Menopause transition is a natural process in a woman’s life associated with altered body fat distribution, increased cardiometabolic risk, and the presentation of vasomotor symptoms including hot flashes and night sweats. A 5-year observational, longitudinal study (MONET: Montreal Ottawa New Emerging Team), was performed to document the effect of menopause transition on body composition and cardiometabolic risk factors. Initially, the study included 102 healthy non-obese premenopausal women between the age of 47 and 55 years. By the end of year 5, 91 women completed the study, 4% were still premenopausal, 29% were perimenopausal and 67% became postmenopausal. The major finding of the first study was that the increases in body fat mass and visceral fat in our cohort of non-obese women followed through the menopause transition were independent of the increase in body weight. Furthermore, these changes in body composition and body fat distribution were not associated with cardiometabolic deteriorations. We further examined whether specific factors such as reporting vasomotor symptoms (hot flashes and/or night sweats), exaggerated exercise systolic blood pressure, physical activity levels and cardiorespiratory fitness, may be associated with adiposity, body fat distribution and cardiometabolic profile. Overall, women that experienced vasomotor symptoms (paper 2) or presented an exaggerated exercise systolic blood pressure (paper 3), did not present any alterations in their body composition, body fat distribution and cardiometabolic profile compared to asymptomatic women and participants with normal blood pressure response to exercise, respectively. Furthermore, exaggerated exercise systolic blood pressure was not predictive of future hypertension after a 5-year follow-up throughout menopause transition. On the other hand, total volume of physical activity was not linked with measures of a cardiometabolic profile, cardiorespiratory fitness appeared to have the greatest cardioprotective effect (paper 4). Therefore, in generally healthy physically active non-obese premenopausal women, the menopause transition does not generally alter cardiometabolic risk factors, and suggests that cardiorespiratory fitness may have greater cardiometabolic protective effects in this cohort.

Background: In the United States, one-third of adults have hypertension (HTN). Among African American (AA) adults, 43% of men and 45.7% of women have HTN. HTN in the AA adult population is more severe and occurs earlier in life compared to Caucasian adults, putting them at increased risk for cardiovascular events and renal disease. The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) Guideline Recommendations 7 and 8 were developed to aid in appropriate treatment and management of hypertensive AA adults. Purpose: The purpose of this Doctor of Nursing Practice (DNP) project was to improve the care, management, and outcomes of hypertensive AA adults by identifying current JNC 8 guideline prescribing patterns among a sample of hospitalized patients. The first project aim was to determine provider-prescribing rates of thiazide diuretics (TDs) and calcium channel blockers (CCBs) in newly diagnosed AA adults with HTN. The second project aim was to determine if AA adults previously diagnosed with HTN were currently prescribed TD and/or CCB medications. Methods: A retrospective medical record review of AA adult patients with a new HTN diagnosis or previously diagnosed with HTN was selected for this project. Participants were discharged from Medical City Dallas between 01/01/2017 and 03/31/2017. Results: In newly diagnosed participants with HTN, none were prescribed a TD (0%) and two were prescribed a CCB (40%). In previously diagnosed participants with HTN, 30 participants (16.3%) were prescribed a TD and/or CCB upon admission and 29 participants (15.76%) were prescribed a TD and/or CCB upon discharge. Among prescribing providers, beta blockers and other class hypertensive medications (i.e., furosemide, hydralazine, clonidine, and spironolactone) were most widely ordered for participants. Conclusions: The results of this DNP project display low provider compliance rates to guideline-recommended pharmacological therapy AA adults. This outcome highlights several potential reasons for the low adherence rates, including lack of provider documentation, lack of provider rationale for treatment selections, provider knowledge of HTN CPGs, and data analysis of prescribed medications. These factors present the opportunity for further research to identify the root cause of low compliance.

Abstract This thesis describes the development of pressure sensor arrays and a range of methods suitable for the long-term measurement of heart rate and blood pressure determination using a cuff and a pressure sensor array on the radial artery. This study also reviews the historical background of noninvasive blood pressure measurement methods, summarizes the accuracies achieved and explains the requirements for common national and international standards of accuracy. Two prototype series of pressure transducer arrays based on electro-mechanical film (EMFi) were designed and tested. By offering high (∼TΩ) resistance, EMFi is an excellent material for low-current long-term measurement applications. About 50 transducer arrays were built using different configurations and electrode materials to sense low-frequency pressure pulsations on the radial artery in the wrist. In addition to uniform quality, essential requirements included an adequate linear response in the desired temperature range. Transducer sensitivity was tested as a function of temperature in the range of 25–45 °C at varying static and alternating pressures. The average sensitivity of the EMFi used in the transducers proved adequate (∼2.2 mV/mmHg and ∼7 mV/mmHg for normal and high sensitive films) for the intended purpose. The thesis also evaluates blood pressure measurements by the electronic palpation method (EP) and compares the achieved accuracy to that of the oscillometric method (OSC) using average intra-arterial (IA) blood pressure as a reference. All of these three measurements were made simultaneously for each person. In one test group, measurements were conducted on healthy volunteers in sitting and supine position during increasing and decreasing cuff pressure. Another group, comprising elderly cardiac patients, was measured only in the supine position during cuff inflation. The results showed that the EP method was approximately as accurate as the OSC method with the healthy subjects and slightly more accurate with the cardiac patient group. The advantage of the EP method is that also the wave shape and velocity of arterial pressure pulses is available for further analysis, including the assessment of arterial stiffness.

Abstract Parkinson's disease (PD) is known to affect both the extrapyramidal system and the autonomic nervous system even in the early phases of the disease. This study was designed to evaluate cardiovascular autonomic regulation in early PD by measuring heart rate (HR) variability from 24-hour ECG recordings. The dynamics of blood pressure (BP), HR and sweating in patients with and without wearing-off were assessed during clinical observations after a morning dose of levodopa. In patients with wearing-off the tests were repeated after selegiline withdrawal. The power spectral components of HR variability and the SD1 value of the Poincaré analysis that quantifies the short-term beat-to-beat variability were suppressed at night in the PD patients. During the daytime only the SD1 of the Poincaré was suppressed. The results indicate impairment of parasympathetic cardiovascular regulation in untreated patients with PD. The dysfunction was more pronounced at night and in patients with more severe PD. The patients with wearing-off had fluctuation of BP during the observation period, BP increasing when the motor performance worsened and vice versa (p < 0.001). The patients without wearing-off did not show fluctuation of BP. Sweating increased during the observation period, and reached its maximum level at the time of the highest UPDRS motor score phase (off-stage) in patients with wearing-off, but in the patients without wearing-off no changes in sweating were observed. Sweating of the hands was significantly higher in PD patients with motor fluctuations than in those without. Selegiline withdrawal decreased systolic BP significantly during the on-stage in a supine position as well as during the orthostatic test. The initial drop of BP in the orthostatic test was significantly smaller after selegiline withdrawal. The HR and sweating remained unaffected. The results show that the autonomic nervous system is affected in the early phases of PD. The dysfunction becomes more pronounced with the disease progression. Wearing-off type motor fluctuations are associated with fluctuation of BP and sweating and these fluctuations may represent autonomic dysfunction caused by PD, the effect of PD medication, or both. Selegiline withdrawal seems to alleviate the orthostatic reaction in patients with advanced PD.

Considerable evidence supports the claim that a hyperactive sympathetic nervous system (SNS) is involved in most cases of human hypertension, and therefore a more thorough understanding of the central regulation of the SNS may help elucidate novel therapeutic options. The PVN is a key region in SNS regulation of blood pressure (BP) and heart rate (HR). Stimulation of the parvocellular PVN neurons has been shown to enhance sympathetic outflow and thereby increase BP. Brain-derived neurotrophic factor (BDNF), a modulator of neuronal activity is upregulated in the paraventricular nucleus of the hypothalamus (PVN) in response to several hypertensive stimuli such as stress and hyperosmolarity, and previous studies from our lab demonstrated that both acute injections or chronic overexpression of BDNF in the PVN elevate SNS activity and BP. However, the BDNF-mediated hypertensive mechanisms are not completely understood. PVN neurons are under tonic inhibition from NTS catecholaminergic projections under baseline condition as indicated by significant BP increase after selective lesioning of NTS NE-ergic neurons. In addition, BDNF has been shown to alter NE-ergic signaling in multiple brain regions raising the possibility that BDNF may increase SNS activity and BP by interfering with NE-ergic inhibition of PVN sympathoregulatory neurons. Therefore, we tested the hypothesis that BDNF increases SNS activity and BP in part by disabling inhibitory actions of NTS catecholaminergic projections to the PVN by altering the expression of adrenergic receptors and NET in the PVN. First, blood pressure was recorded using radiotelemetry in male Sprague-Dawley rats following bilateral microinjections of adeno-associated viral vectors expressing green fluorescent protein (GFP) or myc-tagged BDNF in the PVN and microinjections of phosphate saline buffer (PBS) or Anti-Dopaine Beta Hydroxylase (DBH)-conjugated saporin (DSAP), a catecholaminergic neuron-specific neurotoxin, into the NTS. Blood pressure was monitored both during resting conditions and during acute stress tests. A second group of rats received bilateral microinjections of adeno-associated viral vectors expressing GFP or myc-tagged BDNF in the PVN, and were sacrificed after 5 weeks. PVN and NTS samples were then selectively isolated using a brain punch tool, and expression of TH, DBH, 1a, 1b, 2a, 1, 2 receptors, and norepinephrine transporter (NET) was analyzed using quantitative RT-PCR. Our results show that BDNF overexpression in the PVN leads to increased expression of catecholamine synthesizing enzymes in the NTS. In addition, both BDNF overexpression in the PVN, and DSAP lesioning in the NTS increased MAP compared to control rats. However, combined treatment with BDNF and DSAP failed to have any additional hypertensive effects suggesting that BDNF treatment may abolish the inhibitory effect of NTS catecholaminergic projections. Lesioning the NTS catecholaminergic neurons didn’t appear to have a significant effect on mean arterial pressure response to the stress tests, although DSAP treatment appeared to decrease the initial heart rate response to acute stress, and this effect was most pronounced in GFP rats. These results indicate that BDNF overexpression in the PVN desensitizes sympathoregulatory neurons to inhibitory NTS catecholaminergic projections during baseline conditions.

>Magister Scientiae - MSc / Blood pressure and heart rate is known to increase during smoking. These effects are specifically associated with nicotine while the other components of tobacco smoke seem to be of minor importance. It is becoming increasingly clear that fetal nicotine exposure, through transfer of nicotine via the placenta, has numerous consequences that is detrimental to the health of the fetus and that these effects may last into adulthood or perhaps even manifest itself later in life. In this study, we investigated the effects of maternal nicotine exposure during pregnancy and lactation on the blood pressure of the male offspring. A preliminary study indicated that the female offspring do not become hypertensive. We were particularly interested to determine whether hypertension in the offspring could be prevented or attenuated by vitamin C (an antioxidant) therapy. When confirmed to be pregnant, female Wistar rats were divided into four groups. The control group (group 1) received saline (1ml/day, s.c), the animals in group 2 received nicotine (1mg/kg/day in ml, s.c), group 3 animals received a combination of saline (1 ml/day s.c.) and vitamin C (1g/l in drinking water) and the animals in group 4 received a combination of nicotine (1mg/kg/day, s.c) and vitamin C (1g/l in the drinking water) during pregnancy and lactation. At weaning eight animals from group 2 received vitamin C in the drinking water (1g/l) until the end of the experiment. Blood pressure and body weight were measured every two weeks for 5 months. Blood samples were collected, and serum prepared at 3 weeks and at 5 months for biochemical analysis. Total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS) and superoxide dismutase (SOD) assays were determined at 3 weeks; TAC was also measured at five months. After 5 months, the animals were sacrificed and abdominal aorta was excised for histological (H and E staining) and IHC (AGE) evaluation. From the data generated in this study, it was evident that maternal nicotine exposure during pregnancy and lactation increased blood pressure of male offspring but not female offspring. Exposure to nicotine during pregnancy and lactation significantly increased systolic blood pressure from 115±4.6 mm Hg in the first month to 147±6.1 mm Hg at five months (P<0.05), diastolic blood pressure was increased from 84±3.4 mm Hg in the first month to 110±7.2 mm Hg at 5 months (P<0.05) and MAP was increased from 94.8±3.8 mm Hg in the first month to 121±6.4 mm Hg at 5 months. Interestingly the MAP of the nicotine group was normal during the first two months. HR was similar in all groups at 5 weeks and 5 months. Maternal vitamin C supplementation in rats exposed to nicotine during pregnancy and lactation did not prevent development of hypertension of the offspring (MAP=121±6.4 mm Hg in the nicotine group vs 113.4±1.7 mmHg in the nicotine and vitamin C group, P>0.05). Supplementation with vitamin C in the drinking water after weaning significantly reduced blood pressure of the offspring (MAP=121±6.4 mm Hg vs 97.6±2.9 mm Hg respectively, P<0.05). No significant difference was found in any of the biochemical assays. Maternal nicotine exposure during pregnancy and lactation leads to alteration in aorta structure as evaluated by H and E staining. Structural alterations include protrusion of the intima and irregular arrangement of the vascular smooth muscle cells (VSMC) in the tunica media. Maternal vitamin C supplementation and vitamin C supplementation after weaning did not prevent the structural alteration of the aorta. Immunohistochemistry (IHC) indicated that the accumulation of AGE's in the nicotine group was stronger than in the control group. In conclusion, we show for the first time that hypertension induced by maternal nicotine exposure can be reversed after weaning by supplementation with vitamin C, an antioxidant.

Abstract Patients with idiopathic Parkinson's disease (PD) may suffer from autonomic nervous system dysfunction even in the early phase of the disease. We assessed the autonomic cardiovascular and sudomotor regulation in de novo PD patients with and without medication. We also measured the dopamine (DAT) and serotonin transporter (SERT) uptake in the PD patients using 2β-carboxymethoxy-3β-(4-iodophenyl)tropane (β-CIT) SPECT and studied the clinical correlates of the uptake. Sixty PD patients were included in the study and randomised to receive levodopa, bromocriptine or selegiline (n=20 in each) as their treatment. Thirty patients were examined with β-CIT SPECT. The results of the patients were compared with those of healthy controls and within the subgroups at different time points. Cardiovascular autonomic regulation was assessed using standard cardiovascular reflex tests at baseline, after six months' medication and following a 6-week washout period. The heart rate (HR) and blood pressure (BP) regulation was impaired in PD patients at baseline, and PD medications modified the responses further. Bromocriptine and selegiline, in contrast to levodopa, increased the orthostatic BP fall and suppressed the BP response to isometric exercise. The long-term cardiovascular autonomic function was evaluated from ambulatory ECG recordings by analysis of traditional spectral and non-spectral components of HR fluctuation together with two-dimensional vector analysis and power-law relationship analysis of the HR dynamics. All spectral measures and the slope of the power-law relationship demonstrated impaired tonic cardiovascular regulation in the PD patients. Sympathetic sudomotor activity was evaluated using the sympathetic skin response (SSR). The major finding was suppression of the SSR amplitudes with an inverse correlation to clinical disability, whereas PD medication seemed to have only minor effects. The changes in amplitude and repetitiveness of the SSRs with normal adaptation suggest deficits at several levels of the SSR reflex arc. DAT uptake, assessed by β-CIT SPECT, was diminished in the striatum and especially the putamen of the PD patients, and correlated with the results of the cardiovascular reflex tests and ambulatory ECG recordings. Simultaneous measurement of SERT binding demonstrated decreased SERT availability in the thalamic and frontal areas. The results demonstrate disturbances of the reflectory and tonic cardiovascular autonomic regulation caused by PD itself. PD medications further modify the reflectory responses. The degenerative process in PD also involves the sympathetic sudomotor pathway. β-CIT SPECT provides a useful method for simultaneous assessment of DAT and SERT binding, demonstrating the deficit of serotonin metabolism in PD.

Abstract Multiple sclerosis (MS) is one of the major causes of disability in the young, mostly affecting people between 20–45 years of age. MS is considered as an autoimmune disorder, characterized by discrete areas of central nervous system inflammation, demyelination and axonal injury. Symptoms related to alterations of the autonomic nervous system are frequent in patients with MS. Bladder dysfunction or impairment of sexual performance is highly distressing for most MS patients, whereas the clinical relevance of other autonomic symptoms is less clear. The present study was designed to clarify the involvement of cardiovascular and sudomotor dysfunctions in patients with MS, to study the sudomotor functions in patients with optic neuritis (optic neuritis being a frequent initial manifestation of MS), and to assess the extent of demyelinative lesions in the CNS by using magnetic resonance imaging and by correlating the findings thus obtained with autonomic nervous system responses. The study showed cardiovascular autonomic regulation failure in MS patients manifesting itself both in the heart rate responses to deep breathing and in the heart rate and blood pressure responses in the tilt table test. In particular, midbrain lesions were found to be associated with cardiovascular dysfunction. MS patients also showed abnormal sympathetic skin responses indicating sudomotor failure. Focal MS lesions in the temporal lobe, in the pons and in the cerebellum were also associated with abnormal sympathetic skin responses. MS patients were also found to have an impairment in thermoregulatory sweating, which seemed to be related to disease severity and to total lesion volume in the brain. Sympathetic skin responses were also abnormal in optic neuritis patients, suggesting sudomotor autonomic failure. Patients with optic neuritis showed no thermoregulatory dysfunction.

Abstract Estrogen replacement therapy (ERT) has been associated with favorable effects on risk factors for atherosclerosis. In observational studies ERT was also suggested to reduce the risk of cardiovascular disease in postmenopausal women, but the cardioprotective role of estrogen has been challenged after negative results in randomized trials. However, the mechanisms of estrogen action in atherosclerosis development are only partially known. In order to investigate the regulation of plasma low-density lipoprotein (LDL) cholesterol in postmenopausal women and the effects of ERT on cholesterol and glucose metabolism and blood pressure, 79 hysterectomized, non-diabetic postmenopausal women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate (2 mg/day) or transdermal 17β-estradiol gel (1 mg estradiol/day) for six months. At baseline the level of LDL cholesterol was related to body mass index, the fractional catabolic rate (FCR) and the production of LDL apolipoprotein B (apo B), but not to cholesterol absorption efficiency. Both peroral and transdermal ERT decreased plasma total and LDL cholesterol, while high-density lipoprotein cholesterol and triglycerides increased only in the peroral group. The LDL-lowering response was related to changes in estrogen levels, which presumably enhance LDL receptor activity shown as an increase in FCR for LDL apo B. In contrast, the determined genetic factors, apo E phenotype, EcoRI and XbaI polymorphisms of the apo B gene and polymorphism of 7α-hydroxylase gene, were not significant in regulation of LDL cholesterol, neither did they modify the response of ERT in these postmenopausal women. Similar outcomes were observed with both peroral and transdermal ERT as regards glucose metabolism and blood pressure. The overall effect of ERT on glucose tolerance was found to be neutral. Blood pressure decreased among non-hypertensive subjects on both estrogens, which could be related, at least in part, to the alterations in vasoactive peptides. The data of the present study suggest an overall favorable effect of both peroral and transdermal estrogen on common cardiovascular risk factors. However, the clinical significance of these findings in the prevention of cardiovascular diseases needs to be proven in long-term, randomized trials.

Abstract This thesis describes the laser Doppler technique based on a self-mixing effect in a diode laser to noninvasive cardiovascular pulse detection in a human wrist above the radial artery. The main applications of self-mixing interferometry described in this thesis in addition to pulse detection are arterial pulse shape and autonomic regulation measurements. The elastic properties of the arterial wall are evaluated and compared to pulse wave velocity variation at different pressure conditions inside the radial artery. The main advantages of self-mixing interferometry compared to conventional interferometers are that the measurement set up is simple, because basically only one optical component, the laser diode, is needed. The use of fewer components decreases the price of the device, thus making it inexpensive to use. Moreover, an interferometer can be implemented in a small size and it is easy to control because only one optical axis has to be adjusted. In addition, an accuracy, which corresponds to half of the wavelength of the light source, can be achieved. These benefits make this technique interesting for application to the measurement of different parameters of the cardiovascular pulse. In this thesis, measurement of three different parameters from cardiovascular pulsation in the wrist is studied. The first study considers arterial pulse shape measurement. It was found that an arterial pulse shape reconstructed from the Doppler signal correlates well to the pulse shape of a blood pressure pulse measured with a commercial photoplethysmograph. The second study considers measurement of autonomic regulation using the Doppler technique. It was found that the baroreflex part of autonomic regulation can be measured from the displacement of the arterial wall, which is affected by blood pressure variation inside the artery. In the third study, self-mixing interferometry is superimposed to evaluate the elastic properties of the arterial wall. It was found that the elastic modulus of the arterial wall increases as blood pressure increases. Correlations between measurements and theoretical values were found but deviation in measured values was large. It was noticed that the elastic modulus of the arterial wall and pulse wave velocity behave similarly as a function of blood pressure. When the arterial pressure increases, both the elastic modulus and pulse wave velocity reach higher values than in lower pressure.