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Acute Coronary Syndromes

Acute coronary syndromes have been a major hemodynamic insult to a person's homeostat balance in the normal physiological systems. The main pathophysiologic rational is impaired blood supply to the heart in relation to increased oxygen demand, through vasospasm of coronary vessels or thrombosis in any coronary arteries. It is unquestionably established that atherosclerosis is the leading etiology behind coronary syndromes Acute coronary syndromes include:

1. Acute myocardial infarction

2. Non-Q wave myocardial infarction

3. Acute exacerbation of angina pectoris

4. Unstable angina pectoris

5. Sudden cardiac death

Acute coronary syndromes, are a group of complex coronary artery disease resulting from accumulation of various high risk factors. It is a process of summation of diverse epidemiological risk factors, pathological risk factors and biochemical risk factors acute myocardial infarction, non-Q wave myocardial infarction, acute exacerbation of angina pectoris, unstable angina pectoris, sudden cardiac death. 

Epidemiological Risk Factors

1. Cigarette smoking

2. Hypertension

3. Hyperlipidemia

4. Coronary prone personality

5. Obesity

6. Diabetes Mellitus 

Pathological Risk Factors

1. Atherosclerosis

2. Platelet Activation

3. Endothelial Dysfunction 

Biochemical Risk Factors

1. Total cholesterol >240 mg/dL

2. HDL <35 mg/dL

3. Hyperhomocystinemia

4. Hemochromatosis

Vascular endothelial has a very important and regulating role in normal biological rhythm of the vessel. It has a central regulatory role in maintaining biological functions of the cardiovascular system. Acute coronary syndromes may also be a result of chronic inflammatory reaction of the vascular endothelium. Vascular dysfunction is the term which includes deviation of 

Endothelial dysfunction affects the cardiovascular system in following manner

1. Decreases vasodilator function through oxygen derived free radicals which degrade vasomotor functions through EDRF (Endothelial Derived Relaxing Factor which works through cGMP activation)

2. Releases growth factors and promotes proliferation of vascular smooth muscle cells

3. Releases inflammatory cytokinins like tumor necrosis factor, interleukins, gamma interferons.

4. Increases chemotactic effects of macrophages

5. Activation of platelets

6. Development of LDL oxidation with the help of oxygen derived free radicals

7. Promotion of vascular cell adhesion molecule-l(VCAM-1)

8. Promotes neovascularization 

Pathogenesis of Coronary Syndromes

Higher risk factors responsible for acute coronary syndromes

Oxidative stress & Release of oxidative free radicals

Activation of platelets

Atherosclerotic plaque rupture

Blockage of blood vessels with thrombosis

Impaired blood supply in the coronary artery

Acute Coronary syndromes 

Thrombogenic Risk Factors

Local factors

Type of plaque disruption (erosed, ulcerated)

Severity of stenosis

Accompanied structure

Nature of the wall of residual thrombosis

Vasoconstrictors 

Systemic Factors

Infections (C pneumoniae, CMV, H. Pyroli)

Catecholamines

Fibrinogen and coagulation factors and contents

Cholesterol lipoprotein (a)

With the inflammation of the endothelium, there is release of thromboxane, prostaglandin and

their metabolites in response to ADP induced platelet aggregation, which favors atherosclerotic plaque. This atherosclerotic plaque may have EKG and clinical manifestations of ischemia. Thromboxane A2, stimulates phospholipase C through platelet proteins Gq-a and GB-7, they in turn alters physiological balances by elevating intracellular Ca+2 and further facilitation the actions of Protein Kinase C and Thromboxane A2. All these events enhances activation of fibrogen receptors (GP lib-Ilia), fibrogen binding and platelet aggregation.

Clinical Features

Almost more than half of the patients usually have prior history of major strenuous physical activities, sudden outburst of emotional stress or medical or surgical illness. The usual time of presentation is early in the morning (When higher sympathetic activities present, which may favor thrombosis). The chest pain is of very severe, deep visceral in character (worst pain which has been ever felt). It can be a heavy feeling, squeezing, crushing or pressing in nature. Pain is usually limited to central chest and/or near the epigastrium with radiation to the arms. rarely, it may radiate to the abdomen, back or jaw. There may be certain associations of nausea, vomiting or anxiety or in unusual circumstances of sudden loss of consciousness, acute confusional state or a sensation of profound heaviness. Physical examination related to increased sympathetic activity, signs of ventricular dysfunctions, decreases intensity of heart sounds, gallop rhythm are also present.

Laboratory Examination

In the ER, complete blood counts, chemistry, EKG and chest X-ray should be taken. In acute MI less than 4 to 8 hours of presentation, serum cardiac markers (CK-MBs, Cardiac specific troponin T, Cardiac specific troponin I) are very important. However, they are nonspecific.

Cardiac Imaging: In clinical practice, two dimensional echocardiography is the most commonly performed investigation for the acute coronary syndromes. Abnormalities of the valve movement is very commom feature in echocardiography. Echocardiography is very useful investigation to distinguish previous right ventricular infarction, ventricular aneurysm, pericardial effusion and ventricular thrombosis. Myocardial imaging study with thallium 201 or tech 99m sestamibi have pivotal roles to differentiate old infarction.

EKG Stress Testing: EKG Stress testing is very useful when properly ordered. In acute severe myocardial infarction, stress test is never indicated. It may be planned after stabilization. Definite indications of EKG stress tesing include:

AMI with atypical presentations in men or postmenopausal women

Assessment with previous history of CHD

Evaluation of exercise induced cardiac arrhythmia

 

Contraindications

Large MI within 3 days

Catastrophic emergencies like aortic dissection/rupture

Severe aortic stenosis

Severe uncontrolled hypertension

Uncompensated heart failure

Unstable arrhythmia

Severe left ventricular outflow obstruction

Recent or active cerebral ischemia

Radionuclide stress testing has been evaluated in specific circumstances. Although, it is not indicated in AMI. In presence of contraindications, stress testing increases mortality several times.

 

Treatment

It has been proved that effective prehospital emergency care and initial evaluation in ER is very crucial in the management of acute coronary syndromes. Thrombolysis is the treatment of choice in acute myocardial infarction. The following guidelines for the thrombolytic or non-thrombolytic management strategy, should be followed.

ST elevation of >0.1 mV in at least 2 leads

or

Left Bundle Branch Block

Ischemic chest pain syndrome of >20 minutes duration

 

Present:  Thrombolytic therapy        Absent: Non thrombolytic therapy

                                        

There are different types of treatment approaches offered. Thrombolysis is the preferred strategy. Interventional thrombolysis is also indicated in selected highly beneficial patients. However, controversies exist for the preference of treatment modality. It is accepted that treatment choice should be made according to the circumstances, and facilities available.


The first use of thrombolytic therapy was reported by Flether and his colleagues in 1958. One major drawback of early clinical trials was questionable efficacy of the treatment. In 1969, Chazov administered intracoronary streptokinase in Soviet Union, and now it is since last two decades, reperfusion is the major and important part of management strategy for Acute Myocardial Infarction.

Eligibility

The proportion of patients presenting with AMI are eligible for thrombolytic therapy has varied in reports because of eligibility criteria. Eligibility is based on the admission ECG and time

window criteria or on the discharge diagnosis of myocardial infarction Patients with ineligibility for thrombolysis be considered for PTCA

Criteria for Initiating Thrombolysis

Chest pain consistent with angina

ECG Changes: (1) ST >1 mm, 2 contiguous limb leads (2) ST 2mm, 2 contiguous precordial leads

New left bundle branch block

Absence of contraindications

Timing

The timing of the onset of ischemic symptom is the most important factor to determine occlusion and necrosis of infarct related artery All clinical trials agree unquestionably with early thrombolytic interventions. As implied benefits from treatment occur early. It is mandatory that whichever thrombolytic regimen is used, to administer early treatment. Treatment delays reduce all the benefits for eligible patients.

Treatment delay is possible in the following group of patients

1. Lack of public awareness(Lack of enough education of the disease)

2. Elderly female

3. Diabetic patient

4. Hypertensive patient

5. Previous infarctions

6. Previous bypass surgery

Age

Old age has been associated with higher mortality and morbidity in acute myocardial infarction. Regardless of thrombolytic therapy, the elderly patient population is associated with higher mortality and intracerebral hemorrhage after thrombolytic therapy. With all concerns related to age, physicians are more reluctant to use thrombolytic therapy in patients >75 years of age. According to American College Of Cardiology/American Heart Association's guidelines physicians should be judicious in the selection selection of older patients for thrombolysis and suggested that treatment of patients >75 years old is not established by the available evidence

FTT overview showed that mortality was significantly lower in patients 65 to 74 years old who had received thrombolytic therapy than in control patients(16.1% Vs 13.5%; p<0.00001), and there was a nonsignificant trend towards a reduction in mortality in patients 75 years old(25.3% Vs 24.3%). In the terms of cost effectiveness, the elder population with AMI, are likely to obtain greater benefit from thrombolytic therapy as the average number of life years life years added by treatment with accelerated alteplase is greater than younger patients. The greater cardiac benefit of alteplase in the elderly maintains the advantage of this therapy up to the age of 85 years. For the patients >85 years of age, the best regimen in GUSTO-I was streptokinase plus subcutaneous heparin.

Infarct site

Benefits of the thrombolytic therapy are usually related to ST-segment elevation rather than the site of the infarct. In the FTT overview, patients with inferior ST-segment elevation who were randomized within 12 hours of symptom onset had a mortality reduction of 13%.

Beneficial Group Of patients

Acute inferior wall myocardial infarction

Acute inferior wall myocardial infarction with previous history of AMI

Acute inferior wall MI with anterior ST-segment depression

Acute inferior and right ventricular myocardial infarction

Acute inferior myocardial infarction complicating with second-or third-degree heart block

AMI with occlusive thrombus in circumflex artery

True posterior wall myocardial infarction

AMI complicating with bundle branch block

Contraindications

Since thrombolytic therapy has become more widely used and the results of the all major clinical trials have confirmed its efficacy and safety, the contraindications have widened in some instances and narrowed in other instances.

Factors Affecting Contraindications for the Thrombolytic Therapy in AMI

Size of the infarct

The hemodynamic status

History of previous infarction

Time elapsed since symptom onset

Patient's age

Availability of other reperfusion therapy options

Contraindications for the Thrombolytic Therapy in AMI

Absolute Contraindications:

Any previous history of hemorrhagic stroke

History of stroke, dementia, or central nervous system damage within a year

Head trauma, or brain surgery within six months

 

Relative Contraindications:

Oral anticoagulant therapy

Previous streptokinase therapy

Acute pancreatitis

 

Newer Fibrinolytic/Thrombolytic Agents

Newer fibrinolytic agents are being developed to improve the efficacy of clot lysis and/or ease of administration. Novel plasminogen activators have been purified from natural sources with one or more of the following properties:

Prolongation of half life

Allowing bolus administration

Enhanced fibrin specificity

Resistance to natural inhibitors

 

Streptokinase

Streptokinase is a nonenzyme protein produced by several strains of hemolytic streptococci. It consists of a single polypeptide chain of 414 amino acids with a molecular weight of about 50,0000. It activates plasminogen to plasmin indirectly by following mechanisms:

Formation of an equimolar complex with plasminogen

Catalyzes the activation of plsminogen to plasmin

Plasminogen-streptokinase molecules are converted to plasminogen-streptokinase complexes.

Almost all individuals have measurable circulating streptokinase-neutralizing antibodies, which may be because of previous infections with -hemolytic streptococci. Hence, during thrombolytic therapy, sufficient streptokinase must be infused to neutralize these antibodies.

Anisoylated Plasmino.qen-Streptokinase Complex

Anistreplase is an equimolar noncovalent complex between human Lys-plasminogen and streptokinase. It has a catalytic center located in the carboxy-terminal region of the molecule, while the Lysine-binding sites are found within the amino-terminal region of plasminogen. Thus reversible acylation of the catalytic center would thus not affect the weak fibrin-binding capacity of Lys-plasminogen in the complex. A plasma half-life of 70 minutes was found for anistreplase, compared with 25 minutes for the plasminogen-streptokinase complex formed in vivo after administration of streptokinase. Patients with high streptokinase antibodies do not respond to Antistreplase, and Antistreplase causes a marked increase in streptokinase antibody titer within 2 to 3 weeks, which persists for months.

Reteplase

This is a single-chain nonglycosylated deletion variant of rt-PA consisting only of the K2 and the protease domains of human t-PA. Production of reteplase in E. Coil leads to formation of inactive protein aggregates(inclusion bodies). It is believed that fibrin binding is mediated through both the finger domain and the lysine binding site in the K2 domain of t-PA. Reteplase and t-PA are inhibited by PAl-1 to a similar degree, but affinity of reteplase for binding to endothelial cells and monocytes is reduced, probably as a consequence of deletion of the finger and epidermal growth factor domains in reteplase, which seem to be involved in the interaction with endothelial cell receptors.

TNK-TP

TNK-TPA is a genetically engineered triple-combination mutant of native tissue plasminogen activator with amino acid substitutions at the following sites:

Replacement of threonine by an asparagine

Above replacement is added by a glycosylation site to the position 103

An asparagine is replaced by a glutamine; hence removes a glycosylation site from site 117

Four amino acids, lysine, histidine, arginine, are replaced by four alanines at sites 296-299.

This substitution result in a reduced plasma clearance, increased fibrin specificity, and resistance to plasminogen activator inhibitor-1. A comparison of bolus dose of TNK-TPA with accelerated 90 rain. infusion of native rt-PA demonstrated a similar plasma concentration profile for the two regimes. Based on the pharmacokinetic analysis, it appeared that a 30mg bolus dose of TNK-TPA could provide a similar plasma exposure to 100rag of accelerated infusion of t-PA. TNK-TPA gave an encouraging initial indications that it will be angiographically

Lanoteplase

Lanoteplase(or n-PA) is a deleted mutant of alteplase in which one amino acid is substituted in position 117. In the InTIME-1 trial, a single 120-IU/kg bolus of Lanoteplase produced TIMI grade 3 flow in 57.1% of patients compared with 46.4% in patients treated with alteplase. There were fewer adverse events with lanoteplase. Lanoteplase will be compared with alteplase in a large mortality trial(InTIME-2), and the results should be available in early 1999.

Saruplase

Saruplase, or prourokinase, is a naturally occurring glycoprotein that is rapidly converted into Urokinase by plasmin but appears to have some intrinsic plasminogen activating potential. Compare to sreptokinase, recombinant Saruplase is appeared with earlier reperfusion, higher patency rates, and slightly less fibrinogen breakdown. In the SESAM study, similar TIMI grade 2 and 3 flows were observed with Saruplase and a 3-hour infusion of alteplase. In the COMPASS equivalence trial, 30-day mortality rates were observed lower with Saruplase than with streptokinase, but also increased rate of intracranial hemorrhage.

Staphylokinase

Staphylokinase, a 136 amino acid protein produced by certain strains of Staphylococcus aureus, has a unique mechanism of fibrin selectivity. It has been found as potent as alteplase, and more fibrin specific. It induces antibody formation and resistance to repeated administration. It's immunogenicity can be reduced by site directed mutagenesis. Recombinant Staphylokinase(STAR) was very impressive for venous clot lysis in animal studies with comparable results than that of streptokinase. It is more potent than streptokinase towards platelet rich clots and it is potentially less immunogenic. Recycling of staphylokinase to fibrin bound plasminogen, after neutralization of the complex, will result in more efficient generation of active complex.

Recombinant Chimeric Plasminogen Activators

Recombinant Chimeric plasminogen activators have been constructed primarily using different regions of t-PA and scu-PA. One important variant is KIK2Pu. Preliminary trial suggests that two bolus injections of 10mg K1K2Pu may produce fibrin specific coronary thrombolysis. 

Desmodus Salivary Plasminogen Activators

The saliva of vamp ire bats contains variety of factors that presumably satisfy two essential properties; (1) Maintain prolonged bleeding time (2) Blood fluidity. Different molecular forms have been purified from Desmodus Salivary plasminogen activator (DSPA)

DSPA a1 (Mr43) High molecular form, 85% homology to human t-PA

DSPA a2 (Mr 39)

DSPA Lacks finger like structure

DSPAT gamma Lacks finger and epidermal growth factor structure

Clopidogrel Bisulfate

Clopidogrrel Bisulfate is new antiplatelet agent of thienopyridines class, which acts by direct inhibition of adenosine diphosphate(ADP) by binding to its receptor and subsequent ADP-mediated activation of the glycoprotein GP lib/IliA complex.

In PRISM Study, platelet glycoprotein liB-Ilia receptor inhibitor, Tirofiban along with heparin and aspirin strategy has been proved efficacy with lower incidences of ischemic events and better outcome in acute coronary syndromes. Low molecular weight is also a pivotal issue in treating acute coronary syndromes.

Thrombolysis

Recommendations

Class

1. ST elevation(Greater than 0.1mV in two or more continuous leads at any time during the observation period

2. Time to the therapy 12 hour or less since the onset of symptoms

 

Class IIa 

1. ST elevation (as above), age 75 years or older

 

Class IIb 

1. ST elevation (as above), time to therapy (as above) greater than 12 to 24 hour

2. Blood pressure on presentation greater than 180 mmHg systolic and/or greater than 110 mmHg diastolic with high risk of MI

3. ST segment elevation, time to therapy greater than 24 hour, ischemic pain resolved

4. ST-segment depression only


Failed Coronary Thrombolysis

Thrombolytic therapy because of its wide availability, low cost and impressive outcome still an imperative part in patients management plan. As day by day more and more researches have been conducted to prove efficacy of thrombolytic therapy, failed coronary thrombolysis has become a major issue for the 

 

Pathogenesis of Failed Thrombolysis

There are so many reasons behind failed thrombolysis. Among them mechanisms operating at the site of the original obstruction and, secondly, mechanisms downstream in the microvascular network.

 

Failure of epicardial reperfusion:

1. Inability to achieve a lytic state

2. Mechanical factors at the level of fissured plaque

Management of Failed Thrombolysis

There are therapeutic options for the patients of failed thrombolysis. Apart from them, certain theoretical reasons to support the use of platelet antagonists. Practically none of platele

Rescue Agioplasty

Rescue Angioplasty refers to the use of PTCA in patients in whom reperfusion has not occurred after thrombolysis. All the clinical trials for the Rescue PTCA have suggested some benefits in failed thrombolysis, but its definite role needs to be evaluated through more clinical trials.

 

Indications of Rescue Ptca in Failed Thrombolysis

1 Large Anterior Myocardial Infarction

2. Right Ventricular Infarction

3. Second infarction

4. Hemodynamic instability

It is also imperative to identify patients with failed thrombolysis in a non-invasive way, as there is a low sensitivity for clinical criteria for reperfusion.

Persistent Chest Pain

Unchanged ST Elevation

Absence of "Reperfusion Arrhythmias"

 

Limitations

The time of patients' presentation with the MI, the infarct is very well established.

Microvascular damage is apparent at late presentation of failed thrombolysis

Primary angioplasty is often technically easier than Rescue Angioplasty 

Intra-Aortic Balloon Pump

Insertion of intra-aortic balloon pump in conjunction with rescue angioplasty improves both vessel patency and left ventricular function. Intra-aortic balloon pump can also improve vessel patency after failed thrombolysis even in the absence of rescue angioplasty. 

Repeat Thrombolysis

Technically repeat thrombolysis is a reasonable good alternative if there is no ST segment resolution after streptokinase. Time of presentation of failed thrombolysis, other prognostic factors and hemodynamic stability are very important before repeat thrombolysis. 

Intensified Antiplatelet Therapy

As we know that more intensive antiplatelet therapy at the time of thrombolysis results in higher rates of patency. Whether these agents can be successfully incorporated into regimens for use when initial attempts to secure reperfusion have failed and whether this will reflect into more survival benefits, needs to be evaluated. 

Role of Percutaneous Transluminal Coronary Angioplasty in Acute Coronary Syndromes

Prompt, and complete restoration of coronary flow is the principle mechanism by which reperfusion therapy improves survival and other clinical outcomes in patients with acute myocardial infarction. Intravenous thrombolysis is, however, the standard of care for patients with acute myocardial infarction, because of its widespread availability, its ability to reduce mortality, and its use in more than a million patients over the past decade. Recently, two large studies of registry data raised doubt

about whether the apparent superiority of angioplasty over thrombolytic therapy would be sustained in general practice because treatment delays and technical failure appear to be more common in the selected centers that have participated in the randomized trials. The role of PTCA (Percutaneous Transluminal Coronary Angioplasty) in the management of recurrent myocardial ischemia following thrombolytic therapy for acute myocardial infarction has been very well established.

PTCA is also indicated for a number of other clinical situations in the acute phase of myocardial infarction, but controversy remains about many of its indications.

In acute myocardial infarction, primary angioplasty may be better than fibrinolytic therapy early on, as the GUSTO lib trial confrmed that short term results of primary angioplasty are better than those of fibrinolytic therapy in patients with acute myocardial infarction. 

PTCA Vs. Thrombolytic Therapy

Advantages: GUSTO lib Trial

Earlier studies suggested that angioplasty, performed within 60 minutes of coming to the hospital, can restored TIMI grade 3 flow in 85% to 90% of patients, and reduce the mortality rate by upto 70% compared with thrombolysis.

Compared to that, in the GUSTO I trial, even with the best fibrinolytic strategy to date, only about 54% of patients achieved TIMI grade 3 flow.

After 30 days of the treatment, only 9.6% of the patients in angioplasty group had died or suffered a reinfarction or disabling stroke, compared to 13.6% in the t-PA group.

The 30 days mortality rate in angioplasty patients who achieved TIMI grade 3 flow was strikingly lower than in patients with lower TIMI flow grades.

Advantages of angioplasty were more modest in GUSTO lib trial; a 30% reduction in composite endpoint by 30 days, a 19% reduction in the mortality rate, and 31% reduction in the reinfarction rate.

PAMI I Trial{Primary angioplasty in Myocardial Infarction Study Group)

In PAMI 1, the second largest study with enrolement of 395 patients, hospital mortality was 2.6% vs 6.5% in patients who received t-PA therapy. Relative risk reduction with angioplasty is 60%.

Dutch Primary Angioplasty Study reported a 73% reduction in mortality in patients treated with angioplasty.

PTCA is indicated as primary therapy in patients with evolving myocardial infarction as an alternative to thrombolytic therapy

PTCA has a higher success rate for achieving recanalization of the infarct related vessel(83%-94%) than with the intravenous thrombolytic therapy(41%-89%).

Less residual stenosis is present after PTCA of the infarct related vessel than after successful thrombolytic therapy.

Large numbers of acute myocardial infarction patients treated with immediate PTCA have demonstrated similar mortality to patients treated with thrombolytic therapy. Failure to show an improved mortality may in part be explained by the low mortality of the patients who are eligible for a study of intravenous thrombolytic therapy. Thus, immediate PTCA may achieve similar mortality, but in a higher risk group.

More chances of moderate or severe bleeding was noted in the angioplasty group(12.3%) as compared to t-PA group(9.5%)

A significant limitation to use of immediate PTCA in acute myocardial infarction is the fact that approximately 85% of patients with acute myocardial infarction present to hospitals without a cardiac catheterization laboratories. Even in hospital patients, immediate PTCA may dictate a one to two hour delay from the immediate diagnosis to revascularization. During such type of procedural delay, a majority of arteries would have opened with intravenous therapy.

Compared to angioplasty, fibrinolytic therapy is easy to administered, does not require special equipment, and can be given in patient's home or the ambulance.

Since time is crucial for myocardial salvage, patients with AMI presenting to hospitals without cardiac intervention laboratories, will be best served by intravenous administration of thrombolytic therapy, but selected patients with large areas of myocardial at risk may be best treated with direct PTCA. 

Contraindications of PTCA in AMI: (May Be Eligible for Thrombolytic Therapy)

1. Advanced age

2. Late presentation to the hospital 

PTCA for Cardiogenic Shock Complicating AMI

The mortality of cardiogenic shock complicating acute MI remains high(65%-90%) even with aggressive treatment with right heart catheterization and bedside hemodynamic monitoring.

Role of intra-aortic balloon pump or thrombolytic therapy, is still not clear in improving outcome and survival. Immediate catheterization and PTCA for the cardiogenic shock has been associated with a lower mortality(<50%) than conventional management.