Determining Thresholds for Three Indices of Autoregulation to Identify the Lower Limit of Autoregulation During Cardiac Surgery.

OBJECTIVES: Monitoring cerebral autoregulation may help identify the lower limit of autoregulation in individual patients. Mean arterial blood pressure below lower limit of autoregulation appears to be a risk factor for postoperative acute kidney injury. Cerebral autoregulation can be monitored in real time using correlation approaches. However, the precise thresholds for different cerebral autoregulation indexes that identify the lower limit of autoregulation are unknown. We identified thresholds for intact autoregulation in patients during cardiopulmonary bypass surgery and examined the relevance of these thresholds to postoperative acute kidney injury. DESIGN: A single-center retrospective analysis. SETTING: Tertiary academic medical center. PATIENTS: Data from 59 patients was used to determine precise cerebral autoregulation thresholds for identification of the lower limit of autoregulation. These thresholds were validated in a larger cohort of 226 patients. METHODS AND MAIN RESULTS: Invasive mean arterial blood pressure, cerebral blood flow velocities, regional cortical oxygen saturation, and total hemoglobin were recorded simultaneously. Three cerebral autoregulation indices were calculated, including mean flow index, cerebral oximetry index, and hemoglobin volume index. Cerebral autoregulation curves for the three indices were plotted, and thresholds for each index were used to generate threshold- and index-specific lower limit of autoregulations. A reference lower limit of autoregulation could be identified in 59 patients by plotting cerebral blood flow velocity against mean arterial blood pressure to generate gold-standard Lassen curves. The lower limit of autoregulations defined at each threshold were compared with the gold-standard lower limit of autoregulation determined from Lassen curves. The results identified the following thresholds: mean flow index (0.45), cerebral oximetry index (0.35), and hemoglobin volume index (0.3). We then calculated the product of magnitude and duration of mean arterial blood pressure less than lower limit of autoregulation in a larger cohort of 226 patients. When using the lower limit of autoregulations identified by the optimal thresholds above, mean arterial blood pressure less than lower limit of autoregulation was greater in patients with acute kidney injury than in those without acute kidney injury. CONCLUSIONS: This study identified thresholds of intact and impaired cerebral autoregulation for three indices and showed that mean arterial blood pressure below lower limit of autoregulation is a risk factor for acute kidney injury after cardiac surgery.

The role of anthropogenic habitats in freshwater mussel conservation.

Anthropogenic freshwater habitats may provide undervalued prospects for long-term conservation as part of species conservation planning. This fundamental, but overlooked, issue requires attention considering the pace that humans have been altering natural freshwater ecosystems and the accelerated levels of biodiversity decline in recent decades. We compiled 709 records of freshwater mussels (Bivalvia, Unionida) inhabiting a broad variety of anthropogenic habitat types (from small ponds to large reservoirs and canals) and reviewed their importance as refuges for this faunal group. Most records came from Europe and North America, with a clear dominance of canals and reservoirs. The dataset covered 228 species, including 34 threatened species on the IUCN Red List. We discuss the conservation importance and provide guidance on how these anthropogenic habitats could be managed to provide optimal conservation value to freshwater mussels. This review also shows that some of these habitats may function as ecological traps owing to conflicting management practices or because they act as a sink for some populations. Therefore, anthropogenic habitats should not be seen as a panacea to resolve conservation problems. More information is necessary to better understand the trade-offs between human use and the conservation of freshwater mussels (and other biota) within anthropogenic habitats, given the low number of quantitative studies and the strong biogeographic knowledge bias that persists.

Cerebral autoregulation in the operating room and intensive care unit after cardiac surgery.

BACKGROUND: Cerebral autoregulation monitoring is a proposed method to monitor perfusion during cardiac surgery. However, limited data exist from the ICU as prior studies have focused on intraoperative measurements. Our objective was to characterise cerebral autoregulation during surgery and early ICU care, and as a secondary analysis to explore associations with delirium. METHODS: In patients undergoing cardiac surgery (n=134), cerebral oximetry values and arterial BP were monitored and recorded until the morning after surgery. A moving Pearson's correlation coefficient between mean arterial proessure (MAP) and near-infrared spectroscopy signals generated the cerebral oximetry index (COx). Three metrics were derived: (1) globally impaired autoregulation, (2) MAP time and duration outside limits of autoregulation (MAP dose), and (3) average COx. Delirium was assessed using the 3-Minute Diagnostic Interview for CAM-defined Delirium (3D-CAM) and the Confusion Assessment Method for the ICU (CAM-ICU). Autoregulation metrics were compared using χ2 and rank-sum tests, and associations with delirium were estimated using regression models, adjusted for age, bypass time, and logEuroSCORE. RESULTS: The prevalence of globally impaired autoregulation was higher in the operating room vs ICU (40% vs 13%, P<0.001). The MAP dose outside limits of autoregulation was similar in the operating room and ICU (median 16.9 mm Hg×h; inter-quartile range [IQR] 10.1-38.8 vs 16.9 mm Hg×h; IQR 5.4-35.1, P=0.20). In exploratory adjusted analyses, globally impaired autoregulation in the ICU, but not the operating room, was associated with delirium. The MAP dose outside limits of autoregulation in the operating room and ICU was also associated with delirium. CONCLUSIONS: Metrics of cerebral autoregulation are altered in the ICU, and may be clinically relevant with respect to delirium. Further studies are needed to investigate these findings and determine possible benefits of autoregulation-based MAP targeting in the ICU.

Relationship between endothelial function and vascular stiffness on lower limit of cerebral autoregulation in patients undergoing cardiovascular surgery.

Hemodynamic management based on cerebral autoregulation range is a possible strategy for preserving major organ perfusion during cardiovascular surgery. The purpose of this study was to evaluate the relation of vascular properties with lower limit of cerebral autoregulation (LLA). LLA was monitored in 66 patients undergoing cardiovascular surgery using near-infrared spectroscopy. To determine the clinical importance of LLA monitoring, association of blood pressure excursions below LLA and acute kidney injury (AKI) was evaluated. Flow-mediated dilation (FMD) and pulse wave velocity (PWV) were measured for the evaluation of endothelial function and aortic stiffness. Variables associated with LLA were evaluated. Excluding patients on hemodialysis, there were 15 patients (25.9%) who developed AKI. Blood pressure excursions below LLA were higher in patients who developed AKI (4.55 mm Hg × hr vs. 1.23 mm Hg × hr, P = .017). In the univariate analysis, prevalence of ischemic heart disease (No IHD: 53 ± 13.0 mm Hg vs. IHD: 60.0 ± 13.6 mm Hg, P = .056) and FMD (r = -0.42, 95% CI -0.61 to -0.19, P < .001) were associated with LLA before cardiopulmonary bypass (CPB). During CPB, calcium channel blocker (No Ca blocker: 42 ± 10.6 mm Hg vs. Ca blocker: 49 ± 14.3 mm Hg, P = .033), diabetes (no DM: 44 ± 13.2 mm Hg vs. DM: 55 ± 10.0 mm Hg, P = .024), FMD (r = -0.32, 95% CI -0.55 to -0.05, P = .021), and PWV (r = 0.28, 95% CI 0.012 to 0.513, P = .041) were associated with LLA. Multivariate analysis showed that FMD was correlated with LLA before CPB (r = -2.19, 95% CI -3.621 to -0.755, P = .003), while PWV was correlated with LLA during CPB (r = 0.01, 95% CI 0.001-0.019, P = .023). Endothelial function and aortic stiffness may be important factors in determining LLA at different phases in cardiovascular surgery.

[Anomalous Aortic Origin of a Right Coronary Artery:Report of a Case].

An anomalous right coronary artery originating from the left Valsalva is rare, but sometimes causes sudden cardiac death in a healthy young to middle-aged patient. We present a case of 30-year-old male who was suggested from cardiopulmonary arrest, during playing basketball. He was resuscitated using automated external defibrillator, and was brought to the emergency department. Electrocardiogram showed no ST segment elevation. Coronary angiography and computed tomography revealed anomalous right coronary artery, which originated from the left sinus of Valsalva, and ran between the aorta and the pulmonary artery trunk. Coronary artery bypass grafting was performed using the right internal thoracic arterial graft, with proximal native coronary artery ligation. He was discharged on the nineth postoperative day and had no chest symptoms for seven months.

Endothelial-Specific Overexpression of Histone Deacetylase 2 Protects Mice against Endothelial Dysfunction and Atherosclerosis.

BACKGROUND/AIMS: We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in protecting endothelial cells from oxidized low-density lipoprotein (OxLDL)-induced injury. In this study, we examined the effects of endothelial-specific HDAC2 overexpression on endothelial-dependent vasorelaxation and atherogenesis in vivo. METHODS: Endothelial-specific HDAC2-overexpressing transgenic mice (HDAC2-Tg) were generated under control of the Tie2 promoter. An atherosclerosis model was produced by injecting HDAC2-Tg and wild-type (WT) mice with adeno-associated virus encoding a PCSK9 gain-of-function mutant under control of a liver-specific promoter and feeding them a high-fat diet for 12 weeks. Aortic stiffness in vivo was determined by measuring pulse wave velocity. Wire myography was used to measure endothelium dependent (acetylcholine) and independent (sodium nitroprusside) relaxation in isolated mice aortas. Atherosclerotic plaque burden in aortas was determined by Oil Red O staining and protein expression was determined by western blotting. RESULTS: At baseline, HDAC2-Tg mice had normal mean arterial blood pressure (MAP) and body weight, but pulse wave velocity (PWV), an inverse measure of vascular health and stiffness, was decreased, suggesting that their vessels were more compliant. Moreover, basal nitric oxide production was enhanced in the vessels of HDAC2-Tg mice as compared to that in WT controls, although no significant differences in acetylcholine (endothelial component)- or sodium nitroprusside (non-endothelial component)-mediated relaxation were observed. However, after exposure to OxLDL, aortas from HDAC2-Tg mice exhibited greater acetylcholine-induced relaxation than did those from WT mice. Thus, endothelial-specific vasodilator production was enhanced despite oxidative injury. Atherosclerosis induction in WT mice led to a significant increase in PWV, but in HDAC2-Tg mice, PWV and MAP remained unchanged. Further, aortic rings from HDAC2-Tg exhibited better endothelial-dependent vascular relaxation than did those from WT mice, but not when treated with nitric oxide synthase inhibitor L-NAME. Finally, plaque burden, determined by Oil red O staining, was significantly increased in WT, but not HDAC2-Tg mice, subjected to the atherogenic model. Deletion of endothelial HDAC2 led to impaired endothelial cell-dependent vascular relaxation and increased PWV, compared with those in littermate controls. CONCLUSION: HDAC2 protects against endothelial dysfunction and atherogenesis induced by oxidized lipids. Hence, overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis. HDAC2-Tg mice provide an opportunity to determine the role of endothelial HDAC2 in vascular endothelial homeostasis.

Real-Time Intraoperative Determination and Reporting of Cerebral Autoregulation State Using Near-Infrared Spectroscopy.

BACKGROUND: Cerebral blood flow (CBF) is maintained over a range of blood pressures through cerebral autoregulation (CA). Blood pressure outside the range of CA, or impaired autoregulation, is associated with adverse patient outcomes. Regional oxygen saturation (rSO2) derived from near-infrared spectroscopy (NIRS) can be used as a surrogate CBF for determining CA, but existing methods require a long period of time to calculate CA metrics. We have developed a novel method to determine CA using cotrending of mean arterial pressure (MAP) with rSO2that aims to provide an indication of CA state within 1 minute. We sought to determine the performance of the cotrending method by comparing its CA metrics to data derived from transcranial Doppler (TCD) methods. METHODS: Retrospective data collected from 69 patients undergoing cardiac surgery with cardiopulmonary bypass were used to develop a reference lower limit of CA. TCD-MAP data were plotted to determine the reference lower limit of CA. The investigated method to evaluate CA state is based on the assessment of the instantaneous cotrending relationship between MAP and rSO2 signals. The lower limit of autoregulation (LLA) from the cotrending method was compared to the manual reference derived from TCD. Reliability of the cotrending method was assessed as uptime (defined as the percentage of time that the state of autoregulation could be measured) and time to first post. RESULTS: The proposed method demonstrated minimal mean bias (0.22 mmHg) when compared to the TCD reference. The corresponding limits of agreement were found to be 10.79 mmHg (95% confidence interval [CI], 10.09-11.49) and -10.35 mmHg (95% CI, -9.65 to -11.05). Mean uptime was 99.40% (95% CI, 99.34-99.46) and the mean time to first post was 63 seconds (95% CI, 58-71). CONCLUSIONS: The reported cotrending method rapidly provides metrics associated with CA state for patients undergoing cardiac surgery. A major strength of the proposed method is its near real-time feedback on patient CA state, thus allowing for prompt corrective action to be taken by the clinician.

Functional Outcomes of Frail Patients After Cardiac Surgery: An Observational Study.

BACKGROUND: Although frailty has been associated with major morbidity/mortality and increased length of stay after cardiac surgery, few studies have examined functional outcomes. We hypothesized that frailty would be independently associated with decreased functional status, increased discharge to a nonhome location, and longer duration of hospitalization after cardiac surgery, and that delirium would modify these associations. METHODS: This was an observational study nested in 2 trials, each of which was conducted by the same research team with identical measurement of exposures and outcomes. The Fried frailty scale was measured at baseline. The primary outcome (defined before data collection) was functional decline, defined as ≥2-point decline from baseline in Instrumental Activities of Daily Living (IADL) score at 1 month after surgery. Secondary outcomes were absolute decline in IADL score, discharge to a new nonhome location, and duration of hospitalization. Associations were analyzed using linear, logistic, and Poisson regression models with adjustments for variables considered before analysis (age, gender, race, and logistic European Score for Cardiac Operative Risk Evaluation [EuroSCORE]) and in a propensity score analysis. RESULTS: Data were available from 133 patients (83 from first trial and 50 from the second trial). The prevalence of frailty was 33% (44 of 133). In adjusted models, frail patients had increased odds of functional decline (primary outcome; odds ratio [OR], 2.41 [95% confidence interval {CI}, 1.03-5.63]; P = .04) and greater decline at 1 month in the secondary outcome of absolute IADL score (-1.48 [95% CI, -2.77 to -0.30]; P = .019), compared to nonfrail patients. Delirium significantly modified the association of frailty and change in absolute IADL score at 1 month. In adjusted hypothesis-generating models using secondary outcomes, frail patients had increased discharge to a new nonhome location (OR, 3.25 [95% CI, 1.37-7.69]; P = .007) and increased duration of hospitalization (1.35 days [95% CI, 1.19-1.52]; P < .0001) compared to nonfrail patients. The increased duration of hospitalization, but no change in functional status or discharge location, was partially mediated by increased complications in frail patients. CONCLUSIONS: Frailty may identify patients at risk of functional decline at 1 month after cardiac surgery. Perioperative strategies to optimize frail cardiac surgery patients are needed.

Etiology and impact on outcomes of polycystic kidney disease in abdominal aortic aneurysm.

PURPOSE: We investigated the etiology and impact on outcomes of polycystic kidney disease in patients with abdominal aortic aneurysm. METHODS: Eight-hundred patients who underwent open (n = 603) or endovascular aortic repair (n = 197) were divided into three groups: no cyst (n = 204), non-polycystic kidney (n = 503), and polycystic kidney (≥ 5 cysts in the bilateral kidneys, n = 93). The characteristics and outcomes were compared among the groups. RESULTS: In the polycystic kidney group, the age was increased and the proportions of patients with male sex, hypertension, and estimated glomerular filtration rate < 30 mL/min/1.73 m2 were greater. The overall hospital mortality rates were similar. The incidence of acute kidney injury after elective open aortic repair was increased in the polycystic kidney group (12%, 17%, and 29%, P = 0.020). In the polycystic kidney group, 80 patients did not have renal enlargement or a family history of renal disease, while 13 (corresponding to 1.6% [13/800] of the overall patients), had renal enlargement, suggesting the possibility of hereditary polycystic kidney disease. CONCLUSIONS: In our cohort, 1.6% of the patients with abdominal aortic aneurysm who underwent surgery were at risk of hereditary polycystic kidney disease. Polycystic kidney disease was associated with acute kidney injury after open aortic repair.

Deletion of the microRNA-degrading nuclease, translin/trax, prevents pathogenic vascular stiffness.

Vascular stiffness plays a key role in the pathogenesis of hypertension. Recent studies indicate that the age-associated reduction in miR-181b levels in vascular smooth muscle cells (VSMCs) contributes to increased vascular stiffness. As these findings suggest that inhibiting degradation of miR-181b might prevent vascular stiffening, we have assessed whether the microRNA-degrading translin/trax (TN/TX) complex mediates degradation of miR-181b in the aorta.We found that TN-/- mice display elevated levels of miR-181b expression in the aorta. Therefore, we tested whether TN deletion prevents vascular stiffening in a mouse model of hypertension, induced by chronic high-salt intake (4%NaCl in drinking water for 3 wk; HSW). TN-/- mice subjected to HSW stress do not show increased vascular stiffness, as monitored by pulse wave velocity and tensile testing. The protective effect of TN deletion in the HSW paradigm appears to be mediated by its ability to increase miR-181b in the aorta since HSW decreases levels of miR-181b in WT mice, but not in TN KO mice. We demonstrate for the first time that interfering with microRNA degradation can have a beneficial impact on the vascular system and identify the microRNA-degrading TN/TX RNase complex as a potential therapeutic target in combatting vascular stiffness.NEW & NOTEWORTHY While the biogenesis and mechanism of action of mature microRNA are well understood, much less is known about the regulation of microRNA via degradation. Recent studies have identified the protein complex, translin(TN)/trax(TX), as a microRNA-degrading enzyme. Here, we demonstrate that TN/TX is expressed in vascular smooth muscle cells. Additionally, deletion of the TN/TX complex selectively increases aortic miR-181b and prevents increased vascular stiffness caused by ingestion of high-salt water. To our knowledge, this is first report describing the role of a microRNA RNAse in cardiovascular biology or pathobiology.

Observational Study Examining the Association of Baseline Frailty and Postcardiac Surgery Delirium and Cognitive Change.

BACKGROUND: Frailty is a geriatric syndrome thought to identify the most vulnerable older adults, and morbidity and mortality has been reported to be higher for frail patients after cardiac surgery compared to nonfrail patients. However, the cognitive consequences of frailty after cardiac surgery have not been well described. In this study, we examined the hypothesis that baseline frailty would be associated with postoperative delirium and cognitive change at 1 and 12 months after cardiac surgery. METHODS: This study was nested in 2 trials, each of which was conducted by the same research team with identical measurement of exposures and outcomes. Before surgery, patients were assessed with the validated "Fried" frailty scale, which evaluates 5 domains (shrinking, weakness, exhaustion, low physical activity, and slowed walking speed) and classifies patients as nonfrail, prefrail, and frail. The primary outcome was postoperative delirium during hospitalization, which was assessed using the Confusion Assessment Method, Confusion Assessment Method for the Intensive Care Unit, and validated chart review. Neuropsychological testing was a secondary outcome and was generally performed within 2 weeks of surgery and then 4-6 weeks and 1 year after surgery, and the outcome of interest was change in composite Z-score of the test battery. Associations were analyzed using logistic and linear regression models, with adjustment for variables considered a priori (age, gender, race, education, and logistic European System for Cardiac Operative Risk Evaluation). Multiple imputation was used to account for missing data at the 12-month follow-up. RESULTS: Data were available from 133 patients with baseline frailty assessments. Compared to nonfrail patients (13% delirium incidence), the incidence of delirium was higher in prefrail (48% delirium incidence; risk difference, 35%; 95% CI, 10%-51%) and frail patients (48% delirium incidence; risk difference, 35%; 95% CI, 7%-53%). In both univariable and multivariable models, the odds of delirium were significantly higher for prefrail (adjusted odds ratio, 6.43; 95% CI, 1.31-31.64; P = .02) and frail patients (adjusted odds ratio, 6.31; 95% CI, 1.18-33.74; P = .03) compared to nonfrail patients. The adjusted decline in composite cognitive Z-score was greater from baseline to 1 month only in frail patients compared to nonfrail patients. By 1 year after surgery, there were no differences in the association of baseline frailty with change in cognition. CONCLUSIONS: Compared to nonfrail patients, both prefrail and frail patients were at higher risk for the primary outcome of delirium after cardiac surgery. Frail patients were also at higher risk for the secondary outcome of greater decline in cognition from baseline to 1 month, but not baseline to 1 year, after surgery.

[Hybrid Repair of Distal Arch Aortic Aneurysm:Total Aortic Arch Repair with the Lupiae Vascular Graft and Thoracic Endovascular Aortic Repair;Report of Two Cases].

Surgical treatment for distal arch aortic aneurysm is generally invasive, and there is no definitive approach for it. We report 2 cases of men who was admitted for the treatment of aortic aneurysm. First case is a 78-year-old man. Two saccular aneurysm were observed on distal aortic arch and descending aorta by contrast-enhanced computed tomography. Two staged-repair was performed with using the Lupiae vascular graft and thoracic endovascular aortic repair(TEVAR). The postoperative course was uneventful, and he was discharged on day 21 after 1st operation. Second case is a 68-yearold man. Dessecting aneurysm was observed on distal aortic arch and descending aorta 3 months after incidence of type B aortic dissection. Two staged-repair was performed with using the Lupiae vascular graft and TEVAR. However, additional TEVAR was performed for enlargement of descending aorta half a year after 1st operation. Two staged-repair using Lupiae vascular graft and TEVAR was useful for alleviating a burden of a patient and avoiding paraplegia.

Unionid Freshwater Mussels in Irrigation Ditches are Affected by Physical Environmental Factors and Proximity to Paddy Fields.

Irrigation ditches are the major habitat of lotic unionid mussels in Japan. To conserve and rebuild irrigation ditches facilitating mussel conservation, suitable physical environments must be clarified. The effect on mussels of paddy fields connected to ditches also needs to be determined. In this study, physical environmental factors that affect the density of unionid mussels were studied in irrigation ditches in Hikone City, Shiga Prefecture, Japan, to examine whether mussel densities were higher around paddy fields. Generalized linear models were used to analyze physical and paddy field environmental variables affecting mussel density. Our results show that sediment type, sediment softness, water depth, and flow velocity of irrigation ditches affect the density of unionid mussels; the effects of each environment factor and their relative importance differed by species. Specifically, the density of Nodularia douglasiae biwae was higher in ditches with sand-gravel sediment, soft sediment, and not adjoining paddy fields. The density of Pronodularia japanensis was higher in ditches with sand-gravel sediment and not adjoining paddy fields. The density of Lanceolaria grayana was higher in ditches with high flow velocity, not adjoining paddy fields, close to Lake Biwa. The density of Sinanodonta japonica was higher in ditches with mud sediment, shallow depth, high flow velocity, and not adjoining paddy fields. The densities of all four species were lower in irrigation ditches that were closely connected to paddy fields, suggesting that paddy drainage water negatively affects the survival of the mussels.

Strategic 2-step surgery using thoracic endovascular aortic repair for an infected thoracic aortic aneurysm.

An 81-year-old man with multiple comorbidities developed infected thoracic aortic aneurysm, and we employed a strategic 2-step surgical approach combining thoracic endovascular aortic repair and local debridement with an omental flap during the active phase of infection. No signs of reinfection were observed at the 1-year follow-up. This strategy can be a safe and less invasive alternative to conventional open surgery in patients with high surgical risk.

Cardiopulmonary Bypass Surgery in a Patient with Unexpected Heparin-Induced Thrombocytopenia.

We report a case of a 77-year-old woman with massive pulmonary embolism associated with heparin-induced thrombocytopenia. Before developing a pulmonary embolism, the patient underwent gastrectomy due to gastric cancer and received subcutaneous heparin calcium for deep venous thrombosis prophylaxis for 5 d. Then, thrombectomy with cardiopulmonary bypass using full heparinization was successfully performed. The patient was definitively diagnosed with this condition postoperatively, based on elevated serum antibody levels, in addition to pre- and postoperative thrombocytopenia and thrombosis. Intravenous heparin therapy was switched to argatroban. Although it is uncommon, clinicians should consider this condition in patients with a history of heparin exposure.

Inhibition of HDAC6 Activity Protects Against Endothelial Dysfunction and Atherogenesis in vivo: A Role for HDAC6 Neddylation.

We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) function in vitro. However, whether HDAC6 plays a role in atherogenesis in vivo and the mechanism(s) that control HDAC6 activity/expression in response to atherogenic stimuli are unclear. The goals of this study were to determine whether HDAC6 inhibitor tubacin attenuates atherogenesis and to elucidate specific molecular mechanism(s) that regulate endothelial HDAC6 expression/activity. We evaluated whether administration of tubacin attenuated or reversed the endothelial dysfunction and atherosclerosis induced in mice by a single intraperitoneal injection of adeno-associated viruses encoding liver-target PCSK9 gain-of-function mutant followed by a high fat diet (HFD) for 18 weeks. Tubacin significantly blunted PCSK9-induced increases in pulse wave velocity (index of vascular stiffness and overall vascular health) that are also seen in atherogenic mice. Furthermore, tubacin protected vessels from defective vasorelaxation, as evaluated by acetylcholine-mediated relaxation using wire myograph. Plaque burden defined by Oil Red O staining was also found to be significantly less in mice that received tubacin than in those that received PCSK9 alone. Inhibition of the NEDDylation pathway with MLN4924, an inhibitor of NEDD8-activating enzyme 1 (NAE1), significantly increased HDAC6 activity in HAECs. Interestingly, HDAC6 expression remained unchanged. Further, HAECs exposed to the atherogenic stimulus oxidized low-density lipoprotein (OxLDL) exhibited enhanced HDAC6 activity, which was attenuated by pretreatment with MLN4924. The HDAC6 NEDDylation molecular pathway might regulate genes related to endothelial control of vasomotor tone, reactivity, and atherosclerosis. Tubacin may represent a novel pharmacologic intervention for atherogenesis and other vasculopathies.

The association of bispectral index values and metrics of cerebral perfusion during cardiopulmonary bypass.

STUDY OBJECTIVE: Low bispectral index (BIS) values have been associated with adverse postoperative outcomes. However, trials of optimizing BIS by titrating anesthetic administration have reported conflicting results. One potential explanation is that cerebral perfusion may also affect BIS, but the extent of this relationship is not clear. Therefore, we examined whether BIS would be associated with cerebral perfusion during cardiopulmonary bypass, when anesthetic concentration was constant. DESIGN: Observational cohort study. SETTING: Cardiac operating room. PATIENTS: Seventy-nine patients with cardiopulmonary bypass surgery were included. MEASUREMENTS: Continuous BIS, mean arterial blood pressure (MAP), cerebral blood flow velocity (CBFV), and regional cerebral oxygen saturation (rSO2) were monitored, with analysis during a period of constant anesthetic. Mean flow index (Mx) was calculated as Pearson correlation between MAP and CBFV. The lower limit of autoregulation (LLA) was identified as the MAP value at which Mx increased >0.4 with decreasing blood pressure. Postoperative delirium was assessed using the 3D-Confusion Assessment Method. RESULTS: Mean BIS was lower during periods of MAP < LLA compared with BIS when MAP>LLA (mean 49.35 ± 10.40 vs. 50.72 ± 10.04, p = 0.002, mean difference = 1.38 [standard error: 0.42]). There was a dose response effect, with the BIS proportionately decreasing as MAP decreased below LLA (ß = 0.15, 95% CI for the average slope across all patients 0.07 to 0.23, p < 0.001). In contrast, BIS was relatively unchanged when MAP was above LLA (ß = 0.03, 95% CI for the average slope across all patients -0.02 to 0.09, p = 0.22). Additionally, increasing CBFV and rSO2 were associated with increasing BIS. Patients with postoperative delirium had lower mean BIS and higher percentage of time duration with BIS <45 compared to patients without delirium. CONCLUSIONS: There was an association of BIS and metrics of cerebral perfusion during a period of constant anesthetic administration, but the absolute magnitude of change in BIS as MAP decreased below the LLA was small.

Degradation of Premature-miR-181b by the Translin/Trax RNase Increases Vascular Smooth Muscle Cell Stiffness.

[Figure: see text].

Predictors of Acute Kidney Injury Following Elective Open and Endovascular Aortic Repair for Abdominal Aortic Aneurysm.

Objective: To investigate the predictors of acute kidney injury (AKI) following surgery for abdominal aortic aneurysm. Materials and Methods: Subjects were 642 non-hemodialysis patients (open aortic repair [OAR] group, n=453; endovascular aortic repair [EVAR] group, n=189) who underwent elective surgery between 2009 and 2015. AKI was assessed according to the Kidney Disease Improving Global Outcomes criteria. In-hospital mortality and incidence of AKI were compared between the OAR and EVAR groups. The effect of AKI on outcomes and predictors of AKI were examined in both groups. Results: In-hospital mortalities were 0.7% (3/453) in the OAR group and 0.5% (1/189) in the EVAR group. The incidence of AKI increased in the OAR group (14.1% vs. 3.7%, P<0.01). In the OAR group, in-hospital mortality (0% vs. 4.7%, P<0.01) increased in patients with AKI. In the OAR group, hemoglobin level <10 g/dL, estimated glomerular filtration rate <60 mL/min/1.73 m2, operation time >300 min, history of ischemic heart disease, and amount of bleeding >1,000 mL were predictors of AKI. In the EVAR group, amount of transfusion>1,000 mL was a predictor of AKI, but AKI was not found to worsen outcomes. Conclusion: AKI affected outcomes of OAR. Knowledge of predictors may optimize perioperative care.

Characteristics of Abdominal Aortic Aneurysm in Japanese Patients Aged 50 Years or Younger.

Objective: We investigated the characteristics and surgical outcomes of abdominal aortic aneurysm (AAA), which typically occurs in elderly persons, in Japanese patients aged 50 years or younger. Materials and Methods: Clinical records of 999 patients who underwent open or endovascular repair for AAA at our hospital between 2007 and 2015 were reviewed to identify the clinical characteristics and surgical outcomes of young patients with AAA. The cohort included 14 patients aged 50 years or younger (mean, 40.4 years; young group) and 985 patients aged older than 50 years (mean, 72.8 years; old group). Results: Marfan syndrome, prior aortic dissection, and a history of aortic surgery were more prevalent in the young group, and 50% of the patients in the young group had dissecting aneurysms. All patients in the young group underwent open repair. Overall in-hospital mortality rates were 7.1% (1/14) and 1.9% (19/985) in the young and old groups, respectively (P=0.67). Seven-year survival and aortic event-free survival rates in the young group were 82.5%±11.5%, and 71.2±14.5%, respectively. Conclusion: AAA in patients aged 50 years or younger tended to be associated with Marfan syndrome, a history of aortic surgery, and prior aortic dissection. Early outcomes of AAA among young patients are acceptable, but close postoperative monitoring is important.