Cardiac Norepinephrine Spillover Research Articles

Reduced Cardiac Beta 1 Receptor Expression and Function in a Mouse Model of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disorder. HCMis characterized by cardiac hypertrophy, fibrosis, and an increased risk of fatalarrhythmias and sudden cardiac death. Previous studies in humans with HCM havedemonstrated increased cardiac norepinephrine spillover and reduced beta-1 receptor(B1R) expression in the left ventricle (LV). We have previously demonstrated thatcardiac sympathetic tone is elevated in an alpha-tropomyosin mutant mouse model ofHCM. We hypothesized that HCM mice would demonstrate reduced B1R expression inthe LV and attenuated heart rate (HR) and dP/dt max responses to ramped infusion of theB1R agonist, dobutamine. First, we utilized western blot to measure B1R proteinexpression in LV tissue from HCM and littermate wild-type (WT) mice (n=4 male micein each group). B1R expression was significantly reduced in the LV of HCM micecompared to WT littermate controls (HCM 60±1% vs. WT 100±4%; paired t-test, p<0.05). Next, we recorded left ventricular pressure in male and female HCM andlittermate WT control (n=5 male mice, each group; n=6 female mice, each group) miceanesthetized with isoflurane (2% in O2). Data were analyzed by 2-way ANOVA withgenotype and sex as factors. Baseline HR and dP/dt max were significantly lower inHCM compared to WT mice (genotype p<0.05), however, there were no sex differencesin either variable (sex p>0.05). Next, in order to assess cardiac B1R function, we firstinfused the ganglionic blocker chlorisondamine (6ug/g) to eliminate autonomic reflexfunction in HCM and littermate WT mice (n=4 mice, each group). Then, we performed adobutamine stress test via ramped infusion of dobutamine starting at 2ng/g/min andincreasing the dose in 2ng/g/min increments every 2 minutes up to 12ng/g/min via aprogrammable syringe pump. Data were analyzed by 2-way ANOVA with dose andgenotype as factors. Contrary to our hypothesis, ramped infusion of dobutamine resultedin a similar, significant (dose p<0.05) increase in HR in both HCM and WT mice(genotype p>0.05). Peak increases in HR occurred during the highest dose ofdobutamine (12ng/g/min; ΔHR HCM 58±19 vs. WT 70±20 beats/min) in both groups.Consistent with our hypothesis, increases in dP/dt max were significantly blunted inHCM mice compared to littermate WT controls (dose x genotype p<0.05). Peakincreases in dP/dt max occurred at a lower dose of dobutamine for HCM (4ng/g/min;ΔdP/dt max 1129±767 mmHg/s) compared to WT (8ng/g/min; ΔdP/dt max 4882±499mmHg/s). In summary, LV B1R expression is reduced in HCM mice. Increases in HR inresponse to ramped infusion of dobutamine were similar between HCM and WT micewhereas increases in dP/dt max were attenuated in HCM mice. We speculate that thedifferential inotropic and chronotropic responses to dobutamine could be due to regionaldifferences in B1R expression or contractile dysfunction in HCM mice. Michigan Technological University Startup. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Factors Influencing Muscle Sympathetic Nerve Activity in Human Heart Failure

In heart failure (HF), the magnitude of sympathetic activation predicts both disease progression and mortality. Elevated cardiac norepinephrine (NE) spillover is the earliest documented perturbation, followed later by augmented renal NE spillover and muscle sympathetic nerve activity (MSNA). To date, there is limited understanding of the mechanism(s) responsible for between‐patient variation in MSNA and cohorts studied have been small. To characterize the magnitude of MSNA discharge in HF, its inter‐patient variance, and its principal determinants, we assembled microneurographic data from 177 HF patients (28 females; 53±13 yr; LVEF: 25±11%, range 5‐60%) studied in our laboratory. Data from 658 non‐medicated, normotensive volunteers (CTRL; 260 females; 53±14 yr) acquired contemporaneously under similar conditions served as a reference group. We analyzed, at rest, fibular MSNA, blood pressure (BP), heart rate (HR), LVEF, and etiology of disease, and in a sub‐group (n=63), echocardiographically‐derived stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR). In HF, there was marked inter‐patient variance in MSNA, with burst frequency (BF) ranging from 7 to 90 bursts/minandburst incidence (BI) from 9 to 100 bursts/100 heartbeats. BF was similar in patients dispensed or not dispensed each of the three principal classes of prevailing HF therapy (all P>0.05). BF related directly (R2=0.17), and BI inversely (R2=0.09), to HR (all P<0.001); neither correlated with BP. For each kg/m2 rise in BMI, BF increased, on average, by 0.20 bursts/min (95% CI, 0.02‐0.37; P=0.03); its relation to BI was less pronounced (P=0.05). BF increased non‐linearly when LVEF fell below ~21% (P<0.01); above this inflection point, BF displayed no relationship with LVEF. Overall, LVEF accounted for only 9.8% of the variance in BF (P=0.001), while no relationship existed between LVEF and BI (R2=0.007). BI (P=0.01), but not BF (P=0.14), was greater in patients with ischemic vs. dilated cardiomyopathy. BF and BI exhibited non‐linear, inverse relationships with SV (R2=0.31 and 0.12; all P<0.01) and CO (R2=0.17 and 0.20; all P<0.01), and a non‐linear, direct relationship with TPR (R2=0.18 and 0.21; all P<0.01). Unadjusted BF (52±15 vs. 26±13 bursts/min; P<0.001) was elevated in HF vs. CTRL. With age, BF exhibited little or no change in HF, in contrast to its non‐linear increase in CTRL. BF, adjusted for age, sex, BMI, and HR, was significantly greater throughout the lifespan (estimate 14.20 bursts/min; 95% CI, 12.11‐16.28; P<0.001) in HF, relative to CTRL, and higher in men than in women (estimate 5.01 bursts/min; 95% CI, 3.42‐6.61; P<0.001). Overall, the extent of sympathetic excess in HF, relative to CTRL, diminished with age. In conclusion, resting MSNA in HF is a function of etiology, BMI, HR, LVEF and SV, but not age; these relationships are significant but moderate to weak, as is that between sympathetic vasoconstrictor discharge and TPR. These observations provide insight into the complexity and individual specificity of mechanisms eliciting muscle sympathetic excitation in human HF.

Evaluation of elevated heart rate as a sympathetic nervous system biomarker in essential hypertension.

There is a need for an easily accessible biomarker of sympathetic nervous activation in essential hypertension, but none exists. Heart rate (HR) has been suggested, but requires validation, now doubly important as an elevated HR in hypertension has emerged as an independent cardiovascular risk factor. Isotope dilution methodology was used to measure total and regional noradrenaline spillover and adrenaline secretion rates in 30 patients with unmedicated essential hypertension and in a comparator group of 48 healthy participants with normal blood pressure. The particular interest was in the relationship of measured HR to cardiac noradrenaline spillover, the measure of cardiac sympathetic activity. Sympathetic activation was present in the patients with essential hypertension, evident in significantly increased mean cardiac, renal and total noradrenaline spillover rates. Adrenaline secretion was normal. HR in hypertension correlated directly with cardiac noradrenaline spillover (r = 0.82, P = 9.3 × 10), but not with renal noradrenaline spillover or adrenaline secretion. 67% of the variance in HR was attributable to differences in cardiac sympathetic activity. Among hypertensive patients there was no internal correlation between cardiac noradrenaline spillover, renal noradrenaline spillover and adrenaline secretion; the sympathetic activation commonly was not 'global'. In healthy participants HR did not correlate with measures of sympathetic activity or adrenaline secretion. When sympathetic activation exists in essential hypertension it is differentiated, not necessarily involving all sympathetic outflows. An elevated HR proved to be a biomarker of cardiac sympathetic activation but not activation of the renal sympathetic outflow. Identifying activation of the cardiac sympathetic outflow as the prime mechanism of hypertension tachycardia is relevant to therapies which should now be considered to minimize cardiovascular risk in this clinical setting. Is an elevated HR a valid biomarker of sympathetic activation in essential hypertension? Yes, but only for the cardiac sympathetic outflow. The unavoidable principle is that regional differentiation of sympathetic responses in essential hypertension means that no simple test can ever represent each and every sympathetic outflow.

New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure-Targeting the Sympathetic Nervous System.

Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising results, CVDs are responsible for ~17 million deaths per year globally with ~25% of these attributable to sudden cardiac death (SCD). Pre-clinical data demonstrated that renal denervation (RDN) decreases sympathetic activation as evaluated by decreased renal catecholamine concentrations. RDN is successful in reducing ventricular arrhythmias (VAs) triggering and its outcome was not found inferior to metoprolol in rat myocardial infarction model. Registry clinical data also suggest an advantageous effect of RDN to prevent VAs in HF patients and electrical storm. An in-depth investigation of how RDN, a minimally invasive and safe method, reduces the burden of HF is urgently needed. Myocardial systolic dysfunction is correlated to neuro-hormonal overactivity as a compensatory mechanism to keep cardiac output in the face of declining cardiac function. Sympathetic nervous system (SNS) overactivity is supported by a rise in plasma noradrenaline (NA) and adrenaline levels, raised central sympathetic outflow, and increased organ-specific spillover of NA into plasma. Cardiac NA spillover in untreated HF individuals can reach ~50-fold higher levels compared to those of healthy individuals under maximal exercise conditions. Increased sympathetic outflow to the renal vascular bed can contribute to the anomalies of renal function commonly associated with HF and feed into a vicious cycle of elevated BP, the progression of renal disease and worsening HF. Increased sympathetic activity, amongst other factors, contribute to the progress of cardiac arrhythmias, which can lead to SCD due to sustained ventricular tachycardia. Targeted therapies to avoid these detrimental consequences comprise antiarrhythmic drugs, surgical resection, endocardial catheter ablation and use of the implantable electronic cardiac devices. Analogous NA agents have been reported for single photon-emission-computed-tomography (SPECT) scans usage, specially the 123I-metaiodobenzylguanidine (123I-MIBG). Currently, HF prognosis assessment has been improved by this tool. Nevertheless, this radiotracer is costly, which makes the use of this diagnostic method limited. Comparatively, positron-emission-tomography (PET) overshadows SPECT imaging, because of its increased spatial definition and broader reckonable methodologies. Numerous ANS radiotracers have been created for cardiac PET imaging. However, so far, [11C]-meta-hydroxyephedrine (HED) has been the most significant PET radiotracer used in the clinical scenario. Growing data has shown the usefulness of [11C]-HED in important clinical situations, such as predicting lethal arrhythmias, SCD, and all-cause of mortality in reduced ejection fraction HF patients. In this article, we discussed the role and relevance of novel tools targeting the SNS, such as the [11C]-HED PET cardiac imaging and RDN to manage patients under of SCD risk.

CON: Persistent Central Sleep Apnea/Hunter-Cheyne-Stokes Breathing, Despite Best Guideline-Based Therapy of Heart Failure With Reduced Ejection Fraction, Is Not a Compensatory Mechanism and Should Be Suppressed.

CON: Persistent Central Sleep Apnea/Hunter-Cheyne-Stokes Breathing, Despite Best Guideline-Based Therapy of Heart Failure With Reduced Ejection Fraction, Is Not a Compensatory Mechanism and Should Be Suppressed.

Mechanisms underlying the increased cardiac norepinephrine spillover in heart failure.

Patients with heart failure (HF) have increased levels of cardiac norepinephrine (NE) spillover, which is an independent predictor of mortality. We hypothesized that this increase in NE spillover in HF depends not only on increases in sympathetic nerve activity (SNA) but also on changes in the mechanisms controlling NE release and reuptake. Such changes would lead to differences between the increases in directly recorded SNA and NE spillover to the heart in HF. Experiments were conducted in conscious sheep implanted with electrodes to record cardiac SNA (CSNA). In addition, arterial pressure and cardiac NE spillover were determined. In HF, the levels of both CSNA (102 ± 8 vs. 45 ± 8 bursts/min, P < 0.05) and cardiac NE spillover (21.6 ± 3.8 vs. 3.9 ± 0.8 pmol/min, P < 0.05) were significantly higher than in normal control animals. In HF, baroreflex control of cardiac NE spillover was impaired, and when CSNA was abolished by increasing arterial pressure, there was no reduction in cardiac NE spillover. A decrease in cardiac filling pressures in the HF group led to a significant increase in CSNA, but it significantly decreased cardiac NE spillover. In HF, the levels of cardiac NE spillover were enhanced above those expected from the high level of SNA, suggesting that changes in mechanisms controlling NE release and reuptake further increase the high level of NE at the heart, which will act to enhance the deleterious effects of increased CSNA in HF. NEW & NOTEWORTHY This is the first study, to our knowledge, to compare direct recordings of cardiac sympathetic nerve activity with simultaneously measured cardiac norepinephrine (NE) spillover. Our results indicate that in heart failure, increased cardiac sympathetic nerve activity is a major contributor to the increased NE spillover. In addition, there is enhanced NE spillover for the levels of synaptic nerve activity.

Sympathetic activation in chronic anxiety: not just at the "height" of stress. Editorial Focus on "Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety".

Sympathetic activation in chronic anxiety: not just at the "height" of stress. Editorial Focus on "Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety".

Chemosensitive Cardiac Afferent Reflexes in Mice: Are they Altered in Hypertrophic Cardiomyopathy?

Hypertrophic cardiomyopathy (HCM) is a life‐threatening disease caused by sarcomere gene mutations. Hallmark features include myocyte disarray, left ventricular hypertrophy, fibrosis, and increased risk of arrhythmias and sudden death. Cardiac norepinephrine spillover is augmented in humans with HCM. Similarly, our group has previously reported that cardiac sympathetic tone is increased and vasomotor sympathetic tone is decreased in transgenic mice with cardiac‐specific expression of mutated alpha‐tropomyosin (Glu180Gly), a model of human HCM. Specific aims of this study were to develop protocols to evaluate cardiac reflexes evoked by activation of vagal and ‘sympathetic’ afferents in anesthetized mice, and test the hypothesis that alpha‐tropomyosin mutant HCM mice exhibit enhanced heart rate responses to activation of cardiac ‘sympathetic’ afferents. Cardiac reflexes were evoked via injection of the TRPV1 receptor agonist capsaicin (25 &amp; 50 ng/g, IV) in mice anesthetized with ketamine (91μg/g) and xylazine (9.1 μg/g). Injection of capsaicin (50 ng/g, IV) in C57BL6 mice evoked rapid decreases in heart rate (HR) (−131±17bpm) and mean arterial pressure (MAP) (−30.1±2.7 mmHg) followed by delayed increases in HR (+12.5±7.6bpm) and MAP (+12.7±3.7 mmHg) (n=6, p&lt;0.05). Responses were dose‐dependent and repeatable. Bilateral cervical vagotomy abolished the bradycardic/depressor responses to capsaicin and enhanced the delayed increases in HR (+22.6±4.1bpm) and MAP (+27.6±1.7 mmHg) (n=5). All responses to capsaicin were essentially abolished after ganglionic blockade (p&lt;0.05, n=3) confirming the responses were neurally mediated. The tachycardic response to capsaicin (25ng/g, IV) after vagotomy was significantly (p&lt;0.05) augmented in HCM mice (+32±11bpm, n=5) compared with their wild‐type (WT) controls (+11±3bpm, n=6). In contrast, the MAP response to capsaicin was similar between HCM (+8.5±2.5 mmHg, n=5) and WT (+6.3±1.6 mmHg, n=6). We conclude: (1) Measurements of reflex responses to capsaicin before and after vagotomy enable assessment of both inhibitory and excitatory reflexes in mice, and (2) HCM mice demonstrate an exaggerated tachycardic response to injection of capsaicin, presumably reflecting an increased sensitivity of cardiac ‘sympathetic’ afferent nerves.Support or Funding InformationNIH T32HL007121, AAS‐Lundbeck Fellowship, NIH HL14388, VA 1BX001414This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract 10452: The SYMPLICITY HF Feasibility Study: Twelve Month Outcomes of Renal Denervation in Patients With Chronic Heart Failure and Renal Impairment

Introduction: Renal dysfunction often develops in patients with heart failure with low ejection fraction due to hemodynamic and neurohumoral dysfunction leading to increased risk for mortality. Methods: The multi-center, prospective, open label Renal Denervation in Patients With Chronic Heart Failure &amp; Renal Impairment (SYMPLICITY HF) trial enrolled NYHA Class II-III patients with left ventricular ejection fraction (LVEF) &lt;40% and estimated glomerular filtration rate (eGFR) 30 to 75 mL/min/1.73m 2 . Subjects with systolic blood pressure &lt; 90 mm Hg were excluded. The primary objective was to evaluate both the safety and physiologic response of renal denervation therapy on cardiac and renal function with the Symplicity™ renal denervation system using the Symplicity Flex™ catheter (Medtronic, Inc). Results: A total of 39 patients were enrolled (Table). No vascular complications occurred during the procedure. Available at AHA 2015 will be outcomes to 12 months follow up, including safety, cardiac function by echocardiography, and renal function by eGFR. Additionally, 9 subjects participated in a sub study that evaluated cardiac and renal noradrenaline spillover, muscle sympathetic nerve activity, and electrophysiological parameters by Holter monitor. Conclusions: Twelve-month outcomes in SYMPLICITY HF will provide initial insights into the safety and cardiac and renal physiologic impact of renal denervation in patients with heart failure.

Changes in Directly Recorded Sympathetic Nerve Activity and Noradrenaline Spillover to the Heart and Kidney during Heart Failure

Heart failure (HF) is associated with increased cardiac and renal noradrenaline (NA) spillover, both of which are independent predictors of mortality. We hypothesized that in HF changes in the mechanisms controlling NA release and uptake would lead to differences between directly recorded sympathetic nerve activity (SNA) and NA spillover to the heart and kidney. Experiments were conducted in conscious sheep implanted with cardiac SNA (CSNA) and renal SNA (RSNA) recording electrodes. Together with recordings of SNA and arterial pressure, the spillover of NA from both the heart and the kidney was determined. HF was associated with a two‐fold increase in CSNA (42±8 vs. 95±11 bursts/100hb, p&lt;0.05) but a five‐fold increase in cardiac NA spillover (3.1±0.8 vs. 18.1±4.1 pmol/min, p&lt;0.05). Infusion of sodium nitroprusside in the normal animals significantly increased CSNA to levels similar to those in HF, but the level of cardiac NA spillover (7.1±1.6) reached only 50% of that in HF. Further increases in CSNA in the HF animals were not associated with any further increases in cardiac NA spillover. In HF, RSNA was unchanged (95±8 bursts/100hb), but interestingly spillover of NA from the kidney was significantly increased (10.1±2.4 vs. 52.5±10.2 pmol/min, p&lt;0.05). The mismatch between CSNA and cardiac NA spillover in HF suggests that other mechanisms such as the NA transporter may play an important role in mediating the increased cardiac NA spillover. Further experiments are required to determine what causes the discordance between the baseline levels of RSNA and renal NA spillover in HF.

Sympathetic Nervous System Moves Toward Center Stage in Cardiovascular Medicine

In 1664, the first anatomically correct depiction of the sympathetic nervous system came from Thomas Willis and his circle of London anatomists,1 included in The Anatomy of the Brain and Nerves , 1664 (Figure 1). This, the first work dedicated completely to the nervous system, also described the arterial loops at the base of the brain, which we now know as the Circle of Willis.1 Christopher Wren, an anatomist member of the group, was the principal illustrator1 before being asked by the City Fathers to turn his talents to town planning, architecture, and cathedral building after the 1666 Great Fire of London. Figure 1. An illustration of the human sympathetic nerves of the neck and thorax, from The Anatomy of the Brain and Sympathetic Nerves , published in 1664 by Thomas Willis and reproduced in Soul Made Flesh .1 Almost 2 centuries later, subsequent microscopic examination demonstrated that blood vessel walls were densely innervated, leading Stelling in 18402 to correctly conclude that these vasomotor fibers were in fact sympathetic nerves that were carried from the central nervous system to the blood vessels. In the mid-19th century, celebrated European physiologists, including Brown-Sequard, Waller, and Bernard,2 built on these observations, demonstrating vasoconstriction with electrical stimulation of the cut nerves and vasodilatation on nerve section, which indicated that the sympathetic fibers exerted a tonic, vasoconstrictor influence. The pressor nerves had gained recognition. Identification of the sympathetic neurotransmitter proved to be difficult. Claims for epinephrine3,4 and the hypothetical sympathins I and E confused the picture. Ulf von Euler compared bioassay responses of epinephrine, norepinephrine, and dihydroxy norephedrine with those of cattle splenic nerve extract, by testing blood pressure (BP) responses in the anesthetized cat and contractile responses in the isolated pregnant rabbit uterus, to definitively demonstrate the …

Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing

The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

The hypothalamic paraventricular nucleus may not be at the heart of sympathetic outflow

Heart failure (HF) is associated with activation of various neurohumoral factors including the renin–angiotensin–aldosterone and sympathetic nervous systems. In HF patients, elevated sympathetic nerve activity (SNA) is reflected by increased whole body, as well as regional (e.g. cardiac and renal) noradrenaline spillover (Kaye et al. 1994; Petersson et al. 2005), and increased sympathetic nerve discharge (Leimbach et al. 1986). Importantly, the degree of sympathoexcitation predicts mortality in HF patients (Petersson et al. 2005). Consequently, an immense amount of research effort has been directed towards the identification of mechanisms and circuitry underlying elevated SNA in HF. Neurons of the hypothalamic paraventricular nucleus (PVH) regulate SNA in a variety of physiological conditions and pathophysiological states through mono- and polysynaptic projections to the medulla and spinal cord (Guyenet, 2006). Evidence from studies, largely conducted in anaesthetized rodents, suggests HF activates PVH neurons through a reduction in GABAergic function (Patel, 2000). A critical question is the extent to which PVH neurons contribute to elevated SNA in HF. In this issue of The Journal of Physiology, Ramchandra and colleagues (2013) provide novel data utilizing chronic SNA recordings in conscious sheep to address this important question. Interruption of PVH neurotransmission by radiofrequency ablation or neuronal inhibition by microinjection of glycine or the GABAA agonist muscimol failed to lower cardiac and/or renal SNA in both control and HF sheep. Furthermore, blockade of PVH GABAA receptors with injection of bicuculline increased cardiac SNA, mean arterial blood pressure and heart rate in control but not HF sheep. The absence of sympathetic-cardiovascular responses to GABAA receptor activation or blockade in HF versus control sheep confirms a reduced GABAergic function in the PVH. More importantly, these findings challenge the general notion that PVH neurons contribute to sympathoexcitation in HF. Several issues may explain the discrepancies between the present and past studies: (1) differences between anaesthetized versus conscious animals, (2) differences in the central nervous system circuitry/mechanisms between HF models (i.e. coronary ligation versus ventricular pacing), and (3) the possibility that PVH neurons contribute to the development, but not maintenance, of elevated SNA in HF. A second intriguing finding is the differential contribution of PVH neurons to cardiac and renal sympathoinhibitory responses to volume expansion. In conscious sheep, PVH inhibition with injection of the GABAA agonist muscimol reversed the renal, but not the cardiac, sympathoinhibition during intravenous infusion of gelofusine. At least two critical questions arise from these findings. First, PVH neurons abundantly express the vesicular glutamate transporter but are not GABAergic (e.g. GAD67 positive) (Stocker et al. 2006). If volume expansion reduces the discharge of spinally projecting PVH neurons (Lovick & Coote, 1988), why does further inhibition using muscimol reverse the sympathoinhibition? Second, how do PVH neurons differentially regulate SNA to various end organs? The notion that PVH neurons can selectively increase SNA to one organ but not to another has been reported previously (Deering & Coote, 2000; Ward et al. 2011). Therefore, are there distinct populations of PVH neurons that regulate renal versus cardiac versus muscle SNA? Do these neurons receive different anatomical and neurochemical inputs? Previous studies have utilized transneuronal viruses to map the neuronal circuitry associated with a specific end-organ, but limited data exist to demonstrate whether PVH and other central nuclei contain overlapping or distinct populations of neurons to permit differential regulation of SNA. The findings of Ramchandra and colleagues (2013) provide evidence against a role of PVH neurons in elevating SNA in HF but emphasize the ability of PVH neurons to differentially control sympathetic outflow to distinct end-organs. The present findings highlight our limited understanding of how many CNS structures are anatomically and neurochemically connected to coordinate sympathetic outflow to a variety of organs.

Ganglion-Specific Impairment of the Norepinephrine Transporter in the Hypertensive Rat

Hypertension is associated with enhanced cardiac sympathetic transmission, although the exact mechanisms underlying this are still unknown. We hypothesized that defective function of the norepinephrine uptake transporter (NET) may contribute to the sympathetic phenotype of the spontaneously hypertensive rat, and that this may occur before the development of hypertension itself. The dynamic kinetics of NET were monitored temporally using a novel fluorescent assay of the transporter in cultured postganglionic sympathetic neurons from the cardiac stellate ganglion, the superior cervical ganglion, the celiac ganglia/superior mesenteric ganglia, and the renal sympathetic chain. All NET activity was blocked by desipramine. NET rate was significantly impaired in cardiac stellate sympathetic neurons from the prehypertensive spontaneously hypertensive rat compared with age-matched normotensive Wistar-Kyoto rats. A similar response was seen in hypertensive spontaneously hypertensive rats stellate sympathetic neurons. However, no reduction in transporter rate was observed at either age in the other major noncardiac sympathetic ganglia. Depolarization of cardiac stellate neurons by electrical field stimulation further potentiated the difference in transporter rate observed between the hypertensive and normotensive rats at both developmental ages. In conclusion, dysregulation of the norepinephrine transporter in the hypertensive rat is ganglion-specific, where NET impairment in the stellate neurons may contribute to the increased cardiac norepinephrine spillover seen in hypertension.

489 Activation by Human Heart Failure of a Sympathoexcitatory Cardiopulmonary Reflex

Functionally specific efferent renal sympathetic nerve fibers fire in response to discrete afferent stimuli. We hypothesize that individual efferent sympathetic fibers directed at other vascular beds also may be activated reflexively by specific afferent inputs. Previous work from our group, involving quantification of cardiac norepinephrine spillover, detected activation in heart failure (HF) by high atrial pressure of a normally quiescent cardio-cardiac sympatho-excitatory reflex. Whether individual vasoconstrictor neurons directed at skeletal muscle vessels respond concordantly or differentially to changes in atrial pressure is unknown.

Single‐unit muscle sympathetic nervous activity and its relation to cardiac noradrenaline spillover

Recent work using single-unit sympathetic nerve recording techniques has demonstrated aberrations in the firing pattern of sympathetic nerves in a variety of patient groups. We sought to examine whether nerve firing pattern is associated with increased noradrenaline release. Using single-unit muscle sympathetic nerve recording techniques coupled with direct cardiac catheterisation and noradrenaline isotope dilution methodology we examined the relationship between single-unit firing patterns and cardiac and whole body noradrenaline spillover to plasma. Participants comprised patients with hypertension (n=6), depression (n=7) and panic disorder (n =9) who were drawn from our ongoing studies. The patient groups examined did not differ in their single-unit muscle sympathetic nerve firing characteristics nor in the rate of spillover of noradrenaline to plasma from the heart. The median incidence of multiple spikes per beat was 9%. Patients were stratified according to the firing pattern: low level of incidence (less than 9% incidence of multiple spikes per beat) and high level of incidence (greater than 9% incidence of multiple spikes per beat). High incidence of multiple spikes within a cardiac cycle was associated with higher firing rates (P <0.0001) and increased probability of firing (P <0.0001). Whole body noradrenaline spillover to plasma and (multi-unit) muscle sympathetic nerve activity in subjects with low incidence of multiple spikes was not different to that of those with high incidence of multiple spikes. In those with high incidence of multiple spikes there occurred a parallel activation of the sympathetic outflow to the heart, with cardiac noradrenaline spillover to plasma being two times that of subjects with low nerve firing rates (11.0 ± 1.5 vs. 22.0 ± 4.5 ng min⁻¹, P <0.05). This study indicates that multiple within-burst firing and increased single-unit firing rates of the sympathetic outflow to the skeletal muscle vasculature is associated with high cardiac noradrenaline spillover.

Spinal cord stimulators for treatment of ventricular arrhythmias: Antiarrhythmic in a can

e Sympathetic activation and its dysregulation in the seting of left ventricular systolic dysfunction have been learly documented and are thought to play an important ole in arrhythmogenesis. The paradigm of modulation of ympathetic activation by ganglionectomy has proved to be eneficial in a variety of syndromes in which ventricular rrhythmias lead to mortality. The finding of parasymathetic withdrawal occurs in parallel with cardiac sympahetic activation, a phenomenon that can be documented at he level of the sinoatrial node as well as in the myocardium. Modulation of parasympathetic withdrawal as an ntiarrhythmic strategy has been evaluated by Schwartz t al, who directly stimulated the vagus and demontrated successful prevention of ventricular fibrillation in n ischemic canine model. As such, the arrhythmic risk f left ventricular dysfunction appears to occur as a unction of both sympathetic activation and parasympahetic withdrawal. Most importantly, a complex interaction exists between ympathetic and parasympathetic inputs to a variety of vasular beds, whereby parasympathetic tone is a potent modlator of norepinephrine release. This important complex nteraction of muscarinic receptors and pathways, which lays an important role in “net” sympathetic activation, has een demonstrated in the heart and other vascular territoies. In humans with heart failure in contrast to control ubjects, stimulation of myocardial muscarinic receptors ecreased cardiac norepinephrine spillover, a reflection of fferent myocardial sympathetic outflow. The inhibitory effect of muscarinic stimulation on norepinephrine release displays the functional characteristic of accentuated antagonism whereby the inhibitory effect of parasympathetic input is greatest in the setting of sympathetic activation but has little impact in the setting of unstimulated, basal sympathetic outflow. This concept has been repeatedly documented in animal models and has been directly documented in humans among whom clear differences in modulation of

Relation between QT interval variability and cardiac sympathetic activity in hypertension

Elevated QT interval variability is a predictor of malignant ventricular arrhythmia, but the underlying mechanisms are incompletely understood. A recent study in dogs with pacing-induced heart failure suggests that QT variability is linked to cardiac sympathetic nerve activity. The aim of this study was to determine whether increased cardiac sympathetic activity is associated with increased beat-to-beat QT interval variability in patients with essential hypertension. We recorded resting norepinephrine (NE) spillover into the coronary sinus and single-lead, short-term, high-resolution, body-surface ECG in 23 patients with essential hypertension and 9 normotensive control subjects. To assess beat-to-beat QT interval variability, we calculated the overall QT variability (QTVN) as well as the QT variability index (QTVi). Cardiac NE spillover (12.2 ± 6.5 vs. 20.7 ± 14.7, P = 0.03) and QTVi (-1.75 ± 0.36 vs. -1.42 ± 0.50, P = 0.05) were significantly increased in hypertensive patients compared with normotensive subjects. QTVN was significantly correlated with cardiac NE spillover (r(2) = 0.31, P = 0.001), with RR variability (r(2) = 0.20, P = 0.008), and with systolic blood pressure (r(2) = 0.16, P = 0.02). Linear regression analysis identified the former two as independent predictors of QTVN. In conclusion, elevated repolarization lability is directly associated with sympathetic cardiac activation in patients with essential hypertension.

Sleep apnoea and malignant ventricular arrhythmias in heart failure

This editorial refers to ‘Cheyne–Stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-defibrillator therapies in patients with congestive heart failure’, by T. Bitter et al. doi:10.1093/eurheartj/ehq327 Sleep-related breathing disorders (SRBDs) are present in ∼50% of patients with chronic heart failure (CHF), with fairly equal prevalence of obstructive sleep apnoea (OSA) and central sleep apnoea with Cheyne–Stokes respiration (CSA).1,2 Obstructive apnoeas are characterized by recurring upper airway collapse with ongoing respiratory effort during sleep, causing repetitive surges of negative intra-thoracic pressure. As opposed to OSA, CSA results from a reduction or cessation of output from the central respiratory generator in the brainstem, manifesting as apnoeas or hypopnoeas without accompanying respiratory effort. Common to OSA and CSA are recurrent cycles of apnoea, hypoxia, hypercapnia, and arousal from sleep, each of which acts independently to trigger surges of central sympathetic vasoconstrictor outflow and neuronal noradrenaline release, resulting in a rise, rather than the normal fall, in blood pressure during sleep. Muscle sympathetic nerve activity (MSNA) peaks during the apnoeic phase of OSA but during the hyperpnoeic phase of CSA.3,4 Circadian ventricular metabolic gene expression and metabolic capacity are at their nadir during sleep. Thus, the failing heart of individuals with co-existing sleep apnoea suffers these adverse autonomic, chemical, and haemodynamic burdens at the time of day when it is least able to cope.5 Moreover, the sympathetic activation accompanying these SRBDs does not subside upon waking: daytime MSNA is higher in heart failure patients with than in those without sleep apnoea,6 a finding consistent with the concept that these two stimuli exert independent excitatory effects on central sympathetic outflow.7 In mild heart failure, only cardiac noradrenaline spillover (CNaS) is elevated. Over time, renal and total body noradenaline … *Corresponding author. Fax: +49 551 398918, Email: sandreas{at}lungenfachklinik-immenhausen.de

Cardiac-specific sympathetic activation in men and women with and without heart failure

BackgroundClinical outcomes for cardiovascular syndromes such as heart failure differ between men and women.ObjectiveTo seek phenotypic evidence for sex-differences in cardiac-specific sympathetic nervous system activation, as abnormal sympathetic nervous system...