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- Hait, A. S., et al.
(författare)
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Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans
- 2020
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Ingår i: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 5:54
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Tidskriftsartikel (refereegranskat)abstract
- Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.
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- Holm, Niels R, et al.
(författare)
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OCT or Angiography Guidance for PCI in Complex Bifurcation Lesions.
- 2023
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Ingår i: The New England journal of medicine. - 1533-4406. ; 389:16, s. 1477-1487
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Tidskriftsartikel (refereegranskat)abstract
- Imaging-guided percutaneous coronary intervention (PCI) is associated with better clinical outcomes than angiography-guided PCI. Whether routine optical coherence tomography (OCT) guidance in PCI of lesions involving coronary-artery branch points (bifurcations) improves clinical outcomes as compared with angiographic guidance is uncertain.We conducted a multicenter, randomized, open-label trial at 38 centers in Europe. Patients with a clinical indication for PCI and a complex bifurcation lesion identified by means of coronary angiography were randomly assigned in a 1:1 ratio to OCT-guided PCI or angiography-guided PCI. The primary end point was a composite of major adverse cardiac events (MACE), defined as death from a cardiac cause, target-lesion myocardial infarction, or ischemia-driven target-lesion revascularization at a median follow-up of 2 years.We assigned 1201 patients to OCT-guided PCI (600 patients) or angiography-guided PCI (601 patients). A total of 111 patients (18.5%) in the OCT-guided PCI group and 116 (19.3%) in the angiography-guided PCI group had a bifurcation lesion involving the left main coronary artery. At 2 years, a primary end-point event had occurred in 59 patients (10.1%) in the OCT-guided PCI group and in 83 patients (14.1%) in the angiography-guided PCI group (hazard ratio, 0.70; 95% confidence interval, 0.50 to 0.98; P=0.035). Procedure-related complications occurred in 41 patients (6.8%) in the OCT-guided PCI group and 34 patients (5.7%) in the angiography-guided PCI group.Among patients with complex coronary-artery bifurcation lesions, OCT-guided PCI was associated with a lower incidence of MACE at 2 years than angiography-guided PCI. (Funded by Abbott Vascular and others; OCTOBER ClinicalTrials.gov number, NCT03171311.).
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- Ibsen, H., et al.
(författare)
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Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE Study
- 2004
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Ingår i: Kidney Int Suppl. - 0098-6577. ; :92
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Tidskriftsartikel (refereegranskat)abstract
- Studies have shown that albuminuria is associated with increased risk for cardiovascular events. We tested the relationship between albuminuria (UACR) and cardiovascular risk in 8206 hypertensive patients with left ventricular hypertrophy included in the LIFE Study. Follow-up was 39,122 patient years. The risk for the primary composite cardiovascular end point increases continuously from the lowest to the highest decile of baseline UACR. No specific threshold could be identified. In conclusion, albuminuria predicts the outcome in the LIFE Study. The risk for cardiovascular morbidity and mortality among hypertensive patients with left ventricular hypertrophy increases at much lower UACR than has been reported in diabetic patients.
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- Ibsen, H., et al.
(författare)
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Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy
- 2004
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Ingår i: J Hypertens. - : Ovid Technologies (Wolters Kluwer Health). - 0263-6352. ; 22:9, s. 1805-11
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To examine a possible relationship between baseline albuminuria and effect of losartan versus atenolol on cardiovascular (CV) events in hypertensive patients with left ventricular hypertrophy, the effect of losartan versus atenolol on albuminuria, and whether the benefits of losartan versus atenolol could be explained by influence of losartan on albuminuria. DESIGN: Double-blind, randomized, controlled trial of 4.8 years. SETTING: Out-patient setting. PATIENTS: A total of 8206 with hypertension and left ventricular hypertrophy. INTERVENTIONS: Losartan or atenolol, supplemented with diuretics and/or calcium antagonists to reach blood pressure < 140/90 mmHg MAIN OUTCOME MEASURES: The urine albumin/creatinine ratio, and the primary composite endpoint (CEP) of CV death, myocardial infarction, and stroke. RESULTS: The blood pressure was reduced similarly on losartan (30.2/16.6 mmHg) versus atenolol (29.1/16.8 mmHg). The risk of a primary CEP increased linearly from the lowest to the highest decile of baseline albuminuria. The benefits of losartan versus atenolol for the primary CEP and for stroke tended to be more pronounced among patients above the median value for baseline albuminuria (urine albumin/creatinine ratio, 1.28 mg/mmol). The decrease in albuminuria was significantly greater with losartan versus atenolol throughout the study (a decrease from baseline to year 2 of 33% losartan versus 25% atenolol). One-fifth of the difference in favor of losartan on the primary CEP was explained by the greater reduction in albuminuria on losartan. CONCLUSIONS: Baseline albuminuria is a powerful risk factor for CV events. Baseline albuminuria did not identify the group of patients with greatest benefit on losartan versus atenolol in LIFE. Reduction in albuminuria explained one-fifth of the benefits of losartan versus atenolol.
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- Ibsen, H., et al.
(författare)
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Does albuminuria predict cardiovascular outcomes on treatment with losartan versus atenolol in patients with diabetes, hypertension, and left ventricular hypertrophy? The LIFE study
- 2006
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Ingår i: Diabetes Care. - 0149-5992. ; 29:3, s. 595-600
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our current aims were to investigate whether 1) baseline urinary albumin-to-creatinine ratio (UACR) predicted cardiovascular outcomes, 2) changes in UACR differed between treatments, 3) benefits of losartan were related to its influence on UACR, and 4) reduction in albuminuria reduced cardiovascular events. RESEARCH DESIGN AND METHODS: In 1,063 patients with diabetes, hypertension, and left ventricular hypertrophy, UACR was measured for a mean of 4.7 years. The primary composite end point included cardiovascular death, myocardial infarction, and stroke. Cox models were run including and excluding baseline and time-varying UACR. RESULTS: Increasing baseline albuminuria related to increased risk for cardiovascular events. Reductions in UACR at years 1 and 2 were approximately 33% for losartan vs. 15% for atenolol (P < 0.001). Benefits of losartan seem to be most prominent in patients with the highest level of baseline UACR, although treatment by albuminuria interaction was only significant for total mortality. Approximately one-fifth of the superiority of losartan was explained by the greater reduction of albuminuria. Risk of the primary end point was related to the in-treatment UACR. CONCLUSIONS: Lowering of albuminuria in patients with hypertension and diabetes appears to be beneficial and should be the subject of additional study in future clinical trials.
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- Ibsen, H., et al.
(författare)
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Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study
- 2005
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Ingår i: Hypertension. - 1524-4563. ; 45:2, s. 198-202
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Tidskriftsartikel (refereegranskat)abstract
- Few data are available to clarify whether changes in albuminuria over time translate to changes in cardiovascular risk. The aim of the present study was to examine whether changes in albuminuria during 4.8 years of antihypertensive treatment were related to changes in risk in 8206 patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Urinary albumin/creatinine ratio (UACR) was measured at baseline and annually. Time-varying albuminuria was closely related to risk for the primary composite end point (ie, when UACR decreased during treatment, risk was reduced accordingly). When the population was divided according to median baseline value (1.21 mg/mmol) and median year 1 UACR (0.67 mg/mmol), risk increased stepwise and significantly for the primary composite end point from those with low baseline/low year 1 (5.5%), to low baseline/high year 1 (8.6%), to high baseline/low year 1 (9.4%), and to high baseline/high year 1 (13.5%) values. Similar significant, stepwise increases in risk were seen for the components of the primary composite end point (cardiovascular mortality, stroke, and myocardial infarction). The observation that changes in UACR during antihypertensive treatment over time translated to changes in risk for cardiovascular morbidity and mortality was not explained by in-treatment level of blood pressure. We propose that monitoring of albuminuria should be an integrated part of the management of hypertension. If albuminuria is not decreased by the patient's current antihypertensive and other treatment, further intervention directed toward blood pressure control and other modifiable risks should be considered.
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