Differences in coronary angiographic findings and outcomes between men and postmenopausal women with stable chest pain.

BACKGROUND: Despite the significant increase in cardiovascular events in women after menopause, studies comparing postmenopausal women and men are scarce. METHODS: We analyzed data from a nationwide, multicenter, prospective registry and enrolled 2412 patients with stable chest pain who underwent elective coronary angiography. Binary coronary artery disease (b-CAD) was defined as the ≥50% stenosis of epicardial coronary arteries, including the left main coronary artery. RESULTS: Compared with the men, postmenopausal women were older (66.6 ±â€…8.5 vs. 59.5 ±â€…11.4 years) and had higher high-density lipoprotein cholesterol levels (49.0 ±â€…12.8 vs. 43.6 ±â€…11.6 mg/dl, P  < 0.01). The prevalence of diabetes did not differ significantly ( P  = 0.40), and smoking was more common in men than in postmenopausal women ( P  ≤ 0.01). At enrollment, b-CAD and revascularization were more common in men than in postmenopausal women (50.3% vs. 41.0% and 14.4% vs. 9.7%, respectively; both P  < 0.01). However, multivariate analyses revealed that revascularization [odds ratio (OR): 0.72; 95% confidence interval (CI): 0.49-1.08] was not significantly related to sex and a similar result was found in age propensity-matched population (OR: 0.80; 95% CI: 0.52-1.24). During the follow-up period, the secondary composite cardiovascular outcomes were lower in postmenopausal women than in men (OR: 0.55; 95% CI: 0.31-0.98), also consistent with the result using the age propensity-mated population (OR: 0.33; 95% CI: 0.13-0.85). CONCLUSION: Postmenopausal women experienced coronary revascularization comparable to those in men at enrollment, despite the average age of postmenopausal women was 7 years older than that of men.Postmenopausal women exhibit better clinical outcomes than those of men if optimal treatment is provided.

WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function.

Immune checkpoint therapies, such as programmed cell death ligand 1 (PD-L1) blockade, have shown remarkable clinical benefit in many cancers by restoring the function of exhausted T cells. Hence, the identification of novel PD-L1 regulators and the development of their inhibition strategies have significant therapeutic advantages. Here, we conducted pooled shRNA screening to identify regulators of membrane PD-L1 levels in lung cancer cells targeting druggable genes and cancer drivers. We identified WNK lysine deficient protein kinase 3 (WNK3) as a novel positive regulator of PD-L1 expression. The kinase-dead WNK3 mutant failed to elevate PD-L1 levels, indicating the involvement of its kinase domain in this function. WNK3 perturbation increased cancer cell death in cancer cell-immune cell coculture conditions and boosted the secretion of cytokines and cytolytic enzymes, promoting antitumor activities in CD4+ and CD8+ T cells. WNK463, a pan-WNK inhibitor, enhanced CD8+ T-cell-mediated antitumor activity and suppressed tumor growth as a monotherapy as well as in combination with a low-dose anti-PD-1 antibody in the MC38 syngeneic mouse model. Furthermore, we demonstrated that the c-JUN N-terminal kinase (JNK)/c-JUN pathway underlies WNK3-mediated transcriptional regulation of PD-L1. Our findings highlight that WNK3 inhibition might serve as a potential therapeutic strategy for cancer immunotherapy through its concurrent impact on cancer cells and immune cells.

A Case Report for Acute Myopericarditis After NVX-CoV2373 (Novavax®) COVID-19 Vaccination.

Post-vaccination myocarditis after administration of the NVX-CoV2373 coronavirus disease 2019 (COVID-19) vaccine has been reported in a limited population. We report the first biopsy-proven case of myopericarditis after administration of second dose of NVX-CoV2373 COVID-19 vaccine (Novavax®) in Korea. A 30-year-old man was referred to emergency department with complaints of chest pain and mild febrile sense for two days. He received the second dose vaccine 17 days ago. Acute myopericarditis by the vaccination was diagnosed by cardiac endomyocardial biopsy. He was treated with corticosteroid 1 mg/kg/day for 5 days and tapered for one week. He successfully recovered and was discharged on the 12th day of hospitalization. The present case suggests acute myopericarditis as a vaccination complication by Novavax® in Korea.

Snail acetylation by autophagy-derived acetyl-coenzyme A promotes invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells.

BACKGROUND: Autophagy is elevated in metastatic tumors and is often associated with active epithelial-to-mesenchymal transition (EMT). However, the extent to which EMT is dependent on autophagy is largely unknown. This study aimed to identify the mechanisms by which autophagy facilitates EMT. METHODS: We employed a liquid chromatography-based metabolomic approach with kirsten rat sarcoma viral oncogene (KRAS) and liver kinase B1 (LKB1) gene co-mutated (KL) cells that represent an autophagy/EMT-coactivated invasive lung cancer subtype for the identification of metabolites linked to autophagy-driven EMT activation. Molecular mechanisms of autophagy-driven EMT activation were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting analysis, immunoprecipitation, immunofluorescence staining, and metabolite assays. The effects of chemical and genetic perturbations on autophagic flux were assessed by two orthogonal approaches: microtubule-associated protein 1A/1B-light chain 3 (LC3) turnover analysis by Western blotting and monomeric red fluorescent protein-green fluorescent protein (mRFP-GFP)-LC3 tandem fluorescent protein quenching assay. Transcription factor EB (TFEB) activity was measured by coordinated lysosomal expression and regulation (CLEAR) motif-driven luciferase reporter assay. Experimental metastasis (tail vein injection) mouse models were used to evaluate the impact of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVIS luciferase imaging system. RESULTS: We found that autophagy in KL cancer cells increased acetyl-coenzyme A (acetyl-CoA), which facilitated the acetylation and stabilization of the EMT-inducing transcription factor Snail. The autophagy/acetyl-CoA/acetyl-Snail axis was further validated in tumor tissues and in autophagy-activated pancreatic cancer cells. TFEB acetylation in KL cancer cells sustained pro-metastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. Pharmacological inhibition of this axis via CAMKK2 inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KL cancer cells in vivo. CONCLUSIONS: This study demonstrates that autophagy-derived acetyl-CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells and that inhibition of the autophagy/acetyl-CoA/acetyl-Snail axis using CAMKK2 or ACLY inhibitors could be a potential therapeutic strategy to suppress metastasis of KL lung cancer.

Sex differences in coronary angiographic findings in patients with stable chest pain: analysis of data from the KoRean wOmen'S chest pain rEgistry (KoROSE).

BACKGROUND: Focused evaluations on potential sex differences in the angiographic findings of the coronary arteries are scarce. This study was performed to compare the angiographic extent and localization of coronary stenosis between men and women. METHODS: A total of 2348 patients (mean age 62.5 years and 60% women) with stable chest pain undergoing invasive coronary angiography (CAG) were recruited from the database of the nation-wide chest pain registry. Obstructive coronary artery disease (CAD) was defined as ≥ 50% stenosis of the left main coronary artery and/or ≥ 70% stenosis of any other epicardial coronary arteries. RESULTS: Although women were older than men (64.4 ± 10.3 vs. 59.5 ± 11.4 years, P < 0.001), men had worse risk profiles including high blood pressure, more frequent smoking and elevated triglyceride and C-reactive protein. The prevalence of obstructive CAD was significantly higher in men than in women (37.0% vs. 28.4%, P < 0.001). Men had a higher prevalence of LM disease (10.3% vs. 3.5%, P < 0.001) and three-vessel disease (16.1% vs. 9.5%, P = 0.007) compared to women. In multiple binary logistic regression analysis, the risk of men having LM disease or three-vessel disease was 7.4 (95% confidence interval 3.48-15.97; P < 0.001) and 2.7 (95% confidence interval 1.57-4.64; P < 0.001) times that of women, respectively, even after controlling for potential confounders. CONCLUSIONS: In patients with chest pain undergoing invasive CAG, men had higher obstructive CAD prevalence and more high-risk angiographic findings such as LM disease or three-vessel disease.

Characteristics and Clinical Outcomes of Cancer Patients who Developed Constrictive Physiology After Pericardiocentesis.

BACKGROUND AND OBJECTIVES: This study aimed to identify the characteristics and clinical outcomes of cancer patients who developed constrictive physiology (CP) after percutaneous pericardiocentesis. METHODS: One-hundred thirty-three cancer patients who underwent pericardiocentesis were divided into 2 groups according to follow-up echocardiography (CP vs. non-CP). The clinical history, imaging findings, and laboratory results, and overall survival were compared. RESULTS: CP developed in 49 (36.8%) patients after pericardiocentesis. The CP group had a more frequent history of radiation therapy. Pericardial enhancement and malignant masses abutting the pericardium were more frequently observed in the CP group. Fever and ST segment elevation were more frequent in the CP group, with higher C-reactive protein levels (6.6±4.3mg/dL vs. 3.3±2.5mg/dL, p<0.001). Pericardial fluid leukocytes counts were significantly higher, and positive cytology was more frequent in the CP group. In baseline echocardiography before pericardiocentesis, medial e' velocity was significantly higher in the CP group (8.6±2.1cm/s vs. 6.5±2.3cm/s, p<0.001), and respirophasic ventricular septal shift, prominent expiratory hepatic venous flow reversal, pericardial adhesion, and loculated pericardial fluid were also more frequent. The risk of all-cause death was significantly high in the CP group (hazard ratio, 1.53; 95% confidence interval,1.10-2.13; p=0.005). CONCLUSIONS: CP frequently develops after pericardiocentesis, and it is associated with poor survival in cancer patients. Several clinical signs, imaging, and laboratory findings suggestive of pericardial inflammation and/or direct malignant pericardial invasion are frequently observed and could be used as predictors of CP development.

Clinical impact of echocardiography-defined pulmonary hypertension on the clinical outcome in patients with multiple myeloma.

Pulmonary hypertension (PH) is a complication of multiple myeloma (MM); however, the clinical outcomes and prognosis are relatively not well known. We aimed to investigate the risk factors of transthoracic echocardiography-defined PH and its impact on the clinical outcome in patients with MM.A retrospective study was performed using data from the Chonnam National University Hwasun Hospital database for patients who underwent transthoracic echocardiography (TTE) within 1 month of the MM diagnosis between January 2007 and December 2017. PH was defined as an estimated right ventricular systolic pressure (RVSP) > 40 mmHg. A total of 390 patients were included. TTE-defined PH was observed in 107 patients (27%). During the follow-up period (median, 688 days), all-cause death was noted for 134 patients (34.4%). In the Kaplan-Meier survival analysis, the cumulative overall survival and cardiovascular death-free survival rates were significantly lower in the PH group than in the non-PH group (P < .001). In the propensity score-matched population, RVSP > 40 mmHg on TTE and history of congestive heart failure (CHF) were identified as the significant independent predictors of all-cause and cardiovascular death.This study reports that the prevalence of TTE-defined PH is higher in patients with MM than in the general population. Moreover, TTE-defined PH and a history of CHF are the independent prognostic factors for all-cause and cardiovascular death in patients with MM. These results highlight the risk of associated cardiovascular disease in patients with MM and emphasize the importance of management strategies that prevent the deterioration of cardiac function.

Left atrial longitudinal strain as a predictor of Cancer therapeutics-related cardiac dysfunction in patients with breast Cancer.

BACKGROUND: We investigated the usefulness of the left atrial (LA) strain measurement on the prediction of upcoming cancer therapeutics-related cardiac dysfunction (CTRCD) after trastuzumab therapy in patients with breast cancer who did not develop CTRCD after chemotherapy. METHODS: A total of 72 females with breast cancer who did not develop CTRCD after chemotherapy and underwent additional trastuzumab therapy were divided into CTRCD (n = 13) and no CTRCD group (n = 59). Echocardiographic measurements including left ventricular global longitudinal strain (LVGLS) and peak atrial longitudinal strain (PALS) decline were compared. RESULTS: CTRCD was identified in 13 patients (18.1%) after additional trastuzumab therapy. Baseline echocardiographic findings were not different. After the completion of chemotherapy, conventional echocardiographic parameters were not different, but PALS decline (15.0 ± 4.7 vs. 8.9 ± 3.2%, p < 0.001) and LVGLS decline (10.5 ± 1.3 vs. 9.1 ± 1.1%, p = 0.002) were significantly greater in CTRCD than in no CTRCD group. PALS decline at the time of chemotherapy completion could predict future CTRCD after trastuzumab therapy with better sensitivity and specificity (cutoff value 11.79%, sensitivity 76.9% and specificity 81.4%) than LVGLS decline (cutoff value 9.9%, sensitivity 69.2% and specificity 78.0%). CONCLUSIONS: PALS or LVGLS decline developed before developing overt CTRCD after chemotherapy for breast cancer, and PALS decline showed better sensitivity and specificity in predicting future CTRCD than LVGLS decline. Serial measurement of PALS can be used as a useful parameter in the prediction of future CTRCD.

Very late unusual thrombosis of the remnant pulmonary vasculatures after lung resection complicated by embolic events.

BACKGROUND: Primary thrombosis of the pulmonary vasculatures without extra-pulmonary sources of embolism are uncommon. Here, we report 2 cases of thrombosis of the stump of the remnant pulmonary vasculatures after lung resection complicated by embolic events with review of the literature. CASE PRESENTATION: A 75-year-old female was consulted to evaluate cardiac source of embolism for acute cerebral infarction. The patient underwent left upper lobectomy because of lung cancer 2 years ago. Cardiovascular imaging revealed about 1.6 cm × 1.4 cm sized thrombus within the remnant stump of the left superior pulmonary vein. The patient was treated by anticoagulation with warfarin, because the patients refused surgical removal of thrombus. A 57-year-old female who had a history of right pneumonectomy 10 years ago presented with dyspnea. Cardiovascular imaging revealed 1.7 × 1.5 cm sized thrombus in the right pulmonary artery stump and small pulmonary embolism in the left lower segmental pulmonary artery. The patient was treated by long-term anticoagulation with warfarin, and the thrombus and pulmonary embolism were resolved. CONCLUSION: The present cases demonstrated that very late thrombosis of the remnant pulmonary vascular structures and subsequent fatal embolic complications can develope even several years later after lung resection. Therefore, the dead space of the remnant vascular structures should be minimized during lung resection surgery, and the developement of delayed thromboembolic complications associated with vascular stump thrombosis should be carefully monitored.

Impacts of non-recovery of trastuzumab-induced cardiomyopathy on clinical outcomes in patients with breast cancer.

OBJECTIVES: The impacts of non-recovery of trastuzumab-induced left ventricular dysfunction (LVD) on clinical outcomes in breast cancer have been poorly studied. We investigated the predictors of LV-functional non-recovery and its impacts on clinical outcomes in breast cancer patients with trastuzumab-induced LVD. METHODS AND RESULTS: A total of 243 patients with trastuzumab-induced LVD were divided into the recovered LVD group (n = 195) and non-recovered LVD group (n = 48). Major adverse clinical events (MACEs) including death, symptomatic heart failure (HF), and HF hospitalization (HHF) were compared. Hemoglobin and albumin levels were significantly lower in non-recovered LVD than in recovered LVD group. Non-recovered LVD group showed significantly larger LV end-diastolic and systolic dimension, higher pulmonary artery systolic pressure, lower LV ejection fraction (EF), and decreased global longitudinal strain than in recovered LVD group. Decreased LVEF, enlarged LV size, pulmonary hypertension, and anemia were independent predictors of LV-functional non-recovery. During 45.9 ± 23.5 months of follow-up, MACEs were developed in 32 patients: 15 deaths, 28 symptomatic HF, and 22 HHF. In Kaplan-Meier survival analysis, MACE free survival was significantly lower in non-recovered LVD group than in recovered LVD group (log rank p = 0.002). CONCLUSION: LV-functional non-recovery was not uncommon in breast cancer patients with trastuzumab-induced cardiomyopathy, and non-recovered LVD was significantly associated with MACEs. Decreased LVEF, enlarged LV size, pulmonary hypertension, and anemia were independent predictors of LV-functional non-recovery. Careful monitoring for MACEs and intensive medical management should be considered in trastuzumab-induced cardiomyopathy with these characteristics.

University athletes and changes in cardiac geometry: insight from the 2015 Gwangju Summer Universiade.

AIMS: There is a paucity of data regarding the changes of cardiac geometry in highly trained international and multiracial university athletes. We aimed to investigate the incidence of structural cardiac abnormalities and changes of cardiac geometry in highly trained university athletes. METHODS AND RESULTS: Comprehensive echocardiographic studies were performed in 1185 university athletes through the Check-up Your Heart Program during the 2015 Gwangju Summer Universiade. Participants were divided into two groups: normal vs. abnormal left ventricular (LV) geometry (concentric remodelling, concentric hypertrophy, or eccentric hypertrophy). Structural heart diseases associated with sudden cardiac death were not identified, but minor structural cardiac abnormalities were common in university athletes. One hundred and fifty-six athletes (13.2%) had abnormal LV geometry; concentric remodelling (n = 73, 6.2%), concentric hypertrophy (n = 25, 2.1%), and eccentric hypertrophy (n = 58, 4.9%). Abnormal LV geometry was significantly more common in athletes of African descent and in endurance, mixed, or power disciplines. In multivariate logistic regression analysis, athletes of African descent [odds ratio (OR) 2.16, 95% confidence interval (CI) 1.34-3.46; P = 0.001], endurance disciplines (OR 1.79, 95% CI 1.26-2.54; P = 0.001), and training time (OR 1.01, 95% CI 1.00-1.02; P = 0.045) were independent predictors of abnormal LV geometry. CONCLUSION: A large scale cardiovascular screening programme of the 2015 Summer Universiade demonstrated that abnormal LV geometry is not uncommon (13.2%) and concentric remodelling is the most common pattern of LV geometric change in young trained university athletes. Race, type of sport, and training time are significant predictors of abnormal LV geometry. Structural cardiac abnormalities are common in university athletes even though they are minor abnormalities.

Complete atrioventricular block as an initial manifestation of recurred oral cavity cancer: a case report.

BACKGROUND: Intracardiac invasion of head and neck cancer is extremely rare. Here, we report a case of recurred oral cavity cancer presenting with complete atrioventricular (AV) block caused by cardiac metastasis. CASE PRESENTATION: A 70-year-old male presented with dizziness for 2 days. He had a history of oral cavity cancer a year ago, and the tumor was treated by surgical excision after induction chemotherapy and concurrent chemoradiation therapy. Electrocardiography showed complete AV block with ventricular escape rate of 43 beats per minute. Cardiac imaging revealed about 4.0 × 2.0 cm-sized mass invading interventricular septum and AV nodes and protruding into the right ventricle. Magenetic resonance imaging of head and neck demonstrated recurred mass in oral cavity and maxillary sinus. Fluorodeoxyglucose-positron emission tomography showed hypermetabolic lesion in both oral cavity and the heart around interventricular septum and atrioventricular node indicating recurred oral cavity cancer with cardiac metastasis. Permament pacemaker of DDD type was implanted for the symptomatic complete AV block, and palliative chemotherapy was initiated. CONCLUSION: The present case demonstrated that oral cavity cancer can metastasize to the heart, and complete AV block may be an initial manifestation of the recurrence of extracardiac cancer with intracardiac invasion.

Masked inherited primary arrhythmia syndromes in sudden cardiac death patients accompanied by coronary vasospasm.

BACKGROUND/AIMS: Coronary vasospasms are one of the important causes of sudden cardiac death (SCD). Provocation of coronary vasospasms can be useful, though some results may lead to false positives, with patients potentially experiencing recurrent SCD despite appropriate medical treatments. We hypothesized that it is not coronary vasospasms but inherited primary arrhythmia syndromes (IPAS) that underlie the development of SCD. METHODS: We analyzed 74 consecutive patients (3.8%) who survived out-of-hospital cardiac arrest among 1,986 patients who had angiographically proven coronary vasospasms. Electrical abnormalities were evaluated in serial follow-up electrocardiograms (ECGs) during and after the index event for a 3.9 years median follow-up. Major clinical events were defined as the composite of death and recurrent SCD events. RESULTS: Forty five patients (60.8%) displayed electrocardiographic abnormalities suggesting IPAS: Brugada type patterns in six (8.2%), arrhythmogenic right ventricular dysplasia patterns in three (4.1%), long QT syndrome pattern in one (2.2%), and early repolarization in 38 (51.4%). Patients having major clinical events showed more frequent Brugada type patterns, early repolarization, and more diffuse multivessel coronary vasospasms. Brugada type pattern ECGs (adjusted hazard ratio [HR], 4.22; 95% confidence interval [CI], 1.16 to 15.99; p = 0.034), and early repolarization (HR, 2.97; 95% CI, 1.09 to 8.10; p = 0.034) were ultimately associated with an increased risk of mortality. CONCLUSIONS: Even though a number of aborted SCD survivors have coronary vasospasms, some also have IPAS, which has the potential to cause SCD. Therefore, meticulous evaluations and follow-ups for IPAS are required in those patients.

Clinical significance of NGAL and KIM-1 for acute kidney injury in patients with scrub typhus.

BACKGROUND: The aim of this study is to investigate the clinical significance of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) for acute kidney injury (AKI) in patients with scrub typhus. METHODS: From 2014 to 2015, 145 patients were diagnosed with scrub typhus. Of these, we enrolled 138 patients who were followed up until renal recovery or for at least 3 months. We measured serum and urine NGAL and KIM-1 levels and evaluated prognostic factors affecting scrub typhus-associated AKI. RESULTS: Of the 138 patients, 25 had scrub typhus-associated AKI. The incidence of AKI was 18.1%; of which 11.6%, 4.3%, and 2.2% were classified as risk, injury, and failure, respectively, according to RIFLE criteria. Compared with patients in the non-AKI group, patients in the AKI group were older and showed higher total leukocyte counts and hypoalbuminemia or one or more comorbidities such as hypertension (72% vs 33%, p<0.01), diabetes (40% vs 14%, p<0.01), or chronic kidney disease (32% vs 1%, p<0.01). In addition, serum NGAL values (404± 269 vs 116± 78 ng/mL, P<0.001), KIM-1 values (0.80± 0.52 vs 0.33± 0.68 ng/mL, P<0.001), urine NGAL/creatinine values (371± 672 vs 27± 39 ng/mg, P<0.001) and urine KIM-1/creatinine values (4.04± 2.43 vs 2.38± 1.89 ng/mg, P<0.001) were higher in the AKI group than in the non-AKI group. By multivariate logistic regression, serum NGAL and the presence of chronic kidney disease were significant predictors of AKI. CONCLUSION: Serum NGAL might be an additive predictor for scrub typhus-associated AKI.

Predictors of reversible severe functional tricuspid regurgitation in patients with atrial fibrillation.

BACKGROUND: Atrial remodeling associated with atrial fibrillation (AF) is known to be a risk factor for significant tricuspid regurgitation (TR), but the predictor of reversible TR in patients with severe functional TR and AF has been poorly studied. The aim of this study was to investigate the predictors of reversible TR in patients with severe functional TR and AF. METHODS: Among 232 patients with severe TR, a total of 71 patients with severe functional TR and AF were enrolled and divided into 2 groups: reversible TR group (n=16, 70.1±15.5 years, 7 males) vs. non-reversible TR group (n=55, 72.3±11.8 years, 20 males). Improvement of TR to moderate or lesser degree on follow-up (FU) echocardiography was considered as reversible TR in the present study. RESULTS: During 38.9±26.7 months of FU period, reversible TR was observed in 16 patients (22.5%). The presence of left ventricular (LV) systolic dysfunction was significantly prevalent (43.8% vs. 20.0%, p=0.03) and the improvement in LV ejection fraction (EF) more than 10% on FU echocardiography was more significantly frequent (62.5% vs. 23.3%, p=0.003) in the reversible TR group than in the non-reversible TR group. However, the other echocardiographic parameters, including right ventricular function were not different between the groups. In multivariate analysis using Cox proportional hazard model, the improvement of LVEF more than 10% was the only independent predictor of reversible TR (HR=7.39, 95%CI 1.80-30.28, p=0.005). Nine patients died only in patients with non-reversible TR (12.7%), but the reversibility of TR was not associated with mortality. CONCLUSIONS: The improvement of LV systolic function was the only independent predictor of reversible TR. Appropriate medical therapy including management for heart failure should be considered before performing surgery in patients with severe functional TR and AF, especially in patients with LV dysfunction.

Chemotherapy-Induced Left Ventricular Dysfunction in Patients with Breast Cancer.

PURPOSE: As the numbers of cancer cases and survivors increase, the incidence and natural history of chemotherapy-induced cardiotoxicities in patients with breast cancer may also be expected to change. The present study aimed to investigate the incidence and predictors of chemotherapy-induced left ventricular dysfunction (LVD) in patients with breast cancer. METHODS: From 2003 to 2010, 712 female patients with breast cancer (55.7±10.7 years) were enrolled and divided into the LVD group (n=82, 56.7±10.1 years) and the non-LVD group (n=630, 55.6±10.8 years). Baseline clinical and treatment-related variables were compared. RESULTS: Chemotherapy-induced LVD developed in 82 cases (11.4%). Low body mass index (BMI), low triglyceride level, advanced cancer stage, and the use of doxorubicin, paclitaxel, trastuzumab, or radiotherapy were significant predictors of LVD in a univariate analysis. In a multivariate analysis, low BMI, advanced cancer stage, and the use of target therapy with trastuzumab were independent predictors of chemotherapy-induced LVD. Chemotherapy-induced LVD was recovered in 53 patients (64.6%), but left ventricular function was not recovered in 29 patients (35.4%). CONCLUSION: Chemotherapy-induced LVD was not uncommon and did not reduce in many of our patients with breast cancer. Low BMI, advanced cancer stage, and the use of trastuzumab were independent predictors of chemotherapy-induced LVD in patients with breast cancer. The development of chemotherapy-induced LVD should be carefully monitored in patients with breast cancer who are receiving trastuzumab therapy, have poor nutritional status, and advanced cancer stage.

Circadian rhythm of hyperoxidized peroxiredoxin II is determined by hemoglobin autoxidation and the 20S proteasome in red blood cells.

The catalytic cysteine of the typical 2-Cys Prx subfamily of peroxiredoxins is occasionally hyperoxidized to cysteine sulfinic acid during the peroxidase catalytic cycle. Sulfinic Prx (Prx-SO2H) is reduced back to the active form of the enzyme by sulfiredoxin. The abundance of Prx-SO2H was recently shown to oscillate with a period of ∼24 h in human red blood cells (RBCs). We have now investigated the molecular mechanism and physiological relevance of such oscillation in mouse RBCs. Poisoning of RBCs with CO abolished Prx-SO2H formation, implicating H2O2 produced from hemoglobin autoxidation in Prx hyperoxidation. RBCs express the closely related PrxI and PrxII isoforms, and analysis of RBCs deficient in either isoform identified PrxII as the hyperoxidized Prx in these cells. Unexpectedly, RBCs from sulfiredoxin-deficient mice also exhibited circadian oscillation of Prx-SO2H. Analysis of the effects of protease inhibitors together with the observation that the purified 20S proteasome degraded PrxII-SO2H selectively over nonhyperoxidized PrxII suggested that the 20S proteasome is responsible for the decay phase of PrxII-SO2H oscillation. About 1% of total PrxII undergoes daily oscillation, resulting in a gradual loss of PrxII during the life span of RBCs. PrxII-SO2H was detected in cytosolic and ghost membrane fractions of RBCs, and the amount of membrane-bound PrxII-SO2H oscillated in a phase opposite to that of total PrxII-SO2H. Our results suggest that membrane association of PrxII-SO2H is a tightly controlled process and might play a role in the tuning of RBC function to environmental changes.

Pheochromocytoma as a rare hidden cause of inverted stress cardiomyopathy.

Stress cardiomyopathy (SCMP) is characterized by a transient left ventricular dysfunction associated with apical ballooning and compensatory hyperkinesias of the basal segments after emotional or physical stress, but inverted or mid-ventricular variants of SCMP have also been described. Although catecholamine excess has been suggested as a possible pathophysiologic mechanism of SCMP, the etiology of SCMP is still unknown. Here, we report a case of inverted type of SCMP with clinical presentation mimicking acute coronary syndromes. The cause or precipitating stressor was unclear initially, but pheochromocytoma has been demonstrated as a cause of SCMP during clinical follow-up at out-patient clinic in the present case. Catecholamine-producing tumors should be included in the evaluation or management of SCMP, even though initial clinical manifestations are not suggestive for pheochromocytoma.