Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activation and oxidative stress via Nrf2 regulation under pathological ER stress. We report that sustained ER stress and Pak2 deletion in cardiomyocytes enhance Nrf2 expression. Conversely, AAV9 mediated Pak2 delivery in the heart leads to a significant decrease in Nrf2 levels. Pak2 overexpression enhances the XBP1-Hrd1 UPR axis and ameliorates tunicamycin induced cardiac apoptosis and dysfunction in mice. We found that Pak2 deletion and altered proteostasis render Nrf2 detrimental by switching from its antioxidant role to renin-angiotensin aldosterone system (RAAS) gene regulator. Mechanistically, Pak2 mediated Hrd1 expression targets Nrf2 for ubiquitination and degradation thus preventing its aberrant activation. Moreover, we find a significant increase in Nrf2 with a decrease in Pak2 in human myocardium of dilated heart disease. Using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we find that Pak2 is able to ameliorate Nrf2 induced RAAS activation under ER stress. These findings demonstrate that Pak2 is a novel Nrf2 regulator in the stressed heart. Activation of XBP1-Hrd1 is attributed to prevent ER stress-induced Nrf2 RAAS component upregulation. This mechanism explains the functional dichotomy of Nrf2 in the stressed heart. Thus, Pak2 regulation of Nrf2 homeostasis may present as a potential therapeutic route to alleviate detrimental ER stress and heart failure.

Background: The efficacy and safety of transcatheter aortic-valve replacement (TAVR) vs. surgical aortic valve replacement (SAVR) for low- to intermediate-surgical risk patients remains uninvestigated. Objectives: We aimed to investigate the efficacy and safety of transcatheter aortic-valve replacement (TAVR) vs. surgical aortic valve replacement (SAVR) for low-intermediate surgical risk patients. Methods: PubMed, Cochrane Library, and Embase databases were searched to identify potential references. Only randomized controlled trials (RCTs) or observational studies using propensity score matching were eligible for screening. The primary endpoint was all-cause death. The secondary outcomes were bleeding, stroke, myocardial infarction (MI), and other complications of aortic-valve replacement. In addition, we performed subgroup analysis based on surgical risk and study type. Results: Eight RCTs and 13 observational studies covering 12,467 patients were included in the current meta-analysis. For patients with low-surgical risk, compared with SAVR, TAVR was found to be associated with a lower mortality at a follow-up period of 1 year (odds ratio, OR: 0.66, 95% CI: [0.46, 0.96], P = 0.03). This benefit disappeared when the follow-up was extended to 2 years (OR: 0.89, 95% CI: [0.61, 1.30], P = 0.56). For patients with intermediate-surgical risk, TAVR showed to have similar mortality with SAVR regardless of follow-up period (30-day, 1-year, or 2-year). TAVR could reduce the incidence of bleeding, AF, and AKI. For complications, such as MI and stroke, TAVR exhibited to have similar safety with SAVR. However, TAVR was found to be associated with a higher incidence of reintervention, major vascular complication, paravalvular leak, and PPI. Conclusion: For patients with a low-to-intermediate surgical risk, TAVR has at least an equivalent clinical effect to SAVR for 2 years after the procedure.

Rheumatic heart disease (RHD) remains a severe public health problem in developing countries. Atrial fibrillation (AF) is a medical complication of RHD. Although the understanding of disease pathogenesis has advanced in recent years, the key questions need to be addressed. Transfer RNA-derived small RNAs (tsRNAs) are a novel type of short non-coding RNAs with potential regulatory functions in various physiological and pathological processes. The present study used tsRNAs sequencing to investigate the relationship between RHD and atrial fibrillation (AF). Three paired cardiac papillary muscles were taken from six rheumatic RHD patients with AF (3 cases) or without AF (3 cases) from January 2016 to January 2017 in Xiangya Hospital, Central South University. A total of 219 precisely matched tsRNAs were identified, and 77 tsRNAs (fold change > 2.0 and P < 0.05) were differently changed. Three tsRNAs (AS-tDR-001269, AS-tDR-001363, AS-tDR-006049) were randomly selected and confirmed by qRT-PCR. The results of qRT-PCR were consistent with tsRNAs sequencing, suggesting the tsRNAs sequencing was reliable. Subsequently, we predicted the target mRNAs of the three tsRNAs. Moreover, we verified the functions of tsRNAs targeting mRNAs in vitro. Finally, bioinformatics analysis indicated that the target genes were abundant in regulation of transcription, DNA binding, intracellular. Most of the genes were predicted to interplay with cytokine-cytokine receptor by KEGG analysis. Our findings uncover the pathological process of AF in RHD through tsRNAs sequencing. This research provides a new perspective for future research on elucidating the mechanism of AF in RHD and offers potential new candidates for the treatment and diagnosis.

Background: The association between coronary physiology and immunoinflammation has not been investigated. We performed a retrospective study using quantitative flow ratio (QFR) to evaluate the interaction between immunoinflammatory biomarkers and coronary physiology. Methods: A total of 172 patients with CAD who underwent coronary arteriography (CAG) and QFR were continuously enrolled from May 2020 to February 2021. As a quantitative indicator of coronary physiology, QFR can reflect the functional severity of coronary artery stenosis. The target vessel measured by QFR was defined as that with the most severe lesions. Significant coronary anatomical stenosis was defined as 70% stenosis in the target vessel. Results: Compared with the QFR > 0.8 group, interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were increased and CD3+ and CD4+ T lymphocyte counts were decreased in the QFR ≤ 0.8 group. In addition, patients with DS ≤ 70% had higher IL-6, IL-10, and TNF-α levels and decreased CD3+ and CD4+ T lymphocyte counts than those with DS > 70%. Logistic regression analysis indicated IL-6 to be an independent predictor of significant coronary functional and anatomic stenosis (odds ratio, 1.125; 95% CI, 1.059-1.196; P < 0.001). Receiver operating characteristic (ROC) analyses showed that IL-6 > 6.36 was predictive of QFR ≤ 0.8 of the target vessel. The combination of IL-6, IL-10 and CD4 improved the value for predicting QFR ≤ 0.8 of the target vessel (AUC, 0.737; 95% CI, 0.661-0.810). Conclusion: Among immunoinflammatory biomarkers, IL-6 was independently associated with a higher risk of QFR ≤ 0.8 of the target vessel. The combination of immunoinflammatory biomarkers was highly predictive of significant coronary functional and anatomic stenosis.

Background: Transcatheter aortic valve implantation (TAVI) has achieved satisfactory outcomes in the selected patients with bicuspid aortic valve (BAV), predominately type 1 BAV (~90%). However, there are few reports about the safety and efficacy of TAVI in type 0 BAV. Therefore, in the current study, we aimed to compare procedural and 30-day outcomes after TAVI between type 0 and type 1 BAV. Methods: Studies comparing the outcomes of TAVI in Sievers type 0 vs. type 1 BAV were retrieved from PubMed, EMBASE, Cochrane Library, and Web of Science from inception to May 2021. The data were extracted regarding the study characteristics and outcomes. The odds ratios (ORs) with 95% CIs were pooled for procedural and 30-day outcomes. Results: Six observational studies were included with determined type 0 BAV in 226 patients and type 1 BAV in 902 patients. The patients with type 0 BAV were slightly younger, had larger supra-annular structure, and more frequently implanted self-expanding prosthesis compared with type 1 BAV. In the pooled analyses, the patients with type 0 BAV had a similar incidence of procedural death (OR = 2.6, 95% CI 0.7-10.3), device success (OR = 0.6; 95% CI 0.3-1.3), and ≥ mild (OR = 0.8; 95% CI 0.4-1.6) or moderate (OR = 0.9, 95% CI 0.4-1.8) paravalvular leak, whereas significantly higher mean aortic gradient (mean difference = 1.4 mmHg, 95% CI 0.03-2.7) and increased coronary compromise risk (OR = 7.2; 95% CI 1.5-34.9), compared with type 1 BAV. Meanwhile, the incidence of death (OR = 1.2; 95% CI 0.5-3.1), stroke (OR = 0.5; 95% CI 0.1-2.4), and new pacemaker (OR = 0.6; 95% CI 0.2-2.2) at 30 days were not significantly different between the BAV morphologies (p > 0.05). The treatment effect heterogeneity across the studies for the above outcomes were low. Conclusions: The patients with type 0 BAV appear to have similar short-term outcomes after TAVI compared with type 1 BAV. Whereas, TAVI for type 0 BAV aortic stenosis might lead to an elevated coronary obstruction risk and suboptimal aortic valvular hemodynamics.

Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.