Artery Constriction Research Articles

Long-Term Effects on Retinal Structure and Function in a Mouse Endothelin-1 Model of Retinal Ganglion Cell Degeneration.

To study the long-term effects of endothelin-1 (ET-1)-induced retinal pathologies in mouse, using clinically relevant tools. Adult C57BL/6 mice (7-9 weeks old) were intravitreally injected with PBS (n = 10) or 0.25 (n = 8), 0.5 (n = 8), or 1 nmol ET-1 (n = 9) and examined using electroretinogram, optical coherence tomography (OCT), and Doppler OCT at baseline and postinjection days 10, 28, and 56. Retinal ganglion cell (RGC) survival in retinal whole mount was quantified at days 28 and 56. ET-1 induced immediate retinal arterial constriction. The significantly reduced total blood flow and positive scotopic threshold response in the 0.5- and 1-nmol ET-1 groups at day 10 were recovered at day 28. A-wave magnitude was also significantly reduced at days 10 and 28. While a comparable and significant reduction in retinal nerve fiber layer thickness was detected in all ET-1 groups at day 56, the 1-nmol group was the earliest to develop such change at day 28. All ET-1 groups showed a transient inner retinal layer thinning at days 10 and 28 and a plateaued outer layer thickness at days 10 to 56. The 1-nmol group showed a significant RGC loss over all retinal locations examined at day 28 as compared with PBS control. As for the lower-dosage groups, significant RGC density loss at central and midperipheral retina was detected at day 56 when compared with day 28. ET-1 injection in mice resulted in a transient vascular constriction and reduction in retinal functions, as well as a gradual loss of retinal nerve fiber layer and RGC in a dose-dependent manner.

Synergistic regulation of uterine radial artery adaptation to pregnancy by paracrine and hemodynamic factors.

Fetal growth throughout pregnancy relies on delivery of an increasing volume of maternal blood to the placenta. To facilitate this, the uterine vascular network adapts structurally and functionally, resulting in wider blood vessels with decreased flow-mediated reactivity. Impaired remodeling of the rate-limiting uterine radial arteries has been associated with fetal growth restriction. However, the mechanisms underlying normal or pathological radial artery remodeling are poorly understood. Here, we used pressure myography to determine the roles of hemodynamic (resistance, flow rate, shear stress) and paracrine [β-estradiol, progesterone, placental growth factor (PlGF), vascular endothelial growth factor] factors on rat radial artery reactivity. We show that β-estradiol, progesterone, and PlGF attenuate flow-mediated constriction of radial arteries from nonpregnant rats, allowing them to withstand higher flow rates in a similar manner to pregnant vessels. This effect was partly mediated by nitric oxide (NO) production. To better understand how the combination of paracrine factors and shear stress may impact human radial artery remodeling in the first half of gestation, computational models of uterine hemodynamics, incorporating physiological parameters for trophoblast plugging and spiral artery remodeling, were used to predict shear stress in the upstream radial arteries across the first half of pregnancy. Human microvascular endothelial cells subjected to these predicted shear stresses demonstrated higher NO production when paracrine factors were added. This suggests that synergistic effects of paracrine and hemodynamic factors induce uterine vascular remodeling and that alterations in this balance could impair radial artery adaptation, limiting blood flow to the placenta and negatively impacting fetal growth.NEW & NOTEWORTHY Placenta-specific paracrine factors β-estradiol, progesterone, and placental growth factor attenuate flow-mediated constriction of the rate-limiting uterine radial arteries, enabling higher flow rates in pregnancy. These paracrine factors induce their actions in part via nitric oxide mediated mechanisms. A synergistic combination of paracrine factors and shear stress is likely necessary to produce sufficient levels of nitric oxide during early human pregnancy to trigger adequate uterine vascular adaptation.

Abstract P3061: Development Of Molecular Targeted Therapy Against Right Ventricular Failure: Involvement In Complement C3- Factor D- C3a Pathway

Backgrounds: Right ventricular (RV) failure plays a critical role in right heart failure and left heart failure. However, there is no specific therapy developed for RV failure. To elucidate a novel therapeutic target against RV failure, we focus on RV specific pathway. Methods: Microarray analysis using several parts of adult murine heart was conducted and differentially expressed genes (DEGs) were applied to pathway analysis. Molecular mechanism was examined by using neonatal rat ventricular cardiomyocyte (NRVM) in vitro. To understand the function of target molecule in vivo, we induced RV failure by pulmonary artery constriction (PAC) in mice and inhibition experiments were performed using RV failure model. Results: In microarray analysis elucidated 995 genes as DEGs in RV. Pathway analysis showed that alternative complement pathway-related genes were significantly up-regulated in RV. Moreover, complement factor D (Cfd) and C3a was a potential upstream factor attributable to unique feature of RV. Administration of C3a recombinant protein to primary cultured ventricular myocyte indicated that phosphorylation of several MAP kinases were enhanced. In vivo, in C3KO PAC mice, RV dysfunction was significantly suppressed, and histological study showed that RV fibrosis was significantly suppressed. In wild type mice with PAC, administration of C3a receptor antagonist dramatically improved RV dysfunction and reduced RV fibrosis. Additionally, in vivo electrophysiological study revealed that the inducibility of ventricular arrhythmia was increased in wild type PAC mice, but ventricular arrhythmia was significantly attenuated in C3KO PAC mice. Furthermore, electrophysiological analysis by isolated cardiomyocyte showed that calcium overload was also attenuated in RV cardiomyocyte of C3KO PAC mice. Conclusion: We revealed that complement C3a was highly produced in RV and chemical or genetical blockade of C3a ameliorates RV dysfunction and RV fibrosis in PAC mice. C3a was to be a potent bioactive protein for immunocompetent cells that played an important role in modulating cardiac function. Accordingly, we demonstrated that the blockade of C3a had a potential role for novel therapeutic target to RV failure.

Inverse Correlation of Cholesterol Efflux Capacity with Peripheral Plaque Volume Measured by 3D Ultrasound.

Cardiovascular disease (CVD) is a systemic multifocal illness called atherosclerosis that causes artery constriction and blockage. By causing cholesterol to build up in the artery wall, hypercholesterolemia is a major factor in the pathophysiology of atherosclerotic plaque development. Reverse cholesterol transport is the process of transporting cholesterol from the periphery back to the liver through cholesterol efflux mediated by high-density lipoprotein (HDL). It was suggested that the cholesterol efflux capacity (CEC), which is inversely linked with cardiovascular risk, can serve as a stand-in measure for reverse cholesterol transport. In this work, we sought to investigate a potential link between the peripheral plaque volume (PV) and CEC. Since lipid-lowering therapy interferes with CEC, we performed a cross-sectional study of 176 patients (48.9% females) with one cardiovascular risk factor or known CVD that did not currently take lipid-lowering medication. CEC was determined using cAMP-treated 3H-cholesterol-labeled J774 cells. Cholesterol ester transfer protein (CETP)-mediated cholesterol ester transfer was measured by quantifying the transfer of cholesterol ester from radiolabeled exogenous HDL cholesterol to Apolipoprotein B-containing lipoproteins. PV in the carotid and the femoral artery, defined as the total PV, was measured using a 3D ultrasound system equipped with semi-automatic software. In our patients, we discovered an inverse relationship between high total PV and CEC (p = 0.027). However, there was no connection between total PV and low-density lipoprotein cholesterol, lipoprotein (a), or CETP-mediated cholesterol ester transfer. In patients not receiving lipid-lowering treatment, CEC inversely correlates with peripheral atherosclerosis, supporting its role in the pathophysiology of atherosclerosis.

NOX2 inhibition stabilizes vulnerable plaques by enhancing macrophage efferocytosis via MertK/PI3K/AKT pathway

NADPH oxidases 2 (NOX2) is the main source of ROS in macrophages, which plays a critical role in the formation of atherosclerosis. However, effects of NOX2 inhibition on established vulnerable plaques and the potential role involved remain unclear. The purpose of this study is to investigate the latent mechanism of NOX2-triggered vulnerable plaque development. We generated a vulnerable carotid plaque model induced by carotid branch ligation and renal artery constriction, combined with a high-fat diet in ApoE−/− mice. NOX2 specific inhibitor, GSK2795039 (10 mg/kg/day by intragastric administration for 8 weeks) significantly prevented vulnerable plaque, evaluated by micro-ultrasound imaging parameters. A profile of less intraplaque hemorrhage detection, increased collagen-lipid ratio, fibrous cap thickness and less necrotic core formation were also found in GSK2795039 treated group. Mechanistically, reduced 4-HNE, in situ lesional apoptosis and enhanced efferocytosis were involved in mice treated with NOX2 inhibitor. Further analysis in mouse macrophages confirmed the role of NOX2 inhibition in enhancing macrophage efferocytosis by regulating the MertK/PI3K/AKT pathway. In summary, our data defined previously few recognized roles of NOX2 in vulnerable plaque pathogenesis and an undescribed NOX2-ROS-MerTK axis acts involved in regulating macrophage efferocytosis in the formation of rupture-prone vulnerable plaques.

Acceleration of the Development of Microcirculation Embolism in the Brain due to Capillary Narrowing.

Cerebral microvascular obstruction is critically involved in recurrent stroke and decreased cerebral blood flow with age. The obstruction must occur in the capillary with a greater resistance to perfusion pressure through the microvascular networks. However, little is known about the relationship between capillary size and embolism formation. This study aimed to determine whether the capillary lumen space contributes to the development of microcirculation embolism. To spatiotemporally manipulate capillary diameters in vivo, transgenic mice expressing the light-gated cation channel protein ChR2 (channelrhodopsin-2) in mural cells were used. The spatiotemporal changes in the regional cerebral blood flow in response to the photoactivation of ChR2 mural cells were first characterized using laser speckle flowgraphy. Capillary responses to optimized photostimulation were then examined in vivo using 2-photon microscopy. Finally, microcirculation embolism due to intravenously injected fluorescent microbeads was compared under conditions with or without photoactivation of ChR2 mural cells. Following transcranial photostimulation, the stimulation intensity-dependent decrease in cerebral blood flow centered at the irradiation was observed (14%-49% decreases relative to the baseline). The cerebrovascular response to photostimulation showed significant constriction of the cerebral arteries and capillaries but not of the veins. As a result of vasoconstriction, a temporal stall of red blood cell flow occurred in the capillaries of the venous sides. The 2-photon excitation of a single ChR2 pericyte demonstrated the partial shrinkage of capillaries (7% relative to the baseline) around the stimulated cell. With the intravenous injection of microbeads, the occurrence of microcirculation embolism was significantly enhanced (11% increases compared to the control) with photostimulation. Capillary narrowing increases the risk of developing microcirculation embolism in the venous sides of the cerebral capillaries.

Progesterone protects against ethanol-induced cerebral artery constriction

Progesterone protects against ethanol-induced cerebral artery constriction

Sensitivity analysis of electroosmotic magnetohydrodynamics fluid flow through the curved stenosis artery with thrombosis by response surface optimization

The current numerical investigation focuses on the sensitivity analysis of the pertinent parameters of the electrically conducting fluid (blood) with the suspension of Al2O3 nanoparticles through the constricted arteries in the presence of stenosis, thrombosis and catheter. The mathematical model is developed to simulate the blood flow through the catheterized artery having irregular stenosis at the wall and thrombosis at the centre. The interactions of different physical phenomena like electroosmosis, radiation, Joule heating and a uniform radial magnetic field actuate the fluid flow. The nanoparticles shape effect is taken into account by considering the Crocine model. The governing equations are discretized by employing the Crank-Nicolson scheme, and the graphical portrayals for the impact of significant parameters on the flow characteristics have been devised and discussed. The statistical experiment is designed based on the parametric range of the parameter. The sensitivity analysis is performed on response surfaces after getting the best-fitted response surface relative to each response variable. The WSS profile negatively correlates with hematocrit parameter hm, Hartmann number M and positively related with Debye–Huckel parameter qe, while the reverse trend is observed for the impedance profile. The present work may be helpful in biomedical engineering, such as magnetic resonance angiography (MRA), which creates artery images. The integrated medical imaging and hemodynamic framework assist surgeons and researchers in better understanding the abnormalities caused by cardiovascular diseases and gaining a deeper grasp of the hemodynamic flow and other bodily fluids for surgical restoration.

Inhibition of PCSK9 Improves the Development of Pulmonary Arterial Hypertension Via Down-Regulating Notch3 Expression.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by continuous constriction and occlusion of small pulmonary arteries, leading to the development of right ventricular failure and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a kind of serine protease enzyme that increases low-density lipoprotein cholesterol (LDLC) levels through degrading low-density lipoprotein cholesterol receptors (LDLr). However, whether inhibition of PCSK9 can alleviate PAH has not been reported. We reported that PCSK9 expression was up-regulated in lung tissues of PAH patients. In addition, we used PCSK9 monoclonal antibody subcutaneously to inhibit PCSK9 expression in mice exposed to chronic hypoxia (10%) in combination with SU5416, a VEGF receptor inhibitor. Hypoxia plus SU5416-induced PAH was attenuated in PCSK9 monoclonal antibody-treated mice compared with wild-type mice. PCSK9 inhibited pulmonary vascular remodeling in mice. Moreover, PCSK9 knockdown significantly altered the proliferation and migration of hypoxia-induced PASMCs. We also found that PCSK9 monoclonal antibody inhibited Notch3 expression in vivo and in vitro. Our results suggest that the PCSK9-Notch3 signaling pathway is critical for the proliferation and migration of PASMCs and provides a potential drug target for the treatment of PAH.

Heat transport in magnetohydrodynamic physiological blood flow through a constricted artery

AbstractIn this paper, we study how the magnetohydrodynamic (MHD) pulsatile flow of blood and heat transfer works through a constricted artery with a flexible wall. The human circulatory network consists of veins and arteries that sometimes contain constrictions, allowing the impact of the applied magnetic field on flow fields to be observed. The walls of the flowing medium are considered to be a function of time. The flowing blood is hypothesized as shear‐thinning fluid, emulating Yeleswarapu's viscosity replica. Additionally, we consider the energy equation to understand the impact of a magnetic field on heat transfer rates for such flows. The vorticity transport equation along with the stream function equation is obtained using the vorticity–stream function technique. Numerical solutions of the governing nonlinear MHD equations and energy equation in addition to physically pertinent flow conditions were achieved by adapting a finite difference scheme. Considerable attention has been paid to ensure an accurate comparison between the current and previous results. The two sets of numbers appear to match closely. For an even deeper understanding of the flow and heat transport process, the effects of height of stenosis and diverse physiological parameters on time‐averaged wall shear stress (TAWSS), rate of heat transport, and so on are explored in depth through their graphical depiction. In the vicinity of the constriction, it is observed that the separation becomes longer with increasing constriction height. Higher magnetic force strength leads to a reduction in separation length. Newtonian fluids transfer heat more rapidly in their narrowing regions and downstream than fluids with non‐Newtonian behavior.

Numerical simulation of unsteady generic Newtonian blood flow and heat transfer through discrepant shaped dilatable arterial stenosis

The contemporaneous research was conducted to evaluate the attribute of blood flow and degree of obstruction generated in the arteries pathway through different geometries. Flow of blood via the stenosed afflicted arteries is taken into account in this work. The viscous, unsteady, incompressible and laminar, blood plunge into the artery with a speed of 0.049 m s−1. Partial differential equations were demonstrated for the current problem. Time dependent direct solver was used to obtain the solution. Finite element discretization method (FDM) is used to obtain the solution. The research was accomplished by using advanced computational fluid dynamics (CFD) software. The blood flow behavior was investigated in order to determine velocity, pressure, and temperature changes caused by an arterial stenosis. It was discovered that the shape of the stenosis has a crucial impact on the velocity, total pressure reduction and temperature over the arterial constriction zone. Graphs are plotted to illustrate the solutions. Results shows that the trapezoidal and elliptical stenosis had the greatest pressure decrease, followed by the triangular stenosis. These findings will be extremely beneficial in the treatment of stenotic arteries.

The retinal neurovascular coupling is impaired in men with vasculogenic erectile dysfunction

The aim of this study was to study the retinal vessels in patients affected by vasculogenic erectile dysfunction (ED), using dynamic vessel analyzer (DVA). Patients with vasculogenic ED and control subjects were prospectively enrolled to undergo a complete urological and ophthalmologic evaluation, including DVA and structural optical coherence tomography (OCT). The main outcome measures were: (1) arterial dilation; (2) arterial constriction; (3) reaction amplitude (the difference between arterial dilation and constriction); and, (4) venous dilation. Thirty-five patients with ED and 30 male controls were included in the analysis. Mean ± SD age was 52.0 ± 10.8 years in the ED group and 48.1 ± 16.3 years in the control group (p = 0.317). In the dynamic analysis, the arterial dilation was lower in the ED group (1.88 ± 1.50%), as compared with the control group (3.70 ± 1.56%, p < 0.0001). Neither arterial constriction nor venous dilation differed between groups. The reaction amplitude was decreased in ED patients (2.40 ± 2.02%, p = 0.023), compared to controls (4.25 ± 2.20%). In the Pearson correlation analysis, the ED severity, was directly correlated with both reaction amplitude (R = .701, p = 0.004) and arterial dilation (R = .529, p = 0.042). In conclusion, subjects with vasculogenic ED are featured by a significant dysfunction of the retinal neurovascular coupling, which is inversely correlated with ED severity.

Trifluoromethylated Aryl Sulfonamides as Novel CETP Inhibitors: Synthesis, Induced Fit Docking, Pharmacophore Mapping and Subsequent In vitro Validation.

Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction, resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports the transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL. In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro tested to estimate their CETP inhibitory activity. In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 μM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, the presence of ortho-chloro, meta-chloro and para-methyl substituents results in high inhibitory activity. The induced fit docking studies revealed that hydrophobic interaction guided ligand/ CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.

Loss- and gain-of-function mutations in the Type 1 IP3 receptor (IP3R1) affect myogenic constriction of murine cerebral resistance arteries

Myogenic reactivity in resistance arteries/arterioles in response to changing intraluminal pressure is a key physiological mechanism for the regulation of blood pressure and flow. Although IP3-mediated intracellular Ca2+ release is known to contribute to the myogenic response, a lack of selective pharmacological agents to target the predominant IP3R1 Ca2+ release channel has prevented detailed investigation of this key mechanism. Mutations in the IP3R1 known to produce either loss-of-function (LOF) or gain-of-function (GOF) phenotypes lead to cerebellar ataxia in humans, yet the effect of these mutations on the cardiovascular system remains unclear. Here, we employed a novel genetic knock-in mouse model with a single point mutation in the S6 helix of IP3R1 that confers either a LOF (D2594A) or GOF (D2594K) phenotype. In endothelium-denuded posterior cerebral arteries of 3-4 month old WT mice, myogenic vasoconstriction was evident at ≥40 mmHg, maximal at ~120 mmHg, and began to decline at &gt;120 mmHg (n=9). In contrast, myogenic constriction was initiated at higher pressures (≥50 mmHg) and was less robust in arteries of heterozygous IP3R1 LOF mice (n=11). In GOF arteries (n=10), myogenic tone developed at a lower pressure (~20 mmHg), was maximal at ~80 mmHg, and declined at &gt;90 mmHg. Interestingly, pressure-induced Ca2+ elevations were similar in Fura-2 loaded arteries from WT, LOF and GOF mice. Using high sensitivity western blotting, we observed a similar pressure-dependent increase in phosphorylated myosin regulatory light chain (LC20) and myosin phosphatase targeting subunit (MYPT1) at 10, 40, 80 and 120 mmHg in arteries from WT, LOF and GOF mice (n=5 each). Although phospho-MYPT1-T855 content increased with intraluminal pressure in WT and LOF arteries, it did not change in vessels of GOF mice. Elevation of intraluminal pressure (i.e., from 10 to 60 or 120 mmHg) significantly decreased G-actin content in WT arteries, did not affect G-actin content in LOF vessels, and caused a biphasic effect in GOF arteries. Stabilizing the actin cytoskeleton with 0.1 mM jasplakinolide normalized myogenic reactivity in LOF arteries and left-shifted myogenic responsiveness in WT vessels; a minimal effect was observed in GOF arteries. Both jasplakinolide and the actin depolymerizing agent latrunculin B (2 mM) inhibited myogenic tone development at intraluminal pressures &gt; 40-60 mmHg. Taken together, these data demonstrate that genetic modification of IP3R1-mediated Ca2+ mobilization affects the myogenic response of cerebral arteries to intraluminal pressure, possibly by affecting the dynamics of the actin cytoskeleton. Functionally, the observed vascular impairments may contribute to neurological dysfunction in patients with LOF and GOF IP3R1 mutations. Funding has been provided by the Canadian Institutes of Health Research: MOP-97988 (WCC), MOP-142467 (APB), PJT-173352 (SRWC) and PJT-155963 (APB, WCC, GRG and SRWC). This is the full abstract presented at the American Physiology Summit 2023 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.

Heart rate fragmentation in renovascular hypertensive rats

Although rapid oscillations of the heart rate (HR) are attributed to vagal modulation of the heart, a pattern of ultra-rapid HR variation has been named heart rate fragmentation (HRF). It is a recently proposed approach to evaluate sino-atrial instability characterized by the presence of numerous inflections points in a series of successive values of cardiac intervals. HRF is increased in aging and coronary diseases. Hypertension markedly alters HRV indices and might affect HRF as well. This study aimed to investigate the HRF in renovascular hypertension in rats. Wistar rats were anesthetized, and hypertension was surgically induced by partial constriction of the left renal artery with a silver clip with a 0.2 mm gap. In one kidney one clip (1K1C) hypertension model, the contralateral kidney was removed. In two kidneys one clip (2K1C) model, the contralateral kidney was kept intact. Sham-operated control rats underwent to same surgical procedures without receiving the clip around the renal artery. After 45 days (2K1C) or 60 days (1K1C), animals were instrumented with a catheter into the femoral artery, and on the following day, their arterial pressure (AP) was directly recorded without the effect of anesthesia. For HRF analysis, pulse interval (PI) series were generated and transformed into a sequence of symbols “-1,” “0,” or “1” when the difference between successive PI values (transitions) was negative, zero, or positive, respectively. Following, sequences of 4 consecutive symbols were classified according to the number of transitions. The total percentage of inflection points (PIP) and the percentage of sequences with zero (W0), one (W1), two (W2), or three (W3) inflection points were quantified. As expected, the arterial pressure increased in both groups of hypertension rats compared to control counterparts. All HRF indices were found similar in 1K1C hypertensive rats compared to their control counterparts. Nevertheless, in 2K1C hypertensive rats HRF was found to be lower than normotensive controls (PIP: 64±7 vs. 79±1% and W2: 30±1 vs. 39±1% in 2K1C and normotensive controls, respectively). In conclusion, high blood pressure itself does not affect HRF, although, depending on the model of hypertension used, HRF can be markedly impaired. The interpretation of these findings is challenging, and the high levels of angiotensin in the 2K1C model may affect cardiac pacemaker cells, making their action potentials more stable than unstable. However, the specific mechanisms by which this could happen still need to be studied. Funding Sources: FAPESP, CAPES and CNPq This is the full abstract presented at the American Physiology Summit 2023 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.

Evolution of atrial remodeling and atrial arrhythmogenicity in a rat model of chronic pulmonary artery constriction: A “trialogue” between right heart disease, cardiac inflammation, and atrial fibrillation inducibility

Among all cardiac arrhythmias, atrial fibrillation (AF) is the most commonly diagnosed. Aging and comorbid pathological conditions such as obesity, sleep apnea or myocardial infarction increase the prevalence and incidence of AF. Clinical and experimental evidence have shown that pulmonary hypertension (PH) can initiate the development of right heart disease (RHD), which is also considered an important AF risk factor. Inflammation emerges as a common denominator between cardiovascular comorbidities and AF susceptibility. The underlying mechanisms linking (a) RHD, (b) atrial inflammation, and (c) the development of AF, remain unclear. We hypothesize that a constriction of the pulmonary artery trunk (PAT) progressively generates atrial inflammation and fibrosis responsible for increasing AF susceptibility. Describe the evolution of atrial inflammation and fibrosis in a rat model of RHD. RHD was induced on anesthetized Wistar rats (225–275 g) by performing a Pulmonary Artery Banding (PAB) which permanently reduced the PAT diameter to 1 mm. Sham animals had a PAB-mimicking surgery without suture. At day 0, 7, 14 and 21 post-surgery echocardiography and electrophysiological studies were performed in vivo on every animal. Optical mapping, histological study using Masson's trichrome, qPCR and immunoblotting were performed to analyze atrial tissues at each timepoint. PAB rats showed myocardial hypertrophy and cavity dilation affecting the right atrium (RA) and right ventricle (RV). Optical mapping performed on the RA showed that the conduction velocity was slower, the effective refractory periods were shorter, and the action potential durations were smaller in PAB rats compared to Sham. These electrical and structural remodeling were associated with significantly increased AF inducibility in PAB rats starting at day 7 until day 21 post-surgery. RA Fibrous area was also significantly higher in PAB rats compared to Sham at day 14 to day 21 post-PAT ligation. Inflammation and fibrosis-related genes such as IL6, TGFβ1 and CO1LA1 were progressively and significantly increased in the RA from PAB rats compared to Sham, from the 7th to 21st day post-PAT constriction. PAB-induced RHD provoked a progressively aggravating right atrial inflammatory and fibrotic profile leading to an increased risk of AF in rats.

Bioinformatics exploration of potential common therapeutic targets for systemic and pulmonary arterial hypertension-induced myocardial hypertrophy.

Systemic and pulmonary arterial hypertension (PAH) can induce left and right ventricular hypertrophy, respectively, but common therapeutic targets for both left and right hypertrophy are limited. In this study, we attempt to explore potential common therapeutic targets and screen out potential target drugs for further study. Cardiac mRNA expression profiles in mice with transverse aortic constriction (TAC) and pulmonary arterial constriction (PAC) are obtained from online databases. After bioinformatics analyses, we generate TAC and PAC mouse models to validate the phenotypes of cardiac remodelling as well as the identified hub genes. Bioinformatics analyses show that there are 214 independent differentially expressed genes (DEGs) in GSE136308 (TAC related) and 2607 independent DEGs in GSE30922 (PAC related), while 547 shared DEGs are associated with the function of the extracellular matrix (ECM) or involved in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and ECM-receptor interactions. We identifyd Fn1, Il6, Col1a1, Igf1, Col1a2, Timp1, Col3a1, Cd44, Ctgf and Postn as hub genes of the shared DEGs, and most of them are associated with myocardial fibrosis. Those hub genes and phenotypes of cardiac remodelling are validated in our TAC and PAC mouse models. Furthermore, we identify dehydroisoandrosterone (DHEA), iloprost and 4,5-dianilinophthalimide (DAPH) as potential therapeutic drugs targeting both left and right ventricular hypertrophy and validate the effect of DHEA. These findings suggest that DHEA could be an effective drug for pressure overload-induced left or right ventricular hypertrophy by regulating the shared hub differentially expressed genes associated with fibrosis.

Mobile-HR: An Ophthalmologic-Based Classification System for Diagnosis of Hypertensive Retinopathy Using Optimized MobileNet Architecture

Hypertensive retinopathy (HR) is a serious eye disease that causes the retinal arteries to change. This change is mainly due to the fact of high blood pressure. Cotton wool patches, bleeding in the retina, and retinal artery constriction are affected lesions of HR symptoms. An ophthalmologist often makes the diagnosis of eye-related diseases by analyzing fundus images to identify the stages and symptoms of HR. The likelihood of vision loss can significantly decrease the initial detection of HR. In the past, a few computer-aided diagnostics (CADx) systems were developed to automatically detect HR eye-related diseases using machine learning (ML) and deep learning (DL) techniques. Compared to ML methods, the CADx systems use DL techniques that require the setting of hyperparameters, domain expert knowledge, a huge training dataset, and a high learning rate. Those CADx systems have shown to be good for automating the extraction of complex features, but they cause problems with class imbalance and overfitting. By ignoring the issues of a small dataset of HR, a high level of computational complexity, and the lack of lightweight feature descriptors, state-of-the-art efforts depend on performance enhancement. In this study, a pretrained transfer learning (TL)-based MobileNet architecture is developed by integrating dense blocks to optimize the network for the diagnosis of HR eye-related disease. We developed a lightweight HR-related eye disease diagnosis system, known as Mobile-HR, by integrating a pretrained model and dense blocks. To increase the size of the training and test datasets, we applied a data augmentation technique. The outcomes of the experiments show that the suggested approach was outperformed in many cases. This Mobile-HR system achieved an accuracy of 99% and an F1 score of 0.99 on different datasets. The results were verified by an expert ophthalmologist. These results indicate that the Mobile-HR CADx model produces positive outcomes and outperforms state-of-the-art HR systems in terms of accuracy.

LCZ696 (sacubitril/valsartan) inhibits pulmonary hypertension induced right ventricular remodeling by targeting pyruvate dehydrogenase kinase 4

BackgroundRight ventricular (RV) function is a major prognostic factor in patients with cardiopulmonary disease. Effective medical therapies are available for left heart failure, but they are usually less effective or even ineffective in right heart failure. Here, we tested the hypothesis that LCZ696 (sacubitril/valsartan) can attenuate pressure overload-induced RV remodeling by inhibiting pyruvate dehydrogenase kinase 4 (PDK4). MethodsAdult male C57 mice were subjected to transverse aortic constriction (TAC), pulmonary artery constriction (PAC), or sham surgery. Bioinformatics analysis was used to screen for common differentially expressed genes (DEGs) between TAC and PAC. Chemical compounds targeting DEGs were predicted by molecular docking analysis. Effects of LCZ696 on PAC-induced RV remodeling and the associated PDK4-related mechanisms were investigated. ResultsWe found 60 common DEGs between PAC and TAC, and Pdk4 was one of the downregulated DEGs. From 47 chemical compounds with potential cardiovascular activity and PDK4 protein binding ability, we selected LCZ696 to treat PAC-induced RV remodeling because of its high docking score for binding PDK4. Compared with vehicle-treated PAC mice, LCZ696-treated mice had significantly smaller RV wall thickness and RV diameters, less myocardial fibrosis, lower expression of PDK4 protein, and less phosphorylation of glycogen synthase kinase-3β (p-GSK3β). In PAC mice, overexpression of Pdk4 blocked the inhibitory effect of LCZ696 on RV remodeling, whereas conditional knockout of Pdk4 attenuated PAC-induced RV remodeling. ConclusionsPdk4 is a common therapeutic target for pressure overload-induced left ventricular and RV remodeling, and LCZ696 attenuates RV remodeling by downregulating Pdk4 and inhibiting PDK4/p-GSK3β signal.

Impact of Stenosis Geometry on Blood Flow Behavior in Human Artery

Atherosclerosis in human arteries affects the blood flow behaviour in different ways and sometimes leads to fatal diseases. This study is focused on the impact of the elasticity of human arteries and the geometry of stenosis on non-Newtonian blood flow across the constricted arteries. The mathematical analysis is carried out using MatLab software. The elastic nature of human arteries and the non-Newtonian nature of blood are described under the power-law, Herschel-Bulkley and Casson model. The numerical derivations for blood flow velocity, volume flow rate and wall shear stress are derived for all three types of the model under consideration and results are also depicted graphically. The influence of elasticity, flow index, yield stress and geometry of stenosis on the blood flow is examined. Power-law model gives higher velocity as compared to Herschel-Bulkley model for the fixed magnitude of flow index 𝑛. It is observed that in the constricted region, the volume flow rate amplifies with the increasing value of stenosis shape parameter 𝑚 for the fixed magnitude of flow index 𝑛. The height of stenosis has a diminishing effect on the flow rate. A comparative analysis of the outcomes of the present study and that of the other published work is carried out for authentication.