduced, attenuates insulin but promotes catecholamines and fat metabolites. The effect is a subsequent elevation of fat oxidation, a reduction in CHO oxidation without a concomitant increase in GUR, and an increase in RPE.

Prostaglandin E2 receptor EP3 subtype in the paraventricular hypothalamic nucleus mediates corticotropin-releasing factor-induced elevation of plasma noradrenaline levels in rats

Corticotropin-releasing factor (CRF) plays an important role in sympathetic regulation. Centrally administered CRF elevates plasma catecholamine levels, resulting in CRF-dependent hypertension and tachycardia. We previously reported that brain thromboxane A2 mediates CRF-induced elevation of plasma adrenaline levels, whereas prostanoids other than thromboxane A2 mediate elevations in plasma noradrenaline levels. However, the mechanism by which CRF induces elevations in plasma noradrenaline levels remains unknown. Previous studies have revealed that brain prostaglandin (PG) E2, but not other PGs, causes sympathetic activation. In this study, we examined the roles of brain PGE2 and its receptors in CRF-induced elevation of plasma noradrenaline levels in rats. Our results showed that intracerebroventricular pretreatment with an antagonist of the PGE2 receptor EP3 subtype, but not other subtypes, suppressed CRF-induced elevations in plasma noradrenaline levels. We also examined the role of PGE2 and EP3 receptors in the paraventricular hypothalamic nucleus (PVN), the major integrative center for sympathetic regulation, in CRF-induced elevation of plasma noradrenaline levels. Centrally administered CRF increased PGE2 levels in PVN microdialysates, and microinjection of an EP3 receptor agonist into the PVN elevated plasma noradrenaline levels. Bilateral blockade of EP3 receptors in the PVN suppressed the elevation of plasma noradrenaline levels evoked by intracerebroventricular administration and PVN-microinjection of CRF. Our results suggest that CRF stimulates PGE2 release into the PVN that activates EP3 receptors in the PVN, resulting in the elevation of plasma noradrenaline levels.