Elevated Mean Arterial Pressure Research Articles

Ambient PMs Pollution, Blood Pressure, Potential Mediation by Short-Chain Fatty Acids: A Prospective Panel Study of Young Adults in China

BackgroundThe concurrent effects of particulate matter (PM) on both blood pressure (BP) and short-chain fatty acids (SCFAs) are insufficiently explored, with limited research on the potential mediating roles of SCFAs. MethodsIn this prospective panel study with 4 follow-ups, we recruited 40 college students in Hefei, China, to assess the impacts of short-term exposure to PM (aerodynamic diameter ≤10 μm (PM10), ≤2.5 μm (PM2.5), and ≤1 μm (PM1)) on BP and SCFAs, along with potential mechanisms. Real-time PM data, urinary SCFAs levels, and BP indicators were systematically collected. Linear mixed-effects models assessed the relationships between PM, SCFAs, and BP. Mediation analyses explored SCFAs’ mediating role in the PM-BP association. ResultsPM exposure was positively linked to BP and negatively associated with SCFAs. For a 10μg/m3 rise in PM10 at lag 0-72h, there were notable reductions of 0.0019% (95%CI: -0.0028, -0.0010) in Acetic acid, 0.0262% (-0.0369, -0.0155) in Propionic acid, and 0.0702% (-0.1025, -0.0378) in Butyric acid. Systolic BP, diastolic BP, and mean arterial pressure (MAP) increased by 2.60mmHg (0.96, 4.25), 2.24mmHg (1.18, 3.31), and 2.36mmHg (1.20, 3.53), respectively, per 10-μg/m3 rise in PM1 at lag 0-24h. Decreased SCFAs levels explained significant portions (24.69% to 31.80%) of the elevated MAP due to PM10. Stronger associations were found in females and individuals with abnormal BMI. ConclusionsOur study shows that PM exposure decreases urinary SCFAs levels, which partially mediate the impact of PM on elevated BP. These findings enhance our comprehension of the pathways linking PM exposure to BP changes.

The relationships between age, sex and exercise intensity on cerebral artery haemodynamics during isometric handgrip exercise.

Age and sex may alter the cerebral blood flow (CBF) responses to acute isometric exercise, via associated elevations in mean arterial pressure (MAP) and sympathetic activation. Our aim was to determine the relationships between age, sex and exercise intensity on cerebrovascular responses to isometric handgrip exercise. In 78 healthy adults (18-80 years, N=42 female), cerebrovascular responses were assessed during two minute isometric exercise bouts at three intensities (15, 30, 45% maximal voluntary contraction). Intracranial responses of the middle cerebral artery (MCA) and posterior cerebral artery (PCA) velocity (v) were measured using transcranial Doppler ultrasound. Extracranial responses of the internal carotid artery (ICA) and vertebral artery (VA) were assessed using Duplex ultrasound. Cardiopulmonary haemodynamic and neural parameters were measured throughout, including muscle sympathetic nerve activity, end-tidal carbon dioxide, and MAP. There were significant positive relationships between exercise intensity and the cerebral responses of the MCAv (P<0.001) and PCAv (P=0.005). There were no effects of intensity on ICA and VA responses (P>0.05), despite intensity-dependent increases in MAP (P<0.001). The increased MCAv response to exercise was blunted with advancing age (P=0.01) with no influence of sex (P=0.86). The present study provides data on age, sex and intensity specific relationships with intracranial and extracranial cerebrovascular responses to isometric exercise. Despite similar ICA, VA, and PCA responses, MCAv responses were attenuated with advancing age during handgrip exercise with no sex dependent influence. Further, intracranial responses were intensity dependent, whereas extracranial blood flow, shear-stress and velocity responses were similarly increased at all intensities during handgrip exercise.

Abstract P112: Modifiable Factors Associated with Elevated Mean Arterial Pressure after Lower-Limb Loss

Introduction: Adults with lower-limb loss (LLL) have increased risk of cardiovascular disease even after accounting for risk factors such as physical inactivity and comorbidity burden. Increased risk of cardiovascular mortality may be driven by structural adaptations following LLL, such as increased peripheral vascular resistance. Elevated mean arterial pressure (MAP), the steady component of blood pressure, is a clinical indicator of increased peripheral vascular resistance. Additionally, MAP &gt;100mmHg is known to lead to cardiovascular damage. However, factors associated with elevated MAP among individuals with LLL remain unknown. We aimed to identify factors associated with elevated MAP among adults with LLL, while considering non-modifiable factors. Hypothesis: We hypothesized that LLL-specific non-modifiable variables (e.g., amputation level) and modifiable variables (e.g., prosthesis use) would be significantly associated with elevated MAP presence. Methods: From 2013 to 2023, community-dwelling adults, aged ≥18 years, with LLL and no history of a major adverse cardiac event, who attended a multidisciplinary LLL clinic, underwent standardized evaluations that included medical history review and blood pressure assessment. MAP was calculated using the equation: MAP = diastolic blood pressure + (0.466 × pulse pressure), with a MAP &gt;100mmHg classified as elevated. Variables that were significantly different between-groups, i.e., MAP ≤ 100mmHg and MAP &gt;100mmHg, were input in a forward stepwise logistic regression. Associations between modifiable factors and MAP status were evaluated after controlling for non-modifiable factors. Results: Of 206 participants (54.5±14.1 years old; 74.3% male; 72.8% Caucasian; 81.1% unilateral LLL; 59.2% transtibial; 42.2% dysvascular etiology), n=107 (51.9%) presented with elevated MAP. MAPs &gt;100mmHg were associated with upper extremity pain [odds ratio (OR)=2.74, 95% confidence interval (CI)=1.31-5.74, p=0.008], assistive device use (OR=2.05, 95%CI=1.12-3.74, p=0.020) and elevated pulse rate (OR=1.02, CI=1.00-1.04, p=0.045). Conclusions: More than 50% of adults with LLL and no major adverse cardiac event history present with elevated MAP, indicating a maladaptive increase in peripheral vascular resistance. Identified factors that were significantly associated with elevated MAP may suggest subclinical cardiovascular disease and/or sympathetic overactivity, warranting closer evaluation of cardiovascular risk among adults with LLL.

Abstract P421: Differential Osmolyte Profiles in Hypertensive and Normotensive Rats.

Hypertension is known to be associated with water-electrolyte balance disturbances that lead to changes in osmotic pressure. Osmolytes are small organic molecules essential for cellular adaptation to changes in osmotic pressure. This study investigates the levels of osmolytes in serum and tissues using two well-established rat models of hypertension: spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats with angiotensin II-induced hypertension (WKY-ANG). Experiments were conducted on male Wistar-Kyoto (WKY) rats, SHRs, and WKY-ANG rats. Blood and tissue samples were collected from all groups for liquid chromatography with mass spectrometry (LC-MS) analysis of selected osmolytes. Anesthetized SHR and WKY-ANG rats displayed significantly elevated mean arterial blood pressures compared to WKY rats (118.4±1.3, 110.2±0.9, and 76.5±1.2 mmHg, respectively). The serum and tissue levels of sarcosine were significantly decreased in SHRs compared to WKY rats (1.90±0.21 vs. 3.80±0.80 for serum, 55.55±9.79 vs 92.37±10.57 for liver, 6.06±0.78 vs. 10.55±1.19 for renal cortex, 9.14±0.45 vs.13.83±1.14 for renal medulla, 11.59±1.17 vs. 22.34±3.11 for lungs, 1.80±0.14 vs. 3.30±0.39 for heart, respectively). Reduced levels of beta-alanine were observed only in the serum of SHRs compared to WKY and WKY-ANG rats (6.48±0.93 vs. 59.43±9.47, 41.32±3.13 respectively). Additionally, higher levels of L-alanine were noted in the renal cortex and medulla of WKY than in SHRs and WKY-ANG rats (19685±592.3 vs. 14510±456.8, 14289±719.4 for cortex and 14043±560.3 vs. 11520±206.8, 10651±292.4 for medulla, respectively). Conversely, SHR rats exhibited significantly higher levels of serum glycerophosphocholine (GPC) than WKY-ANG rats (38.21±10.02 vs. 12.47±2.25). Simultaneously, lower levels of betaine were observed in the lungs of SHR rats when compared to WKY and WKY-ANG rats (1 and 351.20±36.02, 607.10±64.20, 606.70±55.88 for lungs respectively). All results are indicated in μmol/L and means±SE. In conclusion significant alterations in osmolyte concentrations are evident in hypertensive rats. These findings suggest that hypertension may be associated with disruptions in osmolyte balance. Further studies are needed to assess the potential clinical significance of osmolyte disturbances in hypertension.

Abstract P147: Inappropriate Activation of the Leptin-Aldosterone-Endothelial Mineralocorticoid Receptor Axis Promotes Salt Sensitivity of Blood Pressure in Young Female Mice

While compelling clinical evidence indicates that women are more salt-sensitive than men, the mechanisms of the onset of women’s salt-sensitive blood pressure (SSBP) remain largely elusive. Herein, we employed salt-sensitive (SS)-Balb/C and salt-resistant (SR)-C57Bl/6 mice to investigate the etiopathology of SSBP in females. We hypothesized that a high-salt diet alters the leptin-aldosterone-endothelial mineralocorticoid receptor axis (ECMR), leading to SSBP and vascular dysfunction in young SS-female mice. Eleven-week-old female mice were fed a normal (0.4%, NSD) or a high salt diet (4%, HSD) for 7-days. We implanted radiotelemeters for BP monitoring at baseline, HSD, and in response to the leptin receptor (LepR) blockade combined with HSD. Following euthanasia, mesenteric arteries are isolated to measure vascular function via wire myography. HSD elevated mean arterial pressure in Balb/C (NSD: 98.4±2.3 vs. HSD: 105.1±0.9 mmHg) but not in C57 mice (NSD: 99.3±0.9 vs. HSD: 101.3±0.5 mmHg). However, SS-Balb/C mice showed superior natriuretic function in response to salt loading experiments (NSD: 13.3% vs. HSD: 42.3%) as opposed to C57 mice (NSD: 25.8% vs. HSD: 35.1%) (N=3). HSD feeding notably blunted endothelial relaxation to acetylcholine in Balb/c (NSD: 96.5% vs. HSD: 75.4%, N=7), an effect not seen in C57. SS-Balb/C mice failed to suppress aldosterone and adrenal aldosterone synthase (CYP11B2) levels (protein and transcript) compared to C57 mice. This concomitated a 1.8-fold increase in adrenal steroidogenic acute regulatory (StAR) mRNA in SS-Balb/C mice. HSD raised CYP11B2 protein levels in the visceral adipose tissue (VAT) of Balb/C mice. Leptin regulating CYP11B2 expression; we measured fat mass, leptin, and LepR expression. HSD enhanced fat accumulation (C57: +0.7% vs. Balb/c: +26.5%, N=12), leptin levels, and LepR transcript in the adrenal and VAT only in Balb/C mice. LepR blockade reduced BP in Balb/C mice fed a HSD (HSD: 105.1±0.9 vs. HSD+Allo-aca: 100.3±1.9 mmHg). HSD elevated ECMR expression only in Balb/C mice (N=6). To test the potential role of aldosterone-mediated ECMR activation in SSBP, we employed mice with selective overexpression of MR in endothelial cells (ECMR-OE). ECMR-OE young female mice exhibited impaired endothelial function (N=7), reproducing the effects of HSD. In conclusion, SSBP involves an over-activation of the leptin-aldosterone axis in both adrenal and adipose tissue, along with an escalated ECMR expression in females.

Association of baseline blood pressure and outcomes in etiology subtypes of large vessel occlusion stroke: Data from ANGEL-ACT registry

BackgroundBlood pressure (BP) management at the initial stage of stroke caused by large-vessel occlusion (LVO) remains challenging. We assessed the association between baseline BP and clinical and safety outcomes of endovascular treatment (EVT) in different stroke etiologies. MethodsPatients with acute ischemic stroke and anterior circulation LVO were screened from a prospective, multicenter registry of EVT from November 2017 to March 2019. The primary outcome was poor 90-day outcome (modified Rankin Scale score 3–6). The safety outcome was 24 h post-procedure parenchymal hematoma (PH). The Trial of Org 101072 in Acute Stroke Treatment criteria were used for etiologic stroke classification. Restricted cubic spline and binary logistic regression analysis were performed to examine the association between study outcomes and natural log-transformed BP. ResultsIn subgroup analyses, a U-shaped correlation existed between baseline mean arterial pressure (MAP) and poor outcome in large-artery atherosclerosis stroke only. Higher MAP was an independent risk factor compared with a central reference value (≥ 133 mm Hg vs 96–115 mm Hg; adjusted OR [aOR], 2.50; 95 % CI, 1.09 to 5.71, P = 0.030). Whereas elevated MAP was associated with PH (aOR, 1.58; 95 % CI 1.04 to 2.39, P = 0.030 for a ln10-unit increase in natural log-transformed MAP) in the range <110 mm Hg exclusively for cardioembolic stroke. ConclusionWhether it is cause or epiphenomenon, baseline BP was associated with 90-day outcome in large-artery atherosclerosis stroke, whereas in cardioembolic stroke baseline BP was correlated with post-procedure PH within a certain range. Identifying these features based on etiological subtypes may offer a reference for BP management in acute LVO stroke.

Evaluation of Nicorandil in Treatment of induced pulmonary arterial hypertension in male Rats

Pulmonary arterial hypertension (PAH) is a chronic, rare, and non-treatable disease, resulting in elevated mean arterial pressure (≥25mmHg) during rest and (≥30mmHg) during exercise. Pulmonary arteries remodeling including endothelial apoptosis, smooth muscle hyperplasia, and endothelial dysfunction are distinct features of PAH. This study aims to evaluate effect of nicorandil as an alternative treatment for PAH in comparison to tadalafil by evaluating its anti-inflammatory effect and histopathological changes. A total of 60 male wistar rats were divided to 6 groups, a control healthy group, and another 5 groups injected with monocrotaline to induce PAH. The induction group was left untreated while the other 4 groups were treated with either nicorandil or tadalafil, with or without treatment blockers (N-Nitroarginine methyl ester and glimepiride), after 21 days they were sacrificed for histopathology and measurement of inflammatory markers. Nicorandil reduced the levels of osteopontin, and cardiac marker brain natriuretic peptide (BNP) significantly (P≤0.05) , also it showed an improved histopathological picture of PAH by reducing smooth muscle proliferation, necrosis, and inflammation in pulmonary arteries. In conclusion, nicorandil in this study showed promising results in reducing inflammation and improving endothelial function.

New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Veno-Arterial Extracorporeal Membrane Oxygenation in the Rat.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.

Ischemic Post-Conditioning in a Rat Model of Asphyxial Cardiac Arrest.

Ischemic post-conditioning (IPoC) has been shown to improve outcomes in limited pre-clinical models. As down-time is often unknown, this technique needs to be investigated over a range of scenarios. As this tool limits reperfusion injury, there may be limited benefit or even harm after short arrest and limited ischemia-reperfusion injury. Eighteen male Wistar rats underwent 7 min of asphyxial arrest. Animals randomized to IPoC received a 20 s pause followed by 20 s of compressions, repeated four times, initiated 40 s into cardiopulmonary resuscitation. If return of spontaneous circulation (ROSC) was achieved, epinephrine was titrated to mean arterial pressure (MAP) of 70 mmHg. Data were analyzed using t-test or Mann-Whitney test. Significance set at p ≤ 0.05. The rate of ROSC was equivalent in both groups, 88%. There was no statistically significant difference in time to ROSC, epinephrine required post ROSC, carotid flow, or peak lactate at any timepoint. There was a significantly elevated MAP with IPoC, 90.7 mmHg (SD 13.9), as compared to standard CPR, 76.7 mmHg (8.5), 2 h after ROSC, p = 0.03. IPoC demonstrated no harm in a model of short arrest using a new arrest etiology for CPR based IPoC intervention in a rat model.

Does Elevated Mean-Arterial Pressure Lead to Better Outcomes in Degenerative Cervical Myelopathy?- A Prospective, Pilot Randomized Control Trial.

Randomized Control Trial. DCM refers to compression of spinal cord either due to static/dynamic causes or commonly, a result of combination of both. Number of variables exist, which determine prognosis post-surgery. Role of intra-operative blood pressure has not been analyzed in depth in current literature. Elevating MAP post SCI is widely practiced and forms a recommendation of AANS/CNS Joint Committee Guidelines. This led us to investigate role played by elevated MAP during surgery for DCM, in order to optimize outcomes. This prospective randomized comparative pilot study was conducted at a tertiary care spine centre. 84 patients were randomly divided in two groups. Group 1 had intra-operative MAP in normal range. Group 2, had intra-operative BP 20 mmHg higher than preoperative average MAP with a variation of + 5mmHg. Outcomes were recorded at 3 months, 6 months and 1 year by mJOA, VAS and ASIA scale. Neurological improvement was documented in 19/30 (63.3%) patients of hypertensive group compared to 16/30 (53.3%) patients of normotensive group. Improvements in mJOA scores were better for hypertensive group during the 1-year follow-up. Improvement in VAS scores were comparable between two groups, but at 1-year follow-up the VAS score of hypertensive groups was significantly lower. MAP should be individualized according to preoperative average blood pressure assessment of patient. Keeping intraoperative MAP at higher level (preoperative MAP + 20mmHg) during surgery for DCM can result in better outcomes.

Lower vascular conductance responses to handgrip exercise are improved following acute antioxidant supplementation in young individuals with post-traumatic stress disorder.

Young individuals with post-traumatic stress disorder (PTSD) display peripheral vascular and autonomic nervous system dysfunction, two factors potentially stemming from a redox imbalance. It is currently unclear if these aforementioned factors, observed at rest, alter peripheral haemodynamic responses to exercise in this population. This study examined haemodynamic responses to handgrip exercise in young individuals with PTSD following acute antioxidant (AO) supplementation. Thirteen young individuals with PTSD (age 23±3years), and 13 age- and sex-matched controls (CTRL) participated in the study. Exercise-induced changes to arm blood flow (BF), mean arterial pressure (MAP) and vascular conductance (VC) were evaluated across two workloads of rhythmic handgrip exercise (3 and 6kg). The PTSD group participated in two visits, consuming either a placebo (PL) or AO prior to their visits. The PTSD group demonstrated significantly lower VC (P=0.04) across all exercise workloads (vs. CTRL), which was significantly improved following AO supplementation. In the PTSD group, AO supplementation improved VC in participants possessing the lowest VC responses to handgrip exercise, with AO supplementation significantly improving VC responses (3 and 6kg: P<0.01) by blunting elevated exercise-induced MAP responses (3kg: P=0.01; 6kg: P<0.01). Lower VC responses during handgrip exercise were improved following AO supplementation in young individuals with PTSD. AO supplementation was associated with a blunting of exercise-induced MAP responses in individuals with PTSD displaying elevated MAP responses. This study revealed that young individuals with PTSD exhibit abnormal, peripherally mediated exercise responses that may be linked to a redox imbalance.

AT1-AA Induced Placental Ischemia Contributes to Hypertension in Female Offspring

Objective: Preeclampsia (PE), new-onset hypertension during the third trimester of pregnancy alongside other organ dysfunction, is associated with chronic inflammation and fetal growth restriction. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA) are produced in PE women and induce a PE-like phenotype when infused into pregnant rats. AT1-AA is still present in maternal circulation up to eight years postpartum. We have shown that AT1-AA exposure during pregnancy contributes to impairment of cerebral blood flow in the postpartum period. Moreover, PE offspring are at higher risk for cardiovascular disease and hypertension but AT1-AA’s role in this elevated risk is unknown. The objective of this study was to determine if AT1-AA contributes to the risk for hypertension in PE offspring. Therefore, we hypothesized that AT1-AA infusion during pregnancy would cause offspring to have low birth weight and hypertension in adulthood. Methods: We infused AT1-AA (1:40) starting on gestational day (GD) 14 and allowed the dams to give birth on GD21. Birth weight was measured within 12 hours. Offspring were aged to 4 months. At that time, one male and female per litter were randomly selected to undergo carotid catheterization. The following day mean arterial pressure (MAP) was measured and blood and tissues were collected. Immune cells were measured by flow cytometry. Sex hormones were measured by mass spectroscopy. AT1-AA was measured by cardiomyocyte bioassay. Renal endothelin was measured by ELISA and RT-PCR. A two-way ANOVA was used for statistical analysis. Results: AT1-AA male and female offspring (6.1±0.1g, n=19, p&lt;0.05; 5.8±0.1g, n=19, p&lt;0.05) were larger at birth than NP male and female offspring (5.8±0.1g, n=11; 5.5±0.1g, n=11). Female AT1-AA offspring had elevated MAP (124±2 mmHg, n=14, p&lt;0.05) compared to NP female offspring (110±5 mmHg, n=8) while male AT1-AA offspring had similar MAP to male NP offspring. Circulating cytolytic NK cells trended higher in female AT1-AA offspring (2.73±0.37 % gated, n=9, p=0.0949) compared to female NP offspring (1.66±0.31 % gated, n=6). Female AT1-AA offspring also had elevated progesterone (41.3±6.0 pg/μL, n=8, p=0.0556) compared to female NP offspring (26.9±4.9 pg/μL, n=7). Renal PPET expression was increased in female AT1-AA offspring (2.6±0.69 fold increase, n=4, p&lt;0.05) compared to female NP offspring. Renal endothelin-1 was increased in female AT1-AA offspring (1.02±0.23 pg/mg, n=7, p=0.062) compared to female NP offspring (0.59±0.06 pg/mg, n=6). Male and female AT1-AA offspring had increased circulating AT1-AA (9.5±2.2 ΔBPM, n=6, p&lt;0.0001; 7.9±0.9 ΔBPM, n=8, p&lt;0.001) compared to male and female NP offspring (-0.4±.4 ΔBPM, n=7; -0.8±0.4 ΔBPM, n=4). Conclusion: These data demonstrate that AT1-AA infusion during pregnancy can predispose female offspring to have elevated blood pressure in adulthood. This study was supported by NIH grants RO1HD067541 (BL), F31HD110230 (NC), P20GM121334 (BL, LMA), HL151407 (DCC) and American heart association (AHA) early career award 19CDA34670055 (LMA). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exercise Mitigates Angiotensin II-Mediated Sympathetic Nerve-Macrophage Interaction in Aortic Adventitia Leading to Vascular Remodeling

Large artery stiffness is a significant risk factor for cardiovascular diseases. Our previous study suggested that angiotensin II (Ang II) stimulates sympathetic innervation in aortic adventitia (AA) leading to elevated mean arterial blood pressure and increased arterial fibrosis, while voluntary wheel-running (VWR) reduces them. The aim of this study is to explore mechanism under Ang II-induced the aortic remodeling through sympathetic nerves and immune cell interactions using transcriptomics. We isolated cells in AA from Ang II (1.5 mg/kg/day) vs. Vehicle (Saline) infused C57BL/6 male mice (n=3 of each group), and we performed single-cell RNA-sequencing (scRNAseq). We profiled 23,419 cells after quality control and filtering steps and annotated 9 cell types in the AA employing a uniform manifold approximation and projection (UMAP) to visualize the remaining cells and the Leiden cluster algorithm. Firstly, we identified the Adrb2 gene for β2-adrenergic receptor (β2-ADR) was predominantly expressed in macrophages/monocytes as compared to other cell types, and significantly more expressed in macrophages vs. monocytes (adjusted p-value, &lt;0.05). We validated the transcriptomic results using immunostaining for β2-ADR and synapsin with CD68 in AA. In addition, Ang II increased AA macrophage proportion which displays M1 phenotype (pro-inflammatory) (adjusted p-value, &lt;0.05). These findings suggest that Ang II promotes M1 like macrophages which interact with sympathetic nerves in AA. Next, we performed Gene Ontology (GO) enrichment test in macrophages and fibroblasts. Ang II Macrophages were enriched in GO terms with inflammation and cytokines, and Ang II fibroblasts were enriched in GO terms involved in extracellular matrix deposition. The GO results indicate that Ang II induced inflammatory macrophages activates fibroblasts to accumulate ECM deposition in AA. Congruent with the scRNAseq results, we found that number of macrophages, ECM accumulation, and vascular stiffness measured by pulse wave velocity were increased with Ang II vs. Vehicle (all, p &lt;0.05), whereas interestingly VWR ameliorated the Ang II effects. This study provides the evidence that Ang II promotes aortic remodeling by interaction between sympathetic nerves and macrophage which results in ECM deposition in AA using transcriptomics approach, while VWR countermeasure to these detrimental effects. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Potassium Ion Channel Modulation as a Potential Remedy for Cadmium-induced Hypertension

Objective: Hypertension remains a chief non-communicable lifestyle disease that is negatively associated with dietary cadmium (Cd). The exact mechanism of Cd toxicity and the mitigating role of potassium supplementation are not fully known, hence, this study aimed to investigate their effects on the aorta. Hypothesis: We hypothesized that potassium supplementation can modulate Cd-induced vascular dysfunction. Method: Six cohorts of control, Cd-exposed, and potassium supplemented male Sprague-Dawley rats were selected. Hypertension was induced using cadmium chloride (2.5 or 5 mg/kg b.w.). Blood pressure was measured twice weekly. Reactivity to pharmacological agents with and without potassium ion channel modulation was assessed in thoracic aortic rings after eight weeks, using an organ bath set-up. Data: Statistical analysis was done using one-way analysis of variance and the results were reported as mean ± standard error of the mean. The Games-Howell or Bonferroni post hoc test was used for multiple comparisons. Summary of Results: Cadmium significantly (p&lt;0.05) elevated systolic, diastolic, mean arterial, and pulse pressures, reduced (p&lt;0.001) phenylephrine-induced contraction mostly via BKCa channels, and augmented (p&lt;0.05) sodium nitroprusside-induced relaxation via K-ATP, KV, and KIR channels, without affecting acetylcholine-induced relaxation. Potassium supplementation ameliorated these effects via KIR and BKCa channels. Conclusions: The results indicate that modulation of potassium ion channels in the vasculature might provide therapeutic management for environmentally-induced hypertension and should be further explored. Funding source: The Mona Campus Committee for Research and Publications and Graduate Awards, School for Graduate Studies and Research, University of the West Indies. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of Renin Angiotensin System Inhibition on Renal Function in Fructose-induced Salt Sensitive Blood Pressure

Combined dietary intake of fructose with high salt at levels comparable to that in the upper quintile of western population increases blood pressure, decreases glomerular filtration rate, and results in albuminuria and insulin resistance. We tested the hypothesis that chronic treatment with either an angiotensin converting enzyme inhibitor (enalapril) or angiotensin receptor blocker (losartan) will preserve glomerular filtration rate (GFR) and reduce albuminuria. Sprague Dawley rats of both sexes were instrumented with telemetry. After a baseline period on glucose+0.4% NaCl, rats were assigned to the following groups: 20% glucose+0.4%NaCl treated with vehicle (GNS+V) or 20% fructose+4% NaCl and treated with either vehicle (FHS+V), losartan 0.42 mg/kg/hr by osmotic minipump (FHS+L) or enalapril 0.21 mg/kg/hr (FHS+E). The doses of losartan and enalapril were chosen to achieve MAP similar to the control GNS+V group. Body weights did not differ among the groups upon entry into the protocol and increased similarly among the groups. Non-fasting blood glucose was elevated in all groups in both male and female rats. Mean arterial pressure (MAP) was 108±2 mmHg in GNS+V but was elevated in the FHS+V male rats, 118±2 mmHg ( P&lt;0.01). FHS+L and FHS+E displayed MAP similar GNS+V rats: 104±2 and 106±2 mmHg, respectively. GFR assessed by transdermal FITC-sinistrin elimination was similar across all groups: 0.85±0.04 (GNS+V), 0.86±0.08 (FHS+V), 0.94±0.10 (FHS+L), 1.13±0.12 ml/min/100 g bw (FHS+E). Female rats did not display elevated MAP: 108±1 mmHg (FHS+V) vs 105±2 mmHg (GNS+V). Losartan and enalapril did not change MAP, but GFR was higher in female FHS+L rats, 1.14± 0.05, vs GNS+V 0.75±0.06 ( P &lt; 0.05). Thus, male but not female fructose-fed rats on high salt diet display significantly higher blood pressure. Short-term fructose high salt feeding did not change GFR in either male or female rats. RAS inhibition did not impact GFR in male rats, but losartan increased GFR in female rats on high fructose plus high salt diet compared with glucose-fed female rats on normal salt diet. R01 HL163844. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Association Between Obesity Measures and Metabolic Syndrome Risk in Korean Adolescents Aged 10-18 Years.

Childhood obesity is strongly linked to an increased risk of metabolic syndrome (MetS), type 2 diabetes, and cardiovascular disease in adulthood, endangering the global healthcare system. No single tool for detecting MetS is suitable for all pediatric populations. This study aimed to investigate the association between obesity measures and MetS in Korean children and adolescents. The data were obtained from 1663 children and adolescents aged 10-19 years (771 girls) who participated in the Fourth and Fifth Korea National Health and Nutrition Examination Surveys. Body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHtR) were included as obesity measures. Fasting blood glucose, triglycerides, high-density lipoprotein cholesterol, and resting blood pressure were included as metabolic risk factors. MetS was defined as the clustering of metabolic risk factors such as elevated fasting blood glucose, elevated mean arterial pressure, elevated triglycerides, and low high-density lipoprotein cholesterol. Regardless of the obesity measures used, obese children and adolescents were more likely to have a clustering of metabolic risk factors compared to their non-obese counterparts: BMI-based obesity (odds ratio, OR=4.151, 95% confidence interval, CI=2.763~6.238, p<0.001), WC-based obesity (OR=1.917, 95% CI=1.066~3.446, p=0.010), and WHtR-based obesity (OR=2.160 and 95% CI=1.203~3.878, p=0.003). A receiver operating curve analysis showed that BMI (area under the curve, AUC=0.849, 95% CI=0.8270.871) outperformed WC (AUC=0.833, 95% CI=0.8090.856) and WHtR (AUC=0.794, 95% CI=0.7670.821) in detecting the presence of MetS. Study findings suggest that obese teenagers are more likely to have metabolic syndrome than non-obese teens. Concerning accuracy, convenience, and ease of use and calculation, BMI is the best screening tool for detecting MetS in Korean children and adolescents.

396 Creating a High-Precision, Dynamic Machine Learning Model Using Time Series Data to Predict Cerebral Vasospsm in Aneurysmal Subarachnoid Hemorrhage

INTRODUCTION: Cerebral vasospasm (CV) occurs in up to one-third of patients who suffer from aneurysmal subarachnoid hemorrhage (aSAH) and can result in significant morbidity. Prior attempts to predict CV after aSAH have failed because they use static data collected on the day of presentation. We hypothesize that trending clinical and radiographic data including transcranial dopplers (TCDs) throughout 14 intensive care unit (ICU) days can be used to create a highly predictive, dynamic machine learning model for CV. METHODS: We conducted an IRB-approved retrospective study including 428 patients with aSAH hemorrhage treated at our institution between June 2014 and December 2018. For each patient, 74 features were trended including vital signs, lab values and ventriculostomy output. TCD measurements included anterior and posterior circulation velocities, Lindegaard Ratios and pulsatility indices. We employed a generative transformer-based model that uses patient representations from aggregate prior time points to predict the likelihood of CV. RESULTS: Of the 428 aSAH patients, 85 had angiographic-proven CV. There was no difference in demographic features including age, gender distribution and BMI between the CV and no-CV groups. Throughout 14 ICU days, the CV patients consistently displayed elevated mean arterial pressure and cerebral perfusion pressure. All TCD measurements were higher for the CV group. Initial logistic regression models based on static data from post-ictus days 1 through 4 showed steadily increasing F1 scores from 0.67 to 0.76. Feature analysis identified Lindegaard Ratios as the most heavily weighted features. CONCLUSIONS: Daily TCDs paired with additional longitudinal clinical data can be used to create a high-precision dynamic machine learning model for predicting CV after aSAH. These methods could also permit identification of patients at low risk of CV for reduced ICU length of stay.

Hemodynamic Determinants of Cardiac Surgery-Associated Acute Kidney Injury.

Examine the: 1) relative role of hemodynamic determinants of acute kidney injury (AKI) obtained in the immediate postcardiac surgery setting compared with established risk factors, 2) their predictive value, and 3) extent mediation via central venous pressure (CVP) and mean arterial pressure (MAP). Retrospective observational study. The main outcome of the study was moderate to severe AKI, per kidney disease: improving global outcomes, within 14 days of surgery. U.S. academic medical center. Adult patients undergoing cardiac surgery between January 2000 and December 2019 (n = 40,426) in a single U.S.-based medical center. Pulmonary artery catheter measurements were performed at a median of 102 minutes (11, 132) following cardiopulmonary bypass discontinuation. None. The median age of the cohort was 67 years (58, 75), and 33% were female; 70% had chronic hypertension, 29% had congestive heart failure, and 3% had chronic kidney disease. In a multivariable model, which included comorbidities and traditional intraoperative risk factors, CVP (p < 0.0001), heart rate (p < 0.0001), cardiac index (p < 0.0001), and MAP (p < 0.0001), were strong predictors of AKI, and superseded factors such as surgery type and cardiopulmonary bypass duration. The cardiac index had a significant interaction with heart rate (p = 0.026); a faster heart rate had a differentiating effect on the relationship of cardiac index with AKI, where a higher heart rate heightened the risk of AKI primarily in patients with low cardiac output. There was also significant interaction observed between CVP and MAP (p = 0.009); where the combination of elevated CVP and low MAP had a synergistic effect on AKI incidence. Hemodynamic factors measured within a few hours of surgery showed a strong association with AKI. Furthermore, determinants of kidney perfusion, namely CVP and arterial pressure are interdependent; as are constituents of stroke volume, that is, cardiac output and heart rate.

Montelukast Ameliorates 2K1C-Hypertension Induced Endothelial Dysfunction and Associated Vascular Dementia.

Declined kidney function associated with hypertension is a danger for cognitive deficits, dementia, and brain injury. Cognitive decline and vascular dementia (VaD) are serious public health concerns, which highlights the urgent need for study on the risk factors for cognitive decline. Cysteinyl leukotriene (CysLT1) receptors are concerned with regulating cognition, motivation, inflammatory processes, and neurogenesis. This research aims to examine the consequence of montelukast (specific CysLT1 antagonist) in renovascular hypertension 2-kidney-1-clip-2K1C model-triggered VaD in experimental animals. 2K1C tactics were made to prompt renovascular hypertension in mature male rats. Morris water maze was employed to measure cognition. Mean arterial pressure (MAP), serum nitrite levels, aortic superoxide content, vascular endothelial activity, brain's oxidative stress (diminished glutathione, raised lipid peroxides), inflammatory markers (IL-10, IL-6, TNF-α), cholinergic activity (raised acetylcholinesterase), and cerebral injury (staining of 2, 3, 5- triphenylterazolium chloride) were also examined. Montelukast in doses of 5.0 and 10.0 mg kg-1 was used intraperitoneally as the treatment drug. Along with cognitive deficits, 2K1C-operated rats showed elevated MAP, endothelial dysfunction, brain oxidative stress, inflammation, and cerebral damage with diminished serum nitrite/nitrate. Montelukast therapy significantly and dose-dependently mitigated the 2K1Chypertension- provoked impaired behaviors, biochemistry, endothelial functions, and cerebral infarction. The 2K1C tactic caused renovascular hypertension and associated VaD, which was mitigated via targeted regulation of CysLT1 receptors by montelukast administration. Therefore, montelukast may be taken into consideration for the evaluation of its complete potential in renovascular-hypertension-induced VaD.

Application and reduction of a nonlinear hyperelastic wall model capturing ex vivo relationships between fluid pressure, area, and wall thickness in normal and hypertensive murine left pulmonary arteries.

Pulmonary hypertension is a cardiovascular disorder manifested by elevated mean arterial blood pressure (>20 mmHg) together with vessel wall stiffening and thickening due to alterations in collagen, elastin, and smooth muscle cells. Hypoxia-induced (type 3) pulmonary hypertension can be studied in animals exposed to a low oxygen environment for prolonged time periods leading to biomechanical alterations in vessel wall structure. This study introduces a novel approach to formulating a reduced order nonlinear elastic structural wall model for a large pulmonary artery. The model relating blood pressure and area is calibrated using ex vivo measurements of vessel diameter and wall thickness changes, under controlled pressure conditions, in left pulmonary arteries isolated from control and hypertensive mice. A two-layer, hyperelastic, and anisotropic model incorporating residual stresses is formulated using the Holzapfel-Gasser-Ogden model. Complex relations predicting vessel area and wall thickness with increasing blood pressure are derived and calibrated using the data. Sensitivity analysis, parameter estimation, subset selection, and physical plausibility arguments are used to systematically reduce the 16-parameter model to one in which a much smaller subset of identifiable parameters is estimated via solution of an inverse problem. Our final reduced one layer model includes a single set of three elastic moduli. Estimated ranges of these parameters demonstrate that nonlinear stiffening is dominated by elastin in the control animals and by collagen in the hypertensive animals. The pressure-area relation developed in this novel manner has potential impact on one-dimensional fluids network models of vessel wall remodeling in the presence of cardiovascular disease.