Genetic correlation between circulating cytokines and risk of three ophthalmic diseases: a bidirectional two-sample Mendelian randomization study.

PURPOSE: Pathogenesis and the associated risk factors of cataracts, glaucoma, and age-related macular degeneration (AMD) remain unclear. We aimed to investigate causal relationships between circulating cytokine levels and the development of these diseases. PATIENTS AND METHODS: Genetic instrumental variables for circulating cytokines were derived from a genome-wide association study of 8293 European participants. Summary-level data for AMD, glaucoma, and senile cataract were obtained from the FinnGen database. The inverse variance weighted (IVW) was the main Mendelian randomization (MR) analysis method. The Cochran's Q, MR-Egger regression, and MR pleiotropy residual sum and outlier test were used for sensitivity analysis. RESULTS: Based on the IVW method, MR analysis demonstrated five circulating cytokines suggestively associated with AMD (SCGF-ß, 1.099 [95%CI, 1.037-1.166], P = 0.002; SCF, 1.155 [95%CI, 1.015-1.315], P = 0.029; MCP-1, 1.103 [95%CI, 1.012-1.202], P = 0.026; IL-10, 1.102 [95%CI, 1.012-1.200], P = 0.025; eotaxin, 1.086 [95%CI, 1.002-1.176], P = 0.044), five suggestively linked with glaucoma (MCP-1, 0.945 [95%CI, 0.894-0.999], P = 0.047; IL1ra, 0.886 [95%CI, 0.809-0.969], P = 0.008; IL-1ß, 0.866 [95%CI, 0.762-0.983], P = 0.027; IL-9, 0.908 [95%CI, 0.841-0.980], P = 0.014; IL2ra, 1.065 [95%CI, 1.004-1.130], P = 0.035), and four suggestively associated with senile cataract (TRAIL, 1.043 [95%CI, 1.009-1.077], P = 0.011; IL-16, 1.032 [95%CI, 1.001-1.064], P = 0.046; IL1ra, 0.942 [95%CI, 0.887-0.999], P = 0.047; FGF-basic, 1.144 [95%CI, 1.052-1.244], P = 0.002). Furthermore, sensitivity analysis results supported the above associations. CONCLUSION: This study highlights the involvement of several circulating cytokines in the development ophthalmic diseases and holds potential as viable pharmacological targets for these diseases.

Mpox-Related Ophthalmic Disease: A Retrospective Observational Study in a Single Center in Mexico.

Mpox-related ophthalmic disease has been reported as infrequent. We retrospectively describe the ocular manifestations present in 11 of 100 patients with confirmed mpox; 9 were people with HIV. We suggest that an ophthalmological evaluation should be performed in all patients with ocular symptoms or moderate and severe mpox disease.

Atypical retinopathy in ataxia with vitamin E deficiency: report of a sibship.

Typical retinitis pigmentosa (RP) may not be the only retinal phenotype encountered in ataxia with vitamin E deficiency (AVED). The following short case series describes a novel form of retinopathy in AVED. We describe two patients with AVED belonging to the same consanguineous sibship. Both presented an unusual retinopathy consisting of scattered, multifocal, nummular, hyperautofluorescent atrophic retinal patches. The retinopathy remained stable under vitamin E supplementation. We hypothesize these changes to be the result of arrested AVED-related RP following early supplementation with α-tocopherol acetate.

Improving the Yield of Genetic Diagnosis through Additional Genetic Panel Testing in Hereditary Ophthalmic Diseases.

Numerous hereditary ophthalmic diseases display significant genetic diversity. Consequently, the utilization of gene panel sequencing allows a greater number of patients to receive a genetic diagnosis for their clinical manifestations. We investigated how to improve the yield of genetic diagnosis through additional gene panel sequencing in hereditary ophthalmic diseases. A gene panel sequencing consisting of a customized hereditary retinopathy panel or hereditary retinitis pigmentosa (RP) panel was prescribed and referred to a CAP-accredited clinical laboratory. If no significant mutations associated with hereditary retinopathy and RP were detected in either panel, additional gene panel sequencing was requested for research use, utilizing the remaining panel. After additional gene panel sequencing, a total of 16 heterozygous or homozygous variants were identified in 15 different genes associated with hereditary ophthalmic diseases. Of 15 patients carrying any candidate variants, the clinical symptoms could be tentatively accounted for by genetic mutations in seven patients. However, in the remaining eight patients, given the in silico mutation predictive analysis, variant allele frequency in gnomAD, inheritance pattern, and genotype-phenotype correlation, fully elucidating the clinical manifestations with the identified rare variant was challenging. Our study highlights the utility of gene panel sequencing in achieving accurate diagnoses for hereditary ophthalmic diseases and enhancing the diagnostic yield through additional gene panel sequencing. Thus, gene panel sequencing can serve as a primary tool for the genetic diagnosis of hereditary ophthalmic diseases, even in cases where a single genetic cause is suspected. With a deeper comprehension of the genetic mechanisms underlying these diseases, it becomes feasible.

Trifluridine for treatment of mpox infection in drug combinations in ophthalmic cell models.

The Mpox virus can cause severe disease in the susceptible population with dermatologic and systemic manifestations. Furthermore, ophthalmic manifestations of mpox infection are well documented. Topical trifluridine (TFT) eye drops have been used for therapy of ophthalmic mpox infection in patients, however, its efficacy against mpox virus infection in this scenario has not been previously shown. In the present study, we have established ophthalmic cell models suitable for the infection with mpox virus. We show, that TFT is effective against a broad range of mpox isolates in conjunctival epithelial cells and keratocytes. Further, TFT remained effective against a tecovirimat-resistant virus strain. In the context of drug combinations, a nearly additive effect was observed for TFT combinations with brincidofovir and tecovirimat in conjunctival epithelial cells, while a slight antagonism was observed for both combinations in keratocytes. Altogether, our findings demonstrate TFT as a promising drug for treatment of ophthalmic mpox infection able to overcome tecovirimat resistance. However, conflicting results regarding the effect of drug combinations with approved compounds warrant close monitoring of such use in patients.

Hospitalization, Overdose, and Mortality After Opioid Prescriptions Tied to Ophthalmic Surgery.

PURPOSE: Opioid prescriptions continue to carry significant short- and long-term systemic risks, even after ophthalmic surgery. The goal of this study was to identify any association of opioid prescription, after ophthalmic surgery, with postoperative hospitalization, opioid overdose, opioid dependence, and all-cause mortality. DESIGN: Retrospective, cross-sectional analysis. PARTICIPANTS: Patients undergoing an ophthalmic surgery in the OptumLabs Data Warehouse. METHODS: We used deidentified administrative claims data from the OptumLabs Data Warehouse to create 3 cohorts of patients for analysis from January 1, 2016, to June 30, 2022. The first cohort consisted of 1-to-1 propensity score-matched patients who had undergone ophthalmic surgery and had filled a prescription for an opioid and not filled a prescription for an opioid. The second cohort consisted of patients who were considered opioid naïve and had filled a prescription for an opioid matched to patients who had not filled a prescription for an opioid. The last cohort consisted of opioid-naïve patients matched across the following morphine milligram equivalents (MME) groups: ≤ 40, 41-80, and > 80. MAIN OUTCOME MEASURES: Short- and long-term risks of hospitalization, opioid overdose, opioid dependency/abuse, and death were compared between the cohorts. RESULTS: We identified 1 577 692 patients who had undergone an ophthalmic surgery, with 312 580 (20%) filling an opioid prescription. Among all patients, filling an opioid prescription after an ophthalmic surgery was associated with increased mortality (hazard rate [HR], 1.28; 95% confidence interval [CI], 1.25-1.31; P < 0.001), hospitalization (HR, 1.51; 95% CI, 1.49-1.53; P < 0.001), opioid overdose (HR, 7.31; 95% CI, 6.20-8.61, P < 0.001), and opioid dependency (HR, 13.05; 95% CI, 11.48-14.84; P < 0.001) compared with no opioid prescription. Furthermore, we found that higher MME doses of opioids were associated with higher rates of mortality, hospitalization, and abuse/dependence. CONCLUSIONS: Patients who filled an opioid prescription after an ophthalmic surgery experienced higher rates of mortality, hospitalization, episodes of opioid overdose, and opioid dependence compared with patients who did not fill an opioid prescription. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Reversal of Pharmacologically Induced Mydriasis with Phentolamine Ophthalmic Solution.

PURPOSE: Evaluate safety and efficacy of 0.75% phentolamine ophthalmic solution (POS), an alpha-1 antagonist, in reversal of pharmacologically induced mydriasis. DESIGN: Two Phase 3, multicenter, placebo-controlled, randomized, double-masked clinical trials in healthy subjects. SUBJECTS: 553 healthy 12 to 80 year old subjects were randomized 1:1 (MIRA-2) and 2:1 (MIRA-3) to receive either POS or placebo eye drops OU. METHODS: Subjects received POS or placebo administered 1 hour after mydriasis, induced by instillation of either 2.5% phenylephrine, 1% tropicamide, or Paremyd (1% hydroxyamphetamine / 0.25% tropicamide). MAIN OUTCOME MEASURES: Primary endpoint was percent of subjects returning to ≤0.2 mm greater than baseline pupil diameter in study eye at 90 minutes after POS administration. Safety measures included treatment-emergent adverse events (TEAEs) and tolerability measures, including conjunctival hyperemia. RESULTS: In MIRA-2, 185 subjects were randomized to treatment with placebo (94) or POS (91). In MIRA-3, 368 subjects were randomized to treatment with placebo (124) or POS (244). A statistically significant greater percentage of subjects treated with POS had study eyes that showed reversal of mydriasis at 90 minutes (primary endpoint) compared with the placebo treatment (48.9% vs 6.6% for MIRA-2; p<0.0001 and 58% VS 6% for MIRA-3; p<0.0001) and as early as 60 minutes (24.5% vs 5.5% for MIRA-2; p<0.0003 and 42% VS 2% for MIRA-3; p<0.0001). Between 28 to 34% of placebo-treated subjects had not returned to baseline PD at 24 hours following pharmacological dilation compared to 8 to 11% treated with POS (p<0.0001). CONCLUSION: POS treatment had a rapid onset in reducing PD within 60- to 90-minutes, with a statistically significant time savings of 3 to 4 hours to return to baseline PD compared to placebo. One or 2 drops of POS rapidly reversed mydriasis in all subjects regardless of mydriatic agent or iris color. More subjects receiving POS reported a perceived benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared to placebo, with statistically significant differences noted as early as 1 hour. The safety profile was favorable, with the most common adverse effects being mild transient conjunctival hyperemia (11.2%), instillation site discomfort (10.9%), and dysgeusia (3.6%).

IL-33/ST2 enhances MMP-12 expression by macrophages to mediate inflammatory and immune response in IgG4-Related Ophthalmic Disease.

IgG4-Related Ophthalmic Disease (IgG4-ROD) is a chronic autoimmune-mediated fibrotic disease that predominantly affects the lacrimal glands, often leading to loss of function in the involved tissues or organs. Recent studies have demonstrated that MMP-12 is highly expressed in IgG4-ROD and plays a significant role in regulating immune responses. In this study, we reviewed nine patients diagnosed with IgG4-ROD based on clinical manifestations and histological analysis, and we investigated the expression of IL-33/ST2 and MMP-12 in IgG4-ROD lacrimal gland tissues using IHC. We found that IL-33 interacts with its specific receptor ST2, both of which are significantly overexpressed in IgG4-ROD tissues. Additionally, we successfully constructed a mouse model by introducing the LatY136F mutation into C57BL/6 mice to mimic IgG4-ROD lacrimal gland involvement, which helped elucidate the mechanisms involved in the induction of MMP-12. Furthermore, immunofluorescence staining confirmed that most MMP-12+ cells were derived from M2 macrophages, and an ELISA assay demonstrated that IL-33 upregulates MMP-12 in IgG4-ROD. Collectively, these data suggest that the IL-33/ST2/MMP-12 signaling pathway is activated in IgG4-ROD, with IL-33/ST2 potentially promoting M2 macrophage polarization and activation to produce MMP-12, which may serve as a novel therapeutic target for IgG4-ROD.

Recent advancements and applications of ophthalmic gene therapy strategies: A breakthrough in ocular therapeutics.

Over the past twenty years, ocular gene therapy has primarily focused on addressing diseases linked to various genetic factors. The eye is an ideal candidate for gene therapy due to its unique characteristics, such as easy accessibility and the ability to target both corneal and retinal conditions, including retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), age-related macular degeneration (AMD), and Stargardt disease. Currently, literature documents 33 clinical trials in this field, with the most promising results emerging from trials focused on LCA. These successes have catalyzed further research into other ocular conditions such as glaucoma, AMD, RP, and choroideremia. The effectiveness of gene therapy relies on the efficient delivery of genetic material to specific cells, ensuring sustained and optimal gene expression over time. Viral vectors have been widely used for this purpose, although concerns about potential risks such as immune reactions and genetic mutations have led to the development of non-viral vector systems. Preliminary laboratory research and clinical investigations have shown a connection between vector dosage and the intensity of immune response and inflammation in the eye. The method of administration significantly influences these reactions, with subretinal delivery resulting in a milder humoral response compared to the intravitreal route. This review discusses various ophthalmic diseases, including both corneal and retinal conditions, and their underlying mechanisms, highlighting recent advances and applications in ocular gene therapies.

Ophthalmic drug effects on the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment.

Drugs that can treat one disease may either be detrimental or beneficial toward another due to possible cross-interactions. Therefore, care in choosing a suitable drug for patients with multiple diseases is crucial in successful patient management. This study explores several currently available ophthalmic drugs used to treat common ocular diseases to understand how they can affect the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment found in abundance in the corneal protein aggregation deposits of lattice corneal dystrophy (LCD) patients. Results from this study provided supporting evidence that some drugs intended to treat other diseases can enhance or inhibit fibrillar aggregation of TGFBIp peptide, which may have potential implication of affecting the disease progression of LCD by either worsening or ameliorating it. Comparisons of the different properties of ophthalmic compounds explored in this study may also provide some guidance for future design of drugs geared toward the treatment of LCD.

High-fat diet causes endothelial dysfunction in the mouse ophthalmic artery.

Obesity is a significant health concern that leads to impaired vascular function and subsequent abnormalities in various organs. The impact of obesity on ocular blood vessels, however, remains largely unclear. In this study, we examined the hypothesis that obesity induced by high-fat diet produces vascular endothelial dysfunction in the ophthalmic artery. Mice were subjected to a high-fat diet for 20 weeks, while age-matched controls were maintained on a standard diet. Reactivity of isolated ophthalmic artery segments was assessed in vitro. Reactive oxygen species (ROS) were quantified in cryosections by dihydroethidium (DHE) staining. Redox gene expression was determined in ophthalmic artery explants by real-time PCR. Furthermore, the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), the receptor for advanced glycation end products (RAGE), and of the lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) was determined in cryosections using immunofluorescence microscopy. Ophthalmic artery segments from mice on a high-fat diet exhibited impaired vasodilation responses to the endothelium-dependent vasodilator acetylcholine, while endothelium-independent responses to nitroprusside remained preserved. DHE staining intensity in the vascular wall was notably stronger in mice on a high-fat diet. Messenger RNA expression for NOX2 was elevated in the ophthalmic artery of mice subjected to high fat diet. Likewise, immunostainings revealed increased expression of NOX2 and of RAGE, but not of LOX-1. These findings suggest that a high-fat diet triggers endothelial dysfunction by inducing oxidative stress in the ophthalmic artery via involvement of RAGE and NOX2.

Evidence that systemic vascular resistance is increased before the development of gestational diabetes mellitus.

BACKGROUND: The ophthalmic artery, which is the first branch of the internal carotid artery, has a Doppler velocity waveform with 2 systolic peaks. The ratio of the peak systolic velocity of the second wave divided by that of the first wave is used to reflect increased peripheral resistance. Previous studies in the first, second, and third trimesters of pregnancy have reported that in pregnant women who subsequently develop preeclampsia, the peak systolic velocity ratio is increased. Both preeclampsia and gestational diabetes mellitus are associated with endothelial dysfunction and an increased risk for cardiovascular diseases during the first decade after pregnancy. OBJECTIVE: This study aimed to compare the ophthalmic artery peak systolic velocity ratio at 11 to 13 weeks' gestation of women who subsequently develop gestational diabetes mellitus with that of unaffected pregnant women and those who develop preeclampsia. STUDY DESIGN: This was a prospective observational study of women who attended the King's College Hospital, London, United Kingdom, for a routine hospital visit at 11+0 to 13+6 weeks' gestation. This visit included recording of the maternal demographic characteristics and medical history, an ultrasound examination for fetal anatomy and growth, assessment of the flow velocity waveforms from the maternal ophthalmic arteries, calculation of the peak systolic velocity ratio, and measurement of the mean arterial pressure. Linear regression was performed to predict the ophthalmic artery peak systolic velocity ratio based on maternal characteristics and the mean arterial pressure. The peak systolic velocity ratio in the group with gestational diabetes mellitus was compared with that of preeclamptic and unaffected pregnancies. RESULTS: A total of 3999 women were included in this study, including 375 (9.8%) who developed gestational diabetes mellitus and 101 (2.5%) who developed preeclampsia. In the gestational diabetes mellitus group, 161 (43.3%) were treated by diet alone, 130 (34.1%) were treated with metformin, and 84 (22.6%) received insulin with or without metformin. Prediction of peak systolic velocity ratio was provided by development of preeclampsia, maternal age, body mass index, mean arterial pressure, first-degree family history of diabetes mellitus, family history of preeclampsia, Asian ethnicity, and smoking. There was no significant contribution from gestational diabetes mellitus. Among women who developed gestational diabetes mellitus that required insulin treatment, the ophthalmic artery peak systolic velocity ratio (0.67±0.09) was higher (P<.001) than that in unaffected pregnancies (0.63±0.10), but it was not significantly different from that in the preeclampsia group (0.69±0.10; P=.90). CONCLUSION: Among women who developed severe gestational diabetes mellitus that required insulin treatment, there was evidence of increased peripheral resistance, which was apparent from the first trimester of pregnancy.

Maternal vascular-placental axis in the third trimester in women with gestational diabetes mellitus, hypertensive disorders, and unaffected pregnancies.

BACKGROUND: Hypertensive disorders of pregnancy and gestational diabetes mellitus are characterized by vascular dysfunction and are associated with long term cardiovascular risks. OBJECTIVE: This study aimed to compare different markers of maternal vascular function in women with gestational diabetes mellitus, preeclampsia, or gestational hypertension and in women whose pregnancies were unaffected by these complications and to assess the association between maternal vascular function and markers of placental perfusion and maternal vascular-placental axis in 4 groups of women. STUDY DESIGN: This was a prospective observational study of women who had routine hospital visits at 35 0/7 to 36 6/7 weeks of gestation at King's College Hospital, London, United Kingdom. The routine hospital visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, Doppler studies of the uterine arteries and ophthalmic arteries, carotid-femoral pulse wave velocity measurements, estimation of the augmentation index and total peripheral resistance, and measurements of serum placental growth factor and soluble fms-like tyrosine kinase 1. Linear regression analysis was performed for the outcomes of uterine artery pulsatility index multiple of the median, placental growth factor multiple of the median, and soluble fms-like tyrosine kinase 1 multiple of the median. The ophthalmic artery peak systolic velocity ratio, pulse wave velocity, augmentation index, and total peripheral vascular resistance were assessed as potential predictors. This analysis was performed on all women and separately in the different groups. RESULTS: The study population of 6502 women included 614 (9.4%) with gestational diabetes mellitus, 140 (2.1%) who subsequently developed preeclampsia, and 129 (2.0%) who developed gestational hypertension. Women with gestational diabetes mellitus had increased pulse wave velocity compared with those with pregnancies unaffected by gestational diabetes mellitus, preeclampsia, or gestational hypertension. Women with preeclampsia or gestational hypertension had lower placental growth factor multiple of the median and higher uterine artery pulsatility index multiple of the median, soluble fms-like tyrosine kinase 1 multiple of the median, augmentation index, pulse wave velocity, total peripheral resistance, and ophthalmic artery peak systolic velocity ratio than those with unaffected pregnancies. In women with unaffected pregnancies, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median, and ophthalmic artery peak systolic velocity ratio, augmentation index, total peripheral resistance, and pulse wave velocity were predictive of the placental growth factor multiple of the median and the soluble fms-like tyrosine kinase 1 multiple of the median. In women with gestational diabetes mellitus, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median; the ophthalmic artery peak systolic velocity ratio, total peripheral resistance, and pulse wave velocity were predictive of the placental growth factor multiple of the median; and total peripheral resistance was predictive of the soluble fms-like tyrosine kinase 1 multiple of the median. In women with preeclampsia, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median, placental growth factor multiple of the median, and soluble fms-like tyrosine kinase 1 multiple of the median. In women unaffected by gestational diabetes mellitus, preeclampsia, or gestational hypertension, the ophthalmic artery peak systolic velocity ratio was predictive of the uterine artery pulsatility index multiple of the median, and the augmentation index, total peripheral resistance, pulse wave velocity, and the ophthalmic artery peak systolic velocity ratio were predictive of the placental growth factor multiple of the median and the soluble fms-like tyrosine kinase 1 multiple of the median. CONCLUSION: In the third trimester of pregnancy, women with preeclampsia, gestational hypertension, and gestational diabetes mellitus present with increased arterial stiffness. In addition, women diagnosed with hypertensive complications showed increased peripheral vascular resistance. The ophthalmic artery peak systolic velocity ratio provided predictive information for placental perfusion and function in all pregnant women, whereas vascular indices were more informative for placental function in women with unaffected pregnancies and those with gestational diabetes mellitus than in those with preeclampsia or gestational hypertension. Our data suggest that vascular assessment in women during pregnancy not only may provide information about maternal vascular health but also can be used to provide information about individual risk factors for placental insufficiency. The selection of the vascular index will have to be tailored according to the maternal profile and pregnancy complication.

Progress in the Application of Microneedles in Eye Disorders and the Proposal of the Upgraded Microneedle with Spinule.

PURPOSE: In the local administration methods for treating eye diseases, the application of microneedles has great potential due to the shortcomings of low efficacy and significant side effects of local administration preparations. This article provides ideas for the research on the application of ophthalmic microneedle in the treatment of eye diseases. RESULTS: This article analyzes the physiological structures of the eyes, ocular diseases and its existing ocular preparations in sequence. Finally, this article reviews the development and trends of ocular microneedles in recent years, and summarizes and discusses the drugs of ocular microneedles as well as the future directions of development. At the same time, according to the inspiration of previous work, the concept of "microneedle with spinule" is proposed for the first time, and its advantages and limitations are discussed in the article. CONCLUSIONS: At present, the application of ocular microneedles still faces multiple challenges. The aspects of auxiliary devices, appearance, the properties of the matrix materials, and preparation technology of ophthalmic microneedle are crucial for their application in the treatment of eye diseases.

Eye Drop Quality Issues: Can the FDA See This One Through?

The Food and Drug Administration (FDA) has long suffered from a lack of resources limiting their inspection capacity. They have fallen behind on proactive surveillance inspections of foreign manufacturing sites, relying instead on for-cause inspections after a problem has been discovered. Over-the-counter (OTC) products are especially vulnerable because the FDA considers them lower priority. This issue recently made big news after improperly manufactured OTC eye drops harmed users across the country, in some cases causing blindness. To prevent future harm to Americans, it is imperative that the FDA receives enough resources to keep up with their routine inspections.

Ophthalmic artery Doppler in women with hypertensive disorders of pregnancy: relationship to blood pressure control and renal dysfunction at 6-9 weeks postnatally.

OBJECTIVES: To examine the postnatal course of ophthalmic artery (OA) Doppler in women with hypertensive disorders of pregnancy (HDP) and to evaluate the correlation between OA Doppler parameters and poor postnatal blood pressure control and renal dysfunction at 2-3 weeks and 6-9 weeks postnatally. METHODS: This was a prospective cohort study of women with a singleton pregnancy and HDP seen at a tertiary pregnancy hypertension clinic between 2019 and 2021. Three visits were included: Visit 1, the last visit to the antenatal hypertension clinic within 2 weeks prior to delivery; Visit 2, at 2-3 weeks postnatally; and Visit 3, at 6-9 weeks postnatally. At each visit, maternal demographic characteristics, medical history, blood pressure and OA Doppler were obtained. In addition, fetal growth and fetal Dopplers were examined antenatally and, at 6-9 weeks postnatally, estimated glomerular filtration rate and proteinuria were quantified. Study participants were divided into four hypertension groups, according to longitudinal changes in blood pressure at the three visits. For the postnatal visits, hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg in the absence of antihypertensive medication, and SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg whilst taking antihypertensives. Group 1 was hypertensive at all three visits; Group 2 was hypertensive at Visits 1 and 2 but normotensive at Visit 3; Group 3 was hypertensive at Visits 1 and 3 but normotensive at Visit 2; and Group 4 was hypertensive at Visit 1 but normotensive at Visits 2 and 3. The longitudinal changes in mean arterial pressure (MAP), peak systolic velocity (PSV) 1, PSV2 and the ratio of PSV2/PSV1 over the three timepoints were examined by a repeated-measures, multilevel, linear mixed-effects analysis, controlling for maternal age, weight at presentation and use of antihypertensive medication. In addition, we examined the longitudinal change in OA Doppler parameters in women with different degrees of postnatal blood pressure control and in those with and those without renal dysfunction at 6-9 weeks postnatally. RESULTS: A total of 108 women were recruited to the study, of whom 86 had new-onset hypertension and 22 had chronic hypertension. When controlling for maternal age, weight at presentation and use of antihypertensive medication, a significant decline in log10 MAP (P < 0.001), log10 PSV1 (P < 0.001) and log10 PSV2 (P = 0.01) was seen between Visits 1 and 3. Log10 PSVR did not change with time. When assessing OA Doppler against hypertension group, log10 PSV1 and log10 PSV2 did not differ between the hypertension groups, whilst Group 4 had a lower log10 PSVR compared with Group 1 (P < 0.01), Group 2 (P = 0.03) and Group 3 (P < 0.01). At 6-9 weeks postnatally, log10 PSVR was lower in those without compared to those with renal dysfunction (-0.021, P = 0.01), whilst log10 MAP, log10 PSV1 and log10 PSV2 values did not differ. Log10 PSVR did not change with time and remained at -0.12 (95% CI, -0.13 to -0.11) across the three visits. CONCLUSIONS: In women with HDP, the OA-PSVR was significantly higher in those with labile or persistently raised blood pressure postnatally compared to women whose blood pressure normalized. Similarly, the OA-PSVR at 6-9 weeks postnatally was significantly higher in women with renal dysfunction vs those without dysfunction. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Impact of hypertensive disorders of pregnancy on offspring cardiovascular function: from fetal life to early childhood.

OBJECTIVE: Epidemiological studies suggest that, following in-utero exposure to hypertensive disorder of pregnancy (HDP), children may be at increased long-term cardiovascular risk, but data in early childhood are lacking. We aimed to investigate the independent influence of HDP on infant cardiac structure and function, after accounting for differences in childhood risk-factor profile. METHODS: This was a longitudinal study of 71 children born of a pregnancy complicated by HDP (gestational hypertension or pre-eclampsia) and 304 children born of a normotensive pregnancy. Detailed cardiovascular assessment was performed at mid gestation and at a median of 2.3 (interquartile range, 2.1-2.4) years postnatally. Linear mixed-effects modeling was used to determine the independent influence of HDP on infant cardiac function and structure after accounting for differences in childhood risk-factor profile. RESULTS: There were no differences in demographic characteristics between children whose mother developed HDP and those born of a normotensive pregnancy, but delivery was earlier and birth weight was lower in the HDP group. In fetal life, there were no significant differences in cardiac function or structure between the HDP and non-HDP groups. In early childhood, in the HDP group compared with the non-HDP group, there was greater relative wall thickness (mean ± SD, 0.7 ± 0.3 vs 0.6 ± 0.3; P = 0.047) and increased left ventricular mass (indexed to body surface area) (mean ± SD, 80.9 ± 20.4 g/m2 vs 75.7 ± 16.5 g/m2; P = 0.024); however, these differences did not persist on multivariable analysis. Longitudinal analysis revealed that there was no difference in the change in cardiac functional indices from fetal life to early childhood between the HDP and non-HDP groups. CONCLUSION: There is no evidence that HDP has an adverse effect on offspring cardiovascular health in fetal life or in early childhood. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Long-term cardiovascular assessment of women with previous pregnancy complicated by hypertensive disorder.

OBJECTIVES: Women with a hypertensive disorder of pregnancy (HDP) are at increased risk of developing hypertension and cardiovascular disease later in life. However, from previous studies, it is difficult to define whether this association reflects pre-existing maternal cardiovascular risk or a potentially causal relationship between HDP and later cardiovascular risk. In this study, we performed detailed cardiovascular assessment in women in midgestation, prior to development of HDP, and at 2 years postpartum, aiming to identify cardiovascular changes prior to development of HDP and to assess persistent cardiovascular alterations long after the HDP event. METHODS: This was a prospective observational study in which we performed detailed cardiovascular assessment in midgestation and at a median of 2.3 (interquartile range, 2.1-2.4) years postpartum. We examined 112 women who developed HDP and 451 women whose pregnancy was not complicated by hypertension. We used conventional and more advanced (i.e. speckle tracking) echocardiographic techniques to determine accurately left ventricular systolic and diastolic function. We used M-mode measurements to determine left ventricular remodeling and estimate left ventricular mass. Maternal vascular status was assessed using ophthalmic artery Doppler and by calculating peak systolic velocity (PSV) ratio, as a marker of peripheral vascular resistance. RESULTS: In midgestation, women who subsequently developed HDP had increased ophthalmic artery PSV ratio. These women also had mild cardiac functional and morphological alterations, which were accounted for mostly by maternal cardiovascular risk factors. At 2 years postpartum, women who had experienced HDP, compared to those who did not, had cardiovascular abnormalities with reduction in left ventricular systolic and diastolic function, which remained after multivariable analysis. Longitudinal analysis demonstrated that the evolution of cardiovascular changes in the HDP and non-HDP groups was similar. CONCLUSIONS: Mild cardiac functional and morphological alterations precede the development of HDP and such changes persist for at least 2 years postpartum. The cardiac changes are likely to be the consequence of pre-existing maternal cardiovascular risk factors rather than an adverse consequence of HDP. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

The Rotterdam Study. Design update and major findings between 2020 and 2024.

The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted.

Dolichoectasia of the ophthalmic artery: a case report on the treatment strategy in endovascular therapy and literature review.

BACKGROUND: Dolichoectasia is a rare arterial condition characterized by the dilatation, tortuosity, and elongation of cerebral blood vessels. The vertebrobasilar artery and internal carotid artery are the common sites of dolichoectasia. However, dolichoectasia of the branch arteries, such as the ophthalmic artery (OA), is extremely rare. To the best of our knowledge, this is the first case of ophthalmic dolichoectasia that was successfully treated with endovascular internal coil trapping. CASE PRESENTATION: A 54-year-old female patient presented with transient left ophthalmalgia and visual disturbance. Magnetic resonance imaging revealed a dilated and elongated left OA compressing the optic nerve at the entrance of the optic canal. However, a previous image that was taken 17 years back revealed that the OA was normal, which suggested the change in dolichoectasia was acquired. Cerebral angiography showed that the dilated and tortuous OA was running from the ophthalmic segment of the left internal carotid artery into the orbit. The symptoms could have been attributed to the direct compression of the dolichoectatic OA in the optic canal. A sufficient anastomosis between the central retinal artery and the middle meningeal artery was identified on external carotid angiography with balloon occlusion of the internal carotid artery. Endovascular treatment with internal trapping of the OA was performed due to ophthalmic symptom progression. Internal coil trapping of the OA was performed at the short segment between the OA bifurcation and the entrance of the optic canal. As expected, the central retinal artery was supplied via the middle meningeal artery after the treatment. The transient visual disturbance was immediately resolved. Ophthalmalgia worsened temporarily after the treatment. However, it completely resolved after several days of oral corticosteroid therapy. Postoperative angiography showed that the origin of the OA was occluded and that the OA in the optic canal was shrunk. The flow of the central retinal arteries via the middle meningeal artery was preserved. CONCLUSIONS: OA dolichoectasia is rare, and its pathogenesis and long-term visual prognosis are still unknown. However, endovascular therapy can improve symptom by releasing the pressure site in the optic canal.