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Comparison of Resveratrol Supplementation and Energy Restriction Effects on Sympathetic Nervous System Activity and Vascular Reactivity: A Randomized Clinical Trial.
Gonçalinho, GHF, Roggerio, A, Goes, MFDS, Avakian, SD, Leal, DP, Strunz, CMC, Mansur, AP
Molecules (Basel, Switzerland). 2021;(11)
Abstract
Background: Chronic sympathetic nervous system activation is associated with endothelial dysfunction and cardiometabolic disease, which may be modulated by resveratrol (RSV) and energy restriction (ER). This study aimed to examine the effects of RSV and ER on plasma noradrenaline (NA), flow-mediated vasodilation (ed-FMD), and endothelium-independent nitrate-mediated vasodilation (ei-NMD). Methods: The study included 48 healthy adults randomized to 30-days intervention of RSV or ER. Results: Waist circumference, total cholesterol, HDL-c, LDL-c, apoA-I, and plasma NA decreased in the ER group, whilst RSV increased apoB and total cholesterol, without changing plasma NA. No effects on vascular reactivity were observed in both groups. Plasma NA change was positively correlated with total cholesterol (r = 0.443; p = 0.002), triglycerides (r = 0.438; p = 0.002), apoA-I (r = 0.467; p = 0.001), apoB (r = 0.318; p = 0.032) changes, and ei-NMD (OR = 1.294; 95%CI: 1.021-1.640). Conclusions: RSV does not improve cardiometabolic risk factors, sympathetic activity, and endothelial function. ER decreases plasma NA and waist circumference as well as improves blood lipids, but does not modify endothelial function. Finally, plasma NA was associated with ei-NMD, which could be attributed to a higher response to nitrate in patients with greater resting sympathetic vasoconstriction.
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Improving obesity and blood pressure.
Tanaka, M
Hypertension research : official journal of the Japanese Society of Hypertension. 2020;(2):79-89
Abstract
Obesity-associated hypertension is a serious public health concern. Sympathetic nervous system (SNS) overactivity, especially in the kidneys, is an important mechanism linking obesity to hypertension. Some adipokines play important roles in elevating blood pressure (BP). Hyperinsulinemia caused by insulin resistance stimulates sodium reabsorption, enhances sodium retention, and increases circulating plasma volume. Hyperinsulinemia also stimulates both the renin-angiotensin-aldosterone system (RAAS) and the SNS, resulting in the acceleration of atherosclerosis through the hypertrophy of vascular smooth muscle cells, which contributes to increased peripheral vascular resistance. Obesity is associated with increased RAAS activity despite volume overload, as the tissue RAASs are stimulated in obese hypertensive individuals. Mineralocorticoid receptor-associated hypertension must also be considered in obese patients with resistant hypertension. Obstructive sleep apnea syndrome (OSAS) is the most common cause of secondary hypertension. Some components of the gut microbiota contribute to BP control; therefore, gut dysbiosis caused by obesity might lead to increased BP. The ratio of visceral fat to subcutaneous fat is higher in Japanese patients than in Caucasian patients, which may explain why Japanese patients are more susceptible to metabolic disorders even though they are less obese than Caucasian individuals. Obesity-associated kidney dysfunction directly increases BP, leading to further deterioration of kidney function. A bodyweight reduction of more than 3% or 5 kg significantly lowers BP. Gastrointestinal bypass surgery is an effective treatment for morbid obesity and its related metabolic disorders, including hypertension. Because both obesity and hypertension are representative lifestyle-related disorders, lifestyle modification, especially to improve obesity, should be performed first as a treatment for hypertension.
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Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.
Shimizu, W, Kubota, Y, Hoshika, Y, Mozawa, K, Tara, S, Tokita, Y, Yodogawa, K, Iwasaki, YK, Yamamoto, T, Takano, H, et al
Cardiovascular diabetology. 2020;(1):148
Abstract
BACKGROUND Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. METHODS This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. RESULTS Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. CONCLUSIONS This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. TRIAL REGISTRATION The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .
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4.
The "Sick-but-not-Dead" Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases.
Goldstein, DS
Seminars in neurology. 2020;(5):502-514
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Abstract
The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases-pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.
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Sensory signals mediating high blood pressure via sympathetic activation: role of adipose afferent reflex.
Dalmasso, C, Leachman, JR, Osborn, JL, Loria, AS
American journal of physiology. Regulatory, integrative and comparative physiology. 2020;(2):R379-R389
Abstract
Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Although there are numerous reviews focused on the role of sympathetic nerves in different models of hypertension, few have revised the contribution of afferent nerves innervating adipose tissue and their role in the development of obesity-induced hypertension. Both clinical and basic research support the beneficial effects of bilateral renal denervation in lowering blood pressure. However, recent studies revealed that afferent signals from adipose tissue, in an adipose-brain-peripheral pathway, could contribute to the increased sympathetic activation and blood pressure during obesity. This review focuses on the role of adipose tissue afferent reflexes and briefly describes a number of other afferent reflexes modulating blood pressure. A comprehensive understanding of how multiple afferent reflexes contribute to the pathophysiology of essential and/or obesity-induced hypertension may provide significant insights into improving antihypertensive therapeutic approaches.
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Sympathetic neural recruitment strategies following acute intermittent hypoxia in humans.
Ott, EP, Jacob, DW, Baker, SE, Holbein, WW, Scruggs, ZM, Shoemaker, JK, Limberg, JK
American journal of physiology. Regulatory, integrative and comparative physiology. 2020;(5):R961-R971
Abstract
We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing patterns and the role of the carotid chemoreceptors. We hypothesized exposure to acute IH would increase muscle sympathetic nerve activity (MSNA) via an increase in action potential (AP) discharge rates and within-burst firing. We further hypothesized any change in discharge patterns would be attenuated during acute chemoreceptor deactivation (hyperoxia). MSNA (microneurography) was assessed in 17 healthy adults (11 male/6 female; 31 ± 1 yr) during normoxic rest before and after 30 min of experimental IH. Prior to and following IH, participants were exposed to 2 min of 100% oxygen (hyperoxia). AP patterns were studied from the filtered raw MSNA signal using wavelet-based methodology. Compared with baseline, multiunit MSNA burst incidence (P < 0.01), AP incidence (P = 0.01), and AP content per burst (P = 0.01) were increased following IH. There was an increase in the probability of a particular AP cluster firing once (P < 0.01) and more than once (P = 0.03) per burst following IH. There was no effect of hyperoxia on multiunit MSNA at baseline or following IH (P > 0.05); however, hyperoxia following IH attenuated the probability of particular AP clusters firing more than once per burst (P < 0.01). Acute IH increases MSNA by increasing AP discharge rates and within-burst firing. A portion of the increase in within-burst firing following IH can be attributed to the carotid chemoreceptors. These data advance the mechanistic understanding of sympathetic activation following acute IH in humans.
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Sympathetic neural modulation of arterial stiffness in humans.
Nardone, M, Floras, JS, Millar, PJ
American journal of physiology. Heart and circulatory physiology. 2020;(6):H1338-H1346
Abstract
Elevated large-artery stiffness is recognized as an independent predictor of cardiovascular and all-cause mortality. The mechanisms responsible for such stiffening are incompletely understood. Several recent cross-sectional and acute experimental studies have examined whether sympathetic outflow, quantified by microneurographic measures of muscle sympathetic nerve activity (MSNA), can modulate large-artery stiffness in humans. A major methodological challenge of this research has been the capacity to evaluate the independent neural contribution without influencing the dynamic blood pressure dependence of arterial stiffness. The focus of this review is to summarize the evidence examining 1) the relationship between resting MSNA and large-artery stiffness, as determined by carotid-femoral pulse wave velocity or pulse wave reflection characteristics (i.e., augmentation index) in men and women; 2) the effects of acute sympathoexcitatory or sympathoinhibitory maneuvers on carotid-femoral pulse wave velocity and augmentation index; and 3) the influence of sustained increases or decreases in sympathetic neurotransmitter release or circulating catecholamines on large-artery stiffness. The present results highlight the growing evidence that the sympathetic nervous system is capable of modulating arterial stiffness independent of prevailing hemodynamics and vasomotor tone.
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Effects of sympathetic modulation in metabolic disease.
Carnagarin, R, Lambert, GW, Kiuchi, MG, Nolde, JM, Matthews, VB, Eikelis, N, Lambert, EA, Schlaich, MP
Annals of the New York Academy of Sciences. 2019;(1):80-89
Abstract
Sympathetic overdrive contributes to the derangement of glucose metabolism evident in clinical conditions, such as obesity, metabolic syndrome, type 2 diabetes, obstructive sleep apnea, and others. Targeting the sympathetic nervous system directly therefore appears as an attractive therapeutic approach to restore impaired glucose metabolism. Indeed, lifestyle interventions, including healthier diets and exercise, have been shown to exert their beneficial effects at least in part by reducing sympathetic nervous system activity. Pharmacologic inhibition of exaggerated central sympathetic outflow has also been demonstrated to beneficially impact on body weight and glucose and lipid metabolism. More recently, catheter-based renal denervation, an intervention applied predominantly to lower elevated blood pressure in patients with resistant hypertension, revealed salutary effects on glucose metabolism. Here, we review the mechanisms that contribute to the beneficial effects of targeting the sympathetic nervous system directly and discuss how these approaches may best be embedded in routine clinical practice.
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Obesity, kidney dysfunction and hypertension: mechanistic links.
Hall, JE, do Carmo, JM, da Silva, AA, Wang, Z, Hall, ME
Nature reviews. Nephrology. 2019;(6):367-385
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Abstract
Excessive adiposity raises blood pressure and accounts for 65-75% of primary hypertension, which is a major driver of cardiovascular and kidney diseases. In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension, which is often mild before the development of target organ injury. Factors that contribute to increased sodium reabsorption in obesity include kidney compression by visceral, perirenal and renal sinus fat; increased renal sympathetic nerve activity (RSNA); increased levels of anti-natriuretic hormones, such as angiotensin II and aldosterone; and adipokines, particularly leptin. The renal and neurohormonal pathways of obesity and hypertension are intertwined. For example, leptin increases RSNA by stimulating the central nervous system proopiomelanocortin-melanocortin 4 receptor pathway, and kidney compression and RSNA contribute to renin-angiotensin-aldosterone system activation. Glucocorticoids and/or oxidative stress may also contribute to mineralocorticoid receptor activation in obesity. Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension. Patient management therefore often requires multiple antihypertensive drugs and concurrent treatment of dyslipidaemia, insulin resistance, diabetes and inflammation. If more effective strategies for the prevention and control of obesity are not developed, cardiorenal, metabolic and other obesity-associated diseases could overwhelm health-care systems in the future.
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Reducing Dietary Sodium to 1000 mg per Day Reduces Neurovascular Transduction Without Stimulating Sympathetic Outflow.
Babcock, MC, Robinson, AT, Migdal, KU, Watso, JC, Wenner, MM, Stocker, SD, Farquhar, WB
Hypertension (Dallas, Tex. : 1979). 2019;(3):587-593
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Abstract
The American Heart Association recommends no more than 1500 mg of sodium/day as ideal. Some cohort studies suggest low-sodium intake is associated with increased cardiovascular mortality. Extremely low-sodium diets (≤500 mg/d) elicit activation of the renin-angiotensin-aldosterone system and stimulate sympathetic outflow. The effects of an American Heart Association-recommended diet on sympathetic regulation of the vasculature are unclear. Therefore, we assessed whether a 1000 mg/d diet alters sympathetic outflow and sympathetic vascular transduction compared with the more commonly recommended 2300 mg/d. We hypothesized that sodium reduction from 2300 to 1000 mg/d would not affect resting sympathetic outflow but would reduce sympathetic transduction in healthy young adults. Seventeen participants (age: 26±2 years, 9F/8M) completed 10-day 2300 and 1000 mg/d sodium diets in this randomized controlled feeding study (crossover). We measured resting renin activity, angiotensin II, aldosterone, blood pressure, muscle sympathetic nerve activity, and norepinephrine. We quantified beat-by-beat changes in mean arterial pressure and leg vascular conductance (femoral artery ultrasound) following spontaneous sympathetic bursts to assess sympathetic vascular transduction. Reducing sodium to 1000 mg/d increased renin activity, angiotensin II, and aldosterone ( P<0.01 for all) but did not alter mean arterial pressure (78±2 versus 77±2 mm Hg, P=0.56), muscle sympathetic nerve activity (13.9±1.3 versus 13.9±0.8 bursts/min, P=0.98), or plasma/urine norepinephrine. Sympathetic vascular transduction decreased ( P<0.01). These data suggest that reducing sodium from 2300 to 1000 mg/d stimulates the renin-angiotensin-aldosterone system, does not increase resting basal sympathetic outflow, and reduces sympathetic vascular transduction in normotensive adults.