Efficacy and safety of sympathetic mapping and ablation of renal nerves for the treatment of hypertension (SMART): 6-month follow-up of a randomised, controlled trial.

Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18-65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin -10% (2.69%; 95% CI -4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (-3.25; 95% CI -5.56, -0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p < 0.001 from Baseline; p > 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP <140 mmHg, with only approximately four targeted ablations per renal main artery, much lower than in previous trials. Funding: SyMap Medical (Suzhou), LTD, Suzhou, China.

Plasma lipocalin-2/NGAL is stable over 12 weeks and is not modulated by exercise or dieting.

Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18-55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise.

Differential sympathetic response to lesion-induced chronic kidney disease in rabbits.

Chronic kidney disease (CKD) is associated with greater sympathetic nerve activity but it is unclear if this is a kidney-specific response or due to generalized stimulation of sympathetic nervous system activity. To determine this, we used a rabbit model of CKD in which quantitative comparisons with control rabbits could be made of kidney sympathetic nerve activity and whole-body norepinephrine spillover. Rabbits either had surgery to lesion 5/6th of the cortex of one kidney by electro-lesioning and two weeks later removal of the contralateral kidney, or sham lesioning and sham nephrectomy. After three weeks, the blood pressure was statistically significantly 20% higher in conscious rabbits with CKD compared to rabbits with a sham operation, but their heart rate was similar. Strikingly, kidney nerve activity was 37% greater than in controls, with greater burst height and frequency. Total norepinephrine spillover was statistically significantly lower by 34%, and kidney baroreflex curves were shifted to the right in rabbits with CKD. Plasma creatinine and urine output were elevated by 38% and 131%, respectively, and the glomerular filtration rate was 37% lower than in sham-operated animals (all statistically significant). Kidney gene expression of fibronectin, transforming growth factor-ß, monocyte chemotactic protein1, Nox4 and Nox5 was two- to eight-fold greater in rabbits with CKD than in control rabbits. Overall, the glomerular layer lesioning model in conscious rabbits produced a moderate, stable degree of CKD characterized by elevated blood pressure and increased kidney sympathetic nerve activity. Thus, our findings, together with that of a reduction in total norepinephrine spillover, suggest that kidney denervation, rather than generalized sympatholytic treatments, may represent a preferable management for CKD associated hypertension.

Pseudopheochromocytoma.

Pseudopheochromocytoma manifests as severe, symptomatic paroxysmal hypertension without significant elevation in catecholamine and metanephrine levels and lack of evidence of tumor in the adrenal gland. The clinical manifestations are similar but not identical to those in excess circulating catecholamines. The underlying symptomatic mechanism includes augmented cardiovascular responsiveness to catecholamines alongside heightened sympathetic nervous stimulation. The psychological characteristics are probably attributed to the component of repressed emotions related to a past traumatic episode or repressive coping style. Successful management can be achieved by strong collaboration between a hypertension specialist and a psychiatrist or psychologist with expertise in cognitive-behavioral panic management.

Does sympathetic dysfunction occur before denervation in pure autonomic failure?

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.

Renal Denervation Reduces Monocyte Activation and Monocyte-Platelet Aggregate Formation: An Anti-Inflammatory Effect Relevant for Cardiovascular Risk.

Overactivation of renal sympathetic nervous system and low-grade systemic inflammation are common features of hypertension. Renal denervation (RDN) reduces sympathetic activity in patients with resistant hypertension. However, its effect on systemic inflammation has not been examined. We prospectively investigated the effect of RDN on monocyte activation and inflammation in patients with uncontrolled hypertension scheduled for RDN. Ambulatory blood pressure, monocyte, and monocyte subset activation and inflammatory markers were assessed at baseline, 3 months, and 6 months after procedure in 42 patients. RDN significantly lowered blood pressure at 3 months (150.5±11.2/81.0±11.2 mm Hg to 144.7±11.8/77.9±11.0 mm Hg), which was sustained at 6 months (144.7±13.8/78.6±11.0 mm Hg). Activation status of monocytes significantly decreased at 3 months (P<0.01) and 6 months (P<0.01) after the procedure. In particular, classical monocyte activation was reduced at 6 months (P<0.05). Similarly, we observed a reduction of several inflammatory markers, including monocyte-platelet aggregates (3 months, P<0.01), plasma monocyte chemoattractant protein-1 levels (3 months, P<0.0001; 6 months, P<0.05), interleukin-1ß (3 months, P<0.05; 6 months, P<0.05), tumor necrosis factor-α (3 months, P<0.01; 6 months, P<0.05), and interleukin-12 (3 months, P<0.01; 6 months, P<0.05). A positive correlation was observed between muscle sympathetic nerve activity and monocyte activation before and after the procedure. These results indicate that inhibition of sympathetic activity via RDN is associated with a reduction of monocyte activation and other inflammatory markers in hypertensive patients. These findings point to a direct interaction between the inflammatory and sympathetic nervous system, which is of central relevance for the understanding of beneficial cardiovascular effects of RDN.

Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension.

OBJECTIVES: To investigate, whether renal denervation (RDN) has a direct effect on cardiac sympathetic activity and innervation density. BACKGROUND: RDN demonstrated its efficacy not only in reducing blood pressure (BP) in certain patients, but also in decreasing cardiac hypertrophy and arrhythmias. These pleiotropic effects occur partly independent from the observed BP reduction. METHODS: Eleven patients with resistant hypertension (mean office systolic BP 180 ± 18 mmHg, mean antihypertensive medications 6.0 ± 1.5) underwent I-123-mIBG scintigraphy to exclude pheochromocytoma. We measured cardiac sympathetic innervation and activity before and 9 months after RDN. Cardiac sympathetic innervation was assessed by heart to mediastinum ratio (H/M) and sympathetic activity by wash out ratio (WOR). Effects on office BP, 24 h ambulatory BP monitoring, were documented. RESULTS: Office systolic BP and mean ambulatory systolic BP were significantly reduced from 180 to 141 mmHg (p = 0.006) and from 149 to 129 mmHg (p = 0.014), respectively. Cardiac innervation remained unchanged before and after RDN (H/M 2.5 ± 0.5 versus 2.6 ± 0.4, p = 0.285). Cardiac sympathetic activity was significantly reduced by 67 % (WOR decreased from 24.1 ± 12.7 to 7.9 ± 25.3 %, p = 0.047). Both, responders and non-responders experienced a reduction of cardiac sympathetic activity. CONCLUSION: RDN significantly reduced cardiac sympathetic activity thereby demonstrating a direct effect on the heart. These changes occurred independently from BP effects and provide a pathophysiological basis for studies, investigating the potential effect of RDN on arrhythmias and heart failure.

Transcatheter aortic valve implantation reduces sympathetic activity and normalizes arterial spontaneous baroreflex in patients with aortic stenosis.

OBJECTIVES: This study sought to measure muscle sympathetic nerve activity (MSNA) in patients with aortic stenosis (AS) before and after transcatheter aortic valve implantation (TAVI) and to compare MSNA with that of control patients. BACKGROUND: TAVI is an emerging therapeutic option in patients with severe AS at high risk of open heart surgery. Whether patients with AS have increased sympathetic activity remains to be established, and the effects of TAVI on the sympathetic nervous system are also unknown. METHODS: We prospectively enrolled 14 patients with severe symptomatic AS treated by TAVI. Fourteen control patients matched for age, body mass index, and unscathed of AS were also included. All patients underwent MSNA and arterial baroreflex gain assessment at baseline and 1 week after TAVI for AS patients. RESULTS: Patients with AS had lower blood pressure (BP) levels, a significant increase in MSNA (61.0 ± 1.7 burst/min vs. 55.4 ± 1.4 burst/min; p < 0.05), and a decrease in arterial baroreflex gain (2.13 ± 0.14% burst/mm Hg vs. 3.32 ± 0.19% burst/mm Hg; p < 0.01) compared with matched control patients. The TAVI procedures induced an increase in BP associated with a significant decrease in MSNA (from 61.0 ± 1.7 burst/min to 54.1 ± 1.0 burst/min; p < 0.01) and was associated with a significant increase in arterial baroreflex gain (from 2.13 ± 0.14% burst/mm Hg to 3.49 ± 0.33% burst/mm Hg; p < 0.01). CONCLUSIONS: We report for the first time, through direct measurement of nerve activity, that patients with AS have increased sympathetic nervous system activity associated with a decrease in sympathetic baroreflex gain and that TAVI normalizes these parameters. This study provides evidence of a new beneficial effect of TAVI, namely, normalization of sympathetic nervous system hyperactivity.

New drugs, procedures, and devices for hypertension.

Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug, and the value of strategies to combat the effect of adverse lifestyle behaviours on blood pressure. In this paper, we discuss two promising therapeutic alternatives for patients with resistant hypertension: novel drugs, including new pharmacological classes (such as vasopeptidase inhibitors and aldosterone synthase inhibitors) and new molecules from present pharmacological classes with additional properties in blood-pressure or metabolism pathways; and new procedures and devices, including stimulation of arterial baroreceptors and catheter-based renal denervation. Although several pharmacological targets have been discovered with promising preclinical results, the clinical development of novel antihypertensive drugs has been more difficult and less productive than expected. The effectiveness and safety of new devices and procedures should be carefully assessed in patients with resistant hypertension, thus leading to a new era of outcome trials and evidence-based guidelines.

Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes.

BACKGROUND: The pathophysiology of vasovagal syncope is poorly understood, and the treatment usually ineffective. Our clinical experience is that patients with vasovagal syncope fall into 2 groups, based on their supine systolic blood pressure, which is either normal (>100 mm Hg) or low (70-100 mm Hg). We investigated neural circulatory control in these 2 phenotypes. METHODS AND RESULTS: Sympathetic nervous testing was at 3 levels: electric, measuring sympathetic nerve firing (microneurography); neurochemical, quantifying norepinephrine spillover to plasma; and cellular, with Western blot analysis of sympathetic nerve proteins. Testing was done during head-up tilt (HUT), simulating the gravitational stress of standing, in 18 healthy control subjects and 36 patients with vasovagal syncope, 15 with the low blood pressure phenotype and 21 with normal blood pressure. Microneurography and norepinephrine spillover increased significantly during HUT in healthy subjects. The microneurography response during HUT was normal in normal blood pressure and accentuated in low blood pressure phenotype (P=0.05). Norepinephrine spillover response was paradoxically subnormal during HUT in both patient groups (P=0.001), who thus exhibited disjunction between nerve firing and neurotransmitter release; this lowered norepinephrine availability, impairing the neural circulatory response. Subnormal norepinephrine spillover in low blood pressure phenotype was linked to low tyrosine hydroxylase (43.7% normal, P=0.001), rate-limiting in norepinephrine synthesis, and in normal blood pressure to increased levels of the norepinephrine transporter (135% normal, P=0.019), augmenting transmitter reuptake. CONCLUSIONS: Patients with recurrent vasovagal syncope, when phenotyped into 2 clinical groups based on their supine blood pressure, show unique sympathetic nervous system abnormalities. It is predicted that future therapy targeting the specific mechanisms identified in the present report should translate into more effective treatment.

Renal denervation: a potential new treatment modality for polycystic ovary syndrome?

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with sympathetic nervous system activation, insulin resistance, and blood pressure elevation. Renal nerve ablation has been demonstrated to reduce sympathetic outflow and improve blood pressure control. Here we report on the effects of renal denervation on hemodynamic, metabolic, and renal parameters in two obese PCOS patients with hypertension. METHODS: Sympathetic nerve activity was assessed at baseline using microneurography and norepinephrine spillover measurements. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Measurements of cystatin-C, creatinine clearance, and urinary albumin-creatinine ratio were also obtained. All measurements were repeated 3 months after bilateral renal denervation achieved via percutaneous endovascular radiofrequency ablation. RESULTS: Muscle sympathetic nerve activity and whole body norepinephrine spillover were substantially elevated at baseline in both patients by approximately 2.5-3-fold. Bilateral renal nerve ablation reduced both indices of sympathetic nerve activity. This was associated with moderate reductions in blood pressure and a substantial improvement in insulin sensitivity by approximately 17.5% in the absence of weight changes at 3-month follow-up. Glomerular hyperfiltration and urinary albumin excretion were also reduced. CONCLUSION: These findings corroborate the relevance of sympathetic activation in PCOS and suggest that renal denervation exerts beneficial effects not only on blood pressure control but also on insulin sensitivity, renal, and endocrine abnormalities characteristic of PCOS.

Persistence of muscle sympathetic nerve activity during vasovagal syncope.

AIMS: To determine whether sympathetic nerve firing to skeletal muscle vasculature is withdrawn during vasovagal syncope (VVS) precipitated by passive graded head-up tilt (HUT) table testing. METHODS AND RESULTS: We performed passive graded HUT table testing in 18 patients with a history of recurrent postural VVS whom we evaluated during the syncopal event. All patients developed typical VVS during testing. Blood pressure was measured continuously via intra-brachial arterial line. Muscle sympathetic nerve activity (MSNA) was measured using an electrode in the peroneal nerve. Passive graded HUT was then applied. No pharmacological agents were used to provoke syncope. The recording site was maintained through the syncopal event in 10 of 18 patients and we were able to demonstrate persistence of MSNA during syncope in 9. The predominant haemodynamic pattern of syncope in this cohort was mixed--hypotension and bradycardia, with heart rate not falling <40 b.p.m. (n = 10). CONCLUSION: Our data challenge the established view that the final trigger for human orthostatic vasovagal reactions is sympathetic nervous system inhibition. Efferent sympathetic nerve traffic to the skeletal muscle vasculature was nearly always maintained through the faint. This finding supports an alternative viewpoint, that vasodilator mechanisms underlie the blood pressure fall in VVS.

Atrial fibrillation impairs cardiac sympathetic response to baroreceptor unloading in congestive heart failure.

AIMS: In this study, we investigated for a potential mechanism by which atrial fibrillation (AF) might convey a worse prognosis in congestive heart failure (CHF). Specifically, we aimed to determine whether AF impaired cardiac sympathetic response to baroreceptor unloading in comparison to sinus rhythm (SR) in CHF. METHODS AND RESULTS: Eighteen CHF patients (ejection fraction 30+/-2%, age 59+/- 2 years), nine in SR and nine in AF, were enrolled. A right heart study and cardiac sympathetic tone assessment by coronary sinus catheter were performed at baseline and after 10 min of 20 degrees and 30 degrees of passive head up tilt (HUT). Filling pressures fell significantly during HUT in both SR and AF groups (AF, P=0.002; SR, P<0.001). The cardiac sympathetic response to HUT was significantly attenuated by AF compared with SR (P=0.014). In conjunction, right atrial appendages were collected from 23 cardiac surgery patients, 12 in SR and 11 in AF to investigate the presence of fibrosis. AF was associated with a significant increase in the collagen density (P=0.025). CONCLUSION: AF is associated with impaired cardiac sympathetic response to baroreceptor unloading compared with SR in CHF, possibly secondary to atrial fibrosis.

"Stress" and coronary heart disease: psychosocial risk factors.

An Expert Working Group of the National Heart Foundation of Australia undertook a review of systematic reviews of the evidence relating to major psychosocial risk factors to assess whether there are independent associations between any of the factors and the development and progression of coronary heart disease (CHD), or the occurrence of acute cardiac events. The expert group concluded that (i) there is strong and consistent evidence of an independent causal association between depression, social isolation and lack of quality social support and the causes and prognosis of CHD; and (ii) there is no strong or consistent evidence for a causal association between chronic life events, work-related stressors (job control, demands and strain), Type A behaviour patterns, hostility, anxiety disorders or panic disorders and CHD. The increased risk contributed by these psychosocial factors is of similar order to the more conventional CHD risk factors such as smoking, dyslipidaemia and hypertension. The identified psychosocial risk factors should be taken into account during individual CHD risk assessment and management, and have implications for public health policy and research.

Dysautonomias: clinical disorders of the autonomic nervous system.

The term dysautonomia refers to a change in autonomic nervous system function that adversely affects health. The changes range from transient, occasional episodes of neurally mediated hypotension to progressive neurodegenerative diseases; from disorders in which altered autonomic function plays a primary pathophysiologic role to disorders in which it worsens an independent pathologic state; and from mechanistically straightforward to mysterious and controversial entities. In chronic autonomic failure (pure autonomic failure, multiple system atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension reflects sympathetic neurocirculatory failure from sympathetic denervation or deranged reflexive regulation of sympathetic outflows. Chronic orthostatic intolerance associated with postural tachycardia can arise from cardiac sympathetic activation after "patchy" autonomic impairment or blood volume depletion or, as highlighted in this discussion, from a primary abnormality that augments delivery of the sympathetic neurotransmitter norepinephrine to its receptors in the heart. Increased sympathetic nerve traffic to the heart and kidneys seems to occur as essential hypertension develops. Acute panic can evoke coronary spasm that is associated with sympathoneural and adrenomedullary excitation. In congestive heart failure, compensatory cardiac sympathetic activation may chronically worsen myocardial function, which rationalizes treatment with beta-adrenoceptor blockers. A high frequency of positive results on tilt-table testing has confirmed an association between the chronic fatigue syndrome and orthostatic intolerance; however, treatment with the salt-retaining steroid fludrocortisone, which is usually beneficial in primary chronic autonomic failure, does not seem to be beneficial in the chronic fatigue syndrome. Dysautonomias are an important subject in clinical neurocardiology.

Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes.

BACKGROUND: In postural tachycardia syndrome (POTS) and repeated neurocardiogenic presyncope (NCS), orthostatic intolerance occurs without persistent sympathetic neurocirculatory failure. Whether these conditions involve abnormal cardiac sympathetic innervation or function has been unclear. METHODS AND RESULTS: Patients with POTS or NCS underwent measurements of neurochemical indices of cardiac release, reuptake, and synthesis of the sympathetic neurotransmitter norepinephrine based on entry of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover), cardiac extraction of circulating (3)H-norepinephrine, and cardiac production of dihydroxyphenylalanine and measurement of left ventricular myocardial innervation density using 6-[(18)F]fluorodopamine positron emission tomographic scanning. Mean cardiac norepinephrine spillover in POTS (171+/-30 pmol/min, N=16) was higher and in NCS (62+/-9 pmol/min, N=20) was lower than in a large group of healthy volunteers (102+/-9 pmol/min, N=52) and in a subgroup of age-matched healthy women (106+/-18 pmol/min, N=11). Both patient groups had normal cardiac extraction of (3)H-norepinephrine, normal cardiac production of dihydroxyphenylalanine, and normal myocardial 6-[(18)F]fluorodopamine-derived radioactivity. CONCLUSIONS: POTS and NCS differ in tonic cardiac sympathetic function, with increased cardiac norepinephrine release in the former and decreased release in the latter. Both groups had normal values for indices of function of the cell membrane norepinephrine transporter, norepinephrine synthesis, and density of myocardial sympathetic innervation. Because POTS and NCS both include specific abnormalities of cardiac sympathetic function, both can be considered forms of dysautonomia.

Oestrogen supplementation attenuates responses to psychological stress in elderly men rendered hypogonadal after treatment for prostate cancer.

BACKGROUND: We have shown previously that oestrogens attenuate cardiovascular and hormonal responses to stress in perimenopausal women. The cardiovascular role of oestrogens in men is uncertain, despite preliminary evidence that endogenous oestrogens produced by aromatization of androgenic precursors are of physiological importance; hypogonadal men have very low levels of circulating oestrogen. METHODS: We therefore studied the haemodynamic and hormonal responses to a standardized laboratory mental stress test in 12 men (mean age 68.9 +/- 2.6 SEM years) rendered hypogonadal as a result of treatment for prostatic cancer, before and after 8 weeks of oestrogen supplementation (oestradiol valerate 1 mg daily, n = 7) or placebo (n = 5). The stress was administered as a standard mental arithmetic test of 10 minutes' duration. Blood pressure, cortisol and ACTH were measured at baseline, and following 5 minutes and 10 minutes of stress, and ACTH again at 25 minutes on both days. Noradrenaline and adrenaline responses to mental stress, as well as changes in total body and forearm spillover of noradrenaline and noradrenaline clearance, were also measured. RESULTS: Oestrogen supplementation was well tolerated, with minimal adverse effects. Mean oestradiol levels increased from < 30 pmol/l to 308 +/- 65 pmol/l after oestrogen treatment. Oestradiol significantly attenuated the mental stress-induced increase in both systolic and diastolic blood pressures. Oestradiol also attenuated mental stress-induced increases in ACTH, cortisol and adrenaline, but did not influence either total body or forearm spillover of noradrenaline. Responses to stress were unchanged after administration of placebo. CONCLUSIONS: We conclude that oestrogen supplementation in men rendered hypogonadal as a result of treatment for prostate cancer is well tolerated and significantly attenuates blood pressure and hormonal responses to psychological stress. These findings suggest the need for further studies to examine a possible clinical role for oestrogen treatment in hypogonadal men.

Influence of leptin on neurotransmitter overflow from the rat brain in vitro.

The 16-kDa polypeptide hormone, leptin along with the neurotransmitters noradrenaline and serotonin (5-HT) have important physiological roles in the regulation of a number of neuroendocrine actions particularly feeding. Leptin receptor mRNA and immunoreactivity has been reported in various brain regions, while recent studies suggest that leptin is released from the human brain. This study investigated the interactions between leptinergic and neurotransmitter systems of the rat brain in vitro. Techniques were established to simultaneously monitor the release of endogenous noradrenaline and its metabolite 3,4 dihydroxyphenylglycol (DHPG), and 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) from the rat brain. The neuromodulatory action of leptin (0.2 and 3 nM) on the overflow of noradrenaline and DHPG from the medulla and hypothalamus was examined. The effect of leptin on 5-HT and 5-HIAA overflow from the hypothalamus was also investigated. Administration of 0.2 and 3 nM leptin significantly increased medullary noradrenaline overflow to 172% and 174% of basal levels, respectively. Leptin had no significant effect on hypothalamic noradrenaline overflow, while leptin perfusion induced a significant increase in 5-HIAA overflow from the hypothalamus. This study lends support to the notion of a complex interaction of the leptinergic and brain neurotransmitters involved in the control of feeding and energy metabolism.