Associated factors and clinical outcomes in mechanical circulatory support use in patients undergoing high risk on-pump cardiac surgery: Insights from the LEVO-CTS trial.

BACKGROUND: We describe variables and outcomes associated with peri-operative mechanical circulatory support (MCS) utilization among patients enrolled in the Levosimendan in patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial. METHODS: In the LEVO-CTS trial, MCS utilization (defined as intra-aortic balloon pump, extracorporeal membrane oxygenation, or surgical ventricular assist device) within 5 days of surgery was examined. The association between MCS use and outcomes including 90-day mortality, 30-day renal-replacement therapy, and hospital and critical stay length of stay were determined. RESULTS: Among the 849 patients from 70 centers randomized to levosimendan or placebo, 85 (10.0%) patients were treated with MCS (71 intra-aortic balloon pump, 7 extracorporeal membrane oxygenation, 7 ventricular assist device); with 89.4% started on post-operative day 0. Inter-institutional use ranged from 0% to 100%. Variables independently associated with MCS utilization included combined coronary artery bypass grafting and valve surgery (adjusted odds ratio [OR] 2.73, 95% confidence interval [CI] 1.70-4.37, P < .001), history of lung disease (OR 1.70, 95% CI 1.06-2.70, P = .029), and history of heart failure (OR 2.44, 95% CI 1.10-5.45, P = .027). Adjusted 90-day mortality (22.4% vs 4.1%, hazard ratio 6.11, 95% CI 3.95-9.44, P < .001) was higher, and median critical care length of stay (8.0 vs 4.0 days, P < .001) was longer in patients managed with MCS. CONCLUSIONS: In a randomized controlled trial of high-risk cardiac surgical patients in North America, we observed patient, and surgical variables associated with MCS utilization. MCS use was associated with a higher risk of post-operative mortality.

A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers.

STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-cancer targets; however, they are also considered to be clinically "undruggable" intracellular molecules, except for KRAS(G12C). Here we report a first-in-class molecule, a novel, single domain camelid VHH antibody (15 kDa), SBT-100, that binds to both STAT3 and KRAS and can penetrate the tumor cell membrane, and significantly inhibit cancer cell growth. Additionally, SBT-100 inhibits KRAS GTPase activity and downstream phosphorylation of ERK in vitro. In addition, SBT-100 inhibits the growth of multiple human cancers in vitro and in vivo. These results demonstrate the feasibility of targeting hard-to-reach aberrant intracellular transcription factors and signaling proteins simultaneously with one VHH to improve cancer therapies.

Clinical features and outcomes in patients with cardiogenic shock complicating acute myocardial infarction: early vs recent experience with impella.

OBJECTIVES: To compare clinical features and outcomes in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) treated in the early experience with Impella percutaneous ventricular assist device and patients treated recently. BACKGROUND: Since pre-market approval (PMA) of Impella device as treatment for AMICS, use of the device has grown considerably. METHODS: We retrospectively analyzed 649 AMICS patients treated with perioperative Impella, with 291 patients treated from 2008 to 2014 comprising the early experience cohort and 358 patients treated from 2017 to 2019 comprising the recent experience cohort. The primary end point was risk adjusted in-hospital mortality. RESULTS: Mean age and gender distribution of patients was similar in the two cohorts. The recent cohort had more invasive hemodynamic monitoring (64% vs 46%; P < .001) and less use of an intra-aortic balloon pump prior to Impella (15% vs 41%; P < .001). Recently treated patients were significantly more likely to receive Impella support prior to PCI (58% vs 44%; P = .005). In-hospital mortality was lower in the recent cohort (48% vs 56%; P = .043). This difference was however no longer significant after risk adjustment (adjusted OR 0.89, 95% CI 0.59-1.34, P = .59). Rates of acute kidney injury, major bleeding, and vascular complications requiring surgery were also significantly lower in the recent cohort. CONCLUSIONS: Use of Impella for AMICS during recent years is associated with lower unadjusted in-hospital mortality, which may reflect better patient selection, earlier device implantation, and improved management algorithms. In-depth understanding of these factors may inform the development of future treatment protocols.

Association between levosimendan, postoperative AKI, and mortality in cardiac surgery: Insights from the LEVO-CTS trial.

OBJECTIVES: We aimed to evaluate the association between levosimendan treatment and acute kidney injury (AKI) as well as assess the clinical sequelae of AKI in cardiac surgery patients with depressed left ventricular function (ejection fraction <35%). METHODS: Patients in the LEVO-CTS trial undergoing on-pump coronary artery bypass grafting (CABG), valve, or CABG/valve surgery were stratified by occurrence and severity of postoperative AKI using the AKIN classification. The association between levosimendan infusion and AKI was modeled using multivariable regression. RESULTS: Among 854 LEVO-CTS patients, 231 (27.0%) experienced postoperative AKI, including 182 (21.3%) with stage 1, 35 (4.1%) with stage 2, and 14 (1.6%) with stage 3 AKI. The rate of AKI was similar between patients receiving levosimendan or placebo. The odds of 30-day mortality significantly increased by AKI stage compared to those without AKI (stage 1: adjusted odds ratio [aOR] 2.0, 95% confidence interval [CI] 0.8-4.9; stage 2: aOR 9.1, 95% CI 3.2-25.7; stage 3: aOR 12.4, 95% CI 3.0-50.4). No association was observed between levosimendan, AKI stage, and odds of 30-day mortality (interaction P = .69). Factors independently associated with AKI included increasing age, body mass index, diabetes, and increasing baseline systolic blood pressure. Increasing baseline eGFR and aldosterone antagonist use were associated with a lower risk of AKI. CONCLUSIONS: Postoperative AKI is common among high-risk patients undergoing cardiac surgery and associated with significantly increased risk of 30-day death or dialysis. Levosimendan was not associated with the risk of AKI.

Functional Significance of Selective Expression of ERα and ERß in Mammary Gland Organ Culture.

Thoracic pair of mammary glands from steroid hormone-pretreated mice respond to hormones structurally and functionally in organ culture. A short exposure of glands for 24 h to 7,12 Dimethylbenz(a)anthracene (DMBA) during a 24-day culture period induced alveolar or ductal lesions. Methods: To differentiate the functional significance of ERα and ERß, we employed estrogen receptor (ER) knockout mice. We compared the effects of DMBA on the development of preneoplastic lesions in the glands in the absence of ERα (αERKO) and ERß (ßERKO) using an MMOC protocol. Glands were also subjected to microarray analyses. We showed that estradiol can be replaced by EGF for pretreatment of mice. The carcinogen-induced lesions developed under both steroids and EGF pretreatment protocols. The glands from αERKO did not develop any lesions, whereas in ßERKO mice in which ERα is intact, mammary alveolar lesions developed. Comparison of microarrays of control, αERKO and ßERKO mice showed that ERα was largely responsible for proliferation and the MAP kinase pathways, whereas ERß regulated steroid metabolism-related genes. The results indicate that ERα is essential for the development of precancerous lesions. Both subtypes, ERα and Erß, differentially regulated gene expression in mammary glands in organ cultures.

Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials.

BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery.

BACKGROUND: Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. METHODS: In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 µg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 µg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. RESULTS: A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. CONCLUSIONS: Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).

Major bleeding in patients with peripheral artery disease: Insights from the EUCLID trial.

BACKGROUND: Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events. METHODS: EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined. RESULTS: TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and ß-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P < .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event. CONCLUSIONS: In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and ß-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

Comparison of nationwide trends in 30-day readmission rates after carotid artery stenting and carotid endarterectomy.

OBJECTIVE: Carotid revascularization procedures, carotid artery stenting (CAS) and carotid endarterectomy (CEA), are among the most common vascular interventions performed in the United States, with significant resource utilization. Whereas multiple studies have reported outcomes after these procedures, data regarding 30-day readmission rates after these interventions remain scant. METHODS: The U.S. Nationwide Readmission Database (2010-2014) was queried to identify all patients ≥18 years who were readmitted within 30 days after a hospital discharge for CEA or CAS. RESULTS: Among 476,260 patients included, 13.5% underwent CAS and 86.5% underwent CEA. The combined 30-day readmission rate for all carotid revascularization procedures was 9.2% (10.6% after CAS and 9.0% after CEA). After 1:3 propensity matching, CAS was associated with higher risk of readmission compared with CEA (10.4% vs 9.4%). Neurologic complications and cardiac conditions were the two most common causes of readmission after both CAS (29.7% and 23.7%, respectively) and CEA (28.2% and 21.7%, respectively). The 30-day readmission rates were higher in CAS patients across all age groups as well as in those with a low or high baseline burden of comorbidities. CONCLUSIONS: In this large nationwide study, CAS was associated with higher 30-day readmission rates compared with CEA irrespective of age or baseline burden of comorbidities. Neurologic or cardiac adverse events were responsible for >50% of readmissions after CAS and CEA.

Imaging Cardiovascular Emergencies: Real World Clinical Cases.

Cardiovascular emergencies represent life-threatening conditions requiring a high index of clinical suspicion. In an emergency scenario, a simple stepwise biomarker/imaging diagnostic algorithm may help prompt diagnosis and timely treatment along with related improved outcomes. This article describes several clinical cases of cardiovascular emergencies, such as coronary stent thrombosis-restenosis, takotsubo syndrome, acute myocarditis, massive pulmonary embolism, type A acute aortic dissection, cardiac tamponade, and endocarditis.

Meta-analysis of drug eluting stents compared with bare metal stents in high bleeding risk patients undergoing percutaneous coronary interventions.

OBJECTIVES: To determine the efficacy and safety of drug-eluting stents (DESs) and bare metal stents (BMSs) when used with short or tailored dual antiplatelet therapy (DAPT) in high bleeding risk (HBR) patients. BACKGROUND: DES have been shown to reduce target lesion revascularization (TLR) as well as stent thrombosis (ST) compared to BMS in patients undergoing percutaneous coronary intervention (PCI). However, patients at HBR continue to receive BMS given the fear of bleeding or ST from premature discontinuation of DAPT in patients receiving DES. METHODS: We performed a meta-analysis of randomized controlled trials by performing systematic search for studies comparing DES with BMS in HBR patients using PUBMED, MEDLINE, and Cochrane Central, reported until March 1, 2018. RESULTS: Three randomized controlled studies met the inclusion criteria with total of 4,460 patients; 50% received DES. Major adverse cardiovascular event (MACE); composite of death, myocardial infarction (MI), and TLR, at 1 year was significantly lower (RR = 0.63, 95% CI 0.50-0.80) in DES group compared to BMS. This difference was primarily driven by lower TLR (RR = 0.46, 95% CI 0.35-0.61) in DES group. Definite or probable ST (RR = 0.59, 95% CI = 0.32-1.08) and major (RR = 0.94, 95% CI = 0.74-1.20) bleeding were similar. CONCLUSIONS: DES was associated with lower MACE without increased risk of bleeding or ST compared to BMS when used with short or tailored DAPT in patients with HBR.

Development of aqueous-based multi-herbal combination using principal component analysis and its functional significance in HepG2 cells.

BACKGROUND: The present study was carried out to prepare multi-herbal combination via comparing antioxidant activity and polyphenolic composition of five medicinal plant extracts of Punica granatum L., Putranjiva roxburghii Wall., Swertia chirata Buch.-Ham., Tinospora cordifolia (Willd.) Miers and Trigonella corniculata L. METHODS: The herbs were individually evaluated using in vitro antioxidant assays and analyzed by HPLC-PDA. The resultant data was examined using principal component analysis (PCA). Further, herbal combination was prepared on the basis of PCA. RESULTS: The PCA divided the plants into three groups. The leading or primary group contained P. granatum and P. roxburghii with the highest antioxidant activity strongly correlated with high amount of kaempferol. S. chirata was acknowledged as nourisher herb in one and T. cordifolia and T. corniculata were identified as stimulator herbs in other group. The herbal combination exhibited high antioxidant activity as compared to the individual plants. The combination revealed good antiproliferative efficacy against hepatocellular carcinoma (HepG2) cells with IC50 of 75.864 µg/ml. CONCLUSIONS: The activity observed in vitro with HepG2 cells suggests that the herbal combination can provide therapeutic activity in vivo in future. The study may provide information regarding precise preparation of multi-herbal formulations using PCA as a tool in pharmaceutical industries.

Incidence and outcomes of emergent cardiac surgery during transfemoral transcatheter aortic valve implantation (TAVI): insights from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI).

Aims: Life-threatening complications occur during transcatheter aortic valve implantation (TAVI) which can require emergent cardiac surgery (ECS). Risks and outcomes of patients needing ECS during or immediately after TAVI are still unclear. Methods and results: Incidence, risk factors, management, and outcomes of patients requiring ECS during transfemoral (TF)-TAVI were analysed from a contemporary real-world multicentre registry. Between 2013 and 2016, 27 760 patients underwent TF-TAVI in 79 centres. Of these, 212 (0.76%) patients required ECS (age 82.4 ± 6.3 years, 67.5% females, logistic EuroSCORE: 17.1%, STS-score 5.8%). The risk of ECS declined from 2013 (1.07%) to 2014 (0.70%) but remained stable since. Annual TF-TAVI numbers have more than doubled from 2013 to 2016. Leading causes for ECS were left ventricular perforation by the guidewire (28.3%) and annular rupture (21.2%). Immediate procedural mortality (<72 h) of TF-TAVI patients requiring ECS was 34.6%. Overall in-hospital mortality was 46.0%, and highest in case of annular rupture (62%). Independent predictors of in-hospital mortality following ECS were age > 85 years [odds ratio (OR) 1.87, 95% confidence interval (95% CI) (1.02-3.45), P = 0.044], annular rupture [OR 1.96, 95% CI (0.94-4.10), P = 0.060], and immediate ECS [OR 3.12, 95% CI (1.07-9.11), P = 0.037]. One year of survival of the 114 patients surviving the in-hospital period was only 40.4%. Conclusion: Between 2014 and 2016, the need for ECS remained stable around 0.7%. Left ventricular guidewire perforation and annular rupture were the most frequent causes, accounting for almost half of ECS cases. Half of the patients could be salvaged by ECS-nevertheless, 1 year of all-cause mortality was high even in those ECS patients surviving the in-hospital period.

Long-term outcomes of patients with diabetes mellitus undergoing percutaneous intervention for popliteal and infrapopliteal peripheral arterial disease.

OBJECTIVES: To evaluate the association of diabetes mellitus (DM) with clinical and angiographic characteristics and outcomes of patients with popliteal and infrapopliteal peripheral arterial disease (PAD) undergoing peripheral vascular intervention (PVI). BACKGROUND: Clinical features and outcomes in patients with DM and popliteal or infrapopliteal PAD undergoing PVI are not well described. METHODS: Using the data from the laser in popliteal and infrapopliteal stenosis study, we retrospectively examined the association of diabetes with clinical and angiographic characteristics and risk adjusted short- and intermediate term outcomes (all cause death, major adverse events (MAE) [composite of death, ipsilateral major amputation, or repeat revascularization]) in patients with popliteal and infrapopliteal PAD undergoing PVI for critical limb ischemia treated either with laser-assisted balloon angioplasty or balloon angioplasty alone. RESULTS: Of 714 patients, 418 had DM (58.5%). Patients with DM were younger with higher prevalence of history of coronary artery disease, heart failure, end-stage renal disease, and prior contralateral limb amputation compared to those without DM. At 5 years, mean event free survival for all cause mortality (39.9 vs. 45.5 months; P = 0.001), MAE (29.3 vs. 36.8 months; P < 0.001), ipsilateral major amputation (55.3 vs. 57.4 months; P = 0.001), and repeat revascularization (42.0 vs. 45.8 months; P = 0.03) were significantly lower in DM patients. On multivariate analysis, DM was associated with significantly higher all cause mortality (HR = 1.83, 95% CI 1.33-2.52), MAE (HR = 1.73, 95% CI 1.35-2.23), and ipsilateral major amputation (HR = 5.52, 95% CI 1.82-16.71). CONCLUSIONS: Among patients with popliteal and infrapopliteal PAD undergoing PVI, DM was associated with higher mortality, major amputations and MAE that was independent of baseline comorbidities. Our data suggested the need for future studies evaluating existing and/or novel therapies to improve the poor long-term outcomes in diabetic patients with popliteal and infrapopliteal PAD.

Progression of conventional hepatic cell culture models to bioengineered HepG2 cells for evaluation of herbal bioactivities.

Cancer cell lines of human tissue origin have been extensively used to investigate antiproliferative activity and toxicity of herbal extracts, isolated compounds, and anticancer drugs. These cell lines are genetically and/or epigenetically well characterized to determine the altered expression of proteins within given cellular pathways and critical genes in cancer. Human derived hepatoma (HepG2) cell line has been extensively exploited to examine cytoprotective, antioxidative, hepatoprotective, anti-hepatoma, hypocholesterolemic, anti-steatosis, bioenergetic homeostatic and anti-insulin resistant properties. Moreover, mechanism of action of various botanicals and bioactive constituents has been reported using these cells. HepG2 cells have significant differences as compared to primary hepatocytes with respect to expression of cytochrome P450 enzymes and xenobiotic receptors in conventional in vitro culture conditions. Therefore, strategies have been employed to overcome limitations of two dimensional (2D) in vitro HepG2 cell culture in order to recognize functional biomarkers more accurately and to boost its predictive value in clinical research. In consequence, three dimensional (3D) human hepatoma cell culture models are being developed as a resource to achieve these goals of simulating the in vivo tumor microenvironment. It is assumed that bioengineered 3D hepatoma cell culture models can provide significant assistance in scrutinizing the molecular response of herbal natural products to recognize novel prognostic targets and crucial biomarkers in treatment strategies for cancer patients in near future.

Association of Hospital and Physician Characteristics and Care Processes With Racial Disparities in Procedural Outcomes Among Contemporary Patients Undergoing Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Previous studies have reported that black patients undergoing coronary artery bypass surgery had worse outcomes than white patients, even after accounting for patient factors. The degree to which clinician, hospital, and care factors account for these outcome differences remains unclear. METHODS AND RESULTS: We evaluated procedural outcomes in 11,697 blacks and 136,362 whites undergoing isolated coronary artery bypass surgery at 663 Society of Thoracic Surgery Database participating sites (January 1, 2010 to June 30, 2011) adjusted for patients' clinical and socioeconomic features, hospital and surgeon effects, and care processes (internal mammary artery graft and perioperative medications use). Relative to whites, blacks undergoing coronary artery bypass surgery were younger, yet had higher comorbidities and more adverse presenting features. Blacks were also more likely to be treated at hospitals with higher risk-adjusted mortality. The use of internal mammary artery was marginally lower in blacks than in whites (93.3% versus 92.2%, P<0.0001). Unadjusted mortality and major morbidity rates were higher in blacks than in whites (1.8% versus 2.5%, P<0.0001) and (13.6% versus 19.4%, P<0.0001), respectively. These racial differences in outcomes narrowed but still persisted after adjusting for surgeon, hospital, and care processes in addition to patient and socioeconomic factors (odds ratio, 1.17; 95% confidence interval, 1.00-1.36 and odds ratio, 1.26; 95% confidence interval, 1.19-1.34, respectively). CONCLUSIONS: The risks of procedural mortality and morbidity after coronary artery bypass surgery were higher among black patients than among white patients. These differences were in part accounted for by patient comorbidities, socioeconomic status, and surgeon, hospital, and care factors, as well, as suggested by the reduction in the strength of the race-outcomes association. However, black race remained an independent predictor of outcomes even after accounting for these differences.

Is mortality a useful parameter for public reporting in pacemaker implantation? Results of an obligatory external quality control programme.

AIMS: To evaluate if public reporting of pacemaker implantation-associated mortality is meaningful in a large contemporary patient cohort. METHODS AND RESULTS: The database of the obligatory external quality control programme in the Federal State of Hessen, Germany, of patients undergoing permanent pacemaker (PPM) implantation was evaluated retrospectively. We compared the baseline features of patients who died compared with those who did not during hospitalization after PPM. Of 5079 patients who underwent PPM implantation in 2009, 74 (1.5%) died during the hospital stay. Cause of death was available in 70/74 patients (94.6%) who died. Deceased patients were older (79.6 ± 8.7 vs. 76.3 ± 9.9 years, P = 0.006), had worse American Society of Anesthesiologists (ASA) physical status (P < 0.001), lower ejection fraction (P < 0.001), a greater prevalence of high-degree atrioventricular-block (44.3 vs. 35.0%, P = 0.001), and were more likely to receive single-chamber devices (41.4 vs. 25.0%, P < 0.002). Perioperative complications were similar in both cohorts. Death was not attributable directly to PPM procedure in any patients but was related to (i) non-device-related infections (28.6%), (ii) heart failure (25.7%), (iii) extracardiac diseases (21.4%), (iv) multiorgan failure (8.6%), (v) previous resuscitation with hypoxic brain damage (8.6%), and (vi) arrhythmogenic death (7.1%). CONCLUSION: Mortality associated with PPM implantation in vast majority of cases was not related to the procedure, but to comorbidities and other existing diseases at the time of PPM implantation. Thus, PPM implantation in-hospital mortality should not be chosen for public reporting comparing hospital quality, even after adjusting for baseline risk.

The association of race with quality of health in peripheral artery disease following peripheral vascular intervention: The Q-PAD Study.

Black patients have a higher prevalence of peripheral artery disease (PAD) than white patients, and also tend to have a greater extent and severity of disease, and poorer outcomes. The association of race with quality of health (QOH) after peripheral vascular intervention (PVI), however, is less well-known. In our study, we hypothesized that after PVI, black patients experience worse QOH than white patients. We retrospectively assessed racial differences in health status using responses to the Peripheral Arterial Questionnaire (PAQ) at baseline (pre-PVI) and up to 6 months following PVI among 387 patients. We used the PAQ summary score (which includes physical limitation, symptoms, social function and quality of life) as a measure of QOH. We compared QOH scores at baseline and at follow-up after PVI between black ( n=132, 34.1%) and white ( n=255, 65.9%) patients. We then computed the change in score from baseline to follow-up for each patient (the delta) and compared the median delta between the two groups. Multivariable regression was used to model the delta QOH after controlling for factors associated with race or with the delta QOH. There was no significant difference in mean QOH by race either at baseline ( p=0.09) or at follow-up ( p=0.45). There was no significant difference in the unadjusted median delta by race (white 25.3 vs black 21.5, p=0.28) and QOH scores improved significantly at follow-up in both groups, albeit the improvement was marginally lower in black compared with white patients after adjustment for baseline confounders ( b = -6.6, p=0.05, 95% CI -13.2, -0.11).

Crosstalk between the vitamin D receptor (VDR) and miR-214 in regulating SuFu, a hedgehog pathway inhibitor in breast cancer cells.

The vitamin D receptor (VDR), and its ligand 1α,25-dihydroxyvitamin D3 (1,25D3) prevent breast cancer development and progression, yet the molecular mechanisms governing this are unclear. MicroRNAs (miRNAs) on the other hand, promote or inhibit breast cancer growth. To understand how VDR regulates miRNAs, we compared miRNA expression of wild-type (WT) and VDR knockout (VDRKO) breast cancer cells by a Mouse Breast Cancer miRNA PCR array. Compared to VDR WT cells, expressions of miR-214, miR-199a-3p and miR-199a-5p of the miR-199a/miR-214 cluster were 42, 15, and 10 fold higher in VDRKO cells respectively. Overexpression of VDR in breast cancer cells reduced the miR-199a/miR-214 cluster expression by 30%. VDR status also negatively correlated with Dnm3os expression, a non-coding RNA transcript of the dynamin-3 gene encoding the miR-199a/miR-214 cluster, suggesting that VDR represses this cluster through Dnm3os. Conversely, overexpression of miR-214 in MCF-7 and T47D cells antagonized VDR mediated signaling. Furthermore, there was a positive correlation between VDR status and the expression of Suppressor of fused gene (SuFu), a hedgehog pathway inhibitor. miR-214 on the other hand suppressed SuFu protein expression. These findings suggest a crosstalk between VDR and miR-214 in regulating hedgehog signaling in breast cancer cells, providing new therapies for breast cancer.

Outcomes of transfemoral transcatheter aortic valve implantation at hospitals with and without on-site cardiac surgery department: insights from the prospective German aortic valve replacement quality assurance registry (AQUA) in 17 919 patients.

AIMS: Performing transcatheter aortic valve implantation (TAVI) at hospitals with only cardiology department but no cardiac surgery (CS) on-site is at great odds with current Guidelines. METHODS AND RESULTS: We analysed data from the official, prospective German Quality Assurance Registry on Aortic Valve Replacement to compare characteristics and in-hospital outcomes of patients undergoing transfemoral TAVI at hospitals with (n = 75) and without CS departments (n = 22). An interdisciplinary Heart Team was established at all centres (internal staff physicians at hospitals with on-site CS; in-house cardiologists and visiting cardiac surgical teams from collaborating hospitals at non-CS hospitals). In 2013 and 2014, 17 919 patients (81.2 ± 6.1 years, 55% females, German aortic valve (GAV) score 2.0 5.6 ± 5.8%, logistic EuroSCORE I 21.1 ± 15.4%) underwent transfemoral TAVI in Germany: 1332 (7.4%) at hospitals without on-site CS department. Patients in non-CS hospitals were older (82.1 ± 5.8 vs. 81.1 ± 6.1 years, P < 0.001), with more frequent co-morbidities. Predicted mortality risks per GAV-score 2.0 (6.1 + 5.5 vs. 5.5 ± 5.9%, P < 0.001) and logEuroSCORE I (23.2 ± 15.8 vs. 21.0 ± 15.4%, P < 0.001) were higher in patients at non-CS sites. Complications, including strokes (2.6 vs. 2.3%, P = 0.452) and in-hospital mortality (3.8 vs. 4.2%, P = 0.396), were similar in both groups. Matched-pair analysis of 555 patients in each group with identical GAV-score confirmed similar rates of intraprocedural complications (9.2 vs. 10.3%, P = 0.543), strokes (3.2% for both groups, P = 1.00), and in-hospital mortality (1.8 vs. 2.9%, P = 0.234). CONCLUSION: Although patients undergoing TAVI at hospitals without on-site CS department were older and at higher predicted perioperative death risk, major complications, and in-hospital mortality were not statistically different, suggesting the feasibility and safety of Heart Team-based TAVI at non-CS sites. These findings need confirmation in future randomized study.