Long-term cerebral white and gray matter changes after preeclampsia.

OBJECTIVE: To determine whether changes in cerebral structure are present after preeclampsia that may explain increased cerebrovascular risk in these women. METHODS: We conducted a case control study in women between 5 and 15 years after either a preeclamptic or normotensive pregnancy. Brain MRI was performed. Analysis of white matter structure was undertaken using voxel-based segmentation of fluid-attenuation inversion recovery sequences to assess white matter lesion volume and diffusion tensor imaging to measure microstructural integrity. Voxel-based analysis of gray matter volumes was performed with adjustment for skull size. RESULTS: Thirty-four previously preeclamptic women (aged 42.8 ± 5.1 years) and 49 controls were included. Previously preeclamptic women had reduced cortical gray matter volume (523.2 ± 30.1 vs 544.4 ± 44.7 mL, p < 0.05) and, although both groups displayed white matter lesions, changes were more extensive in previously preeclamptic women. They displayed increased temporal lobe white matter disease (lesion volume: 23.2 ± 24.9 vs 10.9 ± 15.0 µL, p < 0.05) and altered microstructural integrity (radial diffusivity: 538 ± 19 vs 526 ± 18 × 10-6 mm2/s, p < 0.01), which also extended to occipital and parietal lobes. The degree of temporal lobe white matter change in previously preeclamptic women was independent of their current cardiovascular risk profile (p < 0.05) and increased with time from index pregnancy (p < 0.05). CONCLUSION: A history of preeclampsia is associated with temporal lobe white matter changes and reduced cortical volume in young women, which is out of proportion to their classic cardiovascular risk profile. The severity of changes is proportional to time since pregnancy, which would be consistent with continued accumulation of damage after pregnancy.

Stress-induced cardiomyopathy in Sweden: evidence for different ethnic predisposition and altered cardio-circulatory status.

BACKGROUND: In this paper, we report about new insights regarding clinical course, long-term outcome, ethnic/genetic predisposition and cardio-circulatory status in the large stress-induced cardiomyopathy (SIC) cohort from Sweden. METHODS AND RESULTS: We have included 115 consecutive SIC patients between January 2005 and January 2010 at Sahlgrenska University Hospital in Gothenburg. Hemodynamic status and sympathetic nerve activity were evaluated and compared with those of healthy controls. Mean age was 64, and 14% were males. Thirty-day and 3-year mortality was 6 and 10%, respectively. Eleven percent had ischemic heart disease, 3% developed thromboembolic complications, 6% had cardiac arrest and 14% developed cardiogenic shock. The great majority of SIC patients (93%) were ethnic Swedes. In three families, several close relatives developed SIC. Fourteen percent developed two or more episodes of SIC. Hemodynamic evaluation has shown subnormal systemic vascular resistance, 22% lower sympathetic activity and preserved cardiac output in SIC patients. CONCLUSIONS: SIC affects both men and women of different ages and is associated with significant short- and long-term mortality. There is a strong signal for the presence of ethnic/genetic predisposition to develop SIC. Sympathetic activity and systemic vascular resistance are lower in SIC patients, suggesting that SIC is a cardio-circulatory phenomenon.

Sympathetic nerve activity in women 40 years after a hypertensive pregnancy.

OBJECTIVES: Epidemiological studies show that women with pregnancies complicated by hypertension have an increased risk of cardiovascular morbidity later in life. The underlying mechanisms to the risk increase remain largely unknown. This study evaluated sympathetic nerve activity in women with hypertensive pregnancies 40 years earlier compared to women with normotensive pregnancies. We hypothesized that sympathetic outflow would be increased in women with previous hypertensive pregnancies and that this partly may explain the increased cardiovascular risk. METHODS: Sympathetic nerve activity to the muscle vascular bed [muscle sympathetic nerve activity (MSNA)] was recorded in 28 women, 18 with and 10 without a hypertensive manifestation during pregnancy. Women were also examined with ambulatory blood pressure measurements, pulse wave velocity, blood pressure response during Stroop test and laboratory analysis. RESULTS: Women with previous hypertensive pregnancies did not show an increased sympathetic outflow compared to women with normotensive pregnancies. In eight women with treated hypertension sympathetic outflow was increased compared to normotensive women despite similar ambulatory blood pressure values (P < 0.05). During Stroop test the hypertensive women showed increased systolic blood pressure and also displayed the highest augmentation index compared to normotensive women (P < 0.05). CONCLUSION: Hypertensive pregnancies per se were not associated with increased sympathetic outflow 40 years later. The increased cardiovascular risk in women with previous hypertensive pregnancies cannot be explained by chronic activation of the sympathetic nervous system.In women with previous hypertensive pregnancies, still hypertensive though well controlled, sympathetic outflow and arterial stiffness were, however, increased compared to normotensive counterparts.

Sympathetic nerve activity in stress-induced cardiomyopathy.

PURPOSE: To evaluate directly recorded efferent sympathetic nerve traffic in patients with stress-induced cardiomyopathy (SIC). BACKGROUND: SIC is a syndrome affecting mostly postmenopausal women following severe emotional stress. Though the precise pathophysiology is not well understood, a catecholamine overstimulation of the myocardium is thought to underlie the pathogenesis. METHODS: Direct recordings of multiunit efferent postganglionic muscle sympathetic nerve activity (MSNA) were obtained from 12 female patients, 5 in the acute (24-48 h) and 7 in the recovery phase (1-6 months), with apical ballooning pattern and 12 healthy matched controls. MSNA was expressed as burst frequency (BF), burst incidence (BI) and relative median burst amplitude (RMBA %). One of the twelve patients in this study was on beta blockade treatment due to a different illness, at time of onset of SIC. All patients were investigated with ongoing medication. RESULTS: MSNA was lower in patients with SIC as compared to matched controls, but did not differ between the acute and recovery phase of SIC. RMBA %, blood pressure and heart rate did not differ between the groups. CONCLUSION: MSNA is shown to be lower in patients with SIC compared to healthy controls, suggesting that sympathetic neuronal outflow is rapidly reduced following the initial phase of SIC. A distension of the ventricular myocardium, due to excessive catecholamine release over the heart in the acute phase, may increase the firing rate of unmyelinated cardiac c-fibre afferents resulting in widespread sympathetic inhibition. Such a mechanism may underlie the lower MSNA reported in our patients.

Sex steroids, insulin sensitivity and sympathetic nerve activity in relation to affective symptoms in women with polycystic ovary syndrome.

CONTEXT: Affective symptoms are poorly understood in polycystic ovary syndrome (PCOS). Clinical signs of hyperandrogenism and high serum androgens are key features in PCOS, and women with PCOS are more likely to be overweight or obese, as well as insulin resistant. Further, PCOS is associated with high sympathetic nerve activity. OBJECTIVE: To elucidate if self-reported hirsutism, body mass index (BMI) and waistline, circulating sex steroids, sex hormone-binding globulin (SHBG), insulin sensitivity and sympathetic nerve activity are associated with depression and anxiety-related symptoms in women with PCOS. DESIGN AND METHODS: Seventy-two women with PCOS, aged 21-37 years, were recruited from the community. Hirsutism was self-reported using the Ferriman-Gallway score. Serum estrogens, sex steroid precursors, androgens and glucuronidated androgen metabolites were analyzed by gas and liquid chromatography/mass spectroscopy (GC-MS/LC-MS/MS) and SHBG by chemiluminiscent microparticle immunoassay (CMIA). Insulin sensitivity was measured with euglycemic hyperinsulinemic clamp. Sympathetic nerve activity was measured with microneurography. Symptoms of depression and anxiety were self-reported using the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Brief Scale for Anxiety (BSA-S). RESULTS: Circulating concentrations of testosterone (T) (P=0.026), free T (FT) (P=0.025), and androstane-3α 17ß-diol-3glucuronide (3G) (P=0.029) were lower in women with depression symptoms of potential clinical relevance (MADR-S≥11). The odds of having a MADRS-S score ≥11 were higher with lower FT and 3G. No associations with BSA-S were noted. CONCLUSION: Lower circulating FT and 3G were associated with worse self-reported depression symptoms. The relationship between mental health, sex steroids and corresponding metabolites in PCOS requires further investigation.

Muscle sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy individuals.

BACKGROUND: Evidence from animal studies indicates the importance of an interaction between the sympathetic nervous system and the endothelium for cardiovascular regulation. However the interaction between these two systems remains largely unexplored in humans. The aim of this study was to investigate whether directly recorded sympathetic vasoconstrictor outflow is related to a surrogate marker of endothelial function in healthy individuals. METHODS AND RESULTS: In 10 healthy normotensive subjects (3 f/7 m), (age 37+/-11 yrs), (BMI 24+/-3 kg/m(2)) direct recordings of sympathetic action potentials to the muscle vascular bed (MSNA) were performed and endothelial function estimated with the Reactive Hyperaemia- Peripheral Arterial Tonometry (RH-PAT) technique. Blood samples were taken and time spent on leisure-time physical activities was estimated. In all subjects the rate between resting flow and the maximum flow, the Reactive Hyperemic index (RH-PAT index), was within the normal range (1.9-3.3) and MSNA was as expected for age and gender (13-44 burst/minute). RH-PAT index was inversely related to MSNA (r = -0.8, p = 0.005). RH-PAT index and MSNA were reciprocally related to time (h/week) spent on physical activity (p = 0.005 and p = 0.006 respectively) and platelet concentration (PLT) (p = 0.02 and p = 0.004 respectively). CONCLUSIONS: Our results show that sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy normotensive individuals, indicating that sympathetic outflow may be modulated by changes in endothelial function. In this study time spent on physical activity is identified as a predictor of sympathetic nerve activity and endothelial function in a group of healthy individuals. The results are of importance in understanding mechanisms underlying sympathetic activation in conditions associated with endothelial dysfunction and emphasise the importance of a daily exercise routine for maintenance of cardiovascular health.

Low-frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome.

We have recently shown that polycystic ovary syndrome (PCOS) is associated with high muscle sympathetic nerve activity (MSNA). Animal studies support the concept that low-frequency electroacupuncture (EA) and physical exercise, via stimulation of ergoreceptors and somatic afferents in the muscles, may modulate the activity of the sympathetic nervous system. The aim of the present study was to investigate the effect of these interventions on sympathetic nerve activity in women with PCOS. In a randomized controlled trial, 20 women with PCOS were randomly allocated to one of three groups: low-frequency EA (n = 9), physical exercise (n = 5), or untreated control (n = 6) during 16 wk. Direct recordings of multiunit efferent postganglionic MSNA in a muscle fascicle of the peroneal nerve before and following 16 wk of treatment. Biometric, hemodynamic, endocrine, and metabolic parameters were measured. Low-frequency EA (P = 0.036) and physical exercise (P = 0.030) decreased MSNA burst frequency compared with the untreated control group. The low-frequency EA group reduced sagittal diameter (P = 0.001), while the physical exercise group reduced body weight (P = 0.004) and body mass index (P = 0.004) compared with the untreated control group. Sagittal diameter was related to MSNA burst frequency (Rs = 0.58, P < 0.005) in the EA group. No correlation was found for body mass index and MSNA in the exercise group. There were no differences between the groups in hemodynamic, endocrine, and metabolic variables. For the first time we demonstrate that low-frequency EA and physical exercise lowers high sympathetic nerve activity in women with PCOS. Thus, treatment with low-frequency EA or physical exercise with the aim to reduce MSNA may be of importance for women with PCOS.

Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth?

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disturbance among women of reproductive age and is proposed to be linked with size at birth and increased prevalence of cardiovascular disease. A disturbance in the sympathetic nervous system may contribute to the etiology of PCOS. This study evaluates sympathetic outflow in PCOS and its relation to size at birth. Directly recorded sympathetic nerve activity to the muscle vascular bed (MSNA) was obtained in 20 women with PCOS and in 18 matched controls. Ovarian ultrasonographic evaluation, biometric, hormonal, and biochemical parameters were measured, and birth data were collected. Women with PCOS had increased MSNA (30 +/- 8 vs. 20 +/- 7 burst frequency, P < 0.0005) compared with controls. MSNA was positively related to testosterone (r = 0.63, P < 0.005) and cholesterol (r = 0.55, P = 0.01) levels in PCOS, which, in turn, were not related to each other. Testosterone level was a stronger predictor of MSNA than cholesterol. Birth size did not differ between the study groups. This is the first study to directly address sympathetic nerve activity in women with PCOS and shows that PCOS is associated with high MSNA. Testosterone and cholesterol levels are identified as independent predictors of MSNA in PCOS, although testosterone has a stronger impact. The increased MSNA in PCOS may contribute to the increased cardiovascular risk and etiology of the condition. In this study, PCOS was not related to size at birth.

Epidermal growth factor levels are related to diastolic blood pressure and carotid artery stiffness.

OBJECTIVES: The epidermal growth factor (EGF) is believed to be involved in vascular remodelling. EGF receptors are expressed in human atherosclerotic tissue. DESIGN: In order to study the role of EGF in vascular remodelling and early progression of atherosclerosis, 17 men and 16 women aged 20 to 45 years were recruited. Common Carotid Artery Stiffness index (CCA SI) and blood pressure were evaluated. In addition, serum levels of EGF and blood lipids were measured. RESULTS: The levels of serum EGF were significantly correlated to diastolic blood pressure (p<0.05) and CCA SI (p<0.05). Subjects with EGF concentrations in the upper median had significantly lower levels of HDL (High Density Lipoproteins) (p<0.05) and ApoA1 (Apolipoprotein) (p<0.05) than those with EGF concentrations in the lower median. DISCUSSION: High serum level of EGF is associated with elevated diastolic blood pressure and increased vessel stiffness suggesting a possible functional role of EGF in the cardiovascular system in a healthy population.

Low birth size and final height predict high sympathetic nerve activity in adulthood.

OBJECTIVE: Being born small for gestational age (SGA) is associated with insulin resistance, hypertension and increased cardiovascular morbidity/mortality in adulthood. Sympathetic nerve hyperactivity is a well-known risk factor for cardiovascular disease mortality and is proposed to link insulin resistance with hypertension. The objective of this study was to test the hypothesis that sympathetic nerve activity is altered in individuals born SGA. DESIGN: A cross-sectional, comparative study of 20 healthy adults (21-25 years old) born SGA (birth weight < -2SD score for healthy newborns) with normal and short stature, and 12 age, gender and body mass index matched individuals, born appropriate for gestational age (AGA) with normal stature. METHODS: Direct recordings of resting sympathetic nerve activity to the muscle vascular bed (MSA) were obtained from the peroneal nerve posterior to the fibular head. Heart rate, respiration and blood pressure were recorded during the microneurographic session. RESULTS: MSA was increased in both groups of young adults born SGA as compared to those born AGA (P < 0.05 and P < 0.005, respectively). In the combined study group MSA was inversely correlated to birth weight, length (r = -0.59, P < 0.001 and r = -0.69, P < 0.0005, respectively) and final adult height (r = -0.58; P < 0.001). CONCLUSIONS: Being born SGA and achieving a short final height is associated with increased sympathetic nerve traffic. We suggest that the increase in sympathetic nerve traffic in young adults born SGA with normal and short stature may be the link between low birth size, hypertension and cardiovascular morbidity later in life.

The effect of growth hormone (GH) replacement therapy on sympathetic nerve hyperactivity in hypopituitary adults: a double-blind, placebo-controlled, crossover, short-term trial followed by long-term open GH replacement in hypopituitary adults.

OBJECTIVE: To test whether sympathetic nerve hyperactivity associated with adult hypopituitarism and untreated growth hormone (GH) deficiency is affected by GH treatment. DESIGN AND METHODS: Sympathetic nerve activity to the muscle vascular bed (MSA) expressed as burst frequency (bursts/min) and incidence (bursts/100 heartbeats) was recorded in 10 hypopituitary patients (aged 48-69 years), before and after acute (1 week) randomized, double-blind, crossover treatment with a 1-month washout period and chronic (1 year) GH replacement treatment. RESULTS: MSA burst frequency and incidence remained unchanged from baseline values after the short-term treatment, but exhibited decreases in median values [from 53 to 47 bursts/min (P = 0.02) and from 85 to 70 bursts/100 heartbeats (P = 0.03), respectively] after 12 months of replacement therapy. Twenty-four-hour urinary excretion of nitrate increased after the short-term cross-over treatment and the long-term treatment (P = 0.04). Diastolic blood pressure and waist circumference decreased after the 12-month treatment (P = 0.02 and P = 0.04, respectively). No correlation was found between the reduction in MSA and the increase in 24-h urinary nitrate excretion, the decrease in diastolic blood pressure and waist circumference. CONCLUSIONS: The sympathoexcitation in adult GH deficiency and the modest decline in MSA seen after long-term GH replacement treatment may suggest that the somatotropic axis is involved in the regulation of central sympathetic outflow.

GH increases extracellular volume by stimulating sodium reabsorption in the distal nephron and preventing pressure natriuresis.

Although sodium retention and volume expansion occur during GH administration, blood pressure is decreased or unchanged. The aim was to study the effect of short- and long-term GH replacement in adults on sodium balance, renal hemodynamics, and blood pressure. Ten adults with severe GH deficiency were included into a 7-d, randomized, placebo-controlled, cross-over trial followed by 12 months of open GH replacement. All measurements were performed under metabolic ward conditions. Extracellular water (ECW) was determined using multifrequency bioelectrical impedance analysis. Renal plasma flow and glomerular filtration rate were assessed using renal paraminohippurate and Cr(51) EDTA clearances, respectively. Renal tubular sodium reabsorption was assessed using lithium clearance. Plasma renin activity (PRA), plasma concentrations of angiotensin II, aldosterone, atrial natriuretic peptides and brain natriuretic peptides (BNP) and 24-h urinary norepinephrine excretion were measured. Seven days of GH treatment decreased urinary sodium excretion. Lithium clearance as a marker of proximal renal tubular sodium reabsorption was unaffected by GH treatment. ECW was increased after both short- and long-term treatment. This increase was inversely correlated to the decrease in diastolic blood pressure (r = -0.70, P = 0.02) between baseline and 12 months. Short-term treatment increased PRA and decreased BNP. The increase in PRA correlated with an increase in 24-h urinary norepinephrine excretion (r = 0.77, P < 0.01). Glomerular filtration rate and renal plasma flow did not change during treatment. The sodium- and water-retaining effect of GH takes place in the distal nephron. The sustained increase in ECW in response to GH is associated with an unchanged or decreased blood pressure. This together with unchanged or decreased atrial natriuretic peptides and BNP may prevent pressure-induced escape of sodium.