磁共振成像在肥厚性心肌病中的临床应用研究

【作者】 赵涛；

【导师】 赵世华；

【作者基本信息】 北京协和医学院 ， 影像医学与核医学， 2013， 博士

【摘要】 目的：肥厚性心肌病(Hypertrophic Cardiomyopathy, HCM)是已知病因明确的一种遗传性心血管疾病,是已知心源性猝死(Sudden Cardiac Death, SCD)最常见的原因。室性心律失常在HCM中很常见,尤其是非持续性室性心动过速(Non-sustained Ventricular Tachycardia, NSVT)更是HCM发生SCD最常见的诱因。本研究的目的是评估汉族中国人群的肥厚性心肌病患者发生严重室性心律失常与心脏磁共振钆对比剂延迟强化(Late Gadolinium Enhancement, LGE)之间的相关性。资料与方法：本研究纳入至我院行CMR检查的连续310例HCM患者,并根据有无严重室性心律失常分为两组。室性心律失常包括频发室性早搏、室性二联律、NSVT以及持续性室性心动过速。代表心肌纤维化的LGE的量化方法定义为信号增强区域影像密度超过同一层面远离部位正常心肌的影像密度2个标准差,并以占左心室心肌的百分比表示(%/LV)。将LGE阳性患者按严重程度分为轻度(1%-25%/LV)、中度(25%-50%/LV)和重度(>50%/LV)三组。为评估左心室不同区域/区段的心室壁厚度和LGE程度等参数对室性心律失常的影响,将左心室按17节段法模型分为不同区域/区段进行统计分析。用单因素和多因素Logistic回归分析来判定NSVT的危险因素,用ROC曲线用来评估筛选出的危险因素对NSVT的诊断价值。结果：室壁增厚和LGE在室间隔相关节段明显多于其他节段,心室壁最大厚度与室壁肥厚节段数均与LGE呈明显相关性(r=0.56,p<0.01和r=0.51,p<0.01)。对最大室壁厚度>30mm的室壁极度肥厚区域多位于室间隔的基底段和中间段,有室性心律失常组比无室性心律失常组有更多的患者和节段出现室壁异常肥厚(p<0.01)。在前壁和侧壁区域,不论是基底段、中间段或心尖段,有室性心律失常组的室壁平均厚度均较无室性心律失常组增加(p<0.05)。进一步将心律失常细分后有NSVT患者的平均室壁厚度在后室间隔、前壁和侧壁均较无心律失常患者增加(p=0.024,p=0.004和0.001)。LGE阳性出现在217例(70%)患者中,约占左心室心肌质量约12.0±9.8%(范围1.4%到57.8%)；分别有94例(43%)、83例(38%)和40例(18%)例患者属于延迟强化轻度组、中度组和重度组。LGE主要分布于室间隔各节段以及室间隔与前壁和下壁移行交界区域(64%),有室性心律失常组患者的LGE严重程度在所有区段的均较无室性心律失常组为重,差异有统计学显著性(p<0.01)。频发室性早搏的发病率在不同LGE分组中均无显著性差异；室性二联律仅在LGE中度组和重度组有差异,而在LGE阴性和轻度组及中度组间无显著性差异；NSVT在所有不同程度阳性组及阴性组间均有显著性差异。总体LGE阳性患者发生NSVT的风险是阴性患者的7.4倍,NSVT的发病率与LGE严重程度的相关系数为0.68。多因素Logistic回归分析中,仅有左心房容积指数和LGE严重程度是NSVT的独立预测因子,其各自的ROC曲线下面积分别是0.633和0.798。LGE取临界值为11.5%/LV时预测NSVT的敏感性和特异性分别是67.4%和85.1%。结论：HCM心肌肥厚节段与CMR的LGE分布趋势相关,室性心律失常的发生与LGE阳性及其严重程度有显著相关性。左心房容积指数和LGE严重程度是NSVT的独立预测因子。目的：肥厚性心肌病(Hypertrophic Cardiomyopathy, HCM)是一种最常见的遗传性心血管疾病,可以导致心源性猝死(Sudden Cardiac Death, SCD)、心力衰竭和中风等不良预后终点事件。这些症状主要是由于恶性心律失常或/和左心室流出道梗阻所致,而心肌纤维化及心肌瘢痕被认为是导致严重恶性心律失常和心力衰竭以及心房颤动并发症等的潜在病理基础,是HCM终点事件的独立预测因子。心脏磁共振成像延迟强化(Cardiac Magnetic Resonance Late Gadolinium Enhancement, LGE-CMR)可以无创性检测心肌纤维化,在HCM的临床实践中发挥着非常重要的作用。本研究拟通过前瞻性随访,明确LGE对HCM终点事件的预后价值。资料与方法：从2010年4月至2012年5月,对所有来我院行CMR检查的HCM患者进行筛选和跟踪随访。HCM的诊断标准参照既往文献报道,行CMR检查之前已接受左心室流出道减压手术的患者被排除。每隔3-6个月间歇对所有患者进行随访,只有被纳入研究之后出现的新发事件才被分析和归类为主要或次要终点事件。主要终点事件包括：心源性死亡、心脏移植、SCD及SCD抢救后复苏、持续性室性心动过速、心室颤动以及植入性心律转复除颤器(Implantable Cardiac Defibrillator,ICD)的适度除颤；次要终点事件包括：进行性心力衰竭症状、非计划性心源性入院以及发生非持续性室性心动过速(Non-sustained Ventricular Tachycardia, NSVT)等。CMR-LGE的量化方法以占左心室心肌的百分比表示(%/LV),并将LGE阳性患者按严重程度分为轻度(1%-25%/LV)、中度(25%-50%/LV)和重度(>50%/LV)三组。Kaplan-Meier生存率曲线用来比较不同LGE组间免终点事件生存率,和log-rank检验用来比较组间差异；多因素Cox比例风险回归分析用来评估联合终点事件的独立危险因素；ROC曲线用来评估LGE对终点事件的预测价值。为评估肥厚位置对联合终点事件的影响,将患者分为肥厚性梗阻型心肌病(Hypertrophic Obstructive Cardiomyopathy, HOCM)、非梗阻型和心尖肥厚型,进行生存分析的对比；随访期间接受左心室流出道减压手术的80例患者与未接受手术治疗的HOCM患者也进行如上生存分析,并比较组间差异。结果：420例患者最后共392例HCM患者完成了随访,其中包括80例患者随访期间接受了左室流出道减压手术将进行单独分析,随访时间528±137天(范围158-1379天),随访率93%。自然病程的312例患者中心肌纤维化阳性患者有218例(70%),心肌纤维化阴性组有94例患者。LGE阳性患者在纽约心功能分级、左心室心肌质量、平均室壁厚度、极度室壁肥厚(>30mm)、心房颤动和NSVT发病率等方面较LGE阴性患者有显著性差异。共有35例患者(11.2%)达到了主要终点事件,LGE阴性组和阳性组分别有5例和30例(5.3%比13.8%,p<0.05)；其中3例心源性死亡、1例心脏移植、9例持续性室性心动过速和心室颤动的患者均发生在LGE阳性组。77例患者(24.7%)发生了次要终点事件,LGE阴性组和阳性组分别有10例和67例(10.6%比30.7%,p<0.05)。K-M生存曲线显示患者免终点事件生存率(主要和次要)都随着LGE严重程度的增加而降低。Cox比例风险回归分析显示左心室流出道梗阻(LVOTO)和LGE阳性是主要终点事件的独立危险因素,而LGE阳性是次要终点事件的唯一独立危险因素。ROC曲线显示LGE代表的心肌纤维化对不良终点事件的预测能力满意。HOCM患者的联合终点事件生存率较非梗阻型和心尖肥厚型为差,其中接受流出道减压手术的HOCM患者的联合免终点事件生存率要好于未接受减压手术的患者。结论：CMR检测到HCM的心肌纤维化可以对联合不良终点事件作出满意的预后评估,有左心室流出道梗阻患者预后较差,但接受流出道减压手术可以改善预后。更多还原

【Abstract】 Background Hypertrophic Cardiomyopathy (HCM) is the most common inherited genetic cardiovascular disease and the most frequent cause of sudden cardiac death (SCD) in young people. Ventricular arrhythmias,especially non-sustained ventricular tachycardia (NSVT) or sustained VT, are believed to be the main cause of SCD. The aim of this study was to evaluate the correlation between ventricular arrhythmias and late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) in a large Chinese HCM cohort.Methods310patients were enrolled and divided into two groups regarding ventricular arrhythmias, including frequent premature ventricular contractions (PVCs), couplets and NSVT. The LGE was defined as those with image intensities>2SD above the mean of image intensities in a remote myocardial region in the same section. Total volume of LGE was calculated by summing the planimetered areas of LGE in all short-axis slices and was expressed as a proportion of total LV myocardium (%/LV). LGE positive patients were divided into three groups:mild (1%-25%/LV), moderate (25%-50%/LV) and severe (>50%/LV). Left ventricle was divided into different segments according to American Heart Association17segment model. Prevalence of ventricular arrhythmias was calculated regarding LGE amount. Univariate and multivariate-Logistic regression was analyzed to figure out risk factors of NSVT. Receiver operating curve (ROC) was applied to assess the diagnostic capability of risk determinants on NSVT.Results Left ventricular hypertrophy and the myocardial fibrosis were mainly located in interventricular septum (IVS), and there is good correlation between the segments of hypertrophy and the spectrum of LGE. There were more extreme hypertrophy (>30mm) in the IVS than other segments. Patients with ventricular arrhythmias had more extreme hypertrophic segments than those without ventricular arrhythmias, also the average wall thickness in the anterior and inferior segments of ventricular arrhythmias groupwere larger than the negative group. LGE was present in217(70%) patients, occupying12.0±9.8%(range1.4%to57.8%) of LV myocardium. There were94cases (43%),83cases (38%) and40cases (18%) in the mild, moderate and severe LGE groups, respectively. Prevalence of PVCs didn’t show significant difference among groups, while prevalence of couplets showed statistical significance only between the moderate and severe LGE groups. Prevalence of NSVT arose as LGE amount increased with statistical significance among all groups. LGE positive patients had a7-fold higher risk of NSVT than those without, and the correlation coefficient between them was0.680. In multivariate analysis, LA diameter and LGE amount were independent determinants of NSVT, and their area under ROC curve were0.633and0.798, respectively. The cut-off value of LGE amount as11.5%had a sensitivity of67.4%and specificity of85.1%to predict NSVT.Conclusions Myocardial fibrosis was correlated with the spectrum of hypertrophic segments, and prevalence of ventricular arrhythmias is correlated with LGE amount.Both LGE amount and LA diameter are independent predictors of NSVT. Background Hypertrophic cardiomyopathy is the most common inherited genetic cardiovascular disease and the main cause of sudden cardiac death (SCD) in the young, it can also cause other hard end points such as heart failure death and stroke. Themechanism is believed due to malignant ventricular and/or left ventricular outflow tract obstruction (LVOTO), and myocardial fibrosis was thought to be the pathological substrate, as an independent determinant of adverse cardiac events. This study is aim to evaluate the prognostic role of myocardial fibrosis detected by cardiac magnetic resonance late gadolinium enhancement(LGE-CMR) in the mid-term follow up of HCM.Methods From April2010to May2012, we followed up all HCM patients come to our hospital every3to6month intervals, with exclusion of those who had prior gradient reduction therapy. Only new events occurred during the follow up were regards as end points, which primary end points included cardiovascular death, heart transplantation, SCD/aborted SCD, sustained ventricular tachycardia, ventricular fibrillation and appropriate implantable cardiac defibrillator (ICD) discharge; and secondary end point included progressive heart failure, unplanned cardiovascular hospitalization and non-sustained ventricular tachycardia (NSVT). The extent of LGE was divided into three groups:mild (1%-25%/LV), moderate (25%-50%/LV) and severe (>50%/LV). Kaplan-Meier curves and log-rank test were used to estimate the events free survival distributions and compare the difference among different LGE groups. A multivariable Cox proportional hazard model was constructed with a forward selection procedureto estimate the hazard ratio (HR) for the presence or absence of fibrosis and to estimate the effect on the outcomes of increased amounts of fibrosis. Hypertrophic obstructive cardiomyopathy (HOCM) patients were also compared with non-obstructive patients for the events free survival curves, and patients received gradient reduction therapy were compared with those HOCM who didn’t receive any surgical procedure.Results Totally392patients were followed up; including80patients received gradient reduction therapy during the follow-up. Among the312natural procession patients, LGE was observed in218patients (70%). There were statistical significance on NYHA cardiac class, left ventricular mass, average wall thickness, extreme hypertrophy (>30mm), prevalence of atrial fibrillation and NSVT between patients with and without LGE.35patients reached the primary end points, including5in the LGE negative and30in the LGE positive group (5.3%vs.13.8%, p<0.05); while3cardiac deaths,1heart transplantation and9sustained ventricular tachycardia/ventricular fibrillation were all happened in the fibrosis group.77patients reached the secondary end points, including10in the LGE negative and67in the LGE positive (10.6%vs.30.7, p<0.05). There was statistical significance among Kaplan-Meier survival curves among different LGE groups, no matter regarding to primary or secondary end points. The LVOTO and LGE positive were the independent determinants for the primary end points after Cox proportional hazard regression, while only LGE was the risk factor for the secondary end points. There were statistical significance among the events free survival among HOCM, non-obstructive and apical HCM patients, and patients received gradient reduction therapy had better prognosis than those HOCM patients who didn’t received intervention.Conclusion Myocardial fibrosis detected by CMR can play an important prognostic role in HCM. The prognosis of HOCM was worse than the non-obstructive HCM patients, while receive gradient reduction therapy would benefit the mid-term survival.更多还原