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Journal of the American Heart... Jun 2024Experimental preeclampsia (ePE) has been shown to have worsened outcome from stroke. We investigated the effect of low-dose aspirin, known to prevent preeclampsia, on...
BACKGROUND
Experimental preeclampsia (ePE) has been shown to have worsened outcome from stroke. We investigated the effect of low-dose aspirin, known to prevent preeclampsia, on stroke hemodynamics and outcome, and the association between the vasoconstrictor and vasodilator cyclooxygenase products thromboxane A and prostacyclin.
METHODS AND RESULTS
Middle cerebral artery occlusion was performed for 3 hours with 1 hour of reperfusion in normal pregnant rats on day 20 of gestation and compared with ePE treated with vehicle or low-dose aspirin (1.5 mg/kg per day). Multisite laser Doppler was used to measure changes in cerebral blood flow to the core middle cerebral artery and collateral vascular territories. After 30 minutes occlusion, phenylephrine was infused to increase blood pressure and assess cerebral blood flow autoregulation. Infarct and edema were measured using 2,3,5-triphenyltetrazolium chloride staining. Plasma levels of thromboxane A, prostacyclin, and inflammatory markers in plasma and cyclooxygenase levels in cerebral arteries were measured. ePE had increased infarction compared with normal pregnant rats (<0.05) that was reduced by aspirin (<0.001). ePE also had intact cerebral blood flow autoregulation and reduced collateral perfusion during induced hypertension that was also prevented by aspirin. Aspirin increased prostacyclin in ePE (<0.05) without reducing thromboxane B, metabolite of thromboxane A, or 8-isoprostane-prostaglandin-2α, a marker of lipid peroxidation. There were no differences in cyclooxygenase levels in cerebral arteries between groups.
CONCLUSIONS
Low-dose aspirin in ePE reduced infarction that was associated with increased vasodilator prostacyclin and improved collateral perfusion during induced hypertension. The beneficial effect of aspirin on the brain and cerebral circulation is likely multifactorial and worth further study.
PubMed: 38934871
DOI: 10.1161/JAHA.124.035990 -
Cell Death & Disease Jun 2024Pathological cardiac hypertrophy is one of the major risk factors of heart failure and other cardiovascular diseases. However, the mechanisms underlying pathological...
Pathological cardiac hypertrophy is one of the major risk factors of heart failure and other cardiovascular diseases. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. Here, we identified the first evidence that TNFAIP3 interacting protein 3 (TNIP3) was a negative regulator of pathological cardiac hypertrophy. We observed a significant upregulation of TNIP3 in mouse hearts subjected to transverse aortic constriction (TAC) surgery and in primary neonatal rat cardiomyocytes stimulated by phenylephrine (PE). In Tnip3-deficient mice, cardiac hypertrophy was aggravated after TAC surgery. Conversely, cardiac-specific Tnip3 transgenic (TG) mice showed a notable reversal of the same phenotype. Accordingly, TNIP3 alleviated PE-induced cardiomyocyte enlargement in vitro. Mechanistically, RNA-sequencing and interactome analysis were combined to identify the signal transducer and activator of transcription 1 (STAT1) as a potential target to clarify the molecular mechanism of TNIP3 in pathological cardiac hypertrophy. Via immunoprecipitation and Glutathione S-transferase assay, we found that TNIP3 could interact with STAT1 directly and suppress its degradation by suppressing K48-type ubiquitination in response to hypertrophic stimulation. Remarkably, preservation effect of TNIP3 on cardiac hypertrophy was blocked by STAT1 inhibitor Fludaradbine or STAT1 knockdown. Our study found that TNIP3 serves as a novel suppressor of pathological cardiac hypertrophy by promoting STAT1 stability, which suggests that TNIP3 could be a promising therapeutic target of pathological cardiac hypertrophy and heart failure.
Topics: Animals; Cardiomegaly; STAT1 Transcription Factor; Myocytes, Cardiac; Mice; Rats; Male; Mice, Inbred C57BL; Ubiquitination; Membrane Proteins; Mice, Transgenic; Humans; Phenylephrine; Protein Stability; Mice, Knockout
PubMed: 38926347
DOI: 10.1038/s41419-024-06805-4 -
PloS One 2024The aim of this study was to evaluate the impact of intravenous palonosetron compared to ondansetron on hypotension induced by spinal anesthesia in women undergoing... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The aim of this study was to evaluate the impact of intravenous palonosetron compared to ondansetron on hypotension induced by spinal anesthesia in women undergoing cesarean section.
METHODS
Fifty-four women scheduled for elective cesarean section were, randomly allocated to ondansetron group (n = 27) or palonosetron group (n = 27). Ten minutes prior to the administration of spinal anesthesia, participants received an intravenous injection of either ondansetron or palonosetron. A prophylactic phenylephrine infusion was initiated immediately following the intrathecal administration of bupivacaine and fentanyl. The infusion rate was titrated to maintain adequate blood pressure until the time of fetal delivery. The primary outcome was total dose of phenylephrine administered. The secondary outcomes were nausea or vomiting, the need for rescue antiemetics, hypotension, bradycardia, and shivering. Complete response rate, defined as the absence of postoperative nausea and vomiting and no need for additional antiemetics, were assessed for up to 24 hours post-surgery.
RESULTS
No significant differences were observed in the total dose of phenylephrine used between the ondansetron and palonosetron groups (387.5 μg [interquartile range, 291.3-507.8 μg versus 428.0 μg [interquartile range, 305.0-507.0 μg], P = 0.42). Complete response rates also showed no significant differences between the groups both within two hours post-spinal anesthesia (88.9% in the ondansetron group versus 100% in the palonosetron group; P = 0.24) and at 24 hours post-surgery (81.5% in the ondansetron group versus 88.8% in the palonosetron group; P = 0.7). In addition, there was no difference in other secondary outcomes.
CONCLUSION
Prophylactic administration of palonosetron did not demonstrate a superior effect over ondansetron in mitigating hemodynamic changes or reducing phenylephrine requirements in patients undergoing spinal anesthesia with bupivacaine and fentanyl for cesarean section.
Topics: Humans; Female; Anesthesia, Spinal; Cesarean Section; Palonosetron; Adult; Hypotension; Pregnancy; Ondansetron; Antiemetics; Postoperative Nausea and Vomiting; Phenylephrine; Anesthesia, Obstetrical
PubMed: 38917195
DOI: 10.1371/journal.pone.0305913 -
International Ophthalmology Jun 2024Subluxation of the crystalline lens (Ectopia Lentis, EL) can lead to significant visual impairment and serves as a diagnostic criterion for genetic disorders such as the... (Observational Study)
Observational Study
PURPOSE
Subluxation of the crystalline lens (Ectopia Lentis, EL) can lead to significant visual impairment and serves as a diagnostic criterion for genetic disorders such as the Marfan syndrome. There is no established criterion to diagnose and quantify EL. We prospectively investigated the distance between the zonular fibre insertion and the limbus (ZLD) in healthy subjects as a parameter to assess the position of the lens, quantify EL and provide normative data.
METHODS
This prospective, observational, cross-sectional study includes one-hundred-fifty eyes of 150 healthy participants (mean age 28 years, range 4-68). Pupils were dilated with tropicamide 0.5% and phenylephrine 2.5% eyedrops. ZLD was measured in mydriasis at the slit lamp as the distance between the most central visible insertions of the zonular fibres on the lens surface and the corneoscleral limbus. Vertical pupil diameter (PD) and refractive error were recorded. If zonular fibre insertions were not visible, the distance between limbus and the pupillary margin was recorded as ZLD.
RESULTS
145 right and 5 left eyes were examined. 93% of study subjects were Caucasian, 7% were Asian. In eyes with visible zonular fibre insertions (n = 76 eyes), ZLD was 1.30 ± 0.28 mm (mean ± SD, range 0.7-2.1) and PD was 8.79 ± 0.57 mm (7.5-9.8). In the remaining 74 eyes, ZLD was 1.38 ± 0.28 mm (0.7-2.1), and PD was 8.13 ± 0.58 mm (6.7-9.4). For all eyes, ZLD was 1.34 ± 0.29 mm (0.7-2.1), and PD was 8.47 ± 0.66 mm (6.7-9.8). Refractive error and sex did not significantly affect ZLD. Smaller PD and older age were associated with larger ZLD (P < 0.001 and P = 0.036, respectively).
CONCLUSION
Average ZLD was 1.34 mm in eyes of healthy subjects. Older age correlated with larger ZLD. These normative data will aid in diagnosing and quantifying EL.
Topics: Humans; Ectopia Lentis; Male; Female; Prospective Studies; Cross-Sectional Studies; Adult; Child; Adolescent; Middle Aged; Young Adult; Aged; Child, Preschool; Lens, Crystalline; Limbus Corneae; Pupil
PubMed: 38913255
DOI: 10.1007/s10792-024-03163-0 -
Translational Vision Science &... Jun 2024To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization.
PURPOSE
To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization.
METHODS
This study recruited 138 subjects (eyes): 102 with neovascular age-related macular degeneration (nAMD), 18 with diabetic macular edema (DME), and 18 with cataract (control group). AH samples underwent analysis using Olink Target 96 proteomics and Metabolon's metabolomics platform Data analysis included correlation, differential abundance, and gene-set analysis.
RESULTS
In total, 756 proteins and 408 metabolites were quantified in AH. Total AH protein concentration was notably higher in nAMD (3.2-fold) and DME (4.1-fold) compared to controls. Pseudophakic eyes showed higher total AH protein concentrations than phakic eyes (e.g., 1.6-fold in nAMD) and a specific protein signature indicative of matrix remodeling. Unexpectedly, pupil-dilating drugs containing phenylephrine/tropicamide increased several AH proteins, notably interleukin-6 (5.4-fold in nAMD). Correcting for these factors revealed functionally relevant protein correlation clusters and disease-relevant, differentially abundant proteins across the groups. Metabolomics analysis, for which the relevance of confounder adjustment was less apparent, suggested insufficiently controlled diabetes and chronic hyperglycemia in the DME group.
CONCLUSIONS
AH protein concentration, pseudophakia, and pupil dilation with phenylephrine/tropicamide are important confounding factors for AH protein analyses. When these factors are considered, AH analyses can more clearly reveal disease-relevant factors.
TRANSLATIONAL RELEVANCE
Considering AH protein concentration, lens status, and phenylephrine/tropicamide administration as confounders is crucial for accurate interpretation of AH protein data.
Topics: Humans; Aqueous Humor; Female; Proteomics; Male; Aged; Metabolomics; Eye Proteins; Middle Aged; Cataract; Diabetic Retinopathy; Macular Edema; Wet Macular Degeneration; Aged, 80 and over
PubMed: 38913008
DOI: 10.1167/tvst.13.6.17 -
Microvascular Research Jun 2024Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular...
Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular signalling responsible for catecholamine excess induced endothelial dysfunction. Human cardiac microvascular endothelial cells were challenged by epinephrine to mimic catecholamine excess. Patch clamp, FACS, ELISA, PCR, and immunostaining were employed for the study. Epinephrine (Epi) enhanced small conductance calcium-activated potassium channel current (I) through activating α1 adrenoceptor. Phenylephrine enhanced edothelin-1 (ET-1) and reactive oxygen species (ROS) production, and the effects involved contribution of I. HO enhanced I and ET-1 production. Enhancing I caused a hyperpolarization, which increases ROS and ET-1 production. BAPTA partially reduced phenylephrine-induced enhancement of ET-1 and ROS, suggesting that α1 receptor activation can enhance ROS/ET-1 generation in both calcium-dependent and calcium-independent ways. The study demonstrates that high concentration catecholamine can activate SK1-3 channels through α1 receptor-ROS signalling and increase ET-1 production, facilitating vasoconstriction.
PubMed: 38901735
DOI: 10.1016/j.mvr.2024.104699 -
Aesthetic Surgery Journal. Open Forum 2024The posterior Müller muscle-conjunctival resection (MMCR) procedure is a straightforward procedure for the correction of eyelid ptosis with a relatively short operating...
BACKGROUND
The posterior Müller muscle-conjunctival resection (MMCR) procedure is a straightforward procedure for the correction of eyelid ptosis with a relatively short operating time and fast recovery. Traditionally, its use was limited to patients with mild involutional ptosis and good levator function and a positive phenylephrine test result.
OBJECTIVES
To evaluate the efficacy of the MMCR procedure as a primary step to treat eyelid ptosis with varying etiology and severity, including patients with more severe ptosis and moderate levator function, and to produce a treatment algorithm.
METHODS
A retrospective analysis of the results of 34 patients, comprising 56 operated eyelids, treated with the MMCR procedure for eyelid ptotis between 2016 and 2018, was performed. Preoperative and postoperative pictures were analyzed for determining the margin-to-reflex distance (MRD1), symmetry, and complications.
RESULTS
We found a mean preoperative MRD1 of 1.3 mm (SD 1.1) and postoperative MRD1 of 3.2 mm (SD 1.0). The mean postoperative MRD1 for unilateral and bilateral cases was 3.4 (SD 0.8) and 3.2 (SD 1.1), respectively. Only 2 patients (5.9%) had an asymmetrical postoperative result (>1.0 mm MRD1 difference), and both were unilateral cases. Complications were scarce: only 1 patient (2.9%) developed dry eyes and 2 patients experienced temporary discomfort from the conjunctival sutures.
CONCLUSIONS
The MMCR procedure appears to be an excellent procedure as a primary step to correct eyelid ptosis with varying etiologies and severity, due to its low risk of asymmetry, short learning curve, and high success rate. A flow chart as treatment algorithm is provided for clinical decision making.
PubMed: 38887214
DOI: 10.1093/asjof/ojad111 -
Journal of Clinical Anesthesia Jun 2024Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal...
Norepinephrine or phenylephrine for the prevention of post-spinal hypotension after caesarean section: A double-blinded, randomized, controlled study of fetal heart rate and fetal cardiac output.
STUDY OBJECTIVE
Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal anesthesia-induced hypotension during caesarean delivery. Many studies have shown that norepinephrine can provide more stable maternal hemodynamics than phenylephrine. We therefore tested the hypothesis that norepinephrine preserves fetal circulation better than phenylephrine when used to treat maternal hypotension consequent to spinal anesthesia.
DESIGN
Prospective, randomized, double-blinded study.
SETTING
Operating room.
PATIENTS
We recruited 223 parturients with uncomplicated singleton pregnancies who were scheduled for elective caesarean section under combined spinal-epidural anesthesia.
INTERVENTIONS
The patients received prophylactic intravenous infusion of either 0.08 μg/kg/min norepinephrine or 0.5 μg/kg/min phenylephrine for prevention of spinal anesthesia-induced hypotension.
MEASUREMENTS
Changes in fetal heart rate and fetal cardiac output before and after spinal anesthesia were measured using noninvasive Doppler ultrasound.
MAIN RESULTS
90 subjects who received norepinephrine infusion and 93 subjects who received phenylephrine infusion were ultimately analyzed in the present study. The effects of norepinephrine and phenylephrine on the change of fetal heart rate and fetal cardiac output at 3 and 6 min after spinal block were similar. Although there was a statistically significant decrease in fetal cardiac output at 6 min after subarachnoid block initiation in both the norepinephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.03) and the phenylephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.02), it remained within the normal range.
CONCLUSIONS
Prophylactic infusion of comparable doses of phenylephrine or norepinephrine has similar effects on fetal heart rate and cardiac output changes after spinal anesthesia. Neither phenylephrine nor norepinephrine has meaningful detrimental effects on fetal circulation or neonatal outcomes.
PubMed: 38880002
DOI: 10.1016/j.jclinane.2024.111533 -
Atherosclerosis May 2024Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the...
BACKGROUND AND AIMS
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms.
METHODS
Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry.
RESULTS
Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group.
CONCLUSIONS
Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.
PubMed: 38879387
DOI: 10.1016/j.atherosclerosis.2024.117595 -
Pharmacological Research Jul 2024Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a...
Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.
Topics: Animals; Heart Failure; Histone-Lysine N-Methyltransferase; Myocytes, Cardiac; Endoplasmic Reticulum Stress; Male; Mice, Inbred C57BL; Humans; Mice, Knockout; Rats; Mice; Cells, Cultured; Cardiomegaly; Rats, Sprague-Dawley; Thrombospondins
PubMed: 38876442
DOI: 10.1016/j.phrs.2024.107263