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Pulmonary hypertension (PH) is caused by chronic hypoxia that induces the migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), eventually resulting in right heart failure. PH has been related to aberrant autophagy; however, the hidden mechanisms are still unclear. Approximately 40% East Asians, equivalent to 8% of the universal population, carry a mutation in Aldehyde dehydrogenase 2 (ALDH2), which leads to the aggregation of noxious reactive aldehydes and increases the propensity of several diseases. Therefore, we explored the potential aspect of ALDH2 in autophagy associated with PH. In vitro mechanistic studies were conducted in human PASMCs (HPASMCs) after lentiviral ALDH2 knockdown and treatment with platelet-derived growth factor-BB (PDGF-BB). PH was induced in wild-type (WT) and ALDH2-knockout (ALDH2-/-) mice using vascular endothelial growth factor receptor inhibitor SU5416 under hypoxic conditions (HySU). Right ventricular function was assessed using echocardiography and invasive hemodynamic monitoring. Histological and immunohistochemical analyses were performed to evaluate pulmonary vascular remodeling. EdU, transwell, and wound healing assays were used to evaluate HPASMC migration and proliferation, and electron microscopy and immunohistochemical and immunoblot assays were performed to assess autophagy. The findings demonstrated that ALDH2 deficiency exacerbated right ventricular pressure, hypertrophy, fibrosis, and right heart failure resulting from HySU-induced PH. ALDH2-/- mice exhibited increased pulmonary artery muscularization and 4-hydroxynonenal (4-HNE) levels in lung tissues. ALDH2 knockdown increased PDGF-BB-induced PASMC migration and proliferation and 4-HNE accumulation in vitro. Additionally, ALDH2 deficiency increased the number of autophagosomes and autophagic lysosomes together with autophagic flux and ERK1/2-Beclin-1 activity in lung tissues and PASMCs, indicating enhanced autophagy. In conclusion, the study shows that ALDH2 has a protective role against the migration and proliferation of PASMCs and PH, possibly by regulating autophagy through the ERK1/2-Beclin-1 pathway.

Cardiomyocyte pyroptosis and apoptosis play a vital role in the pathophysiology of several cardiovascular diseases. Our recent study revealed that Gasdermin D (GSDMD) can promote myocardial I/R injury via caspase-11/GSDMD pathway. Furthermore, we also found that GSDMD deletion attenuated myocardial I/R and MI injury by reducing cardiomyocyte apoptosis and pyroptosis. However, how GSDMD mediates cardiomyocyte apoptosis and protects myocardial function remains unclear. We here evaluated that doxorubicin (DOX) treatment resulted in significantly increased apoptosis instead of pyroptosis in cardiomyocytes. Interestingly, GSDMD overexpression promoted cardiomyocyte apoptosis, and GSDMD knockdown attenuated cardiomyocyte apoptosis. Notably, GSDMD overexpression exacerbated DOX-induced cardiotoxicity (DIC) injury, impaired cardiac function in vitro and in vivo, and enhanced DOX-induced cardiomyocyte autophagy. Mechanistically, GSDMD regulated the activity of FAM134B, an endoplasmic reticulum autophagy receptor, by pore formation on the endoplasmic reticulum membrane via its N-terminus, thus activating endoplasmic reticulum stress. In turn, FAM134B interacted with autophagic protein LC3, thus inducing cardiac autophagy, promoting cardiomyocyte apoptosis and aggravating DIC. These results suggest that GSDMD promotes autophagy and induces cardiomyocyte apoptosis by modulating the reaction of FAM134B and LC3, thereby promoting DIC injury. Targeted regulation of GSDMD may be a new target for the prevention and treatment of DIC.

Background Obesity is often considered as a risk factor of cardiovascular events, but recent researches showed conflicting results regarding to the effect of body weight on prognosis of coronary artery disease (CAD). This study aimed to evaluate the relationship between body mass index (BMI) and clinical outcomes of CAD in Asian population. Methods A total of 4315 patients from the FOCUS registry were enrolled into this analysis. Patients were divided into 4 groups according to BMI: lean group (BMI 30 kg/m2). Follow-up was continued to 3 years to evaluate clinical outcomes, and the primary endpoint was a composite of all-cause death and myocardial infarction (MI). Results Patients with higher BMI were more likely to be associated with cardiovascular risk factors like hypertension, hypercholesterolemia and diabetes, but not smoking. At the end of the follow-up period, however, the incidence of a composite endpoint of all-cause death and MI was significantly lower in the higher BMI (overweight and obese) subsets, as compared with the lower BMI group (5.2% vs. 8.0%, p Conclusions In Asian patients with CAD, an inverse association between BMI and long-term prognosis was observed. Although overweight or obese patients were associated with more metabolism-associated comorbidities, they had significantly lower adverse events at 3-year follow up after percutaneous coronary intervention.

During myocardial infarction (MI), the stimulation of the cGAS-STING-IRF3 pathway in infiltrated macrophages can induce the apoptosis of cardiomyocytes and the fibrosis of cardiac fibroblasts, while H-151 is reported as a selective STING inhibitor. We intended to use H-151 to alleviate MI injury.Male C57BL/6J mice were subjected to induce MI, while H-151 (750 nmol) were used for treatment. Myocardial function was assessed through echocardiology and cardiac fibrosis was evaluated by Masson's Trichrome-staining. The stimulation of the STING pathway and the aggravation of inflammation was assessed by levels of protein and mRNA. BMDMs were stimulated by dsDNA extracted from the murine heart, while H-151 was used as treatment. After co-culturing adult cardiomyocytes and cardiac fibroblasts with supernatant of BMDMs, the apoptosis of adult cardiomyocytes and the fibrosis of cardiac fibroblasts was assessed.H-151 treatment showed significant function in preserving myocardial function and decreasing cardiac fibrosis 28 days after MI. H-151 treatment showed significant function in inhibiting the cGAS-STING-IRF3 pathway and inflammation, especially type I interferon response. H-151 could alleviate the type I interferon response in BMDMs elicited by cardiac dsDNA, and thus H-151 could attenuate the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts after co-culturing them with the supernatant of BMDMs.H-151, a selective inhibitor of the cGAS-STING-IRF3 pathway, can preserve myocardial function and alleviate cardiac fibrosis after MI by inhibiting the type I interferon response in infiltrated macrophages triggered by cardiac dsDNA which increase the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts.

Cardiac fibrosis is a common feature of various cardiovascular diseases. Previous studies showed that acetaldehyde dehydrogenase 2 (ALDH2) deficiency exacerbated pressure overload-induced heart failure. However, the role and mechanisms of cardiac fibrosis in this process remain largely unknown. This study aimed to investigate the effect of ALDH2 deficiency on cardiac fibrosis in transverse aortic constriction (TAC) induced pressure overload model in mice. Echocardiography and histological analysis revealed cardiac dysfunction and enhanced cardiac fibrosis in TAC-operated animals; ALDH2 deficiency further aggravated these changes. ALDH2 chimeric mice were generated by bone marrow (BM) transplantation of WT mice into the lethally irradiated ALDH2KO mice. The proportion of circulating fibroblast progenitor cells (FPCs) and ROS level in BM after TAC were significantly higher in ALDH2KO mice than in ALDH2 chimeric mice. Furthermore, FPCs were isolated and cultured for in vitro mechanistic studies. The results showed that the stem cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR4) axis played a major role in the recruitment of FPCs. In conclusion, our research reveals that increased bone marrow FPCs mobilization and myocardial homing contribute to the enhanced cardiac fibrosis and dysfunction induced by TAC in ALDH2 KO mice via exacerbating accumulation of ROS in BM and myocardial SDF-1 expression.

Rationale: Pyroptosis is a morphologically and mechanistically distinct form of cell death and is characterized by GSDMD (gasdermin D) or GSDME (gasdermin E)-mediated necrosis with excessive inflammatory factor release. Cardiomyocyte necrosis and inflammation play key roles in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. However, whether cardiomyocytes undergo pyroptosis and the underlying mechanism in myocardial I/R injury remain unclear. Objective: We aimed to investigate the role of pyroptosis in myocardial I/R injury. Methods and Results: In vivo and in vitro experiments were used to investigate pyroptosis of cardiomyocyte and the associated mechanisms during I/R injury. Wild-type, Myh6-Cre, and cardiomyocyte-specific GSDMD-deficient male mice were subjected to I/R. Human peripheral blood samples were collected from patients with acute ST-segment–elevation myocardial infarction or control patients at 0, 1, and 24 hours after percutaneous coronary intervention in our department. The serum levels of GSDMD were measured by ELISA. Hypoxia/reoxygenation induced cardiomyocyte pyroptosis and the release of mature IL (interleukin)-18 but not IL-1β, which mechanistically resulted from GSDMD cleavage by caspase-11 in cardiomyocytes. Furthermore, GSDMD gene deletion blocked hypoxia/reoxygenation-induced cardiomyocyte pyroptosis and IL-18 release. GSDMD and its pyroptosis-inducing N-terminal fragment were upregulated in myocardial tissues after I/R injury. Immunofluorescence analysis showed that GSDMD was mainly localized in cardiomyocytes. GSDMD deficiency in cardiomyocytes significantly reduced the I/R-induced myocardial infarct size. Moreover, increased GSDMD serum levels were detected in patients exhibiting I/R injury 1 hour after percutaneous coronary intervention for ST-segment–elevation myocardial infarction. Conclusions: Our results show that GSDMD-mediated cardiomyocyte pyroptosis is a key event during myocardial I/R injury and that the caspase-11/GSDMD pathway may be essential to this process. Additionally, GSDMD inhibition significantly reduces cardiomyocyte pyroptosis and I/R-induced myocardial injury.

We compared the efficacy and safety of the transradial approach percutaneous coronary intervention (TRA-PCI) and transfemoral approach percutaneous coronary intervention (TFA-PCI) for bypass grafts lesions. Patients (n = 184) were retrospectively enrolled. Less contrast was used during the procedure in the TRA group than in the TFA group, 201.5 (45.5) mL versus 221.5 (49.1) mL, P = .004, although fluoroscopy time was longer in the TRA group, 22.5 (6.3) minutes versus 20.3 (6.1) minutes; P = .017. The incidence of net adverse clinical events (NACEs) was lower in the TRA group than in the TFA group (3.1% vs 8.8%, respectively, P = .111). The incidence of Bleeding Academic Research Consortium type 3 and 5 bleeding (0% vs 5.5%, respectively, P = .022) was significantly lower in the TRA group than in the TFA group. For 1-year outcomes, there was no difference in the incidence of major adverse cardiovascular events (7.5% vs 9.9%, respectively, P = .569). In conclusion, TRA-PCI was associated with a lower rate of in-hospital NACEs mainly attributed to lower rates of major bleeding. The TRA-PCI showed comparable feasibility and efficacy in bypass grafts as compared with TFA-PCI when carried out by experienced operators.

Background The optimal intervention strategy remains controversial in small vessel disease which is a very common kind of coronary artery lesions. For now, balloon-only percutaneous coronary intervention is the major percutaneous revascularization method in these patients, but the restenosis rate is still at a high level. Drug coated balloon is designed to deliver paclitaxel to target vessel to inhibit the proliferation of vascular endothelial cells, it aims at restraining the stenosis process after intervention so as to reduce the rate of restenosis. Ultrasound controlled paclitaxel releasing balloon catheter (Vasoguard TM ) is a newly designed drug coated balloon, expected to promote the drug release process via external ultrasound intervention so as to improve drug bioavailability. The current trial was designed to assess the efficacy and safety of Vasoguard in the treatment of small vessel coronary disease.Methods A prospective, multicenter, randomized, controlled clinical trial has been designed to compare the safety and efficacy of Vasoguard with plain balloon angioplasty in the treatment of small vessel coronary disease. 230 patients will be included in this trial, the primary endpoint is late lumen loss of target lesion at 9 months post operation measured by quantitative coronary angiography. Secondary endpoints include angiographic findings such as device success rate, operation success rate, in-segment restenosis, clinical outcomes such as target lesion revascularization, target vessel revascularization, device oriented composite endpoint and thrombotic events.Discussion This trial will evaluate the efficacy and safety of Vasoguard in the treatment of small vessel coronary disease by comparing to plain balloon angioplasty. It will clarify the practicability of the newly designed balloon and may lend more credence to the role of drug coated balloon in the treatment of small vessel disease.

Nε-(carboxymethyl) lysine (CML), the major member of advanced glycation end products, was widely studied in diabetic complications and aging-associated diseases. However, the impact of CML on myocardial ischemia/reperfusion injury (MI/RI) was rarely reported. In the present study, CML was increased in both patients with acute myocardial infarction (53.4 ± 7.8

To investigate the impact of sex on clinical outcomes after drug-eluting stent (DES) implantation in real-world patients.A total number of 4720 patients (3365 males and 1355 females) undergoing the second-generation cobalt-chromium sirolimus-eluting stent (CoCr-SES) implantation from the FOCUS registry were included in this analysis. The cumulative incidences of major adverse cardiovascular event (MACE) (1.5% vs. 2.4%; p = .03), cardiovascular death (0.5% vs. 1.0%; p = .02) and target vessel revascularization (TVR) (0.3% vs. 0.8%; p = .01) within six months were significantly higher in females and the risks of MACE (adjusted hazard ratio [HR] 0.5 (0.3-0.9); p = .01) and TVR (adjusted HR 0.1(0.0-0.5); p = .001) remained significant in multivariate analysis. Reversely, the cumulative incidences of MACE (5.4% vs. 4.8%; p = .04) and any revascularization (5.1% vs. 3.3%; p = .01) were significantly higher in males beyond six months and the risks of all-cause death (adjusted HR 1.6 (1.1-2.5); p = .03) and cardiovascular death (adjusted HR 1.9 (1.1-3.6); p = .03) turned out to be significant in multivariate analysis. Notes: All cumulative incidences were presented as male vs. female; all HRs were calculated as male relative to female.Females were associated with higher risk of early adverse events, while, males were associated with higher risk of late adverse events. Key messages Females undergoing PCI are typically older, have more cardiovascular risk factors, while, males in need of PCI are more frequently associated with complex lesions. The overall three-year cumulative incidences of adverse events are not significantly different between males and females but numerically higher in males. Females are associated with significantly higher risks of MACE and TVR within six months, while, males are associated with significantly higher risk of all-cause mortality and cardiac mortality beyond 6 months.

The short- and mid-term outcomes of the second-generation cobalt-chromium sirolimus-eluting stent (CoCr-SES) in real-world patients had been reported previously, but the long-term performance remained unclear. The objective of this analysis was to evaluate the long-term safety and efficacy of the second-generation CoCr-SES from the FOCUS registry.The FOCUS registry (ClinicalTrials.gov Identifier: NCT00868829) enrolled all-comers eligible to receive Firebird-2 CoCr-SES. Follow-up was continued to 3 years to evaluate long-term safety and effectiveness of the second-generation CoCr-SES in real-world practice. Results of the extended-use group and standard-use group are compared to explore performance of CoCr-SES in more severe patients with more complex lesions.The rate of 3-year MACE was 7.37%, consisting of 84 cases (1.78%) of cardiac death, 166 cases (3.52%) of MI and 98 cases (2.08%) of TVR. ARC definite/probable stent thrombosis happened in 34 (0.72%) patients, only 3 new cases (0.1%) of very late stent thrombosis was reported in the third year. Meanwhile, the difference of MACE (7.77% vs. 6.06%; P=0.058), TLF (4.71% vs. 3.49%; P=0.085) and ARC definite/probable stent thrombosis (0.83% vs. 0.37%; P=0.116) between extended-use group and standard-use group showed no significance.The second-generation CoCr-SES was associated with continued low rates of 3-year MACE, TLF and stent thrombosis in a broad spectrum of patients.

Premature coronary artery disease (PCAD) is increasingly common in Asian countries; however, less is known regarding its characteristics and clinical outcomes. This study aims to describe clinical characteristics and investigate clinical outcomes in real-world Asian patients with PCAD.A total of 4700 Asian patients undergoing drug-eluting stent implantation were included in our study and divided into PCAD group and mature CAD (MCAD) group according to their onset age. All patients were followed up for 3 years to observe their clinical outcomes.Patients with PCAD were more likely to be associated with acute coronary syndrome (ACS; P = .03) and acute occlusive lesion ( P.001). Reference diameter ( P.001) and lesion diameter stenosis ( P = .001) were significantly greater in PCAD group. Conversely, the MCAD group was more likely to be associated with left main disease, severe calcification lesion and small vessel involvement. The cumulative incidences of major adverse cardiovascular event (MACE; P = .007), cardiovascular death ( P.001), and all cause death ( P.001) were significantly lower in PCAD group than those in MCAD group.Although more often manifested as ACS, PCAD is associated with lower risks of MACE and cardiovascular death than MCAD in real-world Asian population.

Diabetes mellitus (DM) was broadly acknowledged as a risk factor for adverse events after coronary stent implantation. However, the role of DM in patients treated with second-generation cobalt-chromium sirolimus-eluting stents (CoCr-SES) was less known.A total of 4720 patients available for 3-year follow-up in the prospective FOCUS registry were subdivided into the DM group and the non-DM group to assess the effect of DM on the clinical outcomes after CoCr-SES implantation both before and after propensity score matching.The rates of major adverse cardiovascular event was low (10%) in both DM and non-DM groups but significantly greater in the DM group after matching (9.6% versus 6.1%; p = 0.005). Although the soft endpoints including target vessel revascularization (2.3% versus 2.3%; p = 0.938) and target lesion revascularization (1.2% versus 1.1%; p = 0.828) was not significantly different between two groups, the hard endpoints represented by cardiovascular death or myocardial infarction (7.3% versus 5.3%; p = 0.012) demonstrated a significant increase in the DM group.This subgroup analysis demonstrated that DM significantly increased the risk of adverse events after implantation of CoCr-SES, but the general safety and efficacy performance of CoCr-SES in both diabetic and non-diabetic patients was satisfying and comparable with other types of new-generation drug-eluting stents.