Publications by authors named "Yohei Nomura"

40 Publications

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

Kyobu Geka 2021 Sep;74(9):697-700

Department of Cardiovascular Surgery, Jichi Medical University Saitama Medical Center, Saitama, Japan.

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.
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September 2021

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

Front Physiol 2021 17;12:675724. Epub 2021 Jun 17.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States.

We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) function . However, whether HDAC6 plays a role in atherogenesis 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.
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http://dx.doi.org/10.3389/fphys.2021.675724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245780PMC
June 2021

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

Br J Anaesth 2021 May 23;126(5):967-974. Epub 2021 Mar 23.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

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 χ 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.
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http://dx.doi.org/10.1016/j.bja.2020.12.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132879PMC
May 2021

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

PLoS One 2021 19;16(2):e0247588. Epub 2021 Feb 19.

Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247588PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895360PMC
August 2021

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

Artif Organs 2021 Apr 15;45(4):382-389. Epub 2020 Dec 15.

Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

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.
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http://dx.doi.org/10.1111/aor.13868DOI Listing
April 2021

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

Semin Thorac Cardiovasc Surg 2021 Summer;33(2):429-438. Epub 2020 Nov 10.

Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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.
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http://dx.doi.org/10.1053/j.semtcvs.2020.09.032DOI Listing
July 2021

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

Anesth Analg 2020 11;131(5):1520-1528

From the Medtronic Respiratory & Monitoring Solutions, Edinburgh, United Kingdom.

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.
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http://dx.doi.org/10.1213/ANE.0000000000004614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319873PMC
November 2020

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

Cell Physiol Biochem 2020 Sep;54(5):947-958

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA,

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.
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http://dx.doi.org/10.33594/000000280DOI Listing
September 2020

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

Kyobu Geka 2020 Aug;73(8):619-622

Department of Cardiovascular Surgery, Jichi Medical University Saitama Medical Center, Saitama, Japan.

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.
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August 2020

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

Bioorg Med Chem Lett 2020 09 20;30(17):127362. Epub 2020 Jun 20.

Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bmcl.2020.127362DOI Listing
September 2020

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

Am J Cardiol 2020 08 14;128:35-44. Epub 2020 May 14.

Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.

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.
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http://dx.doi.org/10.1016/j.amjcard.2020.04.037DOI Listing
August 2020

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

Anesth Analg 2020 06;130(6):1534-1544

Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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.
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http://dx.doi.org/10.1213/ANE.0000000000004786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641106PMC
June 2020

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

J Am Heart Assoc 2019 12 5;8(24):e012919. Epub 2019 Dec 5.

Department of Pathology Johns Hopkins School of Medicine Baltimore MD.

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 Ca ([Ca]), but the mechanism by which miR-181c regulates [Ca] is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR-181c/d mice overexpress nuclear-encoded Ca regulatory and metabolic pathway genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca] 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 [Ca] 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 [Ca] through the upregulation of MICU1.
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http://dx.doi.org/10.1161/JAHA.119.012919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951067PMC
December 2019

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

Int Heart J 2019 Nov 15;60(6):1350-1357. Epub 2019 Nov 15.

Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University.

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.
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http://dx.doi.org/10.1536/ihj.19-258DOI Listing
November 2019

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

Am J Physiol Heart Circ Physiol 2019 11 18;317(5):H1116-H1124. Epub 2019 Oct 18.

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.

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. 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.
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http://dx.doi.org/10.1152/ajpheart.00153.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879913PMC
November 2019

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

JAMA Surg 2019 09;154(9):819-826

Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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.
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http://dx.doi.org/10.1001/jamasurg.2019.1163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537779PMC
September 2019

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

Anesth Analg 2019 08;129(2):507-514

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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.
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http://dx.doi.org/10.1213/ANE.0000000000003967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243370PMC
August 2019

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

Surg Today 2019 Feb 12;49(2):130-136. Epub 2018 Sep 12.

Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, Japan.

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.
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http://dx.doi.org/10.1007/s00595-018-1714-zDOI Listing
February 2019

Cognitive Decline after Delirium in Patients Undergoing Cardiac Surgery.

Anesthesiology 2018 09;129(3):406-416

From the Department of Anesthesiology and Critical Care Medicine (C.H.B., R.H., M.P.) Department of Surgery (Y.N., K.Z., K.M.) Department of Psychiatry and Behavioral Sciences (V.K., K.J.N.) Johns Hopkins University School of Medicine, Baltimore, Maryland; New York University School of Medicine, New York, New York (J.P.) Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (A.Y.) Biostatistics Consulting Center, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (J.T.) Department of Anesthesiology and Critical Care Medicine, Northwestern Feinberg School of Medicine, Chicago, Illinois (C.W.H.).

What We Already Know About This Topic: Cardiac surgery is associated with cognitive decline and postoperative delirium. The relationship between postoperative delirium and cognitive decline after cardiac surgery is unclear

What This Article Tells Us That Is New: The development of postoperative delirium is associated with a greater degree of cognitive decline 1 month after cardiac surgery. The development of postoperative delirium is not a predictor of cognitive decline 1 yr after cardiac surgery.

Background: Delirium is common after cardiac surgery and has been associated with morbidity, mortality, and cognitive decline. However, there are conflicting reports on the magnitude, trajectory, and domains of cognitive change that might be affected. The authors hypothesized that patients with delirium would experience greater cognitive decline at 1 month and 1 yr after cardiac surgery compared to those without delirium.

Methods: Patients who underwent coronary artery bypass and/or valve surgery with cardiopulmonary bypass were eligible for this cohort study. Delirium was assessed with the Confusion Assessment Method. A neuropsychologic battery was administered before surgery, at 1 month, and at 1 yr later. Linear regression was used to examine the association between delirium and change in composite cognitive Z score from baseline to 1 month (primary outcome). Secondary outcomes were domain-specific changes at 1 month and composite and domain-specific changes at 1 yr.

Results: The incidence of delirium in 142 patients was 53.5%. Patients with delirium had greater decline in composite cognitive Z score at 1 month (greater decline by -0.29; 95% CI, -0.54 to -0.05; P = 0.020) and in the domains of visuoconstruction and processing speed. From baseline to 1 yr, there was no difference between delirious and nondelirious patients with respect to change in composite cognitive Z score, although greater decline in processing speed persisted among the delirious patients.

Conclusions: Patients who developed delirium had greater decline in a composite measure of cognition and in visuoconstruction and processing speed domains at 1 month. The differences in cognitive change by delirium were not significant at 1 yr, with the exception of processing speed.
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http://dx.doi.org/10.1097/ALN.0000000000002253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513020PMC
September 2018

Cerebral Small Vessel, But Not Large Vessel Disease, Is Associated With Impaired Cerebral Autoregulation During Cardiopulmonary Bypass: A Retrospective Cohort Study.

Anesth Analg 2018 12;127(6):1314-1322

Anesthesiology and the Bluhm Cardiovascular Institute and.

Background: Impaired cerebral blood flow (CBF) autoregulation during cardiopulmonary bypass (CPB) is associated with stroke and other adverse outcomes. Large and small arterial stenosis is prevalent in patients undergoing cardiac surgery. We hypothesize that large and/or small vessel cerebral arterial disease is associated with impaired cerebral autoregulation during CPB.

Methods: A retrospective cohort analysis of data from 346 patients undergoing cardiac surgery with CPB enrolled in an ongoing prospectively randomized clinical trial of autoregulation monitoring were evaluated. The study protocol included preoperative transcranial Doppler (TCD) evaluation of major cerebral artery flow velocity by a trained vascular technician and brain magnetic resonance imaging (MRI) between postoperative days 3 and 5. Brain MRI images were evaluated for chronic white matter hyperintensities (WMHI) by a vascular neurologist blinded to autoregulation data. "Large vessel" cerebral vascular disease was defined by the presence of characteristic TCD changes associated with stenosis of the major cerebral arteries. "Small vessel" cerebral vascular disease was defined based on accepted scoring methods of WMHI. All patients had continuous TCD-based autoregulation monitoring during surgery.

Results: Impaired autoregulation occurred in 32.4% (112/346) of patients. Preoperative TCD demonstrated moderate-severe large vessel stenosis in 67 (25.2%) of 266 patients with complete data. In adjusted analysis, female sex (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25-0.86; P = .014) and higher average temperature during CPB (OR, 1.23; 95% CI, 1.02-1.475; P = .029), but not moderate-severe large cerebral arterial stenosis (P = .406), were associated with impaired autoregulation during CPB. Of the 119 patients with available brain MRI data, 42 (35.3%) demonstrated WMHI. The presence of small vessel cerebral vascular disease was associated with impaired CBF autoregulation (OR, 3.25; 95% CI, 1.21-8.71; P = .019) after adjustment for age, history of peripheral vascular disease, preoperative hemoglobin level, and preoperative treatment with calcium channel blocking drugs.

Conclusions: These data confirm that impaired CBF autoregulation is prevalent during CPB predisposing affected patients to brain hypoperfusion or hyperperfusion with low or high blood pressure, respectively. Small vessel, but not large vessel, cerebral vascular disease, male sex, and higher average body temperature during CPB appear to be associated with impaired autoregulation.
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http://dx.doi.org/10.1213/ANE.0000000000003384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533899PMC
December 2018

Hypoxia Triggers SENP1 (Sentrin-Specific Protease 1) Modulation of KLF15 (Kruppel-Like Factor 15) and Transcriptional Regulation of Arg2 (Arginase 2) in Pulmonary Endothelium.

Arterioscler Thromb Vasc Biol 2018 04 22;38(4):913-926. Epub 2018 Feb 22.

From the Departments of Anesthesiology and Critical Care Medicine (D.P., Y.N., M.C.R., D.H., A.B., L.S., D.B., L.R.), Cell Biology (L.R.), Biomedical Engineering (D.B., L.R.), and Pediatrics, and the Center for Cell Dynamics (L.R.), Division of Cardiology (G.K., T.L.), and Division of Pulmonary and Critical Care Medicine, Department of Medicine (L.A.S.), Johns Hopkins Medical Institutions, Baltimore, MD.

Objective: KLF15 (Kruppel-like factor 15) has recently been shown to suppress activation of proinflammatory processes that contribute to atherogenesis in vascular smooth muscle, however, the role of KLF15 in vascular endothelial function is unknown. Arginase mediates inflammatory vasculopathy and vascular injury in pulmonary hypertension. Here, we tested the hypothesis that KLF15 is a critical regulator of hypoxia-induced Arg2 (arginase 2) transcription in human pulmonary microvascular endothelial cells (HPMEC).

Approach And Results: Quiescent HPMEC express ample amounts of full-length KLF15. HPMECs exposed to 24 hours of hypoxia exhibited a marked decrease in KLF15 protein levels and a reciprocal increase in Arg2 protein and mRNA. Chromatin immunoprecipitation indicated direct binding of KLF15 to the Arg2 promoter, which was relieved with HPMEC exposure to hypoxia. Furthermore, overexpression of KLF15 in HPMEC reversed hypoxia-induced augmentation of Arg2 abundance and arginase activity and rescued nitric oxide (NO) production. Ectopic KLF15 also reversed hypoxia-induced endothelium-mediated vasodilatation in isolated rat pulmonary artery rings. Mechanisms by which hypoxia regulates KLF15 abundance, stability, and compartmentalization to the nucleus in HPMEC were then investigated. Hypoxia triggered deSUMOylation of KLF15 by SENP1 (sentrin-specific protease 1), and translocation of KLF15 from nucleus to cytoplasm.

Conclusions: KLF15 is a critical regulator of pulmonary endothelial homeostasis via repression of endothelial Arg2 expression. KLF15 abundance and nuclear compartmentalization are regulated by SUMOylation/deSUMOylation-a hypoxia-sensitive process that is controlled by SENP1. Strategies including overexpression of KLF15 or inhibition of SENP1 may represent novel therapeutic targets for pulmonary hypertension.
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http://dx.doi.org/10.1161/ATVBAHA.117.310660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738933PMC
April 2018

Validation of a Real-Time Minute-to-Minute Urine Output Monitor and the Feasibility of Its Clinical Use for Patients Undergoing Cardiac Surgery.

Anesth Analg 2017 12;125(6):1883-1886

Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Acute kidney injury after cardiac surgery is associated with increased morbidity and mortality. Methods for measuring urine output in real time may better ensure renal perfusion perioperatively in contrast to the current standard of care where urine output is visually estimated after empiric epochs of time. In this study, we describe an accurate method for monitoring urine output continuously during cardiopulmonary bypass. This may provide a means for setting patient-specific targets for blood pressure and cardiopulmonary bypass flow as a potential strategy to reduce the risk for acute kidney injury.
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http://dx.doi.org/10.1213/ANE.0000000000002217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726301PMC
December 2017

Optimal blood pressure during cardiopulmonary bypass defined by cerebral autoregulation monitoring.

J Thorac Cardiovasc Surg 2017 11 24;154(5):1590-1598.e2. Epub 2017 Jul 24.

Department of Anesthesiology and the Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address:

Objectives: We sought to define the lower and upper limits of cerebral blood flow autoregulation and the optimal blood pressure during cardiopulmonary bypass. We further sought to identify variables predictive of these autoregulation end points.

Methods: Cerebral autoregulation was monitored continuously with transcranial Doppler in 614 patients during cardiopulmonary bypass enrolled in 3 investigations. A moving Pearson's correlation coefficient was calculated between cerebral blood flow velocity and mean arterial pressure to generate the variable mean velocity index. Optimal mean arterial pressure was defined as the mean arterial pressure with the lowest mean velocity index indicating the best autoregulation. The lower and upper limits of cerebral blood flow autoregulation were defined as the mean arterial pressure at which mean velocity index was increasingly pressure passive (ie, mean velocity index ≥0.4) with declining or increasing blood pressure, respectively.

Results: The mean (± standard deviation) lower and upper limits of cerebral blood flow autoregulation, and optimal mean arterial pressure were 65 ± 12 mm Hg, 84 ± 11 mm Hg, and 78 ± 11 mm Hg, respectively, after adjusting for study enrollment. In 17% of patients, though, the lower limit of cerebral autoregulation was above this optimal mean arterial pressure, whereas in 29% of patients the upper limit of autoregulation was below the population optimal mean arterial pressure. Variables associated with optimal mean arterial pressure based on multivariate regression analysis were nonwhite race (increased 2.7 mm Hg; P = .034), diuretics use (decreased 1.9 mm Hg; P = .049), prior carotid endarterectomy (decreased 5.5 mm Hg; P = .019), and duration of cardiopulmonary bypass (decreased 1.28 per 60 minutes of cardiopulmonary bypass). The product of the duration and magnitude that mean arterial pressure during cardiopulmonary bypass was below the lower limit of cerebral autoregulation was associated with the risk for stroke (P = .02).

Conclusions: Real-time monitoring of autoregulation may improve individualizing mean arterial pressure during cardiopulmonary bypass and improving patient outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2017.04.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685671PMC
November 2017

Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition.

Am J Physiol Lung Cell Mol Physiol 2018 01 7;314(1):L93-L106. Epub 2017 Sep 7.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University , Baltimore, Maryland.

We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4 mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous "optogenetic system" that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders.
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http://dx.doi.org/10.1152/ajplung.00091.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335007PMC
January 2018

miR-181b regulates vascular stiffness age dependently in part by regulating TGF-β signaling.

PLoS One 2017 21;12(3):e0174108. Epub 2017 Mar 21.

Department of Cardiovascular Pathology, Ross Research Building, Johns Hopkins University, Baltimore, Maryland, United States of America.

Background: Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. Here we tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening.

Methods And Results: qPCR data showed a significant decrease in miR-181b expression in the aorta of the older mice. Eight miR-181a1/b1-/- mice and wild types (C57BL6J:WT) were followed weekly for pulse wave velocity (PWV) and blood pressure measurements. After 20 weeks, the mice were tested for endothelial function and aortic modulus. There was a progressive increase in PWV and higher systolic blood pressure in miR-181a1/b1-/- mice compared with WTs. At 21 weeks, aortic modulus was significantly greater in the miR-181a1/b1-/- group, and serum TGF-β was found to be elevated at this time. A luciferase reporter assay confirmed miR-181b targets TGF-βi (TGF-β induced) in the aortic VSMCs. In contrast, wire myography revealed unaltered endothelial function along with higher nitric oxide production in the miR-181a1/b1-/- group. Cultured VECs and VSMCs from the mouse aorta showed more secreted TGF-β in VSMCs of the miR-181a1/b1-/- group; whereas, no change was observed from VECs. Circulating levels of angiotensin II were similar in both groups. Treatment with losartan (0.6 g/L) prevented the increase in PWV, blood pressure, and vascular stiffness in miR-181a1/b1-/- mice. Immunohistochemistry and western blot for p-SMAD2/3 validated the inhibitory effect of losartan on TGF-β signaling in miR-181a1/b1-/- mice.

Conclusions: Decreased miR-181b with aging plays a critical role in ECM remodeling by removing the brake on the TGF-β, pSMAD2/3 pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174108PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360327PMC
September 2017

Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6.

Am J Physiol Heart Circ Physiol 2017 Apr 10;312(4):H711-H720. Epub 2017 Feb 10.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;

Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of HS. However, the molecular mechanisms that control CSEγ gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSEγ. Reduced CSEγ mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEγ overexpression or the HS donor NaHS. CSEγ expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE mice were comparable to those in controls, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis. Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and HS production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis.
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http://dx.doi.org/10.1152/ajpheart.00724.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407166PMC
April 2017

Total Occlusion of Abdominal Aortic Endograft Successfully Treated with Axillobifemoral Bypass.

Ann Vasc Dis 2015 7;8(4):314-7. Epub 2015 Oct 7.

Department of Cardiovascular Surgery, Saitama Red Cross Hospital, Saitama, Saitama, Japan.

We report a case of total occlusion of a Zenith bifurcated stent graft 16 months after implantation. A 72-year-old man was admitted to our hospital complaining of bilateral lower extremity numbness, followed by severe rest pain 4 h after sudden onset of symptoms. Computed tomography showed total occlusion of the endograft at the mid-portion of the main body. He underwent left axillobifemoral bypass using a reinforced polytetrafluoroethylene T-shaped graft, leading to resolution of symptoms 7 h after onset. Axillobifemoral bypass successfully relieved acute lower extremity ischemia caused by total occlusion of the abdominal aortic endograft.
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http://dx.doi.org/10.3400/avd.cr.15-00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691506PMC
January 2016

Endovascular repair of thoracic aortic aneurysm associated with right-sided aortic arch: report of two cases.

Gen Thorac Cardiovasc Surg 2016 Sep 30;64(9):552-7. Epub 2014 Dec 30.

Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Amanuma-cho 1-847, Saitama, 330-8503, Japan.

Right-sided aortic arch (RAA) is a rare congenital disorder. We describe herein two cases of thoracic aortic aneurysm with a right aortic arch and right-sided descending aorta treated with thoracic endovascular aortic repair (TEVAR). In one case, a 70-year-old man with Edwards type 1 RAA underwent TEVAR using a Relay stent-graft (Bolton Medical, Barcelona, Spain). In another case, a 72-year-old woman with Edwards type 3 RAA underwent TEVAR using a Kawasumi Najuta stent-graft (Kawasumi Laboratories, Inc., Tokyo, Japan) with the "buffalo horn chimney technique", our original method for left subclavian artery flow preservation. The postoperative courses were uneventful. Postoperative computed tomography showed complete exclusion of the aneurysm without endoleakage. Compared to conventional open surgical repair, TEVAR is challenging in patients with a RAA and right-sided descending aorta. However, our results showed that TEVAR might be feasible and a treatment option even in a patient with a RAA and right-sided descending aorta.
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http://dx.doi.org/10.1007/s11748-014-0514-7DOI Listing
September 2016

Successful endovascular treatment of ruptured bronchial artery aneurysm.

Asian Cardiovasc Thorac Ann 2013 Oct 9;21(5):615-7. Epub 2013 Jul 9.

Department of Cardiovascular Surgery, Fujigaoka Hospital, Showa University, Kanagawa, Japan.

Rupture of a bronchial artery aneurysm occurs rarely and may mimic aortic dissection. A 78-year-old-man was admitted with sudden chest pain. Chest radiography showed widening of the mediastinum, suggestive of aortic dissection, but contrast-enhanced computed tomography revealed hemomediastinum and bronchial artery aneurysm. Although open surgery has been the first choice for ruptured bronchial artery aneurysm, this case was successfully treated by an endovascular procedure with the combined use of coils and a gelatin sponge.
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http://dx.doi.org/10.1177/0218492312463369DOI Listing
October 2013

Enlarged coronary artery pseudoaneurysm after drug-eluting stent implantation.

Asian Cardiovasc Thorac Ann 2013 Oct 9;21(5):608-11. Epub 2013 Jul 9.

Department of Cardiovascular Surgery, Fujigaoka Hospital, Showa University, Kanagawa, Japan.

A 73-year-old man with 2-vessel coronary artery disease underwent a staged percutaneous coronary intervention that resulted in rupture of the right coronary artery and pseudoaneurysm formation. Although the pseudoaneurysm regressed over a week, it reexpanded after a year. Resection of the pseudoaneurysm and coronary artery bypass grafting were performed. The drug-eluting stent at the coronary artery injury site may have delayed healing and remodeling of the artery, thus contributing to reexpansion of the pseudoaneurysm.
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http://dx.doi.org/10.1177/0218492312461454DOI Listing
October 2013
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