This review examines how the sympathetic nervous system plays a major role in the regulation of cardiovascular function over multiple time scales. This is achieved through differential regulation of sympathetic outflow to a variety of organs. This differential control is a product of the topographical organization of the central nervous system and a myriad of afferent inputs. Together this organization produces sympathetic responses tailored to match stimuli. The long-term control of sympathetic nerve activity (SNA) is an area of considerable interest and involves a variety of mediators acting in a quite distinct fashion. These mediators include arterial baroreflexes, angiotensin II, blood volume and osmolarity, and a host of humoral factors. A key feature of many cardiovascular diseases is increased SNA. However, rather than there being a generalized increase in SNA, it is organ specific, in particular to the heart and kidneys. These increases in regional SNA are associated with increased mortality. Understanding the regulation of organ-specific SNA is likely to offer new targets for drug therapy. There is a need for the research community to develop better animal models and technologies that reflect the disease progression seen in humans. A particular focus is required on models in which SNA is chronically elevated.

https://www.physiology.org/doi/pdf/10.1152/physrev.00007.2009

Sympathetic Nervous System Overactivity and Its Role in the Development of Cardiovascular Disease

Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

/pdf/the-sympathetic-nervous-system-alterations-in-human-38166t4vka.pdf

The Sympathetic Nervous System Alterations in Human Hypertension

Physiological studies have long documented the key role played by the autonomic nervous system in modulating cardiovascular functions and in controlling blood pressure values, both at rest and in response to environmental stimuli. Experimental and clinical investigations have tested the hypothesis that the origin, progression, and outcome of human hypertension are related to dysfunctional autonomic cardiovascular control and especially to abnormal activation of the sympathetic division. Here, we review the recent literature on the adrenergic and vagal abnormalities that have been reported in essential hypertension, with emphasis on their role as promoters and as amplifiers of the high blood pressure state. We also discuss the possible mechanisms underlying these abnormalities and their importance in the development and progression of the structural and functional cardiovascular damage that characterizes hypertension. Finally, we examine the modifications of sympathetic and vagal cardiovascular influences induced by current nonpharmacological and pharmacological interventions aimed at correcting elevations in blood pressure and restoring the normotensive state.

The Autonomic Nervous System and Hypertension

Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg ( P for all r =−0.46; P P =0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension.

Renal Hemodynamics and Renal Function After Catheter-Based Renal Sympathetic Denervation in Patients With Resistant Hypertension

Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid-base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches.

Heart failure and kidney dysfunction: epidemiology, mechanisms and management

Direct and indirect indices of neuroadrenergic function have shown that end-stage renal disease is characterized by a marked sympathetic overdrive. It is unknown, however, whether this phenomenon r...

Early Sympathetic Activation in the Initial Clinical Stages of Chronic Renal Failure

Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis in patients with normal renal function. Plasma homocysteine (Hcy) is increased in patients with chronic renal failure (CRF) and could be linked to their high cardiovascular (CV) morbidity and mortality. We prospectively studied 77 patients (47 males and 30 females aged 62.85 +/- 1.53 yrs) who had been on maintenance hemodialysis (HD) (4 hr/x3/week) for 65.5 +/- 7.23 months. Patients were followed-up for 44 months. At baseline, blood samples were taken for hemoglobin (Hb), total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, serum calcium, serum phosphates, parathyroid hormone (PTH), Hcy, vitamin B12, serum and erythrocyte folate and methylentetrahydrofolate-reductase (t-MTH-FR) genotype determination. Plasma Hcy levels of patients were divided into four quartiles. The univariate analysis demonstrated a significant relationship between Hcy and diastolic blood pressure (BP) (r=0.45; p=0.003), and both plasma (r=-0.30; p=0.03) and erythrocyte (r=-0.48; p=0.01) folate levels and CV score (r=0.39; p=0.007). Kaplan-Meier analysis showed that the mortality rate due to CV events was statistically significantly higher in the 4th Hcy quartile (68%; 12 patients) vs. the 3rd quartile (12%; two patients), the 2nd quartile (28%; four patients) and the 1st quartile (14%; two patients) (log-rank test p=0.02). Cox's regression analysis for CV survival showed that Hcy was a positive CV mortality predictor (beta=0.02; hazard ratio=1.031; 95% confidence interval (95% CI): 1.013-1.050; p=0.001), while LDL cholesterol and albumin related negatively to CV mortality (LDL cholesterol: beta=-0.02; hazard ratio=0.095; 95% CI: 0.0957-0.0997; p=0.035; albumin: beta=-2.35; hazard ratio=0.097; 95% CI: 0.011-0.847; p=0.026). Our results show that Hcy is a strong independent mortality predictor in HD patients with a 3% increase in mortality for each 1 micromol/L increase in plasma Hcy concentration. This agrees with previous findings confirming the role of Hcy in predicting CV risk factors in uremic patients.

Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease.

Introduction: Advanced glycation end products (AGEs) are markers of oxidative stress. Aims: To assess if a vitamin-E-coated dialyzer affects plasma AGE levels and endothelial function in hemodialysis patients. Methods: 16 patients were dialyzed with a synthetic modified cellulose membrane (SMC, n = 8) or a vitamin E-coated dialyzer (n = 8), respectively. At week 32 endothelial function was determined as brachial artery flow-mediated dilatation (FMD). Total AGEs, free pentosidine (FP), protein-bound pentosidine (BP) and autoantibodies against oxidized LDL (ox-LDL-autoantibodies) were assessed at baseline (T0) and at 16, 32, 40 and 42 weeks (T16, T32, T40 and T42). Results: At T16 and T32 FP and BP were lower in vitamin E than in SMC (T 16: 88.7 ± 8.96 vs. 124.2 ± 11.90 pmol/ml plasma; p = 0.04, and 22.9 ± 2.99 vs. 32.8 ± 2.98 pmol/mg proteins; p = 0.04. T32: 78.7 ± 8.54 vs. 123.7 ± 10.15 pmol/ml plasma; p = 0.007, and 19.9 ± 2.0 vs. 33.67 ± 2.41 pmol/mg proteins; p = 0.001). In vitamin E, AGEs were lower at T32, T40 and T42 (946.7 ± 80.91 vs. 1,351.2 ± 179.33 AU/ml, p = 0.05; 986.9 ± 59.63 vs. 1,509.9 ± 154.17 AU/ml, p = 0.013; 890.3 ± 73.70 vs. 1,453.9 ± 153.16 AU/ml, p = 0.009). At T32 AGEs, ox-LDL autoantibodies and FMD were inversely correlated (R = –0.70 p = 0.007 and R = –0.59, p = 0.04, respectively). Conclusions: Vit E-coated membrane reduces plasma AGEs levels and AGEs values are negatively correlated with FMD.

Role of Vitamin E-Coated Membrane in Reducing Advanced Glycation End Products in Hemodialysis Patients: A Pilot Study

OBJECTIVES Chronic renal failure is characterized by a marked sympathetic activation. No information exists, however, as to whether the adrenergic overdrive is confined to selected vascular districts or is rather generalized to the whole cardiovascular system. METHODS In 15 patients aged 60.5 +/- 2.0 years (mean +/- SEM) with stable chronic renal failure belonging to stage 2-3 of the Kidney Foundation classification and in 12 age-matched healthy controls, we measured arterial blood pressure (Finapres), heart rate (ECG), venous plasma norepinephrine (high-performance liquid chromatography) and postganglionic sympathetic nerve traffic in skeletal muscle and skin areas (microneurography). Muscle and skin nerve traffic measurements were made in a randomized sequence over two periods of 30 min each, spaced by a 20-30-min interval. Measurements also included evaluation of skin sympathetic responses to emotional stimuli. RESULTS Muscle sympathetic nerve traffic was markedly and significantly greater in renal failure patients compared with controls (58.2 +/- 3.6 vs. 36.8 +/- 5.7 bursts/100 heart beats, P < 0.01), with this also being the case for plasma norepinephrine (380.6 +/- 63 vs. 210.8 +/- 29 pg/ml, P < 0.05). By contrast, skin sympathetic nerve traffic was superimposable in the two groups (11.5 +/- 0.8 vs. 12.7 +/- 1.7 bursts/minute, P = not significant), this being the case also for the responses to emotional arousal. CONCLUSION These data provide the first evidence that the sympathetic activation characterizing renal failure is not generalized to the entire cardiovascular system. This may depend on the fact that the two sympathetic districts are governed by mechanisms that are differently affected by the chronic uraemic state.

Behaviour of regional adrenergic outflow in mild-to-moderate renal failure.

Background. Hyperhomocysteinaemia is an independent risk factor for the development of atherosclerosis. Furthermore, homocysteine induces endothelial dysfunction by an increased inactivation of nitric oxide. In patients with chronic renal failure, the administration of folic acid or its metabolites reduces but does not normalize plasma homocysteine concentrations. Methods. We examined the effect of oral treatment with 15 mg/daily of 5-methyltetrahydrofolate (5-MTHF) for 12 weeks, on homocysteinaemia and endothelial function in 19 patients undergoing peritoneal dialysis and compared them, for the same period of time, to a control group of patients on peritoneal dialysis. Endothelial function was evaluated by B-mode ultrasonography on the brachial artery. Flow-mediated dilation (FMD) was recorded during reactive hyperaemia produced by the inflation of a pneumatic tourniquet. Nitroglycerine-mediated dilation (NMD) was recorded after sublingual administration of glyceryl trinitrate. Finally, oxidative stress was assessed by evaluating the conjugated dienes plasma levels. Results. Plasma homocysteine concentrations fell by 30% after oral treatment with 5-MTHF. Endothelial function improved significantly after oral 5-MTHF treatment (13.8 � 1.2% vs 11.4 � 1.4%; P < 0.02) while in the control group we observed a worsening of basal values from 12.1 � 2.66% to 8.7 � 2.90% (P < 0.02). The conjugated dienes plasma levels did not change either. Conclusions. Our study demonstrated that 5-MTHF administration improves endothelial dysfunction in patients undergoing peritoneal dialysis. This effect appears to be independent of the reduction in homocysteine plasma levels.

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Silvia Furiani

Papers

Early Sympathetic Activation in the Initial Clinical Stages of Chronic Renal Failure

Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease.

Role of Vitamin E-Coated Membrane in Reducing Advanced Glycation End Products in Hemodialysis Patients: A Pilot Study

Behaviour of regional adrenergic outflow in mild-to-moderate renal failure.

Improvement of endothelial function in uraemic patients on peritoneal dialysis: a possible role for 5-MTHF administration