The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane mediates metabolic flow, Ca2+, and cell death signaling between the endoplasmic reticulum (ER) and mitochondrial networks. We demonstrate that VDAC1 is physically linked to the endoplasmic reticulum Ca2+-release channel inositol 1,4,5-trisphosphate receptor (IP3R) through the molecular chaperone glucose-regulated protein 75 (grp75). Functional interaction between the channels was shown by the recombinant expression of the ligand-binding domain of the IP3R on the ER or mitochondrial surface, which directly enhanced Ca2+ accumulation in mitochondria. Knockdown of grp75 abolished the stimulatory effect, highlighting chaperone-mediated conformational coupling between the IP3R and the mitochondrial Ca2+ uptake machinery. Because organelle Ca2+ homeostasis influences fundamentally cellular functions and death signaling, the central location of grp75 may represent an important control point of cell fate and pathogenesis.
Highlights-Neutrophil extracellular traps (NETs) modify the structure and stability of fibrin.-NET content of thrombi varies at different locations (brain, heart, peripheral arteries).-DNA and histones in thrombi correlate with age and systemic inflammatory markers.-The amount of fibrin is similar at all examined arterial locations.-Thicker fibrin fibers are formed in coronaries than in brain and peripheral arteries. 3 Abstract Introduction-The ultrastructure and cellular composition of thrombi has a profound effect on the outcome of acute ischemic stroke (AIS), coronary (CAD) and peripheral artery disease (PAD). Activated neutrophils release a web-like structure composed mainly of DNA and citrullinated histones, called neutrophil extracellular traps (NET) that modify the stability and lysability of fibrin. Here, we investigated the NET-related structural features of thrombi retrieved from different arterial localizations and their interrelations with routinely available clinical data. Patients and methods-Thrombi extracted from AIS (n=78), CAD (n=66) or PAD (n=64) patients were processed for scanning electron microscopy, (immune)stained for fibrin, citrullinated histone H3 (cH3) and extracellular DNA. Fibrin fiber diameter, cellular components, DNA and cH3 were measured and analyzed in relation to clinical parameters. Results-DNA was least present in AIS thrombi showing a 2.5-fold lower DNA/fibrin ratio than PAD, whereas cH3 antigen was unvaryingly present at all locations. The NET content of thrombi correlated parabolically with systemic inflammatory markers and positively with patients' age. The median platelet content was lower in PAD (2.2%) than in either AIS (3.9%) or CAD (3.1%) and thrombi from smokers contained less platelets than non-smokers. Fibrin fibers were significantly thicker in male patients with CAD (median fiber diameter 76.3 nm) compared to AIS (64.1 nm) or PAD (62.1 nm) and their diameter correlated parabolically with systemic inflammatory markers.Conclusions-The observed NET-related variations in thrombus structure shed light on novel determinants of thrombus stability that eventually affect both the spontaneous progress and therapeutic outcome of ischemic arterial diseases.
Aims Left ventricular diastolic pressure estimation is essential for characterization of heart failure (HF). Patients with normal resting left atrial (LA) pressures (LAP), but steep LAP elevation on exertion, pose a particular diagnostic challenge. Current recommendations on echocardiographic LAP estimation have limited accuracy. Our aim was to investigate whether LA mechanical alterations assessed by LA strain (LA-GS) can contribute to non-invasive LAP diagnostics. Methods and results Simultaneous echocardiographic and right heart catheterization (RHC) data at rest and during exercise was analyzed in 164 prospectively enrolled patients, referred for RHC due to HF symptoms. 56% had preserved ejection fraction (pEF). At rest, 97 patients displayed elevated mean pulmonary arterial wedge pressure (PAWP M ); further 32 patients had normal resting, but elevated PAWP M during exercise. LA-GS demonstrated a stronger relationship with resting PAWP M ( r = − 0.61, p < 0.001) than any of the indices ( E / e ′, LAVi, TRV max ) incorporated in the currently recommended diagnostic algorithm. The diagnostic ability of LA-GS for detecting elevated resting PAWP M (AUC: 0.80, p < 0.001) outperformed that of the recommended algorithm (AUC: 0.69). Importantly, resting LA-GS performed even better in identifying patients with pathological PAWP M either at rest or during stress (AUC: 0.90, p < 0.001), whereas the diagnostic potential of the current algorithm was modest and limited to pEF patients (AUC = 0.72). Finally, among the non-invasive indices, LA-GS entailed the strongest prognostic value for death or heart transplantation (OR: 2.7; p < 0.05). Conclusion LA-GS comprises a robust method for PAWP M assessment at rest. More importantly, it reliably discerns pathological PAWP M rise on exertion despite normal resting pressures. Electronic supplementary material The online version of this article (10.1007/s00392-018-1399-8) contains supplementary material, which is available to authorized users.
AimsThe diastolic pulmonary pressure gradient (DPG) has recently been introduced as a specific marker of combined pre-capillary pulmonary hypertension (Cpc-PH) in left heart disease (LHD). However, its diagnostic and prognostic superiority compared with traditional haemodynamic indices has been challenged lately. Current recommendations explicitly denote that in the normal heart, DPG values are greater than zero, with DPG ≥7 mmHg indicating Cpc-PH. However, clinicians are perplexed by the frequent observation of DPG <0 mmHg (DPG NEG ), as its physiological explanation and clinical impact are unclear to date. We hypothesized that large V-waves in the pulmonary artery wedge pressure (PAWP) curve yielding asymmetric pressure transmission might account for DPG NEG Methods and resultsRight heart catheterization and echocardiography were performed in 316 patients with LHD due to primary myocardial dysfunction or valvular disease. A total of 256 patients had PH-LHD, of whom 48% demonstrated DPG NEG . The V-wave amplitude inversely correlated with DPG (r = −0.45, P < 0.001) in patients with low pulmonary vascular resistance (PVR), but not in those with elevated PVR (P > 0.05). Patients with large V-waves had negative and lower DPG than those without augmented V-waves (P < 0.001) despite similar PVR (P >0.05). Positive, but normal DPG (0-6 mmHg) carried a worse 2-year prognosis for death and/or heart transplantation than DPG NEG (hazard ratio 2.97; P < 0.05). ..................................................................................................................................................................... ConclusionOur results advocate against DPG NEG constituting a measurement error. We propose that DPG NEG can partially be ascribed to large V-waves and carries a better prognosis than DPG within the normal positive range.
Untwisting contributes to left ventricular filling through suction generation. We sought to investigate diastolic function and untwisting dynamics in different forms of left ventricular hypertrophy: in athlete?s heart and hypertrophic cardiomyopathy. Elite athletes in kayaking, canoeing and rowing (n=28), patients with hypertrophic cardiomyopathy (HCM, n=15) and healthy sedentary volunteers (n=13) were compared. Left ventricular volumes, wall thickness-to-volume ratio were assessed by cardiac MRI. Following conventional and tissue Doppler measurements, untwist and untwist rate were determined by speckle tracking echocardiography. Wall thickness-to-volume ratio describing remodelling was significantly higher in HCM, but similar in athletes and controls (athlete vs. HCM vs. control: 0.107?0.019 vs. 0.271?0.091 vs. 0.104?0.012?mm?m?/ml, mean?SD, p<0.001). Mitral lateral annulus e? velocity referred to diastolic dysfunction in HCM (15.3?3.6 vs. 7.9?3.3 vs. 15.0?3.0?cm/s, p<0.01). At time point of mitral valve opening, untwist and untwist rate were significantly different: the highest values were measured in athletes, while the lowest were found in HCM (untwist: 51.3?19.1 vs. 11.6?10.4 vs. 35.9?16.3%; untwist rate: ?32.5?13.0 vs. ?10.6?10.8 vs. ?23.0?7.7?/s, p<0.05). Untwisting correlated with E/A, e? and E/e?. Athlete?s heart is characterized by increased untwist and untwist rate, which can aid diastolic function. Evaluation of untwisting dynamics may help to distinguish pathological hypertrophy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.