Search

Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca2+-activated tension and Ca2+ sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca2+ sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.

Standard heart failure (HF) therapies have failed to improve cardiac function or survival in HF patients with right ventricular (RV) dysfunction suggesting a divergence in the molecular mechanisms of RV vs. left ventricular (LV) failure. Here we aimed to investigate interventricular differences in sarcomeric regulation and function in experimental myocardial infarction (MI)-induced HF with reduced LV ejection fraction (HFrEF). MI was induced by LAD ligation in Sprague–Dawley male rats. Sham-operated animals served as controls. Eight weeks after intervention, post-ischemic HFrEF and Sham animals were euthanized. Heart tissue samples were deep-frozen stored (n = 3–5 heart/group) for ELISA, kinase activity assays, passive stiffness and Ca2+-sensitivity measurements on isolated cardiomyocytes, phospho-specific Western blot, and PAGE of contractile proteins, as well as for collagen gene expressions. Markers of oxidative stress and inflammation showed interventricular differences in post-ischemic rats: TGF-β1, lipid peroxidation, and 3-nitrotyrosine levels were higher in the LV than RV, while hydrogen peroxide, VCAM-1, TNFα, and TGF-β1 were increased in both ventricles. In addition, nitric oxide (NO) level was significantly decreased, while FN-1 level was significantly increased only in the LV, but both were unchanged in RV. CaMKII activity showed an 81.6% increase in the LV, in contrast to a 38.6% decrease in the RV of HFrEF rats. Cardiomyocyte passive stiffness was higher in the HFrEF compared to the Sham group as evident from significantly steeper Fpassive vs. sarcomere length relationships. In vitro treatment with CaMKIIδ, however, restored cardiomyocyte passive stiffness only in the HFrEF RV, but had no effect in the HFrEF LV. PKG activity was lower in both ventricles in the HFrEF compared to the Sham group. In vitro PKG administration decreased HFrEF cardiomyocyte passive stiffness; however, the effect was more pronounced in the HFrEF LV than HFrEF RV. In line with this, we observed distinct changes of titin site-specific phosphorylation in the RV vs. LV of post-ischemic rats, which may explain divergent cardiomyocyte stiffness modulation observed. Finally, Ca2+-sensitivity of RV cardiomyocytes was unchanged, while LV cardiomyocytes showed increased Ca2+-sensitivity in the HFrEF group. This could be explained by decreased Ser-282 phosphorylation of cMyBP-C by 44.5% in the RV, but without any alteration in the LV, while Ser-23/24 phosphorylation of cTnI was decreased in both ventricles in the HFrEF vs. the Sham group. Our data pointed to distinct signaling pathways-mediated phosphorylations of sarcomeric proteins for the RV and LV of the post-ischemic failing rat heart. These results implicate divergent responses for oxidative stress and open a new avenue in targeting the RV independently of the LV.

Abstract In response to ER stress, activating transcription factor 6 (ATF6) traffics from ER to Golgi apparatus where it is activated by cleavage before being translocated as transcription factor to the cell nucleus. In this work we describe ATF6α as a newly target of the aspirin metabolite sodium salicylate (NaSal). NaSal treatment of cells induces increases in ATF6α mRNA and protein levels, but these events are not accompanied by ATF6 activation. Conversely, NaSal inhibited ATF6 transactivating activity elicited by various ER stress-inducing stimuli in different cell types. This resulted in reduced expression of a subset of ATF6α target genes. Mechanistically, exposure of cells to NaSal results in ATF6α trapping at the Golgi apparatus, thus preventing nuclear translocation. This study provides evidence that NaSal compound restrains the activity of ATF6α, thereby preventing activation of a specific subset of ER-stress responsive genes implicated in different cellular responses.

Improved expansion of stents using high-pressure implantation technique with subsequent antiplatelet therapy has improved patient outcome regarding the incidence of subacute stent thrombosis, bleeding complications and restenosis. Whether high-pressure implantation per se guarantees adequate stent expansion remains unclear. The aim of the study was to determine (1) stent expansion after high-pressure implantation technique and (2) whether stent expansion influences rate of target lesion revascularization within 6 months of follow-up. One hundred Palmaz-Schatz stents were implanted in 98 lesions (91 native vessels, 7 graft vessels) of 94 patients using high-pressure implantation technique (balloon pressure 12-20 atm). Stent expansion was investigated using intravascular ultrasound imaging (IVUS). Clinical follow-up of the patients was performed for 6 months. After implantation, stent/mean reference ratio was 0.81 +/- 0.16. Noncompliant balloons used for implantation were chosen by angiographic criteria. Mean balloon/reference ratio was 1.08 +/- 0.22; therefore balloons were not undersized. Additional balloon dilataion using higher pressures and/or larger balloons based on IVUS criteria and subsequent IVUS measurements was performed in 52 patients (55%); in these patients, stent expansion improved from 79 +/- 16 to 91 +/- 15% (mean +/- SD) of average reference areas (p < 0.002). Within the 6 months' clinical follow-up, target lesion revascularization was performed in 19 patients (20%). The only prognostic factors for the development of in-stent restenosis requiring target lesion revascularization were the vessel size (p < 0.05) and the extent of plaque distal to the stents (p < 0.05). Implantation of Palmaz-Schatz stents using high-pressure technique does not guarantee adequate stent expansion. Additional dilatation with higher pressures and/or larger balloons improves stent expansion. The size of the stented vessel and the extent of plaque at the distal stent end (residual outflow stenosis) but not the degree of stent expansion were predictors for target lesion revascularization within 6 months' follow-up.

Aim: To compare clinical outcomes among patients with heart failure and reduced ejection fraction (HFrEF) according to body mass index (BMI) after initiating treatment with an angiotensin‐receptor neprilysin inhibitor (ARNI). Methods: We gathered data from 2016 to 2020 at the University Medical Center Mannheim; 208 consecutive patients were divided into two groups according to BMI (< 30 kg/m2; n = 116, ≥ 30 kg/m2; n = 92). Clinical outcomes, including mortality rate, all‐cause hospitalizations and congestion, were systematically analysed. Results: At the 12‐month follow‐up, the mortality rate was similar in both groups (7.9% in BMI < 30 kg/m2 vs. 5.6% in BMI ≥ 30 kg/m2; P =.76). All‐cause hospitalization before ARNI treatment was comparable in both groups (63.8% in BMI < 30 kg/m2 vs. 57.6% in BMI ≥ 30 kg/m2; P =.69). After ARNI treatment, the hospitalization rate was also comparable in both groups at the 12‐month follow‐up (52.2% in BMI < 30 kg/m2 vs. 53.7% in BMI ≥ 30 kg/m2; P =.73). Obese patients experienced more congestion compared with non‐obese patients at follow‐up, without statistical significance (6.8% in BMI < 30 kg/m2 vs. 15.5% in BMI ≥ 30 kg/m2; P =.11). Median left ventricular ejection fraction (LVEF) improved in both groups, but significantly more in non‐obese compared with obese patients at the 12‐month follow‐up (from 26% [3%‐45%] [min.‐max.] vs. 29% [10%‐45%] [min.‐max.] [P =.56] to 35.5% [15%‐59%] [min.‐max.] vs. 30% [13%‐50%] [min.‐max.] [P =.03], respectively). The incidence of atrial fibrillation (AF), non‐sustained (ns) and sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) was less in non‐obese than in obese patients after initiation of sacubitril/valsartan at the 12‐month follow‐up (AF: 43.5% vs. 53.7%; P =.20; nsVT: 9.8% vs. 28.4%; P =.01; VT: 14.1% vs. 17.9%; P =.52; VF: 7.6% vs. 13.4%; P =.23). Conclusions: The incidence of congestion in obese patients was higher compared with non‐obese patients. LVEF improved significantly more in non‐obese compared with obese HFrEF patients. Furthermore, AF and the ventricular tachyarrhythmia rate were revealed more in obesity compared with those without obesity at the 12‐month follow‐up. [ABSTRACT FROM AUTHOR]

Copyright of Eccos - Revista Científica is the property of Eccos - Revista Científica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)