冠状动脉微循环障碍的临床和实验研究
|
摘要
冠状动脉(冠脉)血流缓慢现象(coronary slow flow phenomenon, CSFP)指冠脉造影发现正常或几乎正常的冠脉远端血管造影剂充盈延迟。CSFP在冠脉造影中并不罕见,研究发现CSFP患者可导致胸闷、胸痛,甚至恶性心血管事件的发生,可能是冠脉微血管障碍(coronary microvascular dysfunction, CMD)的一种。临床上CSFP患者常被忽视,而目前关于CSFP还有很多未解之谜,需要进一步的研究。
本研究拟入选在我院行冠脉造影的CSFP患者,使用TIMI帧计数法(TIMI frame count, TFC),分析冠脉内使用硝酸甘油或维拉帕米对CSFP患者的治疗效果。
入选64例因胸痛在我院行冠脉造影证实心外膜主要冠脉血管无狭窄病变但血流缓慢的患者(平均年龄57.43±10.87岁,男性75%),根据术者选用的治疗用药分为硝酸甘油组(n=35)和维拉帕米组(n=29)；选取年龄、性别、心血管危险因素等匹配而冠脉血流正常的29例患者为对照组。冠脉血流缓慢定义为造影剂在3个心动周期内不能到达血管末端。硝酸甘油组患者于造影后经造影管冠脉内注入硝酸甘油100-400μg后重复造影至血流明显改善；维拉帕米组则注入维拉帕米100-400μg至血流明显改善。以TFC法定量评价冠脉血流,比较CSFP患者使用硝酸甘油、维拉帕米前后的TFC值和血流正常者的TFC值,以及两组冠脉血流缓慢患者分别使用硝酸甘油和维拉帕米后的TFC变化值。
正常对照组运动平板试验均为阴性,而CSFP患者有部分运动平板试验阳性,但两组差异无统计学意义；三组患者的其他临床资料差异无统计学意义。维拉帕米组存在血流缓慢的冠脉平均(2.14±0.79)支,硝酸甘油组平均(1.97±0.89)支,两组比较差异无统计学意义。两组分别平均使用(262.06±88.29)μg硝酸甘油和(248.57±110.80)μg维拉帕米,两组剂量比较差异无统计学意义。存在血流缓慢的前降支、回旋支、右冠状动脉的基础TFC值在维拉帕米组分别为78.28±19.40、57.24±14.58、56.87±12.47,硝酸甘油组分别为70.84±21.66、55.33±12.52、51.05±15.35,对照组三支血管的TFC值分别为29.15±4.42、23.14±3.48、19.72±1.75。硝酸甘油组和维拉帕米组患者的基础TFC值差异无统计学意义(P>0.05)。维拉帕米组治疗后前降支、回旋支及右冠状动脉TFC值分别下降至37.68±9.31、31.50±11.30、24.58±4.40(与基础状态相比P<0.05),硝酸甘油组治疗后前降支、回旋支及右冠状动脉的TFC值分别下降至42.32±8.88、36.65±6.78、30.32±5.94(与基础状态相比P<0.05),但均高于正常对照组(P<0.05)。而维拉帕米组用药前后的TFC变化值大于硝酸甘油组(P<0.05)。
CSFP可能是CMD的一种表现,可导致患者胸闷、胸痛症状而反复就诊,但常被临床医生忽视,未得到应有的治疗。TIMI帧计数是研究CSFP的有用工具。本研究发现冠脉内注射维拉帕米的治疗效果优于硝酸甘油,但两组患者冠脉血流仍未恢复到正常水平。
冠状动脉微栓塞(coronary microembolization, CME)指由于冠状动脉斑块破裂或血栓脱落等导致远端微小血管阻塞,引起冠脉微血管结构和功能障碍,是冠脉微循环障碍的一种表现。目前,CME的检测还没有金标准。心脏磁共振(magnetic resonance imaging, MRI)检查在心血管疾病诊断中具有独特的优势,而且在CME的动物模型和临床研究中的应用价值也初露端倪：对比剂增强的心脏MRI首过灌注扫描发现心脏异常的低信号区代表由血管阻塞、水肿导致的心肌低灌注区,延迟增强扫描发现心脏异常高信号区代表局部心肌坏死、水肿。
临床上CME多合并有冠心病,很少有单纯的CME情况,目前的研究多从冠脉内注入微栓塞球建立CME的模型进行研究。但由于建立模型的实验动物和微球的剂量、大小等方法的不同,结论难以系统评价。
本研究拟通过冠脉介入的方法建立猪CME模型,采用心脏MRI检查,通过对比剂增强的首过灌注和延迟增强扫描观察微栓塞的微梗死及其范围大小和室壁活动情况,准确测量左室收缩末容积(LVESV)、舒张末容积(LVEDV)、射血分数(LVEF);从而探讨心脏MRI技术在CME中的诊断价值。
18头小型猪,采用冠脉介入方法在左前降支中段注入不同剂量的惰性塑料微球(直径42μm)建立CME动物模型；按照微球剂量不同分为3组：5万微球剂量组(A组)3头,12万微球组(B组)8头,15万微球组(C组)7头。在术前、CME后6h、1w分别行心脏MRI检查。检查应用1.5T超导MR扫描仪(Magnetom Avanto, Siemens AG, Erlangen, Germany)。首先进行心脏定位,电影检查用以测定心功能及室壁运动情况,然后使用高压注射器经耳静脉注射磁共振对比剂Magnevist,剂量0.05mmol/kg,注射速率为4mL/s,完成首过灌注扫描。首过灌注扫描完成后,给予对比剂0.15mmol/kg,延迟10min后完成延迟增强扫描。扫描结束后利用Argus软件对扫描结果进行分析,主要分析是否存在异常信号区、室壁运动情况及左室功能。1w后取出心脏行硝基四氮唑蓝(NBT)染色观察梗死情况。
C组有1头猪术前麻醉过量死亡,1头术后死亡,其余成功完成所有实验。所有16头猪在术前首过灌注扫描和延迟增强均未发现异常低信号或高信号区。A组和B组术后6h心脏MRI在首过灌注扫描均未见到低信号区。A组术后6h的MRI延迟增强扫描在心尖水平可见位于前壁的少量散在异常强化区；术后1w复查MRI示首过灌注扫描和延长灌注显像均未见异常信号区。B组术后6h的MRI延迟增强扫描可见乳头肌水平至心尖水平位于前壁、前间隔的较多片状异常强化灶,而术后1w复查MRI示首过灌注扫描和延迟增强灌注显像均未见异常信号区。C组术后6h首过灌注扫描在乳头肌水平上呈现散在低信号区,延迟增强扫描在乳头肌水平至心尖水平多层面的前壁及前间隔上存在片状延迟强化灶,乳头肌层面明显,且和首过灌注扫描相的部位一致；术后1w复查MRI首过灌注扫描示乳头肌水平上仍存在散在低信号区,延迟增强相示乳头肌水平层面的前壁及前间隔上存在片状延迟强化灶,但高信号区较术后6h时的MRI延迟增强相明显缩小。不同微栓塞剂量组于CME后6h前壁、前间隔均可见不同程度的收缩活动减弱,1w复查时见收缩活动有改善,但仍弱于基础状态。
不同微栓塞剂量组术前,术后6h、1W后测定的LVEDV、LESDV及LVEF分别见表1。CME后的各剂量组LVEDV、LVESV均逐渐增大；LVEF则先下降(6h后)再恢复(1w后)。但各组之间存在差别：A组LVEDV值1w后明显高于术前、CME后6h(P<0.05),CME后6h与术前比较差异无统计学意义；LVESV值术后1w高于术前(P<0.05),而术后6h和术前、术后1w比较差异无统计学意义；LVEF术后6h达最低值(和术前、术后1w比较,P均<0.05),1w后有所恢复,但和术前比较差异无统计学意义。B组LVEDV值术后1w最大(和术前、术后6h比较,P均<0.05),术后6h和术前无明显差异(P>0.05)；LVESV术前低于术后(和术后6h、1w比较,P均<0.05),但术后1w和6h比较差异并无统计学意义(P>0.05)；LVEF术后6h达最低值(和术前、术后1w比较,P均<0.05),1w后和术前无差异(P>0.05)。C组各指标也变化不同,LVED术后1w明显大于术前及术后6h(P均<0.05),但术后6h和术前并无明显差异(P>O.05)；LVESV的变化和12万相同,术前最小(和术后比较,P均<0.05),术后6h、1w无差异(P>0.05),而LVEF则先降到最低点(6h后),再恢复(1w后),但并不能恢复至术前水平(术前、术后6h、1w比较,p均<0.05)。
术前,术后6h、1w各时间点3种不同剂量微球组之间比较发现,术前仅A组LVESV低于B组(P<0.05),其余指标差异无统计学意义(P均>0.05);术后6h左室大小、LVEF各组之间并无差异(P均>0.05)；术后1w,A组的LVEDV、LVESV均低于B组(P均<0.05),其余指标差异无统计学意义(P均>0.05)。
CME术后1w心肌NBT染色发现只有C组在乳头肌水平前壁部位存在梗死区,且和MRI发现的首过灌注扫描和1w后延迟增强扫描的异常信号区一致。
对比剂增强的首过灌注扫描和延迟增强心脏MRI可以检测CME后的微小梗死灶,但和微球的数量相关,微梗死灶越大,越容易被发现。而CME后左室发生不同程度的重构和收缩功能改变,左室收缩功能6h后下降,1w后渐恢复,但左室重构的程度和左室收缩功能的变化不相关。左室收缩功能的变化和微球剂量、微梗死面积大小之间并没有相关性。心脏MRI可以用来检测冠脉微栓塞后微梗死灶,准确测量左室大小、收缩功能,有很大的临床应用价值。
CME可导致心肌缺血、坏死,引起心脏重构、功能障碍,最终使患者不良事件增多,影响预后。CME后引起心室重构的机制目前不是很清楚,研究证实CME后炎症、肿瘤坏死因子α(tumor necrosis factorα, TNF-1α)表达在影响左室重构起了很重要的作用。Toll样受体(Toll-like receptors, TLRs)家族和核转录因子κB (nuclear factor kappa B, NF-κB)在许多炎症性疾病中参与了的发病过程,是TNF-α的上游传导通路。但TLR4/NF-κB是否参与了CME后的左室重构并不清楚。
本研究拟通过冠脉介入的方法建立不同剂量的猪CME模型,检测心肌组织的TLR4和NF-κB的表达情况,初步探讨TLR4/NF-κB是否也参与了CME后炎症、左室重构的过程。
9头小型猪,采用冠脉介入方法在左前降支中段注入不同剂量的惰性塑料微球建立CME模型,其中5万微球组(A组)、12万微球组(B组)各1头,15万微球组(C组)6头。另1头为假手术组作为对照(假手术组冠脉内注入等量的生理盐水)。1w后取心脏前壁、后壁心肌组织行Western-Blot、Real Time PCR检测TLR4的表达,行Western-Blot检测NF-κB的表达、电泳迁移率检测NF-κB的活性。
和对照组比较,C组后壁组织的TLR4的表达、NF-κB的表达及活性无明显增强,前壁心肌组织TLR4的表达、NF-κB的表达及活性均增强。C组前壁TLR4的表达、NF-κB的表达及活性均比后壁明显增强(P<0.05),而不同剂量的3组前壁TLR4的表达、NF-κB的表达及活性类似。
CME后1w,受累心肌组织中TLR4、NF-κB表达升高、活性增强。CME前后,前、后壁心肌组织中TLR4、NF-κB表达一致,提示TLR4/NF-κB通路可能参与了CME后炎症反应、左室重构的过程。
The coronary slow flow phenomenon (CSFP) was defined as abnormally slow antegrade progression of contrast during coronary arteriography in the normal or near-normal coronary arteries. Although the phenomenon is not rarely found in coronary angiography, CSFP patients have poor life qualities with recurrent chest pain and adverse cardiac events, and CSFP may be one of the diseases of coronary microvascular dysfunction (CMD). The CSFP was ignored usually by cardiologists, and until now, we know little about CSFP. Therefore, it needs further study.
The aim of this study was to assess the benefit of intracoronary administration of nitroglycerin and verapamil in the coronary flow in patients with CSFP according to the TIMI frame count (TFC).
Sixty-four patients (mean age 57.43±10.87, male 75%) with coronary slow flow and no stenotic lesions during diagnostic coronary angiography because of chest pain were enrolled and divided into the nitroglycerin group (n=35) and verapamil group (n=29), and 29 patients with normal coronary flow were selected as control. CSFP was defined as four or more beats for the contrast media to opacify the distal vasculature. Intracoronary injection of 100-400μg nitroglycerin or verapamil through the diagnostic catheter was not given in patients with CSFP until the coronary flow improved. The coronary blood flow was evaluated by Thrombolysis In Myocardial Infarction (TIMI) frame count (TFC) method in this study.
Positive treadmill test was observed in some of patients in nitroglycerin group and verapamil group with CSFP (P>0.05) as compared with none of the 29 patients in the control group. There was no difference regarding the other clinical characteristics among the three groups. Each patient had 2.14±0.79 slow flow coronary arteries with (262.06±88.29)μg nitroglycerin in nitroglycerin group and 1.97±0.89 slow flow coronary arteries with (248.57±110.80)μg verapamil in verapamil group, respectively, and there was no difference in patients with CSFP. The basic TFCs of left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA) were 78.28±19.40,57.24±14.58,56.87±12.47 in the verapamil group, and were 70.84±21.66,55.33±12.52,51.05±15.35 in the nitroglycerin group, respectively, which were significantly higher than those in the normal controls (LAD 29.15±4.42, LCX 23.14±3.48 and RCA 19.72±1.75, respectively). There was no difference in the basic TFCs in the CSFP patients (P＞0.05). After the administration of drugs, the TFCs of LAD, LCX and RCA were 42.32±8.88,36.65±6.78,30.32±5.94 respectively (vs. base, all P＜0.05) in the nitroglycerin group and 37.68±9.31,31.50±11.30,24.58±4.40 respectively (vs. base, all P<0.05) in the verapamil group. The TFCs in both of groups after administration of drugs were still higher than those in normal controls (all P<0.05). The TFCs in the verapamil group had larger decrease than those in the nitroglycerin group (P<0.05).
CSFP may be the result of CMD, which may refer to cardiologists complaint of chest pain and other symptoms of coronary artery diseases once and again and most of them was ignored. TFC is the useful method to study CSFP. Intracoronary administration of verapamil could obtain more improvement of the coronary flow in patients with CSFP than nitroglycerin, although the coronary flow were still slower than normal.
The rupture debris of atherosclerotic plaque and thrombus resulted in coronary microembolization (CME) with the dysfunction of coronary microvessels, which was the manifestation of CMD. Until now, there is no gold standard on the detection of CME. Cardiac magnetic resonance imaging (MRI) has unique advantages in the diagnosis of cardiovascular diseases and became to be applied in clinical settings and models of CME. The contrast enhanced first-pass perfusion imaging of cardiac MRI could reveal the hypoenhanced zone which is the sign of myocardial hypoperfusion caused by coronary obstruction and edema, and the delayed contrast enhancement of cardiac MRI could reveal the abnormal hyperenhanced zone which is the sign of local myocardial necrosis and edema.
There was little simple CME in the clinic that were usually accompanied by coronary artery diseases, and therefore, the CME models were built to study by injection microspheres into coronary arteries. It's hard to evaluate the conclusions of all the studies on this problem because of different CME animals with different methods.
In this study, we built the swine CME models. Cardiac MRI, including cine MRI, first-pass perfusion imaging and delayed contrast enhancement was used to observe the microinfarct area and left ventricular wall motions and evaluate the left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) to assess the value of cardiac MRI in detection of CME.
CME models were made by injection of inertia plastic microspheres (diameter 42μm) into left anterior descending coronary in eighteen swines. According to the doses of microspheres, the swines were divided to three groups, three for group A with 50000 microspheres, eight for group B with 120000 microspheres and seven for group C with 150000 microspheres. Cardiac MRI was performed at base, six hours and one week after CME using 1.5T system (Magnetom Avanto, Siemens AG, Erlangen, Germany). Cine MRI was acquired to observe the motion of ventricular wall. After the cine MRI images were obtained, the swines received intravenous bolus of 0.05 mmol/kg Gd-DTPA (Magnevist) at a rate of 4mL/s for the first-pass perfusion images. Then, a second bolus of 0.15mmol/kg Gd-DTPA was given, and after ten minutes, delayed contrast images were acquired. Results were analyzed with Argus software to observe the abnormal signal regions, the left ventricular wall motions and calculate the left ventricular volume and ejection fraction. After experiment finished one week later, swines were sacrificed and the hearts were taken out for NBT staining to observe the infarction.
Two swines died before the end of study in group C. No abnormality was found at base for all the sixteen swines. Hypoenhanced region on first-pass perfusion imaging was only observed in group C at papillary level six hours after CME and it became less obvious one week later. Delayed enhanced areas were found on short-axis sections in all the swines six hours after CME, and the areas in group A were less than the other two groups which existed only in anterior wall at apical level in group A and in anterior and anterior septal wall from papillary to apical levels in group B and group C. However, the delayed enhanced areas disappeared one week later in group A and group B on repeated MR imaging. And in group C the hyperenhanced regions diminished and only existed at papillary level one week after CME, which were consistent with NBT pathologic findings. Systolic function of anterior and anterior septal wall were impaired in all the swines and improved slightly one week later.
The left ventricular volume of all the swines was enlarged gradually, but the LVEF decreased six hours after CME and recovered one week later. In group A, LVEDV was (32.53±1.13) ml, (33.24±2.11) ml and (38.95±2.67) ml (one week vs. at base and six hours,P<0.05, respectively) at base, six hours and one week later, respectively. LVESV was (16.24±1.14) ml, (19.83±1.58) ml and (20.29±1.52) ml (one week vs. at base, P＜0.05) at base, six hours and one week later, respectively. LVEF was 0.50±0.02,0.40±0.02 and 0.48±0.01 (six hours vs. at base and one week, P<0.05, respectively) at base, six hours and one week later, respectively. In group B, LVEDV was (39.82±4.65) ml, (40.40±4.79) ml and (49.03±3.95) ml for the three different time (one week vs. at base and six hours, P＜0.05, respectively), and LVESV was (20.61±2.42) ml, (24.22±2.69) ml and (26.29±3.10) ml (at base vs. six hours and one week, P<0.05, respectively), and LVEF was 0.48±0.06,0.40±0.07,0.46±0.06 (six hours vs. base, P＜0.05; six hours vs. one week, P＜0.05), respectively. In group C, LVEDV was (39.03±4.89) ml, (40.71±4.22) ml and (47.48±5.53) ml for the three time (one week vs. base, P<0.05; one week vs. six hours, P＜0.05), and LVESV was (18.63±1.93) ml, (23.62±2.41) ml and (24.73±2.07) ml (base vs. six hours, P<0.05; base vs. one week, P＜0.05), and LVEF was 0.52±0.05,0.42±0.05 and 0.48±0.05 (all P<0.05 for each two time).
At base, LVESV of group A was less than group B (P＜0.05) and there was no difference for other parameters for different time. Six hours after CME, there was no difference for other parameters among the three groups. One week later, LVEDV and LVESV of group A was less than that of group B (P<0.05), and there was no difference for other parameters among the three groups.
Myocardial microinfarction were observed only at papillary muscle level in the swines of group C at NBT staining which was consistent with the MRI findings.
First-pass perfusion imaging and delayed contrast enhancement cardiac MRI could detect myocardial microinfarction, which were related to the amount of microspheres and the areas of myocardial infarction, and the larger the necrosis, the more easily it was found. Systolic function of myocardial wall was impaired after CME, and it decreased six hours later and recovered one week later. The change of LVEF was accompanied by the dilation of ventricular cavity, which indicated the procedure of ventricular remodeling was not consistent with the change of systolic function. The change of function of left ventricle was not associated with the dose of microspheres or the infarct sizes. Cardiac MRI is useful for the detection of CME.
The coronary microembolization (CME) could result in myocardial ischemia and necrosis with cardiac remodeling and dysfunction. And the morbidity of adverse coronary events increases in CME patients with worse prognosis. The mechanism of cardiac remodeling and dysfunction remains unknown. Previous studies demonstrated that the inflammation with over-expression of tumor necrosis factorα(TNF-α) played an important role in the change of structure and function of heart with CME. Toll-like receptors (TLRs) family and nuclear factor kappa B (NF-κB) are the upstream signal of TNF-α, which participated in many inflammatory diseases. But it's unclear whether the TLR4/NF-κB signal transduction system is involved in the cardiac remodeling and dysfunction after CME.
In this study, we detected TLR4 and NF-κB expression in the CME model to preliminarily study the role of TLR4/NF-κB system in the progress remodeling and inflammation after CME.
The piglet CME model was built according to Part Two. Six swines were enrolled in group C with 150000 microspheres, and each swine in group A with 50000 microspheres and group B with 120000 microspheres. One swine was selected as control with sham operation (the sham operation group was built by intracoronary injection of same doses of normal saline). One week later, the hearts were removed. TLR4 were detected in myocardial tissue of anterior wall and posterior wall using Western-Blot and Real Time PCR. Western-Blot was used to detect NF-κB expression and electrophoretic mobility shift assay (EMSA) was used to detect NF-κB DNA-binding activity of myocardial tissue of anterior wall and posterior wall. One swine died when operation for group C. Compared to control group, the expression of TLR4 and NF-κB and activity of NF-κB of posterior wall were unchanged, which were enhanced in the anterior wall in group C. And in group C of CME, the expression of TLR4 and NF-κB and activity of NF-κB of anterior wall were elevated than those of posterior wall P＜0.05), but it seemed that there were no difference of TLR4 and NF-κB in anterior wall among all the CME groups.
One week after CME, the expressions of TLR4 and NF-κB in the affected myocardial tissue were elevated. The expression of TLR4 in the abnormal and normal myocardial tissue before and after CME were consistent with NF-κB, which suggested that TLR4/NF-κB signal transduction system may participate in the inflammation and cardiac remodeling after CME.
本研究拟入选在我院行冠脉造影的CSFP患者,使用TIMI帧计数法(TIMI frame count, TFC),分析冠脉内使用硝酸甘油或维拉帕米对CSFP患者的治疗效果。
入选64例因胸痛在我院行冠脉造影证实心外膜主要冠脉血管无狭窄病变但血流缓慢的患者(平均年龄57.43±10.87岁,男性75%),根据术者选用的治疗用药分为硝酸甘油组(n=35)和维拉帕米组(n=29)；选取年龄、性别、心血管危险因素等匹配而冠脉血流正常的29例患者为对照组。冠脉血流缓慢定义为造影剂在3个心动周期内不能到达血管末端。硝酸甘油组患者于造影后经造影管冠脉内注入硝酸甘油100-400μg后重复造影至血流明显改善；维拉帕米组则注入维拉帕米100-400μg至血流明显改善。以TFC法定量评价冠脉血流,比较CSFP患者使用硝酸甘油、维拉帕米前后的TFC值和血流正常者的TFC值,以及两组冠脉血流缓慢患者分别使用硝酸甘油和维拉帕米后的TFC变化值。
正常对照组运动平板试验均为阴性,而CSFP患者有部分运动平板试验阳性,但两组差异无统计学意义；三组患者的其他临床资料差异无统计学意义。维拉帕米组存在血流缓慢的冠脉平均(2.14±0.79)支,硝酸甘油组平均(1.97±0.89)支,两组比较差异无统计学意义。两组分别平均使用(262.06±88.29)μg硝酸甘油和(248.57±110.80)μg维拉帕米,两组剂量比较差异无统计学意义。存在血流缓慢的前降支、回旋支、右冠状动脉的基础TFC值在维拉帕米组分别为78.28±19.40、57.24±14.58、56.87±12.47,硝酸甘油组分别为70.84±21.66、55.33±12.52、51.05±15.35,对照组三支血管的TFC值分别为29.15±4.42、23.14±3.48、19.72±1.75。硝酸甘油组和维拉帕米组患者的基础TFC值差异无统计学意义(P>0.05)。维拉帕米组治疗后前降支、回旋支及右冠状动脉TFC值分别下降至37.68±9.31、31.50±11.30、24.58±4.40(与基础状态相比P<0.05),硝酸甘油组治疗后前降支、回旋支及右冠状动脉的TFC值分别下降至42.32±8.88、36.65±6.78、30.32±5.94(与基础状态相比P<0.05),但均高于正常对照组(P<0.05)。而维拉帕米组用药前后的TFC变化值大于硝酸甘油组(P<0.05)。
CSFP可能是CMD的一种表现,可导致患者胸闷、胸痛症状而反复就诊,但常被临床医生忽视,未得到应有的治疗。TIMI帧计数是研究CSFP的有用工具。本研究发现冠脉内注射维拉帕米的治疗效果优于硝酸甘油,但两组患者冠脉血流仍未恢复到正常水平。
冠状动脉微栓塞(coronary microembolization, CME)指由于冠状动脉斑块破裂或血栓脱落等导致远端微小血管阻塞,引起冠脉微血管结构和功能障碍,是冠脉微循环障碍的一种表现。目前,CME的检测还没有金标准。心脏磁共振(magnetic resonance imaging, MRI)检查在心血管疾病诊断中具有独特的优势,而且在CME的动物模型和临床研究中的应用价值也初露端倪：对比剂增强的心脏MRI首过灌注扫描发现心脏异常的低信号区代表由血管阻塞、水肿导致的心肌低灌注区,延迟增强扫描发现心脏异常高信号区代表局部心肌坏死、水肿。
临床上CME多合并有冠心病,很少有单纯的CME情况,目前的研究多从冠脉内注入微栓塞球建立CME的模型进行研究。但由于建立模型的实验动物和微球的剂量、大小等方法的不同,结论难以系统评价。
本研究拟通过冠脉介入的方法建立猪CME模型,采用心脏MRI检查,通过对比剂增强的首过灌注和延迟增强扫描观察微栓塞的微梗死及其范围大小和室壁活动情况,准确测量左室收缩末容积(LVESV)、舒张末容积(LVEDV)、射血分数(LVEF);从而探讨心脏MRI技术在CME中的诊断价值。
18头小型猪,采用冠脉介入方法在左前降支中段注入不同剂量的惰性塑料微球(直径42μm)建立CME动物模型；按照微球剂量不同分为3组：5万微球剂量组(A组)3头,12万微球组(B组)8头,15万微球组(C组)7头。在术前、CME后6h、1w分别行心脏MRI检查。检查应用1.5T超导MR扫描仪(Magnetom Avanto, Siemens AG, Erlangen, Germany)。首先进行心脏定位,电影检查用以测定心功能及室壁运动情况,然后使用高压注射器经耳静脉注射磁共振对比剂Magnevist,剂量0.05mmol/kg,注射速率为4mL/s,完成首过灌注扫描。首过灌注扫描完成后,给予对比剂0.15mmol/kg,延迟10min后完成延迟增强扫描。扫描结束后利用Argus软件对扫描结果进行分析,主要分析是否存在异常信号区、室壁运动情况及左室功能。1w后取出心脏行硝基四氮唑蓝(NBT)染色观察梗死情况。
C组有1头猪术前麻醉过量死亡,1头术后死亡,其余成功完成所有实验。所有16头猪在术前首过灌注扫描和延迟增强均未发现异常低信号或高信号区。A组和B组术后6h心脏MRI在首过灌注扫描均未见到低信号区。A组术后6h的MRI延迟增强扫描在心尖水平可见位于前壁的少量散在异常强化区；术后1w复查MRI示首过灌注扫描和延长灌注显像均未见异常信号区。B组术后6h的MRI延迟增强扫描可见乳头肌水平至心尖水平位于前壁、前间隔的较多片状异常强化灶,而术后1w复查MRI示首过灌注扫描和延迟增强灌注显像均未见异常信号区。C组术后6h首过灌注扫描在乳头肌水平上呈现散在低信号区,延迟增强扫描在乳头肌水平至心尖水平多层面的前壁及前间隔上存在片状延迟强化灶,乳头肌层面明显,且和首过灌注扫描相的部位一致；术后1w复查MRI首过灌注扫描示乳头肌水平上仍存在散在低信号区,延迟增强相示乳头肌水平层面的前壁及前间隔上存在片状延迟强化灶,但高信号区较术后6h时的MRI延迟增强相明显缩小。不同微栓塞剂量组于CME后6h前壁、前间隔均可见不同程度的收缩活动减弱,1w复查时见收缩活动有改善,但仍弱于基础状态。
不同微栓塞剂量组术前,术后6h、1W后测定的LVEDV、LESDV及LVEF分别见表1。CME后的各剂量组LVEDV、LVESV均逐渐增大；LVEF则先下降(6h后)再恢复(1w后)。但各组之间存在差别：A组LVEDV值1w后明显高于术前、CME后6h(P<0.05),CME后6h与术前比较差异无统计学意义；LVESV值术后1w高于术前(P<0.05),而术后6h和术前、术后1w比较差异无统计学意义；LVEF术后6h达最低值(和术前、术后1w比较,P均<0.05),1w后有所恢复,但和术前比较差异无统计学意义。B组LVEDV值术后1w最大(和术前、术后6h比较,P均<0.05),术后6h和术前无明显差异(P>0.05)；LVESV术前低于术后(和术后6h、1w比较,P均<0.05),但术后1w和6h比较差异并无统计学意义(P>0.05)；LVEF术后6h达最低值(和术前、术后1w比较,P均<0.05),1w后和术前无差异(P>0.05)。C组各指标也变化不同,LVED术后1w明显大于术前及术后6h(P均<0.05),但术后6h和术前并无明显差异(P>O.05)；LVESV的变化和12万相同,术前最小(和术后比较,P均<0.05),术后6h、1w无差异(P>0.05),而LVEF则先降到最低点(6h后),再恢复(1w后),但并不能恢复至术前水平(术前、术后6h、1w比较,p均<0.05)。
术前,术后6h、1w各时间点3种不同剂量微球组之间比较发现,术前仅A组LVESV低于B组(P<0.05),其余指标差异无统计学意义(P均>0.05);术后6h左室大小、LVEF各组之间并无差异(P均>0.05)；术后1w,A组的LVEDV、LVESV均低于B组(P均<0.05),其余指标差异无统计学意义(P均>0.05)。
CME术后1w心肌NBT染色发现只有C组在乳头肌水平前壁部位存在梗死区,且和MRI发现的首过灌注扫描和1w后延迟增强扫描的异常信号区一致。
对比剂增强的首过灌注扫描和延迟增强心脏MRI可以检测CME后的微小梗死灶,但和微球的数量相关,微梗死灶越大,越容易被发现。而CME后左室发生不同程度的重构和收缩功能改变,左室收缩功能6h后下降,1w后渐恢复,但左室重构的程度和左室收缩功能的变化不相关。左室收缩功能的变化和微球剂量、微梗死面积大小之间并没有相关性。心脏MRI可以用来检测冠脉微栓塞后微梗死灶,准确测量左室大小、收缩功能,有很大的临床应用价值。
CME可导致心肌缺血、坏死,引起心脏重构、功能障碍,最终使患者不良事件增多,影响预后。CME后引起心室重构的机制目前不是很清楚,研究证实CME后炎症、肿瘤坏死因子α(tumor necrosis factorα, TNF-1α)表达在影响左室重构起了很重要的作用。Toll样受体(Toll-like receptors, TLRs)家族和核转录因子κB (nuclear factor kappa B, NF-κB)在许多炎症性疾病中参与了的发病过程,是TNF-α的上游传导通路。但TLR4/NF-κB是否参与了CME后的左室重构并不清楚。
本研究拟通过冠脉介入的方法建立不同剂量的猪CME模型,检测心肌组织的TLR4和NF-κB的表达情况,初步探讨TLR4/NF-κB是否也参与了CME后炎症、左室重构的过程。
9头小型猪,采用冠脉介入方法在左前降支中段注入不同剂量的惰性塑料微球建立CME模型,其中5万微球组(A组)、12万微球组(B组)各1头,15万微球组(C组)6头。另1头为假手术组作为对照(假手术组冠脉内注入等量的生理盐水)。1w后取心脏前壁、后壁心肌组织行Western-Blot、Real Time PCR检测TLR4的表达,行Western-Blot检测NF-κB的表达、电泳迁移率检测NF-κB的活性。
和对照组比较,C组后壁组织的TLR4的表达、NF-κB的表达及活性无明显增强,前壁心肌组织TLR4的表达、NF-κB的表达及活性均增强。C组前壁TLR4的表达、NF-κB的表达及活性均比后壁明显增强(P<0.05),而不同剂量的3组前壁TLR4的表达、NF-κB的表达及活性类似。
CME后1w,受累心肌组织中TLR4、NF-κB表达升高、活性增强。CME前后,前、后壁心肌组织中TLR4、NF-κB表达一致,提示TLR4/NF-κB通路可能参与了CME后炎症反应、左室重构的过程。
The coronary slow flow phenomenon (CSFP) was defined as abnormally slow antegrade progression of contrast during coronary arteriography in the normal or near-normal coronary arteries. Although the phenomenon is not rarely found in coronary angiography, CSFP patients have poor life qualities with recurrent chest pain and adverse cardiac events, and CSFP may be one of the diseases of coronary microvascular dysfunction (CMD). The CSFP was ignored usually by cardiologists, and until now, we know little about CSFP. Therefore, it needs further study.
The aim of this study was to assess the benefit of intracoronary administration of nitroglycerin and verapamil in the coronary flow in patients with CSFP according to the TIMI frame count (TFC).
Sixty-four patients (mean age 57.43±10.87, male 75%) with coronary slow flow and no stenotic lesions during diagnostic coronary angiography because of chest pain were enrolled and divided into the nitroglycerin group (n=35) and verapamil group (n=29), and 29 patients with normal coronary flow were selected as control. CSFP was defined as four or more beats for the contrast media to opacify the distal vasculature. Intracoronary injection of 100-400μg nitroglycerin or verapamil through the diagnostic catheter was not given in patients with CSFP until the coronary flow improved. The coronary blood flow was evaluated by Thrombolysis In Myocardial Infarction (TIMI) frame count (TFC) method in this study.
Positive treadmill test was observed in some of patients in nitroglycerin group and verapamil group with CSFP (P>0.05) as compared with none of the 29 patients in the control group. There was no difference regarding the other clinical characteristics among the three groups. Each patient had 2.14±0.79 slow flow coronary arteries with (262.06±88.29)μg nitroglycerin in nitroglycerin group and 1.97±0.89 slow flow coronary arteries with (248.57±110.80)μg verapamil in verapamil group, respectively, and there was no difference in patients with CSFP. The basic TFCs of left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA) were 78.28±19.40,57.24±14.58,56.87±12.47 in the verapamil group, and were 70.84±21.66,55.33±12.52,51.05±15.35 in the nitroglycerin group, respectively, which were significantly higher than those in the normal controls (LAD 29.15±4.42, LCX 23.14±3.48 and RCA 19.72±1.75, respectively). There was no difference in the basic TFCs in the CSFP patients (P＞0.05). After the administration of drugs, the TFCs of LAD, LCX and RCA were 42.32±8.88,36.65±6.78,30.32±5.94 respectively (vs. base, all P＜0.05) in the nitroglycerin group and 37.68±9.31,31.50±11.30,24.58±4.40 respectively (vs. base, all P<0.05) in the verapamil group. The TFCs in both of groups after administration of drugs were still higher than those in normal controls (all P<0.05). The TFCs in the verapamil group had larger decrease than those in the nitroglycerin group (P<0.05).
CSFP may be the result of CMD, which may refer to cardiologists complaint of chest pain and other symptoms of coronary artery diseases once and again and most of them was ignored. TFC is the useful method to study CSFP. Intracoronary administration of verapamil could obtain more improvement of the coronary flow in patients with CSFP than nitroglycerin, although the coronary flow were still slower than normal.
The rupture debris of atherosclerotic plaque and thrombus resulted in coronary microembolization (CME) with the dysfunction of coronary microvessels, which was the manifestation of CMD. Until now, there is no gold standard on the detection of CME. Cardiac magnetic resonance imaging (MRI) has unique advantages in the diagnosis of cardiovascular diseases and became to be applied in clinical settings and models of CME. The contrast enhanced first-pass perfusion imaging of cardiac MRI could reveal the hypoenhanced zone which is the sign of myocardial hypoperfusion caused by coronary obstruction and edema, and the delayed contrast enhancement of cardiac MRI could reveal the abnormal hyperenhanced zone which is the sign of local myocardial necrosis and edema.
There was little simple CME in the clinic that were usually accompanied by coronary artery diseases, and therefore, the CME models were built to study by injection microspheres into coronary arteries. It's hard to evaluate the conclusions of all the studies on this problem because of different CME animals with different methods.
In this study, we built the swine CME models. Cardiac MRI, including cine MRI, first-pass perfusion imaging and delayed contrast enhancement was used to observe the microinfarct area and left ventricular wall motions and evaluate the left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) to assess the value of cardiac MRI in detection of CME.
CME models were made by injection of inertia plastic microspheres (diameter 42μm) into left anterior descending coronary in eighteen swines. According to the doses of microspheres, the swines were divided to three groups, three for group A with 50000 microspheres, eight for group B with 120000 microspheres and seven for group C with 150000 microspheres. Cardiac MRI was performed at base, six hours and one week after CME using 1.5T system (Magnetom Avanto, Siemens AG, Erlangen, Germany). Cine MRI was acquired to observe the motion of ventricular wall. After the cine MRI images were obtained, the swines received intravenous bolus of 0.05 mmol/kg Gd-DTPA (Magnevist) at a rate of 4mL/s for the first-pass perfusion images. Then, a second bolus of 0.15mmol/kg Gd-DTPA was given, and after ten minutes, delayed contrast images were acquired. Results were analyzed with Argus software to observe the abnormal signal regions, the left ventricular wall motions and calculate the left ventricular volume and ejection fraction. After experiment finished one week later, swines were sacrificed and the hearts were taken out for NBT staining to observe the infarction.
Two swines died before the end of study in group C. No abnormality was found at base for all the sixteen swines. Hypoenhanced region on first-pass perfusion imaging was only observed in group C at papillary level six hours after CME and it became less obvious one week later. Delayed enhanced areas were found on short-axis sections in all the swines six hours after CME, and the areas in group A were less than the other two groups which existed only in anterior wall at apical level in group A and in anterior and anterior septal wall from papillary to apical levels in group B and group C. However, the delayed enhanced areas disappeared one week later in group A and group B on repeated MR imaging. And in group C the hyperenhanced regions diminished and only existed at papillary level one week after CME, which were consistent with NBT pathologic findings. Systolic function of anterior and anterior septal wall were impaired in all the swines and improved slightly one week later.
The left ventricular volume of all the swines was enlarged gradually, but the LVEF decreased six hours after CME and recovered one week later. In group A, LVEDV was (32.53±1.13) ml, (33.24±2.11) ml and (38.95±2.67) ml (one week vs. at base and six hours,P<0.05, respectively) at base, six hours and one week later, respectively. LVESV was (16.24±1.14) ml, (19.83±1.58) ml and (20.29±1.52) ml (one week vs. at base, P＜0.05) at base, six hours and one week later, respectively. LVEF was 0.50±0.02,0.40±0.02 and 0.48±0.01 (six hours vs. at base and one week, P<0.05, respectively) at base, six hours and one week later, respectively. In group B, LVEDV was (39.82±4.65) ml, (40.40±4.79) ml and (49.03±3.95) ml for the three different time (one week vs. at base and six hours, P＜0.05, respectively), and LVESV was (20.61±2.42) ml, (24.22±2.69) ml and (26.29±3.10) ml (at base vs. six hours and one week, P<0.05, respectively), and LVEF was 0.48±0.06,0.40±0.07,0.46±0.06 (six hours vs. base, P＜0.05; six hours vs. one week, P＜0.05), respectively. In group C, LVEDV was (39.03±4.89) ml, (40.71±4.22) ml and (47.48±5.53) ml for the three time (one week vs. base, P<0.05; one week vs. six hours, P＜0.05), and LVESV was (18.63±1.93) ml, (23.62±2.41) ml and (24.73±2.07) ml (base vs. six hours, P<0.05; base vs. one week, P＜0.05), and LVEF was 0.52±0.05,0.42±0.05 and 0.48±0.05 (all P<0.05 for each two time).
At base, LVESV of group A was less than group B (P＜0.05) and there was no difference for other parameters for different time. Six hours after CME, there was no difference for other parameters among the three groups. One week later, LVEDV and LVESV of group A was less than that of group B (P<0.05), and there was no difference for other parameters among the three groups.
Myocardial microinfarction were observed only at papillary muscle level in the swines of group C at NBT staining which was consistent with the MRI findings.
First-pass perfusion imaging and delayed contrast enhancement cardiac MRI could detect myocardial microinfarction, which were related to the amount of microspheres and the areas of myocardial infarction, and the larger the necrosis, the more easily it was found. Systolic function of myocardial wall was impaired after CME, and it decreased six hours later and recovered one week later. The change of LVEF was accompanied by the dilation of ventricular cavity, which indicated the procedure of ventricular remodeling was not consistent with the change of systolic function. The change of function of left ventricle was not associated with the dose of microspheres or the infarct sizes. Cardiac MRI is useful for the detection of CME.
The coronary microembolization (CME) could result in myocardial ischemia and necrosis with cardiac remodeling and dysfunction. And the morbidity of adverse coronary events increases in CME patients with worse prognosis. The mechanism of cardiac remodeling and dysfunction remains unknown. Previous studies demonstrated that the inflammation with over-expression of tumor necrosis factorα(TNF-α) played an important role in the change of structure and function of heart with CME. Toll-like receptors (TLRs) family and nuclear factor kappa B (NF-κB) are the upstream signal of TNF-α, which participated in many inflammatory diseases. But it's unclear whether the TLR4/NF-κB signal transduction system is involved in the cardiac remodeling and dysfunction after CME.
In this study, we detected TLR4 and NF-κB expression in the CME model to preliminarily study the role of TLR4/NF-κB system in the progress remodeling and inflammation after CME.
The piglet CME model was built according to Part Two. Six swines were enrolled in group C with 150000 microspheres, and each swine in group A with 50000 microspheres and group B with 120000 microspheres. One swine was selected as control with sham operation (the sham operation group was built by intracoronary injection of same doses of normal saline). One week later, the hearts were removed. TLR4 were detected in myocardial tissue of anterior wall and posterior wall using Western-Blot and Real Time PCR. Western-Blot was used to detect NF-κB expression and electrophoretic mobility shift assay (EMSA) was used to detect NF-κB DNA-binding activity of myocardial tissue of anterior wall and posterior wall. One swine died when operation for group C. Compared to control group, the expression of TLR4 and NF-κB and activity of NF-κB of posterior wall were unchanged, which were enhanced in the anterior wall in group C. And in group C of CME, the expression of TLR4 and NF-κB and activity of NF-κB of anterior wall were elevated than those of posterior wall P＜0.05), but it seemed that there were no difference of TLR4 and NF-κB in anterior wall among all the CME groups.
One week after CME, the expressions of TLR4 and NF-κB in the affected myocardial tissue were elevated. The expression of TLR4 in the abnormal and normal myocardial tissue before and after CME were consistent with NF-κB, which suggested that TLR4/NF-κB signal transduction system may participate in the inflammation and cardiac remodeling after CME.
引文
性塑料微球(直径42μm)建立冠脉微栓塞动物模型；按照微球剂量不同分为3组：5万,12万和15万微球组3组。在术前、CME术后6h、1w分别行心脏电影、对比剂增强的首过灌注扫描和延迟增强MRI检查。我们发现首过灌注扫描和延迟增强心脏MRI可以检测CME后的微小梗死灶,但和微球的数量相关,微梗死灶越大,越容易被发现。而CME后左室发生不同程度的心室重构和收缩功能改变,左室收缩功能6h后下降,1w后渐恢复,但左室重构的程度和左室收缩功能的变化不相关。左室收缩功能的变化和微球剂量、微梗死面积大小之间并没有相关性。心脏MRI可以用来检测冠脉微栓塞后微梗死灶,准确测量左室大小、收缩功能,有很大的临床应用价值。
CME后引起心室重构的机制目前不是很清楚,研究证实CME后炎症、肿瘤坏死因子α (tumor necrosis factor α, TNF-α)表达在影响左室重构起了很重要的作用。Toll样受体(Toll-like receptors, TLRs)家族和核转录因子κB (nuclear factor kappa B, NF-κB)在许多炎症性疾病中参与了的发病过程,是TNF-a的上游传导通路。但TLR4/NF-KB是否参与了冠脉微栓塞后的左室重构并不清楚。我们通过冠脉介入的方法建立不同剂量的猪CME模型,检测心肌组织的TLR4和NF-κB的表达情况,发现CME后1w,受累前壁心肌组织中TLR4、NF-κB表达升高、活性增强。CME术前术后,前、后壁心肌组织中TLR4、NF-κB表达一致,提示TLR4/NF-κB通路可能参与了CME后炎症反应、左室重构的过程。
本次研究,我们回顾分析CSFP患者,探讨了硝酸甘油、维拉帕米的治疗价值；建立CME的动物模型,评价了心脏MRI诊断价值,并初步研究了CME后左室重构、左室功能异常的机制,对临床治疗CMD具有很大的指导价值。
[1]Camici, P. G., Crea, F. Medical progress - Coronary microvascular dysfunction[J]. New England Journal of Medicine,2007,356(8):830-840.
[2]Fineschi, M., Gori, T. Coronary slow flow:Description of a new "cardiac Y" syndrome[J]. International Journal of Cardiology,2009,137(3):308-310.
[3]Heusch, G., Kleinbongard, P., Bose, D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside[J]. Circulation,2009,120(18): 1822-1836. 未能使CSFP患者的冠脉血流达到正常水平。可能由于：(1)不同的患者异常功能小血管的位置不同,有些是直径200μm以下的微血管功能障碍,而维拉帕米对微血管阻力降低的效果优于硝酸甘油。我们的研究也从另一方面支持冠脉微血管功能异常可能是CSFP的原因这一假设。(2)不同CSFP患者冠脉血流缓慢的发病机制不同,体内异常增多的引起微血管收缩的缩血管物质种类也不同,因此对药物的反应也不同,导致其血流不能恢复正常水平。(3)本研究中使用的药物剂量不足以使冠脉血流恢复至正常。
本研究是仅一项回顾性研究,而且入选的病例数较少,冠脉造影过程药物的用量可能也不够,这都是研究的不足之处。
CSFP可能是CMD的一种表现,有别于CSX。CSFP可导致患者胸闷、胸痛症状而反复就诊,但常被临床医生忽视。TIMI帧计数是研究CSFP的有用工具。本研究发现冠脉内注射维拉帕米的治疗效果优于硝酸甘油,但长期口服维拉帕米和硝酸酯类药物是否也能改善这些患者的冠脉血流及其预后,还需要进一步进行前瞻性的大型临床研究。
1. Tambe AA, Demany MA, Zimmerman HA, et al. Angina pectoris and slow flow velocity of dye in coronary arteries-a new angiographic finding [J]. American Heart Journal,1972,84(1):66-71.
2. Mosseri M, Yarom R, Gotsman MS, et al. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries [J]. Circulation,1986,74(5):964-972.
3. Goel PK, Gupta SK, Agarwal A, et al. Slow coronary flow: A distinct angiographic subgroup in syndrome X [J]. Angiology,2001,52(8):507-514.
4. Leone MC, Gori T, Fineschi M. The coronary slow flow phenomenon:A new cardiac "Y" syndrome? [J]. Clinical Hemorheology and Microcirculation,2008, 39(1-4):185-190.
5. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow [J]. Circulation,1996,93(5):879-888.
6. Przybojewski JZ, Becker PH. Angina pectoris and acute myocardial infarction due to "slow-flow phenomenon" in nonatherosclerotic coronary arteries:a case report [J]. Angiology,1986,37(10):751-761.
7. Yetkin E, Turhan H, Erbay AR, et al. Increased thrombolysis in myocardial infarction frame count in patients with myocardial infarction and normal coronary arteriogram:a possible link between slow coronary flow and myocardial infarction [J]. Atherosclerosis,2005,181(1):193-199.
8. Amasyali B, Turhan H, Kose S, et al. Aborted sudden cardiac death in a 20-year-old man with slow coronary flow [J]. International Journal of Cardiology,2006,109(3):427-429.
9. Kapoor A, Goel PK, Gupta S. Slow coronary flow - a cause for angina with ST segment elevation and normal coronary arteries. A case report [J]. International Journal of Cardiology,1998,67(3):257-261.
10. Demirkol MO, Yaymaci B, Mutlu B. Dipyridamole myocardial perfusion single photon emission computed tomography in patients with slow coronary flow [J]. Coronary Artery Disease,2002,13(4):223-229.
11. Mangieri E, Tanzilli G, De Vincentis G, et al. Slow coronary flow and stress myocardial perfusion imaging. Different patterns in acute patients [J]. J Cardiovasc Med (Hagerstown),2006,7(5):322-327.
12. Celik T, Iyisoy A, Kursaklioglu H, et al. ST elevation during treadmill exercise test in a young patient with slow coronary flow: A case report and review of literature [J]. International Journal of Cardiology,2006,112(2):E1-E4.
13. Cutri N, Kucia AM, Beltrame JF. Continuous ST/T Wave Monitoring During an Acute Coronary Syndrome Presentation in Patients with the Coronary Slow Flow Phenomenon (CSFP) [J]. Heart, Lung and Circulation,2008, 17(Supplement 3):S95-S95.
14. Tatli E, Yildirim T, Aktoz M. Does coronary slow flow phenomenon lead to myocardial ischemia? [J]. International Journal of Cardiology,2009, 131(3):e101-e102.
15. Mangieri E, Macchiarelli G, Ciavolella M, et al. Slow coronary flow:clinical and histopathological features in patients with otherwise normal epicardial coronary arteries [J]. Catheterization and Cardiovascular Diagnosis,1996, 37(4):375-381.
16. Beltrame JF, Limaye SB, Wuttke RD, et al. Coronary hemodynamic and metabolic studies of the coronary slow flow phenomenon [J]. American Heart Journal,2003,146(1):84-90.
17. Beltrame JF, Turner SP, Leslie SL, et al. The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon [J]. Journal of the American College of Cardiology,2004,44(1):57-62.
18. Erdogan D, Caliskan M, Gullu H, et al. Coronary flow reserve is impaired in patients with slow coronary flow [J]. Atherosclerosis,2007,191(1):168-174.
19. Fineschi M, Bravi A, Gori T. The "slow coronary flow" phenomenon: Evidence of preserved coronary flow reserve despite increased resting microvascular resistances [J]. International Journal of Cardiology,2008, 127(3):358-361.
20. Fineschi M, Gori T. Coronary slow flow:Description of a new "cardiac Y" syndrome [J]. International Journal of Cardiology,2009,137(3):308-310.
21. Sezgin A, Sigirici A, Barutcu I, et al. Endothelial function and slow coronary flow [J]. Journal of the American College of Cardiology,2003,41(6, Supplement 1):294-295.
22. Riza Erbay A, Turhan H, Yasar AS, et al. Elevated level of plasma homocysteine in patients with slow coronary flow [J]. International Journal of Cardiology,2005,102(3):419-423.
23. Barutcu I, Sezgin AT, Sezgin N, et al. Elevated plasma homocysteine level in slow coronary flow [J]. International Journal of Cardiology,2005, 101(1):143-145.
24. Binak E, Gunduz H, Sahin M, et al. The relation between impaired glucose tolerance and slow coronary flow [J]. International Journal of Cardiology,2006, 111(1):142-146.
25. Turhan H, Yetkin E. The relation between insulin resistance and slow coronary flow: The development of microvascular dysfunction in insulin resistant state may be a plausible explanation [J]. International Journal of Cardiology,2006, 111(3):474-475.
26. Pekdemir H, Polat G, Cin VG, et al. Elevated plasma endothelin-1 levels in coronary sinus during rapid right atrial pacing in patients with slow coronary flow [J]. International Journal of Cardiology,2004,97(1):35-41.
27. Pekdemir H, Cin VG, Cicek D, et al. Slow coronary flow may be a sign of diffuse atherosclerosis. Contribution of FFR and IVUS [J]. Acta Cardiologica, 2004,59(2):127-133.
28. Turkmen M, Barutcu I, Esen AM, et al. Comparison of exercise QRS amplitude changes in patients with slow coronary flow versus significant coronary stenosis [J]. Japanese Heart Journal,2004,45(3):419-428.
29. Camsari A, Ozcan T, Ozer C, et al. Carotid artery intima-media thickness correlates with intravascular ultrasound parameters in patients with slow coronary flow [J]. Atherosclerosis,2008,200(2):310-314.
30. Camsari A, Pekdemir H, Cicek D, et al. Endothelin-1 and nitric oxide concentrations and their response to exercise in patients with slow coronary flow [J]. Circulation Journal,2003,67(12):1022-1028.
31. Pekdemir H, Cicek D, Camsari A, et al. The relationship between plasma endothelin-1, nitric oxide levels, and heart rate variability in patients with coronary slow flow [J]. Annals of Noninvasive Electrocardiology, 2004,9(1):24-33.
32. Sezgin N, Barutcu I, Sezgin AT, et al. Plasma nitric oxide level and its role in slow coronary flow phenomenon [J]. International Heart Journal, 2005,46(3):373-382.
33. Turhan H, Saydam GS, Erbay AR, et al. Increased plasma soluble adhesion molecules; ICAM-1, VCAM-1, and E-selectin levels in patients with slow coronary flow [J]. International Journal of Cardiology,2006,108(2):224-230.
34. Li J-J, Qin X-W, Li Z-C, et al. Increased plasma C-reactive protein and interleukin-6 concentrations in patients with slow coronary flow [J]. Clinica Chimica Acta,2007,385(1-2):43-47.
35. Gokce M, Kaplan S, Tekelioglu Y, et al. Platelet function disorder in patients with coronary slow flow [J]. Clinical Cardiology,2005,28(3):145-148.
36. Yildiz A, Yilmaz R, Demirbag R, et al. Association of serum uric-acid level and coronary blood flow [J]. Coronary Artery Disease,2007,18(8):607-613.
37. Kostner K, Colquhoun D, Franco J, et al. Th-P 15:204 Patients with coronary slow flow have an abnormal lipid and apolipoprotein profile [J]. Atherosclerosis Supplements,2006,7(3):538-538.
38. Sezgin AT, Barutcu I, Sezgin N, et al. Contribution of plasma lipid disturbances to vascular endothelial function in patients with slow coronary flow [J]. Angiology,2006,57(6):694-701.
39. Dumaine R, Bigelow B, Aroesty J, et al. Myocardial reperfusion: its assessment and its relation to clinical outcomes [J]. American Heart Hospital Journal,2003,1(2):120-127.
40. Sezgin AT, Sigirci A, Barutcu I, et al. Vascular endothelial function in patients with slow coronary flow [J]. Coronary Artery Disease,2003,14(2):155-161.
41. Ozcan T, Gen R, Akbay E, et al. The correlation of thrombolysis in myocardial infarction frame count with insulin resistance in patients with slow coronary flow [J]. Coronary Artery Disease,2008,19(8):591-595.
42. Dogan SM, Yildirim N, Gursurer M, et al. P-wave duration and dispersion in patients with coronary slow flow and its relationship with Thrombolysis in Myocardial Infarction frame count [J]. Journal of Electrocardiology, 2008,41(1):55-59.
43. Kemp HG. Left Ventricular Function in Patients with Anginal Syndrome and Normal Coronary Arteriograms [J]. American Journal of Cardiology, 1973,32(3):375-376.
44. Cannon RO, Epstein SE. Microvascular Angina as a Cause of Chest Pain with Angiographically Normal Coronary-Arteries [J]. American Journal of Cardiology,1988,61(15):1338-1343.
45. Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon -A new coronary microvascular disorder [J]. Cardiology,2002,97(4):197-202.
46. Fragasso G, Chierchia SL, Arioli F, et al. Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X:Long-term clinical and functional prognosis [J]. International Journal of Cardiology,2009, 137(2):137-144.
47. Kurtoglu N, Akcay A, Dindar I. Usefulness of oral dipyridamole therapy for angiographic slow coronary artery flow [J]. The American Journal of Cardiology,2001,87(6):777-779.
48. Fam WM, McGregor M. Effect of nitroglycerin and dipyridamole on regional coronary resistance [J]. Circulation Research,1968,22(5):649-659.
49. Sellke FW, Myers PR, Bates JN, et al. Influence of vessel size on the sensitivity of porcine coronary microvessels to nitroglycerin [J]. American Journal of Physiology,1990,258(2 Pt 2):H515-520. 脏MRI可以用来检测CME后微梗死灶,准确测量左室大小、收缩功能,有很大的临床应用价值。
1. Dorge H, Schulz R, Belosjorow S, et al. Coronary Microembolization:the Role of TNF- [alpha] in Contractile Dysfunction [J]. Journal of Molecular and Cellular Cardiology,2002,34(1):51-62.
2. Heusch G, Kleinbongard P, Bose D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside [J]. Circulation,2009,120(18): 1822-1836.
3. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction [J]. Circulation,2007,116(2634-2653.
4. Bahrmann P, Figulla HR, Wagner M, et al. Detection of coronary microembolisation by Doppler ultrasound during percutaneous coronary interventions [J]. Heart,2005,91(9):1186-1192.
5. Bahrmann P, Werner GS, Heusch G, et al. Detection of coronary microembolization by Doppler ultrasound in patients with stable angina pectoris undergoing elective percutaneous coronary interventions [J]. Circulation,2007,115(5):600-608.
6. Ma JY, Qian JY, Jin H, et al. Acute hyperenhancement on delayed contrast-enhanced magnetic resonance imaging is the characteristic sign after coronary microembolization [J]. Chinese Medical Journal,2009,122(6): 687-691.
7. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart - A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association [J]. Circulation,2002,105(4):539-542.
8. Grothues F, Smith GC, Moon JCC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy [J]. American Journal of Cardiology,2002,90(1): 29-34.
9. Krombach GA, Higgins CB, Chujo M, et al. Gadomer-enhanced MR imaging in the detection of microvascular obstruction:Alleviation with nicorandil therapy [J]. Radiology,2005,236(2):510-518.
10. Nassenstein K, Breuckmann F, Bucher C, et al. How Much Myocardial Damage Is Necessary to Enable Detection of Focal Late Gadolinium Enhancement at Cardiac MR Imaging? [J]. Radiology,2008,249(3):829-835.
11. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation [J]. Circulation,2001,103(23):2780-2783.
12. Selvanayagam JB, Porto I, Channon K, et al. Troponin elevation after percutaneous coronary intervention directly represents the extent of irreversible myocardial injury - Insights from cardiovascular magnetic resonance imaging [J]. Circulation,2005,111(8):1027-1032.
13. Porto I, Selvanayagam JB, Van Gaal WJ, et al. Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention:Insights from delayed-enhancement magnetic resonance imaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound [J]. Circulation,2006, 114(7):662-669.
14. Selvanayagam JB, Cheng ASH, Jerosch-Herold M, et al. Effect of distal embolization on myocardial perfusion reserve after percutaneous coronary intervention - A quantitative magnetic resonance perfusion study [J]. Circulation,2007,116(13):1458-1464.
15. Mahrholdt H, Wagner A, Judd RM, et al. Assessment of myocardial viability by cardiovascular magnetic resonance imaging [J]. European Heart Journal, 2002,23(8):602-619.
16. Breuckmann F, Nassenstein K, Bucher C, et al. Systematic analysis of functional and structural changes after coronary microembolization:a cardiac magnetic resonance imaging study [J]. JACC Cardiovasc Imaging,2009, 2(2):121-130.
17. Carlsson M, Martin AJ, Ursell PC, et al. Magnetic Resonance Imaging Quantification of Left Ventricular Dysfunction Following Coronary Microembolization [J]. Magnetic Resonance in Medicine,2009,61(3):595-602.
18. Carlsson M, Wilson M, Martin AJ, et al. Myocardial Microinfarction after Coronary Microembolization in Swine:MR Imaging Characterization [J]. Radiology,2009,250(3):703-713.
19. Carlsson M, Saloner D, Martin AJ, et al. Heterogeneous Microinfarcts Caused by Coronary Microemboli:Evaluation with Multidetector CT and MR Imaging in a Swine Model [J]. Radiology,2010,254(3):718-728.
20. Appelbaum E, Manning WJ. Science to Practice:Can the Combination of Resting First-Pass Myocardial Perfusion and Late Gadolinium-enhanced Cardiovascular MR Imaging Help Identify Myocardial Infarction Resulting from Coronary Microembolization? [J]. Radiology,2009,250(3):609-611.
21. Skyschally A, Haude M, Dorge H, et al. Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization [J]. Circulation,2004,109(19):2337-2342.
22. Skyschally A, Gres P, Hoffmann S, et al. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization:progressive contractile dysfunction versus delayed protection against infarction [J]. Circulation Research,2007,100(1):140-146.
目前研究证实CME后左室功能下降、心肌重构主要与炎症有关。TNF-α在CME疾病发展中起重要作用。心肌组织NF-κB在CME中也被激活,且和心肌组织TNF-α表达呈正相关。因此,我们猜想TLR4/NF-κB TNF-α这个信号传导通路参与了CME后左室重构、功能异常的过程。本研究中我们发现,和假手术组比较,CME后前壁心肌组织TLR4的蛋白及mRNA水平均升高、NF-κB的蛋白及DNA结合活性均增高,心肌组织TLR4和NF-κB表达一致。提示CME后TLR4/NF-κB和炎症因子密切相关,TLR4/NF-κB参与了CME后的炎症反应过程。我们初步发现3组不同剂量微球造成的CME模型中,前壁TLR4/NF-κB的表达无明显差别,结合我们进行的心脏MRI研究(微球的剂量对左室重构、心功能的变化并无太大的影响),这可能说明：1)微栓塞后局部心肌的炎症与微栓塞的大小和面积无关,2)我们微球的大小和剂量不能体现这种差别,3)TLR4/NF-κB系统的激活只是其中的炎症反应的其中一个方面而已。
本研究初步比较了3种不同剂量微球的CME模型中,前壁、后壁TLR4/NF-κB的表达活性。但取样点太少,只取了术前和术后1w两个不同的时间点,并没有设计2h、6h等中间的取样分析,因此心肌TLR4/NF-κB表达活性的改变没有体现时间的差异；本次研究没有检测心肌TNF-α的表达,是根据以前的文献和定论,没有体现出心肌TLR4/NF-KB-TNF-α的相关性；此外,5万微球和12万微球组、对照组的数量太少,未行统计分析。此外,如需证明TLR4/NF-κB传导系统的作用,还需研究传导途径中的其它的一些关键分子的表达情况,这些都是我们以后研究的重点。
本研究通过冠脉介入法建立猪CME模型,发现CME后1w前壁心肌组织中TLR4、NF-κB表达均升高。心肌组织中TLR4、NF-κB表达一致,提示TLR4/NF-κB信号传导通路可能参与了CME后炎症反应,TLR4/NF-κB通路是炎症反应的一个机制。针对TLR4/NF-κB信号传导通路,减轻炎症反应是治疗CME后左室重构、心功能改变的又一希望,我们的研究为临床治疗CME提供了又一方向。
1. Skyschally A, Gres P, van Caster P, et al. Reduced calcium responsiveness characterizes contractile dysfunction following coronary microembolization [J]. Basic Research in Cardiology,2008,103(6):552-559.
2. Li SM, Zhong SS, Zeng K, et al. Blockade of NF-kappa B by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats [J]. Basic Research in Cardiology,2010,105(1):139-150.
3. Jorgense.L, Rowsell HC, Hovig T, et al. Adenosine Diphosphate-Induced Platelet Aggregation and Myocardial Infarction in Swine [J]. Laboratory Investigation,1967,17(6):616-644.
4. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease [J]. Circulation,2000,101(5):570-580.
5. Dorge H, Schulz R, Belosjorow S, et al. Coronary Microembolization:the Role of TNF- [alpha] in Contractile Dysfunction [J]. Journal of Molecular and Cellular Cardiology,2002,34(1):51-62.
6. Heusch G, Kleinbongard P, Bose D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside [J]. Circulation,2009,120(18): 1822-1836.
7. Arras M, Strasser R, Mohri M, et al. Tumor necrosis factor-alpha is expressed by monocytes/macrophages following cardiac microembolization and is antagonized by cyclosporine [J]. Basic Research in Cardiology,1998,93(2): 97-107.
8. Dorge H, Neumann T, Behrends M, et al. Perfusion-contraction mismatch with coronary microvascular obstruction:role of inflammation [J]. American Journal of Physiology-Heart and Circulatory Physiology,2000,279(6): H2587-H2592.
9. Skyschally A, Haude M, Dorge H, et al. Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization [J]. Circulation,2004,109(19):2337-2342.
10. Thielmann M, Belosjorow S, Martin C, et al. Myocardial dysfunction with coronary microembolization:Signal transduction through a sequence of no, TNF[alpha] and sphingosine [J]. Journal of Molecular and Cellular Cardiology,2002,34(6):A63-A63.
11. Skyschally A, Gres P, Hoffmann S, et al. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization:progressive contractile dysfunction versus delayed protection against infarction [J]. Circulation Research,2007,100(1):140-146.
12. Skyschally A, Gres P, Hoffmann S, et al. Delayed myocardial protection following coronary microembolization is mediated by TNF-[alpha] [J]. Journal of Molecular and Cellular Cardiology,2006,40(6):974-975.
13. Hayden MS, Ghosh S. Shared Principles in NF-[kappa]B Signaling [J]. Cell,2008,132(3):344-362.
14. Beinke S, Ley SC. Functions of NF-kappa B1 and NF-kappa B2 in immune cell biology [J]. Biochemical Journal,2004,382(393-409.
15. Valen G, Yan ZQ, Hansson GK. Nuclear factor kappa-B and the heart [J]. Journal of the American College of Cardiology,2001,38(2):307-314.
16. Frantz S, Hu K, Bayer B, et al. Absence of NF-kappa B subunit p50 improves heart failure after myocardial infarction [J]. Faseb Journal,2006,20(11):1918-1920.
17.李淑梅,曾凯,王伟伟,等.核因子-κB激活在大鼠冠状动脉微栓塞后的心肌组织中的作用及机制[J].中华心血管病杂志,2008,36(11)：1016-1020.
18. Hall G, Hasday JD, Rogers TB. Regulating the regulator: NF-kappaB signaling in heart [J]. Journal of Molecular & Cellular Cardiology,2006,41(4):580-591.
19. Sun SC, Ley SC. New insights into NF-kappa B regulation and function [J]. Trends in Immunology,2008,29(10):469-478.
20. Pandey S, Agrawal DK. Immunobiology of Toll-like receptors:Emerging trends [J]. Immunology and Cell Biology,2006,84(4):333-341.
21. Vabulas RM, Ahmad-Nejad P, da Costa C, et al. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells [J]. Journal of Biological Chemistry,2001,276(33):31332-31339.
22. Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates toll-like receptor 4 [J]. Journal of Biological Chemistry,2001,276(13): 10229-10233.
23. Hori M, Nishida K. Toll-like receptor signaling - Defensive or offensive for the heart? [J]. Circulation Research,2008,102(2):137-139.
24. Frantz S, Ertl G, Bauersachs J. Mechanisms of disease:Toll-like receptors in cardiovascular disease [J]. Nature Clinical Practice Cardiovascular Medicine, 2007,4(8):444-454.
25. Frantz S, Kobzik L, Kim YD, et al. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium [J]. Journal of Clinical Investigation,1999,104(3):271-280.
26. Birks EJ, Felkin LE, Banner NR, et al. Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices [J]. Journal of Heart and Lung Transplantation,2004,23(2):228-235.
27. Nemoto S, Vallejo JG, Knuefermann P, et al. Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart [J]. American Journal of Physiology-Heart and Circulatory Physiology,2002,282(6):H2316-H2323.
28. Sha T, Sunamoto M, Kitazaki T, et al. Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model [J]. European Journal of Pharmacology,2007,571(231-239.
29. Kuno M, Nemoto K, Ninomiya N, et al. The Novel Selective Toll-Like Receptor 4 Signal Transduction Inhibitor Tak-242 Prevents Endotoxaemia in Conscious Guinea-Pigs [J]. Clinical and Experimental Pharmacology and Physiology,2009,36(5-6):589-593.
30. Yang J, Yang J, Ding JW, et al. Sequential Expression of TLR4 and its Effects on the Myocardium of Rats with Myocardial Ischemia-Reperfusion Injury [J]. Inflammation,2008,31(5):304-312.
31. Satoh M, Shimoda Y, Maesawa C, et al. Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction [J]. International Journal of Cardiology,2006,109(2):226-234.
32. Medzhitov R, PrestonHurlburt P, Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity [J]. Nature, 1997,388(6640):394-397.
33. Baumgarten G, Knuefermann P, Nozaki N, et al. In Vivo Expression of Proinflammatory Mediator in the Adult Heart after Endotoxin Administration: The Role of Toll-Like Receptor-4 [J]. Journal of Infectious Diseases, 2001,183(11):1617.
1. Camici PG, Crea F. Medical progress - Coronary microvascular dysfunction [J]. New England Journal of Medicine,2007,356(8):830-840.
2. Chilian WM, Bassingthwaighte JB, Cannon RO, et al. Coronary microcirculation in health and disease - Summary of an NHLBI Workshop [J]. Circulation,1997,95(2):522-528.
3. Beltrame JF, Crea F, Camici P. Advances in coronary microvascular dysfunction [J]. Heart Lung Circ,2009,18(1):19-27.
4. Pries AR, Habazettl H, Ambrosio G, et al. A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings [J]. Cardiovascular Research,2008,80(2):165-174.
5. Sato A, Terata K, Miura H, et al. Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease [J]. American Journal of Physiology-Heart and Circulatory Physiology,2005,288(4):H1633-H1640.
6. Lucignani G, Cuocolo A. Advances in quantitative assessment of myocardial blood flow and coronary reserve [J]. European Journal of Nuclear Medicine and Molecular Imaging,2009,36(10):1687-1692.
7. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow [J]. Circulation,1996,93(5):879-888.
8. van't Hof AWJ, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction - Myocardial blush grade [J]. Circulation,1998, 97(23):2302-2306.
9. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs [J]. Circulation,2000,101(2):125-130.
10. Gould KL, Kirkeeide RL, Buchi M. Coronary Flow Reserve as a Physiologic Measure of Stenosis Severity [J]. Journal of the American College of Cardiology,1990,15(2):459-474.
11. Fearon WF, Balsam LB, Farouque HMO, et al. Novel index for invasively assessing the coronary microcirculation [J]. Circulation,2003,107(25): 3129-3132.
12. Ganz W, Tamura K, Marcus HS, et al. Measurement of coronary sinus blood flow by continuous thermodilution in man [J]. Circulation,1971, 44(2):181-195.
13. Knaapen P, Camici PG, Marques KM, et al. Coronary microvascular resistance: methods for its quantification in humans [J]. Basic Research in Cardiology, 2009,104(5):485-498.
14. Meimoun P, Tribouilloy C. Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography:a magic tool for the real world [J]. European Journal of Echocardiography, 2008,9(4):449-457.
15. Husmann L, Tatsugami F, Aepli U, et al. Prevalence of noncardiac findings on low dose 64-slice computed tomography used for attenuation correction in myocardial perfusion imaging with SPECT [J]. International Journal of Cardiovascular Imaging,2009,25(8):859-865.
16. Blankstein R, Shturman LD, Rogers IS, et al. Adenosine-Induced Stress Myocardial Perfusion Imaging Using Dual-Source Cardiac Computed Tomography [J]. Journal of the American College of Cardiology, 2009,54(12):1072-1084.
17. Blankstein R, Okada DR, Rocha-Filho JA, et al. Cardiac myocardial perfusion imaging using dual source computed tomography [J]. International Journal of Cardiovascular Imaging,2009,25(209-216.
18. Daghini E, Lerman LO. Assessment of Myocardial Microvascular Function: New Opportunities in Fast Computed Tomography [J]. Trends in Cardiovascular Medicine,2007,17(1):14-19.
19. Ramkumar PG, Mitsouras D, Feldman CL, et al. New advances in cardiac computed tomography [J]. Current Opinion in Cardiology,2009,24(6): 596-603.
20. Beanlands RSB, Ziadi MC, Williams K. Quantification of Myocardial Flow Reserve Using Positron Emission Imaging The Journey to Clinical Use [J]. Journal of the American College of Cardiology,2009,54(2):157-159.
21. Lortie M, Beanlands RSB, Yoshinaga K, et al. Quantification of myocardial blood flow with Rb-82 dynamic PET imaging [J]. European Journal of Nuclear Medicine and Molecular Imaging,2007,34(1765-1774.
22. Heller GV, Calnon D, Dorbala S. Recent advances in cardiac PET and PET/CT myocardial perfusion imaging [J]. Journal of Nuclear Cardiology,2009, 16(6):962-969.
23. Beller GA. Will cardiac positron emission tomography ultimately replace SPECT for myocardial perfusion imaging? [J]. J Nucl Cardiol,2009, 16(6):841-843.
24. Kemp HG. Left Ventricular Function in Patients with Anginal Syndrome and Normal Coronary Arteriograms [J]. American Journal of Cardiology,1973, 32(3):375-376.
25. Cannon RO, Epstein SE. Microvascular Angina as a Cause of Chest Pain with Angiographically Normal Coronary-Arteries [J]. American Journal of Cardiology,1988,61(15):1338-1343.
26. Lanza GA. Cardiac syndrome X:a critical overview and future perspectives [J]. Heart,2007,93(2):159-166.
27. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging [J]. New England Journal of Medicine,2002, 346(25):1948-1953.
28. Lamendola P, Lanza GA, Spinelli A, et al. Long-term prognosis of patients with cardiac syndrome X [J]. International Journal of Cardiology,In Press, Corrected Proof(
29. Bugiardini R, Manfrini O, Pizzi C, et al. Endothelial function predicts future development of coronary artery disease - A study of women with chest pain and normal coronary angiograms [J]. Circulation,2004,109(21):2518-2523.
30. Lim TK, Choy AJ, Khan F, et al. Therapeutic Development in Cardiac Syndrome X:A Need to Target the Underlying Pathophysiology [J]. Cardiovascular Therapeutics,2009,27(1):49-58.
31. Melikian N, De Bruyne B, Fearon WF, et al. The Pathophysiology and Clinical Course of the Normal Coronary Angina Syndrome (Cardiac Syndrome X) [J]. Progress in Cardiovascular Diseases,2008,50(4):294-310.
32. Hirooka Y, Kimura Y, Ito YSK, et al. Effects of valsartan or amlodipine on endothelial function and oxidative stress after one year follow-up in patients with essential hypertension [J]. Clinical and Experimental Hypertension, 2008,30(3-4):267-276.
33. Kayikcioglu M, Payzin S, Yavuzgil O, et al. Benefits of statin treatment in cardiac syndrome-X [J]. European Heart Journal,2003,24(22):1999-2005.
34. Jadhav S, Ferrell W, Greer IA, et al. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries - A randomized, double-blind, placebo-controlled study [J]. Journal of the American College of Cardiology,2006,48(5):956-963.
35. Celik T, Iyisoy A, Yuksel UC, et al. A new treatment modality in management of patients with cardiac syndrome X:Enhanced external counterpulsation [J]. International Journal of Cardiology,In Press, Corrected Proof(
36. Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for Syndrome X [J]. International Journal of Cardiology, 2009,135(2):256-257.
37. Tambe AA, Demany MA, Zimmerman HA, et al. Angina pectoris and slow flow velocity of dye in coronary arteries-a new angiographic finding [J]. American Heart Journal,1972,84(1):66-71.
38. Mosseri M, Yarom R, Gotsman MS, et al. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries [J]. Circulation,1986,74(5):964-972.
39. Goel PK, Gupta SK, Agarwal A, et al. Slow coronary flow: A distinct angiographic subgroup in syndrome X [J]. Angiology,2001,52(8):507-514.
40. Przybojewski JZ, Becker PH. Angina pectoris and acute myocardial infarction due to "slow-flow phenomenon" in nonatherosclerotic coronary arteries:a case report [J]. Angiology,1986,37(10):751-761.
41. Amasyali B, Turhan H, Kose S, et al. Aborted sudden cardiac death in a 20-year-old man with slow coronary flow [J]. International Journal of Cardiology,2006,109(3):427-429.
42. Kapoor A, Goel PK, Gupta S. Slow coronary flow - a cause for angina with ST segment elevation and normal coronary arteries. A case report [J]. International Journal of Cardiology,1998,67(3):257-261.
43. Cutri N, Kucia AM, Beltrame JF. Continuous ST/T Wave Monitoring During an Acute Coronary Syndrome Presentation in Patients with the Coronary Slow Flow Phenomenon (CSFP) [J]. Heart, Lung and Circulation,2008, 17(Supplement 3):S95-S95.
44. Demirkol MO, Yaymaci B, Mutlu B. Dipyridamole myocardial perfusion single photon emission computed tomography in patients with slow coronary flow [J]. Coronary Artery Disease,2002,13(4):223-229.
45. Mangieri E, Tanzilli G, De Vincentis G, et al. Slow coronary flow and stress myocardial perfusion imaging. Different patterns in acute patients [J]. J Cardiovasc Med (Hagerstown),2006,7(5):322-327.
46. Tatli E, Yildirim T, Aktoz M. Does coronary slow flow phenomenon lead to myocardial ischemia? [J]. International Journal of Cardiology,2009, 131(3):e101-e102.
47. Li J-J, Xu B, Li Z-C, et al. Is slow coronary flow associated with inflammation? [J]. Medical Hypotheses,2006,66(3):504-508.
48. Erdogan D, Caliskan M, Gullu H, et al. Coronary flow reserve is impaired in patients with slow coronary flow [J]. Atherosclerosis,2007,191(1):168-174.
49. Fineschi M, Bravi A, Gori T. The "slow coronary flow" phenomenon: Evidence of preserved coronary flow reserve despite increased resting microvascular resistances [J]. International Journal of Cardiology,2008, 127(3):358-361.
50. Fineschi M, Gori T. Coronary slow flow: Description of a new "cardiac Y" syndrome [J]. International Journal of Cardiology,2009,137(3):308-310.
51. Mangieri E, Macchiarelli G, Ciavolella M, et al. Slow coronary flow: clinical and histopathological features in patients with otherwise normal epicardial coronary arteries [J]. Catheterization and Cardiovascular Diagnosis,1996, 37(4):375-381.
52. Beltrame JF, Limaye SB, Wuttke RD, et al. Coronary hemodynamic and metabolic studies of the coronary slow flow phenomenon [J]. American Heart Journal,2003,146(1):84-90.
53. Beltrame JF, Turner SP, Leslie SL, et al. The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon [J]. Journal of the American College of Cardiology,2004,44(1):57-62.
54. Yildiz A, Yilmaz R, Demirbag R, et al. Association of serum uric-acid level and coronary blood flow [J]. Coronary Artery Disease,2007,18(8):607-613.
55. Li J-J, Qin X-W, Li Z-C, et al. Increased plasma C-reactive protein and interleukin-6 concentrations in patients with slow coronary flow [J]. Clinica Chimica Acta,2007,385(1-2):43-47.
56. Kostner K, Colquhoun D, Franco J, et al. Th-P 15:204 Patients with coronary slow flow have an abnormal lipid and apolipoprotein profile [J]. Atherosclerosis Supplements,2006,7(3):538-538.
57. Sezgin AT, Barutcu I, Sezgin N, et al. Contribution of plasma lipid disturbances to vascular endothelial function in patients with slow coronary flow [J]. Angiology,2006,57(6):694-701.
58.常书福,马剑英,钱菊英,等.冠状动脉内应用硝酸甘油和维拉帕米治疗冠状动脉血流缓慢现象的效果[J].中华心血管病杂志,2010,38(1)：27-30.
59. Kurtoglu N, Akcay A, Dindar I. Usefulness of oral dipyridamole therapy for angiographic slow coronary artery flow [J]. The American Journal of Cardiology,2001,87(6):777-779.
60. Leone MC, Gori T, Fineschi M. The coronary slow flow phenomenon:A new cardiac "Y" syndrome? [J]. Clinical Hemorheology and Microcirculation,2008, 39(1-4):185-190.
61. Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon-A new coronary microvascular disorder [J]. Cardiology,2002,97(4):197-202.
62. Fragasso G, Chierchia SL, Arioli F, et al. Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X:Long-term clinical and functional prognosis [J]. International Journal of Cardiology, 2009,137(2):137-144.
63. Li SM, Zhong SS, Zeng K, et al. Blockade of NF-kappa B by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats [J]. Basic Research in Cardiology,2010,105(1):139-150.
64. Dorge H, Neumann T, Behrends M, et al. Perfusion-contraction mismatch with coronary microvascular obstruction:role of inflammation [J]. American Journal of Physiology-Heart and Circulatory Physiology,2000, 279(6):H2587-H2592.
65. Heusch G, Kleinbongard P, Bose D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside [J]. Circulation,2009,120(18): 1822-1836.
66. Hori M, Inoue M, Kitakaze M, et al. Role of Adenosine in Hyperemic Response of Coronary Blood-Flow in Microembolization [J]. American Journal of Physiology,1986,250(3):H509-H518.
67. Mohlenkamp S, Beighley PE, Pfeifer EA, et al. Intramyocardial blood volume, perfusion and transit time in response to embolization of different sized microvessels [J]. Cardiovascular Research,2003,57(3):843-852.
68. Dorge H, Schulz R, Belosjorow S, et al. Coronary Microembolization:the Role of TNF-[alpha] in Contractile Dysfunction [J]. Journal of Molecular and Cellular Cardiology,2002,34(1):51-62.
69. Skyschally A, Schulz R, Erbel R, et al. Reduced coronary and inotropic reserves with coronary microembolization [J]. American Journal of Physiology - Heart & Circulatory Physiology,2002,282(2):H611-614.
70. Arras M, Strasser R, Mohri M, et al. Tumor necrosis factor-alpha is expressed by monocytes/macrophages following cardiac microembolization and is antagonized by cyclosporine [J]. Basic Research in Cardiology,1998,93(2): 97-107.
71. Skyschally A, Haude M, Dorge H, et al. Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization [J]. Circulation,2004,109(19):2337-2342.
72. Skyschally A, Gres P, Hoffmann S, et al. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization:progressive contractile dysfunction versus delayed protection against infarction [J]. Circulation Research,2007,100(1):140-146.
73. Thielmann M, Belosjorow S, Martin C, et al. Myocardial dysfunction with coronary microembolization:Signal transduction through a sequence of NO, TNF alpha and sphingosine [J]. Journal of Molecular and Cellular Cardiology,2002,34(6):A63-A63.
74. Canton M, Skyschally A, Menabo R, et al. Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolization [J]. European Heart Journal,2006,27(7):875-881.
75. Skyschally A, Gres P, van Caster P, et al. Reduced calcium responsiveness characterizes contractile dysfunction following coronary microembolization [J]. Basic Research in Cardiology,2008,103(6):552-559.
76. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction [J]. Circulation,2007,116(2634-2653.
77. Bahrmann P, Figulla HR, Wagner M, et al. Detection of coronary microembolisation by Doppler ultrasound during percutaneous coronary interventions [J]. Heart,2005,91(9):1186-1192.
78. Bahrmann P, Werner GS, Heusch G, et al. Detection of coronary microembolization by Doppler ultrasound in patients with stable angina pectoris undergoing elective percutaneous coronary interventions [J]. Circulation,2007,115(5):600-608.
79. Krombach GA, Higgins CB, Chujo M, et al. Gadomer-enhanced MR imaging in the detection of microvascular obstruction: Alleviation with nicorandil therapy [J]. Radiology,2005,236(2):510-518.
80. Nassenstein K, Breuckmann F, Bucher C, et al. How Much Myocardial Damage Is Necessary to Enable Detection of Focal Late Gadolinium Enhancement at Cardiac MR Imaging? [J]. Radiology,2008,249(3):829-835.
81. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation [J]. Circulation,2001,103(23):2780-2783.
82. Selvanayagam JB, Porto I, Channon K, et al. Troponin elevation after percutaneous coronary intervention directly represents the extent of irreversible myocardial injury - Insights from cardiovascular magnetic resonance imaging [J]. Circulation,2005,111(8):1027-1032.
83. Porto I, Selvanayagam JB, Van Gaal WJ, et al. Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention:Insights from delayed-enhancement magnetic resonance imaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound [J]. Circulation,2006, 114(7):662-669.
84. Selvanayagam JB, Cheng ASH, Jerosch-Herold M, et al. Effect of distal embolization on myocardial perfusion reserve after percutaneous coronary intervention - A quantitative magnetic resonance perfusion study [J]. Circulation,2007,116(13):1458-1464.
85. Mahrholdt H, Wagner A, Judd RM, et al. Assessment of myocardial viability by cardiovascular magnetic resonance imaging [J]. European Heart Journal,2002,23(8):602-619.
86. Breuckmann F, Nassenstein K, Bucher C, et al. Systematic analysis of functional and structural changes after coronary microembolization:a cardiac magnetic resonance imaging study [J]. JACC Cardiovasc Imaging,2009, 2(2):121-130.
87. Carlsson M, Martin AJ, Ursell PC, et al. Magnetic Resonance Imaging Quantification of Left Ventricular Dysfunction Following Coronary Microembolization [J]. Magnetic Resonance in Medicine,2009,61(3):595-602.
88. Carlsson M, Wilson M, Martin AJ, et al. Myocardial Microinfarction after Coronary Microembolization in Swine:MR Imaging Characterization [J]. Radiology,2009,250(3):703-713.
89. Carlsson M, Saloner D, Martin AJ, et al. Heterogeneous Microinfarcts Caused by Coronary Microemboli:Evaluation with Multidetector CT and MR Imaging in a Swine Model [J]. Radiology,2010,254(3):718-728.
CME后引起心室重构的机制目前不是很清楚,研究证实CME后炎症、肿瘤坏死因子α (tumor necrosis factor α, TNF-α)表达在影响左室重构起了很重要的作用。Toll样受体(Toll-like receptors, TLRs)家族和核转录因子κB (nuclear factor kappa B, NF-κB)在许多炎症性疾病中参与了的发病过程,是TNF-a的上游传导通路。但TLR4/NF-KB是否参与了冠脉微栓塞后的左室重构并不清楚。我们通过冠脉介入的方法建立不同剂量的猪CME模型,检测心肌组织的TLR4和NF-κB的表达情况,发现CME后1w,受累前壁心肌组织中TLR4、NF-κB表达升高、活性增强。CME术前术后,前、后壁心肌组织中TLR4、NF-κB表达一致,提示TLR4/NF-κB通路可能参与了CME后炎症反应、左室重构的过程。
本次研究,我们回顾分析CSFP患者,探讨了硝酸甘油、维拉帕米的治疗价值；建立CME的动物模型,评价了心脏MRI诊断价值,并初步研究了CME后左室重构、左室功能异常的机制,对临床治疗CMD具有很大的指导价值。
[1]Camici, P. G., Crea, F. Medical progress - Coronary microvascular dysfunction[J]. New England Journal of Medicine,2007,356(8):830-840.
[2]Fineschi, M., Gori, T. Coronary slow flow:Description of a new "cardiac Y" syndrome[J]. International Journal of Cardiology,2009,137(3):308-310.
[3]Heusch, G., Kleinbongard, P., Bose, D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside[J]. Circulation,2009,120(18): 1822-1836. 未能使CSFP患者的冠脉血流达到正常水平。可能由于：(1)不同的患者异常功能小血管的位置不同,有些是直径200μm以下的微血管功能障碍,而维拉帕米对微血管阻力降低的效果优于硝酸甘油。我们的研究也从另一方面支持冠脉微血管功能异常可能是CSFP的原因这一假设。(2)不同CSFP患者冠脉血流缓慢的发病机制不同,体内异常增多的引起微血管收缩的缩血管物质种类也不同,因此对药物的反应也不同,导致其血流不能恢复正常水平。(3)本研究中使用的药物剂量不足以使冠脉血流恢复至正常。
本研究是仅一项回顾性研究,而且入选的病例数较少,冠脉造影过程药物的用量可能也不够,这都是研究的不足之处。
CSFP可能是CMD的一种表现,有别于CSX。CSFP可导致患者胸闷、胸痛症状而反复就诊,但常被临床医生忽视。TIMI帧计数是研究CSFP的有用工具。本研究发现冠脉内注射维拉帕米的治疗效果优于硝酸甘油,但长期口服维拉帕米和硝酸酯类药物是否也能改善这些患者的冠脉血流及其预后,还需要进一步进行前瞻性的大型临床研究。
1. Tambe AA, Demany MA, Zimmerman HA, et al. Angina pectoris and slow flow velocity of dye in coronary arteries-a new angiographic finding [J]. American Heart Journal,1972,84(1):66-71.
2. Mosseri M, Yarom R, Gotsman MS, et al. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries [J]. Circulation,1986,74(5):964-972.
3. Goel PK, Gupta SK, Agarwal A, et al. Slow coronary flow: A distinct angiographic subgroup in syndrome X [J]. Angiology,2001,52(8):507-514.
4. Leone MC, Gori T, Fineschi M. The coronary slow flow phenomenon:A new cardiac "Y" syndrome? [J]. Clinical Hemorheology and Microcirculation,2008, 39(1-4):185-190.
5. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow [J]. Circulation,1996,93(5):879-888.
6. Przybojewski JZ, Becker PH. Angina pectoris and acute myocardial infarction due to "slow-flow phenomenon" in nonatherosclerotic coronary arteries:a case report [J]. Angiology,1986,37(10):751-761.
7. Yetkin E, Turhan H, Erbay AR, et al. Increased thrombolysis in myocardial infarction frame count in patients with myocardial infarction and normal coronary arteriogram:a possible link between slow coronary flow and myocardial infarction [J]. Atherosclerosis,2005,181(1):193-199.
8. Amasyali B, Turhan H, Kose S, et al. Aborted sudden cardiac death in a 20-year-old man with slow coronary flow [J]. International Journal of Cardiology,2006,109(3):427-429.
9. Kapoor A, Goel PK, Gupta S. Slow coronary flow - a cause for angina with ST segment elevation and normal coronary arteries. A case report [J]. International Journal of Cardiology,1998,67(3):257-261.
10. Demirkol MO, Yaymaci B, Mutlu B. Dipyridamole myocardial perfusion single photon emission computed tomography in patients with slow coronary flow [J]. Coronary Artery Disease,2002,13(4):223-229.
11. Mangieri E, Tanzilli G, De Vincentis G, et al. Slow coronary flow and stress myocardial perfusion imaging. Different patterns in acute patients [J]. J Cardiovasc Med (Hagerstown),2006,7(5):322-327.
12. Celik T, Iyisoy A, Kursaklioglu H, et al. ST elevation during treadmill exercise test in a young patient with slow coronary flow: A case report and review of literature [J]. International Journal of Cardiology,2006,112(2):E1-E4.
13. Cutri N, Kucia AM, Beltrame JF. Continuous ST/T Wave Monitoring During an Acute Coronary Syndrome Presentation in Patients with the Coronary Slow Flow Phenomenon (CSFP) [J]. Heart, Lung and Circulation,2008, 17(Supplement 3):S95-S95.
14. Tatli E, Yildirim T, Aktoz M. Does coronary slow flow phenomenon lead to myocardial ischemia? [J]. International Journal of Cardiology,2009, 131(3):e101-e102.
15. Mangieri E, Macchiarelli G, Ciavolella M, et al. Slow coronary flow:clinical and histopathological features in patients with otherwise normal epicardial coronary arteries [J]. Catheterization and Cardiovascular Diagnosis,1996, 37(4):375-381.
16. Beltrame JF, Limaye SB, Wuttke RD, et al. Coronary hemodynamic and metabolic studies of the coronary slow flow phenomenon [J]. American Heart Journal,2003,146(1):84-90.
17. Beltrame JF, Turner SP, Leslie SL, et al. The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon [J]. Journal of the American College of Cardiology,2004,44(1):57-62.
18. Erdogan D, Caliskan M, Gullu H, et al. Coronary flow reserve is impaired in patients with slow coronary flow [J]. Atherosclerosis,2007,191(1):168-174.
19. Fineschi M, Bravi A, Gori T. The "slow coronary flow" phenomenon: Evidence of preserved coronary flow reserve despite increased resting microvascular resistances [J]. International Journal of Cardiology,2008, 127(3):358-361.
20. Fineschi M, Gori T. Coronary slow flow:Description of a new "cardiac Y" syndrome [J]. International Journal of Cardiology,2009,137(3):308-310.
21. Sezgin A, Sigirici A, Barutcu I, et al. Endothelial function and slow coronary flow [J]. Journal of the American College of Cardiology,2003,41(6, Supplement 1):294-295.
22. Riza Erbay A, Turhan H, Yasar AS, et al. Elevated level of plasma homocysteine in patients with slow coronary flow [J]. International Journal of Cardiology,2005,102(3):419-423.
23. Barutcu I, Sezgin AT, Sezgin N, et al. Elevated plasma homocysteine level in slow coronary flow [J]. International Journal of Cardiology,2005, 101(1):143-145.
24. Binak E, Gunduz H, Sahin M, et al. The relation between impaired glucose tolerance and slow coronary flow [J]. International Journal of Cardiology,2006, 111(1):142-146.
25. Turhan H, Yetkin E. The relation between insulin resistance and slow coronary flow: The development of microvascular dysfunction in insulin resistant state may be a plausible explanation [J]. International Journal of Cardiology,2006, 111(3):474-475.
26. Pekdemir H, Polat G, Cin VG, et al. Elevated plasma endothelin-1 levels in coronary sinus during rapid right atrial pacing in patients with slow coronary flow [J]. International Journal of Cardiology,2004,97(1):35-41.
27. Pekdemir H, Cin VG, Cicek D, et al. Slow coronary flow may be a sign of diffuse atherosclerosis. Contribution of FFR and IVUS [J]. Acta Cardiologica, 2004,59(2):127-133.
28. Turkmen M, Barutcu I, Esen AM, et al. Comparison of exercise QRS amplitude changes in patients with slow coronary flow versus significant coronary stenosis [J]. Japanese Heart Journal,2004,45(3):419-428.
29. Camsari A, Ozcan T, Ozer C, et al. Carotid artery intima-media thickness correlates with intravascular ultrasound parameters in patients with slow coronary flow [J]. Atherosclerosis,2008,200(2):310-314.
30. Camsari A, Pekdemir H, Cicek D, et al. Endothelin-1 and nitric oxide concentrations and their response to exercise in patients with slow coronary flow [J]. Circulation Journal,2003,67(12):1022-1028.
31. Pekdemir H, Cicek D, Camsari A, et al. The relationship between plasma endothelin-1, nitric oxide levels, and heart rate variability in patients with coronary slow flow [J]. Annals of Noninvasive Electrocardiology, 2004,9(1):24-33.
32. Sezgin N, Barutcu I, Sezgin AT, et al. Plasma nitric oxide level and its role in slow coronary flow phenomenon [J]. International Heart Journal, 2005,46(3):373-382.
33. Turhan H, Saydam GS, Erbay AR, et al. Increased plasma soluble adhesion molecules; ICAM-1, VCAM-1, and E-selectin levels in patients with slow coronary flow [J]. International Journal of Cardiology,2006,108(2):224-230.
34. Li J-J, Qin X-W, Li Z-C, et al. Increased plasma C-reactive protein and interleukin-6 concentrations in patients with slow coronary flow [J]. Clinica Chimica Acta,2007,385(1-2):43-47.
35. Gokce M, Kaplan S, Tekelioglu Y, et al. Platelet function disorder in patients with coronary slow flow [J]. Clinical Cardiology,2005,28(3):145-148.
36. Yildiz A, Yilmaz R, Demirbag R, et al. Association of serum uric-acid level and coronary blood flow [J]. Coronary Artery Disease,2007,18(8):607-613.
37. Kostner K, Colquhoun D, Franco J, et al. Th-P 15:204 Patients with coronary slow flow have an abnormal lipid and apolipoprotein profile [J]. Atherosclerosis Supplements,2006,7(3):538-538.
38. Sezgin AT, Barutcu I, Sezgin N, et al. Contribution of plasma lipid disturbances to vascular endothelial function in patients with slow coronary flow [J]. Angiology,2006,57(6):694-701.
39. Dumaine R, Bigelow B, Aroesty J, et al. Myocardial reperfusion: its assessment and its relation to clinical outcomes [J]. American Heart Hospital Journal,2003,1(2):120-127.
40. Sezgin AT, Sigirci A, Barutcu I, et al. Vascular endothelial function in patients with slow coronary flow [J]. Coronary Artery Disease,2003,14(2):155-161.
41. Ozcan T, Gen R, Akbay E, et al. The correlation of thrombolysis in myocardial infarction frame count with insulin resistance in patients with slow coronary flow [J]. Coronary Artery Disease,2008,19(8):591-595.
42. Dogan SM, Yildirim N, Gursurer M, et al. P-wave duration and dispersion in patients with coronary slow flow and its relationship with Thrombolysis in Myocardial Infarction frame count [J]. Journal of Electrocardiology, 2008,41(1):55-59.
43. Kemp HG. Left Ventricular Function in Patients with Anginal Syndrome and Normal Coronary Arteriograms [J]. American Journal of Cardiology, 1973,32(3):375-376.
44. Cannon RO, Epstein SE. Microvascular Angina as a Cause of Chest Pain with Angiographically Normal Coronary-Arteries [J]. American Journal of Cardiology,1988,61(15):1338-1343.
45. Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon -A new coronary microvascular disorder [J]. Cardiology,2002,97(4):197-202.
46. Fragasso G, Chierchia SL, Arioli F, et al. Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X:Long-term clinical and functional prognosis [J]. International Journal of Cardiology,2009, 137(2):137-144.
47. Kurtoglu N, Akcay A, Dindar I. Usefulness of oral dipyridamole therapy for angiographic slow coronary artery flow [J]. The American Journal of Cardiology,2001,87(6):777-779.
48. Fam WM, McGregor M. Effect of nitroglycerin and dipyridamole on regional coronary resistance [J]. Circulation Research,1968,22(5):649-659.
49. Sellke FW, Myers PR, Bates JN, et al. Influence of vessel size on the sensitivity of porcine coronary microvessels to nitroglycerin [J]. American Journal of Physiology,1990,258(2 Pt 2):H515-520. 脏MRI可以用来检测CME后微梗死灶,准确测量左室大小、收缩功能,有很大的临床应用价值。
1. Dorge H, Schulz R, Belosjorow S, et al. Coronary Microembolization:the Role of TNF- [alpha] in Contractile Dysfunction [J]. Journal of Molecular and Cellular Cardiology,2002,34(1):51-62.
2. Heusch G, Kleinbongard P, Bose D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside [J]. Circulation,2009,120(18): 1822-1836.
3. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction [J]. Circulation,2007,116(2634-2653.
4. Bahrmann P, Figulla HR, Wagner M, et al. Detection of coronary microembolisation by Doppler ultrasound during percutaneous coronary interventions [J]. Heart,2005,91(9):1186-1192.
5. Bahrmann P, Werner GS, Heusch G, et al. Detection of coronary microembolization by Doppler ultrasound in patients with stable angina pectoris undergoing elective percutaneous coronary interventions [J]. Circulation,2007,115(5):600-608.
6. Ma JY, Qian JY, Jin H, et al. Acute hyperenhancement on delayed contrast-enhanced magnetic resonance imaging is the characteristic sign after coronary microembolization [J]. Chinese Medical Journal,2009,122(6): 687-691.
7. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart - A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association [J]. Circulation,2002,105(4):539-542.
8. Grothues F, Smith GC, Moon JCC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy [J]. American Journal of Cardiology,2002,90(1): 29-34.
9. Krombach GA, Higgins CB, Chujo M, et al. Gadomer-enhanced MR imaging in the detection of microvascular obstruction:Alleviation with nicorandil therapy [J]. Radiology,2005,236(2):510-518.
10. Nassenstein K, Breuckmann F, Bucher C, et al. How Much Myocardial Damage Is Necessary to Enable Detection of Focal Late Gadolinium Enhancement at Cardiac MR Imaging? [J]. Radiology,2008,249(3):829-835.
11. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation [J]. Circulation,2001,103(23):2780-2783.
12. Selvanayagam JB, Porto I, Channon K, et al. Troponin elevation after percutaneous coronary intervention directly represents the extent of irreversible myocardial injury - Insights from cardiovascular magnetic resonance imaging [J]. Circulation,2005,111(8):1027-1032.
13. Porto I, Selvanayagam JB, Van Gaal WJ, et al. Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention:Insights from delayed-enhancement magnetic resonance imaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound [J]. Circulation,2006, 114(7):662-669.
14. Selvanayagam JB, Cheng ASH, Jerosch-Herold M, et al. Effect of distal embolization on myocardial perfusion reserve after percutaneous coronary intervention - A quantitative magnetic resonance perfusion study [J]. Circulation,2007,116(13):1458-1464.
15. Mahrholdt H, Wagner A, Judd RM, et al. Assessment of myocardial viability by cardiovascular magnetic resonance imaging [J]. European Heart Journal, 2002,23(8):602-619.
16. Breuckmann F, Nassenstein K, Bucher C, et al. Systematic analysis of functional and structural changes after coronary microembolization:a cardiac magnetic resonance imaging study [J]. JACC Cardiovasc Imaging,2009, 2(2):121-130.
17. Carlsson M, Martin AJ, Ursell PC, et al. Magnetic Resonance Imaging Quantification of Left Ventricular Dysfunction Following Coronary Microembolization [J]. Magnetic Resonance in Medicine,2009,61(3):595-602.
18. Carlsson M, Wilson M, Martin AJ, et al. Myocardial Microinfarction after Coronary Microembolization in Swine:MR Imaging Characterization [J]. Radiology,2009,250(3):703-713.
19. Carlsson M, Saloner D, Martin AJ, et al. Heterogeneous Microinfarcts Caused by Coronary Microemboli:Evaluation with Multidetector CT and MR Imaging in a Swine Model [J]. Radiology,2010,254(3):718-728.
20. Appelbaum E, Manning WJ. Science to Practice:Can the Combination of Resting First-Pass Myocardial Perfusion and Late Gadolinium-enhanced Cardiovascular MR Imaging Help Identify Myocardial Infarction Resulting from Coronary Microembolization? [J]. Radiology,2009,250(3):609-611.
21. Skyschally A, Haude M, Dorge H, et al. Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization [J]. Circulation,2004,109(19):2337-2342.
22. Skyschally A, Gres P, Hoffmann S, et al. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization:progressive contractile dysfunction versus delayed protection against infarction [J]. Circulation Research,2007,100(1):140-146.
目前研究证实CME后左室功能下降、心肌重构主要与炎症有关。TNF-α在CME疾病发展中起重要作用。心肌组织NF-κB在CME中也被激活,且和心肌组织TNF-α表达呈正相关。因此,我们猜想TLR4/NF-κB TNF-α这个信号传导通路参与了CME后左室重构、功能异常的过程。本研究中我们发现,和假手术组比较,CME后前壁心肌组织TLR4的蛋白及mRNA水平均升高、NF-κB的蛋白及DNA结合活性均增高,心肌组织TLR4和NF-κB表达一致。提示CME后TLR4/NF-κB和炎症因子密切相关,TLR4/NF-κB参与了CME后的炎症反应过程。我们初步发现3组不同剂量微球造成的CME模型中,前壁TLR4/NF-κB的表达无明显差别,结合我们进行的心脏MRI研究(微球的剂量对左室重构、心功能的变化并无太大的影响),这可能说明：1)微栓塞后局部心肌的炎症与微栓塞的大小和面积无关,2)我们微球的大小和剂量不能体现这种差别,3)TLR4/NF-κB系统的激活只是其中的炎症反应的其中一个方面而已。
本研究初步比较了3种不同剂量微球的CME模型中,前壁、后壁TLR4/NF-κB的表达活性。但取样点太少,只取了术前和术后1w两个不同的时间点,并没有设计2h、6h等中间的取样分析,因此心肌TLR4/NF-κB表达活性的改变没有体现时间的差异；本次研究没有检测心肌TNF-α的表达,是根据以前的文献和定论,没有体现出心肌TLR4/NF-KB-TNF-α的相关性；此外,5万微球和12万微球组、对照组的数量太少,未行统计分析。此外,如需证明TLR4/NF-κB传导系统的作用,还需研究传导途径中的其它的一些关键分子的表达情况,这些都是我们以后研究的重点。
本研究通过冠脉介入法建立猪CME模型,发现CME后1w前壁心肌组织中TLR4、NF-κB表达均升高。心肌组织中TLR4、NF-κB表达一致,提示TLR4/NF-κB信号传导通路可能参与了CME后炎症反应,TLR4/NF-κB通路是炎症反应的一个机制。针对TLR4/NF-κB信号传导通路,减轻炎症反应是治疗CME后左室重构、心功能改变的又一希望,我们的研究为临床治疗CME提供了又一方向。
1. Skyschally A, Gres P, van Caster P, et al. Reduced calcium responsiveness characterizes contractile dysfunction following coronary microembolization [J]. Basic Research in Cardiology,2008,103(6):552-559.
2. Li SM, Zhong SS, Zeng K, et al. Blockade of NF-kappa B by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats [J]. Basic Research in Cardiology,2010,105(1):139-150.
3. Jorgense.L, Rowsell HC, Hovig T, et al. Adenosine Diphosphate-Induced Platelet Aggregation and Myocardial Infarction in Swine [J]. Laboratory Investigation,1967,17(6):616-644.
4. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease [J]. Circulation,2000,101(5):570-580.
5. Dorge H, Schulz R, Belosjorow S, et al. Coronary Microembolization:the Role of TNF- [alpha] in Contractile Dysfunction [J]. Journal of Molecular and Cellular Cardiology,2002,34(1):51-62.
6. Heusch G, Kleinbongard P, Bose D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside [J]. Circulation,2009,120(18): 1822-1836.
7. Arras M, Strasser R, Mohri M, et al. Tumor necrosis factor-alpha is expressed by monocytes/macrophages following cardiac microembolization and is antagonized by cyclosporine [J]. Basic Research in Cardiology,1998,93(2): 97-107.
8. Dorge H, Neumann T, Behrends M, et al. Perfusion-contraction mismatch with coronary microvascular obstruction:role of inflammation [J]. American Journal of Physiology-Heart and Circulatory Physiology,2000,279(6): H2587-H2592.
9. Skyschally A, Haude M, Dorge H, et al. Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization [J]. Circulation,2004,109(19):2337-2342.
10. Thielmann M, Belosjorow S, Martin C, et al. Myocardial dysfunction with coronary microembolization:Signal transduction through a sequence of no, TNF[alpha] and sphingosine [J]. Journal of Molecular and Cellular Cardiology,2002,34(6):A63-A63.
11. Skyschally A, Gres P, Hoffmann S, et al. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization:progressive contractile dysfunction versus delayed protection against infarction [J]. Circulation Research,2007,100(1):140-146.
12. Skyschally A, Gres P, Hoffmann S, et al. Delayed myocardial protection following coronary microembolization is mediated by TNF-[alpha] [J]. Journal of Molecular and Cellular Cardiology,2006,40(6):974-975.
13. Hayden MS, Ghosh S. Shared Principles in NF-[kappa]B Signaling [J]. Cell,2008,132(3):344-362.
14. Beinke S, Ley SC. Functions of NF-kappa B1 and NF-kappa B2 in immune cell biology [J]. Biochemical Journal,2004,382(393-409.
15. Valen G, Yan ZQ, Hansson GK. Nuclear factor kappa-B and the heart [J]. Journal of the American College of Cardiology,2001,38(2):307-314.
16. Frantz S, Hu K, Bayer B, et al. Absence of NF-kappa B subunit p50 improves heart failure after myocardial infarction [J]. Faseb Journal,2006,20(11):1918-1920.
17.李淑梅,曾凯,王伟伟,等.核因子-κB激活在大鼠冠状动脉微栓塞后的心肌组织中的作用及机制[J].中华心血管病杂志,2008,36(11)：1016-1020.
18. Hall G, Hasday JD, Rogers TB. Regulating the regulator: NF-kappaB signaling in heart [J]. Journal of Molecular & Cellular Cardiology,2006,41(4):580-591.
19. Sun SC, Ley SC. New insights into NF-kappa B regulation and function [J]. Trends in Immunology,2008,29(10):469-478.
20. Pandey S, Agrawal DK. Immunobiology of Toll-like receptors:Emerging trends [J]. Immunology and Cell Biology,2006,84(4):333-341.
21. Vabulas RM, Ahmad-Nejad P, da Costa C, et al. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells [J]. Journal of Biological Chemistry,2001,276(33):31332-31339.
22. Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates toll-like receptor 4 [J]. Journal of Biological Chemistry,2001,276(13): 10229-10233.
23. Hori M, Nishida K. Toll-like receptor signaling - Defensive or offensive for the heart? [J]. Circulation Research,2008,102(2):137-139.
24. Frantz S, Ertl G, Bauersachs J. Mechanisms of disease:Toll-like receptors in cardiovascular disease [J]. Nature Clinical Practice Cardiovascular Medicine, 2007,4(8):444-454.
25. Frantz S, Kobzik L, Kim YD, et al. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium [J]. Journal of Clinical Investigation,1999,104(3):271-280.
26. Birks EJ, Felkin LE, Banner NR, et al. Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices [J]. Journal of Heart and Lung Transplantation,2004,23(2):228-235.
27. Nemoto S, Vallejo JG, Knuefermann P, et al. Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart [J]. American Journal of Physiology-Heart and Circulatory Physiology,2002,282(6):H2316-H2323.
28. Sha T, Sunamoto M, Kitazaki T, et al. Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model [J]. European Journal of Pharmacology,2007,571(231-239.
29. Kuno M, Nemoto K, Ninomiya N, et al. The Novel Selective Toll-Like Receptor 4 Signal Transduction Inhibitor Tak-242 Prevents Endotoxaemia in Conscious Guinea-Pigs [J]. Clinical and Experimental Pharmacology and Physiology,2009,36(5-6):589-593.
30. Yang J, Yang J, Ding JW, et al. Sequential Expression of TLR4 and its Effects on the Myocardium of Rats with Myocardial Ischemia-Reperfusion Injury [J]. Inflammation,2008,31(5):304-312.
31. Satoh M, Shimoda Y, Maesawa C, et al. Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction [J]. International Journal of Cardiology,2006,109(2):226-234.
32. Medzhitov R, PrestonHurlburt P, Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity [J]. Nature, 1997,388(6640):394-397.
33. Baumgarten G, Knuefermann P, Nozaki N, et al. In Vivo Expression of Proinflammatory Mediator in the Adult Heart after Endotoxin Administration: The Role of Toll-Like Receptor-4 [J]. Journal of Infectious Diseases, 2001,183(11):1617.
1. Camici PG, Crea F. Medical progress - Coronary microvascular dysfunction [J]. New England Journal of Medicine,2007,356(8):830-840.
2. Chilian WM, Bassingthwaighte JB, Cannon RO, et al. Coronary microcirculation in health and disease - Summary of an NHLBI Workshop [J]. Circulation,1997,95(2):522-528.
3. Beltrame JF, Crea F, Camici P. Advances in coronary microvascular dysfunction [J]. Heart Lung Circ,2009,18(1):19-27.
4. Pries AR, Habazettl H, Ambrosio G, et al. A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings [J]. Cardiovascular Research,2008,80(2):165-174.
5. Sato A, Terata K, Miura H, et al. Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease [J]. American Journal of Physiology-Heart and Circulatory Physiology,2005,288(4):H1633-H1640.
6. Lucignani G, Cuocolo A. Advances in quantitative assessment of myocardial blood flow and coronary reserve [J]. European Journal of Nuclear Medicine and Molecular Imaging,2009,36(10):1687-1692.
7. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow [J]. Circulation,1996,93(5):879-888.
8. van't Hof AWJ, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction - Myocardial blush grade [J]. Circulation,1998, 97(23):2302-2306.
9. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs [J]. Circulation,2000,101(2):125-130.
10. Gould KL, Kirkeeide RL, Buchi M. Coronary Flow Reserve as a Physiologic Measure of Stenosis Severity [J]. Journal of the American College of Cardiology,1990,15(2):459-474.
11. Fearon WF, Balsam LB, Farouque HMO, et al. Novel index for invasively assessing the coronary microcirculation [J]. Circulation,2003,107(25): 3129-3132.
12. Ganz W, Tamura K, Marcus HS, et al. Measurement of coronary sinus blood flow by continuous thermodilution in man [J]. Circulation,1971, 44(2):181-195.
13. Knaapen P, Camici PG, Marques KM, et al. Coronary microvascular resistance: methods for its quantification in humans [J]. Basic Research in Cardiology, 2009,104(5):485-498.
14. Meimoun P, Tribouilloy C. Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography:a magic tool for the real world [J]. European Journal of Echocardiography, 2008,9(4):449-457.
15. Husmann L, Tatsugami F, Aepli U, et al. Prevalence of noncardiac findings on low dose 64-slice computed tomography used for attenuation correction in myocardial perfusion imaging with SPECT [J]. International Journal of Cardiovascular Imaging,2009,25(8):859-865.
16. Blankstein R, Shturman LD, Rogers IS, et al. Adenosine-Induced Stress Myocardial Perfusion Imaging Using Dual-Source Cardiac Computed Tomography [J]. Journal of the American College of Cardiology, 2009,54(12):1072-1084.
17. Blankstein R, Okada DR, Rocha-Filho JA, et al. Cardiac myocardial perfusion imaging using dual source computed tomography [J]. International Journal of Cardiovascular Imaging,2009,25(209-216.
18. Daghini E, Lerman LO. Assessment of Myocardial Microvascular Function: New Opportunities in Fast Computed Tomography [J]. Trends in Cardiovascular Medicine,2007,17(1):14-19.
19. Ramkumar PG, Mitsouras D, Feldman CL, et al. New advances in cardiac computed tomography [J]. Current Opinion in Cardiology,2009,24(6): 596-603.
20. Beanlands RSB, Ziadi MC, Williams K. Quantification of Myocardial Flow Reserve Using Positron Emission Imaging The Journey to Clinical Use [J]. Journal of the American College of Cardiology,2009,54(2):157-159.
21. Lortie M, Beanlands RSB, Yoshinaga K, et al. Quantification of myocardial blood flow with Rb-82 dynamic PET imaging [J]. European Journal of Nuclear Medicine and Molecular Imaging,2007,34(1765-1774.
22. Heller GV, Calnon D, Dorbala S. Recent advances in cardiac PET and PET/CT myocardial perfusion imaging [J]. Journal of Nuclear Cardiology,2009, 16(6):962-969.
23. Beller GA. Will cardiac positron emission tomography ultimately replace SPECT for myocardial perfusion imaging? [J]. J Nucl Cardiol,2009, 16(6):841-843.
24. Kemp HG. Left Ventricular Function in Patients with Anginal Syndrome and Normal Coronary Arteriograms [J]. American Journal of Cardiology,1973, 32(3):375-376.
25. Cannon RO, Epstein SE. Microvascular Angina as a Cause of Chest Pain with Angiographically Normal Coronary-Arteries [J]. American Journal of Cardiology,1988,61(15):1338-1343.
26. Lanza GA. Cardiac syndrome X:a critical overview and future perspectives [J]. Heart,2007,93(2):159-166.
27. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging [J]. New England Journal of Medicine,2002, 346(25):1948-1953.
28. Lamendola P, Lanza GA, Spinelli A, et al. Long-term prognosis of patients with cardiac syndrome X [J]. International Journal of Cardiology,In Press, Corrected Proof(
29. Bugiardini R, Manfrini O, Pizzi C, et al. Endothelial function predicts future development of coronary artery disease - A study of women with chest pain and normal coronary angiograms [J]. Circulation,2004,109(21):2518-2523.
30. Lim TK, Choy AJ, Khan F, et al. Therapeutic Development in Cardiac Syndrome X:A Need to Target the Underlying Pathophysiology [J]. Cardiovascular Therapeutics,2009,27(1):49-58.
31. Melikian N, De Bruyne B, Fearon WF, et al. The Pathophysiology and Clinical Course of the Normal Coronary Angina Syndrome (Cardiac Syndrome X) [J]. Progress in Cardiovascular Diseases,2008,50(4):294-310.
32. Hirooka Y, Kimura Y, Ito YSK, et al. Effects of valsartan or amlodipine on endothelial function and oxidative stress after one year follow-up in patients with essential hypertension [J]. Clinical and Experimental Hypertension, 2008,30(3-4):267-276.
33. Kayikcioglu M, Payzin S, Yavuzgil O, et al. Benefits of statin treatment in cardiac syndrome-X [J]. European Heart Journal,2003,24(22):1999-2005.
34. Jadhav S, Ferrell W, Greer IA, et al. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries - A randomized, double-blind, placebo-controlled study [J]. Journal of the American College of Cardiology,2006,48(5):956-963.
35. Celik T, Iyisoy A, Yuksel UC, et al. A new treatment modality in management of patients with cardiac syndrome X:Enhanced external counterpulsation [J]. International Journal of Cardiology,In Press, Corrected Proof(
36. Kronhaus KD, Lawson WE. Enhanced external counterpulsation is an effective treatment for Syndrome X [J]. International Journal of Cardiology, 2009,135(2):256-257.
37. Tambe AA, Demany MA, Zimmerman HA, et al. Angina pectoris and slow flow velocity of dye in coronary arteries-a new angiographic finding [J]. American Heart Journal,1972,84(1):66-71.
38. Mosseri M, Yarom R, Gotsman MS, et al. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries [J]. Circulation,1986,74(5):964-972.
39. Goel PK, Gupta SK, Agarwal A, et al. Slow coronary flow: A distinct angiographic subgroup in syndrome X [J]. Angiology,2001,52(8):507-514.
40. Przybojewski JZ, Becker PH. Angina pectoris and acute myocardial infarction due to "slow-flow phenomenon" in nonatherosclerotic coronary arteries:a case report [J]. Angiology,1986,37(10):751-761.
41. Amasyali B, Turhan H, Kose S, et al. Aborted sudden cardiac death in a 20-year-old man with slow coronary flow [J]. International Journal of Cardiology,2006,109(3):427-429.
42. Kapoor A, Goel PK, Gupta S. Slow coronary flow - a cause for angina with ST segment elevation and normal coronary arteries. A case report [J]. International Journal of Cardiology,1998,67(3):257-261.
43. Cutri N, Kucia AM, Beltrame JF. Continuous ST/T Wave Monitoring During an Acute Coronary Syndrome Presentation in Patients with the Coronary Slow Flow Phenomenon (CSFP) [J]. Heart, Lung and Circulation,2008, 17(Supplement 3):S95-S95.
44. Demirkol MO, Yaymaci B, Mutlu B. Dipyridamole myocardial perfusion single photon emission computed tomography in patients with slow coronary flow [J]. Coronary Artery Disease,2002,13(4):223-229.
45. Mangieri E, Tanzilli G, De Vincentis G, et al. Slow coronary flow and stress myocardial perfusion imaging. Different patterns in acute patients [J]. J Cardiovasc Med (Hagerstown),2006,7(5):322-327.
46. Tatli E, Yildirim T, Aktoz M. Does coronary slow flow phenomenon lead to myocardial ischemia? [J]. International Journal of Cardiology,2009, 131(3):e101-e102.
47. Li J-J, Xu B, Li Z-C, et al. Is slow coronary flow associated with inflammation? [J]. Medical Hypotheses,2006,66(3):504-508.
48. Erdogan D, Caliskan M, Gullu H, et al. Coronary flow reserve is impaired in patients with slow coronary flow [J]. Atherosclerosis,2007,191(1):168-174.
49. Fineschi M, Bravi A, Gori T. The "slow coronary flow" phenomenon: Evidence of preserved coronary flow reserve despite increased resting microvascular resistances [J]. International Journal of Cardiology,2008, 127(3):358-361.
50. Fineschi M, Gori T. Coronary slow flow: Description of a new "cardiac Y" syndrome [J]. International Journal of Cardiology,2009,137(3):308-310.
51. Mangieri E, Macchiarelli G, Ciavolella M, et al. Slow coronary flow: clinical and histopathological features in patients with otherwise normal epicardial coronary arteries [J]. Catheterization and Cardiovascular Diagnosis,1996, 37(4):375-381.
52. Beltrame JF, Limaye SB, Wuttke RD, et al. Coronary hemodynamic and metabolic studies of the coronary slow flow phenomenon [J]. American Heart Journal,2003,146(1):84-90.
53. Beltrame JF, Turner SP, Leslie SL, et al. The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon [J]. Journal of the American College of Cardiology,2004,44(1):57-62.
54. Yildiz A, Yilmaz R, Demirbag R, et al. Association of serum uric-acid level and coronary blood flow [J]. Coronary Artery Disease,2007,18(8):607-613.
55. Li J-J, Qin X-W, Li Z-C, et al. Increased plasma C-reactive protein and interleukin-6 concentrations in patients with slow coronary flow [J]. Clinica Chimica Acta,2007,385(1-2):43-47.
56. Kostner K, Colquhoun D, Franco J, et al. Th-P 15:204 Patients with coronary slow flow have an abnormal lipid and apolipoprotein profile [J]. Atherosclerosis Supplements,2006,7(3):538-538.
57. Sezgin AT, Barutcu I, Sezgin N, et al. Contribution of plasma lipid disturbances to vascular endothelial function in patients with slow coronary flow [J]. Angiology,2006,57(6):694-701.
58.常书福,马剑英,钱菊英,等.冠状动脉内应用硝酸甘油和维拉帕米治疗冠状动脉血流缓慢现象的效果[J].中华心血管病杂志,2010,38(1)：27-30.
59. Kurtoglu N, Akcay A, Dindar I. Usefulness of oral dipyridamole therapy for angiographic slow coronary artery flow [J]. The American Journal of Cardiology,2001,87(6):777-779.
60. Leone MC, Gori T, Fineschi M. The coronary slow flow phenomenon:A new cardiac "Y" syndrome? [J]. Clinical Hemorheology and Microcirculation,2008, 39(1-4):185-190.
61. Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon-A new coronary microvascular disorder [J]. Cardiology,2002,97(4):197-202.
62. Fragasso G, Chierchia SL, Arioli F, et al. Coronary slow-flow causing transient myocardial hypoperfusion in patients with cardiac syndrome X:Long-term clinical and functional prognosis [J]. International Journal of Cardiology, 2009,137(2):137-144.
63. Li SM, Zhong SS, Zeng K, et al. Blockade of NF-kappa B by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats [J]. Basic Research in Cardiology,2010,105(1):139-150.
64. Dorge H, Neumann T, Behrends M, et al. Perfusion-contraction mismatch with coronary microvascular obstruction:role of inflammation [J]. American Journal of Physiology-Heart and Circulatory Physiology,2000, 279(6):H2587-H2592.
65. Heusch G, Kleinbongard P, Bose D, et al. Coronary Microembolization From Bedside to Bench and Back to Bedside [J]. Circulation,2009,120(18): 1822-1836.
66. Hori M, Inoue M, Kitakaze M, et al. Role of Adenosine in Hyperemic Response of Coronary Blood-Flow in Microembolization [J]. American Journal of Physiology,1986,250(3):H509-H518.
67. Mohlenkamp S, Beighley PE, Pfeifer EA, et al. Intramyocardial blood volume, perfusion and transit time in response to embolization of different sized microvessels [J]. Cardiovascular Research,2003,57(3):843-852.
68. Dorge H, Schulz R, Belosjorow S, et al. Coronary Microembolization:the Role of TNF-[alpha] in Contractile Dysfunction [J]. Journal of Molecular and Cellular Cardiology,2002,34(1):51-62.
69. Skyschally A, Schulz R, Erbel R, et al. Reduced coronary and inotropic reserves with coronary microembolization [J]. American Journal of Physiology - Heart & Circulatory Physiology,2002,282(2):H611-614.
70. Arras M, Strasser R, Mohri M, et al. Tumor necrosis factor-alpha is expressed by monocytes/macrophages following cardiac microembolization and is antagonized by cyclosporine [J]. Basic Research in Cardiology,1998,93(2): 97-107.
71. Skyschally A, Haude M, Dorge H, et al. Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization [J]. Circulation,2004,109(19):2337-2342.
72. Skyschally A, Gres P, Hoffmann S, et al. Bidirectional role of tumor necrosis factor-alpha in coronary microembolization:progressive contractile dysfunction versus delayed protection against infarction [J]. Circulation Research,2007,100(1):140-146.
73. Thielmann M, Belosjorow S, Martin C, et al. Myocardial dysfunction with coronary microembolization:Signal transduction through a sequence of NO, TNF alpha and sphingosine [J]. Journal of Molecular and Cellular Cardiology,2002,34(6):A63-A63.
74. Canton M, Skyschally A, Menabo R, et al. Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolization [J]. European Heart Journal,2006,27(7):875-881.
75. Skyschally A, Gres P, van Caster P, et al. Reduced calcium responsiveness characterizes contractile dysfunction following coronary microembolization [J]. Basic Research in Cardiology,2008,103(6):552-559.
76. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction [J]. Circulation,2007,116(2634-2653.
77. Bahrmann P, Figulla HR, Wagner M, et al. Detection of coronary microembolisation by Doppler ultrasound during percutaneous coronary interventions [J]. Heart,2005,91(9):1186-1192.
78. Bahrmann P, Werner GS, Heusch G, et al. Detection of coronary microembolization by Doppler ultrasound in patients with stable angina pectoris undergoing elective percutaneous coronary interventions [J]. Circulation,2007,115(5):600-608.
79. Krombach GA, Higgins CB, Chujo M, et al. Gadomer-enhanced MR imaging in the detection of microvascular obstruction: Alleviation with nicorandil therapy [J]. Radiology,2005,236(2):510-518.
80. Nassenstein K, Breuckmann F, Bucher C, et al. How Much Myocardial Damage Is Necessary to Enable Detection of Focal Late Gadolinium Enhancement at Cardiac MR Imaging? [J]. Radiology,2008,249(3):829-835.
81. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation [J]. Circulation,2001,103(23):2780-2783.
82. Selvanayagam JB, Porto I, Channon K, et al. Troponin elevation after percutaneous coronary intervention directly represents the extent of irreversible myocardial injury - Insights from cardiovascular magnetic resonance imaging [J]. Circulation,2005,111(8):1027-1032.
83. Porto I, Selvanayagam JB, Van Gaal WJ, et al. Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention:Insights from delayed-enhancement magnetic resonance imaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound [J]. Circulation,2006, 114(7):662-669.
84. Selvanayagam JB, Cheng ASH, Jerosch-Herold M, et al. Effect of distal embolization on myocardial perfusion reserve after percutaneous coronary intervention - A quantitative magnetic resonance perfusion study [J]. Circulation,2007,116(13):1458-1464.
85. Mahrholdt H, Wagner A, Judd RM, et al. Assessment of myocardial viability by cardiovascular magnetic resonance imaging [J]. European Heart Journal,2002,23(8):602-619.
86. Breuckmann F, Nassenstein K, Bucher C, et al. Systematic analysis of functional and structural changes after coronary microembolization:a cardiac magnetic resonance imaging study [J]. JACC Cardiovasc Imaging,2009, 2(2):121-130.
87. Carlsson M, Martin AJ, Ursell PC, et al. Magnetic Resonance Imaging Quantification of Left Ventricular Dysfunction Following Coronary Microembolization [J]. Magnetic Resonance in Medicine,2009,61(3):595-602.
88. Carlsson M, Wilson M, Martin AJ, et al. Myocardial Microinfarction after Coronary Microembolization in Swine:MR Imaging Characterization [J]. Radiology,2009,250(3):703-713.
89. Carlsson M, Saloner D, Martin AJ, et al. Heterogeneous Microinfarcts Caused by Coronary Microemboli:Evaluation with Multidetector CT and MR Imaging in a Swine Model [J]. Radiology,2010,254(3):718-728.