Blood Pressure Dysregulation Research Articles

Long-Term Exposure to Noise and the Development of Diabetes and Hypertension in Toronto, Canada: A Cohort Study

Background: Exposure to noise has been linked to cardiovascular disease risk factors, such as elevated blood pressure and glucose dysregulation. However, epidemiologic evidence linking road traffic...

Sex-dependent expression of brain medullary MAP and PI3 kinases in adult sheep with antenatal betamethasone exposure.

Antenatal betamethasone (BM) therapy for women in jeopardy of premature delivery accelerates the lung development in preterm infants and reduces infant mortality rates, but may induce early programming events with chronic cardiovascular consequences. In a sheep model of fetal programming, in utero BM-exposed (BMX) offspring as adults exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for the control of heart rate and insulin resistance accompanied by dysregulation of the brain renin-angiotensin (Ang) system (RAS). However, the status of signaling mechanisms in the brain dorsomedial medulla (DMM) of the BMX sheep that comprise both the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cellular pathways is unknown. Given the importance of these signaling pathways in the actions of Ang peptides as well as baroreflex function and autonomic integration, we applied both a kinase signaling array and associated individual immunoblots of the dorsomedial brain medulla from adult female and male sheep with antenatal BMX. MAPK and PI3K pathways were altered significantly in the BMX sheep in a sex-dependent manner. A protein array for kinases (PathScan® Intracellular Signaling Array Kit, Cell Signaling) and subsequent verification by immunoblot revealed that within the DMM, female BMX sheep exhibit lower expression of proteins in the PI3K pathway, while male BMX sheep show greater expression of p-MAPK pathway proteins extracellular signal regulated kinase (ERK) 1/2. We conclude that maladaptive changes in these two kinase pathways in the DMM may contribute to the chronic dysregulation of blood pressure in this model of fetal programming.

The effects of plasma chromium on lipid profile, glucose metabolism and cardiovascular risk in type 2 diabetes mellitus. A case - control study.

BackgroundThe study was aimed at determining the effect of plasma chromium concentration on the metabolism of glucose, and lipids and their subsequent cardiovascular risk in patients with type 2 diabetes in the Bolgatanga district of Ghana.Material and methodsFasting blood glucose and lipids profile were determined by enzymatic assay using the BT 5000® Random Access Chemistry Analyzer. Fasting serum insulin and High sensitive C-reactive protein were determined by ELISA, a solid phase direct sandwich immunoassay method. HOMA-IR, which is based on fasting blood sample for insulin and glucose concentrations measured in a single blood sample, was used to calculate insulin resistance. Plasma chromium was measured using an atomic Absorption Spectrometer.ResultsPatientswith diabeteshad significantly (p<0.0001) increased LDL, TC, TG, VLDL, insulin, CRP and HOMAIR and a significantly reduced plasma chromium (p<0.0001) (0.53± 0.02μg/l and 0.11±0.01μg/l control and case respectively). Low Cr (p ≤0.001) was associated with high blood pressure, obesity and lipid dysregulation. Plasma Cr significantly correlated negatively with blood pressure and LDL.ConclusionLower plasma Cr level was associated with hyperglycaemia, hyperinsulinemia, hypertension, insulin resistance and high inflammation marker HsCRP.

Sodium Chloride Cotransporter Upregulation in Settings of Zinc Deficiency Offers New Insight into Blood Pressure Dysregulation in Chronic Diseases

BackgroundZn2+ deficiency is a common comorbidity with numerous chronic diseases including type II diabetes and chronic kidney disease. Experimental data show that Zn2+ deficiency exacerbates hypertension in these settings. Moreover, Zn2+ deficiency alone is sufficient to alter blood pressure. However, the mechanisms involved are unknown.ObjectiveThe renal distal convoluted tubule sodium chloride cotransporter (NCC) plays a critical role in blood pressure regulation and hypertension. The objective of this study was to determine if NCC plays a role in Zn2+ deficiency‐induced hypertension.Experimental DesignTo this end, WT mice were pair‐fed a diet with 50 ppm Zn2+ (Zn2+ adequate [ZnA]) or a diet with 1 ppm Zn2+ (Zn2+ deficient [ZnD]) for 6 weeks. A subset of mice was administered 50 mg/kg hydrochlorothiazide, a NCC inhibitor. To reduce intracellular Zn2+ levels in vitro, WT mouse distal convoluted tubular (mDCT‐15) cells were cultured in 1 nM N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethylenediamine (TPEN)‐ or vehicle (DMSO)‐containing medium for 24 hours. To replete intracellular Zn2+, TPEN‐exposed cells were then cultured in 1 nM Zn2+‐supplemented medium for 24 hours. Select cell monolayers were treated with 100 nM diphenyliodonium (DPI), a general NADPH oxidase inhibitor, prior to TPEN treatment. In mice, systolic blood pressure was monitored by tail cuff plethysmography. NCC protein expression was examined in vivo and in vitro via western blot and immunohistochemistry. NCC activation was assessed by cellular localization (via biotinylation and immunofluorescence) and Na+ uptake activity (via thiazide‐sensitive assays).ResultsIn ZnD mice, increased blood pressure is accompanied with enhanced NCC protein expression compared to mice receiving a ZnA‐diet. However, NCC inhibition by hydrochlorothiazide treatment reverses blood pressure increases. In the in vitro model of Zn2+ deficiency, Zn2+ chelation with TPEN stimulates NCC protein expression compared to vehicle‐treated cells. Furthermore, TPEN promotes NCC surface localization and Na+ uptake activity. Notably, restoration of intracellular Zn2+ levels by supplementation reverses TPEN effects on NCC. Additionally, NADPH oxidase inhibition with DPI treatment prevents TPEN‐induced NCC upregulation.ConclusionsOur findings indicate that NCC is a Zn2+‐sensitive transporter and is upregulated in settings of Zn2+ deficiency via a NADPH oxidase‐mediated mechanism.SignificanceNCC represents a novel mechanism by which Zn2+ deficiency alters blood pressure and contributes to hypertension in chronic disease settings.Support or Funding InformationCR. Williams (AHA‐SDG), JL. Gooch (VA‐MERIT), RS. Hoover (VA‐MERIT and NIH‐R01)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Stress‐induced Salt Sensitivity is Modulated by Angiotensin II

IntroIncreased sensitivity of blood pressure (BP) to dietary sodium (“salt‐sensitivity”) has been described to partially explain the etiology of hypertension (HTN) in African‐Americans (AAs). Our group has demonstrated a form of salt sensitivity that is induced by mental stress rather than by dietary sodium in a significant percentage of AAs. The underlying mechanism for stress‐induced salt‐sensitivity in AAs has yet to be described. However, animal models provide evidence that it results from increased renal sympathetic nerve activity (SNA) that triggers renal sodium reabsorption through the action of angiotensin II (Ang II).AimOur study sought to test the hypothesis that mental stress‐induced impaired regulation of sodium and subsequent changes in BP are mediated by the action of Ang II in normotensive AAs.MethodsUtilizing a double‐blind, randomized and cross‐over study design, 132 normotensive AAs (25±7 yr) were placed on a controlled sodium diet for 7 days and were treated concomitantly with either a placebo or irbesartan (an Ang II receptor blocker; ARB) in random order. A mental stress by competitive video game challenges were used to provoke the stress response on the final day of each treatment. Urinary sodium excretion (UNaV), blood pressure (BP), total peripheral resistance (TPR) and heart rate (HR) were collected before, during, and 1‐hr after the stress.ResultsBP measured every 15 minutes stayed elevated throughout the stress period on placebo, whereas the stress‐induced increase in BP was delayed on ARB day (p=0.024 for Treatment × Time interaction). ARB treatment also resulted in lower BP and TPR at rest, stress and recovery (p&gt;0.05 for all). Notably, systolic BP at the end of recovery on ARB was significantly lower compared to the placebo (109.8 ±13.3 vs 117.4 ± 12.3 mmHg respectively; p&lt;0.001) and was also significantly decreased from the pre‐stress level (mean difference; −1.9 ±9.4 mmHg; p=0.02). In response to stress, UNaV, BP and HR were all increased in each of placebo and ARB day. However, 30.2% of subjects retained sodium during stress despite an increase in BP on placebo. ARB treatment increased ΔUNaVstress − rest among the sodium retainers (−1.14 ±5.95 mEq/min on placebo, 7.63±9.64 mEq/min on ARB, p=0.001) without changes in UNaV at rest and recovery.ConclusionThe use of ARBs in AAs is controversial despite an unsatisfactory efficacy of the current first line of HPT therapy in AAs. Our data demonstrates that suppression of Ang II, by using ARB, blunted the stress‐induced sodium retention, attenuated BP reactivity to stress and improved post‐stress BP recovery process in AAs. These confirm the Ang II‐dependent antinatriuretic actions in the process of stress responses on renal SNA. Thus, treatment approaches that antagonize Ang II's actions could have significant relevance to potentially lower susceptibility to stress‐induced dysregulation of sodium and BP and eventually the premature development of salt‐sensitive HTN in AAs.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Diabetic Kidney Disease: A Determinant of Cardiovascular Risk in Type 1 Diabetes.

Diabetes, regardless of type, has well-accepted vascular consequences. In fact, atherosclerotic cardiovascular disease (CVD) is the most important cause of death attributable to diabetes (1). Acute complications of diabetes such as hypoglycemia, hyperglycemia, and diabetic ketoacidosis are important causes of morbidity and mortality beginning early in its course. However, microvascular and macrovascular complications drive excess mortality over the long term (2–4). Diabetic kidney disease (DKD) is strongly associated with CVD (5). DKD may be a marker of cumulative vascular damage due to diabetes or may causally promote CVD through several mechanisms, such as blood pressure dysregulation, retention of uremic toxins, anemia, and altered mineral metabolism. Provocative studies suggest that the preponderance of excess CVD risk in both types 1 and 2 diabetes is restricted to people with DKD (6–8). The question posed by Groop et al. (9) in this issue of Diabetes Care was whether patients with type 1 diabetes have heightened CVD mortality risk in the absence of DKD compared with people without diabetes. To examine this question, they looked at two different databases. The first was a registry of 10,737 Finnish children followed for 10 years after the initial diagnosis of type 1 diabetes, a period considered generally too early for DKD development. The mortality rate of children in the Finnish registry was compared with that of the general population as a standardized mortality ratio (SMR) that adjusts for demographic characteristics. Children with diabetes had a mortality rate of 8 per 10,000 person-years, yielding an SMR of 2.6. (An SMR …

Disruption of Accumbens and Thalamic White Matter Connectivity Revealed by Diffusion Tensor Tractography in Young Men with Genetic Risk for Obesity.

Background: Neurovascular coupling is associated with white matter (WM) structural integrity, and it is regulated by specific subtypes of dopaminergic receptors. An altered activity of such receptors, highly expressed in reward-related regions, has been reported in carriers of obesity-risk alleles of the fat mass and obesity associated (FTO) gene. Among the reward-related regions, the thalamus and the nucleus accumbens are particularly vulnerable to blood pressure dysregulation due to their peculiar anatomo-vascular characteristics, and have been consistently reported to be altered in early-stage obesity. We have thus hypothesized that a disruption in thalamus and nucleus accumbens WM microstructure, possibly on neurovascular basis, could potentially be a predisposing factor underlying the enhanced risk for obesity in the risk-allele carriers.Methods: We have tested WM integrity in 21 male participants genotyped on the FTO risk single nucleotide polymorphisms (SNP) rs9939609, through a deterministic tractography analysis. Only homozygous participants (9 AA, 12 TT) were included. 11 tracts were selected and categorized as following according to our hypothesis: “risk tracts”, “obesity-associated tracts”, and a control tract (forcpes major). We investigated whether an association existed between genotype, body mass index (BMI) and WM microstructural integrity in the “risk-tracts” (anterior thalamic radiation and accumbofrontal fasciculus) compared to other tracts. Moreover, we explored whether WM diffusivity could be related to specific personality traits in terms of punishment and reward sensitivity, as measure by the BIS/BAS questionnaire.Results: An effect of the genotype and an interaction effect of genotype and BMI were detected on the fractional anisotropy (FA) of the “risk tracts”. Correlations between WM diffusivity parameters and measures of punishment and reward sensitivity were also detected in many WM tracts of both networks.Conclusions: A disruption of the structural connectivity from the nucleus accumbens and the thalamus might occur early in carriers of the FTO AA risk-allele, and possibly act as a predisposing factor to the development of obesity.

Circadian clock-mediated regulation of blood pressure.

Most bodily functions vary over the course of a 24h day. Circadian rhythms in body temperature, sleep-wake cycles, metabolism, and blood pressure (BP) are just a few examples. These circadian rhythms are controlled by the central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks located throughout the body. Light and food cues entrain these clocks to the time of day and this synchronicity contributes to the regulation of a variety of physiological processes with effects on overall health. The kidney, brain, nervous system, vasculature, and heart have been identified through the use of mouse models and clinical trials as peripheral clock regulators of BP. The dysregulation of this circadian pattern of BP, with or without hypertension, is associated with increased risk for cardiovascular disease. The mechanism of this dysregulation is unknown and is a growing area of research. In this review, we highlight research of human and mouse circadian models that has provided insight into the roles of these molecular clocks and their effects on physiological functions. Additional tissue-specific studies of the molecular clock mechanism are needed, as well as clinical studies including more diverse populations (different races, female patients, etc.), which will be critical to fully understand the mechanism of circadian regulation of BP. Understanding how these molecular clocks regulate the circadian rhythm of BP is critical in the treatment of circadian BP dysregulation and hypertension.

Editors' Note

Editors' Note: In “Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage,” the authors concluded that acute blood pressure (BP) dysregulation in primary intracerebral hemorrhage (ICH) patients was associated with the development of diffusion-weighted imaging (DWI) lesions and, subsequently, worse outcomes. Drs. Lattanzi and Silvestrini consider the complex relationship between BP and ICH outcome, particularly the effect of BP fluctuations on remote ischemia. They also question whether the time to MRI, which differed between the DWI+ and DWI− groups, may have been a significant variable. Authors Kidwell et al. reply that while time to MRI was initially included in their multivariable statistical analysis, it was not found to be a significant factor. In Epilepsy Currents , Dr. Jacqueline French commented on the Neurology® article “Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies.” In her review, Dr. French summarized the results of the original article and used the information to answer several questions about brivaracetam's (BRV) clinical use. She concluded that while clinical studies provide important information about a drug, many details emerge over time. Authors Klein et al. respond to several questions brought up in her commentary, especially with regard to the pharmacologic differences between BRV and levetiracetam and the use of BRV in patients with previous exposure to levetiracetam. —Megan Alcauskas, MD, and Steven Galetta, MD Editors' Note: In “Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage,” the authors concluded that acute blood pressure (BP) dysregulation in primary intracerebral hemorrhage (ICH) patients was associated with the development of diffusion-weighted imaging (DWI) lesions and, subsequently, worse outcomes.

Author response: Ischemic Lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage.

We appreciate the comments by Drs. Lattanzi and Silvestrini on our article,1 and agree that further research is needed to better understand the complex relationship among blood pressure (BP) dysregulation, small vessel disease, and development of remote ischemic lesions in the setting of acute intracerebral hemorrhage.2

Letter re: Ischemic Lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage.

We appreciated the article by Kidwell et al.1 that showed higher first-recorded blood pressure (BP) and greater delta mean arterial pressure are associated with the development of diffusion-weighted imaging (DWI) lesions in acute intracerebral hemorrhage (ICH). The most desirable BP target and optimal antihypertensive strategy in ICH are controversial.2 The relationship between BP and outcome is more complex than simply linear, and mechanisms other than BP reduction play a role. There is accruing evidence that not only absolute BP levels but their variation over time affect ICH prognosis.3 Besides increasing the risk of hematoma enlargement, BP fluctuations could favor remote ischemia by working synergistically with preexistent burden of cerebral small angiopathy, namely leukoaraiosis and microbleeds, and influence the stroke outcome. Both systolic and diastolic BP dysregulation deserve more comprehensive assessment through the proper measures of variability, such as standard and residual deviation, variation coefficient, average real variability, and variation independent of the mean.4 In addition, time to MRI differed among DWI+ and DWI− patient subgroups, which could represent a meaningful bias: it would be appropriate to include this variable among the controlling factors of the multivariable predictive model for DWI lesions development.

Impact of Blood Pressure, Lesion Level, and Physical Activity on Aortic Augmentation Index in Persons with Spinal Cord Injury.

Individuals with chronic spinal cord injury (SCI) are at a heightened risk of cardiovascular disease (CVD) resulting from autonomic nervous system dysfunction, physical inactivity, and increased inflammatory processes. Arterial stiffness (AS) is recognized as an independent risk factor for CVD and, specifically, pulse wave analysis (PWA) has proven to be a useful tool to predict and track structural arterial changes that reflect arteriosclerosis. The augmentation index (AI) can be used to estimate AS and is derived from the amplitude and timing of the blood pressure (BP) wave reflection in a peripheral artery. Recently, AS has been shown to be increased in persons with SCI compared with the uninjured population; however, possible contributors to increased AS in the SCI population have not been fully explored. In this study, increased radial artery AI is demonstrated in persons with high cord lesions (above T6) compared with individuals with low cord lesions (T7 and below) and uninjured controls. The association between age and AI was not significant in the SCI population; however, there was a direct association between AI and level of injury. Further, AI was inversely associated with seated systolic blood pressure (SBP) and was increased in individuals who reported orthostatic hypotension (OH) and in those who were physically inactive. In conclusion, individuals with higher cord lesions have more severe cardiovascular autonomic disruption, leading to orthostatic BP dysregulation and physical inactivity, which appear to contribute independently to increased AS in these individuals.

Relationships between blood pressure and blood glucose among offspring of parents with type 2 diabetes: Prediction of incident dysglycemia in a biracial cohort

AimsWe assessed blood pressure (BP) and blood glucose (BG) values in healthy subjects, and examined baseline BP as a predictor of incident prediabetes during follow-up. MethodsParticipants in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study underwent screening assessments (anthropometry, BP, OGTT) and were stratified into normal BP (NBP), prehypertension, or hypertension, and normal glucose regulation (NGR), prediabetes (IFG/IGT), or type 2 diabetes (T2D) status. NGR subjects who met all inclusion criteria were enrolled in a 5-yr prospective study, with the primary outcome of incident prediabetes. ResultsWe screened 602 adults (341 black, 261 white) and enrolled 343 (193 black, 150 white) for prospective follow-up. Systolic and diastolic BP correlated significantly with fasting and nonfasting BG (P=0.003–<0.0001). Compared to NGR group, more prediabetic subjects had prehypertension (42.5% vs. 36.2%) and fewer had NBP (35.9% vs. 48.6%) (P=0.009). During ~5years of follow-up, 26.3% of NBP and 35.7% of prehypertensive subjects developed prediabetes (P=0.02). Kaplan-Meier analysis showed higher probability of incident prediabetes among participants with prehypertension compared to NBP during ~5years of follow-up (P=0.0012). ConclusionsIn our biracial cohort, BP and BG values were significantly correlated, and BP status predicted incident prediabetes among initially normoglycemic individuals. These findings suggest co-evolution of factors involved in the dysregulation of BP and BG.

Impact of the Metabolic Syndrome on Mortality is Modified by Objective Short Sleep Duration.

BackgroundTo examine whether objective sleep duration is an effect modifier of the impact of metabolic syndrome (MetS) on all‐cause and cardiovascular disease/cerebrovascular mortality.Methods and ResultsWe addressed this question in the Penn State Adult Cohort, a random, general population sample of 1344 men and women (48.8±14.2 years) who were studied in the sleep laboratory and followed up for 16.6±4.2 years. MetS was defined by the presence of 3 or more of obesity (≥30 kg/m2), elevated total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), fasting glucose (≥100 mg/dL), and blood pressure (≥130/85 mm Hg). Polysomnographic sleep duration was classified into clinically meaningful categories. Among the 1344 participants, 22.0% of them died during the follow‐up. We tested the interaction between MetS and polysomnographic sleep duration on mortality using Cox proportional hazard models controlling for multiple potential confounders (P<0.05). The hazard ratios (95% CI) of all‐cause and cardiovascular disease/cerebrovascular mortality associated with MetS were 1.29 (0.89–1.87) and 1.49 (0.75–2.97) for individuals who slept ≥6 hours and 1.99 (1.53–2.59) and 2.10 (1.39–3.16) for individuals who slept <6 hours. Interestingly, this effect modification was primarily driven by the elevated blood pressure and glucose dysregulation components of MetS.ConclusionsThe risk of mortality associated with MetS is increased in those with short sleep duration. Short sleep in individuals with MetS may be linked to greater central autonomic and metabolic dysfunction. Future clinical trials should examine whether lengthening sleep improves the prognosis of individuals with MetS.

Sodium Chloride Cotransporter Upregulation in Settings of Zinc Deficiency Offers New Insight into Blood Pressure Dysregulation in Chronic Diseases

BackgroundZn2+ deficiency is a common comorbidity with numerous chronic diseases including type II diabetes and chronic kidney disease. Experimental data show that Zn2+ deficiency exacerbates hypertension in these settings. Moreover, Zn2+ deficiency alone may be sufficient to alter blood pressure; however, the mechanisms involved are unknown.ObjectiveThe renal distal convoluted tubule sodium chloride cotransporter (NCC) plays a critical role in blood pressure regulation and hypertension. The objective of this study was to determine if Zn2+ deficiency alters NCC expression and/or activation in vivo and in vitro.Experimental DesignTo this end, WT mice were pair‐fed a diet with 50 ppm Zn2+ (Zn2+ adequate [ZnA]) or a diet with 1 ppm Zn2+ (Zn2+ deficient [ZnD]) for 6 weeks. To reduce intracellular Zn2+ levels in vitro, WT mouse distal convoluted tubular (mDCT‐15) cells were cultured in 1 nM N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethylenediamine (TPEN)‐ or vehicle (DMSO)‐containing medium for 24 hours. To replete intracellular Zn2+, TPEN‐exposed cells were then cultured in 1 nM Zn2+‐supplemented medium for 24 hours. NCC mRNA and protein expression were examined in vivo and in vitro via qRT‐PCR, western blot and immunohistochemistry. NCC activation was assessed by cellular localization (via biotinylation and immunofluorescence) and Na+ uptake activity (via thiazide‐sensitive assays).ResultsIn ZnD mice, NCC protein expression is increased in DCT cells compared to mice receiving a ZnA‐diet. In the in vitro model of Zn2+ deficiency, Zn2+ chelation with TPEN stimulates NCC mRNA and protein expression compared to vehicle‐treated cells. Furthermore, TPEN promotes NCC surface localization and Na+ uptake activity. Notably, restoration of intracellular Zn2+ levels by supplementation reverses TPEN effects on NCC.ConclusionsOur findings indicate that NCC is a Zn2+‐sensitive transporter and is upregulated in settings of Zn2+ deficiency.SignificanceThis sodium transporter represents a novel mechanism by which Zn2+ deficiency may alter blood pressure and contribute to hypertension in chronic disease settings. Future experiments are needed to determine what additional factors are involved in Zn2+ deficiency‐induced upregulation of NCC and to test if protecting NCC from Zn2+ regulation has a positive impact on hypertension.

Blood Pressure Regulation by the Rostral Ventrolateral Medulla in Conscious Rats: Effects of Hypoxia, Hypercapnia, Baroreceptor Denervation, and Anesthesia.

Current understanding of the contribution of C1 neurons to blood pressure (BP) regulation derives predominantly from experiments performed in anesthetized animals or reduced ex vivo preparations. Here, we use ArchaerhodopsinT3.0 (ArchT) loss-of-function optogenetics to explore BP regulation by C1 neurons in intact, unanesthetized rats. Using a lentivirus that expresses ArchT under the Phox2b-activated promoter PRSx8 (PRSx8-ArchT), ∼65% of transduced neurons were C1 (balance retrotrapezoid nucleus, RTN). Other rats received CaMKII-ArchT3.0 AAV2 (CaMKII-ArchT), which transduced C1 neurons and larger numbers of unidentified glutamatergic and GABAergic cells. Under anesthesia, ArchT photoactivation reduced sympathetic nerve activity and BP and silenced/strongly inhibited most (7/12) putative C1 neurons. In unanesthetized PRSx8-ArchT-treated rats breathing room air, bilateral ArchT photoactivation caused a very small BP reduction that was only slightly larger under hypercapnia (6% FiCO2), but was greatly enhanced during hypoxia (10 and 12% FiO2), after sino-aortic denervation, or during isoflurane anesthesia. The degree of hypotension correlated with percentage of ArchT-transduced C1 neurons. ArchT photoactivation produced similar BP changes in CaMKII-ArchT-treated rats. Photoactivation in PRSX8-ArchT rats reduced breathing frequency (FR), whereas FR increased in CaMKII-ArchT rats. We conclude that the BP drop elicited by ArchT activation resulted from C1 neuron inhibition and was unrelated to breathing changes. C1 neurons have low activity under normoxia, but their activation is important to BP stability during hypoxia or anesthesia and contributes greatly to the hypertension caused by baroreceptor deafferentation. Finally, C1 neurons are marginally activated by hypercapnia and the large breathing stimulation caused by this stimulus has very little impact on resting BP.SIGNIFICANCE STATEMENT C1 neurons are glutamatergic/peptidergic/catecholaminergic neurons located in the medulla oblongata, which may operate as a switchboard for differential, behavior-appropriate activation of selected sympathetic efferents. Based largely on experimentation in anesthetized or reduced preparations, a rostrally located subset of C1 neurons may contribute to both BP stabilization and dysregulation (hypertension). Here, we used Archaerhodopsin-based loss-of-function optogenetics to explore the contribution of these neurons to BP in conscious rats. The results suggest that C1 neurons contribute little to resting BP under normoxia or hypercapnia, C1 neuron discharge is restrained continuously by arterial baroreceptors, and C1 neuron activation is critical to stabilize BP under hypoxia or anesthesia. This optogenetic approach could also be useful to explore the role of C1 neurons during specific behaviors or in hypertensive models.

Role of Perivascular Adipose Tissue in Vascular Physiology and Pathology.

Blood pressure (BP) regulation is a complex homeostatic process involving multiple organ systems, including the cardiovascular, renal, and central and peripheral nervous systems.1 Inability to properly regulate BP can result in the development of hypertension, which is associated with an increased risk of stroke, myocardial infarction, and cardiac and renal failure,2–4 and is the leading determinant of risk of death worldwide.5 In addition to genetic and environmental factors known to play a role in the development of hypertension,6 body weight and obesity are highly correlated with hypertension in humans.7,8 This is particularly alarming given the increased prevalence of obesity, which now affects 1 in 3 people in the United States.9 The close association between obesity, hypertension, and other cardiovascular disorders suggests an important role for adipose tissue (AT) in the regulation of vascular tone and BP. Until the mid 1900s, AT was considered to be a form of connective tissue with the primary function of storing energy in the form of lipids.10 However, AT is now recognized to be an important endocrine organ that can secrete polypeptides and metabolites, known as adipokines, which are involved in the normal regulation of various physiological processes, including BP regulation and vascular function.10,11 In the setting of obesity, AT undergoes complex remodeling. This is marked by a significant increase in tissue mass, through adipocyte hyperplasia and hypertrophy. Changes in structural and cellular composition also occur, including changes in AT extracellular matrix, composition of lipid droplets, and infiltration of immune cells such as macrophages and lymphocytes, which results in low-grade inflammation.10,11 Most importantly, obesity shifts the secretory profile of AT, which in turn contributes to the dysregulation of BP and eventual development of hypertension.12 This is thought …

Abstract P354: Objective Short Sleep Duration Increases the Risk of Mortality Associated with the Metabolic Syndrome

Background: The metabolic syndrome (MetS), the clustering of cardiometabolic risk factors, has been associated with short sleep duration and mortality. Most studies have been limited by using self-report measures and treating sleep duration as a sole, independent predictor, thus, its role in predicting mortality is still not well-established. Hypothesis: We hypothesized that objective sleep duration is an effect modifier of the impact of the MetS on mortality. Methods: We addressed this question in the Penn State Adult Cohort, a random, general population sample of 1,741 men and women (48.7 ± 13.5 years) who were studied in the sleep laboratory and followed-up for 16.7 ± 4.6 years. MetS was defined by the presence of three or more of obesity (≥30 m 2 /kg), elevated total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), fasting glucose (≥100 mg/dL), and blood pressure (≥85/130 mmHg). Polysomnographic (PSG) sleep duration was classified into clinically meaningful categories. Among the 1,741participants, 23.5% (n=478) of them died during the follow-up. Results: We tested the interaction between MetS and PSG sleep duration on mortality using Cox proportional hazard models controlling for multiple potential confounders (p-value &lt; .05).The hazard ratios (95%CI) of all-cause and cardiovascular / cerebrovascular mortality associated with MetS were 1.28 (0.88-1.86) and 1.49 (0.75-2.97) for individuals who slept ≥ 6 hours and 1.99 (1.53-2.59) and 2.10 (1.39-3.16) for individuals who slept &lt; 6 hours. Interestingly, this effect modification was primarily driven by the elevated blood pressure and glucose dysregulation components of the MetS. Conclusions: The risk of mortality associated with the MetS increases as a function of short sleep duration. Short sleep in individuals with MetS may be linked to greater central autonomic and metabolic dysfunction. Future clinical trials should examine whether lengthening sleep improves the prognosis of individuals with MetS.

Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage.

To evaluate the associations among diffusion-weighted imaging (DWI) lesions, blood pressure (BP) dysregulation, MRI markers of small vessel disease, and poor outcome in a large, prospective study of primary intracerebral hemorrhage (ICH). The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multicenter, observational study of ICH among white, black, and Hispanic patients. Of 600 patients, mean (±SD) age was 60.8 ± 13.6 years, median (interquartile range) ICH volume was 9.1 mL (3.5-20.8), and 79.6% had hypertension. Overall, 26.5% of cases had DWI lesions, and this frequency differed by race/ethnicity (black 33.8%, Hispanic 24.9%, white 20.2%, overall p = 0.006). A logistic regression model of variables associated with DWI lesions included lower age (odds ratio [OR] 0.721, p = 0.002), higher first recorded systolic BP (10-unit OR 1.12, p = 0.002), greater change in mean arterial pressure (MAP) prior to the MRI (10-unit OR 1.10, p = 0.037), microbleeds (OR 1.99, p = 0.008), and higher white matter hyperintensity (WMH) score (1-unit OR 1.16, p = 0.002) after controlling for race/ethnicity, leukocyte count, and acute in-hospital antihypertensive treatment. A second model of variables associated with poor 90-day functional outcome (modified Rankin Scale scores 4-6) included DWI lesion count (OR 1.085, p = 0.034) as well as age, ICH volume, intraventricular hemorrhage, Glasgow Coma Scale score, WMH score, race/ethnicity, acute in-hospital antihypertensive treatment, and ICH location. These results support the hypotheses that acute BP dysregulation is associated with the development of DWI lesions in primary ICH and that DWI lesions are, in turn, associated with poor outcomes.

ROLE OF CEREBROVASCULAR AND CARDIOVASCULAR CO2-REACTIVITY IN THE PATHOGENESIS OF ARTERIAL HYPERTENSION

Intense emotions cause arousal of the central nervous system, sympathetic activation, blood pressure (BP) increase and hyperventilation. Continuous negative emotions coming with hyperventilation lead to increase in CO2-chemosensitivity that keeps chronic hypocapnia constant and results in BP dysregulation and stable arterial hypertension (AH). The key mechanism of a hypertensive effect of chronic hyperventilation probably lies in sensitivity changes of CO2-chemoreceptors. Respiratory training with periodic hypercapnia has potential therapeutic effect in HTN by restoring CO2-chemoreceptor sensitivity and increasing antioxidant activity. Hypocapnia violates autoregulation mechanisms. Cerebral blood vessels lose their ability to neutralize BP surges, which negatively affects chemoreceptor-related processes of respiratory and BP regulation. With the HTN progression, cerebrovascular dysregulation occurs depending on the BP level. Moreover, hypocapnia is accompanied by the reduction of intracranial venous tone which can lead to increased intracranial pressure and problems with BP regulation in the brain. The threshold level of cardiovascular CO2-reactivity is normally higher than the threshold level of cerebrovascular CO2-reactivity. The changes in cardiovascular CO2-reactivity occur already in the initial period of HTN. Compared to healthy people, hypertensive patients develop slower BP reaction to hyper/hypocapnia, and hypercapnia induced low BP does not restore to the baseline level that can result from the BP dysregulation. In general, cerebrovascular CO2-reactivity is decreased in HTN patients. However, the cerebrovascular vasodilator function is preserved better than the vasoconstrictor reserve demonstrating that cerebral vessel remodeling in HTN is characterized by luminal narrowing due to the vascular wall hypertrophy.