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Since 2010, China has made vast financial investments and policy changes to the primary care system. We aimed to assess how hypertension awareness, treatment, and control might be used to assess quality of primary care systems, which reflect the outcomes of public health services and medical care.We used The China Patient-centred Evaluative Assessment of Cardiac Events Million Persons Project, a government-funded public health project that focuses on cardiovascular disease risk in China. We linked primary care institution characteristics that were captured in the survey between 2016 and 2017 to the participant-level data gathered in baseline visits between 2014 and 2021. Participants were included if they had hypertension and lived in the towns or streets that took part in the primary care survey. Participants were excluded if they had missing data for blood pressure measurement, history of hypertension, sex, or age. Primary care institutions were excluded if the catchment area had fewer than 100 participants with hypertension. Hypertension awareness was defined as the proportion of participants with hypertension who self-reported a hypertension diagnosis. Hypertension treatment was defined as the proportion of participants who currently use antihypertensive medications among those who were aware. Hypertension control was defined as the proportion of participants with an average systolic blood pressure less than 140 mm Hg and an average diastolic blood pressure less than 90 mm Hg over two readings among those who were treated during the study. All patients were included in the analysis. This trial was registered at ClinicalTrials.gov, NCT02536456.Between Sept 15, 2014, and March 16, 2021, we assessed 503 township-level primary care institutions for eligibility. 70 institutions were excluded as they could not be linked with individual data or because their catchment area had fewer than 100 participants with hypertension. We analysed 433 township-level primary care institutions across all 31 provinces of mainland China, including 660 565 individuals with hypertension in their catchment areas. Across townships, age-sex standardised hypertension awareness varied from 8·2% to 81·0%, treatment varied from 2·6% to 96·5%, and control proportions varied from 0% to 62·4%. Hypertension awareness, treatment, and control were significantly associated with the following institutional characteristics: government funding through balance allocation (ie, institutions have their human resources funded by local government, but need to be self-supporting in other aspects; awareness odds ratio 0·88, 95% CI 0·78-0·99; p=0·027), having financial problems that interrupted routine service delivery (awareness 0·81, 0·72-0·92; p=0·0007, control 0·84; 0·75-0·94, p=0·0034), setting performance-based bonus (treatment 1·39, 1·07-1·80; p=0·013), basic salary defined by number of patient visits (control 0·85, 0·76-0·95; p=0·0053), using electronic referrals (treatment 1·41, 1·14-1·73; p=0·0012, control 1·17; 1·03-1·33, p=0·014), implementing family physician contract services (awareness 1·13, 1·00-1·28; p=0·045, control 1·30; 1·15-1·46, p0·0001), and proportion of physicians who are formally licensed (awareness per 10% increase 1·04, 1·01-1·08; p=0·019, treatment 1·08; 1·02-1·14, p=0·0077; control per 10% increase 1·07, 1·03-1·10; p=0·0006).The role of primary care role in hypertension management might benefit from new strategies that promote best practices in institutional financing, performance appraisal, service delivery, and information technology.Chinese Academy of Medical Sciences Innovation Fund for Medical Science, and the National High Level Hospital Clinical Research Funding.For the Chinese translation of the abstract see Supplementary Materials section.

The RNA editing tool CRISPR-CasRx has provided a platform for a range of transcriptome analysis tools and therapeutic approaches with its broad efficacy and high specificity. To enable the application of CasRx in vivo, we established a Credependent CasRx knock-in mouse. Using these mice, we specifically knocked down the expression of Meis1 and Hoxb13 in cardiomyocytes, which induced cardiac regeneration after myocardial infarction. We also knocked down the lncRNA Mhrt in cardiomyocytes with the CasRx knock-in mice, causing hypertrophic cardiomyopathy. In summary, we generated a Credependent CasRx knock-in mouse that can efficiently knock down coding gene and lncRNA expression in specific somatic cells. This in vivo CRISPR-CasRx system is promising for gene function research and disease modeling.

Severe mitral regurgitation (MR) is associated with progressive heart failure and impairment of survival. Degenerative MR accounts for most MV repair surgeries. Conventional mitral valve repair surgery requires cardiopulmonary bypass and is associated with significant morbidity and risks. Transapical beating-heart mitral valve repair by artificial chordae implantation with transesophageal echocardiography (TEE) guidance has the potential to significantly reduce surgical morbidity. We report the first-in-human experience of degenerative MR repair using a novel artificial chordae implantation device (MitralstitchTen patients with severe MR underwent transapical artificial chordae implantation using MitralstitchTM system. The procedure was performed through a small left thoracotomy under general anesthesia and TEE guidance. Patients underwent transthoracic echocardiography and other assessments during the follow-up.All 10 patients with an average age of 63.7 ± 9.6 years successfully received transapical artificial chordae implantation. Their MR reduced from severe to none or trace in five patients, mild in five patients before discharge. Five patients received one artificial chordal implantation, four patients received two, and one patient received three and edge-to-edge repair by locking two of them. The safety and efficacy endpoint were achieved in all patients at 1-month follow-up. At 1-year follow-up, six patients had mild MR, three patients had moderate MR, one patient had recurrence of severe MR and underwent surgical repair.The results of this first-in-human study show safety and feasibility of transapical mitral valve repair using MitralStitch system. Patient selection and technical refinement are crucial to improve the outcomes.

The safety and blood management effects of Tranexamic acid (TXA) and its dose effects in coronary artery bypass graft (CABG) were still ambiguous. This study aimed to analyze these TXA effects.Overall, 42,010 patients undergoing CABG were enrolled in this retrospective cohort study. Patients were assigned to the TXA group (n = 29,536) and the no-TXA group (n = 12,474). Furthermore, the TXA group was divided into the high-dose (≥50 mg/kg) (16,488) and the low-dose (50 mg/kg) (13,048) subgroup. Propensity score matching was performed in both groups respectively. The primary endpoint after CABG was composed of hospital death, perioperative myocardial infarction (PMI), stroke, acute kidney injury (AKI), and pulmonary embolism. The secondary endpoint included blood loss and blood transfusion after surgery.TXA led to a 1.40-fold risk of PMI (p 0.001). Patients in the TXA group had fewer re-operations for bleeding or tamponade [Odd ratio (OR) = 0.82, p = 0.044], less blood loss after surgery (p 0.001), and a lower risk for blood transfusion exposure (OR = 0.45, p 0.001) than those in the no-TXA group. The high-dose TXA reduced blood loss after cardiac surgery compared to the low-dose TXA (p 0.001) with no associations with blood exposure or adverse events.The use of TXA during CABG increased the risk of PMI despite better blood control after surgery. The high dose of TXA acquired better bleeding management. Meanwhile, it did not increase the risk of primary endpoint.

Background: Vein graft occlusion is deemed a major challenge in coronary artery bypass grafting. Previous studies implied that the no-touch technique for vein graft harvesting could reduce occlusion rate compared with the conventional approach; however, evidence on the clinical benefit and generalizability of the no-touch technique is scare. Methods: From April 2017 to June 2019, we randomly assigned 2655 patients undergoing coronary artery bypass grafting at 7 hospitals in a 1:1 ratio to receive no-touch technique or conventional approach for vein harvesting. The primary outcome was vein graft occlusion on computed tomography angiography at 3 months and the secondary outcomes included 12-month vein graft occlusion, recurrence of angina, and major adverse cardiac and cerebrovascular events. The generalized estimate equation model was used to account for the cluster effect of grafts from the same patient. Results: During the follow-up, 2533 (96.0%) participants received computed tomography angiography at 3 months after coronary artery bypass grafting and 2434 (92.2%) received it at 12 months. The no-touch group had significantly lower rates of vein graft occlusion than the conventional group both at 3 months (2.8% versus 4.8%; odds ratio, 0.57 [95% CI, 0.41–0.80]; P P P P Conclusions: Compared with the conventional vein harvesting approach in coronary artery bypass grafting, the no-touch technique significantly reduced the risk of vein graft occlusion and improved patient prognosis. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03126409.

Mesenchymal stem cell (MSC) transplantation is regarded as a promising candidate for the treatment of ischaemic heart disease. The major hurdles for successful clinical translation of MSC therapy are poor survival, retention, and engraftment in the infarcted heart. Stromal cell-derived factor-1/chemokine receptor 4 (SDF-1/CXCR4) constitutes one of the most efficient chemokine/chemokine receptor pairs regarding cell homing. In this review, we mainly focused on previous studies on how to regulate the SDF-1/CXCR4 interaction through various priming strategies to maximize the efficacy of mesenchymal stem cell transplantation on ischaemic hearts or to facilitate the required effects. The strengthened measures for enhancing the therapeutic efficacy of the SDF-1/CXCR4 interaction for mesenchymal stem cell transplantation included the combination of chemokines and cytokines, hormones and drugs, biomaterials, gene engineering, and hypoxia. The priming strategies on recipients for stem cell transplantation included ischaemic conditioning and device techniques.

The intraventricular blood flow changed by blood pump flow dynamics may correlate with thrombosis and ventricular suction. The flow velocity, distribution of streamlines, vorticity, and standard deviation of velocity inside a left ventricle failing to different extents throughout the cardiac cycle when supported by an axial blood pump were measured by particle image velocimetry (PIV) in this study. The results show slower and static flow velocities existed in the central region of the left ventricle near the mitral valve and aortic valve and that were not sensitive to left ventricular (LV) failure degree or LV pressure. Strong vorticity located near the inner LV wall around the LV apex and the blood pump inlet was not sensitive to LV failure degree or LV pressure. Higher standard deviation of the blood velocity at the blood pump inlet decreased with increasing LV failure degree, whereas the standard deviation of the velocity near the atrium increased with increasing intraventricular pressure. The experimental results demonstrated that the risk of thrombosis inside the failing left ventricle is not related to heart failure degree. The “washout” performance of the strong vorticity near the inner LV wall could reduce the thrombotic potential inside the left ventricle and was not related to heart failure degree. The vorticity near the aortic valve was sensitive to LV failure degree but not to LV pressure. We concluded that the risk of blood damage caused by adverse flow inside the left ventricle decreased with increasing LV pressure.

Background:Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury.Methods:Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries.Results:Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow–derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide–dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside.Conclusions:PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.

Exosomes derived from human umbilical cord mesenchymal stem cells (UMSC-Exos) have shown encouraging effects in regulating inflammation and attenuating myocardial injury. Macrophages are regulated dynamically in response to environmental cues. However, the underlying mechanisms by which UMSC-Exos regulate macrophage polarization are still not well understood. Herein, it is aimed to explore the effects of UMSC-Exos on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI). These results show that UMSC-Exos improve cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. RNA-sequencing results identify Plcb3 as a key gene involved in UMSC-Exo-facilitated M2 macrophage polarization. Further bioinformatic analysis identifies exosomal miR-24-3p as a potential effector mediating Plcb3 downregulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhances M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in the inflammatory environment. Furthermore, reducing miR-24-3p expression in UMSC-Exos attenuates the effects of UMSC-Exos on M2 macrophage polarization. This study demonstrates that the cardiac therapeutic effects of UMSC-Exos are at least partially through promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanistically, exosomal miR-24-3p is found to inhibit Plcb3 expression and NF-κB pathway activation to promote M2 macrophage polarization.

Objectives Acknowledging lacking of consensus exist in total aortic arch (TAA) surgery for acute type A aortic dissection (AAD), this study aimed to investigate the neurologic injury rate between bilateral and unilateral cerebrum perfusion on the specific population. Methods A total of 595 AAD patients other than Marfan syndrome receiving TAA surgery since March 2013 to March 2022 were included. Among them, 276 received unilateral cerebral perfusion (via right axillary artery, RCP) and 319 for bilateral cerebral perfusion (BCP). The primary outcome was neurologic injury rate. Secondary outcomes were 30-day mortality, serum inflammation response (high sensitivity C reaction protein, hs-CRP; Interleukin-6, IL-6; cold-inducible RNA binding protein, CIRBP) and neuroprotection (RNA-binding motif 3, RBM3) indexes. Results The BCP group reported a significantly lower permanent neurologic deficits [odds ratio: 0.481, Confidence interval (CI): 0.296–0.782, p = 0.003] and 30-day mortality (odds ratio: 0.353, CI: 0.194–0.640, p < 0.001) than those received RCP treatment. There were also lower inflammation cytokines (hr-CRP: 114 ± 17 vs. 101 ± 16 mg/L; IL-6: 130 [103,170] vs. 81 [69,99] pg/ml; CIRBP: 1076 [889, 1296] vs. 854 [774, 991] pg/ml, all p < 0.001), but a higher neuroprotective cytokine (RBM3: 4381 ± 1362 vs 2445 ± 1008 pg/mL, p < 0.001) at 24 h after procedure in BCP group. Meanwhile, BCP resulted in a significantly lower Acute Physiology, Age and Chronic Health Evaluation (APACHE) Ⅱscore (18 ± 6 vs 17 ± 6, p < 0.001) and short stay in intensive care unit (4 [3,5] vs. 3 [2,3] days, p < 0.001) and hospital (16 ± 4 vs 14 ± 3 days, p < 0.001). Conclusions This present study indicated that BCP compared with RCP was associated with lower permanent neurologic deficits and 30-day mortality in AAD patients other than Marfan syndrome receiving TAA surgery.

ObjectiveTricuspid regurgitation (TR) is a common valvular heart disease with unsatisfactory medical therapeutics and high surgical mortality. The present study aims to evaluate the safety and effectiveness of transcatheter tricuspid valve replacement (TTVR) in high-risk patients with severe TR.MethodsThis was a compassionate multicentre study. Between September 2018 and November 2019, 46 patients with TR who were not suitable for surgery received compassionate TTVR under general anaesthesia and the guidance of trans-oesophageal echocardiography and fluoroscopy in four institutions. Access to the tricuspid valve was obtained via a minimally invasive thoracotomy and transatrial approach. Patients’ data at baseline, before discharge, 30 days and 6 months after the procedure were collected.ResultsAll patients had severe TR with vena contracta width of 12.6 (11.0, 14.5) mm. Procedural success (97.8%) was achieved in all but one case with right ventricle perforation. The procedural time was 150.0 (118.8, 180.0) min. Intensive care unit time was 2.0 (1.0, 4.0) days. 6-month mortality was 17.4%. Device migration occurred in one patient (2.4%) during follow-up. Transthoracic echocardiography at 6 months after operation showed TR was significantly reduced (none/trivial in 33, mild in 4 and moderate in 1) and the primary safety end point was achieved in 38 cases (82.6%). Patients suffered from peripheral oedema and ascites decreased from 100.0% and 47.8% at baseline to 2.6% and 0.0% at 6 months.ConclusionsThe present study showed TTVR was feasible, safe and with low complication rates in patients with severe TR.

Although evidence is sufficient to confirm that hybrid coronary revascularization (HCR) is safe and effective in the short term, its value in the long run is debatable.This study sought to compare the long-term outcomes of HCR with coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for multivessel disease.Three groups of patients, 540 each, receiving HCR, CABG, or PCI between June 2007 to September 2018, were matched using propensity score matching. Patients were stratified by EuroSCORE (European System for Cardiac Operative Risk Evaluation) II (low ≤0.9; 0.9 medium 1.5; high ≥1.5) and SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (low ≤22; 22 medium 33; high ≥33). Major adverse cardiac and cerebrovascular events (MACCE) and Seattle Angina Questionnaire (SAQ) scores were compared among the 3 groups.In terms of MACCE and SAQ, HCR performed similarly to off-pump CABG but significantly outperformed PCI (P 0.001). In the low-to-medium EuroSCORE II and medium-to-high SYNTAX score tertiles, MACCE rates in the HCR group were significantly lower than those in the PCI (EuroSCORE II: low, 30.7% vs 41.2%; P = 0.006; medium, 31.3% vs 41.7%; P = 0.013; SYNTAX score: medium, 27.6% vs 41.2%; P = 0.018; high, 32.4% vs 52.7%; P = 0.011) but were similar to those in the CABG group. In the high EuroSCORE II stratum, HCR had a lower MACCE rate than CABG (31.9% vs 47.0%; P = 0.041) and PCI (31.9% vs 53.7%; P = 0.015).Compared with conventional strategies, HCR provided satisfactory long-term outcomes in MACCE and functional status for multivessel disease.

With the rapid development of single‐cell sequencing technology, the Langendorff perfusion system has emerged as a common approach to decompose cardiac tissue and obtain living cardiomyocytes to study cardiovascular disease with the mechanism of cardiomyocyte biology. However, the traditional Langendorff perfusion system is difficult to master, and further, the viability and purity of cardiomyocytes are frequently unable to meet sequencing requirements due to complicated devices and manipulate processes. Here, we provide an optimized Langendorff perfusion system with a simplified and standardized operating protocol which utilizes gravity as the perfusion pressure, includes a novel method for bubbles removing and standardizes the criteria for termination of digestion. We obtained stable cardiomyocyte with high viability and purity after multiple natural gravity sedimentation. The combination of the optimized Langendorff perfusion system and the multiple natural gravity sedimentation provides a stable system for isolating adult mouse heart, which will provide higher‐quality cardiomyocytes for further experiments.

Intraventricular blood stasis is a design consideration for continuous flow blood pumps and might contribute to adverse events such as thrombosis and ventricular suction. However, the blood flow inside left ventricles (LVs) supported by blood pumps is still unclear. In vitro experiments were conducted to imitate how the hydraulic performance of an axial blood pump affects the intraventricular blood flow of a severe heart failure patient, such as velocity distribution, vorticity, and standard deviation of velocity. In this study, a silicone model of the LV was constructed from the computed tomography data of one patient with heart failure and was 3D printed. Then, intraventricular flow was visualized by particle image velocimetry equipment within a mock circulation loop. The results showed that the axial blood pump suctions most of the blood in a severely failing LV, there was an altered flow status within the LV, and blood stasis appeared in the central region of the LV. Some blood may be suctioned from the aortic valve to the blood pump because the patient's native heart was severely failing. Blood stasis at the LV center may cause thrombosis in the LV. The vortex flow near the inner wall of the LV can thoroughly wash the left ventricular cavity.

Background The purpose of this study was to investigate risk factors of in‐hospital mortality and vascular complications after coronary artery bypass grafting (CABG), particularly the effect of different glycemic control levels on outcomes in patients with and without previous evidence of diabetes. Methods A total of 8682 patients with and without previous diabetes undergoing CABG were categorized into strict, moderate, and liberal glucose control groups according to their mean blood glucose control level, Highlights Smoking cessation, treating low‐density lipoprotein cholesterol to target levels, preventing diabetes, and highly individualized glucose control are crucial for minimizing the risk of subsequent in‐hospital death and complications after coronary artery bypass grafting (CABG).Among patients with diabetes, strict glucose control significantly increased the risk of in‐hospital mortality compared with moderate glucose control, whereas among nondiabetic patients with stress hyperglycemia, it reduced the risk of major complications. Thus, optimal glycemic control targets after CABG may differ among patients with and without previous diabetes.

OBJECTIVES The present study evaluated the results of the modified réparation à l’étage ventriculaire (REV) based on the individual anatomical and pathological findings of the patients with an anomalous ventriculo-arterial connection with ventricular septal defect (VSD) and left ventricular outflow tract obstruction. METHODS We reviewed a series of 24 patients who underwent modified REV between 2005 and 2019. Surgical indications included ventricles and atrioventricular valves suitable for biventricular repair, severe left ventricular outflow tract obstruction (peak gradient >30 mmHg), unrestrictive subaortic VSD and coronary arteries not suitable for reimplantation. RESULTS The mean follow-up time was 7.0 ± 4.2 years (range 0.5–14.1 years). Kaplan–Meier analyses showed that overall survival was 100% and freedom from any reoperation was 93.3% ± 6.4%. Longitudinal analyses of the available postoperative echocardiographic data showed that the left ventricular outflow tract peak gradient was less than 10 mmHg in all patients (15/15) and the left ventricular ejection fraction was more than 50% in 93.3% of patients (14/15). The right ventricular outflow tract peak gradient was less than 40 mmHg in 73.3% of patients (11/15). CONCLUSIONS The REV remains an option for selected patients despite the increasing use in recent years of the Nikaidoh procedure and its modifications. The surgical strategy needs to be determined by the specific anatomical and pathological findings of the patient. The modified REV had excellent long-term survival and freedom from reoperation for the treatment of anomalous ventriculo-arterial connection with VSD and left ventricular outflow tract obstruction. The long-term performance of the reconstructed left ventricular outflow tract and right ventricular outflow tract is satisfactory.

Background A percutaneous approach for pulmonary valve replacement (PVR) is a feasible alternative to surgical PVR in selected patients with severe pulmonary regurgitation after repair of tetralogy of Fallot. However, large right ventricular outflow tract (diameter ≥ 25 mm) remains challenging. Methods This retrospective multicenter study enrolled consecutive patients with large right ventricular outflow tract who underwent percutaneous PVR (Venus P-valve, Venus MedTech Inc, Hangzhou, China) (n = 35) or surgical PVR (homograft valve; n = 30) between May 2014 and April 2017. Patients were followed up at 1, 3, 6, and 12 months, and yearly thereafter. Main study outcomes were pulmonary valve function and right ventricular function at discharge and midterm follow-up. Results PVR was successful in all patients. Percutaneous compared with surgical PVR group had: similarly distributed baseline characteristics; shorter hospitalization, intensive care unit stay, and endotracheal intubation duration; lower cost; lower pulmonary valve gradient before discharge; lower pulmonary valve regurgitant grade (mean difference, –0.63; 95% CI –1.11 to –0.20, P = .022), pulmonary valve gradient (mean difference, –5.7 mm Hg; 95% CI –9.4 to –2.2 mm Hg, P = .005), and right ventricular end-diastolic volume index (mean difference, –9.5 mL/m2; 95% CI –16.9 to –3.1 mL/m2, P = .022); and greater right ventricular ejection fraction (mean difference, 5.4%; 95% CI 2.4%-8.3%, P = .002) at median 36 months follow-up, without deaths in either group. Conclusions Percutaneous PVR using Venus P-valve appeared to be a safe, efficacious and minimally invasive alternative to surgical PVR in selected patients with large right ventricular outflow tract yielding better right ventricular and pulmonary valve function at midterm follow-up.

Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA1 and LPA3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA1 and LPA3 in the heart is unknown. Methods and Results: By using LPA3 and LPA1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA1/LPA3 inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA3 knockout mice and the Ki16425-treated rats but not in the LPA1 knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA3 KO mice and increased in the AAV9-mediated cardiac-specific LPA3 overexpression mice. By using lineage tracing and AAV9-LPA3, we further found that LPA3 overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro, whereas only ERK was confirmed to be activated by LPA-LPA3 signaling in vivo. Conclusion: Our study reports that LPA3-mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.

Rationale: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases. Understanding the clinical characteristics and pathogenesis of TGA is, therefore, urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic cause underlying TGA remain largely unexplored. Objective: We sought to systematically examine the clinical characteristics and genetic cause for isolated nonsyndromic TGA. Methods and Results: We recruited 249 patients with TGA (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in patients with TGA. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous, or X-linked recessive variants. Established congenital heart disease–causing genes, such as FOXH1 , were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had >1 candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. Conclusions: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

Left ventricular noncompaction cardiomyopathy (LVNC) is a primary cardiomyopathy with an unclear aetiology. The clinical symptoms range from asymptomatic to heart failure, arrhythmias and sudden cardiac death. This study aimed to characterize the genetic features and clinical outcomes of LVNC who underwent heart transplantation (HTx) to reveal the potential genetic pathogenesis.We recruited 16 cases who underwent HTx in our hospital. Exome-sequencing was performed to reveal genetic background. Clinical information and histopathology features of patients were investigated. Gene expression profiling of tissue fibrosis were evaluated by quantitative PCR. The median age of patients was 21 years. Of the 16 patients, 14 harboured multiple gene variants involved in LVNC. Ten of the patients harboured biallelic variants and/or truncating variants. Young patients (18) with biallelic variants and/or truncating variants and lower LVEF (45%) at initial symptom deteriorated quickly. Except for noncompaction myocardium, myocardial fibrosis was a remarkable pathological feature, and gene profiles related to immune inflammation and extracellular matrix remodelling were upregulated.This study showed that multiple pathologic variants were underlie genetic mechanism of LVNC who in high risks, suggesting that genetic screening should be applied to the diagnosis of LVNC. LVNC patient with multiple variants should be considered carefully follow-up. Genetics involved in the phenotype and cardiac fibrosis, and is the major causing for LVNC.

We investigated whether the totally video-assisted thoracoscopic mitral valve surgery provides superior clinical outcomes and less inflammatory injury reaction compared with conventional sternotomy.A total of 504 consecutive patients admitted for mitral valve surgery from May 2014 through May 2019 in a single center were retrospectively analyzed according to two distinct procedure approach: the totally video-assisted thoracoscopic approach (group A, n = 127) and standard median sternotomy (group B, n = 377). The primary end point was the durations of cardiopulmonary bypass, aortic cross-clamping, the ventilation time and intensive care unit of stay; the secondary endpoints included inflammation indexes like high sensitivity C-reactive protein, neutrophil-lymphocyte ratio and metabolic injury parameters cardiac Troponin and lactate.There was only one in-hospital death due to diffuse intravascular coagulation in group A, but similar complications such as repair failure, re-thoracotomy and stroke in both groups. The durations of cardiopulmonary bypass and aortic cross-clamping were significantly longer in group A. In contrast, ventilation time and intensive care unit of stay were shortened compared with these in group B. In addition, postoperative equivalent lactate clearance but lower high sensitivity C-reactive protein, neutrophil-lymphocyte ratio and cardiac Troponin level was in group A than those in group B within postoperative 24 hours(P 0.05).The analysis of present study indicated despite relatively longer cardiopulmonary bypass time, the totally thoracoscopic mitral valve procedure seemed to be favorable with regard to the extent of inflammatory reaction, cardiac injury and postoperative recovery compared with conventional median sternotomy.

The present study sought to compare postoperative bleeding and renal function in patients with multivessel coronary artery disease undergoing simultaneous hybrid coronary revascularization (HCR) and minimally invasive direct off-pump coronary artery bypass grafting (MIDCABG).The study retrospectively collected the data of 594 consecutive patients who underwent simultaneous HCR and 351 patients who underwent MIDCABG with planned staged HCR (MIDCABG first, then elective percutaneous coronary intervention) in Fuwai Hospital from June 2007 to December 2020. A total of 317 pairs of patients who were matched in a 1:1 ratio with propensity score matching were enrolled in this study. Bleeding and changes in renal function were compared between the 2 groups.Compared with patients who underwent MIDCABG, patients who underwent simultaneous HCR had significantly greater chest tube drainage on the day of the operation (492.7 ± 282.4 mL vs 441.0 ± 261.9 mL; P = .023), but no significant difference was detected in the total amount during the postoperative period (788.8 ± 458.9 mL vs 753.3 ± 409.8 mL; P = .74). The differences in re-exploration for bleeding (0.3% vs 1.6%; P = .13), blood transfusion (18.9% vs 16.4%; P = .13), acute kidney injury (23.3% vs 18.6%; P = .53), and in-hospital major adverse cardiovascular and cerebrovascular events (including all-cause death, myocardial infarction, stroke, and repeated revascularization) (2.5% vs 1.9%; P = .67) between the 2 groups did not reach statistical significance.Compared with MIDCABG, simultaneous HCR (MIDCABG first, instant percutaneous coronary intervention) did not increase postoperative bleeding or the incidence of acute kidney injury.

Background Evidences shows that socioeconomic status is reversely associated with the risk of morbidity and mortality for people with cardiovascular disease via pro-inflammation mechanism, but the population profile is not deeply defined on. We aimed to investigate the impact of medical insurance coverage on postoperative systemic inflammatory reaction in two kinds of disease populations undergoing distinct cardiac procedures. Methods A total of 515 patients receiving open mitral valve procedure with high-total expense from May 2013 through May 2021 in Sichuan Provincial People’s Hospital were retrospectively collected and stratified according to medical insurance reimbursement: low coverage with high out-pocket ( 60%). Another 118 cases undergoing atrium septum defect (ASD) or patent foramen ovale (PFO) occlusion and taking on consistent low-total expense and low-coverage ( Results Low insurance reimbursement population undergoing open mitral valve procedure had a higher level of hs-CRP and NLR but not troponin I protein or lactate within 48 h postoperatively, and higher thoracic drainage, longer ventilation use and stay in intensive care unit. No significant difference in inflammatory indexes existed among diverse medical insurance coverage in population undergoing ASD/PFO occlusion. Conclusions Higher inflammatory reaction and weaker clinical recovery was associated with lower insurance coverage population undergoing open mitral valve procedure but not ASD/PFO interventional occlusion procedure.

Acute rejection (AR) is an important contributor to graft failure, which remains a leading cause of death after heart transplantation (HTX). The regulation of immune metabolism has become a new hotspot in the development of immunosuppressive drugs. In this study, Increased glucose metabolism of cardiac macrophages was found in patients with AR. To find new therapeutic targets of immune metabolism regulation for AR, CD45

The remarkable biocompatibility and supreme physical properties of nanostructured TiO2 have promised itself a strong future for biomedical applications. The present study reported a theoretical study on the adsorption of rutile TiO2 (110) nanosheet for DNA nucleobases using first-principles calculations. The calculations of the binding energy and work function demonstrate that the TiO2 nanosheet has remarkable adsorption strength to the DNA nucleobases, being more than 20 times larger than that of graphene and its derivatives. Further electronic band structure and density of state calculations elucidate the interaction mechanisms, which originate from dramatically reduced energy levels and strong hybridization of the 2p orbital of C, N and/or O with 3d orbital of Ti atoms near the Fermi level. The study directs a promising material at applications in DNA sensors and sequencers.

Inflammation and fibrosis are intertwined mechanisms fundamentally involved in heart failure. Detailed deciphering gene expression perturbations and cell-cell interactions of leukocytes and non-myocytes is required to understand cell-type-specific pathology in the failing human myocardium. To this end, we performed single-cell RNA sequencing and single T cell receptor sequencing of 200,615 cells in both human dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts. We sampled both lesion and mild-lesion tissues from each heart to sequentially capture cellular and molecular alterations to different extents of cardiac fibrosis. By which, left (lesion) and right ventricle (mild-lesion) for DCM hearts were harvest while infarcted (lesion) and non-infarcted area (mild-lesion) were dissected from ICM hearts. A novel transcription factor AEBP1 was identified as a crucial cardiac fibrosis regulator in ACTA2+ myofibroblasts. Within fibrotic myocardium, an infiltration of a considerable number of leukocytes was witnessed, especially cytotoxic and exhausted CD8+ T cells and pro-inflammatory CD4+ T cells. Furthermore, a subset of tissue-resident macrophage, CXCL8hiCCR2+HLA-DRhi macrophage was particularly identified in severely fibrotic area, which interacted with activated endothelial cell via DARC, that potentially facilitate leukocyte recruitment and infiltration in human heart failure.

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiomyopathy characterized as fibro-fatty replacement, and a common cause for sudden cardiac death in young athletes. Development of heart failure (HF) has been an under-recognized complication of ACM for a long time. The current clinical management guidelines for HF in ACM progression have nowadays been updated. Thus, a comprehensive review for this great achievement in our understanding of HF in ACM is necessary. In this review, we aim to describe the research progress on epidemiology, clinical characteristics, risk stratification and therapeutics of HF in ACM.

Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in cardiomyopathy, especially those in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins. Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance. FLNC was first demonstrated to be a causal gene of myofibrillar myopathy; recently, it has been found that FLNC mutation plays a critical role in the pathogenesis of cardiomyopathy. In this review, we summarized the physiological roles of filamin C in cardiomyocytes and the genetic evidence for links between FLNC mutations and cardiomyopathies. Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation. Therefore, it is important to understand the cellular biology and molecular regulation of FLNC to design new therapies to treat patients with FLNC-related cardiomyopathy.

Persistent truncus arteriosus (PTA) is an uncommon and complex congenital cardiac malformation accounting for about 1.2% of all congenital heart diseases (CHDs), which is caused by a deficiency in the embryonic heart outflow tract’s (OFT) septation and remodeling. PDGFRα and PDGFRβ double knockout (DKO) in cardiac neural crest cells (CNCCs) has been reported to cause PTA, but the underlying mechanisms remain unclear. Here, we constructed a PTA mouse model with PDGFRα and PDGFRβ double knockout in Pax3+ CNCCs and described the condensation failure into OFT septum of CNCC-derived cells due to disturbance of cell polarity in the DKO group. In addition, we further explored the mechanism with single-cell RNA sequencing. We found that two main cell differentiation trajectories into vascular smooth muscle cells (VSMCs) from cardiomyocytes (CMs) and mesenchymal cells (MSs), respectively, were interrupted in the DKO group. The process of CM differentiation into VSMC stagnated in a transitional CM I-like state, which contributed to the failure of OFT remodeling and muscular septum formation. On the other hand, a Penk+ transitional MS II cluster closely related to cell condensation into the OFT septum disappeared, which led to the OFT’s septation absence directly. In conclusion, the disturbance of CNCC-derived cells caused by PDGFRα and PDGFRβ knockout can lead to the OFT septation disorder and the occurrence of PTA.

Background The performance of traditional scores is significantly limited to predict mortality in high-risk cardiac surgery. The aim of this study was to compare the performance of STS, ESII and HiriSCORE models in predicting mortality in high-risk patients undergoing CABG. Methods Cross-sectional analysis in the international prospective database of high-risk patients: HiriSCORE project. We evaluated 248 patients with STS or ESII (5–10%) undergoing CABG in 8 hospitals in Brazil and China. The main outcome was mortality, defined as all deaths occurred during the hospitalization in which the operation was performed, even after 30 days. Five variables were selected as predictors of mortality in this cohort of patients. The model’s performance was evaluated through the calibration-in-the-large and the receiver operating curve (ROC) tests. Results The mean age was 69.90±9.45, with 52.02% being female, 25% of the patients were on New York Heart Association (NYHA) class IV and 49.6% had Canadian Cardiovascular Society (CCS) class 4 angina, and 85.5% had urgency or emergency status. The mortality observed in the sample was 13.31%. The HiriSCORE model showed better calibration (15.0%) compared to ESII (6.6%) and the STS model (2.0%). In the ROC curve, the HiriSCORE model showed better accuracy (ROC = 0.74) than the traditional models STS (ROC = 0.67) and ESII (ROC = 0.50). Conclusion Traditional models were inadequate to predict mortality of high-risk patients undergoing CABG. However, the HiriSCORE model was simple and accurate to predict mortality in high-risk patients.