Prenatal immune activation in mice induces long-term alterations in brain mitochondrial function.

Prenatal exposure to infections is a risk factor for neurodevelopmental disorders in offspring, and alterations in mitochondrial function are discussed as a potential underlying factor. Here, using a mouse model of viral-like maternal immune activation (MIA) based on poly(I:C) (POL) treatment at gestational day (GD) 12, we show that adult offspring exhibit behavioral deficits, such as reduced levels of social interaction. In addition, we found increased nicotinamidadenindinucleotid (NADH)- and succinate-linked mitochondrial respiration and maximal electron transfer capacity in the prefrontal cortex (PFC) and in the amygdala (AMY) of males and females. The increase in respiratory capacity resulted from an increase in mitochondrial mass in neurons (as measured by complex IV activity and transcript expression), presumably to compensate for a reduction in mitochondrion-specific respiration. Moreover, in the PFC of control (CON) male offspring a higher excess capacity compared to females was observed, which was significantly reduced in the POL-exposed male offspring, and, along with a higher leak respiration, resulted in a lower mitochondrial coupling efficiency. Transcript expression of the uncoupling proteins (UCP4 and UCP5) showed a reduction in the PFC of POL male mice, suggesting mitochondrial dysfunction. In addition, in the PFC of CON females, a higher expression of the antioxidant enzyme superoxide dismutase (SOD1) was observed, suggesting a higher antioxidant capacity as compared to males. Finally, transcripts analysis of genes involved in mitochondrial biogenesis and dynamics showed reduced expression of fission/fusion transcripts in PFC of POL offspring of both sexes. In conclusion, we show that MIA causes alterations in neuronal mitochondrial function and mass in the PFC and AMY of adult offspring with some effects differing between males and females.

Exploring Chemical Space Using Ab Initio Hyperreactor Dynamics.

In recent years, first-principles exploration of chemical reaction space has provided valuable insights into intricate reaction networks. Here, we introduce ab initio hyperreactor dynamics, which enables rapid screening of the accessible chemical space from a given set of initial molecular species, predicting new synthetic routes that can potentially guide subsequent experimental studies. For this purpose, different hyperdynamics derived bias potentials are applied along with pressure-inducing spherical confinement of the molecular system in ab initio molecular dynamics simulations to efficiently enhance reactivity under mild conditions. To showcase the advantages and flexibility of the hyperreactor approach, we present a systematic study of the method's parameters on a HCN toy model and apply it to a recently introduced experimental model for the prebiotic formation of glycinal and acetamide in interstellar ices, which yields results in line with experimental findings. In addition, we show how the developed framework enables the study of complicated transitions like the first step of a nonenzymatic DNA nucleoside synthesis in an aqueous environment, where the molecular fragmentation problem of earlier nanoreactor approaches is avoided.

Late prenatal immune activation in mice induces transgenerational effects via the maternal and paternal lineages.

Prenatal exposure to infectious or noninfectious immune activation is an environmental risk factor for neurodevelopmental disorders and mental illnesses. Recent research using animal models suggests that maternal immune activation (MIA) during early to middle stages of pregnancy can induce transgenerational effects on brain and behavior, likely via inducing stable epigenetic modifications across generations. Using a mouse model of viral-like MIA, which is based on gestational treatment with poly(I:C), the present study explored whether transgenerational effects can also emerge when MIA occurs in late pregnancy. Our findings demonstrate that the direct descendants born to poly(I:C)-treated mothers display deficits in temporal order memory, which are similarly present in second- and third-generation offspring. These transgenerational effects were mediated via both the maternal and paternal lineages and were accompanied by transient changes in maternal care. In addition to the cognitive effects, late prenatal immune activation induced generation-spanning effects on the prefrontal expression of gamma-aminobutyric acid (GABA)ergic genes, including parvalbumin and distinct alpha-subunits of the GABAA receptor. Together, our results suggest that MIA in late pregnancy has the potential to affect cognitive functions and prefrontal gene expression patterns in multiple generations, highlighting its role in shaping disease risk across generations.

Pulmonary artery sensor system pressure monitoring to improve heart failure outcomes (PASSPORT-HF): rationale and design of the PASSPORT-HF multicenter randomized clinical trial.

BACKGROUND: Remote monitoring of patients with New York Heart Association (NYHA) functional class III heart failure (HF) using daily transmission of pulmonary artery (PA) pressure values has shown a reduction in HF-related hospitalizations and improved quality of life in patients. OBJECTIVES: PASSPORT-HF is a prospective, randomized, open, multicenter trial evaluating the effects of a hemodynamic-guided, HF nurse-led care approach using the CardioMEMS™ HF-System on clinical end points. METHODS AND RESULTS: The PASSPORT-HF trial has been commissioned by the German Federal Joint Committee (G-BA) to ascertain the efficacy of PA pressure-guided remote care in the German health-care system. PASSPORT-HF includes adult HF patients in NYHA functional class III, who experienced an HF-related hospitalization within the last 12 months. Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy. Patients will be randomized centrally 1:1 to implantation of a CardioMEMS™ sensor or control. All patients will receive post-discharge support facilitated by trained HF nurses providing structured telephone-based care. The trial will enroll 554 patients at about 50 study sites. The primary end point is a composite of the number of unplanned HF-related rehospitalizations or all-cause death after 12 months of follow-up, and all events will be adjudicated centrally. Secondary end points include device/system-related complications, components of the primary end point, days alive and out of hospital, disease-specific and generic health-related quality of life including their sub-scales, and laboratory parameters of organ damage and disease progression. CONCLUSIONS: PASSPORT-HF will define the efficacy of implementing hemodynamic monitoring as a novel disease management tool in routine outpatient care. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04398654, 13-MAY-2020.

Contemporary real life cardioversion of atrial fibrillation: Results from the multinational RHYTHM-AF study.

AIMS: Electrical and pharmacological cardioversion (ECV, PCV) are important treatment options for symptomatic patients with recent onset atrial fibrillation (AF). RHYTHM-AF is an international registry of present-day cardioversion providing information that is not currently available on country differences and acute and long-term arrhythmia outcomes of ECV and PCV. METHODS AND RESULTS: 3940 patients were enrolled, of whom 75% underwent CV. All patients were followed for 2 months. There were large variations concerning mode of CV used, ECV being heterogeneous. A choice of PCV drug depended on the clinical patient profile. Sinus rhythm was restored in 89.7% of patients by ECV and in 69.1% after PCV. Among patients not undergoing CV during admission, 34% spontaneously converted to sinus rhythm within 24h. ECV was most successful in patients pretreated with antiarrhythmic drugs (mostly amiodarone). PCV was enhanced by class Ic antiarrhythmic drugs; conversion rate on amiodarone was similar to that seen with rate control drugs. Female patients and those with paroxysmal and first detected AF as well as those without previous ECV responded well to PCV. The median duration of hospital stay was 16.2 and 24.0 h for ECV and PCV patients, respectively. There were very few CV-related complications regardless of mode of CV. Chronic maintenance of sinus rhythm was enhanced in patients on chronic antiarrhythmic drugs, beta-blockers or inhibitors of the renin-angiotensin system. CONCLUSIONS: Mode of CV varied significantly, but both PCV and ECV were safe and effective. Class Ic drugs were most effective conversion drugs, but amiodarone is used most frequently despite providing merely rate control rather than shorten time to conversion.

Overtreatment and undertreatment with anticoagulation in relation to cardioversion of atrial fibrillation (the RHYTHM-AF study).

Antithrombotic therapy is central to the management of atrial fibrillation. This analysis from the RHYTHM-atrial fibrillation (RHYTHM-AF) registry explored the appropriateness of antithrombotic therapy in relation to stroke risk and atrial fibrillation duration in patients with atrial fibrillation. RHYTHM-AF, a prospective multinational registry, enrolled consecutive adult patients with atrial fibrillation considered for cardioversion. We compared the type of antithrombotic therapy administered at the time of cardioversion and at discharge with stroke risk ("high stroke risk" defined by CHA2DS2-VASc >1) and duration of atrial fibrillation (≤48 vs >48 hours or unknown duration). Of 2,972 patients who were cardioverted (34.5% through pharmacologic cardioversion [PCV] and 65.5% through electrical cardioversion [ECV]), 65% were at high risk of stroke and 30% presented with atrial fibrillation of >48-hour or unknown duration. At the time of PCV and ECV, 36% (n = 242) and 84% (n = 1,075) of high-risk patients, respectively, were taking vitamin K antagonists or heparin. At discharge, these rates increased to 62% (n = 414) and 93% (n = 1,191), respectively. Of all low-stroke risk patients with short-duration atrial fibrillation undergoing PCV (n = 260) and ECV (n = 111), 7% (n = 17) and 30% (n = 33), respectively, were taking vitamin K antagonists or heparin at the time of cardioversion. At discharge, these rates increased to 19% (n = 50) and 40% (n = 44), respectively. In conclusion, ECV was frequently performed under appropriate antithrombotic therapy for most high-risk patients with atrial fibrillation, whereas PCV was frequently performed without appropriate antithrombotic therapy. To enhance pericardioversion stroke prevention, cardioversion algorithms should focus less on the type of conversion and more on stroke risk factors and atrial fibrillation duration.

Types and outcomes of cardioversion in patients admitted to hospital for atrial fibrillation: results of the German RHYTHM-AF Study.

BACKGROUND: Atrial fibrillation (AF) accounts for approximately one-third of hospitalizations for cardiac rhythm disturbances. Little is known about the characteristics of current use of cardioversion (CV) and its success rates in clinical practice in Germany. METHODS: As part of the international RHYTHM-AF Study, 655 consecutive patients with documented AF (mean age 68.3 ± 10.5 years, 64.9 % males) who were considered candidates for CV were prospectively enrolled in 22 German hospitals (21 academic/teaching and 1 non-teaching). CV was considered successful if sinus rhythm or atrial rhythm was obtained within 1 day after start of pharmacological CV (PCV) or if sinus rhythm was achieved and maintained for at least 10 min after electrical CV (ECV). RESULTS: Patients with AF considered for CV had ECG in 94.4 %, Holter ECG in 25.8 %, and transesophageal echocardiography (TEE) in 73.1 % of cases. They underwent ECV (after mean 16 h, range 4-48), in 65.3 % and PCV in 6.7 % of patients (amiodarone in 47.7 %, flecainide in 27.3 %, propafenone in 2.3 %) as first CV procedure. No CV was performed in 27.9 %, mainly due to spontaneous CV or pathologic TEE. Primary success rates were 86.7 % for electrical CV and 54.5 % for pharmacological CV. More patients in the ECV group compared to the PCV group received oral anticoagulation at discharge (79.2 vs. 59.1 %, p < 0.001), and at 60 days (77.5 vs. 56.8 %, p < 0.001). Further, at 60 days the proportion of patients in sinus rhythm was not different between groups (ECV 76.8 % vs. PCV 77.3 %). CONCLUSIONS: In large academic centres in Germany, the preferred CV method is electrical, mainly due to its easy access and to its higher success rate for the initial restoration of sinus rhythm. Considering the limitations of the open-label, non-randomised study design, overall short-term success rates appeared higher after ECV compared to PCV during hospitalisation, but not after 60 days.

RHYTHM-AF: design of an international registry on cardioversion of atrial fibrillation and characteristics of participating centers.

BACKGROUND: Atrial fibrillation is a serious public health problem posing a considerable burden to not only patients, but the healthcare environment due to high rates of morbidity, mortality, and medical resource utilization. There are limited data on the variation in treatment practice patterns across different countries, healthcare settings and the associated health outcomes. METHODS/DESIGN: RHYTHM-AF was a prospective observational multinational study of management of recent onset atrial fibrillation patients considered for cardioversion designed to collect data on international treatment patterns and short term outcomes related to cardioversion. We present data collected in 10 countries between May 2010 and June 2011. Enrollment was ongoing in Italy and Brazil at the time of data analysis. Data were collected at the time of atrial fibrillation episode in all countries (Australia, Brazil, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom), and cumulative follow-up data were collected at day 60 (±10) in all but Spain. Information on center characteristics, enrollment data, patient demographics, detail of atrial fibrillation episode, medical history, diagnostic procedures, acute treatment of atrial fibrillation, discharge information and the follow-up data on major events and rehospitalizations up to day 60 were collected. DISCUSSION: A total of 3940 patients were enrolled from 175 acute care centers. 70.5% of the centers were either academic (44%) or teaching (26%) hospitals with an overall median capacity of 510 beds. The sites were mostly specialized with anticoagulation clinics (65.9%), heart failure (75.1%) and hypertension clinics (60.1%) available. The RHYTHM-AF registry will provide insight into regional variability of antiarrhythmic and antithrombotic treatment of atrial fibrillation, the appropriateness of such treatments with respect to outcomes, and their cost-efficacy. Observations will help inform strategies to improve cardiovascular outcomes in patients with atrial fibrillation. TRIAL REGISTRATION: Clinical trials NCT01119716.