Morphologic prognostic factor for thoracoabdominal aortic dilation after acute type A dissection repair.

OBJECTIVES: Risk factors for late-term aortic dilation after acute type A aortic dissection repair have not been well examined. The goal of this study was to determine the relationship between the abdominal aortic true lumen location and thoraco-abdominal aortic dilation after surgical repair for acute type A aortic dissection. METHODS: Patients who were preoperatively diagnosed with acute type A aortic dissection between April 2014 and July 2022 were included in this study. We evaluated the renal artery-level dissected aortic morphology and classified the study population into 2 groups: the ventral (those with the true lumen located on the ventral side) and the dorsal (other patients not assigned to the ventral group) groups, based on the location of the true lumen. Aortic dilation was defined as thoraco-abdominal aortic expansion ≥5 mm on 1-year postoperative computed tomography images. RESULTS: We examined 49 surgical patients who were assigned to the ventral (n = 22) and dorsal (n = 27) groups. The number of patients with ≥5 mm thoraco-abdominal aortic dilation after the operation was significantly higher in the ventral group than in the dorsal group (90.9% vs 51.9%, P = 0.009). The multivariable logistic regression analysis showed that the ventral type was an independent prognostic factor for thoraco-abdominal aortic dilation after the operation (odds ratio, 6.01; 95% confidence interval, 1.56-23.77; P = 0.009). CONCLUSIONS: The location of the true lumen of the abdominal aorta in acute type A aortic dissection may be a prognostic factor for thoraco-abdominal aortic dilation after surgical repair.

The effect of balloon-expandable stent and self-expanding stent on changes in mitral annular motion after aortic valve replacement in patients with aortic stenosis.

OBJECTIVES: The purpose of this study was to evaluate the effect of decalcification and existence of stent at the aortic annulus on mitral annular motion after surgery. METHODS: Patients receiving Inspiris (Edwards, CA, USA, n = 117), Intuity (Edwards, n = 36), Perceval (Corcym, London, UK, n = 36), Evolut (Medtronics, MN, USA, n = 81) and Sapien 3 (Edwards, n = 250) were included in the study. Mitral annular motion was evaluated by E', using tissue doppler imaging. RESULTS: After surgery, a significant increase in E' was observed in patients receiving Inspiris (Before: 4.2 ± 1.21 cm/s vs. Discharge: 5.0 ± 1.23 cm/s, p < 0.001). Mid-term echocardiogram performed at 11.8 ± 2.2 months after the surgery, showed a significant increase in E' in patients receiving Inspiris (Before: 4.2 ± 1.21 cm/s vs. Mid-term: 5.2 ± 1.20 cm/s, p < 0.001) and Perceval (Before: 3.9 ± 1.34 cm/s vs. Mid-term: 4.5 ± 1.24 cm/s, p = 0.008). Univariable analysis showed a higher increase in E' in patients with decalcified annulus compared to those without decalcified annulus (Decalcification: 0.15 ± 1.321 cm/s vs. No Decalcification: 0.66 ± 1.420 cm/s, p < 0.001). Multivariable analysis showed that balloon-expandable stent (ß = - 0.6960, p < 0.001) and self-expanding stent (r = - 0.3592, p = 0.042) were independent limiting factors for an increase in E' at discharge. However, balloon-expandable stent (ß = - 0.8382, p < 0.001), and not self-expanding stent (ß = - 0.3682, p = 0.089), was a remaining independent factor associated with E' at mid-term follow-up. CONCLUSIONS: Decalcification was associated with improvement in E' after surgery. Balloon-expandable stent was an independent limiting factor for improvement in E' up to 1 year after the surgery, while self-expanding stent was not a significant factor after 1 year.

The effect of stent and decalcification on mitral annular motion after aortic valve replacement.

OBJECTIVE: The purpose of this study was to evaluate the changes in mitral annular motion after surgery in patients with aortic stenosis. METHODS: Patients receiving Edwards (Edwards) valves were included in the study. Echocardiographic findings were compared among the three treatments postoperatively, at discharge, and at 1 year after the surgery. Mitral annular motion was evaluated by e prime, using tissue doppler imaging. RESULTS: There were 111 patients receiving Inspiris, 30 patients receiving Intuity and 241 patients receiving Sapien 3. The patients receiving Sapien 3 were significantly older, (Inspiris: 71 ± 6.7 years vs. Intuity: 75 ± 5.2 years vs. Sapien 3: 84 ± 5.1 years, p < .001), and prevalence of hemodialysis were significantly higher in patients receiving Intuity (Inspiris: 11.7% vs. Intuity: 46.7% vs. Sapien 3: 0.0%, p < .001). There was a significant improvement in mean pressure gradient in all groups (Inspiris: 55 ± 21.2-13 ± 5.2 mmHg, p < .001; Intuity: 48 ± 17.6-12 ± 4.9 mmHg, p < .001, Sapien 3: 55 ± 16.6-14 ± 5.2 mmHg, p < .001). Decalcification was associated with increase in e prime after surgery (no decalcification: 0.10 ± 1.280 cm/s vs. decalcification: 0.68 ± 1.405 cm/s, p < .001) Further, existence of stent was associated with less increase in e prime after surgery (no stent: 0.83 ± 1.210 cm/s vs. stent: 0.10 ± 1.356; p < .001). Multivariate analysis showed that existence of stent but not decalcification of the aortic valve was independently associated with changes in e prime after surgery (ß: -.4679, 95% confidence interval: -0.93389 to -0.00200, p = .049). CONCLUSIONS: Although improvement in pressure gradient was achieved in all treatments, existence of stent inhibited mitral annular motion after surgery.

[Subacute Pseudoaneurysm Formation after Sutureless Repair for Postinfarction Left Ventricular Rupture:Report of a Case].

A 71-year-old woman was admitted for cardiac tamponade due to left ventricular free wall rupture after acute myocardial infarction. Sutureless repair was performed for bleeding from the inferior wall. Fifteen days later, computed tomography demonstrated enlargement of a left ventricular pseudoaneurysm. Patch closure using a vascular prosthesis was performed through left thoracotomy. No recurrence of the left ventricular aneurysm has been observed since.

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.

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.

Comparison of long-term outcomes after trans-catheter aortic valve implantation between patients primarily diagnosed by cardiac murmur and those diagnosed by other reasons.

Careful auscultation is the first step to diagnose aortic stenosis (AS). The aim of this study was to compare clinical outcomes following transcatheter aortic valve implantation (TAVI) between the patients primarily diagnosed by heart murmur and those diagnosed by other reasons. We retrospectively included 258 patients who underwent TAVI in our medical center, and divided those into the murmur group (n = 81) and the other-reason group (n = 177) according to the primary reason for AS diagnosis. The primary endpoint was the major adverse cardiovascular and cerebrovascular events (MACCE), which was defined as the composite of cardiovascular death, hospitalization due to acute decompensated heart failure, and disabling stroke. The murmur group included younger patients than the other-reason group (82.8 year-old vs. 84.0 year-old, P = 0.02). History of AF was more frequently observed in the other-reason group than in the murmur group (21.5% vs. 7.4%, P <0.01). STS score and logistic EuroSCORE were lower in the murmur group than in the other-reason group (STS: 4.7% vs. 7.2%, P <0.01, logistic EuroSCORE: 8.3% vs. 11.2%, P <0.01). The median follow-up period was 562 days. MACCE was more frequently observed in the other-reason group than in the murmur group (27.7% vs. 9.9%, Log Rank P <0.01). The multivariate COX hazard analysis revealed that the AS patients primarily diagnosed by heart murmur was inversely associated with MACCE (HR 0.38, 95%CI 0.17-0.86, P = 0.020). Among AS patients who underwent TAVI, the patients primarily diagnosed by heart murmur were significantly associated with favorable long-term clinical outcomes.

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.

Personalized Blood Pressure Management During Cardiac Surgery With Cerebral Autoregulation Monitoring: A Randomized Trial.

The purpose of this study was to determine if setting mean arterial pressure (MAP) targets during cardiopulmonary bypass (CPB) based on individualized cerebral autoregulation data reduces the frequency of neurological complications compared with usual care. Patients (n = 460) ≥ 55 years old at risk for neurological complications were randomized to have MAP targets during CPB to be above the lower limit of transcranial Doppler determined cerebral autoregulation versus usual institutional practices. The primary outcome was the frequency of the composite endpoint of clinical stroke, or new brain magnetic resonance imaging-detected ischemic injury, or cognitive decline 4-6 weeks after surgery from baseline. Secondary outcomes were components of the primary composite outcome and clinically detected delirium. Complete outcome data were available from 194 patients (stroke assessments, n = 460; magnetic resonance imaging data, n = 164; cognitive data n = 336). There was no difference between groups in the frequency of the composite neurological end-point or its components (P = 0.752). Compared with the usual care there was a 45% reduction in the frequency of clinically detected delirium in the autoregulation group (8.2% vs 14.9%, risk ratio = 0.55, 95% confidence interval = 0.32, 0.93, P = 0.035) and improved performance on test of memory 4-6 weeks after surgery from baseline (P = 0.019). Basing MAP during CPB on cerebral autoregulation monitoring did not reduce the frequency of the primary neurological outcome in high-risk patients compared with usual care but it was associated with a reduction in the frequency of delirium and better performance on tests of memory 4-6 weeks after surgery.

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.

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.

[Bioprosthetic Mitral Valve Thrombosis in Patient with Antiphospholipid Antibody Syndrome;Report of a Case].

A 66-year-old woman with primary antiphospholipid antibody syndrome (APS) was admitted due to severe dyspnea. Eight months prior to admission, she underwent bioprosthetic mitral valve replacement for mitral valve stenosis and regurgitation. Transthoracic echocardiogram showed thickening bioprosthetic valve leaflets and severe valve stenosis. Emergency reoperation for artificial valve failure was performed. The explanted bioprosthetic valve showed massive thrombus formation. After the operation, she started strict anticoagulant and antiplatelet therapies and was discharged without recurrence of valve thrombosis.

Improved cytosolic delivery of macromolecules through dimerization of attenuated lytic peptides.

Intracellular delivery of biomacromolecules is a challenging research field in chemical biology and drug delivery. We previously reported a peptide named L17E, which successfully delivered functional proteins, including antibodies, into cells. However, relatively high concentrations of L17E and proteins are needed. In this study, we prepared dimers of L17E and its analog L17E/Q21E. Dimerization of L17E increased cytotoxicity leading to reduced intracellular delivery compared with L17E. On the other hand, the dimers of the L17E analog, L17E/Q21E, especially when tethered at the N-termini, yielded a comparable level of intracellular delivery with L17E at decreased amounts of delivery peptides and cargoes.

Effect of Transcatheter Aortic Valve Implantation on the Immune Response Associated With Surgical Aortic Valve Replacement.

The immune response after transcatheter aortic valve implantation (TAVI) in comparison to that after surgical aortic valve replacement (SAVR) remains to be fully elucidated. In a 2-part study, we assessed laboratory data obtained before, immediately after, and 24 and 48 hours after SAVR (128 patients; age ≥80 [mean 82] years) or transfemoral TAVI (102 patients; age ≥80 [mean 86] years) performed for aortic stenosis. In-hospital mortalities were similar (3% vs 0%), but leukocyte counts and aspartate aminotransferase and creatine kinas concentrations were decreased immediately and 24 hours after surgery (all, p <0.001). We performed cytokine profiling in a SAVR group (11 patients; mean age, 77 years) and transfemoral TAVI group (12 patients; mean age, 84 years). By measuring normalized concentrations of 71 cytokines at 3 time points, we found a significant difference (defined as fold change >1.7 and p <0.05 [by Mann-Whitney U-test]) in 23 cytokines. The differentially expressed cytokines fell into 3 hierarchical clusters: cluster A (high increase after SAVR and suppressed increase after TAVI only immediately after surgery [CCL2, CCL4, and 2 others]), cluster B (high increase after SAVR and suppressed increase after TAVI at 2 time points [IL-1Ra, IL-6, IL-8, IL-10, and 5 others]), and cluster C (various patterns [TRAIL, CCL11, and 8 others]). Gene enrichment analysis identified multiple pathways associated with the inflammatory responses in SAVR and altered responses in TAVI, including cellular responses to tumor necrosis factor (p = 0.0035) and interleukin-1 (p = 0.0062). In conclusion, a robust inflammatory response follows SAVR, and a comparatively attenuated response follows TAVI.

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.

miR-181c Activates Mitochondrial Calcium Uptake by Regulating MICU1 in the Heart.

Background Translocation of miR-181c into cardiac mitochondria downregulates the mitochondrial gene, mt-COX1. miR-181c/d-/- hearts experience less oxidative stress during ischemia/reperfusion (I/R) and are protected against I/R injury. Additionally, miR-181c overexpression can increase mitochondrial matrix Ca2+ ([Ca2+]m), but the mechanism by which miR-181c regulates [Ca2+]m is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR-181c/d-/- mice overexpress nuclear-encoded Ca2+ regulatory and metabolic pathway genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca2+]m regulation. Quantitative polymerase chain reaction validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 (specificity protein) expression in the miR-181c/d-/- hearts. Furthermore, an association of Sp1 with the promoter region of MICU1 was confirmed by chromatin immunoprecipitation-quantitative polymerase chain reaction and higher expression of MICU1 was found in the miR-181c/d-/- hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca2+]m via the miR-181c/MICU1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU1 was knocked down in the miR-181c/d-/- heart by lentiviral expression of a short-hairpin RNA against MICU1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR-181c/d-/- neonatal mouse ventricular myocytes, we confirmed the contribution of both Sp1 and MICU1 in ischemic injury. Conclusions miR-181c regulates mt-COX1, which in turn regulates MICU1 expression through the Sp1-mediated mitochondria-to-nucleus retrograde pathway. Loss of miR-181c can protect the heart from I/R injury by modulating [Ca2+]m through the upregulation of MICU1.

Appetite Predicts Clinical Outcomes in High Risk Patients Undergoing Trans-Femoral TAVI.

Transcatheter aortic valve implantation (TAVI) has been recognized as a standard therapy for severe aortic valve stenosis. However, since some patients who receive TAVI have poor outcomes, the predictors of clinical outcomes after TAVI are important. The aim of this study was to investigate the association between appetite and long-term clinical outcomes.We screened consecutive cases who received TAVI at our medical center between July 2014 and October 2018. A total of 139 patients who received transfemoral TAVI were included as the final study population. They were divided into a good appetite group (n = 105) and a less appetite group (n = 34) according to their dietary intake rate (> 90%: good appetite group, ≤ 90%: less appetite group). We defined the intake rate as the average for breakfast, lunch, and dinner on the day just before discharge. We defined two-year major adverse cardiovascular and cerebrovascular events (MACCE) as a composite of cardiovascular death, myocardial infarction, any coronary revascularization, history of hospitalization due to heart failure, and disabling acute cerebral infarction. Kaplan-Meier analyses and multivariate Cox regression analysis were performed.The median duration of the follow-up period was 372 (189-720) days. Kaplan-Meier curves showed that the less appetite group got MACCE more frequently (event free rate of the less appetite group: 76.5% versus the good appetite group: 94.3%, Log Rank P = 0.01). In multivariate Cox regression analysis, having less appetite was a significant predictor of two-year MACCE (HR 5.26, 95%CI 1.66-16.71, P < 0.01).In conclusion, among the patients who received transfemoral TAVI, appetite status just before discharge was significantly associated with long-term outcome.

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.

Effect of Targeting Mean Arterial Pressure During Cardiopulmonary Bypass by Monitoring Cerebral Autoregulation on Postsurgical Delirium Among Older Patients: A Nested Randomized Clinical Trial.

Importance: Delirium occurs in up to 52% of patients after cardiac surgery and may result from changes in cerebral perfusion. Using intraoperative cerebral autoregulation monitoring to individualize and optimize cerebral perfusion may be a useful strategy to reduce the incidence of delirium after cardiac surgery. Objective: To determine whether targeting mean arterial pressure during cardiopulmonary bypass (CPB) using cerebral autoregulation monitoring reduces the incidence of delirium compared with usual care. Design, Setting, and Participants: This randomized clinical trial nested within a larger trial enrolled patients older than 55 years who underwent nonemergency cardiac surgery at a single US academic medical center between October 11, 2012, and May 10, 2016, and had a high risk for neurologic complications. Patients, physicians, and outcome assessors were masked to the assigned intervention. A total of 2764 patients were screened, and 199 were eligible for analysis in this study. Intervention: In the intervention group, the patient's lower limit of cerebral autoregulation was identified during surgery before CPB. On CPB, the patient's mean arterial pressure was targeted to be greater than that patient's lower limit of autoregulation. In the control group, mean arterial pressure targets were determined according to institutional practice. Main Outcomes and Measures: The main outcome was any incidence of delirium on postoperative days 1 through 4, as adjudicated by a consensus expert panel. Results: Among the 199 participants in this study, mean (SD) age was 70.3 (7.5) years and 150 (75.4%) were male. One hundred sixty-two (81.4%) were white, 26 (13.1%) were black, and 11 (5.5%) were of other race. Of 103 patients randomized to usual care, 94 were analyzed, and of 102 patients randomized to the intervention 105 were analyzed. Excluding 5 patients with coma, delirium occurred in 48 of the 91 patients (53%) in the usual care group compared with 39 of the 103 patients (38%) in the intervention group (P = .04). The odds of delirium were reduced by 45% in patients randomized to the autoregulation group (odds ratio, 0.55; 95% CI, 0.31-0.97; P = .04). Conclusions and Relevance: The results of this study suggest that optimizing mean arterial pressure to be greater than the individual patient's lower limit of cerebral autoregulation during CPB may reduce the incidence of delirium after cardiac surgery, but further study is needed. Trial Registration: ClinicalTrials.gov identifier: NCT00981474.

Perioperative factors associated with aneurysm sac size changes after endovascular aneurysm repair.

PURPOSE: To identify the perioperative factors associated with aneurysm size changes after endovascular aortic aneurysm repair (EVAR). METHODS: Between August, 2008 and December, 2014, 187 patients underwent EVAR treatment in our institution. The subjects of this study were 135 of these patients without peripheral artery disease, who were followed up with computed tomography (CT) for 3 years. Significant aneurysm size change was defined as sac size change of more than 5 mm from the baseline. RESULTS: Sac enlargement was identified in 25 patients (18.5%) and sac shrinkage was identified in 59 (43.7%) patients. The factors associated with sac enlargement were postoperative pulse wave velocity (OR: odds ratio 3.80, p = 0.047), prevalence of a type 2 endoleak 1 week after surgery (OR 4.26, p = 0.022), inner diameter (OR 1.10, p = 0.005), and distance from the lower renal artery to the terminal aorta (OR 1.05, p = 0.017). The factors associated with sac shrinkage were prevalence of a type 2 endoleak (OR 0.09, p < 0.001) and preoperative pulse wave velocity (OR 0.32, p = 0.022). The factors independently associated with type 2 endoleak were the use of an Excluder device (OR 3.99, p = 0.002) and the length of the aneurysm (OR 1.02, p = 0.027). CONCLUSION: Inner diameter, treatment length, perioperative pulse wave velocity, and type 2 endoleak were associated with sac size changes after EVAR.