Revascularization for Patients With Heart Failure With Preserved Ejection Fraction and Coronary Artery Disease.

Coronary artery disease (CAD) is one of the main causes of heart failure (HF) with preserved ejection fraction (HFpEF). The efficacy of revascularization therapy in patients with HFpEF and CAD, however, remains unclear. Patients who underwent coronary angiography from January 2017 to December 2019 were included in this retrospective study if they further satisfied the diagnosis of HFpEF (left ventricular ejection fraction ≥50% plus plasma N-terminal pro-BNP ≥125 pg/ml) and CAD (patients had a history of confirmed myocardial infarction or ≥50% stenosis in at least 1 epicardial coronary vessel). Clinical data, way of revascularization, and outcome events (unplanned repeated revascularization, HF readmission, cardiovascular death, readmission of cerebral hemorrhage/stroke or gastrointestinal bleeding, and all-cause death) were recorded and analyzed. A total of 1,111 patients were enrolled for the present analysis. Based on whether the revascularization was complete or not, the patients were divided into the complete revascularization group (n = 780) and the incomplete/no revascularization group (n = 331). All patients were followed up with a median of 355 days. The overall rates of unplanned repeated revascularization, HF readmission, and cardiovascular death were 6.6%, 5.0%, and 0.4%, respectively. Compared with incompletely/not revascularized patients, completely revascularized patients had a lower rate of unplanned repeated revascularization (10.9% vs 4.7%, p <0.001) and cardiovascular death (0.9% vs 0.1%, p = 0.048). However, HF readmission, readmission of cerebral hemorrhage/stroke or gastrointestinal bleeding, and noncardiac death were comparable between the 2 groups. The regression analysis showed that hyperlipidemia, previous myocardial infarction, in-stent restenosis, and way of revascularization were associated with the composite events of unplanned repeated revascularization, HF readmission, and cardiovascular death during the follow-up. Complete revascularization may reduce unplanned repeated revascularization and cardiovascular death for patients with HFpEF and CAD.

A case of repeated in-stent restenosis of coronary artery as a primary manifestation of seronegative antiphospholipid antibody syndrome.

BACKGROUND: Antiphospholipid antibody syndrome (APS) is a multisystemic autoimmune disorder which affects many organs or systems; however, coronary artery is relatively less frequently involved. CASE PRESENTATION: A 65-year-old female with effort chest pain was hospitalized for unstable angina in Janurary, 2015. Coronary angiography revealed sub-total occlusion of proximal left anterior descending (LAD) coronary artery, where a drug-eluting stent was successfully deployed. The patient experienced multiple in-stent stenosis at LAD coronary artery and coronary artery bypass graft (CABG) surgery was advised. Subsequently, severe stenosis of left circumflex (LCX) coronary artery emerged, and the patient suffered persistent in-stent restenosis. Eventually, the patient was diagnosed with seronegative antiphospholipid antibody syndrome and salvaged by immunosuppressants. CONCLUSIONS: Repeated in-stent restenosis could be a primary manifestation of seronegative antiphospholipid antibody syndrome, and suppression of autoimmune activity and inflammation other than purely coronary revascularization might be a better option.

Erratum: Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling: Erratum.

[This corrects the article DOI: 10.7150/thno.22177.].

Outcomes of contemporary versus conventional reverse controlled and antegrade and retrograde subintimal tracking in chronic total occlusion revascularization.

BACKGROUND: Chronic total occlusion (CTO) lesions remain technically challenging for percutaneous coronary intervention (PCI). The introduction of a retrograde approach has allowed marked improvement in the success rate of CTO recanalization. Reverse controlled anterograde and retrograde sub-intimal tracking (reverse CART) is the predominant retrograde wire crossing technique and can be broadly classified into three categories: (1) conventional (2) contemporary and (3) extended. The present study aimed to compare the safety and efficacy of conventional and contemporary reverse CART techniques. METHODS: From March 2015 to May 2020, 303 patients achieving successful retrograde guidewire crossing with conventional or contemporary reverse CART during CTO PCI were included in the study. The patient characteristics, procedural outcomes and in-hospital and 1-year clinical events were compared between the conventional and contemporary groups. RESULTS: The distributions of the baseline and angiographic characteristics were similar in both study arms, except the CTO lesions of the conventional group were more complex, as reflected by borderline significantly higher mean J-CTO scores (3.4 ± 0.7 vs. 3.3 ± 0.8; p = 0.059). Recanalization using contemporary reverse CART was associated with a short procedure time (189.8 ± 44.4 vs. 181.7 ± 37.3 min; p = 0.044) and decreased procedural complications, particularly target vessel perforation (3.6% vs. 0.6%; p = 0.063) and major side-branch occlusion (36.7% vs. 28.0%; p = 0.051). Technical and procedural success and the in-hospital and 1-year outcomes were not significantly different between the groups. CONCLUSIONS: Contemporary reverse CART is associated with favorably high efficiency and low-complication rates and carries a comparable success rate and 1-year clinical outcomes as conventional reverse CART.

Increased ratio of sST2/LVMI predicted cardiovascular mortality and heart failure rehospitalization in heart failure with reduced ejection fraction patients: a prospective cohort study.

BACKGROUND: Inflammation is one of the principal triggering mechanisms for left ventricular fibrosis and remodeling in heart failure, leading to adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, is assumed to play a significant role in the fibrotic response to inflammation. Left ventricular mass index (LVMI) is a parameter of the prefibrotic inflammatory phase of heart failure preceding remodeling. The present study aimed to investigate the prognostic value of the sST2/LVMI ratio in heart failure with reduced ejection fraction. METHODS: This was a prospective cohort study. A total of 45 consecutive patients with heart failure with reduced ejection fraction, treated between September 2015 and December 2016, were enrolled. The sST2/LVMI ratio was measured at baseline. The primary endpoint was a composite of cardiovascular mortality and readmission for heart failure. The prognostic impact of the sST2/LVMI ratio was evaluated using a multivariable Cox proportional hazards regression model. RESULTS: Forty-five patients were enrolled in this study. Their average age was 48 ± 14 years, and approximately 20% of them were men. Patients were followed for 9 months, during which the primary outcome occurred in 15 patients. Kaplan-Meier analysis showed that patients with a high sST2/LVMI ratio (≥ 0.39) had shorter event-free survival than those with intermediate (between 0.39 and 0.24) and low ratios (< 0.24) (log-rank, P = 0.022). The fully adjusted multivariable Cox regression analysis showed that the sST2/LVMI ratio was positively associated with the composite outcome in patients with heart failure with reduced ejection fraction after adjusting for confounders (hazard ratio 1.64, 95% confidence interval 1.06 to 2.54). By subgroup analysis, a stronger association was found with age between 40 and 55 years, systolic blood pressure < 115 or ≥ 129 mmHg, diastolic blood pressure < 74 mmHg, hematocrit < 44.5%, and interventricular septum thickness ≥ 8.5 mm. CONCLUSION: In patients with heart failure with reduced ejection fraction, the relationship between the sST2/LVMI ratio and the composite outcome was linear. A higher baseline ratio of sST2/LVMI was associated with an increased risk of cardiovascular mortality and heart failure rehospitalization in the short-term follow-up.

Prediction model of in-hospital mortality in intensive care unit patients with heart failure: machine learning-based, retrospective analysis of the MIMIC-III database.

OBJECTIVE: The predictors of in-hospital mortality for intensive care units (ICUs)-admitted heart failure (HF) patients remain poorly characterised. We aimed to develop and validate a prediction model for all-cause in-hospital mortality among ICU-admitted HF patients. DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC-III) database. Data on 1177 heart failure patients were analysed. METHODS: Patients meeting the inclusion criteria were identified from the MIMIC-III database and randomly divided into derivation (n=825, 70%) and a validation (n=352, 30%) group. Independent risk factors for in-hospital mortality were screened using the extreme gradient boosting (XGBoost) and the least absolute shrinkage and selection operator (LASSO) regression models in the derivation sample. Multivariate logistic regression analysis was used to build prediction models in derivation group, and then validated in validation cohort. Discrimination, calibration and clinical usefulness of the predicting model were assessed using the C-index, calibration plot and decision curve analysis. After pairwise comparison, the best performing model was chosen to build a nomogram according to the regression coefficients. RESULTS: Among the 1177 admissions, in-hospital mortality was 13.52%. In both groups, the XGBoost, LASSO regression and Get With the Guidelines-Heart Failure (GWTG-HF) risk score models showed acceptable discrimination. The XGBoost and LASSO regression models also showed good calibration. In pairwise comparison, the prediction effectiveness was higher with the XGBoost and LASSO regression models than with the GWTG-HF risk score model (p<0.05). The XGBoost model was chosen as our final model for its more concise and wider net benefit threshold probability range and was presented as the nomogram. CONCLUSIONS: Our nomogram enabled good prediction of in-hospital mortality in ICU-admitted HF patients, which may help clinical decision-making for such patients.

Clinical Outcomes of Self-Made Polyurethane-Covered Stent Implantation for the Treatment of Coronary Artery Perforations.

OBJECTIVES: The present study aimed to investigate the short- and long-term clinical outcomes of self-made polyurethane-covered stents (PU-CS) in patients for the management of coronary artery perforation (CAP) during percutaneous coronary intervention (PCI). BACKGROUND: Coronary artery perforation is reckoned as a serious complication in PCI and associated with considerable morbidity and mortality. Covered stents have been used for treating the life-threatening CAP during PCI. But in some catheterization laboratories, no commercial CS is immediately available when there is an urgent need for CS to rescue the coronary rupture site. METHODS: We retrospectively identified 24 patients who underwent 31 self-made PU-CS implantations due to CAP in Zhongshan Hospital, Fudan University, from June 2015 to January 2020. RESULTS: The total procedural success rate of CS to seal the perforation was 79.2%. Nine patients (37.5%) developed cardiac tamponade, of which 8 patients (33.3%) underwent pericardiocentesis and 4 patients (16.7%) underwent cardiac surgeries. Except for 4 cardiac death cases (16.7%), none of myocardial infarction (MI), target lesion revascularization (TLR), and stent thrombosis (ST) was reported during hospital stay. Data from 22 patients (91.7%) were available at 610.4 ± 420.9 days of follow-up. Major adverse cardiac events (MACE) occurred in 6 patients (27.3%), including 5 cases of cardiac death and one TLR case. CONCLUSIONS: Self-made PU-CS demonstrates high rates of successful delivery and sealing of severe CAP during PCI. Although the in-hospital mortality remains high after PU-CS implantation, the long-term follow-up shows favorable clinical outcomes, indicating the feasibility of PU-CS in treating CAP.

Reattempt Percutaneous Coronary Intervention of Chronic Total Occlusions after Prior Failures: A Single-Center Analysis of Strategies and Outcomes.

OBJECTIVE: The initial recanalization rate of coronary chronic total occlusions (CTOs) is >85% when performed by experienced operators, but only 10% of prior failed CTO patients receive reattempted recanalization. This retrospective study analyzed the success rate and strategies used in reattempt percutaneous coronary intervention (PCI) of CTOs after prior failures. METHODS: Overall, 206 patients with 212 CTOs were enrolled. All patients with prior recanalization failures received reattempt PCIs from January 2015 to March 2019 at Zhongshan Hospital, Fudan University. Data on clinical factors (age, sex, comorbidities, left ventricular ejection fraction, history of cigarette usage, and revascularization), angiographic characteristics of CTOs (target lesion, Japanese Chronic Total Occlusion (J-CTO) score, the morphology of CTO lesions, and collateral channel scale), strategies (procedural approach and use of devices), and major adverse events were obtained and analyzed. RESULTS: The mean age of enrolled patients was 60.96 ± 12.36 years, with a male predominance of 90.3%. Of the patients, 47.1% had a prior myocardial infarction and 70.4% underwent stent implantation previously, while the in-stent occlusion rate was 6.6%. CTOs were primarily localized in the left anterior descending artery (43.9%) and the right coronary artery (43.9%). 80.7% of lesions were classified as very difficult (J-CTO score ≥3), and the overall success rate was 81.1%. In multivariable regression analysis, J-CTO score, collateral channel scale, application of coronary multispiral computed tomography angiography, dual injection, intravascular ultrasound, active greeting technique, parallel wiring, and CTO morphology were predictors of recanalization success. There were no significant differences in rates of procedural complications between the final recanalization success and failure groups. CONCLUSIONS: Recanalization of complex CTOs is associated with high success rate and low complication rates when performed by high-volume CTO operators and after multiple reattempts.

Qiliqiangxin alleviates Ang II-induced CMECs apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis.

Our previous work revealed the protective effect of Qiliqiangxin (QLQX) on cardiac microvascular endothelial cells (CMECs), but the underlying mechanisms remain unclear. We aimed to investigate whether QLQX exerts its protective effect against high-concentration angiotensin II (Ang II)-induced CMEC apoptosis through the autophagy machinery. CMECs were cultured in high-concentration Ang II (1 µM) medium in the presence or absence of QLQX for 48 h. We found that QLQX obviously inhibited Ang II-triggered autophagosome synthesis and apoptosis in cultured CMECs. QLQX-mediated protection against Ang II-induced CMEC apoptosis was reversed by the autophagy activator rapamycin. Specifically, deletion of ATG7 in cultured CMECs indicated a detrimental role of autophagy in Ang II-induced CMEC apoptosis. QLQX reversed Ang II-mediated ErbB2 phosphorylation impairment. Furthermore, inhibition of ErbB2 phosphorylation with lapatinib in CMECs revealed that QLQX-induced downregulation of Ang II-activated autophagy and apoptosis was ErbB2 phosphorylation-dependent via the AKT-FoxO3a axis. Activation of ErbB2 phosphorylation by Neuregulin-1ß achieved a similar CMEC-protective effect as QLQX in high-concentration Ang II medium, and this effect was also abolished by autophagy activation. These results show that the CMEC-protective effect of QLQX under high-concentration Ang II conditions could be partly attributable to QLQX-mediated ErbB2 phosphorylation-dependent downregulation of autophagy via the AKT-FoxO3a axis.

Qiliqiangxin Prescription Promotes Angiogenesis of Hypoxic Primary Rat Cardiac Microvascular Endothelial Cells via Regulating miR-21 Signaling.

BACKGROUND AND OBJECTIVE: Angiogenesis is the most important repair process of tissues subjected to ischemic injury. The present study aims to investigate whether the pro-angiogenic effect of Qiliqiangxin prescription (QL) is mediated through miR-21 signaling. METHODS: Cardiac microvascular endothelial cells (CMECs) were isolated and cultured from 2-3 weeks old SD rats by the method of planting myocardium tissues. The purity was identified by CD31 immunofluorescence staining. CMECs were then cultured under 1% O2 hypoxia or normoxia condition for 24h in the presence or absence of QL pretreatment (QL, 0.5mg/ml, 24h). The mimics and inhibitors of miR-21 were transfected into CMECs. miR-21, HIF-1α, and VEGF expressions of CMECs were then detected by qRT-PCR and/or Western blot. The proliferation, migration, and tube formation functions of CMECs were assessed using the BrdU assay, wound healing test, and tube formation assay, respectively. RESULTS: The results showed that compared with the control group, hypoxia significantly upregulated the expression of miR-21 and impaired CMECs proliferation, migration, and tube formation functions. Compared with the hypoxia group, QL further upregulated miR-21, HIF-1α, and VEGF expressions, and improved cell proliferation, migration, and tube formation of hypoxic CMECs. These effects of QL were abolished by a knockdown of miR-21. Conversely, treatment with miR-21 mimics further enhanced QL induced changes in hypoxic CMECs. CONCLUSION: Results indicate that the pro-angiogenesis effects of QL on hypoxic CMECs are mediated by activating miR-21 and its downstream HIF-1α/VEGF pathway possibly.

Procedural and In-hospital Outcomes of Rotational Atherectomy in Retrograde Coronary Chronic Total Occlusion Intervention.

Coronary chronic total occlusions (CTOs) are characterized by a high incidence of severe plaque calcifications, which are associated with a high use of the retrograde approach and a low success rate of percutaneous coronary intervention (PCI). However, the feasibility of rotational atherectomy (RA) in retrograde CTO-PCI remains unknown. The aim of the present study is to examine the safety and efficacy of RA in retrograde CTO-PCI. Consecutive patients (n = 129) who underwent RA during CTO-PCI were categorized into anterograde and retrograde groups according to the CTO crossing approach. The distributions of the baseline characteristics were similar in the 2 groups, but the lesion type was more complex (P = .001), and the starting burr size was smaller (P = .003) in the retrograde group than in the anterograde group. There was a trend of a higher incidence of procedural complications in the retrograde group than in the anterograde group (P = .054). Technical and procedural success and in-hospital outcomes were not significantly different between the 2 groups. In conclusion, RA was feasible in retrograde CTO PCI, but some specific precautions are required before and during the procedure. In addition, further investigation of the long-term outcomes of RA in retrograde CTO PCI is necessary.

Qiliqiangxin Improves Cardiac Function through Regulating Energy Metabolism via HIF-1α-Dependent and Independent Mechanisms in Heart Failure Rats after Acute Myocardial Infarction.

The present study is aimed at investigating whether Qiliqiangxin (QL) could regulate myocardial energy metabolism in heart failure rats after acute myocardial infarction (AMI) and further exploring the underlying mechanisms. AMI was established by ligating the left anterior descending coronary artery in adult male SD rats. AMI rats with ejection fraction (EF) < 50% at two weeks after the operation were chosen as heart failure rats for the main study. Rats were randomized into the sham, MI, MI+QL, and MI+QL+2-MeOE2 groups. The results showed that compared with the MI group, QL significantly improved cardiac function, reduced serum NT-proBNP level, and alleviated myocardial fibrosis. QL also increased myocardial capillary density by upregulated protein expressions of vascular endothelial growth factor (VEGF) and CD31 by regulating the HIF-1α/VEGF pathway. Moreover, QL promoted ATP production, glucose uptake, and glycolysis by upregulating HIF-1α and a series of glycolysis-relevant enzymes in a HIF-1α-dependent manner. QL also improved myocardial glucose oxidation enzyme expression and free fatty acid uptake by a HIF-1α-independent pathway. Our results indicate that QL treatment improves cardiac function through regulating glucose uptake, FFA uptake, and key enzymes of energy metabolism via HIF-1α-dependent and independent mechanisms.

Diffuse myocardial fibrosis and the prognosis of heart failure with reduced ejection fraction in Chinese patients: a cohort study.

Evidence regarding the relationship between diffuse myocardial fibrosis and the prognosis of heart failure with reduced ejection fraction (HFrEF) was limited. Therefore, this study set out to investigate whether diffuse myocardial fibrosis was independently related to the prognosis of failure with reduced ejection fraction in Chinese patients after adjusting for other covariates. The present study was a cohort study. A total of 45 consecutive HFrEF patients were involved in Zhongshan Hospital of Fudan University in China from 1/9/2015 to 31/12/2016. The target-independent variable was extracellular volume (ECV) quantified by cardiac magnetic resonance T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence at baseline. To assess the prognostic impact of MOLLI-ECV, its association with hospitalization for heart failure/cardiac death was tested by multivariable Cox regression analysis. Covariates involved in this study included age, gender, body mass index, heart rate, systolic blood pressure diastolic blood pressure, smoking, hypertension, diabetes mellitus, etiology, NYHA functional class, blood urea nitrogen, creatinine, serum uric acid, total bilirubin, and growth stimulation-expressed gene 2. Ten age- and sex-matched healthy participants with no history of cardiovascular disease served as a control group. Mean MOLLI-ECV was significantly higher in HFrEF patients versus healthy controls (29.55 ± 1.46% vs. 23.17 ± 1.93%, P < 0.001). Patients were followed for 9 months, during which the primary outcome (cardiac death or first heart failure hospitalization) occurred in 15 patients. By Kaplan-Meier analysis, patients with high MOLLI-ECV ≥ 30.10% had shorter event-free survival than the middle (MOLLI-ECV between 30.10 and 28.60) and low (MOLLI-ECV < 28.60) MOLLI-ECV patients (log-rank, P = 0.0035). Result of fully-adjusted multivariable Cox regression analysis showed MOLLI-ECV was positively associated with the composite outcome of HFrEF patients after adjusting confounders hazard ratio (HR) 2.57, 95% CI (1.09, 6.04). By subgroup analysis, a stronger association was seen in patients who with NYHA functional class III-IV, hematocrit < 39.8%, left atrial diameter ≥ 53.5 mm, or without the medical history of MRA or diuretics other than MRA. The P for interaction was < 0.05. In HFrEF patients, the relationship between MOLLI-ECV determined by CMR and the composite outcome is linear. High MOLLI-ECV was associated with a higher rate of cardiac mortality and first HF hospitalization in the short term follow up.

Short and long-term outcomes of coronary perforation managed by coil embolization: A single-center experience.

BACKGROUND: Coronary perforation is a serious complication in percutaneous coronary intervention (PCI). In this article, we reported the short and long-term outcomes of patients with coronary perforation managed by coil embolization in our center. METHODS: We retrospectively analyzed 66 patients who had coronary perforation treated by coil embolization during PCI performed in our center from Oct 2012 to June 2018. RESULTS: Of sixty-six cases of coronary perforation, twenty-six cases were distal coronary perforation, while 40 cases were collateral perforation. The average coil number used in distal coronary and collateral perforation lesion is 1.8 ±â€¯0.9 and 1.8 ±â€¯1.0, respectively. The maximum number of coils implanted in each patient is 4 in both groups. Two emergency cardiac surgery to seal the perforation was performed after coil embolization in distal coronary perforation and pericardiocentesis. In collateral perforation, one case of CABG was performed due to myocardial ischemia caused by CTO lesion. During a follow-up of 707 ±â€¯476 days, one patient in collateral perforation group had CABG one month later, while no death or myocardial infarction (MI) was detected. Fifty-four (81.2%) cases of perforations occurred while treating chronic total occlusion, and 74.0% of these perforations were located in collateral vessels, mostly epicardial vessels. Thirty-nine CTO cases (72.2%) were revascularized successfully with the aid of coil embolization. CONCLUSION: Coil embolization is feasible and effective in treating distal coronary perforation and collateral perforation during PCI procedure. In CTO lesions, coil embolization facilitates the success of revascularization by PCI.

Effects of Adiponectin on Diastolic Function in Mice Underwent Transverse Aorta Constriction.

Diastolic dysfunction is common in various cardiovascular diseases, which could be affected by adiponectin (APN). Nevertheless, the effects of APN on diastolic dysfunction in pressure overload model induced by transverse aorta constriction (TAC) remain to be further elucidated. Here, we demonstrated that treatment of APN attenuated diastolic dysfunction and cardiac hypertrophy in TAC mice. Notably, APN also improved active relaxation of adult cardiomyocytes, increased N2BA/N2B ratios of titin isoform, and reduced collagen type I to type III ratio and lysyl oxidase (Lox) expressions in the myocardial tissue. Moreover, APN supplementation suppressed TAC-induced oxidative stress. In vitro, inhibition of AMPK by compound C (Cpc) abrogated the effect of APN on modulation of titin isoform shift and the anti-hypertrophic effect of APN on cardiomyocytes induced by AngII. In summary, our findings indicate that APN could attenuate diastolic dysfunction in TAC mice, which are at least partially mediated by AMPK pathway.

Angiotensin II induces apoptosis of cardiac microvascular endothelial cells via regulating PTP1B/PI3K/Akt pathway.

Endothelial cell apoptosis and renin-angiotensin-aldosterone system (RAAS) activation are the major pathological mechanisms for cardiovascular disease and heart failure; however, the interaction and mechanism between them remain unclear. Investigating the role of PTP1B in angiotensin II (Ang II)-induced apoptosis of primary cardiac microvascular endothelial cells (CMECs) may provide direct evidence of the link between endothelial cell apoptosis and RAAS. Isolated rat CMECs were treated with different concentrations of Ang II to induce apoptosis, and an Ang II concentration of 4 nM was selected as the effective dose for the subsequent studies. The CMECs were cultured for 48 h with or without Ang II (4 nM) in the absence or presence of the PTP1B inhibitor TCS 401 (8 µM) and the PI3K inhibitor LY294002 (10 µM). The level of CMEC apoptosis was assessed by TUNEL staining and caspase-3 activity. The protein expressions of PTP1B, PI3K, Akt, p-Akt, Bcl-2, Bax, caspase-3, and cleaved caspase-3 were determined by Western blot (WB). The results showed that Ang II increased apoptosis of CMECs, upregulated PTP1B expression, and inhibited the PI3K/Akt pathway. Furthermore, cotreatment with PTP1B inhibitor significantly decreased the number of apoptotic CMECs induced by Ang II, along with increased PI3K expression, phosphorylation of Akt and the ratio of Bcl-2/Bax, decreased caspase-3 activity, and a cleaved caspase-3/caspase-3 ratio, while treatment with LY294002 partly inhibited the anti-apoptotic effect of the PTP1B inhibitor. Ang II induces apoptosis of primary rat CMECs via regulating the PTP1B/PI3K/Akt pathway.

Observational Study of Chinese Medicine Syndrome Distribution in Patients with Acute Myocardial Infarction and Its Impact on Prognosis.

OBJECTIVE: To investigate the distribution of Chinese medicine (CM) syndrome in patients with acute myocardial infarction (AMI) on admission and its impact on prognosis. METHODS: A total of 525 AMI patients were prospectively recruited and classifified into 4 groups based on their clinical characteristics: excess-heat, excess-cold, deficiency-heat and deficiency-cold syndromes. Major adverse cardiovascular events (MACEs) were followed up. RESULTS: The excess syndrome was more common than deficiency syndrome (72.95% vs. 27.05%; P<0.05). Totally 495 (94.29%) of 525 AMI patients were followed up (median 277 days). There were 59 (11.92%) MACEs. After adjusted with confounding factors in Cox regression models, the hazard ratio (95% confifidence interval) of excess-heat, excess-cold, defificiency-heat and defificiency-cold syndrome groups were 1, 1.25 (0.63, 2.49; P<0.05), 2.37 (1.14, 4.94; P<0.05), 3.76 (1.71, 8.28; P<0.05), respectively. CONCLUSIONS: Excess syndrome was more common in AMI patients and had better prognosis, while defificiency-cold syndrome had the poorest prognosis. CM syndrome was of value in predicting long-term outcomes in AMI patients.

Qiliqiangxin attenuates hypoxia-induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF-1α-dependent glycolysis.

Protection of cardiac microvascular endothelial cells (CMECs) against hypoxia injury is an important therapeutic strategy for treating ischaemic cardiovascular disease. In this study, we investigated the effects of qiliqiangxin (QL) on primary rat CMECs exposed to hypoxia and the underlying mechanisms. Rat CMECs were successfully isolated and passaged to the second generation. CMECs that were pre-treated with QL (0.5 mg/mL) and/or HIF-1α siRNA were cultured in a three-gas hypoxic incubator chamber (5% CO2 , 1% O2 , 94% N2 ) for 12 hours. Firstly, we demonstrated that compared with hypoxia group, QL effectively promoted the proliferation while attenuated the apoptosis, improved mitochondrial function and reduced ROS generation in hypoxic CMECs in a HIF-1α-dependent manner. Meanwhile, QL also promoted angiogenesis of CMECs via HIF-1α/VEGF signalling pathway. Moreover, QL improved glucose utilization and metabolism and increased ATP production by up-regulating HIF-1α and a series of glycolysis-relevant enzymes, including glucose transport 1 (GLUT1), hexokinase 2 (HK2), 6-phosphofructokinase 1 (PFK1), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Our findings indicate that QL can protect CMECs against hypoxia injury via promoting glycolysis in a HIF-1α-dependent manner. Lastly, the results suggested that QL-dependent enhancement of HIF-1α protein expression in hypoxic CMECs was associated with the regulation of AMPK/mTOR/HIF-1α pathway, and we speculated that QL also improved HIF-1α stabilization through down-regulating prolyl hydroxylases 3 (PHD3) expression.

Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling.

Low density lipoprotein receptor-related protein 6 (LRP6), a wnt co-receptor, regulates multiple functions in various organs. However, the roles of LRP6 in the adult heart are not well understood. Methods: We observed LRP6 expression in heart with end-stage dilated cardiomyopathy (DCM) by western blot. Tamoxifen-inducible cardiac-specific LRP6 knockout mouse was constructed. Hemodynamic and echocardiographic analyses were performed to these mice. Results: Cardiac LRP6 expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to control group. Tamoxifen-inducible cardiac-specific LRP6 knockout mice developed acute heart failure and mitochondrial dysfunction with reduced survival. Proteomic analysis suggests the fatty acid metabolism disorder involving peroxisome proliferator-activated receptors (PPARs) signaling in the LRP6 deficient heart. Accumulation of mitochondrial targeting to autophagosomes and lipid droplet were observed in LRP6 deletion hearts. Further analysis revealed cardiac LRP6 deletion suppressed autophagic degradation and fatty acid utilization, coinciding with activation of dynamin-related protein 1 (Drp1) and downregulation of nuclear TFEB (Transcription factor EB). Injection of Mdivi-1, a Drp1 inhibitor, not only promoted nuclear translocation of TFEB, but also partially rescued autophagic degradation, improved PPARs signaling, and attenuated cardiac dysfunction induced by cardiac specific LRP6 deletion. Conclusions: Cardiac LRP6 deficiency greatly suppressed autophagic degradation and fatty acid utilization, and subsequently leads to lethal dilated cardiomyopathy and cardiac dysfunction through activation of Drp1 signaling. It suggests that heart failure progression may be attenuated by therapeutic modulation of LRP6 expression.

Qiliqiangxin Enhances Cardiac Glucose Metabolism and Improves Diastolic Function in Spontaneously Hypertensive Rats.

Cardiac diastolic dysfunction has emerged as a growing type of heart failure. The present study aims to explore whether Qiliqiangxin (QL) can benefit cardiac diastolic function in spontaneously hypertensive rat (SHR) through enhancement of cardiac glucose metabolism. Fifteen 12-month-old male SHRs were randomly divided into QL-treated, olmesartan-treated, and saline-treated groups. Age-matched WKY rats served as normal controls. Echocardiography and histological analysis were performed. Myocardial glucose uptake was determined by 18F-FDG using small-animal PET imaging. Expressions of several crucial proteins and key enzymes related to glucose metabolism were also evaluated. As a result, QL improved cardiac diastolic function in SHRs, as evidenced by increased E'/A'and decreased E/E' (P < 0.01). Meanwhile, QL alleviated myocardial hypertrophy, collagen deposits, and apoptosis (P < 0.01). An even higher myocardial glucose uptake was illustrated in QL-treated SHR group (P < 0.01). Moreover, an increased CS activity and ATP production was observed in QL-treated SHRs (P < 0.05). QL enhanced cardiac glucose utilization and oxidative phosphorylation in SHRs by upregulating AMPK/PGC-1α axis, promoting GLUT-4 expression, and regulating key enzymes related to glucose aerobic oxidation such as HK2, PDK4, and CS (P < 0.01). Our data suggests that QL improves cardiac diastolic function in SHRs, which may be associated with enhancement of myocardial glucose metabolism.