Connective Tissue Growth Factor: Regulation, Diseases, and Drug Discovery.

In drug discovery, selecting targeted molecules is crucial as the target could directly affect drug efficacy and the treatment outcomes. As a member of the CCN family, CTGF (also known as CCN2) is an essential regulator in the progression of various diseases, including fibrosis, cancer, neurological disorders, and eye diseases. Understanding the regulatory mechanisms of CTGF in different diseases may contribute to the discovery of novel drug candidates. Summarizing the CTGF-targeting and -inhibitory drugs is also beneficial for the analysis of the efficacy, applications, and limitations of these drugs in different disease models. Therefore, we reviewed the CTGF structure, the regulatory mechanisms in various diseases, and drug development in order to provide more references for future drug discovery.

Occult deterioration of an aortic annular abscess: how do we diagnose a pseudoaneurysm periaortic valve? A case report.

BACKGROUND: Infectious endocarditis (IE) is a disease caused by the colonization of toxic microorganisms on the endocardium of heart valves [1]. Although much progress has been made in the diagnosis and treatment of IE, its complications, such as annular abscesses [2], still have a high mortality rate. In this case, we describe a patient with infective endocarditis complicated by occult deteriorated aortic annular abscess. CASE PRESENTATION: A 44-year-old man was admitted due to weakness of his right limbs and unclear speech for 10 h. He had recurrent fevers for 1 month before admission. Transthoracic echocardiography showed a mix-echoic vegetation attached to the bicuspid aortic valve, moderate aortic regurgitation and a possible aortic annular abscess. Blood cultures were negative and empiric antibiotic therapy was begun. The patient did not have fever again and seem to be clinically improved. However, follow-up transesophageal echocardiography revealed a large periaortic abscess led to aortic sinus pseudoaneurysm. The patient underwent mechanical prosthetic valve replacement and annulus reconstruction successfully. Perivalvular abscess may be insidious deterioration in patients who seem to be clinically improved, which requires us to pay more attention. DISCUSSION: Occult deterioration of an aortic annular abscess is rare and more attention should be paid. Re-evaluation of echocardiography is required even if the patient's symptoms improve.

Deacetylation of FOXP1 by HDAC7 potentiates self-renewal of mesenchymal stem cells.

BACKGROUND: Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study. METHODS: Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency. RESULTS: FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages. CONCLUSION: These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials.

"Ghost imaging" in pericardial cavity: Disappeared "tumor-like" masses in tuberculous pericarditis.

A 66-year-old woman was admitted to our hospital due to chest distress and shortness of breath during 1 week. Transthoracic echocardiography (TTE) revealed massive pericardial effusion and multiple, irregular and high-density echo "tumor-like" masses on the heart, with the largest one on the apex. However, there were no masses found by computed tomography (CT) scan, except for increased lipids around the coronary artery. We performed emergency pericardiocentesis and drainage to relieve symptoms. The positron emission tomography/CT (PET/CT) also showed several ununiformly high accumulations in pericardial cavity. However, the high-density echo "tumor-like" masses cannot be seen by TTE after pericardiocentesis, and also cannot be detected when surgery. Pericardiotomy was performed due to severe pericardial adhesion. The diagnosis of tuberculosis (TB) was confirmed by pericardiotomy and pericardial biopsy.

FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis.

Beige adipocytes have a discrete developmental origin and possess notable plasticity in their thermogenic capacity in response to various environmental cues, but the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, forkhead box P4 (FOXP4), that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 in progenitor cells impaired beige cell early differentiation. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis capacity upon cold exposure. Of note, the outcome of Foxp4 deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we suggest that FOXP4 primes beige adipocyte early differentiation, but attenuates their activation by potent transcriptional repression of the thermogenic program.

Forkhead box P1 (Foxp1) in osteoblasts regulates bone mass accrual and adipose tissue energy metabolism.

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the forkhead box P1 (FOXP1) transcriptional factor. Deletion of the Foxp1 gene in osteoblasts led to augmentation of AdipoQ levels accompanied by fueled energy expenditure in adipose tissues. In contrast, overexpression of Foxp1 in bones impaired AdipoQ secretion and restrained energy consumption. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that AdipoQ expression, which increases as a function of bone age, is directly controlled by FOXP1. Our results indicate that bones, especially aged bones, provide an important source of a set of endocrine factors, including AdipoQ, that control body metabolism. © 2021 American Society for Bone and Mineral Research (ASBMR).

Surgical Preparation Reduces Hydrogen Sulfide Released from Human Saphenous Veins in Coronary Artery Bypass Grafting.

The long-term patency rate of saphenous vein (SV) grafts is poor compared to arterial grafts. To investigate the effects of surgical preparation (distention) of SV on hydrogen sulfide (H2S) released from the endothelium, human SV segments were harvested from 43 patients during coronary artery bypass surgery (CABG). Acetylcholine (ACh) induced relaxation that was inhibited by NG-nitro-L-arginine + indomethacin and cysteine aminotransferase inhibitor aminooxyacetic acid in the normal SV. In contrast, ACh did not evoke relaxation in the distended SV (DSV). The concentration of H2S quantified by methylene blue assay in DSV was significantly lower than that in control. Transmission electron microscope and immunohistochemistry studies showed that the preparation destroyed the endothelium, smooth muscle, organelle, and vasa vasorum. We conclude that surgical preparation injures the endothelium and smooth muscle of the SV grafts and reduces H2S release from SV. These effects may contribute to the poor long-term patency of the SV graft.

Perioperative poor grip strength recovery is associated with 30-day complication rate after cardiac surgery discharge in middle-aged and older adults - a prospective observational study.

BACKGROUND: Although perioperative care during heart surgery has improved considerably, the rate of postoperative complications has remained stable. It has not been concluded how to better apply grip strength to clinical, postoperative complications. So our study aimed at researching the best way for using grip value for predicting early postoperative complications. METHODS: A total of 212 patients with mean age 63.8 ± 6.3 who underwent cardiac surgery participated in our study. We analyzed the ROC curve of grip strength, grip/weight and grip recovery with complications, found the best cutoff point. Logistic regression confirmed the association between grip strength grouping and complications. RESULTS: We found that 36 patients had 30-day complications. EuroSCORE were 2.15 ± 1.52 and 2.42 ± 1.58 between normal and complication groups, respectively. The area under the receiver-operating characteristic curve (AUC) of grip recovery take the most area (0.837, p < 0.001), and the cutoff point was 83.92%. In logistic regression, lower grip recovery has higher risk impact on 30-day complications for 25.68 times than normal group, after adjusted surgery-related factors. After regrouped characteristic information by grip recovery cutoff point, we found that percentage of the estimated 6 min walk distance (41.5 vs 48.3, p = 0.028) and hospitalization time (7.2 vs 6.1, p = 0.042) had worse trends in lower recovery group. CONCLUSIONS: Poor grip recovery may be related to higher risk of postoperative complications within 30 days after discharge in middle-aged and older people independent of surgical risk. The results of this study provide a reference for the development of rehabilitation programs in the early postoperative recovery, and may also be a prognostic indicator for postoperative high-risk groups. TRIAL REGISTRATION: Our research was registered on Research Registry website, the registry number was ChiCTR1800018465. Date: 2018/9/20. Status: Successful.

The effects of five days of intensive preoperative inspiratory muscle training on postoperative complications and outcome in patients having cardiac surgery: a randomized controlled trial.

OBJECTIVE: To determine the prophylactic efficacy of short-term intensive preoperative inspiratory muscle training on the incidence of postoperative pulmonary complications in patients scheduled for cardiac surgery. DESIGN: Single-blind, randomized controlled pilot study. SETTING: TEDA International Cardiovascular Hospital, China. SUBJECTS: In total, 197 subjects aged ⩾50 years scheduled for cardiac surgery were selected. INTERVENTION: The intervention group ( n = 98) received five days of preoperative inspiratory muscle training on top of the usual care received by the patients in the control group ( n = 99). MAIN MEASURES: The primary outcome variable was the occurrence of postoperative pulmonary complications. The secondary outcome variables were inspiratory muscle strength, lung function and length of hospitalization. RESULTS: After cardiac surgery, a total of 10 (10.2%) of the 98 patients in the intervention group and 27 (27.3%) of 99 patients in the control group had postoperative pulmonary complications (risk ratio, 0.23; 95% confidence interval (CI), 0.09-0.58, P = 0.002). The study revealed that, compared with the control group, the intervention group had a significant increase in inspiratory muscle strength (by 10.48 cm H2O, P < 0.001), forced expiratory volume in the first second of expiration (FEV1) %predicted (by 3.75%, P = 0.030), forced vital capacity (FVC) %predicted (by 4.15%, P = 0.008) and maximal voluntary ventilation (MVV) %predicted (by 6.44%, P = 0.034). Length of hospital stay was 7.51 (2.83) days in the intervention group and 9.38 (3.10) days in the control group ( P = 0.039). CONCLUSION: A five-day intensive pattern of preoperative inspiratory muscle training reduced the incidence of postoperative pulmonary complications and duration of postoperative hospitalization in patients undergoing cardiac surgery.

Risk factors and clinical significance of acute kidney injury after on-pump or off-pump coronary artery bypass grafting: a propensity score-matched study.

OBJECTIVES: Our goal was to investigate risk factors for acute kidney injury (AKI) after coronary artery bypass grafting (CABG) and the impact of AKI on short-term outcomes. METHODS: Data on 1395 patients (1261 who had isolated CABG and 134 with other operations) who underwent non-emergent CABG from January 2013 to March 2016 were retrospectively collected from a single centre. Logistic regression was performed to analyse risk factors. Cox regression was used to analyse the impact of AKI on the postoperative 30-day death rate. A 1:1 propensity score matching was performed to balance the baseline characteristics. RESULTS: The incidence of AKI with on-pump and off-pump coronary artery bypass was 10.4% and 3.5%, respectively. With logistic regression, duration of surgery was a risk factor for AKI (stage ≥2); previous hypertension, preoperative renal function insufficiency and the presence of cardiopulmonary bypass (CPB) were risk factors for mild AKI (stage ≥1). CPB time >207.5 min could be used to predict AKI (sensitivity 79.2%, specificity 78.6%) in the combined group. After adjusting for the duration of the operation, postoperative AKI (stage ≥1) was a risk factor for 30-day death and there was no difference in the 30-day death rate between on-pump and off-pump CABG. CONCLUSIONS: The use of CPB was a risk factor for mild AKI that did not affect the 30-day death rate of CABG whereas moderate to severe AKI caused by prolonged CPB time associated with surgical complexity affected the 30-day death rate. AKI may indicate surgical injury. The decision to use the on- or off-pump technique does not affect the 30-day death rate of CABG.

Endothelial nitric oxide synthase enhancer AVE3085 reverses endothelial dysfunction induced by homocysteine in human internal mammary arteries.

Homocysteine (Hcy) is an independent risk factor for endothelial dysfunction in cardiovascular diseases. We hypothesized that the eNOS transcription enhancer AVE3085 may protect the endothelial function damaged by Hcy in the human internal mammary artery (IMA). Cumulative concentration-relaxation curves to acetylcholine (-10 to -4.5 log mol/L) or sodium nitroprusside were established in IMA from patients undergoing coronary artery surgery precontracted by U46619 (-8 log mol/L) in the absence/presence of Hcy (100 µmol/L) with/without AVE3085 (30 µmol/L) in vitro in a myograph. RT-qPCR and ELISA were used to quantify the mRNA and protein levels of eNOS. Colorimetric assay method was used to detect the production of nitric oxide (NO). Maximal relaxation was significantly attenuated by Hcy in human IMA. Co-incubation with AVE3085 protected endothelium from the impairment by Hcy and increased the production of NO. Exposure to Hcy for 24 h downregulated eNOS protein expression (P < 0.05) whereas it upregulated the expression of eNOS at mRNA levels (P < 0.05). The presence of AVE3085 in addition to Hcy significantly increased the eNOS protein (P < 0.05) and slightly decreased the mRNA level. The study for the first time revealed that in the human blood vessels (IMA) the clinically-relevant high concentration of Hcy directly causes endothelial dysfunction by downregulating eNOS protein that may be reversed by AVE3085. These findings not only provide new direction for protecting endothelium during coronary artery bypass grafting and improving long-term patency of the grafts, but also provide evidence to the use of eNOS enhancer in the patients with endothelial dysfunction in various pathological conditions.

Diagnostic value of miR-30d-5p and miR-125b-5p in acute myocardial infarction.

Rapid and accurate differential diagnosis of acute myocardial infarction (AMI) is crucial for timely interventions and the improvement of prognosis. However, this is difficult to achieve using current methods. Therefore, the present study aimed to evaluate the suitability of circulating microRNAs (miRNAs) as AMI biomarkers in patients with acute coronary syndrome (ACS). miRNA profiling in plasma samples from patients with AMI (n=3) and healthy controls (n=3) was performed using microarrays. Results were then validated in five patients and five healthy controls. miRNA-125b-5p and miR-30d-5p expression levels were quantified in plasma samples from 230 patients with ACS and 79 healthy controls using reverse transcription-quantitative polymerase chain reaction. Routine diagnostic parameters were assessed, including creatinine kinase MB, cardiac troponin I (cTnI) and myoglobin. A total of 33 miRNAs were differentially expressed in patients with AMI and healthy controls. Following validation based on the previously established roles for these miRNAs, six miRNAs were validated. miR­125b­5p and miR­30d­5p were selected for further investigation. Expression levels of miR­125b­5p and miR­30d­5p in plasma were higher in patients with ACS compared with the healthy controls (P<0.001). Receiver operating characteristic curve analysis revealed that the area under the curve of miR­30d­5p was higher than that of cTnI (0.915 and 0.899). miR­125b­5p (sensitivity, 0.808; specificity, 0.845) and miR­30d­5p (sensitivity, 0.855; specificity, 0.810) were suitable diagnostic predictors of AMI. Kaplan-Meier survival analysis indicated that miR-125b-5p levels were associated with 6 month cardiovascular events in patients with AMI, but not miR­30d­5p. miR-125b-5p and miR-30d-5p presented a diagnostic value for early diagnosis of AMI, and miR­30d­5p may have a higher diagnostic value than cTnI.

Surgical treatment of tricuspid regurgitation after mitral valve surgery: a retrospective study in China.

BACKGROUND: Functional tricuspid regurgitation (TR) occurs in patients with rheumatic mitral valve disease even after mitral valve surgery. The aim of this study was to analyze surgical results of TR after previous successful mitral valve surgery. METHODS: From September 1996 to September 2008, 45 patients with TR after previous mitral valve replacement underwent second operation for TR. In those, 43 patients (95.6%) had right heart failure symptoms (edema of lower extremities, ascites, hepatic congestion, etc.) and 40 patients (88.9%) had atrial fibrillation. Twenty-six patients (57.8%) were in New York Heart Association (NYHA) functional class III, and 19 (42.2%) in class IV. Previous operations included: 41 for mechanical mitral valve replacement (91.1%), 4 for bioprosthetic mitral valve replacement (8.9%), and 7 for tricuspid annuloplasty (15.6%). RESULTS: The tricuspid valves were repaired with Kay's (7 cases, 15.6%) or De Vega technique (4 cases, 8.9%). Tricuspid valve replacement was performed in 34 cases (75.6%). One patient (2.2%) died. Postoperative low cardiac output (LCO) occurred in 5 patients and treated successfully. Postoperative echocardiography showed obvious reduction of right atrium and ventricle. The anterioposterior diameter of the right ventricle decreased to 25.5 ± 7.1 mm from 33.7 ± 6.2 mm preoperatively (P < 0. 05). CONCLUSION: TR after mitral valve replacement in rheumatic heart disease is a serious clinical problem. If it occurs or progresses late after mitral valve surgery, tricuspid valve annuloplasty or replacement may be performed with satisfactory results. Due to the serious consequence of untreated TR, aggressive treatment of existing TR during mitral valve surgery is recommended.

The current strategy of repair of tetralogy of Fallot in children and adults.

OBJECTIVES: The strategies of repair of tetralogy of Fallot change with the age of patients. In children older than 4 years and adults, the optimal strategy may be to use different method of reconstruction of the right ventricular outflow tract from those followed in younger children, so as to avoid, or reduce, the pulmonary insufficiency that is increasingly known to compromise right ventricular function. METHODS: From April, 2001, through May, 2008, we undertook complete repair in 312 patients, 180 male and 132 female, with a mean age of 11.3 years +/-0.4 years, and a range from 4 to 48 years, with typical clinical and morphological features of tetralogy of Fallot, including 42 patients with the ventriculo-arterial connection of double outlet right ventricle. The operation was performed under moderate hypothermia using blood cardioplegia. The ventricular septal defect was closed with a Dacron patch. When it was considered necessary to resect the musculature within the right ventricular outflow tract, or perform pulmonary valvotomy, we sought to preserve the function of the pulmonary valve by protecting as far as possible the native leaflets, or creating a folded monocusp of autologous pericardium. RESULTS: The repair was achieved completely through right atrium in 192, through the right ventricular outflow tract in 83, and through the right atrium, the outflow tract, and the pulmonary trunk in 36 patients. A transjunctional patch was inserted in 169 patients, non-valved in all but 9. There were no differences regarding the periods of aortic cross-clamping or cardiopulmonary bypass. Of the patients, 5 died (1.6%), with no influence noted for the transjunctional patch. Of those having a non-valved patch inserted, three-tenths had pulmonary regurgitation of various degree, while those having a valved patch had minimal pulmonary insufficiency and good right ventricular function postoperatively, this being maintained after follow-up of 8 to 24-months. CONCLUSIONS: Based on our experience, we suggest that the current strategy of repair of tetralogy of Fallot in older children and adults should be based on minimizing the insertion of transjunctional patches, this being indicated only in those with very small ventriculo-pulmonary junctions. If such a patch is necessary, then steps should be taken to preserve the function of the pulmonary valve.