Histone deacetylase inhibitor, mocetinostat, regulates cardiac remodelling and renin-angiotensin system activity in rats with transverse aortic constriction-induced pressure overload cardiac hypertrophy.

Histone deacetylase (HDAC) inhibitors have shown cardioprotective or renoprotective effects in various animal models. Our study proposed that the HDAC inhibitor, mocetinostat, regulates cardiac remodelling and renin-angiotensin system (RAS) activity in rats with transverse aortic constriction (TAC)-induced pressure overload cardiac hypertrophy. Cardiac remodelling was evaluated using echocardiography. Cardiac hypertrophy was visualized with haematoxylin and eosin staining, and related gene (Nppa and Nppb) expression was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cardiac and renal fibrosis were visualized with picrosirius red and trichrome staining, respectively. Fibrosis related gene (Collagen-1, Collagen-3, Ctgf, and Fibronectin) expression was determined by qRT-PCR. Serum concentrations of RAS components (renin, angiotensin II, and aldosterone) were quantified by enzyme-linked immunosorbent assay and related gene (Renin and Agtr1) expression was determined by qRT-PCR. TAC-induced pressure overload cardiac hypertrophy, which mimics hypertensive heart disease, increased cardiac remodelling, cardiac hypertrophy, and fibrosis in our rat models. Upon treatment with mocetinostat, there was a significant regression in cardiac remodelling, cardiac hypertrophy, and fibrosis in TAC rats. Additionally, pressure overload-induced renal fibrosis and activity of RAS-related components were increased in TAC rats, and were decreased on treatment with mocetinostat. The present study indicates that mocetinostat, an HDAC inhibitor, has cardiorenal protective effects in rats with TAC-induced pressure overload cardiac hypertrophy and offers a promising therapeutic agent for hypertension-related diseases.

Prognostic Value of Telomeric Zinc Finger-Associated Protein Expression in Adenocarcinoma and Squamous Cell Carcinoma of Lung.

Background and Objectives: Telomeric zinc finger-associated protein (TZAP) is a telomere regulation protein, previously known as ZBTB48. It binds preferentially to elongated telomeres, competing with telomeric repeat factors 1 and 2. TZAP expression may be associated with carcinogenesis, however; this study has not yet been performed in lung cancer. In this study, we examined the clinicopathological and prognostic values of TZAP expression in non-small cell lung cancer (NSCLC). Materials and Methods: Data were collected from The Cancer Genome Atlas. The clinical and prognostic values of TZAP for NSCLC were examined in adenocarcinoma (AD) and squamous cell carcinoma (SCC). Results: TZAP expression significantly increased in NSCLC tissues compared with normal tissues. In AD, TZAP expression was lower in patients with higher T stage (p = 0.005), and was associated with lymph node stage in SCC (p = 0.005). Survival analysis showed shorter disease-free survival in AD patients with lower TZAP expression (p = 0.047). TZAP expression did not have other clinical or prognostic value for AD and SCC. Conclusions: TZAP expression is a potential prognostic marker for NSCLC, especially in patients with AD.

Upregulation of C/EBPß and TSC2 by an HDAC inhibitor CG200745 protects heart from DOCA-induced hypertrophy.

Histone deacetylases (HDACs) are a vast family divided into four major classes: class I (1, 2, 3, and 8), class II (4, 5, 6, 7, 9 and 10), class III (sirtuin family) and class IV (HDAC11). HDAC inhibition attenuates cardiac hypertrophy through suppression of the mechanistic target of rapamycin complex1 (mTORC1) signaling. HDAC inhibitors upregulate the expression of tuberous sclerosis complex 2 (TSC2), an mTORC1 inhibitor. However, the molecular mechanism underlying HDAC inhibitor-mediated upregulation of TSC2 is unclear. We hypothesized that an HDAC inhibitor, CG200745 (CG), ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling by upregulating of the CCAAT/enhancer-binding protein-ß (C/EBP-ß)/TSC2 pathway. To establish a cardiac hypertrophy model, deoxycorticosterone acetate (DOCA, 40 mg/kg/wk) was subcutaneously injected for 4 weeks into Sprague-Dawley rats. All rats were unilaterally nephrectomized and had free access to drinking water containing 1% NaCl with or without CG of different concentrations. The expression level of TSC2 and C/EBP-ß was measured by quantitative real-time PCR (qRT-PCR) and western blot analysis. Acetylation of C/EBP-ß was analyzed by immunoprecipitation. The recruitment of C/EBP-ß and polymerase II (Pol II) on TSC2 promoter region was analyzed by chromatin immunoprecipitation (ChIP). CG treatment increased the expression of TSC2. In addition, CG treated rats showed an increased in the expression and acetylation of C/EBP-ß, owing to the increase in the recruitment of C/EBP-ß and Pol II at Tsc2 gene promoter. Thus, CG ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling via upregulation of the C/EBP-ß/TSC2 pathway in DOCA-induced hypertensive rats.

Video-Assisted Thoracoscopic Left Cardiac Sympathetic Denervation in Patients with Hereditary Ventricular Arrhythmias.

BACKGROUND: Left cardiac sympathetic denervation (LCSD) has been underutilized in patients with hereditary ventricular arrhythmia syndromes such as congenital long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The purpose of this study was to investigate the safety and efficacy of video-assisted thoracoscopic (VATS) LCSD in such patients. METHODS: Fifteen patients (four men, 24.6 ± 10.5 years old) who underwent VATS-LCSD between November 2010 and January 2015 for hereditary ventricular arrhythmia syndromes at Kyungpook National University Hospital were enrolled in this study. The safety and efficacy of VATS-LCSD were evaluated by periprocedural epinephrine tests and assessing the development of complications and cardiac events during follow-up. RESULTS: Fourteen patients with LQTS and one patient with CPVT underwent VATS-LCSD. Six and one patients developed ventricular tachyarrhythmia during preprocedural and postprocedural epinephrine test, respectively (P = 0.063). No serious complications such as Horner syndrome, pneumothorax, or bleeding developed after LCSD. Mean hospital stay after VATS-LCSD was 3.7 ± 1.5 days. During a mean follow-up of 927 ± 350 days, one LQTS patient and one CPVT patient, neither of whom manifested tachyarrhythmia during post-LCSD epinephrine test, developed torsades de pointes and syncope, respectively. The annual event rates of six patients who were symptomatic during the period preceding LCSD decreased from 0.97 to 0.19 events/year (P = 0.045). CONCLUSIONS: VATS-LCSD was a safe, and effective procedure for patients with hereditary ventricular tachycardia syndrome, with no serious adverse events and with short hospital stay.

Lethal abdominal compartment syndrome after extracorporeal cardiopulmonary resuscitation in a patient with out-of-hospital cardiac arrest: a case report.

BACKGROUND: Clinical attempts of extracorporeal cardiopulmonary resuscitation (ECPR) in patients with out-of-hospital cardiac arrest (OHCA) have increased in recent years; however, it also has life-threatening complications. Massive fluid and transfusion resuscitation, shock status, or low cardiac output status during ECPR may lead to ascites and interstitial edema, resulting in secondary abdominal compartment syndrome (ACS). CASE PRESENTATION: A 43-year-old male patient was admitted to the emergency department due to cardiac arrest. Due to refractory ventricular fibrillation, ECPR was initiated. Approximately, 3 h after extracorporeal membrane oxygenation support, abdominal distension and rigidity developed. Therefore, ACS was suspected. Decompression laparotomy was required to relieve elevated intra-abdominal pressure. CONCLUSIONS: We report a case of a patient with OHCA who developed lethal ACS after ECPR. Despite this, the patient was able to recover from several major crises. Regardless of how lethal the patient is, if compartment syndrome develops in any part of the body, we should aggressively consider surgical decompression.

A case of transient central diabetes insipidus after aorto-coronary bypass operation.

Diabetes insipidus (DI) is characterized by excessive urination and thirst. This disease results from inadequate output of antidiuretic hormone (ADH) from the pituitary gland or the absence of the normal response to ADH in the kidney. We present a case of transient central DI in a patient who underwent a cardiopulmonary bypass (CPB) for coronary artery bypass grafting (CABG). A 44-yr-old male underwent a CABG operation. An hour after the operation, the patient developed polyuria and was diagnosed with central DI. The patient responded to desmopressin and completely recovered five days after surgery. It is probable that transient cerebral ischemia resulted in the dysfunction of osmotic receptors in the hypothalamus or hypothalamus-pituitary axis during CPB. It is also possible that cardiac standstill altered the left atrial non-osmotic receptor function and suppressed ADH release. Therefore, we suggest that central DI is a possible cause of polyuria after CPB.

True Aneurysm of the Common Coronary Button in a Marfan Patient with an Anomalous Right Coronary Artery after a Bentall Procedure: A Case Report.

True aneurysms of the coronary artery after aortic root replacement in Marfan syndrome patients are very rare. An anomalous origin of the right coronary artery (RCA) from the left sinus of Valsalva adds complexity during aortic root surgery. We present a case of a 37-year-old male patient with Marfan syndrome who had an RCA anomaly and a 4.5-cm true aneurysm of the common coronary button 14 years after a previous Bentall procedure. A redo Bentall operation and hemi-arch replacement were successfully performed. The anomalous origin of the RCA from the left sinus of Valsalva was safely divided and anastomosed as separate coronary buttons to the prosthetic composite valve graft. To prevent coronary button aneurysms after aortic root surgery in Marfan patients, the coronary buttons and the corresponding side holes on the prosthetic graft must be reduced to the maximum possible extent.

Cardiopulmonary bypass preparation is mandatory in cardiac exploration for blunt cardiac injury patients: two case reports.

Treating cardiac injuries following blunt trauma to the chest requires thorough examination, accurate diagnosis, and therapeutic plan. We present two cases; pulmonary vein rupture and left atrial appendage laceration, both as a result of blunt chest trauma. Through these cases, our team learned the importance of maintaining hemodynamic stability during the examination of injured cardiac structures. And based on the comprehensive cardiac examination, a decision to surgically intervene with median sternotomy via cardiopulmonary bypass was made, saving lives of the patient. This report introduces how such decision was made based on what supporting evidence and the diagnostic process leading to the initiation of surgical intervention. This report may help with decision-making process when confronted by blunt cardiac injury patients who need cardiac exploration.

Successful Management of a Rare Gastric Mucormycosis Presenting with Massive Melena in a Polytrauma Patient.

Mucormycosis is a rare, life-threatening, and opportunistic fungal infection that usually occurs in immunocompromised patients. Rhinocerebral and pulmonary manifestations are the common form. The rare form of gastrointestinal mucormycosis occur in all parts of the alimentary tract, with emphasis on the stomach being the most common site. Primary gastric mucormycosis following traumatic injury is an extremely rare form that is usually lethal; thus, only a few cases of survival have been reported even after early diagnosis and aggressive surgical resection, combined with antifungal treatment. We herein report a case of delayed-onset gastric mucormycosis in a polytrauma patient without predisposing factors, which was successfully treated by antifungal medical therapy alone with no surgical debridement.

Patch aortoplasty and anatomical lung resection in a patient with aortobronchial fistula due to aortic psuedo-aneurysm.

Aortobronchial fistula (ABF) is a rare and devastating complication, if left untreated. Its main clinical manifestation is hemoptysis, and there are no defined guidelines for its treatment yet. Herein, we present the case of a 74-year-old male who complained of back pain and hemoptysis. The patient was diagnosed with pseudo-aneurysm and ABF, and he underwent hybrid thoracic endovascular aortic repair. However, hemoptysis recurred. With patch aortoplasty and anatomical lung resection, successful management of ABF was achieved, with no relapse for 5 years.

Histone Deacetylase Inhibition Attenuates Aortic Remodeling in Rats under Pressure Overload.

The use of histone deacetylase (HDAC) inhibitor is a novel therapeutic strategy for cardiovascular disease. Studies have shown that many HDAC inhibitors have the ability to reduce the aortic remodeling in various animal models. We hypothesized that the HDAC inhibitor, MGCD0103 (MGCD), attenuates aortic remodeling in rats under pressure overload-induced by transverse aortic constriction (TAC). The aortic ring tension analysis was conducted using the thoracic aorta. Sections of the aorta were visualized after hematoxylin and eosin, trichrome, and Verhoeff-van Gieson staining, and immunohistochemistry. The expression of genes related to aortic remodeling (αSMA, Mmp2, and Mmp9) and angiotensin receptors (Agtr1 and Agtr2) was determined by quantitative real-time polymerase chain reaction. There was a significant decrease in relaxation of the aorta when treated with MGCD. Fibrosis of the aortic wall and expression of angiotensin receptors increased in TAC rats, which was attenuated by MGCD. These results indicate that MGCD, an HDAC inhibitor, attenuates aortic remodeling in rats with TAC-induced pressure overload rats and may serve as a potential therapeutic target of antiaortic remodeling in pressure overload-induced hypertension-related diseases.

Effective strategy in the treatment of aortobronchial fistula with recurrent hemoptysis.

Aortobronchial fistula (ABF) involves the formation of an abnormal connection between the thoracic aorta and the central airways or the pulmonary parenchyma and is associated with an increased risk of mortality. An ABF typically manifests clinically with symptoms of hemoptysis, and currently, there is a lack of defined guidelines for its treatment. Here, we report the cases of two patients who suffered from recurrent hemoptysis due to ABF with pseudoaneurysm. We propose that removal of the aorta with concomitant lung resection and coverage of the aorta using the pericardial membrane is a definite treatment to lower recurrence of ABF and persistent infection.

Complete resection of primary pulmonary malignancy extending into the left atrium via the left pulmonary vein using cardiopulmonary bypass and single incision: A case series.

If the best treatment for a patient with a primary pulmonary tumor extending into the left atrium via the left pulmonary vein is surgical resection, it is necessary to determine the appropriate approach, that is, whether cardiopulmonary bypass (CPB) or complete resection, would be more suitable. Lung resections under CPB are rarely performed because of the unpredictable prognosis. We report two successful cases of safe and rapid complete resection of primary pulmonary malignancy extending into the left atrium with the support of CPB via median sternotomy. Our experiences support the application of CPB in extended left pulmonary resections to achieve complete resection.

Fracture of the Bare Spring of a Thoracic Endograft for Type A Aortic Dissection: A Case Report.

Retrograde type A aortic dissection (RTAD) following thoracic endovascular aortic repair is a devastating complication associated with high mortality rates. In particular, a deployed endograft in a bird-beak formation in an acute curve of the aortic arch can induce injury to the fragile aortic wall, with the subsequent development of RTAD. Here, we describe an extremely rare case of RTAD caused by fracture of the bare spring of the thoracic endograft for type A aortic dissection.

Thoracic aortic aneurysms exerting high extrinsic pressure on the airway.

BACKGROUND: Thoracic aortic aneurysms, although mostly asymptomatic, are life threatening owing to the risk of rupture. Moreover, the extrinsic pressure of a ruptured aneurysm may encroach the mediastinum. CASE PRESENTATION: A 74-year-old woman diagnosed with ruptured descending thoracic aortic aneurysm compressing the lower trachea and both main bronchi underwent thoracic endovascular aortic repair; however, the extrinsic pressure on the airway persisted. Following failing of endobronchial silicon stents insertion, extracorporeal membrane oxygenation support was required, and endobronchial metallic stents were inserted. The patients' hypoventilation resolved, and the patient was withdrawn from the ventilator. CONCLUSIONS: Technological improvement in endovascular or endobronchial procedures has provided more options for managing complex cases. However, we must be aware of how high the extrinsic pressure might be before management and take steps to minimize complications.

The Prognostic Value of Measuring PD-L1 mRNA Expression Levels in Surgically Resected Non-Small Cell Lung Cancer.

The expression of programmed cell death 1-ligand 1 (PD-L1) by tumor cells acts as an immune-checkpoint when it interacts with its receptor on immune cells, effectively preventing the immune system from attacking the tumor. Inhibitors against PD-L1 have shown remarkable therapeutic activity in non-small cell lung cancer (NSCLC); however, the prognostic value of this potential biomarker has yet to be conclusively shown. To investigate the clinicopathological and prognostic value of PD-L1 expression, we examined PD-L1 mRNA levels in surgically resected NSCLC. We compared PD-L1 mRNA expression in tumor and adjacent normal tissue from 71 NSCLC patient samples using real-time polymerase chain reaction. To validate PD-L1 mRNA expression by this method, PD-L1 protein expression by immunohistochemistry was analyzed and their strong correlation was confirmed (r=0.728, P=0.041). PD-L1 mRNA expression was significantly increased in tumor tissue as compared to adjacent normal tissue (P<0.001). Tumor tissue on average expressed 3.72 fold higher levels of PD L1 mRNA compared to normal tissue counterparts, and higher expression levels were found in 25.4% (18/71) of NSCLC samples. PD-L1 mRNA expression levels were not associated with clinicopathological characteristics of NSCLC. However, NSCLC patients with increased PD-L1 mRNA expression have a better prognosis than patients with low levels of PD-L1 mRNA (63.49 months vs. 98.53 months, χ2=3.73, p=0.053). Disease-free survival was 82.23 months and 45.68 months in patients with and without high levels of PD-L1 expression, respectively, although this difference was not significant (χ 2= 3.23, p=0.073). These results suggest that PD-L1 mRNA expression correlates to alterations in NSCLC disease progression; therefore, further comprehensive analyses should be performed.

Mid-term outcomes of endovascular repair for traumatic thoracic aortic injury: a single-center experience.

PURPOSE: Thoracic endovascular aortic repair (TEVAR) for traumatic thoracic aortic injury (TTAI) reports short-term benefits. However, long-term durability and the need of reintervention remain unclear. Here, we determined mid-term outcome of TEVAR for TTAI and investigated the influence of the length of proximal landing zone on aorta. METHODS: Between October 2009 and February 2018, 69 patients diagnosed TTAI and 42 included patients underwent TEVAR. Patients were divided into two groups by the length of proximal landing zone; ≤ 20 mm and > 20 mm. The primary endpoint was success and survival rate, and the secondary endpoint was the increase of aorta size and the need of reintervention. RESULTS: The mean follow-up period was 47.9 ± 29.6 months and 100% success rate. No endoleaks or additional reinterventions during the follow-up period. The cumulative survival of all-cause death was 90.5 ± 2.3%, 85.7 ± 4.1% and 61.7 ± 8.4% at 1, 5 and 7 years, respectively. There was no statistically significant difference in the increase of aorta size due to the length of the proximal landing zone (p = 0.65). CONCLUSION: In selective TTAI patients for TEVAR, the length of proximal landing zone did not considerably influence the aorta size or needed further reintervention.

Traumatic severe tricuspid regurgitation diagnosis after the progression of right ventricle function deterioration.

Traumatic tricuspid regurgitation is a rare complication of blunt cardiac injury and frequently misdiagnosed during the initial assessment. Unfortunately, it may be diagnosed after deterioration of right ventricle function, which may be fatal to the patient. Here, we report a case of a patient with blunt chest injury complicated by a diagnosis of traumatic severe tricuspid regurgitation after deterioration of the right ventricle function even after the patient was subjected to serum cardiac enzyme normalization. The patient was a driver and admitted to the hospital owing to multiple traumatic injuries. Echocardiography was performed suspicious of blunt cardiac injury, which revealed no abnormal findings. Initial cardiac enzyme levels were high, but after serial follow-up, the levels improved. However, on day 4 of hospitalization, hemodynamic deterioration occurred owing to severe tricuspid regurgitation and delayed right ventricle dysfunction. Immediate tricuspid valve replacement was performed, however, the patient had a pronged recovery period. We believe that it is important to take into account the nature of the accident and the presentation of clinical signs and symptoms and not be blinded by laboratory test results alone; it is also important to consider performing repeated serial echocardiographic examinations for blunt cardiac injury patients.

Risk Factors Associated With Reintervention After Thoracic Endovascular Aortic Repair for Descending Aortic Pathologies.

BACKGROUND:: Thoracic endovascular aortic repair (TEVAR) is associated with several short-term benefits, including reduced morbidity and mortality; however, the long-term durability of TEVAR and the need for secondary aortic reintervention remain unclear. We aimed to determine the adverse outcomes, including aortic reintervention, after TEVAR for thoracic aortic aneurysms and dissection. METHODS:: Between October 2009 and July 2016, 130 patients underwent TEVAR at Kyungpook National University Hospital. We excluded 35 patients with traumatic injury and included the remaining 95 patients in our study after TEVAR. The patients included in this study were categorized into 2 groups (reintervention [R] and nonintervention [N] groups) according to the need for reintervention. The mean follow-up period for all 95 patients was 22.4 (20.6) months. RESULTS:: The overall actuarial survival rates were 83.7% (4.1%) and 63.6% (8.8%) at 1 and 5 years, respectively. The rates of freedom from aortic reintervention after TEVAR were 94.0% (3.5%), 72.8% (8.2%), and 48.9% (10.5%) at 2, 3, and 5 years, respectively. The independent risk factors for aortic reintervention were endoleaks after TEVAR (odds ratio [OR] 6.13, P = .017), increase in aortic size by over 5% per year (OR 20.40, P = .001), and peripheral vascular occlusive disease (PVOD; OR 13.62, P = .007). Patients with preoperative hemoptysis tended to show a greater need for aortic reintervention ( P = .059). Increase in aortic size by over 5% per year and PVOD were the primary risk factors for endoleaks (OR 3.82, P = .013 and OR 4.37, P = .021, respectively). CONCLUSION:: Survival after TEVAR for thoracic aortic pathologies was satisfactory in most of the patients chosen as candidates for the procedure. However, the occurrence of endoleaks, increase in aortic size by over 5% per year, and PVOD were the primary causes of aortic reintervention.

Risk factors of postoperative acute lung injury following lobectomy for nonsmall cell lung cancer.

Acute lung injury following lung resection surgery is not rare and often related to mortality. Although it has been a significant clinical and economic impact associated with increased intensive care unit (ICU) utilization, length of hospital stay, and associated cost, it is unpredictable. Aims of this study were to identify the modifiable risk factors of postoperative acute lung injury (PALI) following lung cancer surgery.We retrospectively analyzed medical records of 354 cases of lung cancer surgery in the tertiary university hospital from January 2012 to December 2015. PALI was defined as bilateral diffuse pulmonary infiltration on chest radiography, oxygenation failure (PaO2/FiO2 < 300), and absence of sign of left ventricular failure within a week from operation. We classified patients into either PALI group or non-PALI group and compared clinical characteristics of two groups. Logistic regression model was fitted to evaluate the risk factor of PALI.Among 354 cases of lung cancer surgeries, 287 lobectomies were analyzed. The overall incidence of PALI was 2.79% (8/287); four patients developed pneumonia with acute respiratory distress syndrome, and four patients developed ALI without clinical infection sign. There was no difference in baseline characteristics between PALI group and non-PALI group, but in operative parameters, a larger amount of fluid infusion was observed in PALI group. Logistic regression model showed underlying ischemic heart disease (OR 7.67, 95% CI 1.21-47.44, P = .03), interstitial lung disease (OR 30.36, 95% CI 2.30-401.52, P = .01), intravascular crystalloid fluid during surgery (OR 1.10, 95% CI 1.00-1.20, P = .04), and intraoperative transfusion (OR 56.4, 95% CI 3.53-901.39, P < .01) were risk factors of PALI. PALI increases ICU admission, use of mechanical ventilator, duration of hospital stay, and mortality.The clinical impact of PALI is marked. Significant independent risk factors have been identified in underlying ischemic heart disease, interstitial lung disease, intravascular crystalloid fluid, and transfusion during surgery.