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1.
Sympathetic Neural Overdrive in the Obese and Overweight State.
Grassi, G, Biffi, A, Seravalle, G, Trevano, FQ, Dell'Oro, R, Corrao, G, Mancia, G
Hypertension (Dallas, Tex. : 1979). 2019;(2):349-358
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Abstract
Nerve traffic recordings (muscle sympathetic nerve traffic [MSNA]) have shown that sympathetic activation may occur in obesity. However, the small sample size of the available studies, presence of comorbidities, heterogeneity of the subjects examined represented major weaknesses not allowing to draw definite conclusions. This is the case for the overweight state. The present meta-analysis evaluated 1438 obese or overweight subjects recruited in 45 microneurographic studies. The analysis was primarily based on MSNA quantification in obesity and overweight, excluding as concomitant conditions hypertension, metabolic syndrome, and other comorbidities. Assessment was extended to the relationships of MSNA with other neuroadrenergic markers, such as plasma norepinephrine and heart rate, anthropometric variables, as body mass index, waist-to-hip ratio, presence/absence of obstructive sleep apnea, and metabolic profile. Compared with normoweights MSNA was significantly greater in overweight and more in obese individuals (37.0±4.1 versus 43.2±3.5 and 50.4±5.0 burts/100 heartbeats, P<0.01). This was the case even in the absence of obstructive sleep apnea. MSNA was significantly directly related to body mass index and waist-to-hip ratio ( r=0.41 and r=0.64, P<0.04 and <0.01, respectively), clinic blood pressure ( r=0.68, P<0.01), total cholesterol, LDL (low-density lipoprotein) cholesterol, and triglycerides ( r=0.91, r=0.94, and r=0.80, respectively, P<0.01) but unrelated to plasma insulin, glucose, and homeostatic model assessment for insulin resistance. No significant correlation was found between MSNA, heart rate, and norepinephrine. Thus, obesity and overweight are characterized by sympathetic overactivity which mirrors the severity of the clinical condition and reflects metabolic alterations, with the exclusion of glucose/insulin profile. Neither heart rate nor norepinephrine appear to represent faithful markers of the muscle sympathetic overdrive.
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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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Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity.
Komici, K, Femminella, GD, de Lucia, C, Cannavo, A, Bencivenga, L, Corbi, G, Leosco, D, Ferrara, N, Rengo, G
Aging clinical and experimental research. 2019;(3):321-330
Abstract
Diabetes mellitus (DM) and heart failure (HF) are frequent comorbidities among elderly patients. HF, a leading cause of mortality and morbidity worldwide, is characterized by sympathetic nervous system hyperactivity. The prevalence of diabetes mellitus (DM) is rapidly growing and the risk of developing HF is higher among DM patients. DM is responsible for several macro- and micro-angiopathies that contribute to the development of coronary artery disease (CAD), peripheral artery disease, retinopathy, neuropathy and diabetic nephropathy (DN) as well. Independently of CAD, chronic kidney disease (CKD) and DM increase the risk of HF. Individuals with diabetic nephropathy are likely to present a distinct pathological condition, defined as diabetic cardiomyopathy, even in the absence of hypertension or CAD, whose pathogenesis is only partially known. However, several hypotheses have been proposed to explain the mechanism of diabetic cardiomyopathy: increased oxidative stress, altered substrate metabolism, mitochondrial dysfunction, activation of renin-angiotensin-aldosterone system (RAAS), insulin resistance, and autonomic dysfunction. In this review, we will focus on the involvement of sympathetic system hyperactivity in the diabetic nephropathy.
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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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Sympathetic activity in obesity: a brief review of methods and supportive data.
Lambert, GW, Schlaich, MP, Eikelis, N, Lambert, EA
Annals of the New York Academy of Sciences. 2019;(1):56-67
Abstract
The increase in the prevalence of obesity and the concomitant rise in obesity-related illness have led to substantial pressure on health care systems throughout the world. While the combination of reduced exercise, increased sedentary time, poor diet, and genetic predisposition is undoubtedly pivotal in generating obesity and increasing disease risk, a large body of work indicates that the sympathetic nervous system (SNS) contributes to obesity-related disease development and progression. In obesity, sympathetic nervous activity is regionalized, with activity in some outflows being particularly sensitive to the obese state, whereas other outflows, or responses to stimuli, may be blunted, thereby making the assessment of sympathetic nervous activation in the clinical setting difficult. Isotope dilution methods and direct nerve recording techniques have been developed and utilized in clinical research, demonstrating that in obesity there is preferential activation of the muscle vasoconstrictor and renal sympathetic outflows. With weight loss, sympathetic activity is reduced. Importantly, sympathetic nervous activity is associated with end-organ dysfunction and changes in sympathetic activation that accompany weight loss are often reflected in an improvement of end-organ function. Whether targeting the SNS directly improves obesity-related illness remains unknown, but merits further attention.
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Effect of SGLT2 Inhibitors on the Sympathetic Nervous System and Blood Pressure.
Scheen, AJ
Current cardiology reports. 2019;(8):70
Abstract
PURPOSE OF THE REVIEW Hyperactivity of sympathetic nervous system (SNS) plays a role in the development of arterial hypertension and heart failure, two co-morbidities frequently associated with type 2 diabetes (T2DM). This review aims at analyzing the effects of sodium-glucose cotransporter type 2 inhibitors (SGLT2is) on blood pressure and more especially on SNS activity in patients with T2DM. RECENT FINDINGS By enhancing glucosuria, natriuresis, and osmotic diuresis, SGLT2is improve glucose control, promote weight loss, lower arterial blood pressure, and reduce the risk of major cardiovascular events and hospitalization for heart failure. No rise of heart rate is detected despite reductions in blood pressure and plasma volume, which may suggest a dampening of SNS activity. Indeed, increasing experimental and clinical data demonstrated a reduction in SNS activity, including in key target organs such as the heart and the kidneys. Of potential major interest, a better understanding of the mechanisms linking SGLT2 and SNS deserves further investigation.
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Neurohormonal Imbalance: A Neglected Problem-And Potential Therapeutic Target-In Acute Heart Failure.
Goldsmith, SR, Bart, BA, Pin A, IL
Current problems in cardiology. 2018;(7):294-304
Abstract
Decompensated or acute heart failure (AHF) is characterized by increased ventricular and atrial pressures which may lead to and be caused by circulatory congestion. Unless due to a primary decrease in cardiac function, congestion arises from volume expansion or vasoconstriction. In turn, volume expansion and vasoconstriction are due to neurohormonal imbalance since both result from activation of the sympathetic nervous system, the renin-angiotensin-aldosterone axis and excess secretion of arginine vasopressin. Outcomes in AHF remain dismal. Loop diuretics are the mainstay of therapy for AHF and may themselves aggravate neurohormonal imbalance. No adjunctive pharmacotherapy has yielded improvement in outcomes in AHF despite many attempts with various vasodilators and inotropes. We, therefore, propose that insufficient attention has been paid to neurohormonal imbalance in AHF. As in chronic HF, rectifying the effects of neurohormonal imbalance may lead to better outcomes. The use of alternative decongestive strategies or adjunctive pharmacotherapy directed at neurohormonal activation could yield benefit.
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Polyphenols, Antioxidants and the Sympathetic Nervous System.
Bruno, RM, Ghiadoni, L
Current pharmaceutical design. 2018;(2):130-139
Abstract
BACKGROUND A high dietary intake of polyphenols has been associated with a reduced cardiovascular mortality, due to their antioxidant properties. However, growing evidence suggests that counteracting oxidative stress in cardiovascular disease might also reduce sympathetic nervous system overactivity. METHODS This article reviews the most commonly used techniques to measure sympathetic activity in humans; the role of sympathetic activation in the pathophysiology of cardiovascular diseases; current evidence demonstrating that oxidative stress is involved in the regulation of sympathetic activity and how antioxidants and polyphenols might counteract sympathetic overactivity, particularly focusing on preliminary data from human studies. RESULTS The main mechanisms by which polyphenols are cardioprotective are related to the improvement of vascular function and their anti-atherogenic effect. Furthermore, a blood pressure-lowering effect was consistently demonstrated in randomized controlled trials in humans, when the effect of flavonoid-rich foods, such as tea and chocolate, was tested. More recent studies suggest that inhibition of sympathetic overactivity might be one of the mechanisms by which these substances exert their cardioprotective effects. Indeed, an increased adrenergic traffic to the vasculature is a major mechanism of disease in a number of cardiovascular and extra-cardiac diseases, including hypertension, obesity, metabolic syndrome and heart failure. A considerable body of evidence, mostly from experimental studies, support the hypothesis that reactive oxygen species might exert sympathoexcitatory effects both at the central and at the peripheral level. Accordingly, supplementation with antioxidants might reduce adrenergic overdrive to the vasculature and blunt cardiovascular reactivity to stress. CONCLUSIONS While supplementation with "classical" antioxidants such as ROS-scavengers has many limitations, increasing the intake of polyphenol-rich foods seems to be a promising novel therapeutic strategy to reduce the deleterious effects of increased adrenergic tone, particularly in essential hypertension.
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Pathophysiology of essential hypertension: an update.
Saxena, T, Ali, AO, Saxena, M
Expert review of cardiovascular therapy. 2018;(12):879-887
Abstract
Hypertension is caused by increased cardiac output and/or increased peripheral resistance. Areas covered: The various mechanisms affecting cardiac output/peripheral resistance involved in the development of essential hypertension are covered. These include genetics; sympathetic nervous system overactivity; renal mechanisms: excess sodium intake and pressure natriuresis; vascular mechanisms: endothelial cell dysfunction and the nitric oxide pathway; hormonal mechanisms: the renin-angiotensin-aldosterone system (RAAS); obesity, obstructive sleep apnea (OSA); insulin resistance and metabolic syndrome; uric acid; vitamin D; gender differences; racial, ethnic, and environmental factors; increased left ventricular ejection force and hypertension and its association with increased basal sympathetic activity - cortical connections. Expert commentary: Maximum association of hypertension is found with sympathetic overactivity which is directly or indirectly involved in different mechanisms of hypertension including RAAS, OSA, obesity, etc.. It is not overt sympathetic activity but disturbed basal sympathetic tone. Basal sympathetic tone arises from hypothalamus; possibly affected by cortical influences. Therefore, hypertension is not merely a disease of circulatory system alone. Its pathogenesis involves alteration in ANS (autonomic nervous system) and likely in cortical-hypothalamic connections. Assessment of ANS and cortical-hypothalamic connections may be required for better understanding of hypertension.
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10.
Understanding the Two Faces of Low-Salt Intake.
Braam, B, Huang, X, Cupples, WA, Hamza, SM
Current hypertension reports. 2017;(6):49
Abstract
Fierce debate has developed whether low-sodium intake, like high-sodium intake, could be associated with adverse outcome. The debate originates in earlier epidemiological studies associating high-sodium intake with high blood pressure and more recent studies demonstrating a higher cardiovascular event rate with both low- and high-sodium intake. This brings into question whether we entirely understand the consequences of high- and (very) low-sodium intake for the systemic hemodynamics, the kidney function, the vascular wall, the immune system, and the brain. Evolutionarily, sodium retention mechanisms in the context of low dietary sodium provided a survival advantage and are highly conserved, exemplified by the renin-angiotensin system. What is the potential for this sodium-retaining mechanism to cause harm? In this paper, we will consider current views on how a sodium load is handled, visiting aspects including the effect of sodium on the vessel wall, the sympathetic nervous system, the brain renin-angiotensin system, the skin as "third compartment" coupling to vascular endothelial growth factor C, and the kidneys. From these perspectives, several mechanisms can be envisioned whereby a low-sodium diet could potentially cause harm, including the renin-angiotensin system and the sympathetic nervous system. Altogether, the uncertainties preclude a unifying model or practical clinical guidance regarding the effects of a low-sodium diet for an individual. There is a very strong need for fundamental and translational studies to enhance the understanding of the potential adverse consequences of low-salt intake as an initial step to facilitate better clinical guidance.