Cardiovascular Regulation Research Articles

Abstract 18781: Targeting GPR39 in Pericytes for Preventing No Reflow After Acute Myocardial Infarction

Background: No reflow (NR) continues to contribute towards morbidity and mortality in acute myocardial infarction (AMI). Currently, there is no treatment specific to NR. We demonstrated that NR is caused by pericyte-inducted capillary constriction and identified the G-protein coupled receptor, GPR39, through which the vasoconstrictor 15-Hydroxyeicosatetraenoic acid (15-HETE) results in pericyte contraction during myocardial ischemia. GPR39 knockout mice demonstrate a marked reduction in NR after AMI associated with less pericyte-induced capillary constriction. Consequently, we developed a drug candidate, VC108, that inhibits GPR39 with high specificity (antagonist potency, fpki=7.9) and no effect on 87 other receptors involved in cardiovascular regulation. Methods: Forty-nine Wild-type Sprague Dawley rats (3-4 weeks old) of both sexes underwent 1 hour of coronary occlusion followed by 1 hr of reperfusion. Either vehicle (n=13) or VC108 (in-vivo half-life of 2 hr) at 3 different doses: 0.3 (n=11), 0.5 (n=13), and 1.0 mg/kg (n-12) was injected 5 min before reperfusion. Risk volume (as %of LV volume) was derived from 4-6 short axis slices using Evans Blue staining and NR volume was measured using Thioflavin S. Results: There was no significant difference in the risk volume in animals treated with vehicle and the 3 doses of VC108 (Figure 1). In contradistinction, compared to vehicle, VC108 showed marked reduction in NR at all doses (Figure 2) with a trend towards lower NR volume at the highest dose. Conclusion: Pharmacological inhibition of GPR39 results in marked reduced in NR after AMI. These findings open up a novel approach to treating AMI.

Abstract 13113: Associations of Cerebrovascular Regulation and Arterial Stiffness With Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis

Background: The global incidence of ischemic stroke is projected to increase ~20% by 2030, with one-fifth of these cases attributed to cerebral small vessel disease (cSVD). Stiffening of central arteries potentiates small vessel injury in the brain, which may precede or develop in parallel with disruption of local regulatory mechanisms such as cerebrovascular reactivity. However, evidence of these vascular etiologies of cSVD remains inconclusive. To address this, we conducted separate systematic meta-analyses to characterize the relationship between cerebrovascular reactivity or arterial stiffness and cSVD. Methods: MEDLINE and Web of Science were searched for studies reporting odds ratios (OR) using arterial stiffness or cerebrovascular reactivity as continuous predictors for the presence of cSVD. Data were extracted using predefined tables and random-effects meta-analyses were performed to determine pooled OR and 95% confidence intervals. Results: Four cross-sectional studies were included in the analysis between cerebrovascular reactivity and cSVD, including 294 participants (38.1% women). Decrements in cerebrovascular reactivity were associated with a greater cSVD burden (OR = 1.93, 95% CI: 1.15-3.24, p = 0.01, I 2 = 97.4%). For arterial stiffness, 34 cross-sectional studies comprising of 26,541 participants (52.9% women) were included. Increases in indices of arterial stiffness were associated with a greater burden of cSVD (OR = 1.13, 95% CI: 1.07-1.20, p < 0.0001, I 2 = 60.2%). Conclusion: Impaired cerebrovascular reactivity and elevated arterial stiffness were both associated with an increased incidence of cSVD. While investigation of a link between cerebrovascular reactivity and arterial stiffness is a growing field, our findings suggest that the two measures have either individual or overlapping relationships with cSVD. This highlights the need for monitoring of both local and global cardiovascular regulation in high-risk individuals.

Chemogenetic inhibition of NTS astrocytes normalizes cardiac autonomic control and ameliorate hypertension during chronic intermittent hypoxia

BackgroundObstructive sleep apnea (OSA) is characterized by recurrent episodes of chronic intermittent hypoxia (CIH), which has been linked to the development of sympathoexcitation and hypertension. Furthermore, it has been shown that CIH induced inflammation and neuronal hyperactivation in the nucleus of the solitary tract (NTS), a key brainstem region involved in sympathetic and cardiovascular regulation. Since several studies have proposed that NTS astrocytes may mediate neuroinflammation, we aimed to determine the potential contribution of NTS-astrocytes on the pathogenesis of CIH-induced hypertension.ResultsTwenty-one days of CIH induced autonomic imbalance and hypertension in rats. Notably, acute chemogenetic inhibition (CNO) of medullary NTS astrocytes using Designer Receptors Exclusively Activated by Designers Drugs (DREADD) restored normal cardiac variability (LF/HF: 1.1 ± 0.2 vs. 2.4 ± 0.2 vs. 1.4 ± 0.3, Sham vs. CIH vs. CIH + CNO, respectively) and markedly reduced arterial blood pressure in rats exposed to CIH (MABP: 82.7 ± 1.2 vs. 104.8 ± 4.4 vs. 89.6 ± 0.9 mmHg, Sham vs. CIH vs. CIH + CNO, respectively). In addition, the potentiated sympathoexcitation elicit by acute hypoxic chemoreflex activation in rats exposed to CIH was also completely abolished by chemogenetic inhibition of NTS astrocytes using DREADDs.ConclusionOur results support a role for NTS astrocytes in the maintenance of heightened sympathetic drive and hypertension during chronic exposure to intermittent hypoxia mimicking OSA.

Physiological Approach to Cardio-endurance Training: Indicators of Optimal Parasympathetic Input on Cardiovascular Regulation are Better Predictors of Running Performance of Distance Runners

Poorly organized training schedules that are not focused on optimizing the cardiopulmonary fitness of the runner may lead to negative outcomes in their performance. Further, reduced cardiopulmonary fitness of a distance runner may lead to an imbalance of sympathetic and parasympathetic inputs of cardiac autonomic regulation. This altered balance of the regulation of the heart may recur as a vicious cycle, further hampering the runner's performance. The study assessed the effects of specialized training programs on the remodeling of cardiac autonomic regulation in relation to improving cardiopulmonary fitness and running performance of Sri Lankan male distance runners (N = 22). Before the intervention, runners were found to have more sympathetic dominancy on cardiac autonomic regulation along with suboptimal cardiopulmonary fitness level and suboptimal performance. After the intervention, more parasympathetic dominancy in cardiac autonomic regulation and improved cardiopulmonary fitness parameters were achieved. Post-intervention race timing of long-distance runners was significantly improved (p < 0.05) compared to the pre-intervention race timing irrespective of lower VO2peak level. The specialized training program used in this study optimized the parasympathetic dominancy of the autonomic regulation of the cardiovascular system of the Sri Lankan national long-distance runners. The runners were able to record significantly improved race timing after the specialized training intervention even though their VO2peak level was dropped. Thus, it is concluded that achieving parasympathetic dominant cardiac autonomic regulation is a better indicator than achieving higher VO2max levels given the performance of distance runners.

Econometric predictive model for assessing the functional state of students during the examination period: a cross-sectional exploratory pilot study

Background. Mathematical modeling is widely used in medicine to analyze the body systems in terms of their structure, work and interrelations. The present study investigates factors associated with the adaptation potential of the cardiovascular system, develops multiple regression models for the dependence of the adaptive potential on these factors, and compares the significance of the linear model with non-linear ones. Objectives. To determine changes in the circulatory system in students during the examination period and develop a mathematical model for predicting the adaptive potential of the cardiovascular system. Methods. The cohort observational study enrolled 74 students of Kirov State Medical University, aged 18–23 years, who gave consent to the survey. The participants were divided into two cohorts depending on the dominant type of the autonomic nervous system (group 1 — individuals with the dominance of sympathetic part of the peripheral division of the autonomic nervous system (n = 54) and group 2 — individuals with vagotonic type of regulation (n = 20)). The relationship between the hemodynamic parameters and the initial autonomic tone was considered as the main relevancy criterion of the study. Comparative analysis of hemodynamic parameters depending on the dominant type of autonomic nervous system was carried out in the cohorts. Development of the regression model was based on 74 observations. Data description included median (Me) and interquartile range representing 25th and 75th percentiles. The indicators in independent samples (cohorts) were compared using the non-parametric Mann—Whitney U test. Correlation analysis of relationships between the studied variables involved Spearman’s criterion (r). Differences and correlations were considered significant at p = 0.05. Calculations and analyses were performed using spreadsheets in Statistica Advanced 10 for Windows RU (Statsoft, Russia). Results. The state of the cardiovascular system significantly depends on the dominant type of the autonomic nervous system. Such parameters as stroke volume, cardiac index, cardiac minute output, circulatory efficiency were established to be significantly higher, whereas diastolic blood pressure, mean arterial pressure, cardiovascular index — lower in individuals with activation of the sympathetic part of the autonomic division of the peripheral nervous system. The study revealed significant correlations between the parameters of central hemodynamic and anthropometric parameters depending on the dominant type of the autonomic nervous system. Conclusion. Significant differences of hemodynamic parameters depending on the dominant type of autonomic system indicate the relevance of neurohumoral mechanisms of cardiovascular regulation. The values in adaptive potential exceeded 2.0 points, indicating the stress of the cardiovascular adaptation. The correlation regression analysis showed the greatest significance of the multiple linear regression model developed by the authors for predicting the adaptive potential of the cardiovascular system.

Cardiovascular physiology of embryonic neotropic cormorants (Phalacrocorax brasilianus)

Cardiovascular maturation in avian species has primarily been studied in precocial species of birds, with few studies conducted on altricial species, which make up the majority of avian species. In the precocial species of birds studied to date, cardiovascular regulation is derived primarily from an adrenergic receptor stimulation that is present from approximately 50% to 60% of incubation until hatching. Conversely, the cholinergic modulation of heart rate differs in its timing of activation, as it is reported to be present in some studies at 60% of incubation to as late as after hatching in others. This has led to the speculation that, although adrenergic stimulation is critical to cardiovascular homeostasis, cholinergic stimulation prior to hatching in birds is species-specific and therefore is not critical for cardiovascular homeostasis in embryonic birds. In this work, we conducted a series of studies on an altricial species, the neotropic cormorant (Phalacrocorax brasilianus), to gain novel data regarding cardiovascular development in a largely unstudied group of birds. We investigated cholinergic and adrenergic receptor mediated control of both arterial blood pressure and heart rate. We predicted that, given the state of this altricial species at hatching, both cholinergic and adrenergic tone on the cardiovascular system would be functional in the embryo. Our findings indicate that cholinergic tone was present at 90% of incubation. However, there was a pronounced adrenergic tone on the cardiovascular system that was relatively greater than that reported in the other studies of avian embryos. Therefore, our findings support our prediction regarding the function of cholinergic tone and adrenergic tone prior to hatching.

PACAP regulates VPAC1 expression, inflammatory processes and lipid homeostasis in M1- and M2-macrophages.

Pituitary adenylate cyclase-activating polypeptide (PACAP) acts as an anti-atherogenic neuropeptide and plays an important role in cytoprotective, as well as inflammatory processes, and cardiovascular regulation. Therefore, the aim of this study is to investigate the regulatory effects of PACAP and its receptor VPAC1 in relation to inflammatory processes and lipid homeostasis in different macrophage (MΦ) subtypes. To investigate the role of PACAP deficiency in the pathogenesis of atherosclerosis under standard chow (SC) or cholesterol-enriched diet (CED) in vivo, PACAP-/- mice were crossbred with ApoE-/- to generate PACAP-/-/ApoE-/- mice. Lumen stenosis in the aortic arch and different MΦ-subtypes were analyzed in atherosclerotic plaques by quantitative immunohistochemistry. Undifferentiated bone marrow-derived cells (BMDC) from 30-weeks-old ApoE-/- and PACAP-/-/ApoE-/- mice were isolated, differentiated into BMDM1- and BMDM2-MΦ, and incubated with oxidized low-density lipoprotein (oxLDL). In addition, PMA-differentiated human THP-1 MΦ were further differentiated into M1-/M2-MΦ and subsequently treated with PACAP38, the VPAC1 agonist [(Ala11,22,28)VIP], the antagonist (PG 97-269), and/or oxLDL. Uptake/accumulation of oxLDL was analyzed by oxLDL-DyLight™488 and Bodipy™ 493/503. The mRNA expression was analyzed by qRT-PCR, protein levels by Western blot, and cytokine release by ELISA. In vivo, after 30 weeks of SC, PACAP-/-/ApoE-/- mice showed increased lumen stenosis compared with ApoE-/- mice. In atherosclerotic plaques of PACAP-/-/ApoE-/- mice under CED, immunoreactive areas of VPAC1, CD86, and CD163 were increased compared with ApoE-/- mice. In vitro, VPAC1 protein levels were increased in PACAP-/-/ApoE-/- BMDM compared with ApoE-/- BMDM, resulting in increased TNF-α mRNA expression in BMDM1-MΦ and decreased TNF-α release in BMDM2-MΦ. Concerning lipid homeostasis, PACAP deficiency decreased the area of lipid droplets in BMDM1-/M2-MΦ with concomitant increasing adipose differentiation-related protein level. In THP-1 M1-/M2-MΦ, the VPAC1 antagonist increased the uptake of oxLDL, whereas the VPAC1 agonist decreased the oxLDL-induced intracellular triglyceride content. Our data suggest that PACAP via VPAC1 signaling plays an important regulatory role in inflammatory processes in atherosclerotic plaques and in lipid homeostasis in different MΦ-subtypes, thereby affecting foam cell formation. Therefore, VPAC1 agonists or PACAP may represent a new class of anti-atherogenic therapeutics.

THU124 High Fat Diet Disrupts Blood-Brain Barrier Integrity In Adult Males And Females

Abstract Disclosure: J.A. Sheng: None. R.J. Handa: None. S.A. Tobet: None. Background: The blood-brain barrier (BBB) protects the brain from the influx of harmful compounds in the blood. It is comprised of multiple cells, including endothelial cells sharing tight junctions, pericytes, and astrocyte endfeet. The paraventricular nucleus of the hypothalamus (PVN) is 3-5 times more vascularized than surrounding regions in the brain. The current study focuses on the BBB in the PVN as a function of stress. Recent data further suggests a high fat diet (HFD) disrupts the integrity of the BBB and leads to impairment of brain function (Li et al, 2021), suggesting a potential mechanism that may influence stress-related diseases. Methods: Adult male and female mice were placed on standard mouse chow (2918; Tekland) or a HFD (TD.06414, Tekland) for 6 weeks and further divided into control and stressed groups. Control mice were euthanized directly out of their home cage and stressed mice were euthanized 60-min after a 20-min acute restraint stress. Mice were perfused with fluorescein isothiocyanate in phosphate buffered saline followed by fixation with 4% paraformaldehyde to visualize blood vessel integrity (FITC leakage; Frahm & Tobet, 2015). Immunolabeled Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet) and IBA-1 (microglia) were used to further assess BBB integrity and neuroinflammation. Results: Results showed ∼40% more FITC leakage in the PVN vasculature in adult HFD females (p<0.0001) but not males. Similar leakage was not noted in the region lateral to the PVN. IBA-1 immunoreactivity (microglia) showed a HFD-related 50% increase in raw cell counts (p<0.001) and a HFD x restraint decrease in fluorescence intensity (p<0.02) in both sexes. GFAP immunoreactivity (astrocyte end feet) additionally showed 2-fold increase in cell counts in both sexes by HFD (p<0.0001) and a female-specific HFD-induced increase in area (∼40%; p<0.001). Conclusions: Data suggest a chronic high fat diet impairs BBB integrity in PVN vasculature that can be exacerbated further by a brief exposure to stress in adult mice. This effect is being further studied at the cellular level in astrocytes and microglia. Such changes in these BBB components could indicate critical roles for the uniquely dense PVN vasculature, increasing risk of damage to neural functions that could include obesity, cardiovascular autonomic regulation, or depression-like behaviors. Supported by ORWH-NIMH U54 MH118919 SCORE.

Response of the cardiovascular system to heart rate variability biofeedback intervention in adolescents with different autonomic nervous tone living in northern and southern regions

BACKGROUND: The cardiovascular responses of adolescents during self-regulation are contingent upon their initial autonomic tone and place of residence.
 AIM: To investigate the dynamics of cardiovascular system indices during heart rate variability biofeedback (HRV BF) training in adolescents with different initial autonomic regulation of heart rhythm, taking into account their residence in the northern and southern regions.
 MATERIAL AND METHODS: Schoolchildren aged 1617 years, residents of the northwestern (n=55), northeastern (n=55) and southern (n=55) regions of the Russian Federation were examined. Heart rate variability (HRV) and blood pressure (BP) were recorded. Participants were divided into the following groups according to their baseline autonomic regulation of cardiac rhythm: vagotonics, normotonics and sympathotonics. Normotonics and sympathotonics additionally had a one-time HRV BF session to increase parasympathetic influences on heart rhythm.
 RESULTS: The northwestern/northeastern/southern samples revealed 29/7/16% vagotonics; 42/47/49% normotonics; and 29/46/35% sympathotonics. BP was significantly greater in sympathotonics compared to vagotonics and normotonics in in the northeastern region and sympathotonics in the northwestern and southern regions. HRV BF training was successful in all participants: HRV parameters responded to a greater extent in sympathotonics living in the northwestern region while their BP and baroreflex levels were relatively stable. Sympathotonics of the northeastern and southern regions were characterized by preservation of elevated HR after HRV BF accompanied by a significant decrease in BP and a pronounced baroreflex response.
 CONCLUSION: In the northwestern region, adolescents who are mainly decendants of migrants from the southern regions typically have sympathicotonia and increased vascular response to HRV BF. The descendants of natives of the northwestern region apparently inherited more advanced mechanisms of cardiovascular regulations in the conditions of the Arctic.

The level of adropin and von Willebrand factor in patients with arterial hypertension, excess body weight, and obesity

Objective. To investigate changes in adropin and von Willebrand factor (vWF) levels in patients with arterial hypertension (AH), excess body weight, and obesity.Material and methods. All patients were divided into two main groups: group 1 included 69 patients with AH and excess body weight; group 2 – 55 people with AH and obesity, and 20 healthy people of the control group. Anthropometric measurement, biochemical blood test, echocardiographic examination of the heart, and enzyme immunoassay (adropin, vWF) were performed.Results. The level of vWF was significantly higher in patients with AH, overweight, and obesity compared to healthy individuals (p=0,001). Meanwhile, the adropin level decreased with increasing BMI. The lowest adropin level was observed in individuals with AH and obesity (p=0,011). Additionally, a significant positive correlation was identified between vWF and the size of the LA (r=0,667; p=0,001), RV (r=0,487; p=0,021), MMLV (r=0,795; p=0,001) and IMMLV (r=0,731; p=0,001), whereas a negative correlation was found with EF (r=-0,461; p=0,031).Conclusions. An increase in vWF level was observed in patients with hypertension, overweight, and obesity which contributes to the emergence of endothelial dysfunction and structural myocardial changes, related to AH. The decrease in adropin level – a regulator of the cardiovascular system functions – was associated with an increase in BMI and elevated BP. Negative correlations were found between adropin and systolic and diastolic blood pressure values. It plays an important role in blood pressure and cardiovascular function regulation.

Angiotensinergic and GABAergic transmission in the medial preoptic area: role in urinary bladder and cardiovascular control in female rats.

Introduction: The medial preoptic area (mPOA) participates in thermoregulatory control and blood pressure modulation as shown by studies with electrical stimulation of this area or cobalt chloride injection, a non-selective synapse inhibitor. This study aimed to investigate whether angiotensin II (Ang II) and GABA could act or not in the mPOA to mediate the cardiovascular and micturition control pathways. Methods: Female Wistar rats were submitted to stereotaxic surgery for implantation of a guide cannula into the mPOA 7days prior to the experiments. Afterwards, the animals were isoflurane- anesthetized and submitted to the catheterization of the femoral artery and vein and urinary bladder cannulation for mean arterial pressure (MAP), heart rate (HR), and intravesical pressure (IP) recordings, respectively. After the baseline MAP, HR, and IP recordings for 15min, Ang II (0.1nM, 1μL), losartan (AT-1 receptor antagonist, 100nM, 1μL), GABA (50mM, 1μL) or saline (1μL) were injected into the mPOA, and the variables were measured for additional 30min. In a different group of rats, the AT-1 receptor, angiotensin II converting enzyme (ACE), and GABAa receptor gene expression was evaluated in mPOA samples by qPCR. The data are as mean ± SEM and submitted to One-way ANOVA (Tukey posttest) or paired Student t-test (P <0.05). Results: The injection of Ang II into the mPOA evoked a significant hypotension (-37±10mmHg, n = 6, p = 0.024) and bradycardia (-47 ± 20bpm, p = 0.030) compared to saline (+1 ± 1mmHg and +6 ± 2bpm, n = 6). A significant increase in IP was observed after Ang II injection into the mPOA (+72.25 ± 17.91%, p = 0.015 vs. -1.80 ± 2.98%, n = 6, saline). No significant changes were observed in MAP, HR and IP after the losartan injection in the mPOA compared to saline injection. Injection of GABA into the mPOA evoked a significant fall in MAP and HR (-68 ± 2mmHg, n = 6, p < 0.0001 and -115 ± 14bpm, n = 6, p = 0.0002 vs. -1 ± 1mmHg and +4 ± 2bpm, n = 6, saline), but no significant changes were observed in IP. The AT-1 receptor, ACE and GABAa receptor mRNA expression was observed in all mPOA samples. Discussion: Therefore, in female rats, Ang II mediated transmission in the mPOA is involved in the cardiovascular regulation and in the control of central micturition pathways. A phasic control dependent on AT-1 receptors in the mPOA seems to be involved in the regulation of those cardiovascular and intravesical 3 parameters. In contrast, GABAergic transmission in the mPOA participates in the pathways of cardiovascular control in anesthetized female rats, nevertheless, this neurotransmission is not involved in the micturition control.

Orthostatic Stress and Baroreflex Sensitivity: A Window into Autonomic Dysfunction in Lone Paroxysmal Atrial Fibrillation.

The abnormal neural control of atria has been considered one of the mechanisms of paroxysmal atrial fibrillation (PAF) pathogenesis. The baroreceptor reflex has an important role in cardiovascular regulation and may serve as an index of autonomic function. This study aimed to analyze the baroreceptor reflex's role in heart rate regulation during upright tilt (HUT) in patients with lone PAF. The study included 68 patients with lone PAF and 34 healthy individuals who underwent baroreflex assessment. Parameters such as baroreflex sensitivity (BRS), number of systolic blood pressure (BP) ramps, and the baroreflex effectiveness index (BEI) were evaluated. The study found that PAF patients had comparable resting BPs and heart rates (HRs) to healthy individuals. However, unlike healthy individuals, PAF patients showed a sustained increase in BP with an upright posture followed by the delayed activation of the baroreceptor function with a blunted HR response and lower BEI values. This indicates a pronounced baroreflex impairment in PAF patients, even at rest. Our data suggest that together with BRS, BEI could be used as a marker of autonomic dysfunction in PAF patients, making it important to further investigate its relationship with AF recurrence after ablation and its involvement in cardiovascular autonomic remodeling.

Impaired parasympathetic function in long-COVID postural orthostatic tachycardia syndrome – a case-control study

PurposeEighty percent of patients infected by SARS-CoV-2 report persistence of one symptom beyond the 4-week convalescent period. Those with orthostatic tachycardia and orthostatic symptoms mimicking postural tachycardia syndrome, they are defined as Long-COVID POTS [LCP]. This case-control study investigated potential differences in autonomic cardiovascular regulation between LCP patients and healthy controls.MethodsThirteen LCP and 16 healthy controls, all female subjects, were studied without medications. Continuous blood pressure and ECG were recorded during orthostatic stress test, respiratory sinus arrhythmia, and Valsalva maneuver. Time domain and power spectral analysis of heart rate [HR] and systolic blood pressure [SBP] variability were computed characterizing cardiac autonomic control and sympathetic peripheral vasoconstriction.ResultsLCP had higher deltaHR (+ 40 ± 6 vs. + 21 ± 3 bpm, p = 0.004) and deltaSBP (+ 8 ± 4 vs. -1 ± 2 mmHg, p = 0.04) upon standing; 47% had impaired Valsalva maneuver ratio compared with 6.2% in controls (p = 0.01). Spectral analysis revealed that LCP had lower RMSSD (32.1 ± 4.6 vs. 48.9 ± 6.8 ms, p = 0.04) and HFRRI, both in absolute (349 ± 105 vs. 851 ± 253ms2, p = 0.03) and normalized units (32 ± 4 vs. 46 ± 4 n.u., p = 0.02). LFSBP was similar between groups.ConclusionsLCP have reduced cardiovagal modulation, but normal sympathetic cardiac and vasoconstrictive functions. Impaired parasympathetic function may contribute to the pathogenesis of Long-COVID POTS syndrome.

Serum kisspeptin is higher in hypertensive than non-hypertensive female subjects and positively correlated with systolic blood pressure.

Kisspeptin has a major role in reproductive regulation. Furthermore, it is also involved in metabolic and cardiovascular regulation as well as is a potent vasoconstrictor. This study aimed to: 1) determine correlations between serum kisspeptin levels with obesity/metabolic parameters; 2) compare parameters between non-hypertensive ([non-HT] N.=15) and hypertensive ([HT] N.=15) female subjects; and 3) determine correlations between leptin, systolic blood pressure (SBP) or diastolic blood pressure (DBP) with obesity and metabolic factors. Clinical parameters and fasting blood and adipose tissue samples were collected from women undergoing open abdominal surgery. Serum kisspeptin was not correlated with obesity parameters but was positively correlated with only SBP (P<0.05). Serum kisspeptin, SBP, DBP, body weight, waist circumference, hip circumference, plasma glucose, plasma insulin, the homeostatic model assessment for insulin resistance (HOMA-IR), and height of visceral adipocytes (VA) were higher but the Quantitative Insulin Sensitivity Check Index (QUICKI) was lower in hypertensive compared to non-hypertensive female subjects (P<0.05). Leptin was positively correlated with obesity and metabolic paramters including area, width, and perimeter of subcutaneous adipocytes, and area, width, height, and perimeter of VA (P<0.05) but was negatively correlated the QUICKI (P<0.001). SBP had positive correlations with insulin, glucose, HOMA-IR, and kisspeptin, but had a negative correlation with QUICKI (P<0.05). DBP had positive correlations with body weight, BMI, waist circumference, hip circumference, insulin, glucose, HOMA-IR, and width of VA (P<0.05), but had a negative correlation with the QUICKI (P<0.05). Kisspeptin, obesity especially visceral adiposity, and insulin resistance might contribute to increased blood pressure. Further studies are required to reveal the underlying mechanism of kisspeptin on metabolic and cardiovascular regulation.

Abstract P430: Primary Neuronal Cilium As A Novel Mediator Of Angiotensin II And Hypertension

Cilia are membrane-bound, microtubular projections emanating from the cell surface and present on virtually all cell types including neurons. Cilia abnormalities (ciliopathies) have been linked to a broad range of diseases including hypertension. Moreover, we previously reported that DOCA-salt hypertension is associated with alterations in cilia in select nuclei involved in cardiovascular regulation and fluid homeostasis such as the supraoptic nucleus, but the underlying mechanisms are not known. Given the well-established role of the brain renin-angiotensin system in DOCA-salt hypertension, we hypothesized that Angiotensin II (Ang II) contribute to neuronal cilia abnormalities in hypertension. We began by examining the effect of Ang II on cilia in two different neuronal cell lines, mouse hypothalamic N47 and Cath.a. Ang II treatment (100 nM for 4 hrs) caused a significant increase in cilia length of N47 cells that were transiently transfected with a Flag-tagged AT1a receptor (AT1aR) compared to non-transfected cells (3.83±0.15 μm vs 2.25±0.06 μm, P&lt;0.05). No change in cilia length was observed in AT1aR positive (2.71±0.09 μm) or negative cells (2.55±0.07 μm) treated with vehicle. Moreover, Ang II had no effect on cilia in N47 cells transfected with a Flag-tagged AT2R. Ang II also significantly increased cilia length in Cath.a cells which express the endogenous AT1aR. Truncation of AT1aR at position 318 resulted in loss of Ang II induced cilia elongation in N47 cells, indicating that the C-terminus of the receptor is important for Ang II regulation of cilia. Next, we evaluated the effect of Ang II infusion with minipumps (480ng/kg/min) on neuronal cilia in C57BL/6 mice. Mice infused with Ang II for 5 days which have elevated blood pressure displayed abnormally elongated cilia in the supraoptic nucleus (8.28±0.12 μm vs 6.37± 0.11 μm, P&lt;0.05). Interestingly, Ang II-induced cilia elongation preceded the development of hypertension as it was observed in mice infused with Ang II for 2 days when no change in blood pressure was detected. These findings point to Ang II as an important regulator of neuronal cilia via AT1aR. This represents a novel mechanism for cardiovascular regulation by the renin-angiotensin system.

Intrauterine Cannabis Exposure and Fetal and Maternal Blood Flow: A Case-control Study

(Acta Obstet Gynecol Scand. 2022;101:1207–1214) It is known that consuming cannabis during pregnancy increases the risk of complications for both mother and infant, but the mechanisms of this increased risk are unknown. Endogenous cannabinoid systems are associated with cardiovascular regulation, and exogenous cannabis consumption has been shown to have some cardiovascular effects. This study aimed to examine the effects of cannabis consumption during pregnancy on fetal and maternal blood flow and explore the mechanisms of cardiovascular risk.

Impact of vericiguat on baroreflex-mediated sympathetic circulatory regulation: An open-loop analysis.

To quantify in vivo the effects of the soluble guanylate cyclase (sGC) stimulator, vericiguat, on autonomic cardiovascular regulation in comparison with the nitric oxide (NO) donor, sodium nitroprusside. In anesthetized Wistar-Kyoto rats, baroreflex-mediated changes in sympathetic nerve activity (SNA), arterial pressure (AP), central venous pressure (CVP), and aortic flow (AoF) were examined before and during the intravenous continuous administration (10 μg·kg-1·min-1) of vericiguat or sodium nitroprusside (n = 8 each). Systemic vascular resistance (SVR) was calculated as SVR = (AP-CVP) / AoF. Neither vericiguat nor sodium nitroprusside affected fitted parameters of the baroreflex-mediated SNA response. Both vericiguat and sodium nitroprusside decreased the AP mainly through their peripheral effects. Vericiguat halved the slope of the SNA-SVR relationship from 0.012 ± 0.002 to 0.006 ± 0.002 mmHg·min·mL-1·%-1 (P = 0.008), whereas sodium nitroprusside caused a near parallel downward shift in the SNA-SVR relationship with a reduction of the SVR intercept from 1.235 ± 0.187 to 0.851 ± 0.123 mmHg·min/mL (P = 0.008). Neither vericiguat nor sodium nitroprusside significantly affected the baroreflex-mediated SNA response. The vasodilative effect of vericiguat became greater toward high levels of SNA and AP, possibly reflecting the increased sGC sensitivity to endogenous NO. By contrast, the effect of sodium nitroprusside was more uniform over the range of SNA. These results help better understand cardiovascular effects of vericiguat.

GABAergic and glutamatergic transmission reveals novel cardiovascular and urinary bladder control features in the shell nucleus accumbens

The shell Nucleus Accumbens (NAcc) projects to the lateral preoptic area, which is involved in the central micturition control and receives inputs from medullary areas involved in cardiovascular control. We investigated the role of GABAergic and glutamatergic transmission in the shell NAcc on intravesical pressure (IP) and cardiovascular control. Male Wistar rats with guide cannulas implanted bilaterally in the shell NAcc 7 days prior to the experiments were anesthetized with 2% isoflurane in 100% O2 and subjected to cannulation of the femoral artery and vein for mean arterial pressure (MAP) and heart rate recordings (HR) and infusion of drugs, respectively. The urinary bladder (UB) was cannulated for IP measurement. A Doppler flow probe was placed around the renal arterial for renal blood flow (RBF) measurement. After the baseline MAP, HR, IP and RBF recordings for 15 min, GABA or bicuculline methiodate (BMI) or L-glutamate or kynurenic acid (KYN) or saline (vehicle) were bilaterally injected into the shell NAcc and the variables were measured for 30 min. Data are as mean ± SEM and submitted to Student́s t test. GABA injections into the shell NAcc evoked a significant fall in MAP and HR and increased IP and RC compared to saline. L-glutamate in the shell NAcc increased MAP, HR and IP and reduced RC. Injections of BMI and KYN elicited no changes in the variables recorded. Therefore, the GABAergic and glutamatergic transmissions in neurons in the shell NAcc are involved in the neural pathways responsible for the central cardiovascular control and UB regulation.

Differences in Cardiovascular Regulation to Head-up Tilt between Healthy and Hypertensive Subjects.

To date there have only been limited studies exploring abnormal hemodynamic responses to head-up tilt tests (HUTs) in elderly, treated patients with hypertension. Cardiovascular regulation in response to HUT as well as upright hemodynamics may be altered when older hypertensive patients with antihypertensive treatments are studied. Hypertensive patients with and without receiving antihypertensive medication and above the age of 45 were recruited in this study. This study compared the cardiovascular responses to HUT and at rest between healthy and hypertensives using non-invasive hemodynamic measurements. Parameters such as systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), stroke index (SI) and total peripheral resistance index (TPRI) were measured in 40 subjects (20 healthy and 20 hypertensives) for 10-min supine baseline, 10-min HUT at 70◦ and 6-min supine recovery. At rest and during HUT, SBP and TPRI were significantly higher in hypertensives together with a significantly smaller baseline SI. In response to HUT, both groups showed changes in hemodynamic parameters at differing degrees. During recovery, all parameters returned to the baseline range. Our findings indicated that hypertensive patients of older age being treated by antihypertensive drugs may have different cardiovascular changes in response to orthostatic stress.Clinical Relevance- This pilot study describes how cardiovascular regulation in response to postural change may behave differently in hypertensive elder patients taking antihypertensive drugs.

Heart failure and the heart-brain axis.

In heart failure (HF) strong haemodynamic and neuronal signalling feedback interactions between the heart and the central nervous system (CNS) exist that are able to mutually provoke acute or chronic functional impairment. Cerebral injury secondary to HF may include acute stroke, cognitive decline and dementia and depressive disorders. Also brain stem functions are involved in the cardiac-cerebral interaction in HF as neurohormonal control and neuronal reflex circuits are known to be impaired or imbalanced in HF. In turn, impaired cerebral functions may account for direct and indirect myocardial injury and may contribute to symptomatic severity of HF, to disease progression and to increased mortality. Despite the clinical and pathophysiologic significance of the heart-CNS interaction, this relevant field of HF comorbidity is clinically under-recognized with regard to both diagnostic workup and treatment efforts. Here, principal aspects of pathophysiologic heart-CNS interactions related to HF are discussed such as stroke, effects on cognitive function, on depressive disorder and neurovegetative control and neuronal cardiovascular reflex regulation. Aspects of (limited) treatment options for cerebral functional interactions in HF are examined.