Large-Scale Protein Analysis of Experimental Retinal Artery Occlusion.

Retinal artery occlusion (RAO) is a devastating condition with no effective treatment. The management of RAO could potentially be improved through an in-depth understanding of the molecular alterations in the condition. This study combined advanced proteomic techniques and an experimental model to uncover the retinal large-scale protein profile of RAO. In 13 pigs, RAO was induced with an argon laser and confirmed by fluorescein angiography. Left eyes serving as controls received a sham laser without inducing occlusion. Retinal samples were collected after one, three, or six days and analyzed with liquid chromatography-tandem mass spectrometry. In RAO, 36 proteins were differentially regulated on day one, 86 on day three, and 557 on day six. Upregulated proteins included clusterin, vitronectin, and vimentin, with several proteins increasing over time with a maximum on day six, including clusterin, vimentin, osteopontin, annexin-A, signal transducer, and the activator of transcription 3. On day six, RAO resulted in the upregulation of proteins involved in cellular response to stress, hemostasis, innate immune response, and cytokine signaling. Downregulated proteins were involved in transmission across chemical synapses and visual phototransduction. This study identified the upregulation of multiple inflammatory proteins in RAO and the downregulation of proteins involved in visual pathways.

A review of risk factors for retinal vein occlusions.

INTRODUCTION: Risk factors for retinal vein occlusion have been extensively studied, with varying population sizes. Smaller populations result in less certain measures of associations. The present review included studies with a relevant population size to identify clinically relevant risk factors for retinal vein occlusion. Understanding the risk factors of retinal vein occlusion is important for the management of these patients. AREAS COVERED: A comprehensive literature review was conducted through a systematic literature search in PubMed and Embase. Additional studies were selected from cross references in the assessed studies. Weighted effect measures were calculated for all included risk factors.Risk factors associated with retinal vein occlusion included cardiovascular diseases, eye diseases, systemic diseases, medical interventions, and sociodemographic factors. EXPERT OPINION: This review provided an extensive overview of a wide variety of risk factors increasing the risk of developing retinal vein occlusion. The severity of the identified risk factors indicated that these patients have been in contact with the health care system before their retinal vein occlusion event. Therefore, the clinical course for patients with retinal vein occlusion may benefit from a multidisciplinary collaboration between ophthalmologists and especially cardiologists.

Risk of Stroke, Myocardial Infarction, and Death Among Patients With Retinal Artery Occlusion and the Effect of Antithrombotic Treatment.

Purpose: To evaluate the risk of future stroke, myocardial infarction (MI), and death of patients with retinal artery occlusion (RAO) and the effect of various antithrombotic treatments as secondary prevention. Methods: This cohort study was based on nationwide health registries and included the entire Danish population from 2000 to 2018. All patients with RAO were identified and their adjusted risks of stroke, MI, or death in time periods since RAO were compared with those of the Danish population. Furthermore, antithrombotic treatment of patients with RAO was determined by prescription claims, and the association with the risk of stroke, MI, or death was assessed using multivariate Poisson regression models and expressed as rate ratios (RR) with 95% confidence intervals (95% CIs). Results: After inclusion, 6628 individuals experienced a first-time RAO, of whom 391 had a stroke, 66 had a MI, and 402 died within the first year after RAO. RAO was associated with an increased risk of stroke, MI, or death which persisted for more than 1 year for all three outcomes but was highest on days 3 to 14 after RAO for stroke, with an adjusted RR of 50.71 (95% CI, 41.55-61.87), and on days 14 to 90 after RAO for MI and death, with adjusted RRs of 1.98 (95% CI, 1.25-3.15) and 1.64 (95% CI, 1.28-189), respectively. Overall, antithrombotic treatment was not associated with any protective effect the first year. Conclusions: Patients with RAO had an increased risk of stroke, MI, or death. No protective effect of antithrombotic treatment was shown. Translational Relevance: These findings are relevant to the management of patients with RAO.

Risk of diabetes among related and unrelated family members.

AIMS: The aim was to explore familial aggregation of diabetes in genetically related and unrelated individuals. METHODS: We included citizens from Danish nationwide registries between 1995 and 2018 and calculated rate ratios (RR) of diabetes based on family relation using Poisson regression. RESULTS: Of 7.3 million individuals eligible for inclusion, we identified 343,237 (4.7%) with diabetes. The RR of diabetes was 2.02 (95% CI: 1.99-2.05; p < 0.0001) if any relative had diabetes, 1.79 (95% CI: 1.76-1.83) if a father had diabetes, and 2.06 (95% CI: 2.02-2.10) if a mother had diabetes. If both parents had diabetes, the RR was 3.40 (95% CI: 3.24-3.56). Among full siblings, the RR for developing diabetes was 2.77 (95% CI: 2.71-2.84) and 5.76 (95% CI: 5.00-6.63) for twins. For second-degree relatives, half siblings with a common mother had a RR of 2.35 (95% CI: 2.15-2.56), and with a common father 1.99 (95% CI: 1.81-2.17). Furthermore, the RR was 1.60 (95% CI: 1.56-1.64) if a wife had diabetes, and 1.41 (95% CI: 1.38-1.44) if a husband had diabetes. A subgroup analysis of individuals receiving insulin only treatment (N = 23,054) demonstrated a similar risk pattern, although with slightly higher risk estimates. CONCLUSIONS/INTERPRETATION: Family aggregation of diabetes is associated with genetic disposition with maternal status being the predominant factor. Furthermore, we observed increased risk of diabetes in second-degree relatives, and between unrelated spouses, indicating that environmental factors influence diabetes risk substantially.

Animal Models Used to Simulate Retinal Artery Occlusion: A Comprehensive Review.

PURPOSE: To present an overview of animal models of retinal artery occlusion (RAO). METHODS: Through a systematic literature search in PubMed and Embase, papers describing methods of inducing RAO in animal models were included. The identified methodologic approaches were presented in a narrative synthesis and compared with RAO in humans. RESULTS: In total, 83 papers reporting on 88 experiments were included. Six different species were used with rodents and monkeys being the most common, and a minority were performed using cats, dogs, rabbits, or pigs. The anatomy of pigs and monkeys resemble that of humans most closely. The two most frequently used methods were laser-induced occlusion or ligation of the arteries. Other methods included raised intraocular pressure, arterial clamping, administration of vasoconstricting agents, the use of an occluder, embolization, and endovascular approaches to induce occlusion. In general, occlusions lasted for only 30 to 90 minutes, often followed by reperfusion. CONCLUSIONS: Although a broad range of methods have previously been used, they all have limitations. Preferably, the methods should imitate the human disease as closely as possible and avoid damaging other structures. Therefore, monkeys followed by pigs are to be preferred and ligation or clamping may be a suitable model in larger animals as there is a potential to isolate and occlude the retinal artery only. Being less invasive, laser-induced occlusion is another suitable approach. TRANSLATIONAL RELEVANCE: This review aims at assisting researchers in deciding on the most ideal experimental setting, and thereby increase the translational value to human disease.

Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy: A Nationwide Cohort Study.

Purpose: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in LHON patients. Methods: This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population. Results: Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P < 0.001). The incidence of several diseases was increased for LHON patients, but not for family members. The incidence of stroke was 5.73 per 1000 patient-years for LHON patients compared to 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P < 0.001). The incidence of demyelinating disorders was 2.24 compared to 0.21 for the general population; RR was 12.89 (95% CI: 6.70-24.77; P < 0.001). A 4-fold risk of dementia was seen for LHON patients (RR: 4.26, 95% CI: 1.91-9.48; P < 0.001), incidence 1.45 for LHON and 0.37 for the general population. Moreover, LHON patients had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders. Conclusions: The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy.

Relationship between treatment of erectile dysfunction and future risk of cardiovascular disease: A nationwide cohort study.

Aims Erectile dysfunction is associated with increased risk of cardiovascular disease; however, little is known about patients seeking treatment for erectile dysfunction. This study investigated the risk of cardiovascular disease for patients receiving medication for erectile dysfunction. Methods and results This nationwide cohort study included 71,710 men aged 40-80 years receiving their first erectile dysfunction medication from 2000 to 2012. Their adjusted risk of cardiovascular events in time intervals after the first erectile dysfunction medication was compared to the general male population using multivariate Poisson regression models and was expressed as a risk ratio (RR). The risk for overall cardiovascular disease was decreased in the first 3 years: the RR in the first year was 0.92 (95% confidence interval [CI] 0.87-0.97, p = 0.003; incidence: 23.68 per 1000 patient-years), and after 1-3 years the RR was 0.94 (95% CI 0.90-0.97, p = 0.002; incidence: 24.92 per 1000 patient-years). After 3 years, there was no significant difference. The risk of myocardial infarction was decreased in all time intervals: the RR in the first year was 0.60 (95% CI 0.50-0.73, p < 0.001; incidence: 1.82 per 1000 patient-years), after 1-3 years the RR was 0.72 (95% CI 0.63-0.82, p < 0.001; incidence: 2.16 per 1000 patient-years) and after 3 years the RR was 0.80 (95% CI 0.73-0.88, p < 0.001; incidence: 2.25 per 1000 patient-years). The risk of heart failure was decreased in the first 3 years. Conclusion Receiving medication for erectile dysfunction was associated with a decreased risk of myocardial infarction and cardiovascular diseases for the first 3 years.