Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation

AbstractThe inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a universal intracellular Ca2+-release channel. It is activated after cell stimulation and plays a crucial role in the initiation and propagation of the complex spatio-temporal Ca2+ signals that control cellular processes as different as fertilization, cell division, cell migration, differentiation, metabolism, muscle contraction, secretion, neuronal processing, and ultimately cell death. To achieve these various functions, often in a single cell, exquisite control of the Ca2+ release is needed. This review aims to highlight how protein kinases and protein phosphatases can interact with the IP3R or with associated proteins and so provide a large potential for fine tuning the Ca2+-release activity and for creating efficient Ca2+ signals in subcellular microdomains

Inositol 1,4,5-trisphosphate receptor 1, a widespread Ca2+ channel, is a novel substrate of polo-like kinase 1 in eggs

AbstractTo initiate embryo development, the sperm induces in the egg release of intracellular calcium ([Ca2+]i). During oocyte maturation, the inositol 1,4,5-trisphosphate receptor (IP3R1), the channel implicated, undergoes modifications that enhance its function. We found that IP3R1 becomes phosphorylated during maturation at an MPM-2 epitope and that this persists until the fertilization-associated [Ca2+]i responses cease. We also reported that maturation without ERK activity diminishes IP3R1 MPM-2 reactivity and [Ca2+]i responses. Here, we show that IP3R1 is a novel target for Polo-like kinase1 (Plk1), a conserved M-phase kinase, which phosphorylates it at an MPM-2 epitope. Plk1 and IP3R1 interact in an M-phase preferential manner, and they exhibit close co-localization in the spindle/spindle poles area. This co-localization is reduced in the absence of ERK activity, as the ERK pathway regulates spindle organization and IP3R1 cortical re-distribution. We propose that IP3R1 phosphorylation by Plk1, and possibly by other M-phase kinases, underlies the delivery of spatially and temporally regulated [Ca2+]i signals during meiosis/mitosis and cytokinesis

Clinical and Hemodynamic Effects of Percutaneous Edge-to-Edge Mitral Valve Repair in Atrial Versus Ventricular Functional Mitral Regurgitation.

The present study aims to assess the clinical and hemodynamic impact of percutaneous edge-to-edge mitral valve repair with MitraClip in patients with atrial functional mitral regurgitation (A-FMR) compared with ventricular functional mitral regurgitation (V-FMR). Mitral regurgitation (MR) grade, functional status (New York Heart Association class), and major adverse cardiac events (MACE; all-cause mortality or hospitalization for heart failure) were evaluated in 52 patients with A-FMR and in 307 patients with V-FMR. In 56 patients, hemodynamic assessment during exercise echocardiography was performed before and 6 months after intervention. MR reduction after MitraClip implantation was noninferior in A-FMR compared with V-FMR (MR grade ≤2 at 6 months in 94% vs 82%, respectively, p <0.001 for noninferiority) and was associated with improvement of functional status (New York Heart Association class ≤2 at 6 months in 90% vs 80%, respectively, p = 0.2). Hemodynamic assessment revealed that cardiac output at 6 months was higher in A-FMR at rest (5.1 ± 1.5 L/min vs 3.8 ± 1.5 L/min, p = 0.002) and during peak exercise (7.9 ± 2.4 L/min vs 6.1 ± 2.1 L/min, p = 0.02). In addition, the reduction in systolic pulmonary artery pressure at rest was more pronounced in A-FMR: Δ SPAP -13.1 ± 15.1 mm Hg versus -2.2 ± 13.3 mm Hg (p = 0.03). MACE rate at follow-up was significantly lower in A-FMR versus V-FMR, with an adjusted odds ratio of 0.46 (95% confidence interval 0.24 to 0.88), which was caused by a reduction in hospitalization for heart failure. In conclusion, percutaneous edge-to-edge mitral valve repair with MitraClip is at least as effective in A-FMR as in V-FMR in reducing MR. However, the hemodynamic improvement and reduction of MACE were significantly better in A-FMR

Proof-of-concept trial results of the HeartMan mobile personal health system for self-management in congestive heart failure

This study tested the effectiveness of HeartMan—a mobile personal health system offering decisional support for management of congestive heart failure (CHF)—on health-related quality of life (HRQoL), self-management, exercise capacity, illness perception, mental and sexual health. A randomized controlled proof-of-concept trial (1:2 ratio of control:intervention) was set up with ambulatory CHF patients in stable condition in Belgium and Italy. Data were collected by means of a 6-min walking test and a number of standardized questionnaire instruments. A total of 56 (34 intervention and 22 control group) participants completed the study (77% male; mean age 63 years, sd 10.5). All depression and anxiety dimensions decreased in the intervention group (p &lt; 0.001), while the need for sexual counselling decreased in the control group (p &lt; 0.05). Although the group differences were not significant, self-care increased (p &lt; 0.05), and sexual problems decreased (p &lt; 0.05) in the intervention group only. No significant intervention effects were observed for HRQoL, self-care confidence, illness perception and exercise capacity. Overall, results of this proof-of-concept trial suggest that the HeartMan personal health system significantly improved mental and sexual health and self-care behaviour in CHF patients. These observations were in contrast to the lack of intervention effects on HRQoL, illness perception and exercise capacity

Current Methods for Hyperpolarized [1-13C]pyruvate MRI Human Studies

MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the HP 13C MRI Consensus Group as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods & Equipment study groups. It further aims to provide a comprehensive reference for future consensus building as the field continues to advance human studies with this metabolic imaging modality

Atrial Fibrillation Burden and Atrial Shunt Therapy in Heart Failure With Preserved Ejection Fraction

Background: Atrial fibrillation (AF) is a common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) and in heart failure with mildly reduced ejection fraction (HFmrEF). Objectives: This study sought to describe AF burden and its clinical impact among individuals with HFpEF and HFmrEF who participated in a randomized clinical trial of atrial shunt therapy (REDUCE LAP-HF II [A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure]) and to evaluate the effect of atrial shunt therapy on AF burden. Methods: Study investigators characterized AF burden among patients in the REDUCE LAP-HF II trial by using ambulatory cardiac patch monitoring at baseline (median patch wear time, 6 days) and over a 12-month follow-up (median patch wear time, 125 days). The investigators determined the association of baseline AF burden with long-term clinical events and examined the effect of atrial shunt therapy on AF burden over time. Results: Among 367 patients with cardiac monitoring data at baseline and follow-up, 194 (53%) had a history of AF or atrial flutter (AFL), and median baseline AF burden was 0.012% (IQR: 0%-1.3%). After multivariable adjustment, baseline AF burden ≥0.012% was significantly associated with heart failure (HF) events (HR: 2.00; 95% CI: 1.17-3.44; P = 0.01) both with and without a history of AF or AFL (P for interaction = 0.68). Adjustment for left atrial reservoir strain attenuated the baseline AF burden-HF event association (HR: 1.71; 95% CI: 0.93-3.14; P = 0.08). Of the 367 patients, 141 (38%) had patch-detected AF during follow-up without a history of AF or AFL. Atrial shunt therapy did not change AF incidence or burden during follow-up. Conclusions: In HFpEF and HFmrEF, nearly 40% of patients have subclinical AF by 1 year. Baseline AF burden, even at low levels, is associated with HF events. Atrial shunt therapy does not affect AF incidence or burden.</p

The European Registry for Patients with Mechanical Circulatory Support of the European Association for Cardio-Thoracic Surgery:third report

OBJECTIVES: In the third report of the European Registry for Patients with Mechanical Circulatory Support of the European Association for Cardio-Thoracic Surgery, outcomes of patients receiving mechanical circulatory support are reviewed in relation to implant era. METHODS: Procedures in adult patients (January 2011-June 2020) were included. Patients from centres with 3 months). Risk factors for death were explored using univariable Cox regression with a stepwise time-varying hazard ratio (3 months). RESULTS: In total, 4834 procedures in 4486 individual patients (72 hospitals) were included, with a median follow-up of 1.1 (interquartile range: 0.3-2.6) years. The annual number of implants (range: 346-600) did not significantly change (P = 0.41). Both Interagency Registry for Mechanically Assisted Circulatory Support class (classes 4-7: 23, 25 and 33%; P 3 months: 0.45). Bilirubin and creatinine levels were significant risk factors in the early phase but not in the late phase after the implant. CONCLUSIONS: In its 10 years of existence, EUROMACS has become a point of reference enabling benchmarking and outcome monitoring. Patient characteristics and outcomes changed between implant eras. In addition, both occurrence of outcomes and risk factor weights are time dependent