A novel mouse model for N-terminal truncated Aß2-x generation through meprin ß overexpression in astrocytes.

Neurotoxic amyloid-ß (Aß) peptides cause neurodegeneration in Alzheimer's disease (AD) patients' brains. They are released upon proteolytic processing of the amyloid precursor protein (APP) extracellularly at the ß-secretase site and intramembranously at the γ-secretase site. Several AD mouse models were developed to conduct respective research in vivo. Most of these classical models overexpress human APP with mutations driving AD-associated pathogenic APP processing. However, the resulting pattern of Aß species in the mouse brains differs from those observed in AD patients' brains. Particularly mutations proximal to the ß-secretase cleavage site (e.g., the so-called Swedish APP (APPswe) fostering Aß1-x formation) lead to artificial Aß production, as N-terminally truncated Aß peptides are hardly present in these mouse brains. Meprin ß is an alternative ß-secretase upregulated in brains of AD patients and capable of generating N-terminally truncated Aß2-x peptides. Therefore, we aimed to generate a mouse model for the production of so far underestimated Aß2-x peptides by conditionally overexpressing meprin ß in astrocytes. We chose astrocytes as meprin ß was detected in this cell type in close proximity to Aß plaques in AD patients' brains. The meprin ß-overexpressing mice showed elevated amyloidogenic APP processing detected with a newly generated neo-epitope-specific antibody. Furthermore, we observed elevated Aß production from endogenous APP as well as AD-related behavior changes (hyperlocomotion and deficits in spatial memory). The novel mouse model as well as the established tools and methods will be helpful to further characterize APP cleavage and the impact of different Aß species in future studies.

Non-concealed placebo treatment for menopausal hot flushes: Study protocol of a randomized-controlled trial.

BACKGROUND: Beneficial effects of placebos are high in double-blind hot flush trials. Studies in various conditions suggest that honestly prescribed placebos may elicit symptom improvement. OBJECTIVE: To determine whether open label placebo (OLP) treatment is efficacious in alleviating hot flushes among peri- and postmenopausal women. METHODS/DESIGN: In this assessor-blinded, randomized-controlled trial, n = 100 women experiencing five or more daily hot flushes of at least moderate severity and bothersomeness are assigned 1:1 to a 4-week OLP treatment or no treatment. To explore the duration and maintenance of placebo effects, the OLP group is randomized a second time to either discontinue or continue the OLP treatment for another 4 weeks. All participants receive a briefing about placebo effects and study visits at baseline, post-treatment (4 weeks), and follow-up (8 weeks, OLP group only). Qualitative interviews about subjective experiences with the OLP treatment are conducted. Primary outcomes are differences between the OLP and the no-treatment group in the hot flush composite score (frequency × severity), and bothersomeness of hot flushes as assessed with the Hot Flush Rating Scale at post-treatment. Secondary outcomes include hot flush frequency, health-related quality of life, global improvement, and the number of responders at post-treatment. Data are analyzed by fitting (generalized) linear mixed models. An exploratory analysis of maintenance and duration is performed including follow-up data. DISCUSSION: This trial will contribute to the evaluation of OLP treatments in clinical practice and further our understanding about the magnitude of placebo effects in hot flush treatments. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03838523 . Retrospectively registered on February 12th, 2019. The first patient was enrolled on October 10th, 2018.

Dietary intervention with a specific micronutrient combination for the treatment of patients with cardiac arrhythmias: the impact on insulin resistance and left ventricular function.

BACKGROUND: Cardiac arrhythmias (CA) are very common and may occur with or without heart disease. Causes of these disturbances can be components of the metabolic syndrome (MetS) or deficits of micronutrients especially magnesium, potassium, B vitamins and coenzyme Q10. Both causes may also influence each other. Insulin resistance (IR) is a risk factor for diastolic dysfunction. One exploratory outcome of the present pilot study was to assess the impact of a dietary intervention with specific micronutrients on the lowering of IR levels in patients with CA with the goal to improve the left ventricular (LV) function. METHODS: This was a post hoc analysis of the randomized double blind, placebo-controlled pilot study in patients with CA (VPBs, SVPBs, SV tachycardia), which were recruited using data from patients who were 18-75 years of age in an Outpatient Practice of Cardiology. These arrhythmias were assessed by Holter ECG and LV function by standard echocardiography. Glucose metabolism was measured by fasting glucose, fasting insulin level and the Homeostasis Model Assessment of IR (HOMA-IR) at baseline and after 6 weeks of dietary supplementation. RESULTS: A total of 54 randomized patients with CA received either a specific micronutrient combination or placebo. Dietary intervention led to a significant decrease in fasting insulin ≥58 pmol/l (p = 0.020), and HOMA-IR (p = 0.053) in the verum group after 6 weeks. At the same time, parameters of LV diastolic function were improved after intervention in the verum group: significant reduction of LV mass index (p = 0.003), and in tendency both a decrease of interventricular septal thickness (p = 0.053) as well as an increase of E/A ratio (p = 0.051). On the other hand, the premature beats (PBs) were unchanged under verum. CONCLUSIONS: In this pilot study, dietary intervention with specific micronutrient combination as add-on to concomitant cardiovascular drug treatment seems to improve cardio metabolic health in patients with CA. Further studies are required. STUDY REGISTRATION: The study was approved by the Freiburg Ethics Commission International and was retrospectively registered with the U.S. National Institutes of Health Clinical Trials gov ID NCT 02652338 on 16 December 2015.

Epidemiology of Myocardial Infarction Caused by Presumed Paradoxical Embolism via a Patent Foramen Ovale.

BACKGROUND: Despite several negative prospective randomized trials on the efficacy of patent foramen ovale (PFO) occlusion, the discussion on indications is ongoing. Because the incidence of paradoxical coronary embolism through a PFO is unknown, we investigated the risk of paradoxical embolic myocardial infarction over a period of 13 years.Methods and Results:We conducted a retrospective and a prospective study. In the former, we searched the hospital database of a tertiary referral center for cases of acute myocardial infarction (AMI) during the past 10 years and screened them for possible paradoxical MIs. On this basis we started a prospective evaluation over 39 months in another tertiary referral center. All patients with AMI and normal coronary arteries were screened for PFO and if no other reason for the AMI could be found, the case was judged as presumed paradoxical embolism. In the retrospective analysis we found 22 cases (0.45%) of presumed paradoxical coronary artery embolism under 4,848 AMI. In the prospective study there were 11 presumed paradoxical coronary artery embolisms among 1,654 patients with AMI, representing an incidence of 0.67%. CONCLUSIONS: Our findings demonstrated that well below 1% of AMIs are caused by paradoxical embolism via an interatrial communication. Although this percentage appears low, it is not a negligible number of patients based on the huge number of MIs occurring in the industrialized world.

Occlusion of PFO with a dedicated adjustable device: influence on one year outcome.

AIMS: Though the association of patent foramen ovale with cryptogenic stroke in young patients has been known for 20 years, most interventional closure systems are not specifically designed for PFO closure, but instead are adapted from ASD closure systems. We describe the safety, feasibility and efficacy of transcatheter closure of PFO using a dedicated adjustable device specifically designed to overcome some of the pitfalls of PFO occlusion like erosion, left atrial thrombus formation, embolisation, maladaptation to cardiac structures and excessive foreign material deposition. METHODS AND RESULTS: Seventy-two consecutive patients, aged between 20 and 72 years, underwent PFO occlusion using the Premere® PFO occluder, for the greater part for presumed paradoxical embolism causing cryptogenic stroke or transient ischaemic attack. Forty patients received the 20 mm, while 32 received the 25 mm device. Implantation was successful in all patients. Residual shunt rate, excluding absolutely trivial shunts, was 2.8% at six months on contrast TEE study. Peri- and postprocedural adverse events with some possibility of a causal link to the procedure occurred in six patients. The postprocedural annual recurrence rate (0.99%) was lower than reported in most other series. CONCLUSIONS: PFO occlusion using the dedicated Premere® PFO occluder is effective and safe. The residual shunt rate and post-interventional recurrence rate compares favourably to the literature.

Migraine headache relief after percutaneous transcatheter closure of interatrial communications.

BACKGROUND: Migraine headache (MHA) is present in 12% of adults, but has been reported to have a higher prevalence in patients with presumed paradoxical embolism and patent foramen ovale. PFO closure in these patients has been reported to improve migraine, but follow-up periods in previous studies have been relatively short and concomitant medical therapy as well as placebo effects might have influenced the results. This study investigated the long term course of MHA in a large cohort of patients after closure of PFO well beyond the initial phase of concomitant antiplatelet medication. METHODS: 191 consecutive patients with presumed paradoxical embolism underwent percutaneous transcatheter closure of patent interatrial communications for prevention of recurrent thromboembolism. We report the course of MHA before and after closure. RESULTS: Before the procedure, MHA was present in 24% of patients. At a mean follow-up of 38 months (range 6 to 82) after the procedure MHA had disappeared completely in 24% of patients, and in another 63% symptoms had improved. At a mean duration of follow-up of 38 months a significant reduction (p < 0.000) of number, intensity, duration of episodes, and in the number of accompanying symptoms during an MHA episode was found. CONCLUSIONS: Percutaneous transcatheter closure of patent interatrial communications results in significant amelioration of MHA in 87% of patients (complete resolution in 24% and significant improvement in symptoms in 63%). Ongoing randomized trials and larger epidemiologic surveys need to further elucidate the role of device therapy for MHA.

Fenestrated occluders for treatment of ASD in elderly patients with pulmonary hypertension and/or right heart failure.

Atrial septal defect (ASD) occlusion in adult patients with advanced age and left or right heart diastolic or systolic heart failure and in patients with pulmonary arterial hypertension bears a considerable risk of deterioration of heart failure. Therefore, we conducted this feasibility trial in 15 ASD patients with pulmonary hypertension and/or right heart failure using a fenestrated Amplatzer septal occluder (AGA Medical Corporation, Golden Valley, MN), allowing an overflow of blood in both directions in case of univentricular diastolic or systolic heart failure. In all patients, the device could be implanted without complications. All symptomatic patients showed an improvement in the New York Heart Association (NYHA) class, and no right or left heart decompensation occurred. On echocardiography, right ventricular end diastolic dimension (RVEDD) and pulmonary artery pressure (PAP) decreased significantly, whereas left ventricular end diastolic dimension (LVEDD) increased. Our series of 15 patients with fenestrated ASD occlusion shows that high-risk ASD occlusion can safely be accomplished with excellent clinical results and without complications by a fenestrated occluder.

Exclusion of patients with arteriosclerosis reduces long-term recurrence rate of presumed arterial embolism after PFO closure.

BACKGROUND: Percutaneous transcatheter closure of patent interatrial communications after presumed paradoxical embolism is used as an alternative to surgery or long-term anticoagulation for the treatment of patients who are at risk for recurrent thromboembolism. To avoid atherosclerotic events to be judged as recurrent paradoxical embolism, we prospectively excluded all patients with detectable arteriosclerosis from our series and investigated long-term results. METHODS AND RESULTS: We report the outcome of 180 patients who underwent percutaneous transcatheter closure of patent foramen ovale (PFO), PFO like atrial septal defect (ASD), or an ASD because of paradoxical embolism. One hundred four patients had cerebral embolism, 57 had transient ischemic attacks, 16 coronary embolism, and 3 had peripheral embolism. Twenty-three patients experienced multilocal arterial embolism. One hundred twenty-five patients had a PFO, 63 of them with an atrial septal aneurysm (ASA), 24 a PFO-like ASD (7 of them with an ASA), and 31 had an ASD. After 18 months, only 5 patients (2.8%) showed a trivial residual shunt. At a mean follow-up of 40 months (range 4 to 88), resulting in 602 observed patient-years, only 1 patient experienced a presumed paradoxical (coronary) embolism (calculated annual risk to suffer a recurrent thromboembolic event: 0.16%). CONCLUSIONS: Percutaneous transcatheter closure of PFO/ASD is a safe and effective therapeutic option for the secondary prevention of presumed paradoxical embolism. It is associated with a high success rate, low incidence of hospital complications, and very low frequency of recurrent systemic embolic events.