动脉粥样硬化性心血管疾病高危患者他汀治疗“足剂量”比例堪忧

动脉粥样硬化性心血管疾病高危患者他汀治疗“足剂量”比例堪忧

2013美国心脏病学会/美国心脏学会（ACC/ AHA）血脂管理指南自发布伊始，就引发了大量的关注和争论，其核心焦点就是该指南创新性地提出抛弃沿用已久的血脂管理目标水平，而采用他汀治疗的强度，即血脂下降的幅度来评估他汀治疗是否已经达到“足剂量”。有识之士曾指出，这一举措可能会是“疾病预防史上巨大的模式转换”过程，但同时专家也认为，如何使得医务人员放弃原本对于血脂管理目标值的认知，接受根据他汀治疗强度来判断他汀类药物剂量，将会是一项极富挑战性的工程。

刚刚结束的2016欧洲心脏病学年会（ESC）上，美国杜克临床研究所的Navar博士公布了患者和医务人员血脂管理评价（Patient and Provider Assessment of Lipid Management，PALM）注册研究的分析结果，发现高危患者他汀治疗剂量不足的现象仍普遍存在。

根据2013班美国血脂管理指南推荐，年龄＜75岁的动脉粥样硬化性心血管疾病（ASCVD）患者、任何低密度脂蛋白胆固醇（LDL-C）水平≥190mg/dl的成人以及发生ASCVD风险≥7.5%≥10年的40～75岁高危的糖尿病患者须接受高强度他汀治疗（每日剂量达到平均降低LDL-C≥50%）。而作为一级预防、75岁以上合并ASCVD的老年患者以及ASCVD风险＜7.5%的糖尿病患者仅需中等强度他汀治疗（每日剂量达到平均降低LDL-C 30%～50%）。

Navar博士的报告显示，在分析了5 906例具有他汀治疗适应证并接受常规治疗的成人中，服用了他汀类药物的患者占74%，但只有45%的患者剂量是合适的。引人注意的是指南推荐需高强度他汀治疗的人群中，这组数据分别为80%及29%。而相比之下，推荐接受中等强度他汀治疗的患者中，这组数据为67%及60%。

PALM注册研究通过了入选的140家单位的心内科、内分泌科以及基础保健的门诊患者，共纳入接受中等强度他汀患者2 532例及高强度他汀患者3 374例。当研究人员将患者分为一级预防组以及二级预防组后发现，一级预防组中他汀剂量不足问题更为显著。在指南推荐应接受中等强度他汀治疗的人群中，42%一级预防患者及19%二级预防患者没有服用任何他汀类药物。在指南推荐需高强度他汀治疗的人群中，仅有36%二级预防患者用到了足量，但这仍然比一级预防患者（16%）要高得多。在推荐使用高强度他汀类药物治疗的人群中，他汀剂量不足患者中女性较多（42.2%比29.6%），非洲裔美国人多（15.4%比11%），合并糖尿病比例较高（60.9%比53.7%），心血管专科就诊次数达标百分比更少（43.4%比63.2%），差异均有统计学意义（P＜0.01）。

研究团队进一步了解了患者的LDL-C水平，进而发现他汀类药物使用不足并非是因为患者LDL-C水平已达标而不需要他汀类强化治疗。事实上，其中几乎半数推荐需高强度他汀治疗的患者存在LDL-C升高（≥100 mg/dl），而在足量他汀治疗人群中这一比例仅为22%。这从另一方面也印证了2013版指南所强调的可能从LDL-C降低获益最多的高危人群，进行高强度他汀治疗的必要性。

临床实践中，笔者也深刻感受到对于高危患者他汀治疗强度的认知存在较大的误区。从基层医院转诊至高级别医院进一步诊治的高危患者，抗血小板的治疗通常更容易受到关注，但他汀剂量是否真的达到要求却容易忽视。又或者，门诊随访中经常可见经皮冠状动脉介入（PCI）术后复查的患者，他汀的剂量不断减少，或从中高强度的他汀减量为低强度的他汀使用，而其依据往往只是“病好起来了”或者“费用太高了”。从卫生经济学的角度，患者因体化医疗的迫切需求。诚然，我们认同“指南”并非临床实践的“圣经”，但是科学解读循证医学进展，并指导于实践，将会是新时代赋予医务人员的又一重任。ASCVD导致急性冠状动脉综合征或是脑卒中的费用，只怕比坚持他汀类药物治疗要多得多。我国的文化传统使得我们产生“经验医学”的惯性，而现代医学的进展则越来越凸显出循证医学和个

（陈涵编译）

Ventricular tachycardia（VT）may be classsified based on the clinical characteristic（clinical VT, hemodynamically stable or unstable,repetitive, incessant,etc.）,morphology（monomorphic,multiple morphologies,pleomorphic,polymorphic,bidirectional, etc.）ormechanisms（scar-related reentry,automaticity, and triggered activity）.Incessant VT is defined as continuous sustained VT during several hours,which recurs promptly despite repeated intervention for termination.Multiple monomorphic VTs refer to＞1 morphologically distinct monomorphic VT,occurring as different episodes,or induced at different times. Pleomorphic VT has＞1 morphologically distinct QRS complex occurring during the same episode of VT,but the QRS is not continuously changing.Bidirectional VT （BVT）is characterized by beat-to-beat alternation of the QRS axison the ECG and isusually regular.

Case Report

A 33-year-old male,nondiabetic,nonhypertensive,presented with history of palpitation,chest discom fort,and fatigueof6 hoursduration.He had been otherwise healthy,not on any medications with no history of tobacco,alcohol,or drug use.At presentation, pulse rate was 144 beats per minute,irregular,blood pressure 96/60 mm Hg,and the rest of physical examination was unremarkable.Twelve-lead ECG revealed a wide complex regularly irregular tachycardia at a rate of 144 beats per minute,right bundle morphology,QRS duration of 200 to 220 ms,QRS axis alternating between+160°and-40°,QRS transition alternating from V3to V6,and evidence of atrioventricular dissociation to intravenous lignocaine, esmolol,amiodarone（300 mg during 1 hour）,and 2 attempts of biphasic direct current（DC）cardioversion of 200 J.Because the tachycardiawas incessant,patient was sedated,intubated,ventilated,and continued on intravenous amiodarone（900 mg/24 hours）with further 4 unsuccessful attempts at DC cardioversion. Tachycardia converted to monomorphic VT with occasional VT complexesof the 2ndmorphology（Figure 2）,which terminated 6 hours later while on infusion of amiodarone and lignocaine,and while he was being considered for radiofrequency catheter ablation.ECG in sinus rhythm was essentially normal,chest X-ray revealed superior mediastinal widening,and echocardiogram showed normal left ventricular function. Cardiac MRI revealed focal areas of thickening and increased signal intensity on T2-weighted images.Early gadolinium enhancement was seen in the mid interventricular septum,anterolateral and anteroinferior walls,with the lesions having a target appearance with peripheral slightly hyperintense rim and central hypo intensity（Figure 3A）.Delayed gadolinium enhancement was found predominantly in the midmyocardium and epicardial in basal and lateral segments of the left ventricle.18F-fluoro-2-deoxy-d-glucose（FDG）positron emission tomography scan revealed basal andmid anteroseptal perfusion defect with intense FDG uptake in these regions suggestive of myocardial inflammation along with evidence of inflammation in the paratracheal lymph nodes（Figure 3B）.Serum biochemistry was normal including serum calcium, serum angiotensin-converting enzyme（ACE）,digoxin, blood aconite levels（report received 2 weeks later）, and IgG and IgM assays were negative for tuberculosis bacilli.Transbronchial lymph node biopsy revealed noncaseating granulomas suggestive of sarcoidosis. Patient was initiated on 1 g of methylprednisolone per day for 3 days intravenously and amiodarone infusion of 1 g/d was continued for 3 days after which it was switched to oral therapy and patient was extubated after 36 hours.Later,oral predinsolone was initiated at 60 mg/d for 2 months and was tapered to a maintenancedose of 10 mg/d for 2 years and stopped after a normal repeatpositron emission tomography FDG scan.A single chamber implantable defibrillator was implanted after 5 days of VT-free interval.Amiodarone was tapered and stopped after 6 months.Genetic testing for possible catecholaminergic polymorphic ventricular tachycardia with analysis for 4 genes:RYR2,CASQ2,ANK2,and KCNJ2 were negative.Four years later,patient has not had any device activation and hasnormal leftventricular function.

Figure 1 Tachycardiawasunresponsive.Twelve-lead ECG showingbidirectional ventricular tachycardia.

Figure 2 Twelve-lead ECG showing partial suppression of suppression of focus A resulting in occasional ectopic beats during sustainedmonomorphic ventricular tachycardia（VT）becauseof focusB.

Figure 3 A:T2-weighted cardiac MRI:showing gadolinium enhancement in mid interventricular septum（arrow）.B: 18F-fluoro-2-deoxy-d-glucose（FDG）positron emission tomography scan:showing basal and midanteroseptal perfusion defectwith intense FDG uptake.

Discussion

This case describes an unusual presentation of isolated cardiac sarcoidosis with incessant regularly irregular BVT,normal LV function,and no conduction system involvement as the initial manifestation.Clinical manifestations of cardiac sarcoidosis are dependent on the location,extent,and activity of the disease.The 3 principal sequelae of cardiac sarcoidosis are（1）conduction abnormalities（2）ventricular arrhythmias, and（3）heart failure.Cardiac sarcoidosis usually presents with monomorphic VT or conduction system disturbances.Macroreentry around areas of granulomatous scar is the commonest mechanism of VT in sarcoidosis.

BVT is a rare ventricular tachyarrhythmia.It is usually regular,demonstrates a beat-to-beat alternation of the QRS frontal axis varying between-20°to-30° and+110°.Tachycardia rate is typically between 140 and 180 beats per minute and the QRS is relatively narrowwith duration of120 to150ms.

BVT in present case has many unusual features. The QRS duration is broad at 200 to 220 ms,unlike casesof inmostBVT where it is relatively narrow at120 to 150 ms.Wide QRS in this case possibly indicates intramyocardial/epicardial site of origin,unlike the usual BVT where the origin is supposedly more closer to the His purkinje system.

The most intriguing feature is the regularly irregular rhythm as seen in Figure 1.A careful analysis of relationship between the 2 morphologies of QRS complexesnamely A and B reveals that the A-A interval is72 beatsper minute（0.88 s）and B-B interval is72 beats perminute（0.88 s）,resulting in tachycardia rate of 144 beats per minute.The relationship of A to B interval is constant at 0.56 s,and B to A interval is constant at 0.32 s,and this relationship is constant throughout the tachycardia resulting in a regularly irregular rhythm.The broad QRS,with axis alternating between+160°and-40°,transition alternating from V3to V6in chest leads,possibly indicates2 independent foci.The original hypothesis of dual ventricular foci firing alternatively that was suggested as themechanism was discarded because of the constant R-R interval that would presuppose a perfect alteration of the 2 foci. However,in this case,regularly irregular rhythm can be explained by automatic firing of 2 different foci at constant intervals and presence of entrance block in each of the foci akin toa dual parasystole.

Parasystole requires an area of focal impulse formation which is surrounded by an area that protects （shield）the focus from external impulses thus resulting in an entry block but no exit block of the focus. Automaticity and protection are the hallmarks of parasystole.This feature lead to the diagnostic triad of classical parasystole,that is,varying coupling intervals of the ectopic focus,mathematically related interectopic intervals and the presence of fusion beats.The original assumption of total independence（protection）of parasystolic focus from extraneous beats is no longer considered true.It is now evident that any pacemaker connected to the surrounding tissues by an area of depressed excitability producing entrance conductiondisturbances while allowing the impulses to exit is subject to1some degree of modulation by electrotonic depolarizations arising in the surrounding tissues,that is,depolarization of the surrounding field will induce a partial depolarization of the pacemaker cells.This results in the occurrence of modulated parasystole.This means that nonparasystolic beats falling close to the parasystolic beats can cause（1）maximal delay,（2）maximal acceleration,（3）lesser effects,（4）practically no effect,or（5）pacemaker annihilation of the parasystolic focus.Nonparasystolic beats falling during the first half of the parasystolic interval induce a prolongation of this interval,those occurring during the second half of the parasystolic cycle length cause an abbreviation of this interval.Theelectrotonic modulation （causing either prolongation or shortening of the parasystolic cycle length）ismaximal at themiddle point of the parasystolic interval.Thus,the coupling interval of the ectopic focus may not be constant in modulated parasystole and interectopic interval may also show variation.Modulation may also cause coupling intervals to be fixed,and the fixed coupling intervals may suggest a reciprocating bigeminy.It has been shown that if the impedance of the communication between the ectopic focusand the surrounding ventricle is low,locking of the ectopic pacemaker could be nearly fixed to give the appearance of a reciprocating bigeminy.This is substantiated by Figure 2 in our case,wherein after infusion of amiodarone there is partial suppression of focus A resulting in occasional ectopic beats during sustained monomorphic VT because of focus B. Measurement of B-B intervals shows that there is doubling of the rate from 0.88 s during BVT as seen in Figure 1,compared with 0.44 s in Figure 2 suggesting a parasystole as the mechanism of arrhythmia.The interlocking of the beat A to beat B still persists.But measurementof intervalsbetween A-A in this strip does notshow amathematical relation relationship,which can be explained by modulation of parasystole focus A by the preceding beat（from focus B）.In the presentcase, dual parasystole is the most plausible explanation.The occurrence of only occasional beats of focus A（Figure 2）where the focus B is continuing in an accelerated rate excludes the possibility of a BVT because of a pingpong effect as there is no consistency in occurrence of focus A,which should have regularly alternated with focus B, if itwasbecauseofping-pongeffect2.

Triggered activity and abnormal automaticity have been described secondary tomyocardial inflammation in myocarditis.Incessant nature of the tachycardia, unresponsive tomultiple DC cardioversion,antiarrhythmic agentssuch asβ-blockersand lignocaine,suggests that the possible mechanism of VT is enhanced automaticity because arrhythmias either because of reentry or because of delayed after depolarization typically are responsive to these maneuvers.It is possible that local inflammation around the automatic foci could create an entry block in cardiac sarcoidosis, resulting in parasystole.Multiple areas of granulomatous inflammation which is not uncommon in cardiac sarcoidosis could allow 2 parasystolic foci to coexist as in the presentcase.

词汇

incessant adj.不停的,没完没了，顽固的，连续的

pleomorphic adj.多型的,多晶的

hyperintense n.高信号

paratracheal adj.气管旁的

aconite n.乌头，乌头毒草

granulomatous adj.肉芽肿的

intrigue n.&v.阴谋,情节,私通;耍阴谋,吸引,使...困惑,私通

discard n.&v.丢弃;丢牌,丢弃,打出，放弃，遗弃

extraneous adj.体外的,额外的,非必要的，外来的

impedance n.阻抗

substantiate v.证实,使...具体化,充实

注释

1.be subject to指“易受…的”，如Many physiological measures are continuous variables that are subject to the influence of external stimuli and internal homoeostatic control mechanisms.许多生理测值是连续变量，易受外部刺激和内在体内控制机制的影响。

2.ping-pong effect“乒乓效应”或“乒乓机制”，指的是在两个不同的状态之间来回变化，不同的领域都有此表述。医学上描述双向性室性心动过速的乒乓机制常指延迟后除极介导的触发活动，具有两种特性：（1）高于某一阈值心率的延迟后除极在前一动作电位后触发单一的动作电位，引起室性二联律，（2）与二联律相关的阈值心率因心脏部位而变化。

参考译文

第73课不常见的顽固性室性心动过速——基础病因和可能的机制是什么？

室性心动过速根据临床特征（血流动力学稳定与否、反复的、顽固的）、波形（单形性、多种形态、多形性、双向性等）或发病机制（瘢痕相关折返、自律性增高、促发活动）进行分类。顽固性室性心动过速是指持续数小时、即使反复干预中止后仍会迅速复发的室性心动过速。多发单形性室性心动过速是指不同时段发作或诱发的单形性室性心动过速形态超过一种。多形性室性心动过速是指同一发作时段出现1种以上的QRS形态，但QRS形态不呈连续性变化。双向性室性心动过速特征表现为心电图上QRS心电轴呈每搏交替，通常是规则的。

病例报告

患者男性，33岁，无糖尿病、无高血压，因心悸、胸部不适和疲劳6h而就诊。既往体健，没有服用任何药物，无吸烟饮酒及药瘾史。入院体检：脉率144次/min，不规则，血压96/60mmHg，其他无异常。12导联心电图显示规律性不规律宽QRS波群心动过速，频率144次/min，呈右束支图形，间期200～220ms,QRS电轴在+160°与-40°交替，QRS波群移行从V3到V6，存在房室分离（图1）。心动过速对静脉注射利多卡因、艾斯莫、胺碘酮（1h内300mg）及2次200J的双向直流电击无反应。鉴于心动过速持续，对患者进行镇静、气管插管和机械通气，持续静脉给胺碘酮（900mg/24h），进一步直流电击4次无效。心动过速转为单形性室性心动过速，偶见第2种形态的室性心动过速（图2），6h后在滴注胺碘酮和利多卡因期间中止，此时正准备行射频消融治疗。窦性心律心电图基本正常，X线胸片检查提示上纵隔增宽，超声心动图显示左心室功能正常。心脏MRI显示局灶性增厚和T2WI信号增强。可见间隔中部、前侧壁和前下壁早期钆强化，以及周边轻度强化而中心低强度的靶形病灶（图3A）。延迟强化主要见于左心室基底和侧壁节段的心肌中层和外膜。18F-氟脱氧葡萄糖（FDG）正电子发射扫描显示支持心肌炎症的基底部和前间隔中部灌注缺损伴FDG摄取增加，并有气管旁淋巴结炎症的依据（图3B）。血清钙、ACE、地高辛、血乌头毒草浓度（2周后报告）正常，结核杆菌IgG和IgM阴性。经气管淋巴结活检显示非干酪样肉芽肿，提示类肉瘤病。患者初始接受每天1 g的甲基强的松龙静脉注射3d，胺碘酮每天1g滴注3d，其后改口服，36h后候拔除气管插管。随后，口服强的松龙60 mg/d，2个月，逐渐减量至每天10 mg达2年，复查正电子发射断层FDG扫描正常后停药。在室性心动过速中止后5d植入单腔植入型除颤器。胺碘酮逐渐减量并于6个月后停止。基因检测RYR2,CASQ2,ANK2和KCNJ2阴性，排除儿茶酚胺性多形性室性心动过速。随访4年，除颤器未发生除颤工作，左心室功能正常。

讨论

本病例描述了不常见的孤立性心脏类肉瘤病，初始表现为顽固的规律性不规律双向性室性心动过速，左心室功能正常，未累及传导系统。心脏的类肉瘤病表现决定于部位、范围和疾病的活动性。心脏类肉瘤病的3个主要后果是：（1）传导异常；（2）室性心律失常；（3）心力衰竭。心脏类肉瘤病通常表现为单形性室性心动过速或传导功能障碍。围绕肉芽肿瘢痕形成的大折返环是导致类肉瘤病室性心动过速的最常见机制。

双向性室性心动过速是罕见的室性快速性心律失常。通常是规则的，QRS波群额面心电轴在-20°到-30°与+110°之间每搏交替。心动过速频率在140～180次/min，QRS波群相对较窄，120～150ms。

本例双向性室性心动过速具有许多不常见的特性。QRS间期宽达200～220 ms,而多数双向性室性心动过速是相对较窄的，120～150ms。本例的宽QRS波群提示可能起源于心肌内或心外膜，不像常见的双向性室性心动过速，认为其起源更接近希浦系统。

最令人感兴趣的特征是规律性不规律节律，见图1。仔细分析A和B两种形态的QRS波群之间的关系显示，A-A间期72次/min（0.88s），B-B间期72次/min（0.88s），结果为144次/min的心动过速。A与B的间期为0.56s，而B与A的间期为0.32s，这种关系在整个心动过速中保持不变，形成规律性不规律心律。宽QRS波群、电轴在+160°到-40°之间交替，转折位于胸导联V3到V6，提示存在两个独立的起搏点。要保持R-R间期的恒定，需要两个起搏点的精准交替，因此，有关心室两个起搏点交替起搏作为机制的起始学说遭到遗弃。然而，本病例的规律性不规律心律，可由两个不同的起搏点依恒定的间期自发起搏、合并各自的传入阻滞产生双重平行心律来加以解释。

平行心律需要局灶起搏点周围组织能阻止外来激动侵入但又不引起传出阻滞。自律性与受保护是平行心律的标志。这一特性形成经典平行心律的诊断三联征，即异位起搏点的不固定联律间期、异位搏动之间存在数学上的关系以及出现融合波。不再认为平行起搏点完全独立（受保护）于外来搏动的这一最初学说是正确的。现已证实，与兴奋性受抑导致传入紊乱，但允许冲动外传的周边组织相连的任何起搏点在一定程度上受到周边组织电张除极的影响，即周边区域的除极会引起起搏细胞的部分除极。这可导致调节性平行心律的发生。意味着非平行搏动落在平行心律附近可以引发平行搏动点的（1）最大的延迟、（2）最大的加速、（3）较小效应、（4）实际无效应或（5）平行节律点的起搏点湮灭。非平行搏动落在平行收缩间期前半时段的使这一间期延长，落在平行周期后半部的可使这一间期缩短。在平行收缩间期中点的电张调节（引起平行周期延长或缩短）最大。这样，异位搏动的联律间期在调节性平行心律中可以不固定，异位搏动间期也可变化。调节也可引起偶联间期的固定。固定偶联间期可能提示折返型二联律。业已显示，当异位搏动与周围心室之间传递阻抗低时，异位起搏点的锁定可以近乎固定，以致呈折返型二联律表现。这在本病例的图2中得以证实，在起搏点B的持续性单形性室性心动过速中，滴注胺碘酮后起搏点A的部分抑制导致偶发异位搏动。测定B-B间期显示频率加倍，从图1双向性室性心动过速时0.88s到图2的0.44s，提示平行心律为心律失常的机制。A搏对B搏的锁定呈持续状态。但测定此图片上A-A间期并未显示数学上的关系，这可由其前B搏动对A搏动的调节来解释。对于本病例，双重平行心律是最合理的解释。仅有偶发的A激动（图2）和持续加快节律的B激动排除了乒乓效应的双向性室性心动过速，因为没有持续的A激动发生，如果是乒乓效应，A激动应与B激动呈有规律的交替。

有报道触发活动和异常自律性继发于心肌炎炎症后。对多次直流电击、抗心律失常药如β受体阻滞剂和利多卡因无反应的顽固性特性，提示室性心动过速的机制是自律性增高，因为折返或延迟后除极引起的心律失常这些措施有效。心脏类肉瘤病时自律性起搏点周围的局部炎症可能产生单向阻滞，导致平行心律。心脏类肉瘤病时不常见的多区域肉芽肿炎症，使得本病例中的2个平行起搏点得以并存。

图1 12导联心电图显示双向性室性心动过速。

图2 12导联显示在起搏点B的持续性单形性室性心动过速中，部分抑制起搏点A导致偶发异位搏动。

图3 A.T2W心脏MRI:显示室间隔中部钆强化。B.18F-氟脱氧葡萄糖（FDG）正电子发射扫描显示基底和前中间隔灌注缺损伴FDG摄取增加。

[1]Shenthar J.Unusual Incessant Ventricular Tachycardia-What Is the Underlying Cause and the Possible Mechanism？[J].Circ Arrhythm Electrophysiol，2015，8∶1507-1511.e112（1-11）.

（童鸿）

Unusual incessant ventricular tachycard ia-What is the underlying cause and the possib le mechanism?

Lesson Seventy-three