Microstructural Alterations and Oligodendrocyte Dysmaturation in White Matter After Cardiopulmonary Bypass in a Juvenile Porcine Model.

BACKGROUND: Newly developed white matter (WM) injury is common after cardiopulmonary bypass (CPB) in severe/complex congenital heart disease. Fractional anisotropy (FA) allows measurement of macroscopic organization of WM pathology but has rarely been applied after CPB. The aims of our animal study were to define CPB-induced FA alterations and to determine correlations between these changes and cellular events after congenital heart disease surgery. METHODS AND RESULTS: Normal porcine WM development was first assessed between 3 and 7 weeks of age: 3-week-old piglets were randomly assigned to 1 of 3 CPB-induced insults. FA was analyzed in 31 WM structures. WM oligodendrocytes, astrocytes, and microglia were assessed immunohistologically. Normal porcine WM development resembles human WM development in early infancy. We found region-specific WM vulnerability to insults associated with CPB. FA changes after CPB were also insult dependent. Within various WM areas, WM within the frontal cortex was susceptible, suggesting that FA in the frontal cortex should be a biomarker for WM injury after CPB. FA increases occur parallel to cellular processes of WM maturation during normal development; however, they are altered following surgery. CPB-induced oligodendrocyte dysmaturation, astrogliosis, and microglial expansion affect these changes. FA enabled capturing CPB-induced cellular events 4 weeks postoperatively. Regions most resilient to CPB-induced FA reduction were those that maintained mature oligodendrocytes. CONCLUSIONS: Reducing alterations of oligodendrocyte development in the frontal cortex can be both a metric and a goal to improve neurodevelopmental impairment in the congenital heart disease population. Studies using this model can provide important data needed to better interpret human imaging studies

Total cavo-pulmonary connection conversion後の中遠隔期成績の検討

〔背景〕Fontan手術は当初三尖弁閉鎖症に対する根治術として行われていたが,次第に適応は拡大され単心室性の房室結合を示す症例やさまざまな複雑心奇形により二心室修復が不可能な症例に対しても行われるようになっている.〔目的〕Fontan手術遠隔期には上室性不整脈,蛋白漏出性胃腸症,チアノーゼの進行や心不全等の合併症が認められる.こうした症例に対しTotal cavo-pulmonary connection(TCPC)conversionが施行されるようになってきているが手術適応は明確でなく,術後成績も明らかでない.今回われわれはTCPC conversion後の中期遠隔期成績より手術適応を検討した.〔症例と方法〕対象症例は1992年3月から2008年1月までに当科にてTCPC conversionを行った26例とした.手術時平均年齢,体重,初回Fontan手術年齢と初回Fontan手術からの期間はそれぞれ26.3±7.6歳,47.2±9.0 kg,12.0±6.5歳と14.6±5.1年であった.上室性不整脈を16例(64%)に,右房内血栓を13例(50%)に認めた.術前NYHA心機能分類は4例(15%)がclass I,20例(77%)がclass II,2例(8%)がclass IIIであった.これらの症例を後方視的に検討した.〔結果〕全例にTCPC conversionを施行し,同時手術として12例(46%)にMAZE手術を,右房内血栓を認める症例には血栓除去術を施行した.病院死亡を4例に認め,いずれも低拍出量症候群よる多臓器不全で失った.遠隔期死亡を4例に認め,心不全,肺炎,肝機能障害に伴う合併症で失った.遠隔期死亡群では2例(50%)が術前NYHA class I,2例(50%)がclass IIで術後は全例class IIIで改善が認められず手術介入時期に問題があると考えられた.生存症例の術後rhythmは洞調律8例(44%),ペースメーカー調律6例(33%)と14例(77%)に整調律を認め,術前12例(66%)に認めていた不整脈は4人(23%)に滅少し,NYHA心機能分類では術前4人がclass I,14人がclass IIであったが,術後12人がclass I,6人がclass IIと改善が認められた.手術時期および術中因子が遠隔死亡および病院死亡に関与し,整脈化が日常生活を改善していることが示唆された.〔結論〕TCPC conversionはriskの高い複式で手術手技に関連する因子と手術介入時期が術後経過に関与すると考えられた.整脈化が日常生活を改善することが示唆されたが,今後更なる検討が必要である.Objective: Some investigators reported the efficacy of the conversion to total cavo-pulmonary connection in the patients having the long term issue associated with the systemic venous connection. However, it\u27s indication is still controversial and surgical outcomes are uncertain. The purpose of this retrospective observational study was to investigate the optimal timing and midterm results. Patients and Methods: Twenty-six patients, average age was 26.3 ± 7.6 years and years after Fontan completion was 14.6 ± 5.1 years, underwent TCPC conversion between March 1992 and January 2008. There was atrial tachyarrhythmia in 16 patients (64%) and thrombus formation in 13 patients (50%). The medical records from those patients were observed and reviewed. Results: There were 4 hospital deaths and 4 late deaths. Operative factor and timing were implied, although the exact reason was not detected statistically. In midterm survivors, New York Heart Association classification was improved from 4 (22%) to 12 (67%) in class I, from 14 (78%) to 6 (33%) in class II and from 2 (8%) to none in class III, respectively. Post operative cardiothoracic ratio and Sp02 were 51 ± 6% and was 94 ± 1%. Conclusion: Clinical status in the patients enduring TCPC conversion was improved, although total cavo-pulmonary connection conversion was still high risk operation. Further investigation was needed

Total cavo-pulmonary connection conversion後の中遠隔期成績の検討

〔背景〕Fontan手術は当初三尖弁閉鎖症に対する根治術として行われていたが,次第に適応は拡大され単心室性の房室結合を示す症例やさまざまな複雑心奇形により二心室修復が不可能な症例に対しても行われるようになっている.〔目的〕Fontan手術遠隔期には上室性不整脈,蛋白漏出性胃腸症,チアノーゼの進行や心不全等の合併症が認められる.こうした症例に対しTotal cavo-pulmonary connection(TCPC)conversionが施行されるようになってきているが手術適応は明確でなく,術後成績も明らかでない.今回われわれはTCPC conversion後の中期遠隔期成績より手術適応を検討した.〔症例と方法〕対象症例は1992年3月から2008年1月までに当科にてTCPC conversionを行った26例とした.手術時平均年齢,体重,初回Fontan手術年齢と初回Fontan手術からの期間はそれぞれ26.3±7.6歳,47.2±9.0 kg,12.0±6.5歳と14.6±5.1年であった.上室性不整脈を16例(64%)に,右房内血栓を13例(50%)に認めた.術前NYHA心機能分類は4例(15%)がclass I,20例(77%)がclass II,2例(8%)がclass IIIであった.これらの症例を後方視的に検討した.〔結果〕全例にTCPC conversionを施行し,同時手術として12例(46%)にMAZE手術を,右房内血栓を認める症例には血栓除去術を施行した.病院死亡を4例に認め,いずれも低拍出量症候群よる多臓器不全で失った.遠隔期死亡を4例に認め,心不全,肺炎,肝機能障害に伴う合併症で失った.遠隔期死亡群では2例(50%)が術前NYHA class I,2例(50%)がclass IIで術後は全例class IIIで改善が認められず手術介入時期に問題があると考えられた.生存症例の術後rhythmは洞調律8例(44%),ペースメーカー調律6例(33%)と14例(77%)に整調律を認め,術前12例(66%)に認めていた不整脈は4人(23%)に滅少し,NYHA心機能分類では術前4人がclass I,14人がclass IIであったが,術後12人がclass I,6人がclass IIと改善が認められた.手術時期および術中因子が遠隔死亡および病院死亡に関与し,整脈化が日常生活を改善していることが示唆された.〔結論〕TCPC conversionはriskの高い複式で手術手技に関連する因子と手術介入時期が術後経過に関与すると考えられた.整脈化が日常生活を改善することが示唆されたが,今後更なる検討が必要である.Objective: Some investigators reported the efficacy of the conversion to total cavo-pulmonary connection in the patients having the long term issue associated with the systemic venous connection. However, it's indication is still controversial and surgical outcomes are uncertain. The purpose of this retrospective observational study was to investigate the optimal timing and midterm results. Patients and Methods: Twenty-six patients, average age was 26.3 ± 7.6 years and years after Fontan completion was 14.6 ± 5.1 years, underwent TCPC conversion between March 1992 and January 2008. There was atrial tachyarrhythmia in 16 patients (64%) and thrombus formation in 13 patients (50%). The medical records from those patients were observed and reviewed. Results: There were 4 hospital deaths and 4 late deaths. Operative factor and timing were implied, although the exact reason was not detected statistically. In midterm survivors, New York Heart Association classification was improved from 4 (22%) to 12 (67%) in class I, from 14 (78%) to 6 (33%) in class II and from 2 (8%) to none in class III, respectively. Post operative cardiothoracic ratio and Sp02 were 51 ± 6% and was 94 ± 1%. Conclusion: Clinical status in the patients enduring TCPC conversion was improved, although total cavo-pulmonary connection conversion was still high risk operation. Further investigation was needed

Rodent brain slice model for the study of white matter injury

ObjectiveCerebral white matter (WM) injury is common after cardiac surgery in neonates and young infants who have brain immaturity and genetic abnormalities. To understand better the mechanisms associated with WM injury, we tested the adequacy of a novel ex vivo brain slice model, with a particular focus on how the maturational stage modulates the injury.MethodsTo replicate conditions of cardiopulmonary bypass, we transferred living brain slices to a closed chamber perfused by artificial cerebrospinal fluid under controlled temperature and oxygenation. Oxygen-glucose deprivation (OGD) simulated circulatory arrest. The effects of maturation were investigated in 7- and 21-day-old mice (P7, P21) that are equivalent in maturation stage to the human fetus and young adult.ResultsThere were no morphologic changes in axons after 60 minutes of OGD at 15°C in both P7 WM and P21 WM. Higher temperature and longer duration of OGD were associated with significantly greater WM axonal damage, suggesting that the model replicates the injury seen after hypothermic circulatory arrest. The axonal damage at P7 was significantly less than at P21, demonstrating that immature axons are more resistant than mature axons. Conversely, a significant increase in caspase3+ oligodendrocytes in P7 mice was identified relative to P21, indicating that oligodendrocytes in immature WM are more vulnerable than oligodendrocytes in mature WM.ConclusionsNeuroprotective strategies for immature WM may need to focus on reducing oligodendrocyte injury. The brain slice model will be helpful in understanding the effects of cardiac surgery on the immature brain and the brain with genetic abnormalities

Prolonged white matter inflammation after cardiopulmonary bypass and circulatory arrest in a juvenile porcine model.

BACKGROUND: White matter (WM) injury is common after neonatal cardiopulmonary bypass (CPB). We have demonstrated that the inflammatory response to CPB is an important mechanism of WM injury. Microglia are brain-specific immune cells that respond to inflammation and can exacerbate injury. We hypothesized that microglia activation contributes to WM injury caused by CPB. METHODS: Juvenile piglets were randomly assigned to one of three CPB-induced brain insults (1: no-CPB, 2: full-flow CPB, 3: CPB/Circulatory-arrest). Neurobehavioral tests were performed. Animals were sacrificed 3-days or 4-weeks post-operatively. Microglia and proliferating cells were immunohistologically identified. Seven analyzed WM regions were further categorized into 3-fiber connections (1: Commissural, 2: Projection, 3: Association fibers). RESULTS: Microglia numbers significantly increased on day 3 after CPB/Circulatory-arrest, but not after full-flow CPB. Fiber categories did not affect these changes. On post-CPB week 4, proliferating cell number, blood leukocyte number and IL-6 levels, and neurological scores had normalized. However, both full-flow CPB and CPB/Circulatory-arrest displayed significant increases in the microglia number compared with Control. Thus brain-specific inflammation after CPB persists despite no changes in systemic biomarkers. Microglia number was significantly different among fiber categories, being highest in Association and lowest in Commissural connections. Thus there was a WM fiber-dependent microglia reaction to CPB. CONCLUSIONS: This study demonstrates prolonged microglia activation in WM after CPB. This brain-specific inflammatory response is systemically silent. It is connection fiber-dependent which may impact specific connectivity deficits observed after CPB. Controlling microglia activation after CPB is a potential therapeutic intervention to limit neurological deficits following CPB