David A.S.G. Mary

Impact of Type 2 Diabetes Mellitus on Sympathetic Neural Mechanisms in Hypertension

Background—Essential hypertension (EHT) is a major cardiovascular risk factor, and the additional presence of type 2 diabetes mellitus (DM2) increases this risk. However, although the sympathetic nerve hyperactivity of EHT is known to play a role in cardiovascular risk, the level of sympathetic nerve activity is known neither in DM2 nor in hypertensive type 2 diabetic patients (EHT+DM2). Therefore, we planned to quantify the vasoconstrictor sympathetic nerve activity in patients with EHT+DM2 and with DM2 relative to that in matched groups with EHT and normal blood pressure (NT). Methods and Results—In 68 closely matched subjects with EHT+DM2 (n=17), DM2 (n=17), EHT (n=17), and NT (n=17), we measured resting muscle sympathetic nerve activity as the mean frequency of multiunit bursts (MSNA) and of single units (s-MSNA) with defined vasoconstrictor properties. The s-MSNA in EHT+DM2 (97±3.8 impulses/100 beats) was greater (at least P <0.001) than in EHT (69±3.4 impulses/100 beats) and DM2 (78±4.1 impulses/100 beats), and all these were significantly greater (at least P <0.01) than in NT (53±3.3 impulses/100 beats) despite similar age and body mass index. The MSNA followed a similar trend. In addition, the level of insulin was also raised in EHT+DM2 (20.4±3.6 &mgr;U/mL) and DM2 (18.1±3.1 &mgr;U/mL; at least P <0.05) compared with HT or NT. Conclusions—Patients with EHT+DM2, EHT, or DM2 had central sympathetic hyperactivity, although plasma insulin levels were raised only in EHT+DM2 and DM2. The combination of EHT and DM2 resulted in the greatest sympathetic hyperactivity and level of plasma insulin, and this hyperactivity could constitute a mechanism for the increased risks of this condition.

Sympathetic Neural Activation in Nondiabetic Metabolic Syndrome and Its Further Augmentation by Hypertension

Hypertension is a major cardiovascular risk factor in the metabolic syndrome (MS) in which the presence of insulin resistance, glucose intolerance, abnormal lipoprotein metabolism, and central obesity all confer an increased risk. Because essential hypertension (EHT), insulinemia, and visceral fat are associated with sympathetic hyperactivity, which is itself known to increase cardiovascular risk, the aim of this study was to see if MS is a state of sympathetic nerve hyperactivity and if the additional presence of EHT intensifies this hyperactivity. In 69 closely matched subjects, comprising hypertensive MS (MS+EHT, 18), normotensive MS (MS-EHT, 17), hypertensives without MS (EHT, 16), and normotensive controls without MS (NC, 18), we measured resting muscle sympathetic nerve activity (MSNA) as assessed from multiunit discharges and from single units with defined vasoconstrictor properties (s-MSNA). The s-MSNA in MS+EHT (76±3.1 impulses/100 beats) was greater (at least P<0.01) than in MS-EHT (62±3.2 impulses/100 beats) and in EHT (60±2.3 impulses/100 beats), and all these were significantly greater (at least P<0.01) than in NC (46±2.7 impulse/100 beats). The multi-unit MSNA followed a similar trend. These findings suggest that MS is a state of sympathetic nerve hyperactivity and that the additional presence of hypertension further intensifies this hyperactivity. The degree of sympathetic hyperactivity seen in this study could be argued at least partly to contribute to the higher cardiovascular risk and metabolic abnormalities seen in MS+EHT patients.

Relationship Between Central Sympathetic Drive and Magnetic Resonance Imaging–Determined Left Ventricular Mass in Essential Hypertension

Background— Sympathetic activation has been implicated in the development of left ventricular hypertrophy (LVH). However, the relationship between sympathetic activation and LV mass (LVM) has not been clearly defined across a range of arterial pressure measurements. The present study was planned to determine that relationship, using cardiac magnetic resonance imaging to accurately quantify LVM, in hypertensive patients with and without LVH and in normal subjects. Methods and Results— Twenty-four patients with uncomplicated and untreated essential hypertension (LVH[−]) were compared with 25 patients with essential hypertension and left ventricular hypertrophy (LVH[+]) and 24 normal control subjects. Resting muscle sympathetic nerve activity was quantified as multiunit bursts and single units. Cardiac magnetic resonance imaging–determined LVM was indexed to body surface area (LVM index); in the LVH[−] group, LVM index was 67±2.1 g/m2, a value between those of the LVH[+] (91±3.4 g/m2) and normal control (57±2.2 g/m2) groups, respectively. The sympathetic activity in the LVH[−] group (53±1.3 bursts per 100 cardiac beats and 63±1.6 impulses per 100 cardiac beats) was between (at least P<0.001) those of the LVH[+] (66±1.7 bursts per 100 cardiac beats and 77±2.2 impulses per 100 cardiac beats) and normal control (39±3.0 bursts per 100 cardiac beats and 45±3.4 impulses per 100 cardiac beats) groups. Significant positive correlation existed between sympathetic activity and LVM index in the LVH[−] and LVH[+] groups (at least r=0.76, P<0.0001) but not in the normal control group. However, no consistent relationship existed between arterial blood pressure and sympathetic activity or LVM index. Conclusions— These findings further support the hypothesis that central sympathetic activation is associated with the development of LVH in human hypertension.

Water ingestion increases sympathetic vasoconstrictor discharge in normal human subjects

A marked pressor response to water drinking has been observed in patients with autonomic failure and in the elderly, and has been attributed to sympathetic vasoconstrictor activation, despite the absence of such a pressor response in healthy subjects with intact sympathetic mechanisms. We investigated whether water drinking in normal subjects affected peripheral sympathetic neural discharge and its effect on vascular resistance. In nine normal human subjects, we examined the effect of water ingestion on muscle sympathetic neural activity from the peroneal nerve, as multi-unit bursts (muscle sympathetic nerve activity; MSNA) and as single-unit impulses (s-MSNA) with vasoconstrictor function, and on calf vascular resistance for 120 min. In each subject, water ingestion caused increases in s-MSNA and MSNA which peaked at 30 min after ingestion; they increased respectively (mean+/-S.E.M.) from 42+/-4 to 58+/-5 impulses/100 beats (P<0.01) and from 36+/-4 to 51+/-5 bursts/100 beats (P<0.001). There were corresponding increases in calf vascular resistance and in plasma noradrenaline levels. A significant correlation occurred between all of these data. In conclusion, measurement of MSNA has provided direct evidence that water drinking in normal human subjects increases sympathetic nerve traffic, leading to peripheral vasoconstriction. This sympathetic activation was not accompanied by significant changes in arterial blood pressure.

Sympathetic neural mechanisms in white-coat hypertension

OBJECTIVES This study planned to establish whether sympathetic hyperactivity exists in white-coat hypertension (WHT) in the clinical setting, relative to matched groups with normotension (NT) and untreated essential hypertension (EHT). BACKGROUND White-coat hypertension differs from EHT by the presence of normal ambulatory blood pressure. Sympathetic hyperactivity exists in patients with EHT in the clinical setting and is believed to contribute to the development of target organ damage. Similar organ damage has been reported in WHT, yet little is known about sympathetic neural activity in this condition. METHODS Using microneurography, we examined groups of 12 matched subjects with WHT, EHT and NT during the same clinical setting to quantify muscle sympathetic nerve activity as multiunit discharge (MSNA) and single units (s-MSNA). RESULTS The s-MSNA in WHT (54 +/- 4.2 impulses/100 beats) was greater (p < 0.05) than in NT (37 +/- 5.4 impulses/100 beats) despite similar age and body mass index (BMI). The EHT values of s-MSNA (73 +/- 5.2 impulses/100 beats) were significantly (p < 0.05) greater than in WHT despite similar age, BMI and blood pressure levels. The MSNA followed a similar trend. White-coat hypertension had a similar cardiac baroreceptor reflex sensitivity to NT, but this was impaired in EHT relative to both NT and WHT. CONCLUSIONS It was shown, in the clinical setting, that central sympathetic hyperactivity exists in WHT, albeit to a lesser degree than EHT. These findings suggest that WHT may not be entirely benign and that the observed sympathetic hyperactivity may be responsible for development of target organ damage in this group of patients.

Hypertensive left ventricular hypertrophy: Relation to peripheral sympathetic drive

OBJECTIVES This study was designed to examine whether the occurrence of left ventricular hypertrophy (LVH) in moderate to severe essential hypertension (EHT) was associated with alteration in peripheral sympathetic drive. BACKGROUND In hypertension, LVH is an independent predictor of increased morbidity and mortality. The reported mechanisms leading to LVH remain unclear but include hemodynamic and humoral factors. The sympathetic nervous system may be important, particularly as catecholamines have been shown to have trophic properties. We tested the hypothesis that sympathetic activity measured using microneurography could be different in patients with hypertension depending on the presence of LVH. METHODS We examined 28 subjects with moderate to severe EHT (stages 2 to 3; Joint National Committee [JNC]-VI classification). Fourteen had echocardiographic evidence of LVH (EHT + LVH), while the other 14 subjects (EHT) did not. Subjects were matched in terms of age, body mass index and levels of arterial blood pressure. Peripheral muscle sympathetic nerve activity was measured from both multiunit bursts (MSNA) and single unit (s-MSNA) vasoconstrictor impulses via the peroneal nerve. RESULTS The mean frequency of s-MSNA and MSNA was greater in the EHT + LVH group than it was in the EHT group (mean +/- SEM; 75.9 +/- 6.9 impulses/100 beats vs. 52.1 +/- 2.9 impulses/100 beats, p < 0.001 and 64.2 +/- 5.7 bursts/100 beats vs. 48.9 +/- 2.8 bursts/100 beats, p < 0.05). CONCLUSIONS These results indicate that, in subjects with moderate to severe hypertension, the presence of LVH is associated with higher sympathetic discharge, evidenced by an increase in unitary firing frequency and also by fiber recruitment.

Time Course of Sympathetic Neural Hyperactivity After Uncomplicated Acute Myocardial Infarction

Background—Little information is available on sympathetic activity after acute myocardial infarction (AMI), despite the belief that sympathetic drive is important in relation to morbidity and mortality. Indirect indices such as plasma catecholamines are transiently elevated after uncomplicated AMI, whereas other prognostically important autonomic indices may be affected longer. We planned to quantify central sympathetic output to the periphery after uncomplicated AMI and to investigate its progress over time. Methods and Results—After uncomplicated AMI, 13 patients had muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units with defined vasoconstrictor properties (s-MSNA). Measurements were obtained 2 to 4 days after AMI and were repeated after 3 and 6 months. We also examined 3 matched control groups comprising normal subjects, patients with coronary artery disease, and hospitalized patients without AMI. MSNA and s-MSNA after AMI (84±4.6 bursts/100 beats and 95±5.8 impulses/100 beats) were unchanged at 3 months but decreased (P <0.01 and P <0.001) after 6 months (75±4.0 bursts/100 beats and 80±4.4 impulses/100 beats). These were still greater (at least P <0.01) than values in normal subjects, patients with coronary artery disease, and hospitalized patients without AMI (51±3.9 bursts/100 beats, 58±4.7 impulses/100 beats ; 56±2.2 bursts/100 beats, 61±2.2 impulses/100 beats; and 55±3.6 bursts/100 beats, 61±3.3 impulses/100 beats, respectively). This sympathetic hyperactivity was inversely correlated to left ventricular ejection fraction but not to changes in blood pressure. Conclusions—A protracted state of sympathetic hyperactivity was shown to occur after uncomplicated AMI. It is suggested that this hyperactivity may explain delayed cardiovascular morbidity and mortality and that it arises because of an impairment of reflexes from cardiac receptors.

Sympathetic nerve discharge in normal pregnancy and pregnancy-induced hypertension.

Background Microneurographic assessment of processed bursts that represent multi-unit nerve discharge has suggested that sympathetic hyperactivity occurs in pregnancy induced hypertension and preeclampsia in comparison with normal pregnancy. Objective To examine the differences between peripheral sympathetic outputs in pregnancy-induced hypertension and normal pregnancy by directly measuring single impulses of neural discharge. Design We compared the sympathetic neural discharge at rest and its reflex responses in subjects with pregnancy-induced hypertension and normal pregnancy and re-examined their progress at least 6 weeks post partum. The patients with pregnancy-induced hypertension were hospital in-patients for whom the diagnosis could be strictly defined and the normally pregnant women were recruited to match the former. Methods Standard microneurography was performed to quantify single impulses of action potentials, together with the processed multi-unit bursts from fibres innervating the leg muscles. We measured neural discharge with vascular vasoconstrictive properties, heart rate and finger arterial blood pressure at rest and their responses to standard isometric hand-grip exercise and cold pressor tests. Results As expected, patients with pregnancy-induced hypertension (n = 13) had higher levels of finger arterial blood pressure than did women with normal pregnancies (n = 11). The number of single impulses of action potentials (per min and per 100 cardiac beats) in resting patients with pregnancy-induced hypertension was more than three times greater than that in resting women with normal pregnancies, and the number of multi-unit bursts was twofold greater. After delivery of their child, sympathetic activity and heart rate in nine patients decreased, but finger arterial blood pressure decreased in patients with pregnancy-induced hypertension only. Conclusions From results of cross-sectional and longitudinal studies, pregnancy-induced hypertension is associated with a greater resting sympathetic output than that of women with normal pregnancies. Follow-up data after parturition suggest that this hyperactivity is not the only cause of hypertension. J Hypertens 16:617–624

Gender-related differences in the sympathetic vasoconstrictor drive of normal subjects

The risk of cardiovascular disease has been linked to sympathetic activation and its incidence is known to be lower in women than in men. However, the effect of gender on the sympathetic vasoconstrictor drive has not yet been established. In the present study, we investigated whether there is a gender difference in MSNA (muscle sympathetic nerve activity) and blood flow, and to determine the mechanisms involved. We examined 68 normal subjects, 34 women and 34 men, matched for age, BMI (body mass index) and waist circumference. MSNA was measured as the mean frequency of single units (s-MSNA) and as multi-unit bursts (m-MSNA) from the peroneal nerve simultaneously with its supplied muscle CBF (calf blood flow). Women had lower (P=0.0007) s-MSNA (24+/-2.0 impulses/100 cardiac beats) than men (34+/-2.3 impulses/100 cardiac beats), and a greater baroreceptor reflex sensitivity controlling efferent sympathetic nerve activity than men. The sympathetic activity was inversely and directly correlated respectively, with CBF (P=0.03) and CVR (calf vascular resistance; P=0.01) in men only. The responses of an increase in CVR to cold pressor and isometric handgrip tests were significantly smaller in women (P=0.002) than in men, despite similar increases in efferent sympathetic nerve activity. Women had a lower central sympathetic neural output to the periphery, the mechanism of which involved differences in central and reflex control, as well as a lower vasoconstrictor response to this neural output. It is suggested that this may partly explain the observed lower incidence of cardiovascular events in women compared with men.

Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity

BACKGROUND Vagus nerve stimulation (VNS) is currently used to treat refractory epilepsy and is being investigated as a potential therapy for a range of conditions, including heart failure, tinnitus, obesity and Alzheimers disease. However, the invasive nature and expense limits the use of VNS in patient populations and hinders the exploration of the mechanisms involved. OBJECTIVE We investigated a non-invasive method of VNS through electrical stimulation of the auricular branch of the vagus nerve distributed to the skin of the ear--transcutaneous VNS (tVNS) and measured the autonomic effects. METHODS The effects of tVNS parameters on autonomic function in 48 healthy participants were investigated using heart rate variability (HRV) and microneurography. tVNS was performed using a transcutaneous electrical nerve stimulation (TENS) machine and modified surface electrodes. Participants visited the laboratory once and received either active (200 μs, 30 Hz; n = 34) or sham (n = 14) stimulation. RESULTS Active tVNS significantly increased HRV in healthy participants (P = 0.026) indicating a shift in cardiac autonomic function toward parasympathetic predominance. Microneurographic recordings revealed a significant decrease in frequency (P = 0.0001) and incidence (P = 0.0002) of muscle sympathetic nerve activity during tVNS. CONCLUSION tVNS can increase HRV and reduce sympathetic nerve outflow, which is desirable in conditions characterized by enhanced sympathetic nerve activity, such as heart failure. tVNS can therefore influence human physiology and provide a simple and inexpensive alternative to invasive VNS.