ß-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer's Disease.

Hyperactivity mediated by synaptotoxic ß-amyloid (Aß) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer's disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aß peptides before Aß plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aß binding anticalin protein (Aß-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of ß-amyloidosis. Our results suggest that the sole targeting of Aß monomers is sufficient for the hyperactivity-suppressing effect of the Aß-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aß-anticalin-dependent depletion of naturally secreted Aß monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aß monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.

Population imaging of synaptically released glutamate in mouse hippocampal slices.

Glutamatergic neurotransmission is a widespread form of synaptic excitation in the mammalian brain. The development of genetically encoded fluorescent glutamate sensors allows monitoring synaptic signaling in living brain tissue in real time. Here, we describe single- and two-photon imaging of synaptically evoked glutamatergic population signals in acute hippocampal slices expressing the fluorescent glutamate sensor SF-iGluSnFR.A184S in CA1 or CA3 pyramidal neurons. The protocol can be readily used to study defective synaptic glutamate signaling in mouse models of neuropsychiatric disorders, such as Alzheimer disease. For complete details on the use and execution of this protocol, please refer to Zott et al. (2019).

A vicious cycle of ß amyloid-dependent neuronal hyperactivation.

ß-amyloid (Aß)-dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer's disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of Aß-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to Aß-mediated hyperactivation. Aß-containing AD brain extracts and purified Aß dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of Aß-dependent neuronal dysfunction that can be active before plaque formation.

Retroesophageal right subclavian artery (lusoria) as origin of traumatic aortic rupture.

A retroesophageal right subclavian artery (lusoria) is unusual for the surgeon, yet common regarding pathological findings (0.5-2%). Complications arising from it are rare (dysphagia). We report a case of traumatic descending aortic tear originating from a lusoria. The patient had experienced chest trauma due to a skiing accident. CT scan revealed an intramural haematoma of the proximal descending aorta. As a coincidence finding, a retroesophageal right subclavian artery was diagnosed. The patient was first treated conservatively. After an initial period--of stable patient conditions--repeated CT scan revealed a haematoma enlargement and surgery was scheduled: A localized aortic tear was suspected through CT scan, yet no aortic tear or flap was visible. During a two-staged surgical procedure, transpositioning of the lusoria into the right common carotid artery was performed, followed by replacement of the distal aortic arch during a second session using a single-branched Dacron tube graft. The left subclavian artery was then reinserted into the side-branched graft after reuptake of extracorporeal circulation. Extracorporeal circulation was applied via the femoral vessels and circulatory arrest in combination with deep hypothermia. After surgery, the patient was stable, having no signs of neurocognitive dysfunction or dysphagia.

Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial.

OBJECTIVES: The long-term (five-year) comparative results of treatment of multivessel coronary artery disease with stenting or coronary artery bypass grafting (CABG) is at present unknown. BACKGROUND: The Arterial Revascularization Therapies Study (ARTS) was designed to compare CABG and stenting in patients with multivessel disease. METHODS: A total of 1,205 patients with the potential for equivalent revascularization were randomly assigned to CABG (n = 605) or stent implantation (n = 600). The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events (MACCE) at one year; MACCE at five-year follow-up constituted the final secondary end point. RESULTS: At five years, there were 48 and 46 deaths in the stent and CABG groups, respectively (8.0% vs. 7.6%; p = 0.83; relative risk [RR], 1.05; 95% confidence interval [CI], 0.71 to 1.55). Among 208 diabetic patients, mortality was 13.4% in the stent group and 8.3% in the CABG group (p = 0.27; RR, 1.61; 95% CI, 0.71 to 3.63). Overall freedom from death, stroke, or myocardial infarction was not significantly different between groups (18.2% in the stent group vs. 14.9% in the surgical group; p = 0.14; RR, 1.22; 95% CI, 0.95 to 1.58). The incidence of repeat revascularization was significantly higher in the stent group (30.3%) than in the CABG group (8.8%; p < 0.001; RR, 3.46; 95% CI, 2.61 to 4.60). The composite event-free survival rate was 58.3% in the stent group and 78.2% in the CABG group (p < 0.0001; RR, 1.91; 95% CI, 1.60 to 2.28). CONCLUSIONS: At five years there was no difference in mortality between stenting and surgery for multivessel disease. Furthermore, the incidence of stroke or myocardial infarction was not significantly different between the two groups. However, overall MACCE was higher in the stent group, driven by the increased need for repeat revascularization.

Three-year outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease.

BACKGROUND: The primary results of Arterial Revascularization Therapy Study reported a greater need for repeated revascularization after percutaneous coronary intervention with stenting (PCI). However, PCI was less expensive than coronary artery bypass grafting (CABG) and offered the same degree of protection against death, stroke, and myocardial infarction. METHODS AND RESULTS: Patients with multivessel disease (n=1205) were randomly assigned to either CABG or PCI and followed up for up to 3 years. Survival rates without stroke or myocardial infarction were similar in each group at 1 year and 3 years (90.5% versus 91.4% for PCI versus CABG at 1 year and 87.2% versus 88.4% for PCI versus CABG at 3 years). However, the respective repeat revascularization rates were 21.2% and 26.7% at 1 and 3 years in patients allocated to PCI, compared with 3.8% and 6.6% in patients allocated to CABG (P<0.0001). Diabetes (P<0.0009) and maximal pressure for stent deployment (P<0.002) are the strongest independent predictors of events at 3 years after PCI, whereas left anterior descending coronary artery grafting (P<0.006) is the best predictor of event-free survival at 3 years after CABG. The incremental cost of surgery compared with PCI for an event-free patient was 19 257 at 1 year but decreased to 10 492 at 3 years. It remained at 142 391 at 3 years when revascularization procedures were excluded in the efficacy end point, however. CONCLUSIONS: Three-year survival rates without stroke and myocardial infarction are identical in both groups, and the cost/benefit ratio of stenting is determined primarily by the increasing need for revascularization in the PCI group.

The effect of completeness of revascularization on event-free survival at one year in the ARTS trial.

OBJECTIVES: We sought to assess the relationship between completeness of revascularization and adverse events at one year in the ARTS (Arterial Revascularization Therapies Study) trial. BACKGROUND: There is uncertainty to what extent degree of completeness of revascularization, using up-to-date techniques, influences medium-term outcome. METHODS: After consensus between surgeon and cardiologist regarding the potential for equivalence in the completeness of revascularization, 1,205 patients with multivessel disease were randomly assigned to either bypass surgery or stent implantation. All baseline and procedural angiograms and surgical case-record forms were centrally assessed for completeness of revascularization. RESULTS: Of 1,205 patients randomized, 1,172 underwent the assigned treatment. Complete data for review were available in 1,143 patients (97.5%). Complete revascularization was achieved in 84.1% of the surgically treated patients and 70.5% of the angioplasty patients (p < 0.001). After one year, the stented angioplasty patients with incomplete revascularization showed a significantly lower event-free survival than stented patients with complete revascularization (i.e., freedom from death, myocardial infarction, cerebrovascular accident and repeat revascularization) (69.4% vs. 76.6%; p < 0.05). This difference was due to a higher incidence of subsequent bypass procedures (10.0% vs. 2.0%; p < 0.05). Conversely, at one year, bypass surgery patients with incomplete revascularization showed only a marginally lower event-free survival rate than those with complete revascularization (87.8% vs. 89.9%). CONCLUSIONS: Complete revascularization was more frequently accomplished by bypass surgery than by stent implantation. One year after bypass, there was no significant difference in event-free survival between surgically treated patients with complete revascularization and those with incomplete revascularization, but patients randomized to stenting with incomplete revascularization had a greater need for subsequent bypass surgery.

Impact of body mass index on the outcome of patients with multivessel disease randomized to either coronary artery bypass grafting or stenting in the ARTS trial: The obesity paradox II?

The effect of body mass index (BMI) on outcomes after coronary artery revascularization remains controversial. We studied 1,203 patients who had multivessel coronary artery disease and underwent stenting (n = 599) or coronary artery bypass grafting (CABG; n = 604) in the Arterial Revascularization Therapies Study. Patients were assigned to 1 of 3 groups according to BMI: <25, 25 to 30, and >30 kg/m(2). At 3-year follow-up, the incidence of death, cerebrovascular events, or myocardial infarction was similar for these BMI categories regardless of the revascularization technique used. Rates of repeat revascularization procedures were significantly higher among patients who had been randomized to stenting but were similar across BMI groups. For patients who had been randomized to undergo CABG, there was a significant decrease in repeat revascularization procedures in obese patients (p = 0.03). Among patients who underwent stenting, BMI had no effect on the 3-year combined end point of rate of major adverse cardiac or cerebrovascular events. Among patients who underwent CABG, major adverse cardiac or cerebrovascular event rates were significantly lower for patients who were obese (11%) or overweight (16%) compared with patients who had a normal BMI (24%; p = 0.008). Thus, in a large cohort of patients who had multivessel coronary artery disease and underwent surgical or percutaneous revascularization, BMI had no effect on 3-year outcome of those who underwent stenting. Conversely, among patients who underwent CABG, those who were overweight or obese had a significantly better outcome than did those who had a normal BMI with regard to survival without major adverse cardiac or cerebrovascular events, mainly due to lower rates of repeat revascularization procedures.

Revascularization in multivessel disease: comparison between two-year outcomes of coronary bypass surgery and stenting.

OBJECTIVE: The recent appreciation that stenting has improved the short- and long-term outcomes of patients treated with coronary angioplasty has made it imperative to reconsider the comparison between surgery and percutaneous interventions in patients with multivessel disease. METHODS: One thousand two hundred five patients were randomly assigned to undergo bypass surgery or angioplasty with stent implantation when there was consensus between the cardiac surgeon and interventional cardiologist as to equivalent treatability. The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events at 1 year. Major adverse cardiac and cerebrovascular events at 2 years constituted a secondary end point. RESULTS: At 2 years, 89.6% of the surgical group and 89.2% of the stent group were free from death, stroke, and myocardial infarction (log-rank test P =.65). Among patients who survived without stroke or myocardial infarction, 19.7% in the stent group underwent a second revascularization, as compared with 4.8% in the surgical group (P <.001). At 2 years, 84.8% of the surgical group and 69.5% of the stent group were event-free survivors (log-rank test P <.001), and 87.2% in the surgical cohort and 79.6 % in the stent group were angina-free survivors (P =.001). In the diabetes subgroup, 82.3% of the surgical group and 56.3% of the stent group were free from any events after 2 years (log-rank test P <.001). CONCLUSION: The difference in outcome between surgery and stenting observed at 1 year in patients with multivessel disease remained essentially unchanged at 2 years. Stenting was associated with a greater need for repeat revascularization. In view of the relatively greater difference in outcome in patients with diabetes, surgery clearly seems to be the preferable form of treatment for these patients.

Does gender affect outcome of cardiac surgery in octogenarians?

The long-term results of cardiac surgery in 212 consecutive octogenarians (116 men, 96 women) were reviewed retrospectively. Preoperative functional status, Euroscore, and the incidences of hypertension and chronic obstructive pulmonary disease were similar in both sexes. Women had more diabetes mellitus (45% versus 25%; p < 0.05) but less renal dysfunction (16% versus 29%; p < 0.05). Men required emergency procedures more frequently (p < 0.05). Women underwent complete revascularization more often and had more arterial grafts. Hospital mortality was similar (11.5% in women versus 12.9% in men), but women had more complications (76% versus 64%), longer convalescence (24.3 versus 18.5 days), fewer psychiatric disorders (14% versus 23%) and less heart block (9% versus 19%). Men had a slightly better outcome in terms of functional class and Euroqol score during follow-up of up to 114 months. Median survival was longer in women (3.15 versus 2.96 years) but 1-, 3-, and 5-year survival rates and late deaths were similar. Outcomes appear to be equitable for both sexes among octogenarians.

Analysis of stroke occurring in the SYNTAX trial comparing coronary artery bypass surgery and percutaneous coronary intervention in the treatment of complex coronary artery disease.

OBJECTIVES: This study sought to analyze stroke rates in the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial's randomized and registry cohorts of patients being treated with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) for treatment of complex coronary artery disease. BACKGROUND: The SYNTAX trial compared PCI to CABG in patients with de novo 3-vessel and/or left main coronary disease. METHODS: The SYNTAX randomized trial was conducted at 85 U.S. and European sites (n = 1,800). All strokes (up to 4 years) were independently adjudicated by a clinical events committee that included a neurologist. An additional 1,077 (of which 644 were followed for 5 years) and 198 patients were included in the CABG and PCI registries, respectively. RESULTS: In the randomized cohort, 31 CABG and 19 PCI patients experienced 33 and 20 strokes post-randomization at 4-year follow-up, respectively (p = 0.062). Three strokes occurred pre-procedurally but following randomization in CABG-treated patients. After CABG, a large proportion of strokes occurred acutely (0 to 30 days: 9 of 33), whereas in the PCI arm, most strokes occurred >30 days after the procedure (18 of 20). Stroke resulted in death in 3 patients in both the PCI and CABG groups. Of the patients who developed stroke, 68% (21 of 31) in the CABG group had residual deficits at discharge; in the PCI group, 47% (9 of 19) had residual deficits. In a multivariate analysis, treatment with CABG was not significantly associated with increased stroke rates (odds ratio: 1.67, 95% confidence interval: 0.93 to 3.01, p = 0.089). The incidence and outcomes of stroke were similar in the randomized trial and registries. CONCLUSIONS: There is a higher risk of periprocedural stroke in patients undergoing CABG versus PCI; however, the risk converges over the first 4 years of follow-up. (SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries; NCT00114972).

Short- and long- term health related quality-of-life and anginal status after randomisation to coronary stenting versus bypass surgery for the treatment of multivessel disease: results of the Arterial Revascularisation Therapy Study (ARTS).

BACKGROUND: Health related quality-of-life (HRQL) beyond one year of treatment of multivessel coronary artery disease with stenting or coronary artery bypass grafting (CABG) is yet unknown. The Arterial Revascularisation Therapy Study (ARTS) was designed to compare CABG and stenting in multivessel disease. METHODS AND RESULTS: HRQL was evaluated at baseline, at 1- month and at 6-, 12- and 36 months after revascularisation using the Short Form Health Survey (SF-36) in patients randomised to stenting (n=483) versus CABG (n=492). Both stenting and CABG resulted in significant improvement of HRQL and anginal status. Although there was a trend for better HRQL after CABG up to one year, the disparity between the two procedures decreased long-term. Most of the difference between the two procedures was attributed to repeat interventions in the stent group; at three years, 19% of stent patients versus 13% of CABG patients (p<0.0001) had undergone a repeat intervention. On most of the SF-36 scores, there was no difference between diabetics and non-diabetics, with diabetic patients having a worse score only on general health and physical functioning at all time points (p<0.0001). CONCLUSIONS: Both stenting and CABG resulted in a significant improvement in HRQL especially up to one year, but CABG was associated with less angina at all time points. There was a trend for better HRQL after CABG, but this difference was mainly attributed to repeat revascularisation in the stent group. Based on these findings, patients should select for themselves whether or not they would prefer the improved HRQL benefits after CABG, or whether they would prefer more angina after PCI and avoid a major operation.

Drug eluting stents - a nightmare?

As a contribution to the controversial discussion for the use of drug-eluting stents, the European Heart Institute of the European Academy of Sciences and Arts is emphasizing important factors: a) drug eluting stents (DES) should be used only in accordance with their on-label indications for use; b) to avoid off-label use of DES and to assure that patients are apprized of all their revascularization options, patients should have informed consent between the patient, interventionist and a cardiac surgeon; c) without informed consent, off-label use of DES may be considered a legal offence against the interventionist; d) at onset of new symptoms, patients must be informed that surgery is a viable and recommended option.

Surgical treatment of coronary multivessel disease.

Coronary artery bypass grafting has had a significant impact on the treatment of angina, and has been the 'gold standard' since 1969. Its use and efficacy has been increased by revascularization in cardiac arrest and the use of the internal mammary artery. In parallel, catheter techniques have evolved by means of balloon dilatation and additional stenting. This has effected the referral to surgery despite the development of new arterialization techniques and minimally invasive surgery. As competing techniques, an acceptable equilibrium between surgery and stenting will be found within the next years.

Five year clinical effect of coronary stenting and coronary artery bypass grafting in renal insufficient patients with multivessel coronary artery disease: insights from ARTS trial.

AIMS: To compare coronary stent implantation and bypass surgery for multivessel coronary disease in patients with renal insufficiency. METHODS AND RESULTS: In the ARTS trial, 142 moderate renal insufficient patients (Ccr<60 mL/min) with multivessel coronary disease were randomly assigned to stent implantation (n=69) or CABG (n=73). At 5 years, there was no significant difference between the two groups in terms of mortality (14.5% in the stent group vs. 12.3% in the CABG group, P=0.81), or combined endpoint of death, cerebrovascular accident (CVA), or myocardial infarction (MI) (30.4% in the stent group vs. 23.3% in the CABG group, P=0.35). Among patients who survived without CVA or MI, 18.8% in the stent group underwent a second revascularization procedure when compared with 8.2% in the surgery group (P=0.08). The event-free survival at 5 years was 50.7% in the stent group and 68.5% in the surgery group (P=0.04). CONCLUSION: At 5 years, the differences in mortality and combined incidence of death, CVA, and MI between coronary stenting and surgery did not reach statistically significant level. However, the occurrence of MACCE in the stent group was higher than in the CABG group, mainly driven by the higher incidence of repeat revascularization in the stent group.

Five year clinical effect of coronary stenting and coronary artery bypass grafting in renal insufficient / patients with multivessel coronary artery disease: insights from ARTS trial

Aims to compare coronary stent implantation and bypass surgery for multivessel coronary disease in patients with renal insufficiency. Methods and results In the ARTS trial, 142 moderate renal insufficient patients (Ccr , 60 mL/min) with multivessel coronary disease were randomly assigned to stent implantation (n » 69) or CABG (n » 73).At 5 years, there was no significant difference between the two groups in terms of mortality (14.5% in the stent group vs. 12.3% in the CABG group, P » 0.81), or combined endpoint of death, cerebrovascular accident (CVA), or myocardial infarction (MI) (30.4% in the stent group vs. 23.3% in the CABG group, P » 0.35). Among patients who survived without CVA or MI, 18.8% in the stent group underwent a second revascularization procedure when compared with 8.2% in the surgery group (P » 0.08). Theevent-free survival at 5 years was 50.7% in the stent group and 68.5% in the surgery group (P » 0.04).Conclusion At 5 years, the differences in mortality and combined incidence of death, CVA, and MI between coronary stenting and surgery did not reach statistically significant level. However, the occurrence of MACCE in the stent group was higher than in the CABG group, mainly driven by the higher incidence of repeat revascularization in the stent group...

Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary disease patients

Background—Our aims were to compare coronary artery bypass grafting (CABG) and stenting for the treatment of diabetic patients with multivessel coronary disease enrolled in the Arterial Revascularization Therapy Study (ARTS) trial and to determine the costs of these 2 treatment strategies. Methods and Results—Patients (n51205) were randomly assigned to stent implantation (n5600; diabetic, 112) or CABG (n5605; diabetic, 96). Costs per patient were calculated as the product of each patient’s use of resources and the corresponding unit costs. Baseline characteristics were similar between the groups. At 1 year, diabetic patients treated with stenting had the lowest event-free survival rate (63.4%) because of a higher incidence of repeat revascularization compared with both diabetic patients treated with CABG (84.4%, P,0.001) and nondiabetic patients treated with stents (76.2%, P50.04). Conversely, diabetic and nondiabetic patients experienced similar 1-year event-free survival rates when treated with CABG (84.4% and 88.4%). The total 1-year costs for stenting and CABG in diabetic patients were $12 855 and $16 585 (P,0.001) and in the nondiabetic groups, $10 164 for stenting and $13 082 for surgery. Conclusions—Multivessel diabetic patients treated with stenting had a worse 1-year outcome than patients assigned to CABG or nondiabetics treated with stenting. The strategy of stenting was less costly than CABG, however, regardless of diabetic status.

Clinical and economic impact of diabetes mellitus on percutaneous and surgical treatment of multivessel coronary disease

Our aims were to compare coronary artery bypass grafting (CABG) and stenting for the treatment of diabetic patients with multivessel coronary disease enrolled in the Arterial Revascularization Therapy Study (ARTS) trial and to determine the costs of these 2 treatment strategies.Patients (N= 1205) were randomly assigned to stent implantation (n= 600; diabetic, 112) or CABG (n=605; diabetic, 96). Costs per patient were calculated as the product of each patient's useof resources and the corresponding unit costs.Baseline charcteristics were similar between the groups. At 1 year , diabetic patient treated with stenting had the lowest event-free survival rate (63,4%) because of a higher incidence of repeat revascularization compared with both diabetics patients...