Left ventricular remodeling and function in ischemic heart disease and aortic valve disease

Background: Cardiac remodeling is a broad term that refers to structural and functional alterations of the heart in response to chronic changes in loading conditions or left ventricular (LV) contractile performance. Different loading conditions will affect the heart in different ways, some leading to impaired heart function, symptoms of heart failure, or even death. However, the process of remodeling may not be permanent. If the heart is relieved of the underlying cause of the remodeling, the heart function and structure may normalize in a process referred to as reverse remodeling. The complex interplay of factors that determine the process of reverse remodeling is not fully elucidated. Cardiac remodeling can be evaluated by many different diagnostic modalities, but the most widely used diagnostic tool is two-dimensional echocardiography (2DE). In recent years, three-dimensional echocardiography (3DE) has emerged with possible advantages in the assessment of LV volume and function. The thesis aimed to evaluate 3DE in the assessment of LV function and remodeling, and to study different aspects of remodeling in response to pressure and volume overload in patients with aortic stenosis (AS) and aortic regurgitation (AR), respectively. Methods: Studies I and II investigated patients with ischemic heart disease (n = 15 and n = 32, respectively). In Study I, the assessments of LV volume and ejection fraction (EF) were compared using 3DE, cardiac magnetic resonance (CMR), and single-photon emission computer tomography (SPECT). Study II compared the performance of 2DE, contrast-enhanced 2DE, 3DE, and contrast-enhanced 3DE in the assessment LV volumes and EF, using CMR as a reference standard. In Studies III and IV, 65 patients with severe AR and 120 patients with severe AS, respectively, were examined using 2DE and 3DE before and at one year after aortic valve replacement (AVR). In Study III, LV volumes, systolic and diastolic LV function, and left atrial strain (LAS) were analyzed to identify predictors of impaired LV reverse remodeling in AR. Study IV assessed LV functional indices, including 2D global longitudinal strain (GLS) and 3D strain, to assess predictors of incomplete reverse remodeling in AS. Results and conclusions: There were significant differences among 3DE, SPECT and CMR regarding the measurement of LV volumes. However, the estimation of EF showed good agreement. 3DE was more accurate and showed more favorable reproducibility than 2DE for the assessment of EF and LV volumes. Contrast enhancement improved accuracy and reproducibility for both 2DE and 3DE. One-third of patients with AR had signs of impaired LV diastolic function. After AVR, diastolic LV functional indices improved, LV and left atrial (LA) volumes decreased, and indices of LA function increased. LA conduit strain had an incremental prognostic value for the prediction of impaired LV functional and structural recovery. In patients with AS, AVR was associated with a decrease in LV mass, an improvement in 2D GLS, and a decrease in LV twist. 2D GLS and left ventricular mass index were predictive of incomplete reverse remodeling during the follow-up period. 3D GLS did not add discriminatory or predictive information over 2D GLS

Modulating Vaccinia Virus Immunomodulators to Improve Immunological Memory.

The increasing frequency of monkeypox virus infections, new outbreaks of other zoonotic orthopoxviruses and concern about the re-emergence of smallpox have prompted research into developing antiviral drugs and better vaccines against these viruses. This article considers the genetic engineering of vaccinia virus (VACV) to enhance vaccine immunogenicity and safety. The virulence, immunogenicity and protective efficacy of VACV strains engineered to lack specific immunomodulatory or host range proteins are described. The ultimate goal is to develop safer and more immunogenic VACV vaccines that induce long-lasting immunological memory

Effect of Substituents of Cerium Pyrazolates and Pyrrolates on Carbon Dioxide Activation

Homoleptic ceric pyrazolates (pz) Ce(RR’pz)4 (R = R’ = tBu; R = R’ = Ph; R = tBu, R’ = Me) were synthesized by the protonolysis reaction of Ce[N(SiHMe2)2]4 with the corresponding pyrazole derivative. The resulting complexes were investigated in their reactivity toward CO2, revealing a significant influence of the bulkiness of the substituents on the pyrazolato ligands. The efficiency of the CO2 insertion was found to increase in the order of tBu2pz < Ph2pz < tBuMepz < Me2pz. For comparison, the pyrrole-based ate complexes [Ce2(pyr)6(µ-pyr)2(thf)2][Li(thf)4]2 (pyr = pyrrolato) and [Ce(cbz)4(thf)2][Li(thf)4] (cbz = carbazolato) were obtained via protonolysis of the cerous ate complex Ce[N(SiHMe2)2]4Li(thf) with pyrrole and carbazole, respectively. Treatment of the pyrrolate/carbazolate complexes with CO2 seemed promising, but any reversibility could not be observed

Contrast Enhancement and Image Quality Influence Two- and Three-dimensional Echocardiographic Determination of Left Ventricular Volumes: Comparison With Magnetic Resonance Imaging

Purpose: To evaluate the effect of image quality and contrast enhancement (CE) on left ventricular (LV) volume determination by two- (2D) and three-dimensional (3D) echocardiography (2DE/3DE). Methods: We studied 32 post-myocardial infarction (MI) patients without (2DE/3DE) and with CE (CE2DE/CE3DE), in comparison with cardiac magnetic resonance imaging (CMR). Results: Two-dimensional echocardiography showed the largest negative bias versus CMR for diastolic and systolic volumes (−59, −28 mL, respectively) with lower biases for CE2DE (−37, −22 mL), 3DE (−31, −17 mL), and CE3DE (−17, −11 mL). Bias for ejection fraction (EF) ranged from −2.1% for 2DE to +1.4% for CE3DE. Agreement (intraclass correlation coefficient, ICC) for EF between CMR and 3DE (0.86 without and 0.85 with contrast) was better than for 2DE (0.73 without and 0.69 with contrast). The inter-/intra-observer coefficients of variation for EF varied from 16%/10% (2DE) to 6.9%/6.6% (CE2DE), and 8.3%/4.8% (3DE) to 6.7%/6.8% (CE3DE), respectively. The agreement (ICC) with CMR for EF measured by 2DE/3DE changed from 0.64/0.84 with poor image quality to 0.81/0.87 with moderate to good image quality. Conclusions: Three-dimensional echocardiography was more accurate than 2DE for estimating LV volumes, with less inter-/intra-observer variability in EF values. Contrast enhancement improved accuracy for both 2DE and 3DE and improved the inter-observer variability of EF estimates for 2DE and 3DE. Image quality had more impact on the agreement of EF values with CMR for 2DE than for 3DE. Our results emphasize the importance of using the same technique for longitudinal studies of LV EF and specially LV volumes

A Pseudoscorpion's Promising Pinch: The venom of Chelifer cancroides contains a rich source of novel compounds

With pedipalps modified for venom injection, some pseudoscorpions possess a unique venom delivery system, which evolved independently from those of other arachnids like scorpions and spiders. Up to now, only a few studies have been focused on pseudoscorpion venom, which either identified a small fraction of venom compounds, or were based on solely transcriptomic approaches. Only one study addressed the bioactivity of pseudoscorpion venom. Here, we expand existing knowledge about pseudoscorpion venom by providing a comprehensive proteomic and transcriptomic analysis of the venom of Chelifer cancroides. We identified the first putative genuine toxins in the venom of C. cancroides and we showed that a large fraction of the venom comprises novel compounds. In addition, we tested the activity of the venom at specific ion channels for the first time. These tests demonstrate that the venom of C. cancroides causes inhibition of a voltage-gated insect potassium channel (Shaker IR) and modulates the inactivation process of voltage-gated sodium channels from Varroa destructor. For one of the smallest venomous animals ever studied, today's toolkits enabled a comprehensive venom analysis. This is demonstrated by allocating our identified venom compounds to more than half of the prominent ion signals in MALDI-TOF mass spectra of venom samples. The present study is a starting point for understanding the complex composition and activity of pseudoscorpion venom and provides a potential rich source of bioactive compounds useable for basic research and industrial application.Copyright: © The Authors. This document is the authors' submitted version of the journal article. You are advised to consult the published version if you wish to cite from it

A Pseudoscorpion's Promising Pinch: The venom of Chelifer cancroides contains a rich source of novel compounds

With pedipalps modified for venom injection, some pseudoscorpions possess a unique venom delivery system, which evolved independently from those of other arachnids like scorpions and spiders. Up to now, only a few studies have been focused on pseudoscorpion venom, which either identified a small fraction of venom compounds, or were based on solely transcriptomic approaches. Only one study addressed the bioactivity of pseudoscorpion venom. Here, we expand existing knowledge about pseudoscorpion venom by providing a comprehensive proteomic and transcriptomic analysis of the venom of Chelifer cancroides. We identified the first putative genuine toxins in the venom of C. cancroides and we showed that a large fraction of the venom comprises novel compounds. In addition, we tested the activity of the venom at specific ion channels for the first time. These tests demonstrate that the venom of C. cancroides causes inhibition of a voltage-gated insect potassium channel (Shaker IR) and modulates the inactivation process of voltage-gated sodium channels from Varroa destructor. For one of the smallest venomous animals ever studied, today's toolkits enabled a comprehensive venom analysis. This is demonstrated by allocating our identified venom compounds to more than half of the prominent ion signals in MALDI-TOF mass spectra of venom samples. The present study is a starting point for understanding the complex composition and activity of pseudoscorpion venom and provides a potential rich source of bioactive compounds useable for basic research and industrial application

Stationary tissue background correction increases the precision of clinical evaluation of intra-cardiac shunts by cardiovascular magnetic resonance

We aimed to evaluate the clinical utility of stationary tissue background phase correction for affecting precision in the measurement of Qp/Qs by cardiovascular magnetic resonance (CMR). We enrolled consecutive patients (n = 91) referred for CMR at 1.5T without suspicion of cardiac shunt, and patients (n = 10) with verified cardiac shunts in this retrospective study. All patients underwent phase contrast flow quantification in the ascending aorta and pulmonary trunk. Flow was quantified using two semi-automatic software platforms (SyngoVia VA30, Vendor 1; Segment 2.0R4534, Vendor 2). Measurements were performed both uncorrected and corrected for linear (Vendor 1 and Vendor 2) or quadratic (Vendor 2) background phase. The proportion of patients outside the normal range of Qp/Qs was compared using the McNemar's test. Compared to uncorrected measurements, there were fewer patients with a Qp/Qs outside the normal range following linear correction using Vendor 1 (10% vs 18%, p < 0.001), and Vendor 2 (10% vs 18%, p < 0.001), and following quadratic correction using Vendor 2 (7% vs 18%, p < 0.001). No patient with known shunt was reclassified as normal following stationary background correction. Therefore, we conclude that stationary tissue background correction reduces the number of patients with a Qp/Qs ratio outside the normal range in a consecutive clinical population, while simultaneously not reclassifying any patient with known cardiac shunts as having a normal Qp/Qs. Stationary tissue background correction may be used in clinical patients to increase diagnostic precision

The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation

BAX and BAK are key apoptosis regulators that mediate the decisive step of mitochondrial outer membrane permeabilization. However, the mechanism by which they assemble the apoptotic pore remains obscure. Here, we report that BAX and BAK present distinct oligomerization properties, with BAK organizing into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers that continue to grow during apoptosis. As a result, BAX and BAK regulate each other as they co-assemble into the same apoptotic pores, which we visualize. The relative availability of BAX and BAK molecules thereby determines the growth rate of the apoptotic pore and the relative kinetics by which mitochondrial contents, most notably mtDNA, are released. This feature of BAX and BAK results in distinct activation kinetics of the cGAS/STING pathway with implications for mtDNA-mediated paracrine inflammatory signaling