PCSK9 inhibitor added to high-intensity statin therapy to prevent cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention: a randomized, double- blind, placebo-controlled, multicenter SHAWN study.

BACKGROUND: It is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. METHODS: This study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1,212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at 1-year follow-up between 2 groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. CONCLUSION: The SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.

C/EBPZ modulates the differentiation and proliferation of preadipocytes.

BACKGROUND/OBJECTIVES: This study investigated the functions of CCAAT/enhancer-binding protein zeta (C/EBPZ; Gene ID: 10153) in adipose tissue. SUBJECTS/METHODS: Bioinformatics analysis were used to study the expression pattern of C/EBPZ in human adipose tissue. The expression and function of C/EBPZ in adipose tissue were further studied using chicken as animal model in vivo and in vitro. RESULTS: The human C/EBPZ transcripts were greater and more stable in subcutaneous adipose tissue than in visceral adipose tissue (P < 0.01), and they were increased with age in adipose tissue (P < 0.05). In addition, the chicken C/EBPZ transcripts (C/EBPZ /ACTB) of visceral (abdominal) adipose tissue were significantly different between fat and lean broilers and decreased with age during development (P < 0.01). RNA-seq analysis showed that the C/EBPZ overexpression associated with adipose tissue development and DNA replication in chicken preadipocytes (P < 0.05). Additionally, overexpression of chicken C/EBPZ inhibited preadipocytes differentiation and promoted preadipoytes proliferation in vitro (P < 0.05). In addition, C/EBPZ overexpression suppressed the promoter activities of PPARγ, C/EBPα, FASN and LPL, and promoted the promoter activities of GATA2 and FABP4 in chicken preadipocytes (P < 0.05). CONCLUSIONS: C/EBPZ modulated the differentiation and proliferation of preadipocytes, and it might be a new negative regulator of adipogenesis.

Ticagrelor versus clopidogrel for prevention of subclinical stent thrombosis detected by optical coherence tomography in patients with drug-eluting stent implantation-a multicenter and randomized study.

Introduction: This prospective, multicenter, randomized study was designed to analyze the benefits of ticagrelor over clopidogrel in reducing subclinical stent thrombosis (ST) in patients with coronary artery disease who underwent implantation of a second-generation drug-eluting stent (DES).Methods: About 352 patients with single de novo coronary stenosis were randomly assigne`d to either clopidogrel group (aspirin plus clopidogrel) or ticagrelor group (aspirin plus ticagrelor) after DES implantation for 1 year. Baseline clinical characteristics, blood chemistry markers, coronary artery angiography (CAG), and optical coherence tomography (OCT) were obtained during the index procedure. Data about clinic, CAG and OCT were also collected after 1 year follow-up. Intention-to-treat (ITT), per protocol set (PPS), and sensitivity analysis of subclinical ST were performed. Major factors associated with subclinical ST were analyzed by multivariable and univariable logistic regression models.Results: The incidence of subclinical ST in ticagrelor group was significantly low as compared to clopidogrel group (P < .05) at 1-year follow-up. Ticagrelor use was an independent factor in reducing subclinical ST (P < .05). The percentage of endothelial coverage, neointimal hyperplasia, malapposition, and edge dissection about stents were not different between the two groups (P > .05). Bleeding ratio was not markedly altered after ticagrelor treatment (P > .05). Not any significant differences were detected with regard to baseline clinical characteristics, CAG results, and DES between ticagrelor and clopidogrel groups (P > .05).Conclusion: In patients who underwent a second-generation DES implantation, using aspirin plus ticagrelor was associated with a significant reduction in subclinical ST. (ClinicalTrials.gov. Number: NCT02140801).

Relationship between neointimal strut bridge and jailed side-branch ostial area.

BACKGROUND: Our study analyzed the relationship between the neointimal strut bridge and jailed side-branch (SB) ostial area in patients with coronary heart disease (CHD) who had a single drug-eluting stent (DES) crossover of the left anterior descending coronary artery (LAD)/diagonal branch (D) bifurcation. PATIENTS AND METHODS: A total of 64 CHD patients with an LAD/D bifurcation treated by optical coherence tomography (OCT)-guided single-DES implantation and followed up at 1 year after primary percutaneous intervention (pPCI) were enrolled in our study. According to the two-dimensional OCT results, patients were divided into a non-neointimal bridge group (n = 44) and a neointimal bridge group (n = 20). Basic clinical, angiographic, 2D and 3D OCT, and DES results were analyzed. RESULTS: The blood lipid levels of the two groups after the 1­year follow-up were lower than the levels 1 year earlier (p < 0.05). There was a notable decrease in the SB ostial minimum lumen diameter and area directly after pPCI vs. before pPCI in both groups. The diameter stenosis directly after pPCI showed a clear increase compared with the pre-pPCI value in both groups (p < 0.05 or p < 0.01, respectively). The strut distance of the neointimal bridges in the neointimal bridge group was greater than in the non-neointimal bridge group (p < 0.05). A clearly short strut distance of the neointimal bridge was observed compared with the strut distance of the non-neointimal bridge in the neointimal bridge group (p < 0.05). A larger neointimal bridge area and a smaller SB ostial area were found in the neointimal bridge group compared with the non-neointimal bridge group (p < 0.05 or p < 0.01, respectively). CONCLUSION: A short strut distance facilitated formation of a neointimal bridge, which significantly influenced the SB ostial area after single crossover stenting of the SB orifice at the 1­year follow-up.

Amelioratory effect of neoandrographolide on myocardial ischemic-reperfusion injury by its anti-inflammatory and anti-apoptotic activities.

In the present study, we aimed to evaluate the cardioprotective effect of neoandrographolide (Neo) on myocardial ischemia/reperfusion injury (I/R) models and explore its possible mechanism. We randomly and equally divided male mice into sham-operation, I/R, and I/R + Neo groups. H9C2 cell line and primary neonatal rat cardiomyocytes were induced into the simulated I/R's status and used to further validate the Neo's role in vitro. Heart systolic function, indexes of myocardial injury (IMI), infarct size, pathological change, cell apoptosis, inflammatory cytokines, and indexes related to apoptotic and NF-κB signaling pathways were analyzed in vivo or in vitro after the Neo treatment. Compared to the I/R group, Neo significantly suppressed IMI, infarct size, inflammatory cell infiltration, cell apoptosis, inflammatory cytokines, bax, cleaved caspase-3, P-IKBa, and P-NF-κB protein expressions, and the translocation of NF-kB subunit p65 from the cytoplasm to the nucleus in vivo or in vitro. Still, ejected fraction, fractional shortening, and the bcl-2 protein expression were notably increased after the Neo treatment. Neo could be developed into a new drug for treating myocardial I/R by inhibiting myocardial inflammation and apoptosis, which was closely related to suppressing the activation of bax/bcl-2 and NF-κB signaling pathways.

Zinc finger protein 91 loss induces cardiac hypertrophy through adenosine A1 receptor down-regulation under pressure overload status.

The function of zfp91 is mainly studied in vitro, but there is no study in vivo. Accumulative data suggest that zfp91 may be an important gene to regulate all aspects of human response. However, there are no data to date about the function of zfp91 on cardiac homeostasis. Thus, we aimed to observe the role of zfp91 gene in mouse cardiomyocytes on myocardial homeostasis and related mechanisms under pressure overload. In the study, zfp91 mRNA and protein levels were significantly reduced in TAC-operated WT mice as compared with controls. Genetic ablation of zfp91 dramatically led to pathological cardiac dysfunction and hypertrophy after transverse aortic constriction (TAC). Adenosine A1 receptor (Adora1) mRNA and protein expressions were significantly down-regulated in the heart of zfp91-deletion mice with TAC. Zfp91 overexpression reversed isoproterenol-induced cardiomyocyte hypertrophy, which was abolished by selective Adora1 antagonist. Dual-luciferase reporter and ChIP-qPCR assays indicated that zfp91 acted on Adora1 promoter through its binding site. Last, Adora1 agonist rescued heart dysfunction and cardiac hypertrophy in zfp91 loss mice after TAC. Zfp91 may transcriptionally regulate Adora1 expression in the heart, which mainly maintained cardiac homeostasis under pressure overload status. It will provide a new approach to treat cardiac hypertrophy.

Apnea Hypopnea Index is an Independent Predictor of Coronary Microcirculatory Dysfunction in Stable Angina Pectoris Patients with a Single Borderline Lesion.

BACKGROUND: To investigate the effect and possible mechanism of obstructive sleep apnea hypopnea syndrome on coronary microcirculation in stable angina pectoris (SAP) patients with a single borderline lesion. METHODS: We retrospectively analyzed 102 SAP patients with a single critical lesion [fractional flow reserve > 0.80] who were divided into an abnormal microcirculatory function group [index of microcirculatory resistance (IMR) ≥ 25, n = 52] and normal microcirculatory function (NMF) group (IMR < 25, n = 50). We compared indexes including biochemical indicators, coronary lesion characteristics, apnea hypopnea index (AHI), lowest oxygen saturation (LSaO2), night average heart rate, endothelin-1 (ET-1), nitric oxide (NO) and high-sensitivity C-reactive protein in serum between the two groups. Furthermore, risk factors affecting coronary microcirculation were analyzed. RESULTS: There were no significant differences in biochemical indexes and coronary lesion characteristics between the two groups (p > 0.05). Compared to the NMF group, AHI (23.76 ± 8.41 times/h) and ET-1 (1.96 ± 0.43 ng/L) were obviously increased (p < 0.01), and LSaO2 (77.96 ± 7.26%) and NO (23.63 ± 7.09 µmol/L) was significantly lower in the AMF group (p < 0.01). Moreover, AHI and ET-1 were positively associated with IMR (r1 = 0.887, 0.835, respectively). However, LSaO2 and NO had a negative correlation with IMR (r3 = 0.659, 0.691, respectively). Logistic regression analysis showed that AHI was an independent predictor of coronary microcirculatory dysfunction (odds ratio = 1.260, 95% confidence interval 1.083~1.467, p < 0.01). Receiver operating characteristic (ROC) curve analysis indicated an AHI cut-off value of 13.7 times/h to predict microcirculatory dysfunction (sensitivity 0.942, specificity 0.880). CONCLUSIONS: In SAP patients with a single critical lesion, AHI was associated with coronary microcirculatory dysfunction.

Ginkgolide A protects adverse cardiac remodeling through enhancing antioxidation and nitric oxide utilization in mice with pressure overload.

In this study, we aimed to explore whether ginkgolide A (GA) would exhibit cardio-protective effects in mice with pressure overload through enhancing antioxidation and nitric oxide (NO) bioavailability. 21 male mice were randomly assigned into three groups as follows: sham group (10 ml/kg/day PBS, n=7), transverse aortic constriction (TAC) group (TAC and 10 ml/kg/day PBS, n=7) and GA group (TAC and 20 mg/kg/day GA, n=7). All groups received an intraperitoneal injection for four weeks. Heart and body mass were measured. Cardiac function was assessed by echocardiography. The collagen deposition, area of cardiomyocytes, number of capillaries and cell apoptosis were evaluated using Masson's staining, WGA staining, CD31 staining and TUNEL assay, respectively. Cadiac oxidative and antioxidative indexes were measured by colorimetry. Nitrotyrosine (NT) and transforming growth factor-ß (TGF-ß) were determined by ELISA. Phospho-endothelial NO synthases (eNOS) (Ser1177), phospho-eNOS (Thr 495), eNOS, neuronal NOS (nNOS), inducible NOS (iNOS) and GAPDH were analyzed by western blot. GA treatment greatly improved cardiac dysfunction, suppressed cardiac hypertrophy and increased capillary number at 4 weeks after TAC (P<0.05). Fibrotic area, cardiomyocyte area, and cell apoptosis of GA group were declined notably as compared to those of TAC group (P<0.05). GA administration substantially attenuated cardiac oxidative stress, and reduced NT and TGF-ß levels (P<0.05). Besides, GA medication can enhance eNOS signaling, resulting in increased cardiac NO production (P<0.05). GA had a cardioprotective effect in mice with pressure overload, which was closely related with reducing oxidative stress and enhancing NO bioavailability in hearts.

Cardamonin protects against adverse cardiac remodeling through mTORC1 inhibition in mice with myocardial infarction.

The mTORC1-dependent signaling pathway is mainly involved in the adverse left ventricular remodeling (ALVR) process after myocardial infarction (MI). However, whether mTORC1 inhibition by cardamonin attenuates ALVR after MI is still not reported. Twenty mice were randomly assigned into three groups: sham group (10 ml/kg/day PBS, n=6), model group (MI and 10 ml/kg/day PBS, n=7) and cardamonin-treated group (MI and 20 mg/kg/day cardamonin, n=7). All groups received an intraperitoneal injection accordingly for two weeks. Heart and body mass were measured. Cardiac function was assessed by echocardiography. The collagen deposition, area of cardiomyocytes and cell apoptosis of border area were evaluated using Masson's staining, WGA staining and TUNEL assay, respectively. The 4E-binding protein 1 (4E-BP1) and ribosomal S6 (S6) in myocardium were determined by western blot. mTOR-Raptor association was tested by co-immunoprecipitation assay in H9C2 cell line. Treatment with cardamonin, MI mice displayed that heart hypertrophy and heart dysfunction were alleviated, and cardiac fibrosis, cardiomyocyte size and cell apoptosis of border area were decreased (P<0.05). Besides, cardamonin can inhibit 4E-BP1 and S6 phosphorylation in heart of MI mice and H9C2 cell line (P<0.05). Furthermore, cardamonin disrupted mTOR-Raptor association in vitro. Cardamonin exerted cardio-protection against ALVR through mTORC1 inhibition.

Advantages of Transradial Rotational Atherectomy versus Transfemoral Approach in Elderly Patients with Hard-Handling Calcified Coronary Lesions - A Single Center Experience.

BACKGROUND: Balloons cannot pass through severely calcified coronary lesion (SCCL), and sometimes they cannot be opened at a high pressure even if they can pass through the lesion. There are limited data on rotational atherectomy (RA) via transradial access (TRA) in this setting. The aim of this study was to evaluate in-hospital and 1-year outcomes in elderly patients with SCCL who underwent RA via TRA. METHODS: Eighty-six consecutive elderly patients with de novo SCCL who underwent RA were enrolled and divided into TRA (n = 45) and transfemoral access (TFA, n = 41) groups in this retrospective analysis from 2008 to 2013. Baseline characteristics and in-hospital and 1-year endpoints were compared between both groups. RESULTS: Compared to TFA, 6Fr guide catheters were used significantly more in the radial approach (p < 0.001). In the TRA group, the rate of burr size (1.25 mm) was higher and the mean burr size was smaller (p = 0.021) than that in the TFA group. Vascular access site complications, bed rest time and hospital stay were significantly lower in the TRA group compared with the TFA group (p = 0.029, < 0.001, < 0.001, respectively). However, there was no significant difference in major adverse cardiac events during hospitalization and after 1 year follow-up between both groups (p = 0.338, 1.000, respectively). CONCLUSIONS: TRA is a useful alternative to TFA in elderly patient with SCCL. The advantages of TRA over TFA include reduced time of bed rest and hospital stay and vascular complications at the puncture site.

Cardamonin Alleviates Pressure Overload-induced Cardiac Remodeling and Dysfunction Through Inhibition of Oxidative Stress.

Pressure overload-induced cardiac remodeling and dysfunction progress to heart failure, which is mainly due to excessive oxidative stress. Hence, our study aimed to illustrate whether cardamonin, a kind of chalcone, could attenuate maladaptive cardiac changes and ameliorate cardiac insufficiency through its antioxidant mechanism. In vivo, our study revealed that cardamonin treatment could attenuate transverse aortic contraction-induced cardiac remodeling and dysfunction. Histological observations have suggested that cardamonin inhibited the occurrence of excessive cardiac oxidative stress and apoptosis. In vitro, we found that 3 treatments with angiotensin II (Ang II), hydrogen peroxide, and Nox4 overexpression in H9C2 cells markedly augmented intracellular oxidative stress as measured by superoxide dismutase, L-glutathione, and malonaldehyde. Conversely, cardamonin treatment notably alleviated oxidative stress induced by the 3 above-mentioned treatments. Furthermore, all 3 treatments resulted in increased apoptotic cell death, whereas cardamonin treatment reduced apoptosis in H9C2 cells. Moreover, cardamonin significantly abrogated the expression of Bax, apoptosis inducing factor, cytochrome c, and caspase-3 and caspase-9 and enhanced the expression of Bcl-2 and Bcl-xl. In conclusion, these findings provide a new possibility for cardamonin to alleviate pressure overload-induced heart failure.

Plasma Lipoprotein-Associated Phospholipase A2 Level Is an Independent Predictor of High Thrombus Burden in Patients With Acute ST-segment Elevation Myocardial Infarction.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor for plaque rupture and atherothrombotic events. However, the associations between serum Lp-PLA2 level and thrombus burden in ST-segment elevation myocardial infarction (STEMI) patients remain unknown.We consecutively enrolled 351 STEMI patients who underwent primary percutaneous coronary intervention (pPCI). Patients were assigned to a high thrombus burden (HTB) group (n = 230) and a low thrombus burden (LTB) group (n = 121). Baseline data were recorded during hospital admission. Plasma Lp-PLA2 concentration, coronary angiography results, and in-hospital mortality were measured. Plasma Lp-PLA2 level had a high correlation with thrombus burden score (TBS) before pPCI and it was found to be a significant independent predictor of HTB in STEMI patients (P < 0.05). Moreover, TBS, corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC), and plasma Lp-PLA2 level after pPCI in patients with HTB were significantly higher than those in patients with LTB (P < 0.05). Meanwhile, TIMI flow grade (TFG) and TIMI myocardial perfusion grade (TMPG) of HTB patients were markedly lower than those of LTB patients (P < 0.05). Additionally, correlations of plasma Lp-PLA2 level before pPCI with TFG before pPCI and TBS, cTFC, and TMPG after pPCI were modest (P < 0.05). However, the associations of plasma Lp-PLA2 level after pPCI with TFG, TBS, cTFC and TMPG were low (P < 0.05).These results demonstrated that the plasma Lp-PLA2 level before pPCI is an independent predictor of HTB in STEMI patients, resulting in modestly predicting blood flow and myocardial perfusion of the culprit artery.

Genetic and pharmacological inhibition of Rheb1-mTORC1 signaling exerts cardioprotection against adverse cardiac remodeling in mice.

A previous study indicated that Rheb1 is required for mammalian target of TOR complex 1 (mTORC1) signaling in the brain. However, the function of Rheb1 in the heart is still elusive. In the present study, we deleted Rheb1 specifically in cardiomyocytes and found that reduced Rheb1 levels conferred cardioprotection against pathologic remodeling in myocardial infarction (MI) and pressure overload (transverse aortic constriction) mouse models. Cardiomyocyte apoptosis was reduced and mTORC1 activity was suppressed in cardiomyocyte Rheb1-deletion mice, suggesting that Rheb1 regulates mTORC1 activation in myocardium. Furthermore, we demonstrated that astragaloside IV (As-IV) could inhibit mTORC1, and As-IV treatment displayed similar protection against MI and transverse aortic constriction as Rheb1 genetic inhibition. This study indicates that Rheb1 is essential for mTORC1 activation in cardiomyocytes and suggests that targeting Rheb1-mTORC1 signaling, such as by As-IV treatment, may be an effective therapeutic method for treating patients with adverse cardiac remodeling after MI and hypertrophy.

Clinical Value of the Quantitative Flow Ratio to Predict Long-term Target Vessel Failure in Patients with In-stent Restenosis after Drug-coated Balloon Angioplasty.

OBJECTIVE: The study sought to investigate the clinical predictive value of quantitative flow ratio (QFR) for the long-term target vessel failure (TVF) outcome in patients with in-stent restenosis (ISR) by using drug-coated balloon (DCB) treatment after a long-term follow-up. METHODS: This was a retrospective study. A total of 186 patients who underwent DCB angioplasty for ISR in two hospitals from March 2014 to September 2019 were enrolled. The QFR of the entire target vessel was measured offline. The primary endpoint was TVF, including target vessel-cardiac death (TV-CD), target vessel-myocardial infarction (TV-MI), and clinically driven-target vessel revascularization (CD-TVR). RESULTS: The follow-up time was 3.09±1.53 years, and 50 patients had TVF. The QFR immediately after percutaneous coronary intervention (PCI) was significantly lower in the TVF group than in the no-TVF group. Multivariable Cox regression analysis indicated that the QFR immediately after PCI was an excellent predictor for TVF after the long-term follow-up [hazard ratio (HR): 5.15×10-5 (6.13×10-8-0.043); P<0.01]. Receiver-operating characteristic (ROC) curve analysis demonstrated that the optimal cut-off value of the QFR immediately after PCI for predicting the long-term TVF was 0.925 (area under the curve: 0.886, 95% confidence interval: 0.834-0.938; sensitivity: 83.40%, specificity: 88.00; P<0.01). In addition, QFR≤0.925 post-PCI was strongly correlated with the TVF, including TV-MI and CD-TVR (P<0.01). CONCLUSION: The QFR immediately after PCI showed a high predictive value of TVF after a long-term follow-up in ISR patients who underwent DCB angioplasty. A lower QFR immediately after PCI was associated with a worse TVF outcome.

Dynamic natural components and morphological changes in nonculprit subclinical atherosclerosis in patients with acute coronary syndrome and mild chronic kidney disease at the 1-year follow-up and clinical significance at the 5-year follow-up.

INTRODUCTION: The natural outcome of coronary plaque in acute coronary syndrome (ACS) patients with chronic kidney disease (CKD) is unique, which can be analyzed quantitatively by optical flow ratio (OFR) software. METHODS: A total of 184 ACS patients with at least one nonculprit subclinical atherosclerosis (NSA) detected by optical coherence tomography (OCT) at baseline and 1-year follow-up were divided into non-CKD group (n = 106, estimated glomerular filtration rate (eGFR)> 90 mL/(min×1.73 m2)) and mild CKD group (n = 78, 60≤eGFR<90 mL/(min×1.73 m2)). Changes of normalized total atheroma volume (TAVn) of NSA was the primary endpoint at the 1-year follow-up. RESULTS: Patients with mild CKD showed more TAVn progression of NSA than non-CKD (p = 0.019) from baseline to the 1-year follow-up, which was mainly due to an increase in calcium TAVn (p<0.001). The morphological change in the maximal calcification thickness (p = 0.026) was higher and the change in the distance from the calcified surface to the contralateral coronary media membrane (ΔC-to-M) at the maximal cross-sectional calcium area was lower (p<0.001) in mild CKD group than in non-CKD group. Mild CKD had more NSA related MACEs at the 5-year follow-up than non-CKD (30.8% vs. 5.8%, p = 0.045). CONCLUSIONS: Mild CKD patients had more plaque progression of NSA which showed the increase of calcium component with more protrusion into the lumen morphologically at the 1-year follow-up and a higher corresponding incidence of NSA-related MACEs at the 5-year follow-up. TRIAL REGISTRATION: Clinical Trial registration ClinicalTrials.gov. NCT02140801. https://classic.clinicaltrials.gov/ct2/show/NCT02140801.

Effect of negative remodeling of the side branch ostium on the efficacy of a two-stent strategy for distal left main bifurcation lesions: an intravascular ultrasound study.

OBJECTIVES: To investigate whether negative remodeling (NR) detected by intravascular ultrasound (IVUS) of the side branch ostium (SBO) would affect in-stent neointimal hyperplasia (NIH) at the one-year follow-up and the clinical outcome of target lesion failure (TLF) at the long-term follow-up for patients with left main bifurcation (LMb) lesions treated with a two-stent strategy. METHODS: A total of 328 patients with de novo true complex LMb lesions who underwent a 2-stent strategy of percutaneous coronary intervention (PCI) treatment guided by IVUS were enrolled in this study. We divided the study into two phases. Of all the patients, 48 patients who had complete IVUS detection pre- and post-PCI and at the 1-year follow-up were enrolled in phase I analysis, which aimed to analyze the correlation between NR and in-stent NIH at SBO at the 1-year follow-up. If the correlation was confirmed, the cutoff value of the remodeling index (RI) for predicting NIH ≥ 50% was analyzed next. The phase II analysis focused on the incidence of TLF as the primary endpoint at the 1- to 5-year follow-up for all 328 patients by grouping based on the cutoff value of RI. RESULTS: In phase I: according to the results of a binary logistic regression analysis and receiver operating characteristic (ROC) analysis, the RI cutoff value predicting percent NIH ≥ 50% was 0.85 based on the ROC curve analysis, with a sensitivity of 85.7%, a specificity of 88.3%, and an AUC of 0.893 (0.778, 1.000), P = 0.002. In phase II: the TLR rate (35.8% vs. 5.3%, P < 0.0001) was significantly higher in the several NR (sNR, defined as RI ≤ 0.85) group than in the non-sNR group. CONCLUSION: The NR of LCxO is associated with more in-stent NIH post-PCI for distal LMb lesions with a 2-stent strategy, and NR with RI ≤ 0.85 is linked to percent NIH area ≥ 50% at the 1-year follow-up and more TLF at the 5-year follow-up.

Compared analysis of LncRNA expression profiling in pdk1 gene knockout mice at two time points.

BACKGROUND/AIMS: Previous studies have indicated that long non-coding RNAs (lncRNA) are related to the occurrence and development of many human diseases, such as cancer and the HELLP and the brachydactyly syndromes. However, studies of LncRNA in heart failure have not yet been reported. Here, we investigated cardiac lncRNA expression profiles in the myocardial-specific knockout pdk1 gene (KO) mouse model of heart failure. METHODS: Cardiac samples were obtained from PDK1 KO and WT mice on postnatal (P) day 8 (P8) and day 40 (P40), and lncRNA expression profiles were analyzed by sequencing and screening using the Arraystar mouse lncRNA microarray. Quantitative real-time PCR analysis of these lncRNAs confirmed the identity of some genes. RESULTS: Comparisons of the KO and control groups showed fold changes of >1.5 in the expression levels of 2,024 lncRNAs at P8, while fold changes of >2 in the expression levels of 4,095 lncRNAs were detected at P40. Nineteen lncRNAs were validated by RT-PCR. Bioinformatic and pathway analyses indicated that mkk7, a sense overlap lncRNA, may be involved in the pathological processes of heart failure through the MAPK signaling pathway. CONCLUSION: These data reveal differentially expressed lncRNA in mice with a myocardial-specific deletion of the pdk1 gene, which may provide new insights into the mechanism of heart failure in PDK1 knockout mice.

S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt.

In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.

Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice.

Ras homologue enriched in brain 1 (Rheb1) plays an important role in a variety of cellular processes. In this study, we investigate the role of Rheb1 in the post-natal heart. We found that deletion of the gene responsible for production of Rheb1 from cardiomyocytes of post-natal mice resulted in malignant arrhythmias, heart failure, and premature death of these mice. In addition, heart growth impairment, aberrant metabolism relative gene expression, and increased cardiomyocyte apoptosis were observed in Rheb1-knockout mice prior to the development of heart failure and arrhythmias. Also, protein kinase B (PKB/Akt) signaling was enhanced in Rheb1-knockout mice, and removal of phosphatase and tensin homolog (Pten) significantly prolonged the survival of Rheb1-knockouts. Furthermore, signaling via the mammalian target of rapamycin complex 1 (mTORC1) was abolished and C/EBP homologous protein (CHOP) and phosphorylation levels of c-Jun N-terminal kinase (JNK) were increased in Rheb1 mutant mice. In conclusion, this study demonstrates that Rheb1 is important for maintaining cardiac function in post-natal mice via regulation of mTORC1 activity and stress on the endoplasmic reticulum. Moreover, activation of Akt signaling helps to improve the survival of mice with advanced heart failure. Thus, this study provides direct evidence that Rheb1 performs multiple important functions in the heart of the post-natal mouse. Enhancing Akt activity improves the survival of infant mice with advanced heart failure.

Prolonged infusion of bivalirudin after elective percutaneous coronary intervention protects against procedural myocardial injury (a COBER study)-a randomized trial.

Procedural myocardial injury (PMI), which is the most common complication of elective percutaneous coronary intervention (ePCI), is associated with future adverse cardiac events. In this randomized pilot trial, we assessed the effects of prolonged use of the anti-coagulant bivalirudin on PMI after ePCI. Patients undergoing ePCI were randomized into the following two groups: the bivalirudin use during operation group (BUDO, 0.75 mg/kg bolus plus 1.75 mg/kg/h) and the bivalirudin use during and after operation for 4 h (BUDAO, 0.75 mg/kg bolus plus 1.75 mg/kg/h). Blood samples were collected before and 24 h after ePCI (per 8 h). The primary outcome, PMI, was defined as an increase in post-ePCI cardiac troponin I (cTnI) levels of > 1 × 99th% upper reference limit (URL) when the pre-PCI cTnI was normal or a rise in cTnI of > 20% of the baseline value when it was above the 99th percentile URL, but it was stable or falling. Major PMI (MPMI) was defined as a post-ePCI cTnI increase of > 5 × 99th% URL. A total of 330 patients were included (n = 165 per group). The incidences of PMI and MPMI were not significantly higher in the BUDO group than in the BUDAO group (PMI: 115 [69.70%] vs. 102 [61.82%], P = 0.164; MPMI: 81 [49.09%] vs. 70 [42.42%], P = 0.269). However, the absolute change in cTnI levels (calculated as the peak value 24 h post-PCI minus the pre-PCI value) was notably larger in the BUDO group (0.13 [0.03, 1.95]) than in the BUDAO group (0.07 [0.01, 0.61]) (P = 0.045). Moreover, the incidence of bleeding events was similar between the two groups (BUDO: 0 [0.00%]; BUDAO: 2 [1.21%], P = 0.498). Prolonged infusion of bivalirudin for 4 h after ePCI reduces PMI severity without increasing the risk of bleeding.ClinicalTrials.gov.Number: NCT04120961, 09/10/2019.