Search

BackgroundHeart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized.MethodWe investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts.ResultsIn contrast to the post-trans-aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-trans-aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress.ConclusionsThese findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

Background Branched-chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a small-molecule inhibitor of branched-chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle-treated mice, whereas the BT2-treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure.

Nitrogen–slick water composite fracturing is a novel, recently developed fracturing technology. Due to its impact on increasing permeability, this technology outperforms hydraulic fracturing. This study adopted the horizontal well XJ-1L, Xinjing coal mine, Qinshui Basin, China, as a study area to statistically analyze the fracture properties, stress drop, and b-value distribution characteristics of 1217 effective micro-seismic events generated during nitrogen–water composite fracturing. The results show that: (1) gradually reducing the proportion of gas in fracturing fluid reduced the proportion of tensile fractures at a ratio of between 15.6% and 0.8%, whereas the proportion of strike-slip fractures gradually increased by between 1.6% and 15.2%; (2) the stress drop and b-values in the nitrogen fracturing (NF) stage, representative of stress disturbance, exceeded those in the hydraulic fracturing (HF) stage, consistent with greater numbers of tensile fractures formed in the NF stage; (3) the greater number of tensile fractures and their increasing permeability could be explained based on the influences of gas compressibility and pore pressure on coal fractures. This study provides a theoretical and practical basis for optimizing the exploitation of low-permeability coal reservoirs. [ABSTRACT FROM AUTHOR]

Titanium dioxide ( TiO 2 ) is a commonly employed electron transport layer in perovskite solar cells (PSCs) due to its exceptional attributes such as high mobility, a wide bandgap and remarkable stability against moisture and high temperatures. This holds particularly true for inorganic PSCs. Nevertheless, the substantial hysteresis and elevated trap defect levels following annealing present challenges to enhance the efficiency of the PSCs. Herein, we proposed a chemical bath deposition (CBD) method to fabricate the TiO 2 layer, serving as the electron transport layer in CsPbBr 3 solar cells. This method is coupled with KCl, which supplies an ample quantity of K ions capable of diffusing into the CsPbBr 3 perovskite film during the annealing process. The inclusion of K ions significantly diminishes the solar cell hysteresis and enhances the crystalline quality of the perovskite material, thereby enhancing the performance of CsPbBr 3 solar cells. By implementing the TiO 2 and KCl treatments, we achieved an impressive efficiency of 9.49%. Furthermore, the device also exhibited excellent stability in air for 30 days. We introduced KCl as a buffer layer to improve the quality of the TiO 2 films, which was used as the electron transport layer in CsPbBr 3 perovskite solar cells. This strategic addition of K ions serves not only to alleviate hysteresis in the perovskite solar cells, but also to enhance the crystallinity of the perovskite material. These cells have achieved an impressive champion efficiency of 9.49%, while maintaining their performance for over 30 days in ambient conditions. [ABSTRACT FROM AUTHOR]