Comparison of two ellipsoidal models for the estimation of left ventricular end-systolic stress in patients with significant coronary artery disease.

Background: The shape of the left ventricle (LV) is an important index to explore cardiac pathophysiology. A comparison was provided to estimate circumferential, longitudinal, and radial wall stress in LV based on the thick-walled ellipsoidal models of Mirsky and Ghista-Sandler for discriminating significant coronary artery disease (CAD) patients from no CAD patients. Materials and Methods: According to the angiography findings, 82 patients with CAD were divided into two groups: 25 patients without significant CAD and 57 patients with significant CAD of single vessel and multivessel. An ellipsoidal LV geometry was used to calculate end-systolic passive stress as the mechanical behavior of LV. Echocardiographic views-based measurements of LV diameters used to estimate the end-systolic wall stress. Results: Circumferential wall stress between the control group and significant CAD groups was significantly elevated for the Ghista model (P = 0.008); also, radial and longitudinal stress of the multi-vessel CAD group was significantly higher than the control group (P = 0.01 and P = 0.005, respectively). All stress parameters of the multi-vessel CAD group were statistically significant compared to the control group for the Mirsky model. Receiver operating characteristics curve analysis was shown the circumferential stress of multi-vessel CAD with an area under the curve (AUC) of 0.736 for the Ghista model and an AUC of 0.742 for the Mirsky model. Conclusion: These results indicated that Ghista and Mirsky model estimates of circumferential passive stress were the potential biomechanical markers to predict patients with multi-vessel CAD. It could be a noninvasive and helpful tool to quantify the contractility of LV.

Estimation of the segmental left ventricular physical and mechanical parameters using echocardiographic imaging for stent candidate patients.

PURPOSE: Left ventricular (LV) dysfunction can be assessed by quantifying LV structure. In this study, physical parameters were extracted, including the systolic strain, wall stress, and elastic modulus of LV to diagnose stent candidate patients from the control group. METHODS: Based on angiography results, 88 patients with coronary artery disease (CAD) were divided into 64 patients candidates for PCI (percutaneous coronary intervention) and 24 patients in the control group. With the thick-walled ellipsoidal model, the passive wall stresses at end-systole and end-diastole were estimated. Regional circumferential strain and regional longitudinal strain were obtained by speckle tracking technique. RESULTS: The inferoseptal circumferential wall stress in end-systole was statistically significant for the PCI group compared to the control group (p = .026). Anterior and inferoseptal circumferential strain for the PCI group (-17.25 ± 4.22 and -18.21 ± 4.04%) compared to the control group (-21.71 ± 4.74 and 20.58 ± 3.04%) were statistically significant, respectively (p = .000 and p = .011). Anterior and inferoseptal circumferential elastic modulus were statistically significant (p = .000 and p = .005). The receiver operator characteristic (ROC) curve analysis revealed that anterior and inferoseptal circumferential elastic modulus had the highest area under the curve with 76.6% sensitivity, 83.3% specificity for anterior circumferential, 68.8% sensitivity, and 70.8% specificity for inferoseptal circumferential, for the diagnosis of stent candidate patients. CONCLUSIONS: Regional elastic modulus parameter is suggested as a noninvasive and quantitative method for measuring LV function. Strain and stress parameters using the STE method and geometrical model can be helpful for diagnostic stent candidate patients.

Regulation of mitochondrial proteostasis by the proton gradient.

Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multiproteomic approach to demonstrate the regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+ /H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.

AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.

The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.

The status of the terminal regions of α-synuclein in different forms of aggregates during fibrillization.

The α-synuclein (αSN) amyloid fibrillization process is known to be a crucial phenomenon associated with neuronal loss in various neurodegenerative diseases, most famously Parkinson's disease. The process involves different aggregated species and ultimately leads to formation of ß-sheet rich fibrillar structures. Despite the essential role of αSN aggregation in the pathoetiology of various neurological disorders, the characteristics of various assemblies are not fully understood. Here, we established a fluorescence-based model for studying the end-parts of αSN to decipher the structural aspects of aggregates during the fibrillization. Our model proved highly sensitive to the events at the early stage of the fibrillization process, which are hardly detectable with routine techniques. Combining fluorescent and PAGE analysis, we found different oligomeric aggregates in the nucleation phase of fibrillization with different sensitivity to SDS and different structures based on αSN termini. Moreover, we found that these oligomers are highly dynamic: after reaching peak levels during fibrillization, they decline and eventually disappear, suggesting their transformation into other αSN aggregated species. These findings shed light on the structural features of various αSN aggregates and their dynamics in synucleinopathies.