Nancy R Keller

Vanderbilt University, Nashville, Michigan, United States

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Publications (17)66.03 Total impact

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    ABSTRACT: PURPOSE: Vasovagal syncope (VVS) is a chronic debilitating condition seen mostly in young women of reproductive age. There are anecdotal reports of increased syncope and presyncope around menstruation. This case-control study assessed the effects of the menstrual cycle on lightheadedness episodes and compared the gynecological and pregnancy history of VVS patients to healthy subjects. METHODS: A custom-designed gynecological and menstrual cycle questionnaire was previously developed for patients with orthostatic intolerance. This questionnaire was administered to female patients with VVS (n = 128) as a part of the multicenter Second Prevention of Syncope Trial, and to gender-matched healthy subjects (n = 92). RESULTS: VVS patients and healthy subjects reported significant variability in self-reported lightheadedness throughout the menstrual cycle. Both cohorts experienced greatest lightheadedness during menses (53 ± 2 vs. 56 ± 4), which decreased during the follicular phase (44 ± 2 vs. 41 ± 4). VVS patients reported less severity in premenstrual symptoms (Fisher's method P = 2.7E-06) compared to healthy controls. There is no difference in the incidence of gynecological abnormalities (Fisher's exact P = 0.193) and pregnancy complications (P = 1.0) between the two cohorts. VVS patients have similar pregnancy rates compared to healthy subjects (P = 0.674). CONCLUSION: The severity of lightheadedness varies during the menstrual cycle and is similar in both VVS patients and healthy controls. VVS patients have no greater risk of gynecological abnormalities and pregnancy complications than healthy subjects.
    Clinical Autonomic Research 03/2013; · 1.48 Impact Factor
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    ABSTRACT: To assess differences in gynecologic history and lightheadedness during menstrual cycle phases among patients with POTS and healthy control women. In a prospective, questionnaire-based study carried out at Paden Autonomic Dysfunction Center, Vanderbilt University, between April 2005 and January 2009, a custom-designed questionnaire was administered to patients with POTS (n=65) and healthy individuals (n=95). The results were analyzed via Fisher exact test and Mann-Whitney U test. Patients with POTS reported increased lightheadedness through all phases of the menstrual cycle phases as compared with healthy controls. Both groups experienced the greatest lightheadedness during menses, and a decrease in lightheadedness during the follicular phase. Patients with POTS reported a higher incidence of gynecologic diseases as compared with healthy controls. The severity of lightheadedness was found to vary during the menstrual cycle, which may relate to changes in estrogen levels. Patients with POTS also reported an increase in estrogen-related gynecologic disease.
    International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 06/2012; 118(3):242-6. · 1.41 Impact Factor
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    ABSTRACT: Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT(-/-)) mice exhibit early postnatal lethality, CHT heterozygous (CHT(+/-)) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT(+/-) mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT(+/-) mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT(+/-) mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease.
    AJP Heart and Circulatory Physiology 09/2010; 299(3):H799-810. · 4.01 Impact Factor
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    ABSTRACT: Human subjects with impaired baroreflex function cannot buffer rises or falls in blood pressure (BP), thus allowing BP effects of endogenous or environmental stimuli that previously escaped detection to emerge dramatically. Studies in these patients led us to discover that water ingestion induced a robust increase in BP and vascular resistance. Here, using a mouse model of baroreflex impairment, we show that the increase in blood pressure after water ingestion is mediated through sympathetic nervous system activation and that the osmosensitive transient receptor potential vanilloid 4 channel (Trpv4) is an essential component of the response. Although portal osmolality decreases after water ingestion in both wild-type and Trpv4(-/-) mice, only the wild-type animals show a pressor response. The same volume of physiological saline does not elicit an increase in BP, suggesting osmolality as the stimulus. The osmopressor response to water, and Trpv4 thus represent new factors now implicated in the physiology of BP regulation.
    Hypertension 04/2010; 55(6):1438-43. · 6.87 Impact Factor
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    ABSTRACT: Abnormal autonomic nerve traffic has been associated with a number of peripheral neuropathies and cardiovascular disorders prompting the development of genetically altered mice to study the genetic and molecular components of these diseases. Autonomic function in mice can be assessed by directly recording sympathetic nerve activity. However, murine sympathetic spikes are typically detected using a manually adjusted voltage threshold and no unsupervised detection methods have been developed for the mouse. Therefore, we tested the performance of several unsupervised spike detection algorithms on simulated murine renal sympathetic nerve recordings, including an automated amplitude discriminator and wavelet-based detection methods which used both the discrete wavelet transform (DWT) and the stationary wavelet transform (SWT) and several wavelet threshold rules. The parameters of the wavelet methods were optimized by comparing basal sympathetic activity to postmortem recordings and recordings made during pharmacological suppression and enhancement of sympathetic activity. In general, SWT methods were found to outperform amplitude discriminators and DWT methods with similar wavelet coefficient thresholding algorithms when presented with simulations with varied mean spike rates and signal-to-noise ratios. A SWT method which estimates the noise level using a "noise-only" wavelet scale and then selectively thresholds scales containing the physiologically important signal information was found to have the most robust spike detection. The proposed noise-level estimation method was also successfully validated during pharmacological interventions.
    IEEE Transactions on Biomedical Engineering 02/2007; 54(1):82-93. · 2.35 Impact Factor
  • Annals of the New York Academy of Sciences 12/2006; 828(1):137 - 145. · 4.38 Impact Factor
  • Nancy R Keller, David Robertson
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    ABSTRACT: Postural tachycardia syndrome is an autonomic disorder primarily of younger women. The patient population is heterogeneous, making diagnosis and treatment a challenge. A mutation in the norepinephrine (noradrenaline) transporter gene prompted further genetic analysis. Eleven new mutations were found in the human norepinephrine transporter gene, although none were directly associated with postural tachycardia syndrome. The 5'-flanking -1012C --> T variant of the dopamine beta-hydroxylase gene was slightly increased and protection was associated with a reduced incidence of two mutations in the endothelial nitric oxide synthase gene, and one in endothelin-1. Mutations in other disease-related genes suggest a potential relationship with the pathogenesis of postural tachycardia syndrome. Benign joint hypermobility syndrome, for example, shares similar autonomic symptoms and is linked to a mutation in tenascin-X. Additional genetic findings are discussed as potential contributors to vascular health and neurodegeneration. Genetic testing can reveal molecular mechanisms of disease and provide an additional strategy for diagnosis and treatment of heterogeneous patient populations such as postural tachycardia syndrome. It is quite likely that the pathogenesis of this disorder will be attributed to numerous genetic mutations, both subtle and overt. Therefore, continued study of the relationships between genotype and phenotype are necessary to better understand this syndrome and others with associated dysautonomia.
    Current Opinion in Cardiology 06/2006; 21(3):173-9. · 2.56 Impact Factor
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    ABSTRACT: The study of anxiety and fear involves complex interrelationships between psychiatry and the autonomic nervous system. Altered noradrenergic signaling is linked to certain types of depression and anxiety disorders, and treatment often includes specific transporter blockade. The norepinephrine transporter is crucial in limiting catecholaminergic signaling. Norepinephrine transporter-deficient mice have increased circulating catecholamines and elevated heart rate and blood pressure. We hypothesized, therefore, that reduced norepinephrine clearance would heighten the autonomic cardiovascular response to anxiety and fear. In separate experiments, norepinephrine transporter-deficient (norepinephrine transporter-/-) mice underwent tactile startle and trace fear conditioning to measure hemodynamic responses. A dramatic tachycardia was observed in norepinephrine transporter-/- mice compared with controls following both airpuff or footshock stimuli, and pressure changes were also greater. Interestingly, in contrast to normally elevated home cage levels in norepinephrine transporter-deficient mice, prestimulus heart rate and blood pressure were actually higher in norepinephrine transporter+/+ animals throughout behavioral testing. Upon placement in the behavioral chamber, norepinephrine transporter-deficient mice demonstrated a notable bradycardia and depressor effect that was more pronounced in females. Power spectral analysis indicated an increase in low frequency oscillations of heart rate variability; in mice, suggesting increased parasympathetic tone. Finally, norepinephrine transporter-/- mice exhibited sexual dimorphism in freeze behavior, which was greatest in females. Therefore, while reduced catecholamine clearance amplifies immediate cardiovascular responses to anxiety- or fear-inducing stimuli in norepinephrine transporter-/- mice, norepinephrine transporter deficiency apparently prevents protracted hemodynamic escalation in a fearful environment. Conceivably, chronic norepinephrine transporter blockade with transporter-specific drugs might attenuate recognition of autonomic and somatic distress signals in individuals with anxiety disorders, possibly lessening their behavioral reactivity, and reducing the cardiovascular risk factors associated with persistent emotional arousal.
    Neuroscience 02/2006; 139(3):931-46. · 3.12 Impact Factor
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    ABSTRACT: The human endometrium exhibits regular cycles of growth, differentiation, and breakdown in response to changing levels of ovarian steroids. Following the tissue loss and repair processes of menstruation, rising levels of estradiol initiate a development-like process leading to a complete restructuring of the endometrial surface. In contrast, while under the predominate influence of progesterone, proliferation declines as cell-specific differentiation prepares the endometrium for pregnancy over a 5- to 6-day period. In the absence of nidation, steroid support is lost; the endometrial surface begins a complex process of tissue breakdown and bleeding, producing a viscous mixture of cellular debris within a bloody menstrual effluent. Although most of the menstrual fluid exits the body, reflux of some material occurs in most women, providing a poorly understood opportunity for ectopic endometrial growth and establishment of the disease endometriosis. The cyclic restructuring of the endometrium requires numerous matrix metalloproteinases (MMPs) that mediate normal and pathological tissue turnover throughout the reproductive tract. The expression of multiple MMPs facilitates degradation of extracellular matrix during growth-related remodeling as well as tissue breakdown at the time of menstruation. However, these enzymes are absent during the early and midsecretory phase and the suppression of endometrial MMPs remains important to maintaining the integrity of the endometrium during the highly invasive events required to establish a normal hemochorial placenta. Several research groups have suggested that steroid-mediated expression and action of MMPs during the menstrual cycle may provide a key mechanistic link between endometrial turnover and the invasive processes necessary for establishment of endometriosis.
    Annals of the New York Academy of Sciences 01/2006; 955(1):37 - 47. · 4.38 Impact Factor
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    ABSTRACT: Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the norepinephrine transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance. We telemetrically monitored NET-deficient (NET(-/-)) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET(-/-) mice compared with NET(+/+) controls (103+/-0.6 versus 99+/-0.4 mm Hg; P<0.01), and corresponding pressures increased to 122+/-0.3 and 116+/-0.3 mm Hg (P<0.0001) with activity. Heart rate was also greater in resting NET(-/-) mice (565+/-5 versus 551+/-3 bpm; P<0.05), and genotypic differences were highly significant during the active phase (640+/-5 versus 607+/-3 bpm; P<0.0001). Conversely, the respiratory rate of resting NET(-/-) mice was dramatically reduced, whereas increases after the day/night shift surpassed those of controls. Plasma catecholamines in NET(-/-) and NET(+/+) mice were as follows: NE, 69+/-8 and 32+/-7; dihydroxyphenylglycol, 2+0.4 and 17+/-3; epinephrine, 15+/-3 and 4+/-0.6; and dopamine, 13+/-4 and 4+/-1 pmol/mL. Catechols in urine, brain, and heart also were determined. Resting mean arterial pressure and heart rate are maintained at nearly normal levels in NET-deficient mice, most likely as a result of increased central sympathoinhibition. However, sympathetic activation with wakefulness and activity apparently overwhelms central modulation, amplifying peripheral catecholaminergic signaling, particularly in the heart.
    Circulation 10/2004; 110(10):1191-6. · 15.20 Impact Factor
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    ABSTRACT: Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.
    Annals of the New York Academy of Sciences 11/2002; 971:506-14. · 4.38 Impact Factor
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    ABSTRACT: The human endometrium exhibits regular cycles of growth, differentiation, and breakdown in response to changing levels of ovarian steroids. Following the tissue loss and repair processes of menstruation, rising levels of estradiol initiate a development-like process leading to a complete restructuring of the endometrial surface. In contrast, while under the predominate influence of progesterone, proliferation declines as cell-specific differentiation prepares the endometrium for pregnancy over a 5- to 6-day period. In the absence of nidation, steroid support is lost; the endometrial surface begins a complex process of tissue breakdown and bleeding, producing a viscous mixture of cellular debris within a bloody menstrual effluent. Although most of the menstrual fluid exits the body, reflux of some material occurs in most women, providing a poorly understood opportunity for ectopic endometrial growth and establishment of the disease endometriosis. The cyclic restructuring of the endometrium requires numerous matrix metalloproteinases (MMPs) that mediate normal and pathological tissue turnover throughout the reproductive tract. The expression of multiple MMPs facilitates degradation of extracellular matrix during growth-related remodeling as well as tissue breakdown at the time of menstruation. However, these enzymes are absent during the early and mid-secretory phase and the suppression of endometrial MMPs remains important to maintaining the integrity of the endometrium during the highly invasive events required to establish a normal hemochorial placenta. Several research groups have suggested that steroid-mediated expression and action of MMPs during the menstrual cycle may provide a key mechanistic link between endometrial turnover and the invasive processes necessary for establishment of endometriosis.
    Annals of the New York Academy of Sciences 04/2002; 955:37-47; discussion 86-8, 396-406. · 4.38 Impact Factor
  • Fertility and Sterility - FERT STERIL. 01/2002; 78.
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    ABSTRACT: Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to maintain tissue stability during the invasive events of implantation and placental development. Several laboratories have shown that inflammatory cytokines, including interleukin-lalpha (IL-1alpha), can oppose progesterone suppression of MMPs in the human endometrium. Furthermore, we have recently demonstrated colocalization of epithelial cell IL-1alpha and MMP-7 expression at sites of ectopic pregnancy. The current study extends these findings, revealing a previously unrecognized interrelationship between progesterone and IL-1alpha in regulation of MMP-3. Although IL-1alpha is a potent stimulator of MMP-3 in proliferative phase endometrium in organ culture, we demonstrate that progesterone exposure in vivo reduces IL-1alpha stimulation of MMP-3 in secretory phase tissue. This loss of sensitivity to IL-1alpha was duplicated in isolated stromal cells treated with progesterone in vitro, and IL-1alpha stimulation of MMP-3 returned in a dose-dependent manner with progesterone withdrawal. The antiprogestin, onapristone, partially blocked the ability of progesterone to prevent stimulation of MMP-3 by IL-1alpha. These data suggest a novel mechanism by which progesterone may preserve tissue integrity during the establishment and maintenance of pregnancy by limiting stimulation of MMPs by inflammatory cytokines such as IL-1a.
    Journal of Clinical Endocrinology &amp Metabolism 05/2000; 85(4):1611-9. · 6.43 Impact Factor
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    ABSTRACT: Endometrial expression of matrix metalloproteinase (MMP)-3, MMP-7 and MMP-11 occurs during menstrual breakdown and subsequent estrogen-mediated growth, but not during the secretory phase. These enzymes are suppressed by progesterone treatment. Paracrine factors, including transforming growth factor-beta (TGF-beta) and retinoic acid, are also critical for MMP regulation in the endometrium. In contrast, inflammatory cytokines such as interleukin-1alpha may block or interfere with steroid-mediated MMP regulation at ectopic sites of growth. Using in vitro models, our laboratory has investigated the complex interactions between progesterone and locally produced cytokines that may affect MMP expression during the development of endometriosis. Our results indicate that targeting the regulation of MMPs may represent an appropriate therapeutic strategy for the treatment of endometriosis. Copyrightz1999S. KargerAG,Basel
    Gynecologic and Obstetric Investigation 02/1999; 48 Suppl 1:2-13. · 1.10 Impact Factor
  • Journal of The Society for Gynecologic Investigation - J SOC GYNECOL INVESTIGATION. 01/1998; 5(1).
  • Annals of the New York Academy of Sciences 10/1997; 828:137-45. · 4.38 Impact Factor