Ascending Aortic Progression After Isolated Aortic Valve Replacement Among Patients with Bicuspid and Tricuspid Aortic Valves.

OBJECTIVES: The aims of the present study were to compare the long-term outcomes for ascending aortic dilatation and adverse aortic events after isolated aortic valve replacement between patients with bicuspid aortic valve (BAV) and tricuspid aortic valve ( TAV). METHODS: This retrospective study included 310 patients who had undergone isolated aortic valve replacement with an ascending aorta diameter ≤ 45 mm between January 2010 and September 2021. The patients were divided into BAV group (n=90) and TAV group (n=220). The differences in the dilation rate of the ascending aorta and long-term outcomes were analyzed. RESULTS: Overall survival was 89 ± 4% in the BAV group vs. 75 ± 6% in the TAV group at 10 years postoperatively (P=0.007), yet this difference disappeared after adjusting exclusively for age (P=0.343). The mean annual growth rate of the ascending aorta was similar between the two groups during follow-up (0.5 ± 0.6 mm/year vs. 0.4 ± 0.5 mm/year; P=0.498). Ten-year freedom from adverse aortic events was 98.1% in the BAV group vs. 95.0% in the TAV group (P=0.636). Multivariable analysis revealed preoperative ascending aorta diameter to be a significant predictor of adverse aortic events (hazard ratio: 1.76; 95% confidence interval: 1.33 to 2.38; P<0.001). CONCLUSION: Our study revealed that the long-term survival and the risks of adverse aortic events between BAV and TAV patients were similar after isolated aortic valve replacement. BAV was not a risk factor of adverse aortic events.

Persistence of SARS-CoV-2 colonization and high expression of inflammatory factors in cardiac tissue 6 months after COVID-19 recovery: a prospective cohort study.

Background: The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in myocardial autopsy tissues has been observed in certain individuals with coronavirus disease 2019 (COVID-19). However, the duration of cardiac involvement remains uncertain among recovered COVID-19 patients. Our study aims to evaluate the long-term persistence of SARS-CoV-2 within cardiac tissue. Methods: We prospectively and consecutively evaluated the patients undergoing mitral valve replacement (MVR) and left atrial (LA) volume reduction surgery from May 25 to June 10, 2023 at our center, who had been approximately 6 months of recovery after Omicron wave. Patients tested positive for SARS-CoV-2 upon admission were excluded. The surgical LA tissue was collected in RNA preservation solution and stored at -80 ℃ immediately. Then SARS-CoV-2, interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) RNA expression in LA tissues were assessed through thrice-repeated reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Categorical variables were assessed using the Chi-square or Fisher's exact tests, and continuous variables was analyzed using the Mann-Whitney U test. Results: Nine of 41 patients were enrolled, all of whom tested negative for SARS-CoV-2 upon admission (two antigen and PCR tests). In four of nine patients, SARS-CoV-2 RNA was detected in their LA tissue, indicating viral colonization. Among the four positive cases, the IL-6 and IL-1ß relative expression levels in the LA tissue of one patient were increased approximately 55- and 110-fold, respectively, compared to those of SARS-CoV-2 (-) patients. Increased expression of IL-6 and IL-1ß were observed in the myocardium of this patient. Another patient demonstrated a remarkable 7-fold increase in both IL-6 and IL-1ß expression, surpassing that of SARS-CoV-2 (-) patients. Additionally, no other cardiac inflammation-related diseases or conditions were presented in these two patients. The IL-6 and IL-1ß expression levels of the remaining two patients were not significantly different from those of SARS-CoV-2 (-) patients. The relative expression levels of IL-6 and IL-1ß in cardiac tissues of all SARS-CoV-2 (-) patients were relatively low. Interestingly, despite abnormally elevated levels of IL-6 and IL-1ß within their cardiac tissue, two patients did not show a significant increase in serum IL-6 and IL-1ß levels when compared to other patients. Conclusions: Our research suggests that certain COVID-19-recovered patients have persistent colonization of SARS-CoV-2 in their cardiac tissue, accompanied by a local increase in inflammatory factors.

A new minimal invasive technique with in-situ stent-graft fenestration for type A aortic dissection.

Background: Aortic surgery successfully improves the prognosis of patients with type A aortic dissection. However, total arch replacement and reconstruction remain challenging. This study presents a new surgical modality, the in-situ stent-graft fenestration (ISSF) technique, for simplifying aortic arch reconstruction and assesses its short-term efficacy and safety in patients with type A aortic dissection. Methods: Data from 177 patients with type A aortic dissection who underwent aortic arch reconstruction were retrospectively analyzed. Sun's procedure was performed in 90 patients and ISSF was performed in the other 87. Results: The in-hospital mortality rate was 7.8% in the Sun's procedure group and 3.4% in the ISSF group (p = 0.357). Compared to the Sun's procedure group, the ISSF group had significantly shorter surgical duration, cardiopulmonary bypass time, circulatory arrest time, mechanical ventilation time, and aortic cross-clamp time (p < 0.05). Additionally, intraoperative blood loss was lower in the ISSF group than in the Sun's procedure group (p < 0.05). Patients who underwent ISSF also had a lower incidence of postoperative complications, including lung injury, renal failure, peripheral nerve injury, and chylothorax, than those who underwent Sun's procedure (p < 0.05). During the 6-month follow-up period after surgery, both groups showed significant improvements in the true lumen diameter of the descending thoracic aorta post-operation compared with the pre-operation measurements; meanwhile, the false lumen diameter decreased (p < 0.05). Conclusions: The ISSF technique appears to be an effective and safe alternative to conventional surgical procedures for patients with type A aortic dissection, with the potential to simplify the procedure, shorten the operation time, and yield satisfactory operative results. However, further investigation is needed to determine its long-term benefits.

Systematic review of the effect of cerebrospinal fluid drainage on outcomes after endovascular type B aortic dissection repair.

OBJECTIVE: The aim of the present systematic review was to determine whether prophylactic use of cerebrospinal fluid drainage (CSFD) contributes to a lower rate of spinal cord ischemia (SCI) after thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (TBAD). METHODS: PubMed, Embase, Web of Science and Cochrane Library databases were systematically searched to identify all relevant studies reported before May 7, 2023. A systematic review was conducted in accordance with PRISMA guidelines (PROSPERO registration no. CRD42023441392). The primary outcome was permanent SCI. Secondary outcomes were temporary SCI and 30-day/in-hospital mortality. The data were presented as the pooled event rates (ERs) and 95% confidence intervals (CIs). RESULTS: A total of 1008 studies were screened, of which 34 studies with 2749 patients were included in the present analysis. The mean Downs and Black quality assessment score was 8.71 (range, 5-12). The pooled rate of permanent SCI with prophylactic CSFD was identical to that without prophylactic CSFD (2.0%; 95% CI, 1.0-3.0; P = 0.445). No statistically significant difference was found between the rates of permanent SCI with routine vs. selective prophylactic CSFD (P = 0.596). The pooled rate of temporary SCI was 1.0% (95% CI, 0.00-1.0%). The pooled rate for 30-day or in-hospital mortality was not significantly different (P = 0.525) in patients with prophylactic CSFD (4.0, 95% CI 2.0-6.0) or without prophylactic CSFD (5.0, 95% CI 2.0-7.0). CONCLUSIONS: The systematic review has shown that prophylactic CSFD was not associated with a lower rate of permanent SCI and 30-day or in-hospital mortality after TEVAR for TBAD.

Ascending Aortic Progression After Isolated Aortic Valve Replacement Among Patients with Bicuspid and Tricuspid Aortic Valves

ABSTRACT Objectives: The aims of the present study were to compare the long-term outcomes for ascending aortic dilatation and adverse aortic events after isolated aortic valve replacement between patients with bicuspid aortic valve (BAV) and tricuspid aortic valve ( TAV). Methods: This retrospective study included 310 patients who had undergone isolated aortic valve replacement with an ascending aorta diameter ≤ 45 mm between January 2010 and September 2021. The patients were divided into BAV group (n=90) and TAV group (n=220). The differences in the dilation rate of the ascending aorta and long-term outcomes were analyzed. Results: Overall survival was 89 ± 4% in the BAV group vs. 75 ± 6% in the TAV group at 10 years postoperatively (P=0.007), yet this difference disappeared after adjusting exclusively for age (P=0.343). The mean annual growth rate of the ascending aorta was similar between the two groups during follow-up (0.5 ± 0.6 mm/year vs. 0.4 ± 0.5 mm/year; P=0.498). Ten-year freedom from adverse aortic events was 98.1% in the BAV group vs. 95.0% in the TAV group (P=0.636). Multivariable analysis revealed preoperative ascending aorta diameter to be a significant predictor of adverse aortic events (hazard ratio: 1.76; 95% confidence interval: 1.33 to 2.38; P<0.001). Conclusion: Our study revealed that the long-term survival and the risks of adverse aortic events between BAV and TAV patients were similar after isolated aortic valve replacement. BAV was not a risk factor of adverse aortic events.

Effect of transcatheter aortic valve replacement on ascending aorta dilatation rate in patients with tricuspid and bicuspid aortic stenosis.

Objectives: The aim of the present study was to assess the differences between BAV and TAV patients with chronic moderate to severe or severe AS regarding presentation, incidence of TAVR, survival, ascending aorta diameter and dilatation rate before and after TAVR. Methods: The study included 667 consecutive patients with chronic moderate to severe or severe AS from January 2012 and December 2022. Outcomes included all-cause mortality, incidence of TAVR, and ascending aorta diameter and dilatation rate. Results: There were 185 BAV-AS and 482 TAV-AS patients, and BAV-AS patients were younger (67 vs 78 years, P = 0.027). Total follow-up was 4.5 years (IQR: 2.7-8.9 years), 290 patients underwent TAVR, and 165 patients died. The 8-year TAVR incidence was higher in BAV-AS (55% ± 4%) vs TAV-AS (41% ± 5%; P = 0.02). The 8-year survival was higher in BAV-AS (85% ± 6%) vs TAV-AS (71% ± 6%; P < 0.0001) and became insignificant after age adjustment (P = 0.33). The dilatation rate of ascending aorta was significantly faster in BAV-AS patients compared with TAV-AS patients before TAVR. However, the ascending aorta dilatation rate for BAV-AS and TAV-AS patients was not significantly different after TAVR. Conclusions: Compared with TAV-AS, BAV-AS patients were younger and underwent TAVR more frequently, resulting in a considerable survival advantage. After TAVR, ascending aorta dilatation rates were similar in BAV-AS and TAV-AS patients, suggesting an important role of hemodynamics on ascending aorta dilatation in BAV-AS.

Early outcome of simplified total arch reconstruction under mild hypothermia (30-32 °C) with distal aortic perfusion.

OBJECTIVE: We designed a simplified total arch reconstruction (s-TAR) technique which could be performed under mild hypothermia (30-32 °C) with distal aortic perfusion. This study aimed to compare its efficacy of organ protection with the conventional total arch reconstruction (c-TAR). METHODS: We reviewed the clinical data of 195 patients who had ascending aortic aneurysm with extended aortic arch dilation and underwent simultaneous ascending aorta replacement and TAR procedure between January 2018 and December 2022 in our center. 105 received c-TAR under moderate hypothermia (25-28 °C) with circulatory arrest (c-TAR group); rest 90 received s-TAR under mild hypothermia (30-32 °C) with distal aortic perfusion (s-TAR group). RESULTS: The s-TAR group demonstrated shorter CPB time, cross-clamp time and lower body circulatory arrest time compared with the c-TAR group. The 30-day mortality was 2.9% for the c-TAR group and 1.1% for the s-TAR group (P = 0.043). The mean duration of mechanical ventilation was shorter in the s-TAR group. Paraplegia was observed in 4 of 105 patients (3.8%) in the c-TAR group, while no such events were observed in the s-TAR group. The incidence of temporary neurologic dysfunction was significantly higher in the c-TAR group. The incidence of permanent neurologic dysfunction also showed a tendency to be higher in the c-TAR group, without statistical significance. Furthermore, the incidence of reoperation for bleeding were significantly lower in the s-TAR group. The rate of postoperative hepatic dysfunction and all grades of AKI was remarkably lower in the s-TAR group. The 3-year survival rate was 95.6% in the s-TAR group and 91.4% in the c-TAR group. CONCLUSIONS: s-TAR under mild hypothermia (30-32℃) with distal aortic perfusion is associated with lower mortality and morbidity, offering better neurological and visceral organ protection compared with c-TAR.

A modified prosthesis eversion technique for proximal anastomosis in ascending aorta replacement.

Background: One of the crucial aspects of ascending aorta replacement is to achieve hemostasis of the proximal anastomosis. This study aimed to describe a modified prosthesis eversion technique for proximal anastomosis in ascending aorta replacement and compare its operative outcomes with the conventional prosthesis eversion technique. Methods: We conducted a retrospective analysis of all consecutive patients who had ascending aortic aneurysm and underwent ascending aorta replacement with the modified or conventional prosthesis eversion technique between January 2019 and December 2022 in our center. Results: A total of 108 patients were included: 55 in the modified group and 53 in the conventional group. The durations of cardiopulmonary bypass, aortic cross-clamping and total operation in the conventional group were longer than those in the modified group. Furthermore, perioperative blood loss and the incidence of re-exploration for bleeding were significantly lower in the modified group. Accordingly, patients in the conventional group accepted more blood transfusion. The modified group had a shorter duration in intensive care unit (ICU) and hospital, and lower total hospitalization costs than those in the conventional group. Conclusions: The modified prosthesis eversion technique is an effective alternative for proximal anastomosis in ascending aorta replacement, with less blood loss, shorter operation time, and lower rate of postoperative complications compared with the conventional technique.

Comparison and Evaluation of Two Combination Modes of Angiotensin for Establishing Murine Aortic Dissection Models.

Aortic dissection (AD) is a potentially fatal cardiovascular emergency caused by separation of different layers of aortic wall. However, because of limited time window available for clinical research, there is an urgent need for an ideal animal research model. In recent years, the incidence of AD complicated by atherosclerosis has increased with improvements of living standards and changes of eating habits. Accordingly, considering multiple risk factors, we successfully and efficiently established a novel AD model through a high-fat diet combined with chronic angiotensin II (AngII) infusion. Compared with traditional chemical induction model using AngII and ß-aminopropionitrile, our model is more clinically relevant for atherosclerosis-related AD. Moreover, infiltration of neutrophils and apoptosis of vascular smooth muscle cells in AD tissues were more significant. In addition to enriching the existing models, the novel model may be a long-term useful tool for more in-depth investigation of AD mechanisms and preclinical therapeutic developments.

Prognostic impact of new permanent pacemaker implantation following transcatheter aortic valve replacement.

BACKGROUND: Conduction disturbances requiring permanent pacemaker implantation (PPI) are common following transcatheter aortic valve replacement (TAVR). There were conflicting data regarding the impact of new PPI on clinical outcomes after TAVR. OBJECTIVES: The study sought to evaluate the impact of new PPI on clinical outcomes in patients undergoing TAVR. METHODS: This study was a retrospective analysis of prospectively collected data. Data were from 210 consecutive patients without prior PPI who underwent TAVR due to severe symptomatic aortic stenosis at our center between June 2018 and July 2020. Clinical, echocardiographic, and pacing data were assessed at 30-day, 1- and 2-year follow-up. RESULTS: New PPI was required in 35 (16.7%) patients within 30 days after TAVR. The median time from TAVR to PPI was 3 days. The most common indication for PPI was high-degree or complete atrioventricular block. The median follow-up was 798.0 (interquartile range, 669.0-1115.0) days. There were no differences in all-cause mortality (adjusted hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.85-2.36; p = 0.415) and cardiovascular mortality (adjusted HR: 0.92; 95% CI: 0.57-1.89; p = 0.609) between groups. However, PPI group had a higher risk of heart failure (HF) rehospitalization (adjusted HR: 1.53; 95% CI: 1.26-2.28; p = 0.027). Echocardiography showed no significant improvement of LVEF over time in patients with PPI. At the latest follow-up, 31.3% of patients exhibited low (≤10%) pacing burdens, whereas 28.1% of patients had near constant (>90%) right ventricular pacing. CONCLUSIONS: New PPI within 30 days following TAVR was not associated with an increased risk of all-cause or cardiovascular mortality. However, patients with PPI had a higher risk of HF rehospitalization and lack of LVEF improvement.

Transfemoral transcatheter aortic valve replacement for pure native aortic regurgitation: one-year outcomes of a single-center study.

BACKGROUND: Evidence about safety and efficacy of transcatheter aortic valve replacement (TAVR) with the Venus A-Valve system (Venus Medtech, Hangzhou, China) remains limited for patients with pure native aortic regurgitation (PNAR). OBJECTIVES: The single-center study sought to report the one-year clinical outcomes of the Venus A-Valve in the treatment of PNAR. METHODS: This study was a retrospective analysis of prospectively collected data. Data was from all consecutive patients who had PNAR and underwent TAVR with the Venus A-Valve system at our center from July 2020 and June 2021. Procedural and clinical outcomes up to one year were analyzed using Valve Academic Research Consortium-2 criteria. RESULTS: A total of 45 consecutive patients with PNAR underwent transfemoral TAVR with the Venus A-Valve system. The Mean age was 73.5 ± 5.5 years and 26.7% were female. All the TAVR procedures were performed via transfemoral access. Implantations were successful in 44 cases (97.8%). Only one patient was converted to surgical aortic valve replacement. No patient died intraoperatively. No second valve was implanted. In-hospital mortality rate was 2.3%. The one-year all-cause mortality rate was 4.7% without cardiovascular related death. No patient had moderate or severe paravalvular leakage during follow-up. At one year, the mean pressure gradient was 8.8 ± 0.9 mmHg, and left ventricular ejection fraction increased to 61.5 ± 3.6%. CONCLUSIONS: This single-center study demonstrated the safety and efficacy of transfemoral TAVR with the Venus A-Valve in the treatment of patients with PNAR.

Simplified total arch reconstruction with a stented graft for extended aortic arch dilation.

Background: Reconstruction of the aortic arch and its three supra-aortic vessels remains a great surgical challenge with postoperative complications. We present a simplified total arch reconstruction with a modified stent graft (s-TAR) and compared its operative outcomes with conventional total arch replacement (c-TAR). Methods: This retrospective analysis of prospectively collected data from all consecutive patients who had ascending aortic aneurysm with extended aortic arch dilation and underwent simultaneous ascending aorta replacement and aortic arch reconstruction with the s-TAR or c-TAR between 2018 and 2021. The indication for intervention was maximum diameter of ascending aorta >55 mm and aortic arch in zone II >35 mm. Results: A total of 84 patients were analyzed: 43 in the s-TAR group and 41 in the c-TAR group. No inter-group differences were found for sex, age, comorbidities, or EuroSCORE II results. All patients were successfully treated with s-TAR or c-TAR, and none died intraoperatively. Cardiopulmonary bypass, selective cerebral perfusion, and lower-body circulatory arrest time were significantly shorter in the s-TAR group, which also had a lower incidence of prolonged ventilation and transient neurologic dysfunction. No patient in either group experienced permanent neurologic dysfunction. The incidence of recurrent laryngeal nerve injury and paraplegia was markedly increased in the c-TAR group; however, no such events were observed in the s-TAR group. Both perioperative blood loss and the incidence of reoperation for bleeding were significantly lower in the s-TAR group. The in-hospital mortality rate was 0% in the s-TAR group and 4.9% in the c-TAR group. The s-TAR group had significantly shorter intensive care unit (ICU) stay and lower total hospitalization costs. Conclusions: The s-TAR technique is a safe and effective alternative for total arch reconstruction with shorter operation time, lower rate of postoperative complications and lower total hospitalization costs compared with c-TAR.

Effect of High-Flow Nasal Cannula for Hypoxemia Following Sun's Procedure in Acute Aortic Dissection Type a Patients.

Background: Patients with acute aortic dissection type A (AADA) often have hypoxemia (partial pressure of oxygen [PaO2]/fraction of inspired oxygen [FiO2] <300 mmHg) before weaning in the intensive care unit (ICU). This study compared the efficacy of high-flow nasal cannula (HFNC) with that of conventional oxygen therapy (COT) in patients with AADA following Sun's procedure. Methods: The medical records of 87 adult patients with AADA who underwent Sun's procedure and met the inclusion criteria (PaO2/FiO2 <300 mmHg before weaning) were retrospectively analyzed. After surgery, 41 patients were treated with HFNC and 46 were treated with COT. The oxygenation level, FiO2, partial pressure of carbon dioxide, heart rate, respiratory rate, subjective discomfort, and reintubation rate were recorded. The difference in lung volume loss between the HFNC and COT groups was assessed using the radiological atelectasis score (chest radiograph) or calculated from three-dimensional (3D) reconstructed computed tomography (CT) images. Results: From day 1 to day 5 after weaning, there was no significant difference in PaO2/FiO2 between the HFNC and COT groups, although the FiO2 was significantly lower in the HFNC group than in the COT group (P < 0.05). Further studies indicated that the percentage of lung volume loss (pleural effusion and/or pulmonary atelectasis) by 3D reconstruction of CT images at 4-8 days post-operation was significantly lower in the HFNC group (P < 0.05). The subjective experience of breathing discomfort, reintubation rate, and length of stay in the ICU were significantly reduced in the HFNC group (P < 0.05). There was no significant difference in readmission to the ICU and in-hospital mortality between the two groups. Conclusions: HFNC can be used as an effective oxygen therapy for AADA patients with hypoxemia after Sun's procedure.

PPARA genetic variants increase the risk for cardiac pumping function reductions following acute high-altitude exposure: A self-controlled study.

BACKGROUND: Left cardiac pumping function determines the compensatory capacity of the cardiovascular system following acute high-altitude exposure. Variations in cardiac output (CO) at high altitude are inconsistent between individuals, and genetic susceptibility may play a crucial role. We sought to identify genetic causes of cardiac pumping function variations and describe the genotype-phenotype correlations. METHODS: A total of 151 young male volunteers were recruited and transferred to Lhasa (3,700 m) from Chengdu (<500 m) by plane. Genetic information related to hypoxic signaling and cardiovascular-related pathways was collected before departure. Echocardiography was performed both before departure and 24 hr after arrival at high altitude. RESULTS: Here we reported that PPARA variants were closely related to high-altitude cardiac function. The variants of rs6520015 C-allele and rs7292407 A-allele significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure. In addition, the individuals carrying haplotypes in PPARA, namely, rs135538 C-allele, rs4253623 A-allele, rs6520015 C-allele and rs7292407 A-allele (C-A-C-A), suffered a 7.27-fold risk for cardiac pumping function reduction (95% CI: 2.39-22.15, p = .0006) compared with those carrying the wild-type haplotype. CONCLUSIONS: This self-controlled study revealed that PPARA variations significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure, providing a potential predictive marker before high-altitude exposure and targets in mechanistic studies.

Trimetazidine attenuates high-altitude fatigue and cardiorespiratory fitness impairment: A randomized double-blinded placebo-controlled clinical trial.

Trimetazidine (TMZ) has been shown to optimize myocardial energy metabolism and is a common anti-ischemic agent. Our trial (ChiCTR-TRC-13003298) aimed to explore whether TMZ has any preventive effect on high-altitude fatigue (HAF), cardiac function and cardiorespiratory fitness upon acute high-altitude exposure and how it works on HAF. Thirty-nine healthy young subjects were enrolled in a randomized double-blinded placebo-controlled trial and were randomized to take oral TMZ (n = 20) or placebo (n = 19), 20 mg tid, 14 days prior to departure until the end of study. The 2018 Lake Louise Score questionnaire, echocardiography, assessments of physical working capacity, circulating markers of myocardial energy metabolism and fatigue were performed both before departure and arrival at highland. At follow-up, TMZ significantly reduced the incidence of HAF (p = 0.038), reversed cardiorespiratory fitness impairment, decreased left ventricular end-systolic volume (LVESV, p = 0.032) and enhanced left ventricular ejection fraction (LVEF, p = 0.015) at highland. Relative to the placebo group, the TMZ group had significantly lower LDH (p = 0.025) and lactate levels before (p < 0.001) and after (p = 0.012) physical exercise after acute high-altitude exposure. Additionally, improved left ventricular systolic function might have contributed to ameliorating HAF during TMZ treatment (LVEF, OR = 0.859, 95% CI = 0.741-0.996, p = 0.044). In conclusion, our results demonstrated that TMZ could prevent HAF, cardiorespiratory fitness impairment and improves left ventricular systolic function during acute high-altitude exposure. This trial provides new insights into the effect of TMZ and novel evidence against HAF and cardiorespiratory fitness impairment at highland.

PACS2 is required for ox-LDL-induced endothelial cell apoptosis by regulating mitochondria-associated ER membrane formation and mitochondrial Ca2+ elevation.

Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell (EC) apoptosis is the initial step of atherogenesis and associated with Ca2+ overload. Mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), regulated by tethering proteins such as phosphofurin acidic cluster sorting protein 2 (PACS2), is essential for mitochondrial Ca2+ overload by mediating ER-mitochondria Ca2+ transfer. In our study, we aimed to investigate the role of PACS2 in ox-LDL-induced apoptosis in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms. Ox-LDL dose- and time-dependently increased cell apoptosis concomitant with mitochondrial Ca2+ elevation, mitochondrial membrane potential (MMP) loss, reactive oxygen species (ROS) production, and cytochrome c release. Silencing PACS2 significantly inhibited ox-LDL-induced cell apoptosis at 24 h in addition to the effects of ox-LDL on mitochondrial Ca2+, MMP, and ROS at 2 h. Besides, ox-LDL promoted PACS2 localization at mitochondria as well as ER-mitochondria contacts at 2 h. Not only that, ox-LDL upregulated PACS2 expression at 24 h. Furthermore, silencing PACS2 inhibited ox-LDL-induced mitochondrial localization of PACS2 and MAM formation at 24 h. Altogether, our findings suggest that PACS2 plays an important role in ox-LDL-induced EC apoptosis by regulating MAM formation and mitochondrial Ca2+ elevation, implicating that PACS2 may be a promising therapeutic target for atherosclerosis.

C/EBPß Acts Upstream of NF-κB P65 Subunit in Ox-LDL-Induced IL-1ß Production by Macrophages.

BACKGROUND/AIMS: Interleukin-1ß (IL-1ß) is one of the critical inflammatory factors during atherogenesis. CCAAT/enhancer binding proteins ß (C/EBPß), a regulator of IL-1ß production, recently been evidenced as a key player in the development of atherosclerosis. However, the mechanisms of how C/EBPß regulates the production of IL-1ß are unclear. In this study, we aimed to explore the role of C/EBPß in regulating IL-1ß production in macrophages after oxidized low-density lipoprotein (ox-LDL) exposure and the underlying mechanisms. METHODS: RAW264.7 macrophages were treated with 0, 25, 50 or 100 µg/ml ox-LDL for 12, 24 or 48 h. Small interfering RNAs were used to silence related proteins. The gene and protein expression levels were determined by quantitative real-time polymerase chain reaction or western blot (WB). IL-1ß secretion was assessed by enzyme-linked immunosorbent assay. The cytoplasmic and nuclear proteins were evaluated by nuclear fractionation followed by WB. Localization of p65 was observed by immunofluorescence. The binding activity of p65 to IL-1ß was tested by dual-luciferase reporter assay. RESULTS: Ox-LDL increased IL-1ß production, accompanied with increasing C/EBPß and p65 expression in a dose- and time-dependent manner. Moreover, C/EBPß deficiency in macrophages blocked ox-LDL-induced increases in IL-1ß expression, maturation as well as p65 activation. However, p65 deficiency inhibited the increase in IL-1ß production, but not C/EBPß expression. Dual-luciferase reporter results showed that overexpression of C/EBPß significantly enhanced binding activity of p65 to IL-1ß promoter. In addition, C/EBP 1ß deficiency in macrophages abolished the ox-LDL-induced gene transcription increases of IL-1ß, IL-6, p65 and caspase-1. CONCLUSIONS: Our results demonstrate that C/EBPß acts upstream of NF-κB p65 subunit in ox-LDL-induced IL-1ß production in macrophages and may regulate IL-1ß maturation by promoting caspase-1. C/EBPß may be a promising candidate for the prevention and treatment of atherosclerosis.

Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure.

Improving biological functions of endothelial progenitor cells (EPCs) is beneficial to maintaining endothelium homeostasis and promoting vascular re-endothelialization. Because macroautophagy/autophagy has been documented as a double-edged sword in cell functions, its effects on EPCs remain to be elucidated. This study was designed to explore the role and molecular mechanisms of store-operated calcium entry (SOCE)-activated autophagy in proliferation of EPCs under hypercholesterolemia. We employed oxidized low-density lipoprotein (ox-LDL) to mimic hypercholesterolemia in bone marrow-derived EPCs from rat. Ox-LDL dose-dependently activated autophagy flux, while inhibiting EPC proliferation. Importantly, inhibition of autophagy either by silencing Atg7 or by 3-methyladenine treatment, further aggravated proliferative inhibition by ox-LDL, suggesting the protective effects of autophagy against ox-LDL. Interestingly, ox-LDL increased STIM1 expression and intracellular Ca2+ concentration. Either Ca2+ chelators or deficiency in STIM1 attenuated ox-LDL-induced autophagy activation, confirming the involvement of SOCE in the process. Furthermore, CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, ß) activation and MTOR (mechanistic target of rapamycin [serine/threonine kinase]) deactivation were associated with autophagy modulation. Together, our results reveal a novel signaling pathway of SOCE-CAMKK2 in the regulation of autophagy and offer new insights into the important roles of autophagy in maintaining proliferation and promoting the survival capability of EPCs. This may be beneficial to improving EPC transplantation efficacy and enhancing vascular re-endothelialization in patients with hypercholesterolemia.

Protein submitochondrial localization from integrated sequence representation and SVM-based backward feature extraction.

Mitochondrion, a tiny energy factory, plays an important role in various biological processes of most eukaryotic cells. Mitochondrial defection is associated with a series of human diseases. Knowledge of the submitochondrial locations of proteins can help to reveal the biological functions of novel proteins, and understand the mechanisms underlying various biological processes occurring in the mitochondrion. However, experimental methods to determine protein submitochondrial locations are costly and time consuming. Thus it is essential to develop a fast and reliable computational method to predict protein submitochondrial locations. Here, we proposed a support vector machine (SVM) based approach for predicting protein submitochondrial locations. Information from the position-specific score matrix (PSSM), gene ontology (GO) and the protein feature (PROFEAT) was integrated into the principal features of this model. Then a recursive feature selection scheme was employed to select the optimal features. Finally, an SVM module was used to predict protein submitochondrial locations based on the optimal features. Through the jackknife cross-validation test, our method achieved an accuracy of 99.37% on benchmark dataset M317, and 100% on the other two datasets, M1105 and T86. These results indicate that our method is economic and effective for accurate prediction of the protein submitochondrial location.

Sequence-based identification of recombination spots using pseudo nucleic acid representation and recursive feature extraction by linear kernel SVM.

BACKGROUND: Identification of the recombination hot/cold spots is critical for understanding the mechanism of recombination as well as the genome evolution process. However, experimental identification of recombination spots is both time-consuming and costly. Developing an accurate and automated method for reliably and quickly identifying recombination spots is thus urgently needed. RESULTS: Here we proposed a novel approach by fusing features from pseudo nucleic acid composition (PseNAC), including NAC, n-tier NAC and pseudo dinucleotide composition (PseDNC). A recursive feature extraction by linear kernel support vector machine (SVM) was then used to rank the integrated feature vectors and extract optimal features. SVM was adopted for identifying recombination spots based on these optimal features. To evaluate the performance of the proposed method, jackknife cross-validation test was employed on a benchmark dataset. The overall accuracy of this approach was 84.09%, which was higher (from 0.37% to 3.79%) than those of state-of-the-art tools. CONCLUSIONS: Comparison results suggested that linear kernel SVM is a useful vehicle for identifying recombination hot/cold spots.