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.

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.

Whole genome resequencing reveal patterns of genetic variation within Colletotrichum acutatum species complex from rubber trees in China.

The Colletotrichum acutatum species complex possesses a diverse number of important traits, such as a wide host range and host preference, different modes of reproduction, and different strategies of host infection. Research using comparative genomics has attempted to find correlations between these traits. Here, we used multi-locus techniques and gene genealogical concordance analysis to investigate the phylogenetic relationships and taxonomic status of the Colletotrichum acutatum species complex using field isolates obtained from rubber trees. The results revealed that the dominant species was C. australisinense, followed by C. bannaense, while strain YNJH17109 was identified as C. laticiphilum. The taxonomic status of strains YNLC510 and YNLC511 was undetermined. Using whole-genome single nucleotide polymorphism data to analyze population structure, 18 strains of C. australisinense were subsequently divided into four populations, one of which was derived from an admixture of two populations. In addition, the strains LD1687, GD1628, and YNLC516, did not belong to any populations, and were considered to be admixtures of two or more populations. A split decomposition network analysis also provided evidence for genetic recombination within Colletotrichum acutatum species complex from rubber trees in China. Overall, a weak phylogeographic sub-structure was observed. Analysis also revealed significant differences in morphological characters and levels of virulence between populations.

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.

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.

Elevated N-terminal pro C-type natriuretic peptide is associated with mortality in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Unlike N-terminal pro-B-type natriuretic peptide (NT-proBNP), which have been extensively studied, little is known about the role of N-terminal pro-C-type natriuretic peptide (NT-proCNP) for predicting survival post transcatheter aortic valve replacement (TAVR). METHODS: A total of 309 patients were included in the analysis. Patients were grouped into quartiles (Q1-4) according to the baseline NT-proCNP value. Blood for NT-proCNP analysis was obtained prior to TAVR procedure. The primary endpoint was mortality after a median follow-up of 32 months. Multivariable Cox proportional hazards regression models analyzed prognostic factors. The predictive capability was compared between NT-proBNP and NT-proCNP using receiver operator curve (ROC) analysis. RESULTS: A total of 309 subjects with the mean age of 76.8 ± 6.3 years, among whom 58.6% were male, were included in the analysis. A total of 58 (18.8%) patients died during follow-up. Cox multivariable analyses indicated society of thoracic surgeons (STS)-score was a strong independent predictor for mortality (hazard ratio (HR) 1.08, 95% confidential interval (CI) 1.05-1.12, P < 0.001). Elevated NT-proCNP was associated with a higher risk of cardiovascular mortality (HR 1.02, 95% CI 1.00-1.03, P = 0.025) and All-cause mortality (HR 1.01, 95% CI 1.00-1.03, P = 0.027), whereas NT-proBNP showed a small effect size on mortality. ROC analysis indicated that NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with left ventricular ejection fraction (LVEF) < 50% [(Area under the curve (AUC)-values of 0.79 (0.69; 0.87) vs. 0.59 (0.48; 0.69), P = 0.0453]. CONCLUSIONS: NT-proCNP and STS-Score were the independent prognostic factors of mortality among TAVR patients. Furthermore, NT-proCNP was superior to NT-proBNP for TAVR risk evaluation in patients with LVEF < 50%. Trial registration NCT02803294, 16/06/2016.

Aldo-keto reductase family 1 member B induces aortic valve calcification by activating hippo signaling in valvular interstitial cells.

AIMS: Calcific aortic valve disease (CAVD) is a primary cause of cardiovascular mortality; however, its mechanisms are unknown. Currently, no effective pharmacotherapy is available for CAVD. Aldo-keto reductase family 1 member B (Akr1B1) has been identified as a potential therapeutic target for valve interstitial cell calcification. Herein, we hypothesized that inhibition of Akr1B1 can attenuate aortic valve calcification. METHODS AND RESULTS: Normal and degenerative tricuspid calcific valves from human samples were analyzed by immunoblotting and immunohistochemistry. The results showed significant upregulation of Akr1B1 in CAVD leaflets. Akr1B1 inhibition attenuated calcification of aortic valve interstitial cells in osteogenic medium. In contrast, overexpression of Akr1B1 aggravated calcification in osteogenic medium. Mechanistically, using RNA sequencing (RNAseq), we revealed that Hippo-YAP signaling functions downstream of Akr1B1. Furthermore, we established that the protein level of the Hippo-YAP signaling effector active-YAP had a positive correlation with Akr1B1. Suppression of YAP reversed Akr1B1 overexpression-induced Runx2 upregulation. Moreover, YAP activated the Runx2 promoter through TEAD1 in a manner mediated by ChIP and luciferase reporter systems. Animal experiments showed that the Akr1B1 inhibitor epalrestat attenuated aortic valve calcification induced by a Western diet in LDLR-/- mice. CONCLUSION: This study demonstrates that inhibition of Akr1B1 can attenuate the degree of calcification both in vitro and in vivo. The Akr1B1 inhibitor epalrestat may be a potential treatment option for CAVD.

Effect of a novel transcatheter edge-to-edge repair device on the three-dimensional geometry of mitral valve in degenerative mitral regurgitation.

OBJECTIVES: We sought to assess the acute intraprocedural effects of the ValveClamp system in DMR patients on the mitral valve (MV) three-dimensional (3D) geometry and the association of these effects with mitral regurgitation (MR) reduction. BACKGROUND: Few data are available about the specific impact of transcatheter edge-to-edge repair in patients with degenerative mitral regurgitation (DMR). METHODS: Thirty-five symptomatic patients (age 74.26 ± 6.61 years) with Grade 3 to 4+ degenerative MR underwent 3D transoesophageal echocardiography (TEE) during ValveClamp implantation. Volumetric data sets were retrospectively analyzed using mitral valve quantitative 3D modeling software. RESULTS: Mitral valve annular anterior-posterior (AP) diameter decreased from 33.24 ± 4.03 to 31.12 ± 3.66 mm (p < .001), and prolapse height from 4.78 ± 2.19 to 2.32 ± 1.92 mm (p < .001), and total exposed leaflet area from 1,110.29 ± 224.21 mm2 to 1,013.44 ± 228.71 mm (p = .004). Accordingly, we observed a significant reduction of MR severity after ValveClamp implantation. Multivariable analysis revealed postprocedural MR reduction was associated with shortening in anterior-posterior diameter (coefficient 0.427, p = .008) and reduction in prolapse height (coefficient 0.369, p = .021). CONCLUSIONS: ValveClamp implantation exerts an acute effect on the 3D MV geometry. Postprocedural reduction in AP diameter and reduction in prolapse height correlates with MR downgrading in patients with degenerative MR.

Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.

RATIONALE: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC. OBJECTIVE: The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. METHODS AND RESULTS: Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. CONCLUSIONS: GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.

Incidence and Predictors of Permanent Pacemaker Implantation in Patients Who Underwent Transcatheter Aortic Valve Replacement: Observation of a Chinese Population.

AIMS: Permanent pacemaker (PPM) implantation is one of the most common complications after transcatheter aortic valve replacement (TAVR). We studied the incidence of PPM implantation and identified the predictors in patients who underwent TAVR in a Chinese population. METHODS AND RESULTS: A total of 256 patients who underwent TAVR with self-expandable valves were included. The incidence of PPM implantation in our study population was 14.8%. In patients who received PPM implantation, the proportion of bicuspid aortic valve (BAV) patients was much lower compared to tricuspid aortic valve (TAV) patients (18.4 vs. 81.6%, p < 0.05). Patients with BAV were associated with a significantly lower PPM implantation rate and shallower implantation depth compared to patients with TAV (6.4 vs. 21.7% and 4.2 ± 4.4 vs. 6.2 ± 5.0 mm, respectively, p < 0.05 for both). In the multivariable logistic regression analysis, prior right bundle branch block (RBBB; OR 8.3, 95% CI 2.2-32.1, p < 0.05), implantation depth (OR 1.3, 95% CI 1.1-1.5, p = 0.01), and TAV (OR 4.7, 95% CI 1.5-14.4, p < 0.05) were independent predictors of PPM implantation after TAVR. There was no difference in 30-day and 1-year all-cause mortality between the 2 groups. CONCLUSIONS: The incidence of PPM implantation in patients with self-expandable valves after TAVR was 14.8% in our cohort study. Independent predictors of PPM implantation included prior RBBB, TAV, and implantation depth at the noncoronary sinus side. TAVR in BAV with a supra-annular structure-based sizing strategy might decrease the risk of PPM implantation.

Left ventricular remodeling and dysfunction in obstructive sleep apnea : Systematic review and meta-analysis.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular mortality and morbidity. Several studies have reported that it affects the left ventricle; however, large randomized controlled trials are lacking. The current study aimed to summarize the association between OSAS and left ventricular (LV) structure and function. METHODS: Electronic databases (PubMed, Embase, and Cochrane) and references were searched for articles published until March 2018. A systematic review and meta-analysis were performed to assess LV structure and function in OSAS patients based on echocardiography. RESULTS: In total, 17 studies with 747 OSAS patients and 426 control participants were included. Patients with OSAS showed an increase in LV diastolic diameter (weighted mean difference [WMD], 95% CI: 1.24 [0.68, 1.80]; p < 0.001), LV systolic diameter (WMD, 95% CI: 1.14 [0.47, 1.81]; p = 0.001), and LV mass (WMD, 95% CI: 35.34 [20.67, 50.00]; p < 0.001). In addition, left ventricular ejection fraction (LVEF) significantly decreased in the OSAS group compared with the controls (WMD, 95% CIs: -1.82 [-2.76, -0.87]; p < 0.001), and the reduction in LVEF was consistent with the severity of OSAS. The OSAS group also showed an increase in left atrial diameter (WMD, 95% CI: 2.13 [1.48, 2.77]; p < 0.001) and left atrial diameter volume index (WMD, 95% CIs: 3.96 [3.32, 4.61]; p < 0.001). CONCLUSION: Obstructive sleep apnea syndrome leads to atrial dilatation, left ventricular hypertrophy, enlargement, mass increase and reduction of systolic function. Treatments for OSAS might be beneficial for the preservation of left cardiac structure and function.

First Report on Neopestalotiopsis aotearoa of Rubber Tree in China.

Natural rubber is an important industrial raw material and an economically important perennial in China. In recent years, A new leaf fall disease, caused by Neopestalotiopsis aotearoa Maharachch., K.D. Hyde & Crous, has occurred in Indonesia, Malaysia, Thailand, Sri Lanka, and other major rubber planting countries. In May and July of 2020, this disease was first found on 2-year-old rubber seedlings in two plantations located in Ledong and Baisha counties in Hainan Province, China. In the two plantations of approximately 32 ha, 15% of the rubber seedlings had the disease and the defoliation was more than 20%. The infected leaves turned yellow and watery, and dark brown and nearly round lesions of 1-2 mm in diameter were formed on the leaves. When the humidity was high, the center of the lesion was grey-white, and the lesions had many small black dots, black margins and surrounded by yellow halos. When the disease was severe, leaves fell off. To identify the pathogen, leaf tissues were collected from lesion margins after leaf samples were surface-sterilized in 75% ethanol, rinsed with sterile water for three times, and air dried. The leaf tissues were plated on potato dextrose agar (PDA) and incubated at 28°C for seven days. Fungal cultures with similar morphology were isolated from 90% of tested samples and two isolates (HNPeHNLD2001 and HNPeHNLD2002) were used in pathogenicity and molecular tests. Rubber leaves (clone PR107) were inoculated with conidial suspension (106 conidia/ml), and inoculated with PDA were used as the control, Each treatment had 3 leaves, and each leaf was inoculated with 3 spots and incubated at 28oC under high moisture conditions. Five days later, leaves inoculated with conidial suspension showed black leaf spots resembling the disease in the field, whereas the control leaves remained symptomless. The fungal cultures isolated from the inoculated tissues, had identical morphology compared with the initial isolates. Colonies on PDA were 55-60 mm in diameter after seven days at 28°C, with undulate edges, pale brown, thick mycelia on the surface with black, gregarious conidiomata; and the reverse side was similar in color. Black conidia were produced after eight days of culture on PDA. Conidia were fusoid, ellipsoid, straight to slightly curved, 4-septate, ranged from 18.35 to 27.12 µm (mean 22.34 µm) × 4.11 to 7.03 µm (mean 5.41 µm). The basal cells were conic with a truncate base, hyaline, rugose and thin-walled, 4.35 to 6.33 µm long (mean 4.72 µm). Three median cells were doliform, 12.53 to 18.97 µm long (mean 15.26 µm), hyaline, cylindrical to subcylindrical, thin- and smooth-walled, with 2-3 tubular apical appendages, arising from the apical crest, unbranched, filiform, 14.7 to 25.3 µm long (mean 19.94 µm). The basal appendages were singlar, tubular, unbranched, centric, 3.13 to 7.13 µm long (mean 5.48 µm). Morphological characteristics of the isolates were similar to the descriptions of N. aotearoa (Maharachchikumbura et al. 2014). The rDNA internal transcribed spacer (ITS) region, translation elongation factor 1-αgenes (TEF), and beta-tubulin (TUB2) gene were amplified using the primer pairs ITS1/ITS4, EF1-728F/EF1-986R and T1/Bt-2b (Pornsuriya et al. 2020), respectively. The sequences of these genes were deposited in GenBank (ITS Accession Nos.: MT764947 and MT764948; TUB2: MT796262 and MT796263; TEF: MT800516 and MT800517). According to the latest classification of Neoprostalotiopsis spp. (Maharachchikumbura et al. 2014) and multilocus phylogeny, isolates HNPeHNLD2001 and HNPeHNLD2002 were clustered in the same branch with N. aotearoa. Thus, the pathogen was identified as N. aotearoa, which is different from N. cubana and N. formicarum reported in Thailand (Pornsuriya et al. 2020; Thaochan et al. 2020). The Neopestalotiopsis leaf spotdisease of rubber tree (H. brasiliensis) was one of the most serious and destructive leaf diseases in major rubber planting countries in Asia. ( Tajuddin et al. 2020) The present study of leaf fall disease on rubber tree caused byN. aotearoa is the first report in China. The finding provides the basic pathogen information for further monitoring the disease and its control.

Supra-annular structure assessment for self-expanding transcatheter heart valve size selection in patients with bicuspid aortic valve.

OBJECTIVES: To explore assessment of supra-annular structure for self-expanding transcatheter heart valve (THV) size selection in patients with bicuspid aortic stenosis (AS). BACKGROUND: Annulus-based device selection from CT measurement is the standard sizing strategy for tricuspid aortic valve before transcatheter aortic valve replacement (TAVR). Because of supra-annular deformity, device selection for bicuspid AS has not been systemically studied. METHODS: Twelve patients with bicuspid AS who underwent TAVR with self-expanding THVs were included in this study. To assess supra-annular structure, sequential balloon aortic valvuloplasty was performed in every 2 mm increments until waist sign occurred with less than mild regurgitation. Procedural results and 30 day follow-up outcomes were analyzed. RESULTS: Seven patients (58.3%) with 18 mm; three patients (25%) with sequential 18 mm, 20 mm; and only two patients (16.7%) with sequential 18 mm, 20 mm, and 22 mm balloon sizing were performed, respectively. According to the results of supra-annular assessment, a smaller device size (91.7%) was selected in all but one patient compared with annulus based sizing strategy, and the outcomes were satisfactory with 100% procedural success. No mortality and 1 minor stroke were observed at 30 d follow-up. The percentage of NYHA III/IV decreased from 83.3% (9/12) to 16.7% (2/12). No new permanent pacemaker implantation and no moderate or severe paravalvular leakage were found. CONCLUSIONS: A supra-annular structure based sizing strategy is feasible for TAVR in patients with bicuspid AS.

Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells.

OBJECTIVE: Cigarette smoking is an independent risk factor for atherosclerosis. Nicotine, the addictive component of cigarettes, induces mast cell (MC) release and contributes to atherogenesis. The purpose of this study was to determine whether nicotine accelerates atherosclerosis through MC-mediated mechanisms and whether MC stabilizer prevents this pathological process. APPROACH AND RESULTS: Nicotine administration increased the size of atherosclerotic lesions in apolipoprotein E-deficient (Apoe-/-) mice fed a fat-enriched diet. This was accompanied by enhanced intraplaque macrophage content and lipid deposition but reduced collagen and smooth muscle cell contents. MC deficiency in Apoe-/- mice (Apoe-/-KitW-sh/W-sh) diminished nicotine-induced atherosclerosis. Nicotine activated bone marrow-derived MCs in vitro, which was inhibited by a MC stabilizer disodium cromoglycate or a nonselective nicotinic acetylcholine receptor blocker mecamylamine. Further investigation revealed that α7 nicotinic acetylcholine receptor was a target for nicotine activation in MCs. Nicotine did not change atherosclerotic lesion size of Apoe-/-KitW-sh/W-sh mice reconstituted with MCs from Apoe-/-α7nAChR-/- animals. CONCLUSIONS: Activation of α7 nicotinic acetylcholine receptor on MCs is a mechanism by which nicotine enhances atherosclerosis.

Transcatheter Aortic Valve Replacement for Pure Native Aortic Valve Regurgitation: A Systematic Review.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a recent and an effective treatment option for high- or extreme-surgical-risk patients with symptomatic severe aortic stenosis. However, pure severe native aortic valve regurgitation (NAVR) without aortic stenosis remains a contraindication to TAVR. The aim of our systemic review analysis was to evaluate TAVR in patients with pure NAVR. METHODS: We searched the published articles in the PubMed and Web of Science databases (2002-2017) using the Boolean operators for studies of NAVR patients undergoing TAVR. Reference lists of all returned articles were searched recursively for other relevant citations. Pooled estimates were calculated using a random-effects meta-analysis. RESULTS: Finally, a total of 10 studies were included in this analysis. The CoreValve was more frequently used with a lower rate of device success and a higher rate of residual aortic regurgitation. The new-generation transcatheter heart valves (THVs) performed a significantly higher rate with less residual aortic regurgitation and a success rate close to 100%. The 30-day all-cause mortality rates ranged from 0 to 30% with an estimate summary rate of 9% (95% CI: 5-15%; I2 = 33%). Cerebrovascular events, major or life-threatening bleeding, major vascular complications, acute kidney disease, and new permanent pacemaker implantation occurred similarly in both the new- and old-generation THV devices. CONCLUSIONS: Aortic regurgitation remains a challenging pathology for TAVR. TAVR is a feasible and reasonable option for carefully selected patients with pure aortic regurgitation.

Predictors of Thrombocytopenia after Self-Expandable Transcatheter Aortic Valve Replacement: A Single-Center Experience from China.

OBJECTIVES: The importance of thrombocytopenia (TP) has been discussed previously. However, data are still limited, especially on predictors of TP. We sought to investigate predictors of TP after transcatheter aortic valve replacement (TAVR), in particular, clinically significant TP. METHODS: We reviewed a total of 123 consecutive patients undergoing TAVR in our medical center. They were stratified into 3 groups according to the nadir platelet count post-TAVR: no/mild TP, moderate TP, and severe TP. Clinically significant TP, also known as major TP, was defined as moderate-to-severe TP (a nadir platelet count <100 × 109/L and a >50% decrease in platelet count). RESULTS: Baseline platelet, baseline hemoglobin, general anesthesia (GA), valve malpositioning and post-TAVR left ventricular ejection fraction were found to be predictors of post-TAVR nadir platelet count. Major TP was associated with a higher risk of major bleeding (OR 3.524, 95% CI 1.546-8.031) and 1-month mortality (OR 11.226, 95% CI 1.208-104.328). Age (OR 1.110, 95% CI 1.014-1.215) and GA (OR 6.494, 95% CI 2.058-20.408) were predictors of major TP. CONCLUSION: Post-TAVR nadir platelet count can be predicted based on baseline and procedural data. Old age and GA contribute to clinically significant TP.