Regional epinephrine kinetics in human heart failure: evidence for extra-adrenal, nonneural release

A number of neurohumoral processes are activated in heart failure, including an increase in the plasma concentration of epinephrine. Radiotracer methods were applied in 42 patients with severe heart failure and 31 healthy volunteers to ascertain the rate at which epinephrine is released to plasma and to evaluate the contribution of extra-adrenal sources. The increase in arterial plasma epinephrine observed in the heart failure patients was explained principally by a 34% (P < 0.001) reduction in the whole body clearance rate of epinephrine from plasma. Regional venous sampling from the heart, lungs, and hepatomesenteric beds was performed in a subgroup of the study population, revealing a significant increase in the release rate of epinephrine to plasma from these organs in heart failure which accounted for 26% of the whole body plasma epinephrine appearance rate. To establish whether the cardiac epinephrine release was of neuronal origin, a physical (cycling) or mental (difficult mental arithmetic) stressor was applied as a sympathoexcitatory stimulus, given that a proportional release of norepinephrine and epinephrine could be expected if sympathetic nerves were the source. These interventions caused significant increases in the regional spillover of norepinephrine to plasma but not that of epinephrine. These findings suggest that nonadrenal tissues contribute significantly to the whole body epinephrine release rate in heart failure and that this may arise from a site other than sympathetic neurons.

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Abstract 389: Human Cardiac Sympathetic Nerves Switch the Neurotransmitter Property from Catecholaminergic to Cholinergic in Patients with Severe Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_297 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Hideaki Kanazawa ◽

Masaki Ieda ◽

Kensuke Kimura ◽

Takahide Arai ◽

Haruko Manabe ◽

...

Keyword(s):

Heart Failure ◽

Interstitial Fibrosis ◽

Severe Heart Failure ◽

Sympathetic Nerves ◽

Cholinergic Neuron ◽

Heart Weight ◽

Control Group ◽

Down Regulation ◽

Stellate Ganglia ◽

Nerve Bundles

[Background] Congestive heart failure (CHF) is characterized by activation of the sympathetic nervous system (SNS) with depletion of norepinephrine (NE) stores, which was initially considered to be the result of excess NE secretion and the loss of noradrenergic nerve terminals. Recent studies however have revealed that it is caused by down regulation of NE synthesis and re-uptake, although the molecular mechanism of down regulation of the sympathetic neuronal function remains unknown. We recently found in an animal model of CHF that the cardiac SNS switches the neurotransmitter property from catecholaminergic to cholinergic, mediated by cytokines LIF and CT-1 secreted from failing myocardium. This study was designed to investigate whether or not this cholinergic transdifferentiation of cardiac SNS occurs in patients with CHF. [Methods & Results] (1) We analyzed 8 samples from patients who died of non-cardiac causes obtained at autopsy (control group), and 8 samples from patients with CHF (CHF group). Five of them died of CHF, and 3 were obtained from native hearts of transplant recipients. (2) The heart weight was significantly higher in the CHF group. (3) The gross morphology of the cardiac SNS did not differ between the two groups. HE and Masson trichrome staining showed disorganized cardiomyocytes and interstitial fibrosis in CHF. (4) Immunostaining for tyrosine hydroxylase (TH, sympathetic nerve marker) revealed that the epicardial nerve bundles and stellate ganglia of the control group had a predominance of TH + nerves, whereas those of CHF group were significantly decreased. (5) Immunostaining for choline transporter (CHT, cholinergic neuron marker) revealed that CHT + neurons were markedly increased in the epicardial nerve bundles of CHF hearts compared with the control group. Some nerves co-expressed both TH and CHT markers. (6) Immunostaining for choline acetyl transferase (ChAT, a cholinergic neuron marker) revealed that stellate ganglia had a lot of ChAT + neurons compared with the control. (7) Nissl staining showed that there was no difference between the two groups in neuron number in the stellate ganglia. [Conclusions] These results indicated that in patients with CHF the cardiac sympathetic nerves also had cholinergic nerve properties.

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Abstract 17736: Cardiomyocyte Specific Loss of Diacylglycerol Acyl Transferase 1 (Dgat1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure

Circulation ◽

10.1161/circ.130.suppl_2.17736 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Chad M Trent ◽

Li Liu ◽

Xiang Fang ◽

Ni-Huiping Son ◽

Hongfeng Jiang ◽

...

Keyword(s):

Heart Failure ◽

Heart Function ◽

Severe Heart Failure ◽

Fatty Acid Uptake ◽

Metabolic Effects ◽

Acid Uptake ◽

Acyl Transferase ◽

Human Heart Failure ◽

Protein Kinase Cα ◽

Ceramide Content

Diacylglycerol acyl transferase 1 (DGAT1) catalyzes the final step in triglyceride (TG) synthesis, the conversion of diacylglycerol (DAG) to TG. Dgat1-/- mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function we created cardiomyocyte specific DGAT1 knockout (hDgat1-/-) mice. hDgat1-/- mice hearts had 95% increased DAG and 85% increased ceramides compared to floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide (Bnp) increased 5-fold in hDgat1-/- hearts and fractional shortening (FS) was reduced. This was associated with a 30% increase in PPARalpha and a 40% increase in Cd36. We crossed hDgat1-/- mice with previously described enterocyte-specific Dgat1 knockout mice (hiDgat1-/-). This corrected the early mortality, improved FS 40%, and reduced cardiac ceramide and DAG content. Treatment of hDgat1-/- mice with GLP-1 receptor agonist exenatide for 1 week reduced Bnp mRNA by 50%, improved FS, and reduced heart DAG and ceramide content by 30-40%. Increased fatty acid uptake into hDgat1-/- hearts was normalized by exenatide. Reduced activity of protein kinase Cα (PKCα), which is known to be increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.

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Pancreatic sympathetic nerves contribute to increased glucagon secretion during severe hypoglycemia in dogs

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.1.e20 ◽

1996 ◽

Vol 270 (1) ◽

pp. E20-E26 ◽

Cited By ~ 10

Author(s):

P. J. Havel ◽

T. O. Mundinger ◽

G. J. Taborsky

Keyword(s):

Severe Hypoglycemia ◽

Glucagon Secretion ◽

Sympathetic Nerves ◽

Plasma Glucagon ◽

Plasma Epinephrine ◽

Pancreatic Glucagon ◽

Parasympathetic Nerves ◽

Anesthetized Dogs ◽

Arterial Plasma

To determine if pancreatic sympathetic nerves can contribute to increased glucagon secretion during hypoglycemia, plasma glucagon and pancreatic glucagon secretion in situ were measured before and during insulin-induced hypoglycemia in three groups of halothane-anesthetized dogs. All dogs were bilaterally vagotomized to eliminate the input from pancreatic parasympathetic nerves. One group of dogs received only vagotomy (VAGX). A second group was vagotomized and adrenalectomized (VAGX + ADX). A third group received vagotomy, adrenalectomy, plus surgical denervation of the pancreas (VAGX + ADX + NERVX) to prevent activation of pancreatic sympathetic nerves. In dogs with VAGX only, hypoglycemia increased plasma epinephrine (Epi), pancreatic norepinephrine (NE) output (+320 +/- 140 pg/min, P < 0.05), arterial plasma glucagon (+28 +/- 12 pg/ml, P < 0.01), and pancreatic glucagon output (+1,470 +/- 370 pg/min, P < 0.01). The addition of ADX eliminated the increase of Epi but did not increase pancreatic NE output (+370 +/- 190 pg/min, P < 0.025), arterial plasma glucagon (+20 +/- 5 pg/ml, P < 0.01), or pancreatic glucagon output (+810 +/- 200 pg/min, P < 0.01). In contrast, the addition of pancreatic denervation eliminated the increase of pancreatic NE output (-20 +/- 40 pg/min, P < 0.05 vs. VAGX), the arterial glucagon (+1 +/- 2 pg/ml, P < 0.01 vs. VAGX), and pancreatic glucagon output responses (+210 +/- 280 pg/min, P < 0.025 vs. VAGX) to hypoglycemia. Thus activation of pancreatic sympathetic nerves can contribute to the increased glucagon secretion during severe insulin-induced hypoglycemia in dogs.

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Carotid chemoreceptor discharge during epinephrine infusion in anesthetized cats

Journal of Applied Physiology ◽

10.1152/jappl.1992.73.6.2420 ◽

1992 ◽

Vol 73 (6) ◽

pp. 2420-2424 ◽

Cited By ~ 4

Author(s):

R. A. Linton ◽

D. M. Band ◽

C. B. Wolff

Keyword(s):

Direct Effect ◽

Carotid Sinus ◽

Whole Body ◽

Co2 Production ◽

Plasma Epinephrine ◽

Epinephrine Infusion ◽

Arterial Pco2 ◽

Carotid Chemoreceptors ◽

Arterial Plasma ◽

Stimulation Of

It is known that during exercise there is an increase in plasma epinephrine. The purpose of the present investigation was to determine whether stimulation of carotid chemoreceptors by epinephrine is a direct effect or secondary to epinephrine-induced increases in arterial plasma [K+] and whole body CO2 production (VCO2). Chemoreceptor discharge was recorded from single fiber preparations of the carotid sinus nerves in anesthetized cats ventilated to a constant arterial PCO2 (PaCO2). Infusion of epinephrine (1 microgram.kg-1 x min-1) caused arterial [K+] to increase from a mean of 2.7 to 3.8 mM. VCO2 increased so that ventilation had to be increased by 60% to maintain PaCO2 constant. Mean chemoreceptor discharge increased by 50%, but this was no greater than would be predicted on the basis of the increases in arterial [K+] and VCO2. In a further group of experiments epinephrine was infused at 0.1 microgram.kg-1 x min-1 and produced no significant increase in chemoreceptor firing. These experiments provide no evidence for epinephrine having a direct effect on the carotid chemoreceptor.

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Abstract 5361: PDK1 Plays Crucial Roles in β-Adrenergic Response and Cell Survival in the Heart

Circulation ◽

10.1161/circ.118.suppl_18.s_535-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kaoru Ito ◽

Hiroshi Akazawa ◽

Noritaka Yasuda ◽

Haruaki Nakaya ◽

Issei Komuro

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Gene Disruption ◽

Systolic Function ◽

Severe Heart Failure ◽

Left Ventricular ◽

Cardiomyocyte Apoptosis ◽

Adrenergic Stimulation ◽

Human Heart Failure ◽

Bax Protein

Background: The 3-phosphoinositide-dependent protein kinase-1 (PDK1) plays a homeostatic role in the regulation of cellular function in multiple organs, by working downstream of phosphatidylinositol-3 kinase (PI3-K) through activating several kinases including Akt and p70 S6 kinase. We found that myocardial expression of PDK1 was decreased in murine models of heart failure. Although previous studies have reported that PDK1 is important for the regulation of cardiomyocyte size, the precise role of PDK1 in the heart remains to be fully characterized. Methods and Results: To elucidate the roles of PDK1 in the postnatal heart, we generated tamoxifen-inducible heart specific PDK1 knockout (PDK1-KO) mice. Deletion of PDK1 at the age of 10 weeks caused severe heart failure. At 1 week after Pdk1 gene disruption, left ventricular systolic function was already deteriorated without reduction in cardiomyocyte size. Langendorff-perfused hearts from PDK1-KO mice exhibited impaired responsiveness to isoproterenol in spite of preserved responsiveness to forskolin. In PDK1-KO hearts, PI3-K γ activity was enhanced and the expression levels of β1-adrenergic receptor (β1AR) in membrane fraction were decreased. Overexpression of PIK-domain of PI3-K γ blocked β1AR internalization by competitively inhibiting the association between PI3-K γ and G-protein coupled receptor kinase 2, and improved cardiac function in PDK1-KO hearts. In addition, we found that cardiomyocyte apoptosis was significantly increased 1 week after Pdk1 gene disruption. PDK1-KO hearts showed reduction of Akt and SGK activities, upregulation of Bax protein and endoplasmic reticulum stress signals, which were the potential causes of cardiomyocyte apoptosis. Overexpression of Bcl-2 in PDK1-KO hearts prevented cardiomyocyte apoptosis and partially improved cardiac function in PDK1-KO mice. Conclusions : These results suggest that PDK1 is essential for normal cardiac function by not only preserving responsiveness to β-adrenergic stimulation but also preventing cardiomyocyte apoptosis. Since PDK1-KO mice reproduces many aspects of human heart failure, we propose that PDK1 may be a promising molecule targeted for the treatment of heart failure.

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Periodic whole body acceleration: A novel therapy for cardiovascular disease

VASA ◽

10.1024/0301-1526.36.4.261 ◽

2007 ◽

Vol 36 (4) ◽

pp. 261-266 ◽

Cited By ~ 11

Author(s):

Kohler ◽

Amann-Vesti ◽

Clarenbach ◽

Brack ◽

Noll ◽

...

Keyword(s):

Quality Of Life ◽

Heart Failure ◽

Endothelial Function ◽

Severe Heart Failure ◽

Walking Distance ◽

Whole Body ◽

Therapeutic Effects ◽

Motion Platform ◽

Body Acceleration

Background: Periodic whole body acceleration in the spinal axis (pGz) applied by a motion platform is a novel treatment modality that induced endothelial nitric oxide release into the circulation of animals, healthy subjects and patients with inflammatory diseases during single treatment sessions in previous studies. We hypothesized that patients with advanced arteriosclerotic diseases who are not candidates for a surgical intervention would clinically benefit from repeated pGz treatments over several weeks through improvement of endothelial function. Patients and methods: 11 patients, 5 men (37 to 71y) with stable ischemic heart disease, LVEF < 35%, NYHA stage > II, and 6 patients (51 to 83y, 1 woman) with intermittent leg claudication, Fontaine stage II, were enrolled after optimization of pharmacological therapy. PGz was applied for 40 min, 5 days/week during 5 weeks. Quality of life (SF-36 questionnaire), exercise performance, and endothelial function were assessed at baseline, during the treatment period, and 4 weeks after discontinuation of pGz. Results: PGz was well tolerated. In heart failure paitents, pGz therapy improved quality of life, increased 6 min walking distance by a mean ± SE of 105 ± 24 m, and improved postischemic skin hyperemia (p < .05 in all instances). In 4 of 6 patients with intermittent claudication, quality of life, treadmill walking distance and post-ischemic skin hyperemia improved with pGz therapy (p < .05). Four weeks after discontinuation of pGz, most therapeutic effects had vanished in both patient groups. Conclusions: In patients with severe heart failure and with leg claudication who remain symptomatic despite maximal medical therapy and who were not candidates for surgery, periodic acceleration applied over several weeks improved quality of life and exercise capacity. The clinical benefits appear to be mediated through improved endothelial function.

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