Atrial fibrillation and heart failure with preserved ejection fraction "twindemic"-Shared root causes and treatment targets.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are comorbid conditions that are increasingly prevalent and have a high socioeconomic burden. This article discusses their shared pathophysiology, focusing on the triad of hypertension, obesity, and aging. We highlight the misperception that pharmacological heart rate lowering is beneficial, which has resulted in an overprescription of β-blockers in HFpEF and AF.

Emission lines due to ionizing radiation from a compact object in the remnant of Supernova 1987A.

The nearby Supernova 1987A was accompanied by a burst of neutrino emission, which indicates that a compact object (a neutron star or black hole) was formed in the explosion. There has been no direct observation of this compact object. In this work, we observe the supernova remnant with JWST spectroscopy, finding narrow infrared emission lines of argon and sulfur.

Rationale and design of the PACE HFpEF trial: Physiologic accelerated pacing as a holistic treatment of heart failure with preserved ejection fraction.

Background: In heart failure with preserved ejection fraction (HFpEF), it has been assumed that pharmacologic heart rate suppression should provide clinical benefits through an increase in diastolic filling time. Contrary to this assumption, heart rate lowering in patients with preserved left ventricular ejection fraction and hypertension or coronary artery disease results in adverse outcomes and suggests that the opposite may be beneficial. Namely, shortening the diastolic filling time with a higher heart rate might normalize the elevated filling pressures that are the of HFpEF.

Effects of Continuous Accelerated Pacing on Cardiac Structure and Function in Patients With Heart Failure With Preserved Ejection Fraction: Insights From the myPACE Randomized Clinical Trial.

Background: Heart failure with preserved ejection fraction ≥50% is prevalent with few evidence-based therapies. In a trial of patients with heart failure with preserved ejection fraction with specialized pacemakers, treatment with accelerated personalized pacing averaging 75 bpm (myPACE) markedly improved quality of life, NT-proBNP (N-terminal pro-brain natriuretic peptide), physical activity, and atrial fibrillation burden compared with the standard lower rate setting of 60 bpm (usual care).

Methods And Results: In this exploratory study, provider-initiated echocardiographic studies obtained before and after the trial were assessed for changes in left ventricular (LV) structure and function among participants who continued their pacing assignment.

Personalized accelerated physiologic pacing.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent with a high socioeconomic burden. Pharmacological heart rate lowering was recommended to improve ventricular filling in HFpEF. This article discusses the misperceptions that have resulted in an overprescription of beta-blockers, which in all likelihood have untoward effects on patients with HFpEF, even if they have atrial fibrillation or coronary artery disease as a comorbidity.

Effect of Personalized Accelerated Pacing on Quality of Life, Physical Activity, and Atrial Fibrillation in Patients With Preclinical and Overt Heart Failure With Preserved Ejection Fraction: The myPACE Randomized Clinical Trial.

Importance: Patients with heart failure with preserved ejection fraction (HFpEF) with a pacemaker may benefit from a higher, more physiologic backup heart rate than the nominal 60 beats per minute (bpm) setting.

Objective: To assess the effects of a moderately accelerated personalized backup heart rate compared with 60 bpm (usual care) in patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony.

Design, Setting, And Participants: This blinded randomized clinical trial enrolled patients with stage B and C HFpEF from the University of Vermont Medical Center pacemaker clinic between June 2019 and November 2020.

Clinical impact of Bachmann's bundle pacing defined by electrocardiographic criteria on atrial arrhythmia outcomes.

Aims: Evaluate whether Bachmann's bundle pacing (BBp) defined by electrocardiographic (ECG) criteria is associated with less atrial fibrillation/tachycardia (AF/AT) compared with anatomically defined right atrial septal pacing (RASp) and right atrial appendage pacing (RAAp).

Methods And Results: This is a retrospective study comparing BBp with non-specific RASp and RAAp on new incidence, burden, and recurrence of AF/AT. We included patients who underwent atrial lead placement between 2006 and 2019 and received > 20% atrial pacing.

Personalized pacing for diastolic dysfunction and heart failure with preserved ejection fraction: Design and rationale for the PACE randomized controlled trial.

Background: Patients with pacemakers and heart failure with preserved ejection fraction (HFpEF) or isolated diastolic dysfunction (DD) may benefit from a higher backup heart rate (HR) setting compared with the standard setting of 60 bpm.

Objective: The purpose of this study was to assess the effects of a personalized backup HR setting (PACE group) compared with 60 bpm (control group).

Methods: In this prospective, blinded, randomized controlled study, pacemaker patients with DD or HFpEF and atrial pacing with intrinsic ventricular conduction or conduction system or biventricular pacing are randomized to the PACE group or control group for 1 year.

Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma.

Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades.

Purpose: Here, we investigated the effect of simvastatin as adjuvant therapy on chemotherapy.

An Update on the Role of Ubiquitination in Melanoma Development and Therapies.

The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cutaneous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances.

FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells.

Ubiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene.

Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.

To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo.

HVEM has a broader expression than PD-L1 and constitutes a negative prognostic marker and potential treatment target for melanoma.

HVEM (Herpes Virus Entry Mediator) engagement of BTLA (B and T Lymphocyte Attenuator) triggers inhibitory signals in T cells and could play a role in evading antitumor immunity. Here, HVEM expression levels in melanoma metastases were analyzed by immunohistochemistry, correlated with overall survival (OS) in 116 patients, and validated by TCGA transcriptomic data. Coincident expression of HVEM and its ligand BTLA was studied in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry (n = 21) and immunofluorescence (n = 5).

CYR61 triggers osteosarcoma metastatic spreading via an IGF1Rβ-dependent EMT-like process.

Background: Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples.

Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells.

HACE1 is an E3 ubiquitin ligase described as a tumour suppressor because HACE1-knockout mice develop multi-organ, late-onset cancers and because HACE1 expression is lost in several neoplasms, such as Wilms' tumours and colorectal cancer. However, a search of public databases indicated that HACE1 expression is maintained in melanomas. We demonstrated that HACE1 promoted melanoma cell migration and adhesion in vitro and was required for mouse lung colonisation by melanoma cells in vivo.

Prospectively quantifying the propensity for atrial fibrillation: a mechanistic formulation.

The goal of this study was to determine quantitative relationships between electrophysiologic parameters and the propensity of cardiac tissue to undergo atrial fibrillation. We used a computational model to simulate episodes of fibrillation, which we then characterized in terms of both their duration and the population dynamics of the electrical waves which drove them. Monte Carlo sampling revealed that episode durations followed an exponential decay distribution and wave population sizes followed a normal distribution.

Mapping multi-wavelet reentry without isochrones: an electrogram-guided approach to define substrate distribution.

Aims: A key mechanism responsible for atrial fibrillation is multi-wavelet reentry (MWR). We have previously demonstrated that ablation in regions of increased circuit density reduces the duration of, and decreases the inducibility of MWR. In this study, we demonstrate a method for identifying local circuit density using electrogram frequency and validated its effectiveness for map-guided ablation in a computer model of MWR.

Cyr61 silencing reduces vascularization and dissemination of osteosarcoma tumors.

Osteosarcoma is the most prevalent primary pediatric cancer-related bone disease. These tumors frequently develop resistance to chemotherapy and are highly metastatic, leading to poor outcome. Thus, there is a need for new therapeutic strategies that can prevent cell dissemination.

Principles of differential diagnostic pacing maneuvers: serial versus parallel conduction.

In this article we will review differential diagnostic pacing maneuvers. It is not meant to be an exhaustive review of all such maneuvers. Rather, we offer some general analytic principles as they apply to electrophysiology (EP) and illustrate their use through several examples.

Zinc chelation: a metallothionein 2A's mechanism of action involved in osteosarcoma cell death and chemotherapy resistance.

Osteosarcoma is the most common primary tumor of bone occurring in children and adolescents. The histological response to chemotherapy represents a key clinical factor related to survival. We previously showed that statins exhibit antitumor effects in vitro, inducing apoptotic cell death, reducing cell migration and invasion capacities and strengthening cytotoxic effects in combination with standard drugs.