Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases.

BACKGROUND: Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS: By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS: Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS: Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.

Extracellular Matrix Disorganization Caused by ADAMTS16 Deficiency Leads to Bicuspid Aortic Valve With Raphe Formation.

BACKGROUND: A better understanding of the molecular mechanism of aortic valve development and bicuspid aortic valve (BAV) formation would significantly improve and optimize the therapeutic strategy for BAV treatment. Over the past decade, the genes involved in aortic valve development and BAV formation have been increasingly recognized. On the other hand, ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family members have been reported to be able to modulate cardiovascular development and diseases. The present study aimed to further investigate the roles of ADAMTS family members in aortic valve development and BAV formation. METHODS: Morpholino-based ADAMTS family gene-targeted screening for zebrafish heart outflow tract phenotypes combined with DNA sequencing in a 304 cohort BAV patient registry study was initially carried out to identify potentially related genes. Both ADAMTS gene-specific fluorescence in situ hybridization assay and genetic tracing experiments were performed to evaluate the expression pattern in the aortic valve. Accordingly, related genetic mouse models (both knockout and knockin) were generated using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) method to further study the roles of ADAMTS family genes. The lineage-tracing technique was used again to evaluate how the cellular activity of specific progenitor cells was regulated by ADAMTS genes. Bulk RNA sequencing was used to investigate the signaling pathways involved. Inducible pluripotent stem cells derived from both BAV patients and genetic mouse tissue were used to study the molecular mechanism of ADAMTS. Immunohistochemistry was performed to examine the phenotype of cardiac valve anomalies, especially in the extracellular matrix components. RESULTS: ADAMTS genes targeting and phenotype screening in zebrafish and targeted DNA sequencing on a cohort of patients with BAV identified ADAMTS16 (a disintegrin and metalloproteinase with thrombospondin motifs 16) as a BAV-causing gene and found the ADAMTS16 p. H357Q variant in an inherited BAV family. Both in situ hybridization and genetic tracing studies described a unique spatiotemporal pattern of ADAMTS16 expression during aortic valve development. Adamts16+/- and Adamts16+/H355Q mouse models both exhibited a right coronary cusp-noncoronary cusp fusion-type BAV phenotype, with progressive aortic valve thickening associated with raphe formation (fusion of the commissure). Further, ADAMTS16 deficiency in Tie2 lineage cells recapitulated the BAV phenotype. This was confirmed in lineage-tracing mouse models in which Adamts16 deficiency affected endothelial and second heart field cells, not the neural crest cells. Accordingly, the changes were mainly detected in the noncoronary and right coronary leaflets. Bulk RNA sequencing using inducible pluripotent stem cells-derived endothelial cells and genetic mouse embryonic heart tissue unveiled enhanced FAK (focal adhesion kinase) signaling, which was accompanied by elevated fibronectin levels. Both in vitro inducible pluripotent stem cells-derived endothelial cells culture and ex vivo embryonic outflow tract explant studies validated the altered FAK signaling. CONCLUSIONS: Our present study identified a novel BAV-causing ADAMTS16 p. H357Q variant. ADAMTS16 deficiency led to BAV formation.

Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI.

BACKGROUND: In patients with coronary artery disease who are being evaluated for percutaneous coronary intervention (PCI), procedures can be guided by fractional flow reserve (FFR) or intravascular ultrasonography (IVUS) for decision making regarding revascularization and stent implantation. However, the differences in clinical outcomes when only one method is used for both purposes are unclear. METHODS: We randomly assigned 1682 patients who were being evaluated for PCI for the treatment of intermediate stenosis (40 to 70% occlusion by visual estimation on coronary angiography) in a 1:1 ratio to undergo either an FFR-guided or IVUS-guided procedure. FFR or IVUS was to be used to determine whether to perform PCI and to assess PCI success. In the FFR group, PCI was to be performed if the FFR was 0.80 or less. In the IVUS group, the criteria for PCI were a minimal lumen area measuring either 3 mm2 or less or measuring 3 to 4 mm2 with a plaque burden of more than 70%. The primary outcome was a composite of death, myocardial infarction, or revascularization at 24 months after randomization. We tested the noninferiority of the FFR group as compared with the IVUS group (noninferiority margin, 2.5 percentage points). RESULTS: The frequency of PCI was 44.4% among patients in the FFR group and 65.3% among those in the IVUS group. At 24 months, a primary-outcome event had occurred in 8.1% of the patients in the FFR group and in 8.5% of those in the IVUS group (absolute difference, -0.4 percentage points; upper boundary of the one-sided 97.5% confidence interval, 2.2 percentage points; P = 0.01 for noninferiority). Patient-reported outcomes as reported on the Seattle Angina Questionnaire were similar in the two groups. CONCLUSIONS: In patients with intermediate stenosis who were being evaluated for PCI, FFR guidance was noninferior to IVUS guidance with respect to the composite primary outcome of death, myocardial infarction, or revascularization at 24 months. (Funded by Boston Scientific; FLAVOUR ClinicalTrials.gov number, NCT02673424.).

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

Comparison of downsizing strategy (HANGZHOU Solution) and standard annulus sizing strategy in type 0 bicuspid aortic stenosis patients undergoing transcatheter aortic valve replacement: Rationale and design of a randomized clinical trial.

BACKGROUND: There has not been a consensus on the prothesis sizing strategy in type 0 bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR). Modifications to standard annular sizing strategies might be required due to the distinct anatomical characteristics. We have devised a downsizing strategy for TAVR using a self-expanding valve specifically for patients with type 0 bicuspid AS. The primary aim of this study is to compare the safety and efficacy of downsizing strategy with the Standard Annulus Sizing Strategy in TAVR for patients with type 0 bicuspid AS. TRIAL DESIGN: It is a prospective, multi-center, superiority, single-blinded, randomized controlled trial comparing the Down Sizing and Standard Annulus Sizing Strategy in patients with type 0 bicuspid aortic stenosis undergoing transcatheter aortic valve replacement. Eligible participants will include patients with severe type 0 bicuspid AS, as defined by criteria such as mean gradient across aortic valve ≥40 mmHg, peak aortic jet velocity ≥4.0 m/s, aortic valve area (AVA) ≤1.0 cm², or AVA index ≤0.6 cm2/m2. These patients will be randomly assigned, in a 1:1 ratio, to either the Down Sizing Strategy group or the Standard Sizing Strategy group. In the Down Sizing Strategy group, a valve one size smaller will be implanted if the "waist sign" manifests along with less than mild regurgitation during balloon pre-dilatation. The primary end point of the study is a composite of VARC-3 defined device success, absence of both permanent pacemaker implantation due to high-degree atrioventricular block and new-onset complete left bundle branch block. CONCLUSION: This study will compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy and provide valuable insights into the optimal approach for sizing in TAVR patients with type 0 bicuspid AS. We hypothesize that the Down Sizing Strategy will demonstrate superiority when compared to the Standard Annulus Sizing Strategy. (Down Sizing Strategy (HANGZHOU Solution) vs Standard Sizing Strategy TAVR in Bicuspid Aortic Stenosis (Type 0) (TAILOR-TAVR), NCT05511792).

2024 Statement from Asia expert operators on transcatheter pulmonary valve replacement.

Transcatheter pulmonary valve replacement (TPVR), also known as percutaneous pulmonary valve implantation, refers to a minimally invasive technique that replaces the pulmonary valve by delivering an artificial pulmonary prosthesis through a catheter into the diseased pulmonary valve under the guidance of X-ray and/or echocardiogram while the heart is still beating not arrested. In recent years, TPVR has achieved remarkable progress in device development, evidence-based medicine proof and clinical experience. To update the knowledge of TPVR in a timely fashion, and according to the latest research and further facilitate the standardized and healthy development of TPVR in Asia, we have updated this consensus statement. After systematical review of the relevant literature with an in-depth analysis of eight main issues, we finally established eight core viewpoints, including indication recommendation, device selection, perioperative evaluation, procedure precautions, and prevention and treatment of complications.

Flavin Containing Monooxygenase 2 Prevents Cardiac Fibrosis via CYP2J3-SMURF2 Axis.

BACKGROUND: Cardiac fibrosis is a common pathological feature associated with adverse clinical outcome in postinjury remodeling and has no effective therapy. Using an unbiased transcriptome analysis, we identified FMO2 (flavin-containing monooxygenase 2) as a top-ranked gene dynamically expressed following myocardial infarction (MI) in hearts across different species including rodents, nonhuman primates, and human. However, the functional role of FMO2 in cardiac remodeling is largely unknown. METHODS: Single-nuclei transcriptome analysis was performed to identify FMO2 after MI; FMO2 ablation rats were generated both in genetic level using the CRISPR-cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) technology and lentivirus-mediated manner. Gain-of-function experiments were conducted using postn-promoter FMO2, miR1a/miR133a-FMO2 lentivirus, and enzymatic activity mutant FMO2 lentivirus after MI. RESULTS: A significant downregulation of FMO2 was consistently observed in hearts after MI in rodents, nonhuman primates, and patients. Single-nuclei transcriptome analysis showed cardiac expression of FMO2 was enriched in fibroblasts rather than myocytes. Elevated spontaneous tissue fibrosis was observed in the FMO2-null animals without external stress. In contrast, fibroblast-specific expression of FMO2 markedly reduced cardiac fibrosis following MI in rodents and nonhuman primates associated with diminished SMAD2/3 phosphorylation. Unexpectedly, the FMO2-mediated regulation in fibrosis and SMAD2/3 signaling was independent of its enzymatic activity. Rather, FMO2 was detected to interact with CYP2J3 (cytochrome p450 superfamily 2J3). Binding of FMO2 to CYP2J3 disrupted CYP2J3 interaction with SMURF2 (SMAD-specific E3 ubiquitin ligase 2) in cytosol, leading to increased cytoplasm to nuclear translocation of SMURF2 and consequent inhibition of SMAD2/3 signaling. CONCLUSIONS: Loss of FMO2 is a conserved molecular signature in postinjury hearts. FMO2 possesses a previously uncharacterized enzyme-independent antifibrosis activity via the CYP2J3-SMURF2 axis. Restoring FMO2 expression exerts potent ameliorative effect against fibrotic remodeling in postinjury hearts from rodents to nonhuman primates. Therefore, FMO2 is a potential therapeutic target for treating cardiac fibrosis following injury.

Cardiovascular diseases burden attributable to ambient PM2.5 pollution from 1990 to 2019: A systematic analysis for the global burden of disease study 2019.

BACKGROUND: Ambient PM2.5 pollution (APMP2.5) was the leading environmental risk factor for cardiovascular diseases (CVDs) worldwide. An up-to-date comprehensive study is needed to provide global epidemiological patterns. METHODS: Detailed data on CVDs burden attributable to APMP2.5 were obtained from the Global Burden of Disease Study (GBD) 2019. We calculated the estimated annual percentage change (EAPC) to assess temporal trends in age-standardized rates of deaths and disability-adjusted life years (DALYs) over 30 years. RESULTS: Globally, CVDs attributable to APMP2.5 resulted in 2.48 million deaths and 60.91 million DALYs, with an increase of 122%, respectively from 1990 to 2019. In general, men suffered markedly higher burden than women, but the gap will likely turn narrow. As for age distribution, CVDs deaths and DALYs attributable to APMP2.5 mainly occurred in the elder group (>70 years). Low- and middle-income regions endured the higher CVDs burden due to the higher exposure to APMP2.5, and the gap may potentially expand further compared with high-income regions. For regions, the highest age-standardized rates of APMP2.5-related CVDs deaths and DALYs were observed mainly in Central Asia, while the lowest was observed in Australasia. At the national level, countries with the largest ASDR decline were clustered in western Europe, while Equatorial Guinea, Timor-Leste and Bhutan exhibited relatively rapid increases over this period. CONCLUSIONS: The global CVDs burden attributable to APMP2.5 has contributed to the heterogeneity of spatial and temporal distribution. APMP2.5-related CVDs deaths have largely shifted from higher SDI regions to those with a lower SDI. Globally, APMP2.5-attributable CVDs pose a significant threat to public health and diseases burden has increased over time, particularly in male, old-aged populations. The governments and health systems should take measures to reduce air pollution to impede this rising trend.

Current optimized strategies for stem cell-derived extracellular vesicle/exosomes in cardiac repair.

Ischemic heart diseases remain the leading cause of death globally, and stem cell-based therapy has been investigated as a potential approach for cardiac repair. Due to poor survival and engraftment in the cardiac ischemic milieu post transplantation, the predominant therapeutic effects of stem cells act via paracrine actions, by secreting extracellular vesicles (EVs) and/or other factors. Exosomes are nano-sized EVs of endosomal origin, and now viewed as a major contributor in facilitating myocardial repair and regeneration. However, EV/exosome therapy has major obstacles before entering clinical settings, such as limited production yield, unstable biological activity, poor homing efficiency, and low tissue retention. This review aims to provide an overview of the biogenesis and mechanisms of stem cell-derived EV/exosomes in the process of cardiac repair and discuss the current advancements in different optimized strategies to produce high-yield EV/exosomes with higher bioactivity, or engineer them with improved homing efficiency and therapeutic potency. In particular, we outline recent findings toward preclinical and clinical translation of EV/exosome therapy in ischemic heart diseases, and discuss the potential barriers in regard to clinical translation of EV/exosome therapy.

Drug-coated balloon for the treatment of small vessel disease: 9 months of angiographic results and 12 months of clinical outcomes of the PEPCAD China SVD study.

BACKGROUND: Whether the drug-coated balloons (DCBs)-alone strategy was superior to plain old balloon angioplasty (POBA) in treating SVD remains unknown. AIMS: We aimed to evaluate the efficacy and safety of DCBs for the treatment of coronary de novo small vessel disease (SVD) and provide further evidence for extending the clinical indications of DCBs. (ChiCTR1800014966). METHODS: Eligible patients were randomized at a 2:1 ratio to receive DCB treatment or POBA in this prospective, multicenter clinical trial. The reference vessel diameter of lesions was visually assessed to be 2.0 to 2.75 mm. The primary endpoint of the study was angiographic in-segment late luminal loss (LLL) at the 9-month follow-up to demonstrate the superiority of DCB treatment to POBA in SVD. The composite clinical endpoints included clinically driven target lesion revascularization (CD-TLR), target lesion failure (TLF), major adverse cardiac events (MACEs), and thrombosis at the 12-month follow-up. RESULTS: A total of 270 patients were enrolled (181 for DCB, 89 for POBA) at 18 centers in China. The primary endpoint of 9-month in-segment LLL in the intention-to-treat population was 0.10 ± 0.33 mm with DCB and 0.25 ± 0.38 mm with POBA (p = 0.0027). This difference indicated significant superiority of DCB treatment (95% CI: -0.22, -0.04, psuperiority = 0.0068). The rates of the clinical endpoints-CD-TLR, TLF, and MACEs-were comparable between groups. No thrombosis events were reported. CONCLUSIONS: DCB treatment of de novo SVD was superior to POBA with lower 9-month in-segment LLL. The rates of clinical events were comparable between the two devices.

Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction.

[Figure: see text].

Semisynthesis and in Vitro Anti-cancer Effect of New Magnolol Derivatives on the Cell Proliferation, Apoptosis, Migration, and Invasion of Human Hepatocellular Carcinoma SMMC-7721 Cells.

Four new magnolol derivatives were synthesized and evaluated for their in vitro anti-cancer properties. Among these, compound 3 showed the most potent cytotoxic activity against the SMMC-7721, SUN-449, and HepG2 human hepatocellular carcinoma cell lines, with IC50 values of 3.39, 4.11, and 6.88 µM, respectively. Compound 3 also induced apoptosis of SMMC-7721 cells by down-regulating Bcl-2 and Akt protein levels, up-regulating of Bax protein level, and cleaving caspase-9 and -3. In addition, transwell assays showed that compound 3 significantly suppressed the migration and invasion of SMMC-7721 cells, which was confirmed based on the down-regulation of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-2 and -9 (MMP-2, and MMP-9) protein levels.

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.

BACKGROUND: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood. METHODS: We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model. RESULTS: LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart. CONCLUSIONS: LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.

Angiographic quantitative flow ratio-guided coronary intervention (FAVOR III China): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Compared with visual angiographic assessment, pressure wire-based physiological measurement more accurately identifies flow-limiting lesions in patients with coronary artery disease. Nonetheless, angiography remains the most widely used method to guide percutaneous coronary intervention (PCI). In FAVOR III China, we aimed to establish whether clinical outcomes might be improved by lesion selection for PCI using the quantitative flow ratio (QFR), a novel angiography-based approach to estimate the fractional flow reserve. METHODS: FAVOR III China is a multicentre, blinded, randomised, sham-controlled trial done at 26 hospitals in China. Patients aged 18 years or older, with stable or unstable angina pectoris or patients who had a myocardial infarction at least 72 h before screening, who had at least one lesion with a diameter stenosis of 50-90% in a coronary artery with a reference vessel of at least 2·5 mm diameter by visual assessment were eligible. Patients were randomly assigned to a QFR-guided strategy (PCI performed only if QFR ≤0·80) or an angiography-guided strategy (PCI based on standard visual angiographic assessment). Participants and clinical assessors were masked to treatment allocation. The primary endpoint was the 1-year rate of major adverse cardiac events, a composite of death from any cause, myocardial infarction, or ischaemia-driven revascularisation. The primary analysis was done in the intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT03656848). FINDINGS: Between Dec 25, 2018, and Jan 19, 2020, 3847 patients were enrolled. After exclusion of 22 patients who elected not to undergo PCI or who were withdrawn by their physicians, 3825 participants were included in the intention-to-treat population (1913 in the QFR-guided group and 1912 in the angiography-guided group). The mean age was 62·7 years (SD 10·1), 2699 (70·6%) were men and 1126 (29·4%) were women, 1295 (33·9%) had diabetes, and 2428 (63·5%) presented with an acute coronary syndrome. The 1-year primary endpoint occurred in 110 (Kaplan-Meier estimated rate 5·8%) participants in the QFR-guided group and in 167 (8·8%) participants in the angiography-guided group (difference, -3·0% [95% CI -4·7 to -1·4]; hazard ratio 0·65 [95% CI 0·51 to 0·83]; p=0·0004), driven by fewer myocardial infarctions and ischaemia-driven revascularisations in the QFR-guided group than in the angiography-guided group. INTERPRETATION: In FAVOR III China, among patients undergoing PCI, a QFR-guided strategy of lesion selection improved 1-year clinical outcomes compared with standard angiography guidance. FUNDING: Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Centre for Cardiovascular Diseases, Fuwai Hospital.

Knockdown of estrogen-related receptor α inhibits valve interstitial cell calcification in vitro by regulating heme oxygenase 1.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in adults. The cellular mechanisms of CAVD are still unknown, but accumulating evidence has revealed that osteogenic differentiation of human valve interstitial cells (hVICs) plays an important role in CAVD. Thus, we aimed to investigate the function of estrogen-related receptor α (ERRα) in the osteogenic differentiation of hVICs. We found that the level of ERRα was significantly increased in CAVD samples compared to normal controls. In addition, ERRα was significantly upregulated during hVIC osteogenic differentiation in vitro. Gain- and loss-of-function experiments were performed to identify the function of ERRα in hVIC calcification in vitro. Inhibition of endogenous ERRα attenuated hVIC calcification, whereas overexpression of ERRα in hVICs promoted this process. RNA sequencing results suggested that heme oxygenase-1 (Hmox1) was a downstream target of ERRα, which was further confirmed by western blotting. Additionally, we also found that downregulation of Hmox1 by shHmox1 efficiently reversed the inhibition of calcification induced by ERRα shRNA in hVICs. ChIP-qPCR and luciferase assays indicated that Hmox1 was negatively regulated by ERRα. We found that overexpression of Hmox1 or its substrates significantly inhibited hVIC calcification in vitro. In conclusion, we found that knockdown of ERRα can inhibit hVIC calcification through upregulating Hmox1 and that ERRα and Hmox1 are potential targets for the treatment of CAVD.

Insights into male androgenetic alopecia using comparative transcriptome profiling: hypoxia-inducible factor-1 and Wnt/ß-catenin signalling pathways.

BACKGROUND: The key pathophysiological changes in androgenetic alopecia (AGA) are limited to hair follicles (HFs) in frontal and vertex regions, sparing the occipital region. OBJECTIVES: To identify biological differences among HF subpopulations. METHODS: Paired vertex and occipital HFs from 10 male donors with AGA were collected for RNA sequencing assay. Furthermore, HF and cell experiments were conducted on the identified key genes to reveal their roles in AGA. RESULTS: Transcriptome profiles revealed that 506 mRNAs, 55 microRNAs and 127 long noncoding RNAs were differentially expressed in the AGA vertex HFs. Pathway analysis of mRNAs and microRNAs revealed involvement of the hypoxia-inducible factor (HIF)-1, Wnt/ß-catenin, and focal adhesion pathways. Differential expression of HIF-1 prolyl hydroxylase enzymes (EGLN1, EGLN3) and Wnt/ß-catenin pathway inhibitors (SERPINF1, SFRP2) was experimentally validated. In vitro studies revealed that reduction of EGLN1, EGLN3, SERPINF1 and SFRP2 stimulated proliferation of dermal papilla cells. Ex vivo HF studies showed that downregulation of EGLN1, EGLN3 and SERPINF1 promoted HF growth, postponed HF catagen transition, and prolonged the anagen stage, suggesting that these genes may be potentially utilized as therapeutic targets for AGA. CONCLUSIONS: We characterized key transcriptome changes in male AGA HFs, and found that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (SERPINF1, SFRP2) may play important roles in AGA. What is already known about this topic? Multiple differentially expressed genes and signalling pathways have been found between hair follicles (HFs) in the balding area (frontal and vertex regions) and nonbalding area (occipital region) of individuals with androgenetic alopecia (AGA). A whole-transcriptome atlas of the vertex and occipital region is lacking. What does this study add? We identified a number of differentially expressed genes and pathways between balding vertex and nonbalding occipital AGA HFs by using whole-transcriptome analyses. We identified pathways not previously reported in AGA, such as the hypoxia-inducible factor (HIF)-1 signalling pathway. We verified that HIF-1 pathway-related genes (EGLN1, EGLN3) and Wnt pathway inhibitors (PEDF, SFRP2) played important roles in dermal papilla cell activity, hair growth and the hair cycle. What is the translational message? The EGLN1, EGLN3, SERPINF1 and SFRP2 genes may be potentially utilized as therapeutic targets for AGA.

Transcatheter mitral valve repair in patient with atrial functional mitral regurgitation using novel DragonFly™ device.

We report the first case of transcatheter mitral valve repair with the novel DragonFly™ device, a transcatheter edge-to-edge mitral regurgitation (MR) repair device, in a patient with severe, symptomatic MR due to annular dilation from atrial functional disease (Carpentier type I). The patient had experienced multiple heart failure events and was unsuitable for surgery due to pulmonary dysfunction and obesity.

Transcatheter mitral valve repair in a high-surgical risk patient with severe degenerative mitral regurgitation using the novel DragonFly™ Transcatheter Repair device-First in man implantation in China.

Transcatheter repair of mitral regurgitation (MR) by edge-to-edge therapy has become increasingly accepted for patients with severe MR at high or prohibitive surgical risk in primary or degenerative mitral regurgitation (DMR). The technological approach has evolved from the initial transcatheter edge-to-edge device to improve on its acute reduction in MR and durability of results, particularly in complex primary pathology. In this study, we reported the first case of DragonFly™ Transcatheter Valve Repair device in a patient with severe DMR.

Self-expanding transcatheter aortic valve replacement in patients with extremely horizontal aortas.

OBJECTIVES: To evaluate the feasibility of self-expanding transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis and extremely horizontal aortas (aortic angulation ≥70°). BACKGROUND: As TAVR using a self-expanding prosthesis is an off-label treatment for patients with extremely horizontal aortas, these patients are often excluded from randomized controlled trials involving self-expanding TAVR. METHODS: This study enrolled 27 consecutive patients with extremely horizontal aortas who underwent self-expanding TAVR for severe aortic stenosis. RESULTS: The patients' average age was 76.4 years, with a median Society of Thoracic Surgeons score of 4.53%. The device success and 30-day mortality rates were 66.7% and 7.4%, respectively. The sinotubular junction (STJ) was significantly smaller in the device success group (p = 0.001). The receiver operating characteristic curve analysis found that the area under the curve was 0.907 (95% confidence interval: 0.790-1.000, p = 0.001), validating the association between STJ diameter and device success. An optimal cutoff of 33.6 mm was determined using the Youden index, with a sensitivity and specificity of 88.9% and 77.8%, respectively. The device success rate was significantly higher (93.3% vs. 33.3%, p = 0.003) in patients with STJ diameters ≤33.6 mm (n = 15). In the subgroup analyses, severe valve calcification (n = 9) was associated with a higher incidence of moderate or severe paravalvular leakage (44.0% vs. 0%, p = 0.008), while a higher rate of second valve implantation (60.0% vs. 9.1%, p = 0.030) was found in patients with less than moderate valve calcification (n = 5). CONCLUSION: Self-expanding TAVR could be suitable for patients with extremely horizontal aortas after careful preoperative evaluation.

Validation of a novel staging classification system based on the extent of cardiac damage among Chinese patients after transcatheter aortic valve replacement: A single-center retrospective study.

OBJECTIVES: We aimed to validate a novel staging system for aortic stenosis (AS) in a Chinese patient cohort undergoing transcatheter aortic valve replacement (TAVR), and to compare this classification system to the traditional Society of Thoracic Surgeons (STS) score for TAVR risk stratification. BACKGROUND: A novel staging system for AS based on the extent of cardiac damage upon echocardiography was recently proposed. METHODS: Patients were prospectively enrolled into the Transcatheter Aortic Valve Replacement Single Center Registry in Chinese Population and analyzed retrospectively following additional exclusion criteria. On the basis of echocardiographic findings of cardiac damage, patients were classified into five stages (0-4). RESULTS: A total of 427 patients were included in the current analysis. Forty-eight deaths occurred during a median follow-up of 730 days following TAVR. The staging system showed a statistically significant association between cardiac damage and all-cause mortality; advanced stages were associated with higher mortality. In a multivariate-adjusted Cox proportional hazards regression model, stage and STS scores served as risk factors for 2-year mortality. Each increment in the staging class was associated with an increased risk of mortality (hazard ratio, 1.275; 95% confidence interval [CI], 1.052-1.545). Receiver operating characteristic (ROC) curves were plotted for stage (area under the curve, 0.644; 95% CI, 0.562-0.725) and STS score (0.661; 0.573-0.749), and with no statistically significant differences between ROC curves (p = 0.920). CONCLUSIONS: We validated a novel staging system as a key risk factor for 2-year mortality in a Chinese TAVR patient cohort. Efficacy for risk stratification was comparable to the STS score.