Coronary slow flow and angiography-derived index of microcirculatory resistance as prognostic predictors in patients with angina and normal coronary arteries: a retrospective cohort study.

BACKGROUND: This study aims to investigate prognostic implications of coronary slow flow (CSF) and angiography-derived index of microcirculatory resistance (caIMR) in patients with angina and normal coronary arteries. METHODS: A total of 582 patients were enrolled with angiographically normal coronary arteries. caIMR was calculated using a commercial software. Patients were followed up for a median of 45 months. The primary endpoint was defined as major adverse cardiovascular events (MACEs) comprising death, myocardial infarction and readmission for angina or heart failure. RESULTS: CSF was diagnosed when TIMI grade 2 flow presented in at least one coronary artery. Multivariate analysis indicated TIMI-flow-based determination of CSF was not significantly associated with MACEs [hazard ratio (HR): 2.14; 95% confidence interval (CI): 0.87-5.31; p = 0.099), while caIMR >42 (HR: 2.53; 95% CI: 1.02-6.32; p = 0.047) were independent predictors of MACEs. Incorporation of caIMR improved the area under the curve from 0.587 to 0.642. CONCLUSIONS: caIMR was an independent prognostic factor of long-term cardiovascular events in patients with CSF. Evaluation of caIMR improved the risk stratification of patients with angiographically-normal coronary arteries.

Real-world performance of indobufen versus aspirin after percutaneous coronary intervention: insights from the ASPIRATION registry.

BACKGROUND: Indobufen is widely used in patients with aspirin intolerance in East Asia. The OPTION trial launched by our cardiac center examined the performance of indobufen based dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, the vast majority of patients with acute coronary syndrome (ACS) and aspirin intolerance were excluded. We aimed to explore this question in a real-world population. METHODS: Patients enrolled in the ASPIRATION registry were grouped according to the DAPT strategy that they received after PCI. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. Propensity score matching (PSM) was adopted for confounder adjustment. RESULTS: A total of 7135 patients were reviewed. After one-year follow-up, the indobufen group was associated with the same risk of MACCE versus the aspirin group after PSM (6.5% vs. 6.5%, hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.65 to 1.52, P = 0.978). However, BARC type 2, 3, or 5 bleeding was significantly reduced (3.0% vs. 11.9%, HR = 0.24, 95% CI = 0.15 to 0.40, P < 0.001). These results were generally consistent across different subgroups including aspirin intolerance, except that indobufen appeared to increase the risk of MACCE in patients with ACS. CONCLUSIONS: Indobufen shared the same risk of MACCE but a lower risk of bleeding after PCI versus aspirin from a real-world perspective. Due to the observational nature of the current analysis, future studies are still warranted to further evaluate the efficacy of indobufen based DAPT, especially in patients with ACS. TRIAL REGISTRATION: Chinese Clinical Trial Register ( https://www.chictr.org.cn ); Number: ChiCTR2300067274.

3D Printing of Flexible BaTiO3/Polydimethylsiloxane Piezocomposite with Aligned Particles for Enhanced Energy Harvesting.

With the rapid development of human-machine interactions and artificial intelligence, the demand for wearable electronic devices is increasing uncontrollably all over the world; however, an unsustainable power supply for such sensors continues to restrict their applications. In the present work, piezoelectric barium titanate (BaTiO3) ceramic powder with excellent properties was prepared from milled precursors through a solid-state reaction. To fabricate a flexible device, the as-prepared BaTiO3 powder was mixed with polydimethylsiloxane (PDMS) polymer. The BaTiO3/PDMS ink with excellent rheological properties was extruded smoothly by direct ink writing technology (DIW). BaTiO3 particles were aligned due to the shear stress effect during the printing process. Subsequently, the as-printed composite was assembled into a sandwich-type device for effective energy harvesting. It was observed that the maximum output voltage and current of this device reached 68 V and 720 nA, respectively, for a BaTiO3 content of 6 vol %. Therefore, the material extrusion-based three-dimensional (3D) printing technique can be used to prepare flexible piezoelectric composites for efficient energy harvesting.

Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway.

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction.

Fabrication of translucent graded dental crown using zirconia-yttrium multi-slurry tape casting 3D printer.

This paper aims to fabricate functionally graded dental crown using a multi-slurry tape casting additive manufacturing technology. The different luminescence of the dental crown was obtained with different composition of zirconia and yttria. Zirconia with tunable mechanical properties and translucency are obtained by adding 3, 3.5, 4, 4.5, and 5 mol% of yttrium oxide to zirconia powder. After obtaining the printable slurry with maximum solid loading, the green bodies are prepared using the in-house built high-speed multi-ceramic tape casting technology. They are later sintered with two-stage sintering method. After the successful fabrication, the mechanical properties and translucency of the specimens were evaluated with Vickers hardness, three-point bending and translucency parameter tests. Finally, an FGM tooth crown with five photocurable slurries is proposed to demonstrate the translucent gradient effect of sintered part. The solid loading of 80% zirconia and 20% resin delivered samples without any surface cracks. The shrinkage ratio analysis showed that the sintered sample dimension was reduced by 20%, 20%, and 23% along X, Y, and Z directions. The samples fabricated with 3% yttrium oxide to zirconia delivered excellent hardness (1687 HV) and flexural strength (650.6 MPa). However, the relative luminescence increased with increasing the yttrium oxide for 3-5 mol%. With the optimized process parameters, the proposed dental crown is fabricated and analyzed for their shrinkage ratio, mechanical, and translucency properties. The study proposes the potential of fabricating customized dental crown with gradient translucent appearance.

Pinacidil ameliorates cardiac microvascular ischemia-reperfusion injury by inhibiting chaperone-mediated autophagy of calreticulin.

Calcium overload is the key trigger in cardiac microvascular ischemia-reperfusion (I/R) injury, and calreticulin (CRT) is a calcium buffering protein located in the endoplasmic reticulum (ER). Additionally, the role of pinacidil, an antihypertensive drug, in protecting cardiac microcirculation against I/R injury has not been investigated. Hence, this study aimed to explore the benefits of pinacidil on cardiac microvascular I/R injury with a focus on endothelial calcium homeostasis and CRT signaling. Cardiac vascular perfusion and no-reflow area were assessed using FITC-lectin perfusion assay and Thioflavin-S staining. Endothelial calcium homeostasis, CRT-IP3Rs-MCU signaling expression, and apoptosis were assessed by real-time calcium signal reporter GCaMP8, western blotting, and fluorescence staining. Drug affinity-responsive target stability (DARTS) assay was adopted to detect proteins that directly bind to pinacidil. The present study found pinacidil treatment improved capillary density and perfusion, reduced no-reflow and infraction areas, and improved cardiac function and hemodynamics after I/R injury. These benefits were attributed to the ability of pinacidil to alleviate calcium overload and mitochondria-dependent apoptosis in cardiac microvascular endothelial cells (CMECs). Moreover, the DARTS assay showed that pinacidil directly binds to HSP90, through which it inhibits chaperone-mediated autophagy (CMA) degradation of CRT. CRT overexpression inhibited IP3Rs and MCU expression, reduced mitochondrial calcium inflow and mitochondrial injury, and suppressed endothelial apoptosis. Importantly, endothelial-specific overexpression of CRT shared similar benefits with pinacidil on cardiovascular protection against I/R injury. In conclusion, our data indicate that pinacidil attenuated microvascular I/R injury potentially through improving CRT degradation and endothelial calcium overload.

Chronologic evolution and prognostic implications of impaired coronary flow after chronic total occlusion angioplasty.

Background: Although vessels have the potential to recover following successful recanalization of chronic total occlusion (CTO), evidence is limited about the clinical significance of slow flow (SF) phenomenon after recanalization. The aim of this study was to evaluate the determinants, development and prognostic impact of SF after percutaneous coronary intervention (PCI) for CTO. Methods: This was a retrospective cohort study, 500 patients were consecutively enrolled undergoing CTO PCI and consecutive follow-up angiography in Zhongshan Hospital, Fudan University, between 2015 and 2020. Coronary flow was assessed by corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (CTFC). The association between SF and outcomes of CTO PCI was evaluated by analyzing the clinical, angiographic, and procedural characteristics. Results: SF was observed in 29 (5.8%) patients immediately after CTO PCI. Prior myocardial infraction, right coronary artery (RCA) revascularization and lack of bilateral collaterals were independent predictors of SF. SF was associated with increased risks of periprocedural myocardial infarction (PMI) [adjusted odds ratio (adOR): 4.12; 95% confidence interval (CI): 1.68-10.07; P=0.002] and target lesion restenosis (adOR: 2.50; 95% CI: 1.10-5.72; P=0.030). In patients with baseline left ventricular ejection fraction (LVEF) ≤60%, systolic improvement was compromised in the SF group (LVEF: 55.4%±9.6% in follow up vs. 52.1%±9.4% before CTO PCI, P=0.147) compared with that of the normal group (LVEF: 55.7%±9.3% vs. 51.6%±8.5%, P<0.001). Conclusions: SF has a significant influence on the prognosis of patients undergoing CTO PCI. Achieving normal coronary flow is essential in CTO revascularization.

Integrative Proteomic Analysis Reveals the Cytoskeleton Regulation and Mitophagy Difference Between Ischemic Cardiomyopathy and Dilated Cardiomyopathy.

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are the two primary etiologies of end-stage heart failure. However, there remains a dearth of comprehensive understanding the global perspective and the dynamics of the proteome and phosphoproteome in ICM and DCM, which hinders the profound comprehension of pivotal biological characteristics as well as differences in signal transduction activation mechanisms between these two major types of heart failure. We conducted high-throughput quantification proteomics and phosphoproteomics analysis of clinical heart tissues with ICM or DCM, which provided us the system-wide molecular insights into pathogenesis of clinical heart failure in both ICM and DCM. Both protein and phosphorylation expression levels exhibit distinct separation between heart failure and normal control heart tissues, highlighting the prominent characteristics of ICM and DCM. By integrating with omics results, Western blots, phosphosite-specific mutation, chemical intervention, and immunofluorescence validation, we found a significant activation of the PRKACA-GSK3ß signaling pathway in ICM. This signaling pathway influenced remolding of the microtubule network and regulated the critical actin filaments in cardiac construction. Additionally, DCM exhibited significantly elevated mitochondria energy supply injury compared to ICM, which induced the ROCK1-vimentin signaling pathway activation and promoted mitophagy. Our study not only delineated the major distinguishing features between ICM and DCM but also revealed the crucial discrepancy in the mechanisms between ICM and DCM. This study facilitates a more profound comprehension of pathophysiologic heterogeneity between ICM and DCM and provides a novel perspective to assist in the discovery of potential therapeutic targets for different types of heart failure.

Association between NLRP3 inflammasome and periprocedural myocardial injury following elective PCI.

Background: Periprocedural myocardial injury (PMI) is a common complication of percutaneous coronary intervention (PCI) associated with poor prognosis. Inflammation has been demonstrated to exert a crucial role in PMI. However, how the inflammation is initiated or sustained in PMI remains elusive. Methods: RNA-seq in peripheral blood mononuclear cells (PBMCs) from 3 Non-PMI and 6 PMI patients was performed with subsequent bioinformatics analysis. RNA-seq results were verified in a patient cohort. We also established the coronary microembolization (CME) mice model to mimic PMI. The activity of caspase-1 in PBMCs was detected by flow cytometry. The levels of interleukin (IL)-1ß, IL-18 and cardiac troponin in plasma were measured by enzyme-linked immunosorbent assay. Results: We identified a total of 901 differentially expressed genes (DEGs) between Non-PMI and PMI patients. These DEGs participated in several inflammation-related processes. NOD-like receptor signaling pathway was significantly enriched in pathway analysis. All the key genes composed in the NLRP3 inflammasome, including NLRP3, PYCARD, CASP1 and IL1B, were upregulated in PMI patients. The activation of NLRP3 inflammasome was then verified by increased activity of caspase-1 in PBMCs, and elevated levels of IL-1ß and IL-18 in plasma in PMI patients. Spearman analysis confirmed tight correlations between caspase-1 activity, IL-1ß, IL-18 levels and troponin T level. In addition, caspase-1 activity, IL-1ß and IL-18 levels were also enhanced in CME mice. Conclusions: We discovered that NLRP3 inflammasome was involved in PMI, thus providing evidence supporting the therapeutic value of NLRP3 inflammasome-targeted strategies in PMI.

Are baseline conditions of coronary arteries sufficient for calculating angio-based index of microcirculatory resistance and fractional flow reserve?

Background: Angio-based index of microcirculatory resistance (IMR) and fractional flow reserve (FFR) have been developed, however, the differences between baseline and hyperemic data and their effects on their computation have not yet been discussed. This study aimed to compare the diagnostic performance of a novel method for calculating IMR and FFR from coronary angiography under baseline and hyperemic conditions. Methods: We performed a retrospective study to investigate the diagnostic performance of angiography-derived IMR (AccuIMR) and FFR (AccuFFRangio) computed from the hyperemic condition (AccuIMRhyp, AccuFFRangiohyp) and baseline condition (AccuIMRbase, AccuFFRangiobase) in 101 consecutive patients with chronic coronary syndrome (CCS) who underwent measurements of IMR and FFR at a single center, using wire-based IMR and FFR as the reference standard. Results: AccuIMRhyp showed much better correlation with IMR than AccuIMRbase (r=0.77 vs. 0.47, P<0.001). The diagnostic accuracy and area under the curve (AUC) for identifying significant microvascular dysfunction was higher for AccuIMRhyp than AccuIMRbase [92.1% (95% CI: 85.0-96.5%) vs. 83.2% (95% CI: 74.4-89.9%), P=0.012; 0.942 (95% CI: 0.877-0.979) vs. 0.815 (95% CI: 0.726-0.886), P=0.003]. The computed AccuFFRangio showed good correlations with FFR and good diagnostic performance under both hyperemic and baseline conditions [r=0.68 vs. 0.68, P>0.99; diagnostic accuracy =95.9% (95% CI: 89.8-98.9%) vs. 94.9% (95% CI: 88.4-98.3%), P=0.728; AUC =0.989 (95% CI: 0.942-1.000) vs. 0.973 (95% CI: 0.919-0.995), P=0.381]. The net reclassification index (NRI) demonstrated that hyperemic group had improved reclassification ability compared to the baseline group in identification of IMR >25 (NRI =0.20, P<0.001) and FFR ≤0.8 (NRI =0.11, P<0.001). Conclusions: By comparing the calculated angio-derived IMR and FFR under the baseline and hyperemic conditions, this study demonstrates that AccuIMR calculation is more accurate using the hyperemic condition, while AccuFFRangio calculation is accurate under both conditions.

Prognostic value and clinical usefulness of PIANO score in patients undergoing primary percutaneous coronary intervention.

BACKGROUND: In our previous study, the PIANO score was constructed to predict the occurrence of no-reflow phenomenon in patients undergoing primary percutaneous coronary intervention (PCI). In the current analysis, we sought to evaluate the prognostic value and clinical usefulness of the PIANO score in this population. METHODS: Patients with acute myocardial infarction (AMI) undergoing primary PCI were consecutively enrolled and followed up in this register. The endpoint of interest was all-cause mortality at 2 years after the procedure. The clinical benefits of thrombus aspiration (TA) during primary PCI in certain subgroups were also evaluated as exploratory analyses. RESULTS: A total of 2100 patients were identified, and 54.3% had high (≥8) PIANO score. After 2-year follow-up, patients with high PIANO score had higher risk of all-cause mortality after adjustment for propensity score (6.7% vs. 3.1%, adjusted hazard ratio = 2.11 [1.21-3.68], p = 0.008), especially in the first month (adjusted hazard ratio = 2.33 [1.17-4.65], p = 0.017). Restricted cubic spline analysis indicated the linear association between the PIANO score and 2-year all-cause mortality (nonlinear p = 0.556). Further analysis demonstrated that TA did not reduce all-cause mortality in the overall patients, as well as in those with visible thrombus, high thrombus burden, or occlusive lesions. However, the PIANO score defined "high-risk" (PIANO score ≥ 8) patients could benefit from it. CONCLUSIONS: The PIANO score had potential prognostic value in patients with AMI undergoing primary PCI. It might also be helpful for identifying patients who would benefit from TA. These observations require further confirmation in future studies.

Efficiency of the Guide Extension Catheter-Facilitated Tip-in Technique in the Recanalization of Coronary Chronic Total Occlusion.

Background: The tip-in technique, which involves advancing an antegrade microcatheter cross the lesion over a retrograde guidewire, is an elaborated maneuver in the recanalization of coronary chronic total occlusion (CTO). We seek to assess the efficiency of a guide extension catheter-facilitated tip-in technique in comparison to the traditional retrograde approach, which is accomplished by an externalization wire. Methods: Thirty-three CTO patients successfully revascularized using guide extension catheter-facilitated "tip-in" were included and matched with another 33 patients by J-CTO score and operators, whose CTO was recanalized using an externalized wire. The manipulation time from the first retrograde wire entering the antegrade guide to the first antegrade balloon inflation in the occlusion was calculated. Results: Compared with the wire-externalization group, the manipulation time in the tip-in group was significantly shortened [389s; interquartile range (IQR), 272-478 vs 706s; IQR, 560-914; p < 0.001]. There was a trend in decreasing total operation time and radiation dose, but it did not reach statistical significance. Conclusion: Guide extension catheter-facilitated tip-in is an efficient method to achieve the recanalization of CTO in a retrograde way, which would be pivotal when the retrograde microcatheter could not be advanced into the antegrade guide catheter.

Quantitative Profiling of Serum Carnitines Facilitates the Etiology Diagnosis and Prognosis Prediction in Heart Failure.

BACKGROUND: The perturbation of fatty acid metabolism in heart failure (HF) has been a critical issue. It is unclear whether the amounts of circulating carnitines will benefit primary etiology diagnosis and prognostic prediction in HF. This study was designed to assess the diagnostic and prognostic values of serum carnitine profiles between ischemic and non-ischemic derived heart failure. METHODS: HF patients (non-ischemic dilated cardiomyopathy: DCM-HF, n = 98; ischemic heart disease: IHD-HF, n = 63) and control individuals (n = 48) were enrolled consecutively. The serum carnitines were quantitatively measured using the UHPLC-MS/MS method. All patients underwent a median follow-up of 28.3 months. Multivariate Cox regression analysis was performed during the prognosis evaluation. RESULTS: Amongst 25 carnitines measured, all of them were increased in HF patients, and 20 acylcarnitines were associated with HF diagnosis independently. Seven acylcarnitines were confirmed to increase the probability of DCM diagnosis independently. The addition of isobutyryl-L-carnitine and stearoyl-L-carnitine to conventional clinical factors significantly improved the area under the receiver operating characteristic curve (ROC) from 0.771 to 0.832 (p = 0.023) for DCM-HF diagnosis (calibration test for the composite model: Hosmer-Lemeshow χ2 = 7.376, p = 0.497 > 0.05). Using a multivariate COX survival analysis adjusted with clinical factors simultaneously, oleoyl L-carnitine >300 nmol/L (HR = 2.364, 95% CI = 1.122-4.976, p = 0.024) and isovaleryl-L-carnitine <100 nmol/L (HR = 2.108, 95% CI = 1.091-4.074, p = 0.026) increased the prediction of all-cause mortality independently, while linoleoyl-L-carnitine >420 nmol/L, succinyl carnitine >60 nmol/L and isovaleryl-L-carnitine <100 nmol/L increased the risk of HF rehospitalization independently. CONCLUSIONS: Serum carnitines could not only serve as diagnostic and predictive biomarkers in HF but also benefit the identification of HF primary etiology and prognosis.

Mitochondrial aspartate/glutamate carrier AGC1 regulates cardiac function via Drp1-mediated mitochondrial fission in doxorubicin-induced cardiomyopathy.

Mitochondrial fission has been noted in the pathogenesis of dilated cardiomyopathy (DCM), but the underlying specific regulatory mechanism, especially in the development of doxorubicin (DOX)-induced cardiomyopathy remains unclear. In the present study, we explore whether the aspartate-glutamate carrier1 (AGC1) interacts with the fission protein dynamin-related protein 1 (Drp1) and reveal the functional and molecular mechanisms contributing to DOX-induced cardiomyopathy. Results of co-immunoprecipitation mass spectrometry (CO-IP MS) analysis based on heart tissue of DCM patients revealed that AGC1 expression was significantly upregulated in DCM-induced injury and AGC1 level was closely correlated with mitochondrial morphogenesis and function. We showed that AGC1 knockdown protected mice from DOX-induced cardiomyopathy by preventing mitochondrial fission, while the overexpression of AGC1 in the mouse heart led to impairment of cardiac function. Mechanistically, AGC1 overexpression could upregulate Drp1 expression and contribute to subsequent excessive mitochondrial fission. Specifically, AGC1 knockdown or the use of Drp1-specific inhibitor Mdivi-1 alleviated cardiomyocyte apoptosis and inhibited impairment of mitochondrial function induced by DOX exposure. In summary, our data illustrate that AGC1, as a novel contributor to DCM, regulates cardiac function via Drp1-mediated mitochondrial fission, indicating that targeting AGC1-Drp1 axis could be a potential therapeutic strategy for DOX-induced cardiomyopathy.

COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis.

Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy.

Lipidome, central carbon metabolites, and sleep rhythm in coronary heart disease with nontraditional risks: An exploratory pilot study.

Aims: Altered lipid, energy metabolism and sleep disorders had been linked with coronary heart disease (CHD), however, the metabolic signatures and sleep rhythm in non-obstructive coronary atherosclerosis-CHD remain unclear. This pilot study aims to investigate the lipidome and central carbon metabolites profiles and associated sleep characteristics among CHD patients without traditional risk factors. Methods: From January to July 2021, 15 CHD patients and 15 healthy controls were randomly selected from the cardiology unit of Zhongshan Hospital, Shanghai. A total of 464 lipids and 45 central carbon metabolites (CCM) were quantified in blood plasma. Metabolic signatures were selected through orthogonal projections to latent structures discriminant analysis (OPLS-DA) and principal component analysis (PCA) was conducted to link the profiles of identified metabolites with CHD risk, sleep patterns, cardiometabolic traits and cardiac electrophysiologic parameters. Results: Using OPLS-DA, we identified 40 metabolites (variable influence on projection >1) that were altered in CHD patients, with 38 lipids, including 25 triacylglycerols (TAGs), 8 diacylglycerols (DAGs), being elevated and two CCM metabolites (i.e., succinic acid and glycolic acid) being reduced. Using PCA, four principal components (PCs) were identified and associated with increased risk of CHD. Specifically, one standard unit increasement in the PC that was characterized by high levels of DAG (18:1) and low succinic acid and the PC that was characterized by high levels of two sphingomyelins [SM (26:0) and SM (24:0)] was associated with 21% [odds ratio (OR) = 1.21, 95% CI: 1.02,1.43] and 14% (OR = 1.14,1.02,1.29) increased risk of CHD, respectively. Further regression analyses confirmed that the identified metabolites and the four PCs were positively associated with TG and ALT. Interestingly, glycolic acid was negatively associated with sleep quality and PSQI. Participants with night sleep mode tended to have a high level of the identified lipids, especially FFA (20:4). Conclusion: In the present pilot study, our findings provide clues on alterations of lipid and energy metabolism in CHD patients without traditional risk factors, with multiple triacylglycerols and diacylglycerols metabolites seemingly elevated and certain nonlipids metabolites (e.g., succinic acid and glycolic acid) decreased in cases. Considering the limit sample size, further studies are warranted to confirm our results.

L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways.

AIM: To explore the beneficial effects of L-carnitine on cardiac microvascular dysfunction in diabetic cardiomyopathy from the perspectives of mitophagy and mitochondrial integrity. METHODS: Male db/db and db/m mice were randomly assigned to groups and were treated with L-carnitine or a solvent for 24 weeks. Endothelium-specific PARL overexpression was attained via adeno-associated virus serotype 9 (AAV9) transfection. Adenovirus (ADV) vectors overexpressing wild-type CPT1a, mutant CPT1a, or PARL were transfected into endothelial cells exposed to high glucose and free fatty acid (HG/FFA) injury. Cardiac microvascular function, mitophagy, and mitochondrial function were analyzed by immunofluorescence and transmission electron microscopy. Protein expression and interactions were assessed by western blotting and immunoprecipitation. RESULTS: L-carnitine treatment enhanced microvascular perfusion, reinforced endothelial barrier function, repressed the endothelial inflammatory response, and maintained the microvascular structure in db/db mice. Further results demonstrated that PINK1-Parkin-dependent mitophagy was suppressed in endothelial cells suffering from diabetic injury, and these effects were largely alleviated by L-carnitine through the inhibition of PARL detachment from PHB2. Moreover, CPT1a modulated the PHB2-PARL interaction by directly binding to PHB2. The increase in CPT1a activity induced by L-carnitine or amino acid mutation (M593S) enhanced the PHB2-PARL interaction, thereby improving mitophagy and mitochondrial function. In contrast, PARL overexpression inhibited mitophagy and abolished all the beneficial effects of L-carnitine on mitochondrial integrity and cardiac microvascular function. CONCLUSION: L-carnitine treatment enhanced PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction via CPT1a, thereby reversing mitochondrial dysfunction and cardiac microvascular injury in diabetic cardiomyopathy.

Pre-stenting angiography-FFR based physiological map provides virtual intervention and predicts physiological and clinical outcomes.

BACKGROUND: Angiography-derived fractional flow reserve (FFR) (angio-FFR) has been validated against FFR and could provide virtual pullback. However, whether a physiological map can be generated by angio-FFR and its clinical value remains unclear. We aimed to investigate the feasibility of physiological map created from angio-FFR pullback and its value in predicting physiological and clinical outcomes after stenting. METHODS: An angio-FFR physiological map was generated by overlaying the virtual pullback onto coronary angiogram, to calculate physiological stenosis severity, length, and intensity (Δangio-FFR/mm). This map in combination with virtual stenting was used to predict the best-case post-percutaneous coronary intervention (PCI) angio-FFR (angio-FFRpredicted ) according to the stented segments, and this was compared with the actual achieved post-PCI angio-FFR (angio-FFRachieved ). Additionally, prognostic value of predicted angio-FFR was investigated. RESULTS: Three hundred twenty-nine vessels with paired analyzable pre- and post-PCI angio-FFR were included. Physiological map was created successfully in all vessels. After successful PCI, angio-FFRpredicted and angio-FFRachieved were significantly correlated (r = 0.82, p < 0.001) with small difference (mean difference: -0.010 ± 0.035). In the virtual PCI only covering the segment with high angio-FFR intensity, the same physiological outcome can be achieved with shorter stent length (14.1 ± 8.9 vs. 34.5 ± 15.8 mm, p < 0.001). Suboptimal angio-FFRpredicted was associated with increased risk of 2-year vessel-oriented composite endpoint (adjusted hazard ratio: 3.71; 95% confidence interval: 1.50-9.17). CONCLUSIONS: Angio-FFR pullback could provide a physiological map of the interrogated coronary vessels by integrating angio-FFR pullback and angiography. Before a PCI, the physiological map can predict the physiological and clinical outcomes after stenting.

Coronary CT angiography-derived plaque characteristics and physiologic patterns for peri-procedural myocardial infarction and subsequent events.

AIMS: Peri-procedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI) has been shown to be associated with worse clinical outcomes. We aimed to investigate the value of coronary plaque characteristics and physiologic disease patterns (focal vs. diffuse) assessed by coronary computed tomography angiography (CTA) in predicting PMI and adverse events. METHODS AND RESULTS: Three hundred fifty-nine patients with normal pre-PCI high-sensitivity cardiac troponin T (hs-cTnT) underwent CTA before PCI were analysed. The high-risk plaque characteristics (HRPC) were assessed on CTA. The physiologic disease pattern was characterized using CTA fractional flow reserve-derived pullback pressure gradients (FFRCT PPG). PMI was defined as an increase in hs-cTnT to >5 times the upper limit of normal after PCI. The major adverse cardiovascular events (MACE) were a composite of cardiac death, spontaneous myocardial infarction, and target vessel revascularization. The presence of ≥3 HRPC in the target lesions [odds ratio (OR) 2.21, 95% confidence interval (CI) 1.29-3.80, P = 0.004] and low FFRCT PPG (OR 1.23, 95% CI 1.02-1.52, P = 0.028) were independent predictors of PMI. In a four-group classification according to HRPC and FFRCT PPG, patients with ≥3 HRPC and low FFRCT PPG had the highest risk of MACE (19.3%; overall P = 0.001). Moreover, the presence of ≥3 HRPC and low FFRCT PPG was an independent predictor of MACE and showed incremental prognostic value compared with a model with clinical risk factors alone [C index = 0.78 vs. 0.60, P = 0.005, net reclassification index = 0.21 (95% CI: 0.04-0.48), P = 0.020]. CONCLUSIONS: Coronary CTA can evaluate plaque characteristics and physiologic disease patterns simultaneously, which plays an important role for risk stratification before PCI.