Ultrasound-enhanced thrombolysis

Problems with current thrombolytic therapy include slow and incomplete thrombolysis and frequent bleeding complications. Increasing evidence from in vitro, animal, and initial patient studies indicates that application of ultrasound as an adjunct to thrombolytic therapy offers unique potential to improve effectiveness and decrease bleeding complications. Numerous studies in vitro demonstrate that low intensity ultrasound increases enzymatic fibrinolysis through mechanisms that include improving drug transport, reversibly altering fibrin structure, and increasing tPA binding to fibrin. These observations have been confirmed in animal models that demonstrated that ultrasound delivered transcutaneously or with an endovascular catheter accelerates thrombolysis in models of venous, arterial, and small vessel thrombosis. Ultrasound delivered at higher intensities using either an endovascular vibrating wire or transcutaneously in conjunction with stabilized microbubbles can cause mechanical fragmentation of thrombus without administration of plasminogen activator. Recent studies indicate that ultrasound at lower frequencies in the range of 20-40 kHz has a greater effect on thrombolysis with improved tissue penetration and less heating. These studies form the basis for clinical trials investigating the potential of ultrasound as an adjunct to improve thrombolytic therapy.     

Management of the patient following coronary thrombolysis

Myocardial salvage can be maximized by the early institution of thrombolytic therapy and aspirin. Certain patients may benefit from the administration of intravenous heparin, beta blockers, or nitroglycerin. The routine use of percutaneous transluminal coronary angioplasty (PTCA) or calcium-channel blockers does not appear to be warranted. Recurrent myocardial ischemia should be vigorously treated with medical therapy and there may be value in cardiac catheterization, followed by PTCA or bypass surgery, depending upon the extent of myocardium at risk and the underlying coronary anatomy. Long-term morbidity and mortality may be reduced by instituting aspirin and beta blockers as well as by modifying risk factors. There is no evidence for the long-term benefit from any calcium-channel blocker. Oral anticoagulation may be warranted in those patients with a mural thrombus, congestive heart failure, or atrial fibrillation. ACE inhibitors may be of value in the presence of left ventricular dysfunction and certainly in the presence of symptomatic congestive heart failure. Antiarrhythmic therapy is generally indicated only for symptomatic or life-threatening arrhythmias. Residual myocardial ischemia should be sought by exercise testing, and those patients with poor exercise tolerance generally warrant cardiac catheterization in consideration for revascularization.     

冠状动脉内超声溶栓治疗急性冠脉综合征的临床观察

目的　探讨低频高能超声溶解急性冠状动脉综合征(ACS)闭塞相关血管或“罪犯”血管血栓及粥样硬化斑块的有效性和安全性。　方法　ACS患者26例,其中ST段抬高急性心肌梗死19例,非ST段抬高心肌梗死3例,不稳定性心绞痛4例;左前降支闭塞 10 例,左冠状动脉闭塞 4 例,右冠状动脉闭塞5例。超声溶栓后对闭塞相关血管行急诊经皮冠状动脉腔内成形术。　结果　超声溶栓后,闭塞相关血管前向血流达心肌梗死溶栓试验3 级 19 例,开通 19 例,开通率为 73%(19/26),其中冠状动脉左前降支成功率最高。超声溶栓成功患者胸痛能完全缓解,心电图ST段下降50%以上,但术后残余狭窄平均为(73±11)%。急诊经皮冠状动脉腔内成形术后6例,残余狭窄降至(13±7)%(P<0. 05)。在超声溶栓中,7例出现并发症。　结论　低频高能超声可有效、安全溶解闭塞相关血管血栓,对富含血栓的病变可进行超声溶栓,可作为经皮冠状动脉腔内成形术的互补手段在临床应用。     

Heparin inhibits spontaneous thrombolysis and the thrombolytic effect of both streptokinase and tissue-type plasminogen activator. An in vitro study of the dislodgement of platelet-rich thrombi formed from native blood

Two in vitro models of coronary thrombolysis in man, i.e. dislodgement of thrombi formed from non-anticoagulated human blood, either by (i) shear-stress or (ii) interaction of platelets with type I collagen fibre, were studied. Heparinization (1 U/ml) of blood prior to thrombus formation by (i) strongly inhibited spontaneous dislodgement (P less than 0.0001). Heparin (1 U/ml), when added with streptokinase (SK) or tissue-type plasminogen activator (rt-PA) prior to thrombus formation, considerably delayed thrombolysis. Furthermore, thrombolysis occurred much earlier when thrombi were perfused with SK or rt-PA in native than in heparinized blood. Heparin inhibited binding of 125I-rt-PA (17%, P less than 0.02) and plasminogen (88%, P less than 0.0005) to platelets activated by ADP in citrated platelet-rich plasma. We conclude that heparin interferes with the fibrinolytic system at the surface of activated platelets. Our findings suggest that heparin administration prior to thrombolytic therapy for acute myocardial infarction should be questioned.     

Fatal hemoptysis during coronary thrombolysis

Abstract Cerebral hemorrhage is the most dreaded complication of coronary thrombolysis. Significant bleeding has also been described from catheter-entry sites, the retroperitoneum, and the gastrointestinal and genitourinary tracts. However, hemoptysis induced by thrombolysis has rarely been described in the literature. We present a 66-year-old male who received front-loaded tissue plasminogen activator (tPA) for acute transmural anterior wall myocardial infarction and developed massive hemoptysis from preexisting cavitary lung disease. The patient died within 5 hours. We believe this is the first case report of fatal hemoptysis induced by coronary thrombolysis. A history of cavitary lung disease may be a risk factor for life-threatening hemoptysis in patients receiving thrombolytic therapy.     

Intravascular ultrasound imaging in human peripheral and coronary arteries in vivo.

To determine the feasibility of intravascular ultrasound imaging in vivo, a miniaturized high frequency transducer catheter was introduced into human peripheral (n = 10) and coronary (n = 4) arteries. Cross-sectional ultrasound images were obtained from iliofemoral arteries in 10 patients using a 20 MHz transducer catheter (1.2 mm in diameter) and from coronary arteries in 4 patients using a 30 MHz transducer catheter 5 French size (Fr) following successful coronary angioplasty. Ultrasound images obtained from peripheral arteries showed a three-layered appearance (echo-reflective intima, echo-lucent media and echo-reflective adventitia) in the normal arteries. In diseased arteries, the location, amount and extent of atheromatous plaque were clearly documented. The arterial diameters measured by ultrasound closely correlated with the measurements by angiography (r = 0.91) in the peripheral arteries. Coronary angiograms obtained following balloon angioplasty revealed smooth edges at the dilatation sites without significant narrowing in all patients. However, a significant amount of residual atheromatous plaque was clearly observed on the ultrasound images at the previously dilated sites. Coronary dissection, which was identified as an echo-lucent area behind the plaque, was noted in 2 patients. Ultrasound images also revealed the presence of calcium in the plaque which was unrecognized on the angiograms in 3 patients. In addition, direct measurement of the lumen cross-sectional area was possible on the ultrasound images.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlation between high frequency intravascular ultrasound and histomorphology in human coronary arteries

OBJECTIVE—To test the efficacy of high frequency intravascular ultrasound (IVUS) transducers in identifying lipid/necrotic pools in atherosclerotic plaques.
METHODS—40 MHz transducers were used for in vitro IVUS assessment of 12 arterial segments (10 coronary and two carotid arteries, dissected from five different necropsy cases). IVUS acquisition was performed at 0.5 mm/s after ligature of the branching points to generate a closed system. Lipid/necrotic areas were defined by IVUS as large echolucent intraplaque areas surrounded by tissue with higher echodensity. To obtain histopathological sections corresponding to IVUS cross sections, vessels were divided into consecutive 3 mm long segments using the most distal recorded IVUS image as the starting reference. Samples were then fixed with 10% buffered formalin, processed for histopathological study, serially cut, and stained using the Movat pentacrome method.
RESULTS—122 sections were analysed. Lipid pools were observed by histology in 30 sections (25%). IVUS revealed the presence of lipid pools in 19 of these sections (16%; sensitivity 65%, specificity 95%).
CONCLUSIONS—In vitro assessment of lipid/necrotic pools with high frequency transducers was achieved with good accuracy. This opens new perspectives for future IVUS characterisation of atherosclerotic plaques.


Keywords: intracoronary ultrasound; atherosclerosis; plaque morphology     

Percutaneous transluminal therapeutic ultrasound for high-risk thrombus-containing lesions in native coronary arteries.

We assessed the short-term outcome of percutaneous coronary ultrasound thrombolysis (CUT) for high-risk thrombus-containing lesions in native coronaries in the setting of acute coronary syndromes (ACS). Data were prospectively collected in a multicenter (n = 32) registry of consecutive ACS patients. The study population (n = 126) had mostly (84%) totally occluded vessels. The mean age of clot was 5.7 +/- 9.5 days (range, 0-60 days). CUT (41 kHz, 18 W) led to device success in 112 (89%) patients, with a residual stenosis of 69% +/- 20%. Adjunct PTCA or stenting was used in 97% of the patients. Procedural success was achieved in 124 (98%) patients, with a final residual stenosis of 6% +/- 10%. There were no major adverse clinical events during hospitalization. Ultrasound thrombolysis is a feasible procedure that offers a safe and probably effective adjuvant device solution for the treatment of high-risk, thrombus-containing lesions in the native coronary arteries.     

Noninvasive markers of intravenous streptokinase coronary thrombolysis

Early creatine kinase (CK) enzyme peaking, rapid electrocardiographic (EKG) changes toward normal, reperfusion arrhythmias, pain disappearance, and 201thallium myocardial scintigraphy appear useful to identify the success or failure of intravenous (i.v.) thrombolytic therapy in patients with acute myocardial infarction (AMI). Most patients with AMI are treated currently in community hospitals which do not possess coronary angiographic capabilities. Recent evidence indicates that early intravenous streptokinase results in coronary thrombolysis in the majority of patients treated. A composite of noninvasive markers of coronary reperfusion was assessed in two similar patients with transmural AMI. One received intravenous streptokinase (STK) 750,000 U 90 min after AMI onset; the other received intracoronary (i.c.) STK 4000 U/min 140 min after onset. Within one hour each showed a sudden change in elevated EKG ST segments toward normal, followed by frequent premature ventricular beats and pain disappearance. Posttreatment angiograms documented recanalization of each infarct-related artery. Early CK peaking occurred at 10 hours after the onset of chest pain in the first patient and at 12 hours in the second. This contrasts with delayed CK peaking at 26.4 hours among 384 patients reviewed with untreated AMI. Early CK peaking appears the most accurate indirect marker of successful coronary thrombolysis.     

Prediction of degree of residual stenosis in coronary thrombolysis

In order to predict the residual stenosis in coronary thrombolysis, the factors easily obtained from clinical history--age, gender, history of angina before acute myocardial infarction (AMI), family history, hypertension, diabetes, hypercholesterolemia, smoking, and interval between onset of AMI and recanalization--were observed in 114 patients with successful coronary thrombolysis. In 55 patients with angina before AMI, 29 patients had residual stenosis greater than or equal to 75% and 26 patients had residual stenosis less than 75%. In 59 patients without angina before AMI, 15 patients had residual stenosis greater than or equal to 75%, and 44 patients had residual stenosis less than 75%. The presence or absence of angina before AMI was the main variable that discriminated the groups of residual stenosis of more or less than 75%, which was the only significant independent variable to predict the residual stenosis. These data suggest that the presence of angina pectoris before AMI is likely to be associated with a significant degree of residual stenosis after thrombolysis.     

Intra-arterial thrombolysis in acute ischaemic stroke

Several thrombolytic agents for the treatment of acute ischaemic stroke have been examined; however, to date, only the i.v. administration of recombinant tissue plasminogen activator is licensed in Australia. Although no trials directly comparing intra-arterial and i.v. delivery of thrombolytics exist, intra-arterial thrombolysis has several potential advantages, including angiographic assessment of the thrombus and the site of occlusion and collateral circulation, improved recanalization, and delivery of higher local concentrations of thrombolytic agents and extending the therapeutic time window for treatment. We conducted a retrospective audit of our experience with the use of intra-arterial urokinase to treat acute ischaemic stroke at an Australian tertiary-care hospital between June 1993 and June 2003. We examined time from stroke onset to assessment, computerized tomography scan, cerebral angiography and thrombolysis, anatomical classification of intra-arterial thrombus, rates of symptomatic intracerebral haemorrhage, and clinical outcome at 3 months. We believe that in carefully selected individuals in appropriate centres of expertise, intra-arterial thrombolytic therapy holds great promise.     

Laser angioplasty and laser-induced thrombolysis in revascularization of anomalous coronary arteries

Acute coronary syndromes such as unstable angina and myocardial infarction are attributed to a pathophysiologic process that involves rupture of atherosclerotic plaque and subsequent thrombosis. Percutaneous intervention of anomalous coronary arteries in patients who present with acute coronary syndromes impose unique technical challenges related to the specific anatomic course and morphology of these vessels. Selection of appropriate guiding catheter configuration, choice of supportive guidewire, and proper delivery and activation of debulking devices and stents are important steps toward achieving adequate results. Excimer laser angioplasty is a debulking technology for removal of atherosclerotic plaque and associated thrombi. To date, application of laser angioplasty in anomalous coronary arteries is unreported. We herein present clinical data and discuss technical aspects related to performance of excimer laser angioplasty in three symptomatic patients with acute coronary syndrome, two having an anomalous right coronary artery and one with an anomalous circumflex artery. The delivery of laser energy in these cases resulted in rapid thrombolysis of an occlusive thrombus, successful debulking of the underlying atherosclerotic plaque, facilitation of adjunct balloon angioplasty and stenting, and ultimately, improved clinical condition.     

Noninvasive studies of coronary and peripheral arterial blood-flow

Noninvasive vascular imaging may identify the high-risk, asymptomatic atherosclerotic patient who will substantially benefit from aggressive preventive therapies. Endothelium is a key player in the early stages of atherogenesis. Positron emission tomography (PET) and ultrasound-measured brachial artery vasoreactivity have emerged as potentially useful tools for the identification of endothelial dysfunction and, as such, early atherosclerosis. Both have been used successfully to demonstrate the association between endothelial dysfunction and established coronary artery disease risk factors, as well as clinically evident coronary artery disease. Abnormal coronary endothelial function recently has been associated with poor clinical outcomes in long-term follow-up studies. Given the close association between endothelial function in the coronary and peripheral circulation, there is particular promise for the validation of brachial artery vasoreactivity as a clinically useful tool. Finally, surveillance of endothelial function with these techniques may prove helpful in guiding aggressiveness of antiatherosclerotic therapy and effectiveness of new regimens.     

Fiberoptic observation of thrombosis and thrombolysis in isolated human coronary arteries

Coronary arteries isolated from cadavers autopsied within 7 hours after death were perfused with canine arterial blood, and the processes of thrombus formation at the segments stenosed with atheroma and the thrombolytic effects of urokinase were investigated by angioscopy. Ten minutes of blood perfusion caused thin mural thrombi localized at the stenotic or nonstenotic segments. During 30 minutes of blood perfusion, the thin mural thrombi of the outlet or inlet of the segment grew into a doughnut-shaped thrombus. Also, the thin mural thrombi in the stenotic segment grew into a streamer-like thrombus and drifted downstream. These thrombi grew in size with increasing perfusion time and finally obstructed the stenotic segment. Globular thrombi close to the outlet also were formed in a few preparations. Unlike the thrombi at the stenotic segment, the mural thrombi in the nonstenotic segments did not grow into massive thrombi. The thrombi were reduced in size within 10 minutes of perfusion with 320 U/ml or more of urokinase. During thrombolysis, sandstorm-like dispersion of the blood cells occurred, small fragments detached from the mother thrombus and flew downstream, or the fibrin core of the thrombus was exposed. The results indicate the usefulness of angioscopy for the dynamic and serial investigation of thrombosis and thrombolysis.     

Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke

Background

We studied whether 2 MHz transcranial color-coded duplex ultrasound (TCCD), combined with a second generation ECA, accelerate IV rtPA-thrombolysis in the acute phase of MCA stroke more than TCCD monitoring alone.

Methods

Non-randomized acute MCA stroke patients undergoing IV rtPA-thrombolysis and 2 MHZ-TCCD monitoring over 60 min, with (N = 11) or without (N = 15) additional continuous ECA (5 ml, SonoVue®) perfusion, were compared. Recanalization of the MCA was measured pre- and post-thrombolysis with the thrombolysis in brain ischemia (TIBI) grading system, clinical outcome was assessed at admission and 24 h after treatment using the NIH stroke scale (NIHSS).

Results

Patients who received ECA improved their NIHSS significantly more than those who were only TCCD monitored (Mann–Whitney U = 48.0; P = 0.050), and their flow signal improved more (Mann–Whitney U = 40.0; P < 0.03).

Conclusions

The results of this pilot study show that in IV-thrombolysis the use of ECA in addition to TCCD monitoring lead to a greater immediate clinical improvement and to a better flow signal.     

Audit of prehospital thrombolysis by general practitioners in peripheral practices in Grampian

Background—In the Grampian region early anistreplase trial (GREAT), domiciliary thrombolysis by general practitioners was associated with a halving of one year mortality compared with hospital administration. However, after completion of the trial and publication of the results, the use of this treatment by general practitioners declined sharply.
Objective—To increase the proportion of eligible patients receiving timely thrombolytic treatment from their general practitioners.
Setting—Practices in Grampian located  30 minutes' travelling time from Aberdeen Royal Infirmary, where patients with suspected acute myocardial infarction were referred after being seen by general practitioners.
Audit standard—A call-to-needle time of 90 minutes, as proposed by the British Heart Foundation (BHF).
Methods—Findings of this audit of prehospital management of acute myocardial infarction were periodically fed back to the participating doctors, when practice case reviews were also conducted.
Results—Of 414 administrations of thrombolytic treatment, 146 (35%) were given by general practitioners and 268 (65%) were deferred until after hospital admission. Median call-to-needle times were 45 (94%  90) and 145 (7%  90) minutes, respectively. Survival at one year was improved with prehospital compared with hospital thrombolysis (83% v 73%; p < 0.05). The proportion of patients receiving thrombolytic treatment from their general practitioners did not increase during the audit.
Conclusions—In practices  30 minutes from hospital, the BHF audit standard was readily achieved if general practitioners gave thrombolytic treatment, but not otherwise. Knowledge of the benefits of early thrombolysis, and feedback of audit results, did not lead to increased prehospital thrombolytic use. Additional incentives are required if general practitioners are to give thrombolytic treatment.

Keywords: thrombolysis;  general practitioners;  prehospital care;  acute myocardial infarction     

Calcium channel antagonists in the modern era of coronary thrombolysis: Benefit or detriment?

Summary Calcium channel antagonists are among the world's most widely prescribed class of drugs and are used most often in patients with hypertension and coronary artery disease. However, in the recent past serious questions have been raised concerning their potentially detrimental effects. One area of considerable clinical importance that deserves close inspection is the role of calcium channel antagonists following coronary reperfusion. Specifically, is there benefit or detriment?     

Impact of different definitions on the interpretation of coronary remodeling determined by intravascular ultrasound.

The objective of this study was to compare the categorizations and determinants related to remodeling by the three definitions commonly used. Several morphological and intravascular ultrasound (IVUS) studies have demonstrated the fundamental importance of arterial remodeling in atherosclerosis. However, lack of consensus on how to define remodeling has led to conflicting analyses of factors that influence this process. Analysis of pre-interventional IVUS images of 514 lesions in native coronary arteries was performed. Arterial remodeling was defined as outward by definition 1, when [cross-sectional area (CSA) of the external elastic membrane (EEM) at the lesion site (EEM(lesion))]/[EEM CSA either at the proximal (EEM(prox ref)) or distal (EEM(distal ref)) reference site with the least amount of plaque] was > 1.05, intermediate when this ratio was between 0.95 and 1.05, and inward when < 0.95. Remodeling was defined as outward by definition 2 when EEM(lesion) > both EEM(prox ref) and EEM(distal ref), inward when EEM(lesion) < both EEM(prox ref) and EEM(distal ref), and intermediate when EEM(lesion) was intermediate between EEM(prox ref) and EEM(distal ref). By definition 3, vessel remodeling was defined as outward when EEM(lesion) > (EEM(prox ref) + EEM(distal ref))/2 and intermediate/inward when EEM(lesion) < or = (EEM(prox ref) + EEM(distal ref))/2. The frequency of outward remodeling was significantly higher by definitions 1 and 3 than by definition 2, whereas a higher frequency of inward remodeling was observed in definition 1, resulting in significantly different remodeling distributions between the three definitions (P < 0.0001). By multivariate logistic analysis, the only clinical determinants related to outward remodeling was younger age, and only by definition 3. IVUS determinants varied significantly between the three definitions. The only consistent determinants among the three definitions were smaller lumen CSA at the reference site and larger plaque + media CSA at the lesion site. This study demonstrates the significant impact of different remodeling definitions on the incidence and determinants of remodeling patterns. The marked variability in categorization of remodeling underscores the importance of developing a standard methodology.     

Rescue percutaneous coronary intervention for failed thrombolysis in a patient with anomalous coronary arteries

Coronary artery anomalies (CAA) often render technically difficult the completion of coronary angiography and intervention. Their presence in patients undergoing emergency angiography for acute myocardial infarction (AMI) is particularly challenging for interventional cardiologists. In this article, we report, for the first time in the literature, a case of rescue percutaneous coronary intervention for failed thrombolysis in a patient with AMI due to occlusion of a left circumflex coronary artery with anomalous origin from right sinus of Valsalva (in an anomalous left coronary system also including an anomalous origin of the left anterior descending artery from the right sinus). In particular, the present clinical vignette emphasizes the importance of a thorough search for the culprit vessel during cardiac catheterization. Especially in the emergency setting, non-invasive methods of ischemia localization, such as ST-segment elevation at the ECG and wall motion abnormalities at echocardiography, are of pivotal usefulness to guide the interventional cardiologist in identifying and treating the diseased coronary vessel in a timely and effective fashion.