[Bibliometrics Analysis of Studies on Hypertrophic Cardiomyopathy From 2018 to 2022].

Objective To analyze the research progress and hot topics in hypertrophic cardiomyopathy from 2018 to 2022.Methods The publications in the field of hypertrophic cardiomyopathy from January 1,2018 to December 31,2022 were retrieved from Web of Science core collection database and included for a bibliometric analysis.Results A total of 6355 publications were included,with an average citation frequency of 7 times.The year 2021 witnessed the most publications (1406).The analysis with VOSviewer showed that the research on sudden death related to hypertrophic cardiomyopathy,especially the predictive value of late gadolinium-enhanced cardiac MRI in sudden death,was a hot topic.In addition,gene detection and the new drug mavacamten became hot research topics.The United States was the country with the largest number of publications and the highest citation frequency in this field.Chinese scholars produced the second largest number of publications,which,however,included few high-quality research results.Conclusions Risk stratification and prevention of sudden death is still an important and hot research content in the field of hypertrophic cardiomyopathy.Chinese scholars should carry out multi-center cooperation in the future to improve the research results.

New insights into metabolomics profile generation in fermented tea: the relevance of bacteria and metabolites in Fuzhuan brick tea.

BACKGROUND: The contribution of bacteria to fermented tea is not clear and the associated research is relatively limited. To reveal the role of microorganisms in fermented tea processing, the microbial community and metabolites of Fuzhuan brick tea (FBT), a Chinese traditional fermented tea, were revealed via high-throughput sequencing and liquid chromatography-mass spectrometry (LC-MS). RESULTS: In FBT, bacterial communities had a higher abundance and diversity, Lactococcus and Bacillus were the main bacteria, and Eurotium was the predominant fungus. The predictive metabolic function indicated the pathways of cellular growth, environmental information, genetics and material metabolism of bacterial communities were abundant, whereas the fungal community predictive metabolic function was almost saprotroph. Using LC-MS, 1143 and 536 metabolites were defined in positive and negative ion mode, respectively. There were essential correlations between bacterial populations and metabolites, such that Bacillus was correlated significantly with 44 metabolites (P < 0.05) and Enterococcus was significantly associated with 15 metabolites (P < 0.05). Some of the main active components were significantly correlated with the bacteria, such as Enterococcus, Lactococcus and Carnobacterium. CONCLUSION: Not only Eurotium, but also the bacteria were involved in the changes of metabolomics profile in fermented FBT. The present study assists in providing new insights into metabolomics profile generation in fermented tea. The present research lays a foundation for controlling the FBT fermentation by artificial inoculation to improve quality. © 2021 Society of Chemical Industry.

In vitro and in vivo induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor.

Pharmacological induction of fetal hemoglobin (HbF) expression is an effective therapeutic strategy for the management of beta-hemoglobinopathies such as sickle cell disease. DNA methyltransferase (DNMT) inhibitors 5-azacytidine (5-aza) and 5-aza-2'-deoxycytidine (decitabine) have been shown to induce fetal hemoglobin expression in both preclinical models and clinical studies, but are not currently approved for the management of hemoglobinopathies. We report here the discovery of a novel class of orally bioavailable DNMT1-selective inhibitors as exemplified by GSK3482364. This molecule potently inhibits the methyltransferase activity of DNMT1, but not DNMT family members DNMT3A or DNMT3B. In contrast with cytidine analog DNMT inhibitors, the DNMT1 inhibitory mechanism of GSK3482364 does not require DNA incorporation and is reversible. In cultured human erythroid progenitor cells (EPCs), GSK3482364 decreased overall DNA methylation resulting in de-repression of the gamma globin genes HBG1 and HBG2 and increased HbF expression. In a transgenic mouse model of sickle cell disease, orally administered GSK3482364 caused significant increases in both HbF levels and in the percentage HbF-expressing erythrocytes, with good overall tolerability. We conclude that in these preclinical models, selective, reversible inhibition of DNMT1 is sufficient for the induction of HbF, and is well-tolerated. We anticipate that GSK3482364 will be a useful tool molecule for the further study of selective DNMT1 inhibition both in vitro and in vivo.

A hit deconstruction approach for the discovery of fetal hemoglobin inducers.

Beta-hemoglobinopathies such as sickle cell disease represent a major global unmet medical need. De-repression of fetal hemoglobin in erythrocytes is a clinically validated approach for the management of sickle cell disease, but the only FDA-approved medicine for this purpose has limitations to its use. We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules with the ability to de-repress fetal hemoglobin, which resulted in the identification of the benzoxaborole-containing hit compound 1. This compound was found to have modest cellular potency and lead-like pharmacokinetics, but no identifiable SAR to enable optimization. Systematic deconstruction of a closely related analog of 1 revealed the fragment-like carboxylic acid 12, which was then optimized to provide tetrazole 31, which had approximately 100-fold improved cellular potency compared to 1, high levels of oral exposure in rats, and excellent solubility.

Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group.

In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.

High throughput screening identifies ATP-competitive inhibitors of the NLRP1 inflammasome.

Nod-like receptors (NLRs) are cytoplasmic pattern recognition receptors that are promising targets for the development of anti-inflammatory therapeutics. Drug discovery efforts targeting NLRs have been hampered by their inherent tendency to form aggregates making protein generation and the development of screening assays very challenging. Herein we report the results of an HTS screen of NLR family member NLRP1 (NLR family, pyrin domain-containing 1) which was achieved through the large scale generation of recombinant GST-His-Thrombin-NLRP1 protein. The screen led to the identification of a diverse set of ATP competitive inhibitors with micromolar potencies. Activity of these hits was confirmed in a FP binding assay, and two homology models were employed to predict the possible binding mode of the leading series and facilitate further lead-optimization. These results highlight a promising strategy for the identification of inhibitors of NLR family members which are rapidly emerging as key drivers of inflammation in human disease.

Analysis and evaluation of patient-specific three-dimensional printing in complex septal myectomy.

OBJECTIVES: This study aimed to assess the effectiveness of three-dimensional printing (3DP) in patients with complex hypertrophic cardiomyopathy requiring combined transaortic and transapical septal myectomy. METHODS: We created 3DP models for 7 patients undergoing this surgery approach between June and October 2022 using silicone-like resin and conducted mock operations. The models were compared with echocardiography to identify abnormal muscle bundles and heart structures. These patients were then compared with a 1:2 matched group without 3DP, considering age, sex and additional operations. RESULTS: The models mostly presenting with midventricular obstruction showed high consistency with original computed tomography data (r = 0.978, P < 0.001). 3DP identified more abnormal muscle bundles than echocardiography, primarily between the interventricular septum and apex. Excised specimens in mock operations mirrored those in actual myectomies. While cardiopulmonary bypass time was not significantly different, a near-20-min decrease was observed in the 3DP group (135.5 ± 31.1 vs 154.4 ± 36.6 min, P = 0.054). CONCLUSIONS: While no significant differences in surgical outcomes were observed, 3DP appeared to enhance the visualization and understanding of spatial structures (average Likert scale score 4.0), potentially contributing to surgical proficiency (overall rating score 3.9). The use of 3DP may offer additional value in the preparation and execution of operations for complex hypertrophic cardiomyopathy cases.

Influence of Preoperative Serum Albumin on Acute Kidney Injury after Aortic Surgery for Acute Type A Aortic Dissection: A Retrospective Cohort Study.

There are relatively few articles on the relationship between serum albumin and acute kidney injury (AKI). Therefore, the objective of this research was to study the relationship between serum albumin and AKI in patients who were undergoing surgery for acute type A aortic dissection. METHODS: We retrospectively collected data from 624 patients attending a Chinese hospital between January 2015 and June 2017. The target independent variable was serum albumin measured before surgery after hospital admission, and the dependent variable was AKI, defined in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: The mean age of these 624 selected patients was 48.5 ± 11.1 years, and almost 73.7% were male. A nonlinear association was detected between serum albumin and AKI; the turning point was 32 g/L. The risk of AKI decreased gradually as the serum albumin level increased up to 32 g/L (adjusted OR = 0.87; 95% CI 0.82-0.92; p < 0.001). When the serum albumin level exceeded 32 g/L, the level of serum albumin was not associated with the risk of AKI (OR = 1.01, 95% CI 0.94-1.08; p = 0.769). CONCLUSIONS: The findings suggest that preoperative serum albumin below 32 g/L was an independent risk factor for AKI in patients undergoing surgery for acute type A aortic dissection. TRIAL REGISTRATION: A retrospective cohort study.

Mitral annular calcification in obstructive hypertrophic cardiomyopathy: Incidence, risk factors, and prognostic value after myectomy.

BACKGROUND: Mitral annular calcification (MAC) is a risk factor for cardiac surgery, but there is limited study on the prognosis value and the impact for valve function of MAC based on computed tomography (CT) diagnosis after myectomy for hypertrophic obstructive cardiomyopathy (OHCM). METHODS: Consecutive OHCM patients underwent septal myectomy were compared according to the existence of MAC and its severity in preoperative CT scans. The survival data were evaluated and compared by Kaplan Meier analysis and log rank test. Cox regression analysis was used to evaluate the impact of MAC on endpoint events. RESULTS: From the entire cohort of 1035 patients, 10.8% had MAC. In multivariate regression, female (OR = 2.23), age (OR = 1.07), aortic annular calcification (OR = 2.52), aortic calcification (OR = 2.56), systolic anterior motion of the mitral valve (SAM) (OR = 0.42), mitral valve thickening (OR = 2.13), and tricuspid regurgitation (OR = 3.12) were independent predictors of MAC. All-cause mortality (3.57% vs. 1.08%, p = 0.031), major adverse cardiovascular and cerebrovascular events (MACCE) (23.32% vs. 13.65%, p = 0.014), recurrent MR > 2+ (8.04% vs. 2.49%, p = 0.001) and NYHA III-IV (11.61% vs. 5.53%, p = 0.012) were more frequent in OHCM patients with MAC after myectomy. MAC was discovered to be an independent predictor of postoperative recurrent MR > 2+ after other risk factors were taken into account (HR 2.47, 95% CI 1.08-5.67, p = 0.0329). Moderate-to-severe MAC was an independent risk factor (HR 2.03, 95% CI 1.09-3.75, p = 0.0244) for long-term major adverse cardiovascular and cerebrovascular events (MACCE). CONCLUSION: MAC was detected in one-tenth of OHCM patients in preoperative CT scanning and is mainly associated with aging and atherosclerosis. OHCM patients with MAC had a worse prognosis and more recurrent mitral valve regurgitation than those without MAC after septal myectomy.

High-Burden Premature Atrial Contractions Predict New-Onset Atrial Fibrillation After Surgical Septal Myectomy.

Although increased premature atrial contractions (PACs) reportedly predict atrial fibrillation (AF) in both general and specific (e.g., patients with stroke) populations, early postoperative AF (POAF) risk in patients with increased PAC burden who require cardiac surgery remains unclear. We examined the correlation between different preoperative PAC burdens and POAF in patients with obstructive hypertrophic cardiomyopathy (OHCM) who underwent surgical treatment. We analyzed 304 consecutively admitted patients with OHCM without previous AF who underwent isolated septal myectomy between January 2015 and December 2018. All patients underwent preoperative 24-hour Holter electrocardiogram monitoring. PACs were present in 259 patients (85.20%) and absent in 45 patients (14.80%). According to the cut-off PAC number of 100 beats/24 hours, there were 211 patients (69.41%) with low-burden PACs and 48 patients (15.79%) with high-burden PACs. AF after septal myectomy occurred in 73 patients, which consisted of 3/45 in the non-PAC group (6.67%), 47/211 in the low-PAC-burden group (22.27%), and 23/48 in the high PAC burden group (47.92%). POAF incidence was higher in both low- and high-burden patients than in patients without PAC (p <0.01). Multivariate logistic regression analyses demonstrated that high-burden PACs (p = 0.02) and age (p <0.01) but not low-burden PACs (p = 0.22) independently predicted POAF in patients with OHCM. The area under the receiver operating characteristic curve for preoperative PACs was 0.72 (95% confidence interval 0.66 to 0.79, p <0.01, sensitivity: 68.49%, specificity: 69.26%). In conclusion, POAF incidence was significantly higher in patients with preoperative high-burden PACs and can predict POAF in patients with OHCM.

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction.

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.

Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.

2' biaryl amides as novel and subtype selective M1 agonists. Part I: Identification, synthesis, and initial SAR.

Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described.

Are dilated ascending aortas of Chinese patients more likely to dissect?

BACKGROUND: Ascending aortic aneurysm is a disease requiring surgical intervention. However, the timing of operation is still controversial. The purpose of this study is to compare the ascending aortic diameter and postoperative outcomes in hospital between patients with simple ascending aortic dissection and patients with simple ascending aortic dilation in China, and to investigate the accuracy of the timing of operation determined by ascending aortic diameter alone. METHODS: We reviewed the data from 2,520 hospitalized patients of aortic aneurysm and aortic dissection who underwent surgical treatment from January 2010 to June 2017 in our hospital. A total of 139 simple ascending aortic dissection and simple ascending aortic aneurysm hospitalized patients excluding Marfan syndrome and heart valve diseases etc. (56 in the aortic dilatation group and 83 in the aortic dissection group) were enrolled. The t-test and univariable analysis were used to compare the differences between two groups. RESULTS: For the aortic diameter, the group of aneurysm has greater ascending aortic diameter and the index of ascending aortic diameter compared with the group of dissection (P<0.001, P<0.001). For male patients, the result is the same (P<0.001, P<0.001). But for female patients, there was no significant statistical significance between the two groups (P=0.631, P=0.288). For the postoperative outcomes, the dissection group had higher mortality, incidence of tracheotomy and postoperative re-exploration for hemorrhage (P=0.040, P=0.011, P=0.028). CONCLUSIONS: The majority of patients with simple ascending aortic dissection present with aortic diameters <5.5 cm and this is not consistent with the current operation indications of aortic aneurysm. It is far from enough to predict aortic dissection with aortic diameter alone. More indicators are needed to do this.

Does preoperative serum creatinine affect the early surgical outcomes of acute Stanford type A aortic dissection?

BACKGROUND: Acute Stanford type A aortic dissection is a lethal disease requiring surgery. Evidence regarding the effects of preoperative creatinine in mortality is limited, and few studies have evaluated the effect of postoperative dialysis treatment on it. METHODS: In this cohort study, we continuously recruited 632 surgical patients who were treated for acute type A aortic dissection in our hospital between January 2015 and May 2017. The preoperative level of serum creatinine was measured. All patients were followed up after surgery for 30 days to determine early mortality. RESULTS: The 30-day mortality after surgery increased with elevated levels of preoperative serum creatinine. Median (interquartile range) serum creatinine levels in survivors were 9.61 µmol/dL (7.28-12.62 µmol/dL) versus 13.41 µmol/dL (10.28-20.63 µmol/dL) in death (p < 0.01). Adjusted odds ratios for increasing per µmol/dL serum creatinine were 1.09 (95% confidence interval, 1.03-1.15). We also found that the effect of preoperative creatinine on 30-day mortality was diminished by dialysis treatment after surgery. CONCLUSION: Preoperative serum creatinine predicts outcome in patients undergoing surgery for Stanford type A aortic dissection, and postoperative dialysis treatment can reduce its hazard.

Increased frequency of FBN1 frameshift and nonsense mutations in Marfan syndrome patients with aortic dissection.

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disease that mainly involves Fibrillin-1 (FBN1) mutations and aortic manifestations. In this study, we investigated the correlations between the FBN1 genotype-phenotype and aortic events (aortic dissection and aortic aneurysm) in patients with Marfan syndrome. METHODS: Genotype and phenotype information was evaluated in 180 patients with MFS. DNA sequencing was performed on each patient. According to the clinical manifestation, these patients were split into two groups: the aortic dissection group and the aortic aneurysm group. Aortic wall tissue was obtained from Marfan patients who underwent surgery and was used for staining. RESULTS: A total of 180 patients with FBN1 mutations were grouped into four categories: 90 with missense mutations, 32 with splicing mutations, 29 with frameshift mutations, and 29 with nonsense mutations. There was a significantly higher frequency of frameshift and nonsense mutations observed in aortic dissection than in aortic aneurysm (25.58% vs. 4.35%, p = .005; 25.58% vs. 8.70%, p = .033, respectively;), while missense mutations showed a higher frequency in aortic aneurysm than in aortic dissection (69.57% vs. 32.56%, respectively; p < .001) and a higher rate of lens dislocation (34.78% vs. 13.95%, respectively; p = .008). Pathological staining showed that elastic fibers were sparser in patients with a frameshift and nonsense mutations, and the smooth muscle cells were sparser and more disorganized than those observed in patients with missense mutations. CONCLUSION: This study showed that FBN1 gene frameshift and nonsense mutations are more common in patients with aortic dissection and may have meaningful guidance for the treatment of Marfan syndrome patients.

New quinoline NK3 receptor antagonists with CNS activity.

Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.

Camphor sulfonamide derivatives as novel, potent and selective CXCR3 antagonists.

A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described.

Comparison of prognostic ability of perioperative myocardial biomarkers in acute type A aortic dissection.

Stanford type A aortic dissection (AD) is a lethal disease requiring surgery. Evidence regarding the prognostic ability of perioperative myocardiac markers on long-term outcome is limited.In this cohort study, we measured perioperative myocardiac markers level in 583 surgical patients with type A AD in our hospital between 2015 and 2017. All patients were followed up after surgery for a median period of 864 days to determine short- and long-term mortality.About one-fifth of patients has a positive preoperative myocardial markers, which was increased significantly after operation. Increase log10 post-creatine kinase MB isoenzyme (CK-MB) (hazard ratio [HR], 4.64; 95% confidence interval [CI] 1.89-11.43; P = .0008), log10 post-TnI (HR, 3.11; 95% CI 1.56-6.21; P = .0013), log10 post-Mb (HR, 3.00; 95% CI 1.40-6.43; P = .0048), log10 pre-CK-MB (HR,1.82; 95% CI 1.03-3.21; P = .0377), and upper tertile of post-CK-MB (HR,1.52; 95% CI 1.05-2.20; P = .0261) were the independent risk factor for 30 days mortality adjusted for potential confounders. None of cardiac markers was significantly associated with long-term outcome independent of other factors.Perioperative myocardiac predicts early outcome in type A AD patients undergoing surgery. Increasing perioperative myocardial markers do not appear to be a predictor for long-term all-cause mortality.

Protocol for creation of a risk scoring system for acute type A aortic dissection surgery.

Stanford type A aortic dissection is a kind of cardiovascular disease which seriously threatens human life and health. It has the characteristics of rapid onset, rapid progress and high mortality. Surgical treatment is a recognized treatment for type A aortic dissection. There are many disputed places in the actual clinical work about the timing, prognosis and methods of the operation. This study aims to establish an early mortality risk scoring system for acute Stanford A aortic dissection surgery patients. METHODS AND ANALYSIS: The structured data of patients with acute type A aortic dissection were collected. The primary outcome is death during hospitalization. Secondary outcomes will include re-operation and related complications. A risk scoring system of patients with acute type A aortic dissection undergoing surgical treatment will be established. Prospective data will be used to validate the risk stratification ability and accuracy of the model in operative risk prediction.