交感神经过度且不均一支配与钙调控蛋白表达变化在长期左房压力超负荷致心房颤动中的作用
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摘要
目的:有关长期左房压力超负荷导致心房电生理变化及心房颤动(房颤)发生的具体机制尚不十分清楚,而交感神经系统和钙调控蛋白及其磷酸化水平变化在其中的作用也有待于探讨。因此,本研究采用腹主动脉缩窄法建立兔压力负荷型左室肥厚和心力衰竭模型,研究高血压左室肥厚和心力衰竭病理状态下,长期左房压力超负荷对兔心房电生理参数和房颤诱发率的影响,同时评价心房及左上肺静脉交感神经分布的变化,观察钙调控蛋白RyR2及其调节蛋白FKBP12.6,L-型Ca~(2+)通道,SERCA_(2a)及其调节蛋白PLB表达水平的变化,并对RyR2和PLB的磷酸化水平进行分析,探讨左房交感神经支配与钙调控蛋白表达变化在长期左房压力超负荷所致心房颤动中的作用。
方法:雄性日本大耳白兔42只随机分为假手术组(14只)、左室肥厚组(肥厚组,16只)和心力衰竭组(心衰组,12只)。肥厚组腹主动脉缩窄约50～60%,心衰组腹主动脉缩窄约70～80%,假手术组仅开腹而不予腹主动脉缩窄。术后8周进行超声心动图检查测定左房内径(LAD)、左室舒张末内径(LVED)、左室间隔舒张末厚度(IVSDT)、左室后壁舒张末厚度(LVPWDT)、右室内径(RVD)和左室射血分数(LVEF)等心脏超声指标,然后在假手术组和肥厚组中各随机选取8只动物进行Langendorff灌流的离体电生理检查测定窦性心动周长(SCL)、房室传导文氏周长(AVWCL)、心房各点有效不应期(AERP)、心房有效不应期离散度(AERPD)、房间传导时间(IACT)及房颤诱发率和诱发次数的评估。其余兔假手术组(n=6)、左室肥厚组(n=8)和心衰组(n=5)进行血流动力学检查测定心率(HR)、主动脉收缩压(SBP)、主动脉舒张压(DBP)、左室舒张末压(LVEDP)、左室压力最大上升速率及下降速率
Objective: The mechanisms of atrial electrophysiological changes and atrial fibrillation(AF) induced by long-term left atrial pressure overload are not fully understood, and the role of sympathetic nervous system and calcium regulatory proteins and their phosphorylation level changes are also need to be evaluated. Therefore, left ventricular hypertrophy and heart failure rabbit models were made by abdominal aortic coarctation. Our study is to evaluate the effects of long-term left atrial pressure overload on atrial electrophysiological parameters and AF inducibility. We also observe the changes of sympathetic nerve distribution and calcium regulatory proteins, such as cardiac ryanodine receptor(RyR2) and its phosphorylation state (RyR2-2809P), FKBP12.6, L-type calcium channel, SERCA_(2a), phospholamban (PLB) and its phosphorylation state (PLBp-Ser~(16)). Hence, the main objective of our study is to evaluate the role of left atrial sympathetic innervation and calcium regulatory protein expression alterations in long-term left atrial overload-induced atrial fibrillation.Methods: 42 male japanese rabbits were randomized into Sham group(n=14) without abdominal aortic coarctation, left ventricular hypertrophy group(LVH group)(n=16) with 50-60% abdominal aortic coarctation and heart failure group(HF group)(n=12) with 70-80% abdominal aortic coarctation. Echocardiographic parameters such as left atrial diameter(LAD), left ventricular end diastolic diameter(LVED), interventricular septum diastolic thickness(IVSDT), left ventricular
posterior wall diastolic thickness (LVPWDT), right ventricular diameter(RVD) and left ventricular ejection firaction(LVEF) were assessed 8 weeks after operation. 8 animals were selected randomly from Sham and LVH group to perform Langendorff-perfiised electrophysiological study and measure sinus cycle length(SCL), wenckbach cycle length of AV conduction(AVWCL), atrial effective refractory period(AERP), dispersion of AERP(AERPD) and intra-atrial conduction time(IACT) and AF inducibility. The remaining rabbits which included 6 from Sham group, 8 from LVH group and 5 from HF group were used in hemodynamic measurements to assess heart rate (HR), systolic blood pressure(SBP), diastolic blood pressure(DBP), left ventricular end diastolic pressure(LVEDP), LW+dp/dtmaii and -dp/dtmax. Then, blood sample were obtained to measure atrial natriuretic peptide(ANP) and norepinephrine(NE), and atrial and left pulmonary superior vein(LPSV) tissue were excised. Westernblot analyses were performed to test P-ARK1, LTCCs, FKBP12.6, RyR2-5029, RyR2-2809P, SERCA2a, PLB and PLBp-Ser16 protein expressions. Pathological examination and Tyrosine hydroxylase(TH) immunohistochemistry test were performed, and atrial tissue cyclic adenosine monophosphate(cAMP) level was also measured.Results: 1) Echocardiographic results 8 weeks after operation: Compared with Sham group, LAD, IVSDT and LVPWDT in LVH group were increased significantly, and LAD, LVED and RVD in HF group were also increased significantly;compared with LVH group, HF group had increased LAD, LVED and RVD, decreased LVEF. 2) Hemodynamic measurements: Compared with Sham group, SBP^ DBP^ LV+dp/dtmax and -dp/dtmax in LVH group were increased significantly, and SBP and LVEDP in HF group were also increased significantly, LY+dp/dtmax and -dp/dtmsx were decreased significantly;compared with LVH group, HF group had decreased SBP, DBP,
LV+dp/dtmax and -dp/dtmaK, increased LVEDP. 3) Electrophysiological study results:Compared with Sham group, High left AERP(77.75±14.36 vs 96.50±8.47ms, /><0.01)was shortened, AERPD (32.75±12.65 vs 12.63±7.31ms, PO.01) and IACT(39.11±2.99 vs 25.60±3.70ms, P<0.01) was increased in LVH rabbits. There was alsosignificant increase in vulnerability to AF in LVH group(4/8 vs 0/8, PO.05). 4)Plasma ANP , NE and atrial tissue cAMP levels: ANP in HF group was higher thanLVH and Sham group;NE in HF and LVH group were higher than Sham group, andNE in HF group was also higher than LVH group;cAMP in Sham group was higherthan LVH and HF. 5) Pathological examination and immunohistochemistry testresults: (T)Left atrial cross sectional area(LACSA) in LVH and HF group werehigher than Sham group. ?Ostial LPSV diameter and vessel wall thickness in LVHand HF group were larger than Sham group. ?Left atrial collagen volumefraction(CVF) and LAACVF in LVH and HF group were higher than Sham group.?TH immunohistochemistry test: Left atrial nerve density were more heterogeneousin LVH group compared with Sham group;left atrial max nerve density and nerveheterogeneity were higher in HF group than Sham group. LPSV max and mean nervedensity were lower in LVH group than Sham and HF group. 6) Westernblot analysis:?P-ARK1 protein expressions in LVH and HF group were higher than Sham group.?LTCCs protein expressions in LVH and HF were lower than Sham group.(3)FKBP12.6 protein expressions in LVH and HF group were higher than Shamgroup, and FKBP12.6 in HF group was lower than LVH group. ?Compared withSham group, RyR2-5029 protein expression in LVH was increased significantly,RyR2-5029 protein expression in HF was decreased significantly, and RyR2-5029protein expression in HF was lower than LVH group. (§)RyR2-2809P proteinexpressions in LVH and HF group were higher than Sham group. ?RyR2 relative
phosphorylation levels in LVH and HF group were higher than Sham group, and RyR2 relative phosphorylation level in HF group was higher than LVH group. (7)SERCA2a protein expression in HF group was lower than Sham and LVH group. (§)PLB and PLBp-Ser16 protein expressions in LVH and HF group were lower than Sham group, and PLB and PLBp-Ser16 protein expressions in HF group were lower than LVH group. (9)PLB relative phosphorylation levels in LVH and HF group were lower than Sham group, and PLB relative phosphorylation level in HF group was lower than LVH group.Conclusion: 1) Long-term left atrial pressure over-load can shorten high left AERP, prolong AERPD and IACT, increase AF inducibility. 2) Long-term left atrial pressure over-load can induce left atrial myocardial hypertrophy, atrial interstitial fibrosis and a series of pathologic changes named as atrial structural remodeling. 3) Long-term left atrial pressure over-load can cause left atrial heterogeneous sympathetic hyperinnervation, decreased LTCCs and SERCA2a protein expressions, increased RyR2 relative phosphorylation level, decreased PLB relative phosphorylation level, which may be associated with AF. 4) Long-term left atrial pressure over-load can increase ostial LPSV diameter accompanied with left atrial dilation, which may participate in AF development.
方法:雄性日本大耳白兔42只随机分为假手术组(14只)、左室肥厚组(肥厚组,16只)和心力衰竭组(心衰组,12只)。肥厚组腹主动脉缩窄约50～60%,心衰组腹主动脉缩窄约70～80%,假手术组仅开腹而不予腹主动脉缩窄。术后8周进行超声心动图检查测定左房内径(LAD)、左室舒张末内径(LVED)、左室间隔舒张末厚度(IVSDT)、左室后壁舒张末厚度(LVPWDT)、右室内径(RVD)和左室射血分数(LVEF)等心脏超声指标,然后在假手术组和肥厚组中各随机选取8只动物进行Langendorff灌流的离体电生理检查测定窦性心动周长(SCL)、房室传导文氏周长(AVWCL)、心房各点有效不应期(AERP)、心房有效不应期离散度(AERPD)、房间传导时间(IACT)及房颤诱发率和诱发次数的评估。其余兔假手术组(n=6)、左室肥厚组(n=8)和心衰组(n=5)进行血流动力学检查测定心率(HR)、主动脉收缩压(SBP)、主动脉舒张压(DBP)、左室舒张末压(LVEDP)、左室压力最大上升速率及下降速率
Objective: The mechanisms of atrial electrophysiological changes and atrial fibrillation(AF) induced by long-term left atrial pressure overload are not fully understood, and the role of sympathetic nervous system and calcium regulatory proteins and their phosphorylation level changes are also need to be evaluated. Therefore, left ventricular hypertrophy and heart failure rabbit models were made by abdominal aortic coarctation. Our study is to evaluate the effects of long-term left atrial pressure overload on atrial electrophysiological parameters and AF inducibility. We also observe the changes of sympathetic nerve distribution and calcium regulatory proteins, such as cardiac ryanodine receptor(RyR2) and its phosphorylation state (RyR2-2809P), FKBP12.6, L-type calcium channel, SERCA_(2a), phospholamban (PLB) and its phosphorylation state (PLBp-Ser~(16)). Hence, the main objective of our study is to evaluate the role of left atrial sympathetic innervation and calcium regulatory protein expression alterations in long-term left atrial overload-induced atrial fibrillation.Methods: 42 male japanese rabbits were randomized into Sham group(n=14) without abdominal aortic coarctation, left ventricular hypertrophy group(LVH group)(n=16) with 50-60% abdominal aortic coarctation and heart failure group(HF group)(n=12) with 70-80% abdominal aortic coarctation. Echocardiographic parameters such as left atrial diameter(LAD), left ventricular end diastolic diameter(LVED), interventricular septum diastolic thickness(IVSDT), left ventricular
posterior wall diastolic thickness (LVPWDT), right ventricular diameter(RVD) and left ventricular ejection firaction(LVEF) were assessed 8 weeks after operation. 8 animals were selected randomly from Sham and LVH group to perform Langendorff-perfiised electrophysiological study and measure sinus cycle length(SCL), wenckbach cycle length of AV conduction(AVWCL), atrial effective refractory period(AERP), dispersion of AERP(AERPD) and intra-atrial conduction time(IACT) and AF inducibility. The remaining rabbits which included 6 from Sham group, 8 from LVH group and 5 from HF group were used in hemodynamic measurements to assess heart rate (HR), systolic blood pressure(SBP), diastolic blood pressure(DBP), left ventricular end diastolic pressure(LVEDP), LW+dp/dtmaii and -dp/dtmax. Then, blood sample were obtained to measure atrial natriuretic peptide(ANP) and norepinephrine(NE), and atrial and left pulmonary superior vein(LPSV) tissue were excised. Westernblot analyses were performed to test P-ARK1, LTCCs, FKBP12.6, RyR2-5029, RyR2-2809P, SERCA2a, PLB and PLBp-Ser16 protein expressions. Pathological examination and Tyrosine hydroxylase(TH) immunohistochemistry test were performed, and atrial tissue cyclic adenosine monophosphate(cAMP) level was also measured.Results: 1) Echocardiographic results 8 weeks after operation: Compared with Sham group, LAD, IVSDT and LVPWDT in LVH group were increased significantly, and LAD, LVED and RVD in HF group were also increased significantly;compared with LVH group, HF group had increased LAD, LVED and RVD, decreased LVEF. 2) Hemodynamic measurements: Compared with Sham group, SBP^ DBP^ LV+dp/dtmax and -dp/dtmax in LVH group were increased significantly, and SBP and LVEDP in HF group were also increased significantly, LY+dp/dtmax and -dp/dtmsx were decreased significantly;compared with LVH group, HF group had decreased SBP, DBP,
LV+dp/dtmax and -dp/dtmaK, increased LVEDP. 3) Electrophysiological study results:Compared with Sham group, High left AERP(77.75±14.36 vs 96.50±8.47ms, /><0.01)was shortened, AERPD (32.75±12.65 vs 12.63±7.31ms, PO.01) and IACT(39.11±2.99 vs 25.60±3.70ms, P<0.01) was increased in LVH rabbits. There was alsosignificant increase in vulnerability to AF in LVH group(4/8 vs 0/8, PO.05). 4)Plasma ANP , NE and atrial tissue cAMP levels: ANP in HF group was higher thanLVH and Sham group;NE in HF and LVH group were higher than Sham group, andNE in HF group was also higher than LVH group;cAMP in Sham group was higherthan LVH and HF. 5) Pathological examination and immunohistochemistry testresults: (T)Left atrial cross sectional area(LACSA) in LVH and HF group werehigher than Sham group. ?Ostial LPSV diameter and vessel wall thickness in LVHand HF group were larger than Sham group. ?Left atrial collagen volumefraction(CVF) and LAACVF in LVH and HF group were higher than Sham group.?TH immunohistochemistry test: Left atrial nerve density were more heterogeneousin LVH group compared with Sham group;left atrial max nerve density and nerveheterogeneity were higher in HF group than Sham group. LPSV max and mean nervedensity were lower in LVH group than Sham and HF group. 6) Westernblot analysis:?P-ARK1 protein expressions in LVH and HF group were higher than Sham group.?LTCCs protein expressions in LVH and HF were lower than Sham group.(3)FKBP12.6 protein expressions in LVH and HF group were higher than Shamgroup, and FKBP12.6 in HF group was lower than LVH group. ?Compared withSham group, RyR2-5029 protein expression in LVH was increased significantly,RyR2-5029 protein expression in HF was decreased significantly, and RyR2-5029protein expression in HF was lower than LVH group. (§)RyR2-2809P proteinexpressions in LVH and HF group were higher than Sham group. ?RyR2 relative
phosphorylation levels in LVH and HF group were higher than Sham group, and RyR2 relative phosphorylation level in HF group was higher than LVH group. (7)SERCA2a protein expression in HF group was lower than Sham and LVH group. (§)PLB and PLBp-Ser16 protein expressions in LVH and HF group were lower than Sham group, and PLB and PLBp-Ser16 protein expressions in HF group were lower than LVH group. (9)PLB relative phosphorylation levels in LVH and HF group were lower than Sham group, and PLB relative phosphorylation level in HF group was lower than LVH group.Conclusion: 1) Long-term left atrial pressure over-load can shorten high left AERP, prolong AERPD and IACT, increase AF inducibility. 2) Long-term left atrial pressure over-load can induce left atrial myocardial hypertrophy, atrial interstitial fibrosis and a series of pathologic changes named as atrial structural remodeling. 3) Long-term left atrial pressure over-load can cause left atrial heterogeneous sympathetic hyperinnervation, decreased LTCCs and SERCA2a protein expressions, increased RyR2 relative phosphorylation level, decreased PLB relative phosphorylation level, which may be associated with AF. 4) Long-term left atrial pressure over-load can increase ostial LPSV diameter accompanied with left atrial dilation, which may participate in AF development.
引文
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