BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes.

Diabetic cardiomyopathy (DCM) is a major cause of mortality/morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous cardiovascular target, its effect on myocardial cells and mitochondria in DCM and the underlying mechanisms remain unknown. Here, we determined the involvement of BH4 deficiency in DCM and the therapeutic potential of BH4 supplementation in a rodent DCM model. We observed a decreased BH4:total biopterin ratio in heart and mitochondria accompanied by cardiac remodeling, lower cardiac contractility, and mitochondrial dysfunction. Prolonged BH4 supplementation improved cardiac function, corrected morphological abnormalities in cardiac muscle, and increased mitochondrial activity. Proteomics analysis revealed oxidative phosphorylation (OXPHOS) as the BH4-targeted biological pathway in diabetic hearts as well as BH4-mediated rescue of down-regulated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) signaling as a key modulator of OXPHOS and mitochondrial biogenesis. Mechanistically, BH4 bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and activated downstream AMP-activated protein kinase/cAMP response element binding protein/PGC-1α signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.

Major recanalization occurs more often in young patients after unruptured aneurysm coil embolization.

BACKGROUND: The recanalization rate after coil embolization of unruptured aneurysms was compared between young and old age groups. METHODS: From May 2003 to December 2010, 636 patients with 715 saccular unruptured intracranial aneurysms (UIA) underwent endovascular coiling and were followed for at least 6 months. For comparative analysis, patients were categorized into two groups according to age 40: 42 patients with 46 aneurysms who were 40 years or younger (young age group) and 594 patients with 669 aneurysms who were older than 40 years (old age group). Angiographic and clinical outcomes including recanalization rates were compared. RESULTS: Angiographically, class 1 or 2 occlusion according to the Raymond-Roy Occlusion Classification system was achieved in 89.2 % of the patients (91.3 % in the young age group and 89.1 % in the old age group, p = 0.74). Procedure-related complication rate was 2.2 % and 3.4 % in the young and the old age group (p = 0.16), respectively. The mean follow-up duration was 30.51 ± 18.59 months. Major recanalization occurred in seven aneurysms (15.2 %) in the young age group and in 44 aneurysms (6.6 %) in the old age group (p = 0.03). Retreatment was performed in seven patients (15.2 %) in the young age group and in 35 patients (5.2 %) in the old age group (p = 0.01). CONCLUSIONS: The present study showed that the technical feasibility and safety of endovascular coiling for UIA did not differ between the two age groups. However, the major recanalization rate was higher in the young age group.

Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial.

IMPORTANCE: Thromboembolism is the most common complication in coiling for an unruptured aneurysm and is frequent in patients with high on-treatment platelet reactivity (HTPR) who are prescribed a standard antiplatelet preparation for its prevention. OBJECTIVE: To evaluate the effect of a modified antiplatelet preparation compared with a standard preparation in patients with HTPR undergoing coiling. DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized open-label active-control trial with blinded outcome assessment at the Seoul National University Bundang Hospital from May 27, 2013, to April 7, 2014. Patients with HTPR were randomly assigned (1 to 1) to the standard or modified preparation group. Patients without HTPR were assigned to the non-HTPR group. A total of 228 patients undergoing coiling for unruptured aneurysms were enrolled and allocated to the study, 126 in the HTPR group (63 to the standard preparation group and 63 to the modified preparation group) and 102 to the non-HTPR group. Intent-to-treat analysis was performed. INTERVENTIONS: The modified preparation (HTPR to aspirin, 300 mg of aspirin and 75 mg of clopidogrel bisulfate; and HTPR to clopidogrel, 200 mg of cilostazol added to the standard regimen) was performed before coiling in the modified preparation group. Standard preparation (100 mg of aspirin and 75 mg of clopidogrel) was maintained in the standard preparation and non-HTPR groups. MAIN OUTCOMES AND MEASURES: The primary outcome was a thromboembolic event defined as thromboembolism during coiling and a transient ischemic attack or ischemic stroke within 7 days after coiling. The principal secondary outcome was a bleeding complication according to Thrombolysis in Myocardial Infarction bleeding criteria within 30 days after coil embolization. RESULTS: The thromboembolic event rate was low in the modified preparation group (1 of 63 [1.6%]) compared with the standard preparation group (7 of 63 [11.1%]; adjusted risk difference, -11.7% [95% CI, -21.3% to -2.0%]; P = .02), which had a higher thromboembolic risk than the non-HTPR group (1 of 102 [1.0%]; adjusted risk difference, 8.6% [95% CI, 1.0% to 16.3%]; P = .03). All bleeding complications were of minimal grade according to Thrombolysis in Myocardial Infarction bleeding criteria. The bleeding rate was not different between the modified (6 of 63 [9.5%]) and standard (4 of 63 [6.3%]) preparation groups (adjusted risk difference, 5.6% [95% CI, -4.2% to 15.4%]; P = .26). CONCLUSIONS AND RELEVANCE: Modified antiplatelet preparation for patients with HTPR compared with standard antiplatelet preparation reduced the thromboembolic event rate in coiling for an unruptured aneurysm without increasing bleeding. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0000804.

Delayed ischemic stroke after stent-assisted coil placement in cerebral aneurysm: characteristics and optimal duration of preventative dual antiplatelet therapy.

PURPOSE: To evaluate characteristics of delayed ischemic stroke after stent-assisted coil placement in cerebral aneurysms and to determine the optimal duration of dual antiplatelet therapy for its prevention. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement to obtain written informed consent was waived. Of 1579 patients with 1661 aneurysms, 395 patients (25.0%) with 403 aneurysms (24.3%) treated with stent-assisted coil placement were included and assigned to groups stratified as early (126 patients [31.9%]; 3 months of coil placement), midterm (160 patients [40.5%]; 6 months), or late (109 patients [27.6%]; ≥ 9 months), according to the time points of switching dual antiplatelet therapy to monotherapy from coil placement. Cumulative rates of delayed ischemic stroke in each group were calculated by using Kaplan-Meier estimates that were compared with log-rank tests. Risk factors of delayed ischemic stroke were identified by using Cox proportional hazard analysis. RESULTS: Delayed ischemic stroke occurred in 3.5% of all cases (embolism, 3.0%; thrombotic occlusion, 0.5%) within 2 months following the switch. Late switch yielded no delayed ischemic stroke, unlike early (seven of 126 patients [5.6%]; P = .013) or midterm (seven of 160 patients [4.4%]; P = .028) switch. Incomplete occlusion (hazard ratio, 6.68 [95% confidence interval: 1.490, 29.900]) was identified as a risk factor. CONCLUSION: Delayed ischemic stroke after stent-assisted coil placement is caused by embolism from or thrombotic occlusion of stent-containing vessels after switching from dual antiplatelet therapy to monotherapy. The stent-containing vessel with incomplete aneurysm occlusion presents as a long-term thromboembolic source. Therefore, dual antiplatelet therapy for more than 9 months and late switch to monotherapy are recommended for its prevention.

Coil embolization of intracranial saccular aneurysms using the Low-profile Visualized Intraluminal Support (LVIS™) device.

INTRODUCTION: The novel Low-profile Visualized Intraluminal Support (LVIS™, LVIS and LVIS Jr.) device was recently introduced for stent-supported coil embolization of intracranial aneurysms. Periprocedural and midterm follow-up results for its use in stent-supported coil embolization of unruptured aneurysms are presented herein. METHODS: In this prospective multicenter study, clinical and radiologic outcomes were analyzed for 55 patients with saccular aneurysms undergoing LVIS-assisted coil embolization between October 2012 and February 2013. Magnetic resonance angiography or digital subtraction angiography was performed to evaluate midterm follow-up results. RESULTS: The standard LVIS device, deployed in 27 patients, was more often used in internal carotid artery (ICA) aneurysms (n=19), whereas the LVIS Jr. (a lower profile stent, n=28) was generally reserved for anterior communicating artery (n=14) and middle cerebral artery (n=8) aneurysms. With LVIS-assisted coil embolization, successful occlusion was achieved in 45 aneurysms (81.8 %). Although no instances of navigation failure or stent malposition occurred, segmentally incomplete stent expansion was seen in five patients where the higher profile LVIS was applied to ICA including carotid siphon. Procedural morbidity was low (2/55, 3.6 %), limited to symptomatic thromboembolism. In the imaging of lesions (54/55, 98.2 %) at 6-month follow-up, only a single instances of major recanalization (1.9 %) occurred. Follow-up angiography of 30 aneurysms (54.5 %) demonstrated in-stent stenosis in 26 (86.7 %), with no instances of stent migration. Only one patient suffered late delayed infarction (modified Rankin Scale 1). CONCLUSION: The LVIS device performed acceptably in stent-assisted coil embolization of non-ruptured aneurysms due to easy navigation and precise placement, although segmentally incomplete stent expansion and delayed in-stent stenosis were issues.

Simple coiling using single or multiple catheters without balloons or stents in middle cerebral artery bifurcation aneurysms.

INTRODUCTION: We evaluated the outcomes of middle cerebral artery bifurcation (MCAB) aneurysms treated with simple coiling using single or multiple catheters without stents or balloons. METHODS: This study included 100 patients with 103 MCAB aneurysms who underwent a simple coiling procedure without the adjuvant use of stents or balloons. The angiographic clinical outcomes and recurrence of these aneurysms were evaluated. RESULTS: Of the 103 aneurysms, 102 (99.0 %) aneurysms were successfully treated with simple coiling. One patient died from the consequences of a procedural aneurysm rupture. The treatment-associated permanent morbidity and mortality rates were 0 and 1.0 %, respectively. Post-coiling angiograms showed 28 complete occlusions (27.2 %), 60 neck remnants (58.3 %), and 14 partial occlusions (13.6 %). A follow-up angiography (median duration, 30 months; range, 3-73 months) was performed in 80 lesions. Recanalisation was found in 28 lesions (35.0 %), of which 6 were complete occlusions, 18 were neck remnants, and 4 were partial occlusions, as determined by post-coiling angiograms. Among these lesions, 14 major recurrences were retreated with coiling (n = 12) and clipping (n = 2) without complications. Age (odds ratio [OR], 0.93; 95 % confidence interval [CI], -0.11 to -0.01; p = 0.03), the presence of a rupture (OR, 3.89; 95 % CI, 0.12 to 2.60; p = 0.03), and a wide aneurysm neck (OR, 6.40; 95 % CI, 0.57 to 3.14; p = 0.005) were significantly associated with the aneurysm recurrence, as determined by multivariable analyses. CONCLUSION: Our study suggests that simple coiling of MCAB aneurysms is feasible and safe; however, it has limitations in durability, particularly in ruptured or wide-necked aneurysms and in young patients.