Wellens Syndrome

Background Wellens syndrome was first described in the early 1980s by de Zwaan, Wellens, and colleagues, who identified a subset of patients with unstable angina who had specific precordial T-wave changes and subsequently developed a large anterior wall myocardial infarction (MI). [1] Wellens syndrome refers to these specific electrocardiographic (ECG) abnormalities in the precordial T-wave segment, which are associated with critical stenosis of the proximal left anterior descending (LAD) coronary artery. Wellens syndrome is also referred to as LAD coronary T-wave syndrome. [2, 3] Syndrome criteria include the following:

Characteristic T-wave changes
History of anginal chest pain
Normal or minimally elevated cardiac enzyme levels
ECG without Q waves, without significant ST-segment elevation, and with normal precordial R-wave progression

Recognition of this ECG abnormality is of paramount importance because this syndrome represents a preinfarction stage of coronary artery disease (CAD) that often progresses to a devastating anterior wall MI.

Pathophysiology Wellens syndrome represents critical stenosis of the proximal LAD artery. The LAD arises from the left coronary artery and travels in the interventricular groove along the anterior portion of the heart to the apex. This groove is situated between the right and left ventricles of the heart. The LAD gives rise to 2 main branches, the diagonals and the septal perforators. [4] A lesion in the proximal LAD can have severe consequences, as suggested by the common nickname given to this lesion: “widow maker.” The LAD supplies the anterior wall of the heart, including both ventricles, as well as the septum. An occlusion in this vessel can result in serious ventricular dysfunction, thus placing the patient at serious risk for congestive heart failure (CHF) and death.

Etiology Wellens syndrome is a preinfarction stage of CAD. Thus, the causes of Wellens syndrome are similar to the conditions that cause CAD, including the following:

Atherosclerotic plaque
Coronary artery vasospasm (cocaine is one possible cause)
Increased cardiac demand
Generalized hypoxia

Risk factors for Wellens syndrome are essentially those of CAD and include the following:

Smoking history
Diabetes mellitus
Hypertension
Increased age
Hypercholesterolemia
Hyperlipidemia
Metabolic syndrome
Family history of premature heart disease
Occupational stress

Epidemiology and Prognosis The characteristic ECG pattern of Wellens syndrome is relatively common in patients who have symptoms consistent with unstable angina. Of patients admitted with unstable angina, this ECG pattern is present in 14-18%. [1, 5] Wellens syndrome represents critical proximal LAD disease; accordingly, its natural progression leads to anterior wall MI. This progression is so likely that medical management alone is not enough to stop the natural process. Evolution to an anterior wall MI is rapid, with a mean time of 8.5 days from the onset of Wellens syndrome to infarction. [1] If anterior wall MI occurs, there is the potential for substantial morbidity or mortality. Thus, it is of utmost importance to recognize this pattern early.

History Wellens syndrome represents stenosis of the proximal left anterior descending coronary artery (LAD), and patients typically present with symptoms or complaints consistent with coronary artery disease (CAD). Generally, the history is most consistent with unstable angina. Angina can have varying presentations, but the classic presentation includes the following complaints:

Chest pain described as pressure, tightness, or heaviness
Pain that is typically induced by activity and relieved by rest
Radiation of pain to the jaw, shoulder, or neck
May experience multiple associated symptoms, including (but not limited to) diaphoresis, nausea, vomiting, and fatigue

Elderly, diabetic, and female patients are more likely to present with atypical symptoms.

Physical Examination Physical examination does not provide any indicators that would give the examiner strong grounds for suspecting Wellens syndrome specifically. However, the results of the patient’s examination may show evidence of ongoing ischemic injury (eg, congestive heart failure [CHF]). In addition, most of the electrocardiographic (ECG) changes are recognized when the patient is pain-free, which again underscores the importance of a repeat pain-free ECG in the emergency department.

Diagnostic Considerations

Potential diagnostic pitfalls with Wellens syndrome include the following:

Failing to recognize Wellens syndrome T-wave changes on electrocardiography (ECG)
Ordering a stress test without recognizing risks (see Workup); this may provoke a large anterior wall myocardial infarction (MI) [3]
Underestimating the seriousness of the ECG finding in a pain-free patient
Failing to properly admit or consult cardiology on patients with the characteristic ECG changes

In addition to the conditions listed in the differential diagnosis (see below), other conditions to be considered include the following:

Central nervous system injury
Persistent juvenile T-wave pattern
Left ventricular hypertrophy
Bundle-branch block
Digitalis effect
Acute myocarditis
Preexcitation syndromes
Later stages of pericarditis

Differential Diagnoses

Laboratory Studies The following laboratory studies may be indicated as adjunctive tests in patients with suspected coronary artery disease (CAD), acute coronary syndrome (ACS), and Wellens syndrome:

Complete blood count (CBC) - To ensure that anemia is not precipitating the angina, red blood cell (RBC) transfusions may be necessary
Basic metabolic profile - This includes electrolyte, blood urea nitrogen (BUN), creatinine, and glucose levels
Typing and screening - These are indicated if immediate cardiac catheterization is planned
D-dimer, international normalized ratio (INR), partial thromboplastin time (PTT) - These are ordered only as medically necessary
Cardiac biomarkers - In Wellens syndrome, cardiac biomarkers can be falsely reassuring, in that they are typically normal or only minimally elevated; only 12% of patients with this syndrome have elevated cardiac biomarker levels, and these are always less than twice the upper limit of normal, in the absence of myocardial infarction (MI) [5]

Plain Radiography and CT of Chest Chest radiography should be performed to look for side effects of ischemia, such as pulmonary edema. In addition, this test should be performed to help exclude other possible causes of chest pain, such as thoracic aneurysm or dissection, pneumonia, and rib fracture. Computed tomography (CT) of the chest is performed only as indicated to help rule out other causes of chest pain, such as aortic dissection or pulmonary embolus. The value of CT angiography of the chest in the evaluation of chest pain, CAD, and ACS is currently being investigated.

Electrocardiography ECG should be performed on any patient with a complaint of chest pain if noncardiac causes cannot be diagnosed by other means, including physical examination. It may be helpful to perform ECG both while the pain is present and after the pain has resolved. The ECG changes seen in Wellens syndrome typically are manifested when the patient is pain-free but usually occur in the context of recent anginal chest pain. In Wellens syndrome, the ECG pattern shows significant involvement of the T wave, with minimal ST-segment alteration. The ST segments themselves are usually isoelectric, but if they are abnormal, there will be less than 1 mm of elevation, with a high takeoff of the ST segment from the QRS complex. The characteristic ECG changes of this syndrome occur in the T-wave and occur in 2 forms. The more common of the 2 forms, which occurs 76% of the time, is deep inversion of the T-wave segment in the precordial leads (see the images below). [6] The ST segment will be straight or concave and will pass into a deep negative T wave at an angle of 60°-90°. The T wave is symmetric. In Wellens syndrome, these changes generally occur in leads V1 -V4 but occasionally may also involve V5 and V6. V1 is involved in approximately 66% of patients, and V4 is involved nearly 75% of the time. [7]

This ECG represents a patient who came in to the emergency department with 8/10 chest pain. The patient had old right bundle-branch block (RBBB) and left ventricular hypertrophy (LVH), and this compared similarly to his previous ECGs.

Classic Wellens syndrome T-wave changes. ECG was repeated on a patient who came in to the emergency department with 8/10 chest pain after becoming pain free secondary to medications. Notice the deep T waves in V3-V5 and slight biphasic T wave in V6 in this chest pain– free ECG. The patient had negative cardiac enzyme levels and later had a stent placed in the proximal left anterior descending (LAD) artery. The less common of the 2 forms of Wellens syndrome, which occurs in 24% of patients, consists of biphasic T waves (see the images below), most commonly in leads V2 and V3 but also, on occasion, in leads V1 through V5 or even V6. [5]

A 57-year-old with 4/10 pressurelike chest pain. Improvement with treatment by EMS. The patient had this ECG on arrival. Notice perhaps the beginning of a small biphasic T wave in V2.

Pain-free ECG of a 57-year-old patient who presented with 4/10 pressurelike chest pain. Notice after the patient was treated with medications and pain subsided, the ECG shows T-wave inversion in V2 and biphasic T waves in V3-V5. This more closely resembles the less common presentation of Wellens syndrome with a biphasic T-wave pattern. This patient had a cardiac catheterization that showed a subtotal occlusion of the proximal left anterior descending (LAD) artery, which was stented, and the patient did well. The characteristic pattern classically presents only during chest pain–free periods. Noticing this pattern is crucial because it is a sign of LAD disease. This association underscores the importance of serial ECGs and a pain-free ECG on patients with unstable angina. Because the LAD supplies the anterior myocardium, failure to recognize this pattern can result in anterior wall myocardial infarction (MI), significant left ventricular dysfunction, or death. Reperfusion of the posterior wall following posterior MI leads to a larger T-wave amplitude in the right precordial leads and an even higher T-wave amplitude in leads V2 and V3. [8]

Other Tests

Angiography has demonstrated that 100% of patients with Wellens syndrome will have 50% or greater stenosis of the proximal LAD. [5] More specifically, 83% will have the lesion proximal to the second septal perforator. [7] Stress testing is generally not indicated in patients with this ECG presentation, because it places them at risk for acute anterior wall MI. Ideally, therefore, these patients would bypass stress testing and undergo urgent angiography to determine the extent of disease and potentially provide information about the need for percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or medical management. [6, 9] If provocative testing is determined to be necessary, it should be done cautiously and only in close conjunction with a cardiologist. [6, 10] Treatment & Management

Approach Considerations A cardiologist should be consulted early in the management of a patient with Wellens syndrome. If the patient remains pain-free, it is appropriate to admit him or her to an internist on a telemetry floor, but the internist should be notified that the patient is at high risk and should not undergo stress testing unless clearly recommended by cardiologists. If symptoms persist or electrocardiography (ECG) shows evolution into ST-segment elevations, an interventional cardiologist should be consulted immediately. Transfer of these patients to institutions with cardiac catheterization capabilities is generally appropriate.

Prehospital Care Because Wellens syndrome occurs because of stenosis of the proximal left anterior descending (LAD) coronary artery, patients typically complain of chest pain presenting as unstable angina. During episodes of pain, they should be treated in the same manner as any patient experiencing chest pain thought to be cardiac in origin. Immediate arrangements should be made for transport to the nearest hospital. Careful attention should be paid to the ABCs (airway, breathing, and circulation). During transport, efforts should be made to carry out the following:

Oxygen supplementation
Assessment of vital signs
Intravenous (IV) access
Administration of aspirin
ECG, if available before arrival at the hospital
If pain persists, administration of nitroglycerin or morphine, according to local protocols

If Wellens syndrome is identified on an outpatient basis, then arrangements should be made for urgent evaluation. Stress testing should be avoided.

Emergency Stabilization, MI Prevention, and Pharmacotherapy Patients presenting with symptoms consistent with unstable angina should generally receive medications and other therapies and measures that may help prevent myocardial infarction (MI). Usually, these would include the following:

IV access
Supplemental oxygen, when appropriate
ECG (initially) – Serial examinations and pain-free tracings may be helpful
Telemetry monitoring
Chest radiography
Laboratory studies (see Laboratory Studies)
Aspirin
Consideration should be given to providing beta-blocker therapy, nitroglycerin, morphine, heparin, clopidogrel, and glycoprotein (GP) IIb/IIa inhibitors

Once again, the ECG changes in Wellens syndrome are typically only present when the patient is free of chest pain. Thus, obtaining serial ECGs on patients with unstable angina may be helpful. Even though the ECG changes may be subtle, it is vital to recognize Wellens syndrome because these patients can rarely undergo stress testing safely. [11, 12, 13] Because Wellens syndrome is a sign of a preinfarction stenosis of the LAD, a stress test has the potential to result in acute MI and severe damage to the left ventricle. Therefore, these patients should generally forgo a stress test and instead may undergo angiography to evaluate the need for angioplasty or coronary artery bypass surgery (CABG). Even with ideal medical management, the natural progression of Wellens syndrome is to acute anterior wall MI. Approximately 75% of patients with Wellens syndrome who receive only medical management and do not undergo revascularization (either through CABG or through angioplasty) will go on to develop extensive anterior wall MI within days. [14, 1] Anterior wall MI carries substantial morbidity and mortality: it will result in left ventricular dysfunction and possibly even death. Thus, patients generally should be medically stabilized if possible while arrangements are made for urgent angiography and revascularization if appropriate. Further inpatient care for patients with Wellens syndrome includes the following:

Attempts to keep the patient pain-free
Provision of a telemetry bed to monitor the patient.
Consultation with a cardiologist

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications. Agents used in the management of Wellens syndrome include salicylates, antihypertensive drugs, antianginal drugs, antiplatelet drugs, analgesics, low-molecular-weight heparins (LMWHs), antiarrhythmic drugs, and anticoagulants.

Salicylates Class Summary Salicylates have antiplatelet properties. Aspirin (Ecotrin, Ascriptin, Bayer Aspirin, Bayer Aspirin Extra Strength, Tri-Buffered Aspirin)

Aspirin is an odorless white powdery substance that is available in 81-mg, 325-mg, and 500-mg tablets for oral use. When exposed to moisture, it hydrolyzes into salicylic acid and acetic acids. Aspirin is a stronger inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives are. Its acetyl group is responsible for inactivation of cyclooxygenase via acetylation. Aspirin is hydrolyzed rapidly in plasma, and elimination follows zero-order pharmacokinetics. Aspirin irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to prostaglandin I2 (PGI2, a potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (TXA2, a potent vasoconstrictor and platelet aggregator). Platelet inhibition lasts for the life of cell (approximately 10 days). Aspirin may be used in low doses to inhibit platelet aggregation and improve complications of venous stasis and thrombosis. It reduces the likelihood of myocardial infarction (MI) and is also very effective in lowering the risk of stroke. Early administration of aspirin in patients with acute MI may reduce cardiac mortality in the first month.

Antihypertensive Agents Class Summary These agents reduce high blood pressure. Metoprolol (Lopressor, Toprol XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous (IV) administration, carefully monitor blood pressure, heart rate, and electrocardiography (ECG). The goal of treatment is to reduce the heart rate to 60-90 beats/min.

Nitrates, Angina Class Summary Antianginal agents can reduce blood pressure. Nitroglycerin translingual (Nitro-Dur, Nitro-Bid, NitroMist, Nitrolingual, Nitrostat)

Sublingual nitroglycerin causes relaxation of the vascular smooth muscle via stimulation of intracellular cyclic guanosine monophosphate production, causing a decrease in blood pressure.

Antiplatelet Agents Class Summary Antiplatelet agents inhibit platelet aggregation. Abciximab (ReoPro)

Abciximab is a chimeric human-murine monoclonal antibody approved for use in elective, urgent, or emergency percutaneous coronary intervention (PCI). It binds to the receptor with high affinity and reduces platelet aggregation by 80% for as long as 48 hours after infusion. Clopidogrel (Plavix)

Clopidogrel selectively inhibits adenosine diphosphate (ADP) binding to platelet receptors and subsequent ADP-mediated activation of the glycoprotein (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation. Clopidogrel may have a positive influence on several hemorrhagic parameters and may exert protection against atherosclerosis not only through inhibition of platelet function but also through changes in the hemorrhagic profile. It has been shown to lower the rates of cardiovascular death, MI, and stroke in patients with acute coronary syndrome (ie, unstable angina and non-Q-wave MI).

Opioid Analgesics Class Summary Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties, which are beneficial for patients who experience pain. Morphine sulfate (Astramorph, Duramorph, Avinza, MS Contin, Oramorph)

Morphine sulfate is the drug of choice for narcotic analgesia because of its reliable and predictable effects, good safety profile, and easy reversibility with naloxone. IV morphine sulfate may be dosed in a number of ways and is commonly titrated until the desired effect is obtained.

Low-Molecular-Weight Heparins Class Summary LMWHs inhibit thrombogenesis. LMWH differs from unfractionated heparin (UFH) in that it has a higher ratio of anti–factor Xa to anti–factor IIa. It binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin). It does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis. Enoxaparin (Lovenox)

Enoxaparin is an LMWH produced by partial chemical or enzymatic depolymerization of UFH. Its advantages include intermittent dosing and a decreased requirement for monitoring. Heparin anti-Xa levels may be obtained if needed to establish adequate dosing. There is no utility in checking the activated partial thromboplastin time (aPTT), because the drug has a wide therapeutic window and aPTT does not correlate with anticoagulant effect. Maximal anti-Xa and antithrombin activities occur 3-5 hours after administration. Enoxaparin is indicated for treatment of acute ST-segment elevation MI (STEMI) managed either medically or with subsequent PCI. It is also indicated for prophylaxis of ischemic complications caused by unstable angina and non-Q-wave MI.

Antidysrhythmics, II Class Summary Antiarrhythmic agents reduce episodes of chest pain and clinical cardiac events. Esmolol (Brevibloc)

Esmolol is an ultra–short-acting agent that selectively blocks beta1-receptors with little or no effect on beta2-receptor types. It is particularly useful in patients with elevated arterial pressure, especially if surgery is planned. Esmolol has been shown to reduce episodes of chest pain and clinical cardiac events in comparison with placebo. It can be discontinued abruptly if necessary. Esmolol is useful in patients at risk for complications from beta blockade, particularly those with reactive airway disease, mild-to-moderate left ventricular dysfunction, or peripheral vascular disease. Its short half-life (8 min) allows titration to the desired effect and quick discontinuance if necessary. Propranolol (Inderal LA, InnoPran XL)

Propranolol has membrane-stabilizing activity and decreases the automaticity of contractions. It is not suitable for emergency treatment of hypertension. Do not administer it intravenously in hypertensive emergencies. Sotalol (Betapace, Sorine)

This class II antiarrhythmic agent blocks K+ channels, increases sinus cycle length, slows the heart rate, increases AV nodal refractoriness, and decreases AV nodal conduction. It has been shown to be effective in the maintenance of sinus rhythm, even in patients with underlying structural heart disease. It is a non–cardiac selective beta-adrenergic blocker. It has both beta1 and beta2 receptor blocking activity. Acebutolol (Sectral)

Acebutolol selectively blocks beta1-adrenergic receptors. It has intrinsic activity and membrane stabilizing activity.

Anticoagulants, Cardiovascular Class Summary Anticoagulants are used for anticoagulation in patients with unstable angina. Lepirudin (Refludan)

Lepirudin is a recombinant hirudin derived from yeast cells. When compared with UFH in unstable angina trials, hirudin demonstrated a modest short-term reduction in the composite endpoint of death or nonfatal MI. The risk of bleeding is modestly increased. Currently, hirudin is indicated only in patients who are unable to receive heparin because of heparin-induced thrombocytopenia. Bivalirudin (Angiomax)

Bivalirudin is a synthetic analogue of recombinant hirudin. It inhibits thrombin and is used for anticoagulation in patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA). With provisional use of a GPIIb/IIIa inhibitor, it is indicated for anticoagulation in patients undergoing PCI. The potential advantages of bivalirudin therapy over conventional heparin therapy include more predictable and precise levels of anticoagulation, activity against clot-bound thrombin, absence of natural inhibitors (eg, platelet factor 4 and heparinase), and continued efficacy after clearance from plasma (because of binding to thrombin). Argatroban

Argatroban is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. It inhibits thrombin-induced platelet aggregation. Dabigatran etexilate (Pradaxa)

Dabigatran etexilate is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. It inhibits thrombin-induced platelet aggregation.

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