Takotsubo (Stress) Cardiomyopathy (Broken Heart Syndrome)

Takotsubo cardiomyopathy, also known as stress cardiomyopathy and "broken heart syndrome," is a sudden, transient cardiac syndrome that involves dramatic left ventricular apical akinesis and mimics acute coronary syndrome (ACS). It was first described in Japan in 1990 by Sato et al.

Patients often present with chest pain, have ST-segment elevation on electrocardiography (ECG), and have elevated cardiac enzyme levels consistent with myocardial infarction (MI).[1]  (See the images below.)[2, 3]  However, when the patient undergoes cardiac angiography, left ventricular (LV) apical ballooning is present, and there is no significant coronary artery stenosis. (See Presentation and Workup.)[4]

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Electrocardiogram of a patient with takotsubo cardiomyopathy demonstrating ST-segment elevation in the anterior and inferior leads.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Electrocardiogram (ECG) from the same patient discussed in the previous ECG, obtained several days after the initial presentation. This ECG demonstrates resolution of the ST-segment elevation, and now shows diffuse T-wave inversion and poor R-wave progression.

The Japanese word takotsubo translates to "octopus pot," which refers to the resemblance of the LV shape during systole to this pot on imaging studies. Although the exact etiology of takotsubo cardiomyopathy remains unknown, the syndrome appears to be triggered by a significant emotional or physical stressor.[1, 5]  (See Etiology.)

The modified Mayo Clinic criteria for diagnosis of takotsubo cardiomyopathy[6]  can be applied to a patient at the time of presentation. The diagnosis requires the presence of all four of the following (see Workup):

• Transient hypokinesis, dyskinesis, or akinesis of the LV midsegments, with or without apical involvement; the regional wall-motion abnormalities extend beyond a single epicardial vascular distribution, and a stressful trigger is often, but not always, present
• Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture
• New ECG abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in the cardiac troponin level
• Absence of pheochromocytoma or myocarditis ^[6]

Normal myocardium utilizes approximately 90% of its energy from fatty acid metabolism at rest and with aerobic activity. During ischemia, this pathway is suppressed, and glucose is largely utilized instead, which results in impaired cardiac function. Patients with takotsubo (stress) cardiomyopathy (broken heart syndrome) are found to have a shift toward the glucose pathway despite relatively normal myocardial perfusion and a lack of ischemia in the left ventricular (LV) segments.[7]

The most commonly discussed possible mechanism for takotsubo cardiomyopathy is stress-induced catecholamine release, with toxicity to and subsequent stunning of the myocardium.[5]  Endomyocardial biopsy of patients with takotsubo cardiomyopathy demonstrates reversible focal myocytolysis, mononuclear infiltrates, and contraction band necrosis. The sympathetic/catecholamine theory is gaining momentum, because takotsubo cardiomyopathy was induced in rats exposed to physical stress and, in some instances, was prevented by pretreatment with an alpha blocker or beta blocker. Other evidence for this theory has been demonstrated through myocardial imaging studies using catecholamine analogues that evaluated cardiac sympathetic activity.

Some authors have proposed a unifying hypothesis stating that in susceptible individuals, notably women, neurohormonal stimulation results in acute myocardial dysfunction, as reflected by the characteristic LV wall-motion abnormality of takotsubo cardiomyopathy. Whether this is triggered by multivessel spasm, thrombosis, epicardial vessel occlusion, or direct myocardial toxicity remains to be seen. These authors point out that the wall-motion abnormality of takotsubo cardiomyopathy can be seen in other conditions, including those with certain left anterior descending lesions,[8]  making wall motion alone insufficient for the diagnosis of takotsubo cardiomyopathy.[9]

Cases of takotsubo cardiomyopathy have been reported in the literature following cocaine, methamphetamine, and excessive phenylephrine use.[10, 7]  Exercise stress testing, which is known to cause increased levels of catecholamines, has resulted in false positives attributable to takotsubo cardiomyopathy.[11]  Studies have found that patients with takotsubo cardiomyopathy have, by a statistically significant margin, higher levels of serum catecholamines (norepinephrine, epinephrine, and dopamine) than do patients with myocardial infarction.[12]  The apical portions of the LV have the highest concentration of sympathetic innervation found in the heart and may explain why excess catecholamines seem to selectively affect its function.[7]

Underlying coronary endothelial dysfunction may also play a role in takotsubo cardiomyopathy, wherein an abnormal tendency toward spasticity in the coronary tree can manifest as angina and as takotsubo cardiomyopathy.[13] One theory indicates that "substantially increased coronary spasticity may lead to diffuse, transient spastic obliteration of coronary arteries and to critical ischemia, which can be reproduced by acetylcholine testing early after" an episode of takotsubo cardiomyopathy.[13]

The exact etiology of takotsubo (stress) cardiomyopathy (broken heart syndrome) is still unknown, but several theories have been proposed and are under investigation.[14] These include the following[10, 15] :

• Multivessel coronary artery spasm
• Impaired cardiac microvascular function
• Impaired myocardial fatty acid metabolism
• Acute coronary syndrome (ACS) with reperfusion injury
• Endogenous catecholamine-induced myocardial stunning and microinfarction
• Underlying coronary endothelial dysfunction ^[13]

Risk factors for takotsubo cardiomyopathy

A significant emotional or physical stressor or neurologic injury typically precedes the development of the takotsubo cardiomyopathy.[1, 5]  Stressors include the following:

• Learning of a death of a loved one
• Bad financial news
• Legal problems
• Natural disasters
• Motor vehicle collisions
• Exacerbation of a chronic medical illness
• Newly diagnosed, significant medical condition
• Surgery
• Intensive care unit stay
• Use of or withdrawal from illicit drugs

Takotsubo cardiomyopathy has also been reported after near-drowning episodes.[16]

Seizures may also trigger takotsubo cardiomyopathy,[17] but it is rare for takotsubo cardiomyopathy to result in sudden unexpected death in epilepsy (SUDEP).[18]

In a systematic review of 104 cases of takotsubo cardiomyopathy (1965-2013), investigators noted that young patients with takotsubo cardiomyopathy were more likely to be female and physical stress was more likely to exacerbate takotsubo cardiomyopathy than mental stress was.[19, 20]  The clinical presentation of takotsubo cardiomyopathy in this patient population was similar to that of other cardiac diseases (eg, coronary heart disease) but could be differentiated from them by means of echocardiography in conjunction with ventriculography.[19]

Similarly, the International Takotsubo Registry reported that patients with takotsubo cardiomyopathy, as compared with ACS patients, were more likely to be female (89.8%) and that physical triggers were more common than emotional triggers (36% vs 27.7%), although more than one quarter (28.5%) had no clear triggers.[20] Patients with takotsubo cardiomyopathy also had higher rates of neurologic or psychiatric disorders and a significantly lower left ventricular ejection fraction (LVEF). Both groups (takotsubo cardiomyopathy and ACS) had similar rates of severe inpatient complications (eg, shock, death), and independent predictors of such complications included physical triggers, acute neurologic/psychiatric diseases, elevated troponin levels, and low LVEF.[20]

Controversy exists regarding whether or not takotsubo cardiomyopathy is associated with malignancy.[13]  Although it appears that takotsubo cardiomyopathy occurs more frequently than would be expected in noncancer patients,[13, 21] it is unclear whether chemotherapy itself is a more significant risk factor for takotsubo cardiomyopathy than the cancer itself.[13]

Studies reported that 1.7-2.2% of patients who had suspected acute coronary syndrome were subsequently diagnosed with takotsubo (stress) cardiomyopathy (broken heart syndrome).[22, 23] Patients are typically Asian or white. In a literature review of cases in which race was reported, 57.2% of patients were Asian, 40% were white, and 2.8% were other races.[24]

Literature reviews report a mean patient age of 67 years, although cases of takotsubo cardiomyopathy have occurred in children and young adults[10, 12] Nearly 90% of reported cases involve postmenopausal women.[25]  

The prognosis in takotsubo (stress) cardiomyopathy (broken heart syndrome) is typically excellent, with nearly 95% of patients experiencing complete recovery within 4-8 weeks.[26, 27] A study by Singh et al indicated that the annual recurrence rate is approximately 1.5% but that the frequency of ongoing symptoms is greater.[28] Estimates of mortality have ranged from 1% to 3.2%.[24, 25]

Complications occur in 20% of cases of takotsubo cardiomyopathy, particularly in the early stage,[3] and include the following:

• Left heart failure with and without pulmonary edema
• Cardiogenic shock
• Left ventricular (LV) outflow obstruction
• Mitral regurgitation
• Ventricular arrhythmias
• LV mural thrombus formation
• LV free-wall rupture
• Death ^{[29, 30]}

The clinical presentation of patients ultimately diagnosed with takotsubo (stress) cardiomyopathy (broken heart syndrome) is usually indistinguishable from that of patients with acute coronary syndrome (ACS). The most common presenting symptoms of takotsubo cardiomyopathy are chest pain and dyspnea, although palpitations, nausea, vomiting, syncope and, rarely, cardiogenic shock have been reported.

One of the more unique features of takotsubo cardiomyopathy is its association with a preceding emotionally or physically stressful trigger event, occurring in approximately two thirds of patients. Unlike ACS, for which the peak occurrence is during the morning hours, takotsubo cardiomyopathy events are most prevalent in the afternoon, when stressful triggers are more likely to take place.[31]

A large systematic review found that patients with takotsubo cardiomyopathy tend to have a lower incidence of traditional cardiac risk factors, such as hypertension, hyperlipidemia, diabetes, smoking, or positive family history for cardiovascular disease.[26]

Physical examination findings in patients with takotsubo (stress) cardiomyopathy (broken heart syndrome) are nonspecific and often normal, but the patient may exhibit the clinical appearance of acute coronary syndrome or acute congestive heart failure. Patients may appear anxious and diaphoretic. Tachydysrhythmias and bradydysrhythmias have been reported, but the average heart rate in one review was 102 bpm.[7]

Hypotension can occur from a reduction in stroke volume because of acute left ventricular systolic dysfunction or outflow tract obstruction. Murmurs and rales may be present on auscultation in the setting of acute pulmonary edema.

Cardiac markers, specifically troponin I (TnI) and troponin T (TnT), are elevated in 90% of patients with takotsubo (stress) cardiomyopathy (broken heart syndrome), although to a lesser magnitude than is seen in ST-segment elevation myocardial infarction (STEMI). The brain natriuretic peptide (BNP) level is also frequently elevated.

As with any patient in whom acute coronary syndrome (ACS) is suspected, electrocardiography (ECG) should be the initial test obtained soon after presentation to the emergency department (ED).

Transthoracic echocardiography (TTE) provides a quick method of diagnosing wall-motion abnormalities typically seen in takotsubo cardiomyopathy, specifically hypokinesis or akinesis of the midsegment and apical segment of the left ventricle. The diagnosis of takotsubo cardiomyopathy is typically confirmed with cardiac angiography.

In patients with takotsubo (stress) cardiomyopathy (broken heart syndrome), the mean troponin T (TnT) level at the time of admission has been found to be 0.49 ng/mL (normal, < 0.01), and the mean TnI (troponin I) level has been reported as 4.2 ng/mL (normal, < 0.04); during hospitalization, mean peak values for TnT and TnI have been demonstrated to be 0.64 and 8.6 ng/mL, respectively.

As mentioned earlier, the brain natriuretic peptide (BNP) level is also frequently elevated, especially in those patients demonstrating left heart failure; it is an indicator of increased left ventricular (LV) end-diastolic pressures (EDDs) that result from the stunned myocardium.

Takotsubo cardiomyopathy mimics ST-segment elevation myocardial infarction (STEMI). In a study of 66 consecutive patients who were hospitalized with takotsubo cardiomyopathy and 66 patients with STEMI, cardiac biomarkers were determined during 12 hours from admission and compared with demographic, clinical, and echocardiographic findings.[33] Investigators found evidence that the following ratios were capable of distinguishing takotsubo cardiomyopathy from STEMI at an early stage:

• Ratio of N-terminal pro-BNP (NTproBNP) to TnI
• Ratio of NTproBNP to creatine kinase MB (CKMB) mass
• Ratio of NTproBNP to ejection fraction (EF)

Of these, the most accurate marker was the NTproBNP-to-TnI ratio.[33]

Several studies looked at levels of circulating catecholamines in the acute phase and found that nearly 75% of patients had elevations markedly higher than did patients with STEMI.[34, 35]

As previously stated, Transthoracic echocardiography (TTE) provides a quick method of diagnosing wall-motion abnormalities typically seen in takotsubo (stress) cardiomyopathy (broken heart syndrome),[36] specifically hypokinesis or akinesis of the midsegment and apical segment of the left ventricle (LV). Perhaps most important, these wall-motion abnormalities extend beyond the distribution of any single coronary artery.

The LV ejection fraction (EF) can be estimated by means of echocardiography, cardiac magnetic resonance imaging (MRI), or left ventriculography. Mean LVEF on admission has been found to be in the range of 20%-49%.

Echocardiography is commonly used in following the resolution of the cardiomyopathy and impaired LV function, with LVEF improving to 59%-76% on average, by day 18. (See the images below.)

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram of a patient with takotsubo cardiomyopathy during diastole several days after presenting to the emergency department.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram of a patient with takotsubo cardiomyopathy during systole, which demonstrates apical akinesis. The patient's ejection fraction was 40%.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram of the same patient with takotsubo cardiomyopathy during systole discussed in the previous image, nearly 2 months after presenting to the emergency department. Note the improved contractility of the apex. The ejection fraction increased from 40% to 65%.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram of a patient with takotsubo cardiomyopathy during diastole, approximately 2 months after presenting to the emergency department.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram focused on the left ventricle of a patient with takotsubo cardiomyopathy during diastole.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram focusing on the left ventricle of a patient with takotsubo cardiomyopathy during systole. Note the apical akinesis.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram focusing on the left ventricle of a patient with takotsubo cardiomyopathy during systole discussed in the previous image, approximately 2 months after presenting to the emergency department. Note the improved apical contraction.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Echocardiogram focusing on the left ventricle of a patient with takotsubo cardiomyopathy during diastole, approximately 2 months after presenting to the emergency department.

The diagnosis of takotsubo (stress) cardiomyopathy (broken heart syndrome) is typically confirmed in the cardiac catheterization laboratory. In a review of 240 patients diagnosed with takotsubo cardiomyopathy, 211 were found to have completely normal coronary arteries, whereas the remainder had noncritical stenoses. The prevalence of normal coronary arteries by angiography in patients presenting with ST-segment elevation myocardial infarction (STEMI) ranges from 1% to 12%. Aside from takotsubo cardiomyopathy, this phenomenon may be explained by transient vessel occlusion with spontaneous thrombolysis, by vasospasm, or by drug effects.

Left ventriculography is perhaps the best imaging modality for demonstrating the pathognomonic wall motion and evaluating left ventricular ejection fraction (LVEF).[26, 27] (See the images below.)

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Coronary angiogram of a patient with takotsubo cardiomyopathy demonstrating normal coronary arteries.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Coronary angiogram of a patient with takotsubo cardiomyopathy demonstrating normal coronary arteries.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Ventriculogram during systole in a patient with takotsubo cardiomyopathy demonstrating apical akinesis.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Ventriculogram during diastole in a patient with takotsubo cardiomyopathy.

Chest radiographs in takotsubo (stress) cardiomyopathy (broken heart syndrome) are often normal, but they may demonstrate pulmonary edema.

Cardiac magnetic resonance imaging (MRI) is increasingly being used as a diagnostic modality that is uniquely suited for establishing the diagnosis of takotsubo cardiomyopathy by accurately visualizing regional wall-motion abnormalities, quantifying ventricular function, and identifying reversible injury to the myocardium by the presence of edema/inflammation and the absence of necrosis/fibrosis.[37, 38, 39, 40]

In addition to evaluating wall-motion abnormalities and left ventricular ejection fraction, cardiac MRI has been found to differentiate takotsubo cardiomyopathy, which is characterized by the absence of delayed gadolinium hyperenhancement, from myocardial infarction and myocarditis, in which the opposite occurs.

Although not indicated in the initial evaluation of patients with takotsubo cardiomyopathy, coronary computed tomography angiography has been used in the subsequent evaluation of patients with the disorder.[41]

As with any patient in whom acute coronary syndrome (ACS) is suspected, electrocardiography (ECG) should be the initial test obtained soon after presentation to the emergency department. ST-segment elevation (67-75%) and T-wave inversion (61%) are the most common abnormalities seen on the initial ECG. Ninety-five percent of ST-segment elevations have been found to involve the precordial leads and to be maximal in leads V2 -V3. In comparison with patients with ST-segment elevation myocardial infarction (STEMI) from left anterior descending (LAD) coronary artery occlusion, patients with takotsubo cardiomyopathy had significantly lower amplitude of ST-segment elevations. (See the images below.)

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Electrocardiogram of a patient with takotsubo cardiomyopathy demonstrating ST-segment elevation in the anterior and inferior leads.

Takotsubo (stress) cardiomyopathy (broken heart syndrome). Electrocardiogram (ECG) from the same patient discussed in the previous ECG, obtained several days after the initial presentation. This ECG demonstrates resolution of the ST-segment elevation, and now shows diffuse T-wave inversion and poor R-wave progression.

An initially normal or nonspecific ECG finding is seen in 15% of patients with takotsubo cardiomyopathy. Diffuse T-wave inversions tend to occur in the days and weeks following presentation as the ST segments normalize. takotsubo cardiomyopathy cannot be reliably differentiated from STEMI solely on the basis of ECG findings.[26, 30]

In a retrospective study of 33 patients with takotsubo cardiomyopathy, the authors proposed ECG criteria to distinguish takotsubo cardiomyopathy from anterior acute MI in those who presented within 6 hours of symptom onset. The combination of absent abnormal Q waves, absent reciprocal changes, lack of ST-segment elevation in lead V1, and presence of ST-segment elevation in lead aVR had more than 91% sensitivity and 96% specificity for takotsubo cardiomyopathy.[42]

Prehospital care

Because takotsubo (stress) cardiomyopathy (broken heart syndrome) mimics acute coronary syndrome and no initial electrocardiographic (ECG) finding reliably differentiates takotsubo cardiomyopathy from ST-segment elevation myocardial infarction (STEMI), prehospital personnel should follow their established protocols for evaluating and transporting patients with chest pain and/or acute coronary syndrome (ACS).

Inpatient care

Patients with takotsubo cardiomyopathy will require admission to the appropriate cardiology service. Treatment options are largely empiric and supportive; however, when hemodynamics permit, beta blockers seem to be helpful. Serial imaging studies may be necessary. Patients who are found to have left ventricular (LV) thrombus, which occurs in 5% of patients with takotsubo cardiomyopathy, require anticoagulation.[43]

Outpatient care

Close follow-up care with a cardiologist in the weeks after diagnosis is recommended for patients with takotsubo cardiomyopathy to ensure resolution of the cardiomyopathy, usually with serial echocardiograms. Thereafter, annual clinical follow-up is advised, because the long-term effects and natural history of takotsubo cardiomyopathy are unknown.[27, 44]

Consultations and transfer for suspected takotsubo cardiomyopathy

Consultation with a cardiologist is necessary, in that coronary angiography is required for the diagnosis of takotsubo cardiomyopathy. Patients may need to be transferred to a facility with a cardiologist and a cardiac catheterization laboratory.[30, 34, 35, 44]

Patients with takotsubo (stress) cardiomyopathy (broken heart syndrome) should be treated as having acute coronary syndrome (ACS) until proved otherwise. Addressing the airway, breathing, and circulation; establishing intravenous (IV) access; and providing supplemental oxygen and cardiac monitoring should take precedence. Testing in the emergency department should include electrocardiography (ECG), chest radiography, cardiac biomarker levels, brain natriuretic peptide (BNP) level, and other appropriate laboratory studies.

If the patient continues to manifest a clinical picture consistent with ACS, especially ST-segment elevation myocardial infarction (STEMI), then standard therapies, such as the following, may be indicated:

• Aspirin
• Beta blockers
• Nitrates
• Heparin or enoxaparin
• Platelet glycogen (GP) IIb/IIIa inhibitors
• Morphine
• Clopidogrel

Patients in acute congestive heart failure (CHF) may require diuresis, and patients with cardiogenic shock may require resuscitation with IV fluids and inotropic agents. If available, bedside echocardiography could show the characteristic wall-motion abnormality.

The insertion of an intra-aortic balloon pump (IABP) has also been reported as being a successful resuscitative intervention, because of left ventricular (LV) outflow obstruction that can result from a hyperkinetic basal segment and dyskinetic apex. Fluids and beta blockers, or calcium-channel blockers, are beneficial in this situation, whereas inotropes may exacerbate the problem and should be used with caution.

Arrhythmias are common in takotsubo cardiomyopathy and are a major determinant of patient outcome. In a cohort of 286 consecutive takotsubo cardiomyopathy patients, Stiermaier et al assessed treatment strategies for arrhythmias, including ventricular fibrillation, ventricular tachycardia, asystole, pulseless electrical activity, and complete atrioventricular or sinoatrial block (mean follow-up, 3.3±2.4 years).[45] The results suggested that whereas bradyarrhythmias in the acute setting of takotsubo cardiomyopathymight necessitate permanent pacemaker implantation, polymorphic ventricular arrhythmias might be manageable with a temporary approach (eg, wearable cardioverter-defibrillators) until recovery of repolarization time and LV function.[45]

Dysrhythmias and cardiopulmonary arrest should be treated according to current advanced cardiac life support (ACLS) protocols. Although thrombolytics will not benefit patients with takotsubo cardiomyopathy, their use should not be withheld when percutaneous coronary intervention (PCI) is not available and patients otherwise meet criteria.[30, 44]

Currently, no randomized controlled trials have been performed to evaluate medical therapies for takotsubo (stress) cardiomyopathy (broken heart syndrome); however, it is common practice to prescribe angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), at least until left ventricular (LV) function is restored. Beta blockers are also indicated and may be useful in the long term. However, a review study and meta-analysis by Singh et al suggested that while ACEIs and ARBs may reduce the recurrence rate of takotsubo cardiomyopathy, beta blockers may not.[28]

Other standard outpatient post-ST-segment elevation myocardial infarction (STEMI) medications, such as statins, aspirin, and clopidogrel, are of unknown benefit.

Patients with a known LV thrombus should be anticoagulated until LV function normalizes and the thrombus is no longer present on echocardiogram.[43] Chronic beta-blocker therapy may reduce the likelihood of recurrent episodes.[27]

Class Summary

These agents inhibit platelet aggregation.

Aspirin (Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin, Ecotrin)

Aspirin is an odorless, white, powdery substance available in 81 mg, 325 mg, and 500 mg for oral use. When exposed to moisture, aspirin hydrolyzes into salicylic acid and acetic acid. It is a stronger inhibitor of prostaglandin synthesis and platelet aggregation than are other salicylic acid derivatives. The acetyl group is responsible for the inactivation of cyclooxygenase via acetylation.

Aspirin is hydrolyzed rapidly in plasma, and elimination follows zero-order pharmacokinetics. It irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits the conversion of arachidonic acid to PGI2 (a potent vasodilator and an inhibitor of platelet activation) and thromboxane A2 (a potent vasoconstrictor and platelet aggregate). Platelet inhibition lasts for life of cell (approximately 10 d).

Aspirin may be used in low dose to inhibit platelet aggregation and improve the complications of venous stases and thrombosis. It reduces the likelihood of myocardial infarction and is also very effective in reducing the risk of stroke. Early administration of aspirin in patients with acute myocardial infarction may reduce cardiac mortality in the first month.

Class Summary

These agents reduce blood pressure.

Nitroglycerin topical (Nitro-Bid, Nitrolingual pumpspray, Nitrostat, Nitro-Dur)

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

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, MS Contin, Oramorph SR, Avinza)

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

Class Summary

Anticoagulants inhibit thrombogenesis.

Heparin

Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents the recurrence of a clot after spontaneous fibrinolysis.

Class Summary

Low ̶ molecular weight heparins (LMWHs) inhibit thrombogenesis.

Enoxaparin (Lovenox)

Enoxaparin is produced by the partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa.

Enoxaparin 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, preventing clot reaccumulation after spontaneous fibrinolysis.

The advantages of enoxaparin include intermittent dosing and a decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing. There is no utility in checking activated partial thromboplastin time (aPTT); the drug has a wide therapeutic window, and aPTT does not correlate with the anticoagulant effect. The maximum antifactor Xa and antithrombin activities occur 3-5 hours after administration.

Enoxaparin is indicated for the treatment of acute STEMI managed medically or with subsequent percutaneous coronary intervention (PCI). It is also indicated as prophylaxis for ischemic complications caused by unstable angina and non-Q-wave myocardial infarction.

Class Summary

Antiarrhythmic agents reduce episodes of chest pain.

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 compared with placebo. It can be discontinued abruptly if necessary.

Esmolol is useful in patients at risk of experiencing complications from beta blockade, particularly those with reactive airway disease, mild-moderate left ventricular dysfunction, and/or peripheral vascular disease. The drug's short, 8-minute half-life allows for titration to the desired effect and for quick discontinuation if needed.

Class Summary

These agents reduce platelet aggregation.

Abciximab (ReoPro)

Abciximab is a chimeric human-murine monoclonal antibody that has been approved for use in elective/urgent/emergent PCI. It binds to the receptor with high affinity and reduces platelet aggregation by 80% for up to 48 hours following infusion.

Class Summary

Loop diuretics reduce blood pressure.

Furosemide (Lasix)

Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. It increases renal blood flow without increasing the filtration rate. The onset of action generally is within 1 hour. Furosemide increases potassium, sodium, calcium, and magnesium excretion.

The dose must be individualized to the patient. Depending on the response, administer furosemide at increments of 20-40 mg, until the desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose increments until a satisfactory effect is achieved.

Diuretics have major clinical uses in managing disorders involving abnormal fluid retention (edema) or in treating hypertension, in which their diuretic action causes decreased blood volume.

Class Summary

These agents reduce blood pressure.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits the reabsorption of sodium in distal tubules, causing the increased excretion of sodium and water, as well as of potassium and hydrogen ions.

Class Summary

Antihypertensive agents reduce blood pressure.

Spironolactone (Aldactone)

Spironolactone is used for the management of edema resulting from excessive aldosterone excretion. It competes with aldosterone for receptor sites in the distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Class Summary

These agents inhibit platelet aggregation.

Eptifibatide (Integrilin)

Eptifibatide is an antagonist of the GP IIb/IIIa receptor; it reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor. Eptifibatide inhibits platelet aggregation. Its effects persist over the duration of maintenance infusion and are reversed when infusion ends.

Tirofiban (Aggrastat)

Tirofiban is a nonpeptide antagonist of the GP IIb/IIIa receptor. It is a reversible antagonist of fibrinogen binding. When tirofiban is administered intravenously, more than 90% of platelet aggregation is inhibited. The drug is approved for use in combination with heparin for patients with unstable angina who are being treated medically and for those undergoing PCI.

Clopidogrel (Plavix)

Clopidogrel selectively inhibits adenosine diphosphate (ADP) binding to the platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. The drug may have a positive influence on several hemorrhagic parameters and may exert protection against atherosclerosis not only through the inhibition of platelet function but also through changes in the hemorrhagic profile.

Clopidogrel has been shown to decrease cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ie, unstable angina, non-Q-wave myocardial infarction).

Class Summary

ACE inhibitors help to control blood pressure.

Lisinopril (Prinivil, Zestril)

Lisinopril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Enalapril (Vasotec)

Enalapril also prevents the conversion of angiotensin I to angiotensin II, leading to increased levels of plasma renin and reduced aldosterone secretion. The drug helps to control blood pressure and proteinuria. Enalapril decreases the pulmonary-to-systemic flow ratio in the catheterization laboratory and increases the systemic blood flow in patients with relatively low pulmonary vascular resistance.

The drug has a favorable clinical effect when it is administered over a long period. It helps to prevent potassium loss in the distal tubules; the body conserves potassium, and thus, less oral potassium supplementation is needed.

Class Summary

These agents are used to reduce blood pressure.

Atenolol (Tenormin)

Atenolol is used to treat hypertension. It selectively blocks beta1 receptors, with little or no affect on beta2 types. Beta-adrenergic blocking agents affect blood pressure via multiple mechanisms; actions include a negative chronotropic effect that decreases the heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, a reduction of sympathetic outflow from the central nervous system (CNS), and a suppression of renin release from the kidneys.

Atenolol is used to improve and preserve hemodynamic status by acting on myocardial contractility, reducing congestion, and decreasing myocardial energy expenditure.

Beta-adrenergic blockers reduce the inotropic state of the left ventricle, decrease diastolic dysfunction, and increase left ventricular compliance, thereby reducing the pressure gradient across the left ventricular outflow tract.

Atenolol reduces the heart rate, thus lowering myocardial oxygen consumption and reducing the potential for myocardial ischemia. During intravenous administration, carefully monitor the patient's blood pressure, heart rate, and ECG.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous administration, carefully monitor the patient's blood pressure, heart rate, and ECG.

Class Summary

Calcium channel blockers improve oxygen delivery to myocardial tissue.

Verapamil (Calan, Calan SR, Covera-HS, Verelan)

During depolarization, verapamil inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.

Diltiazem (Cardizem CD, Cardizem LA, Dilacor XR, Diltzac, Tiazac)

During depolarization, diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

Diltiazem decreases the conduction velocity in the atrioventricular (AV) node. It also increases the refractory period, via the blockade of calcium influx. This, in turn, stops reentrant phenomenon.

Diltiazem decreases myocardial oxygen demand by reducing peripheral vascular resistance, reducing the heart rate by slowing conduction through the sinoatrial (SA) and AV nodes, and reducing LV inotropy. The drug slows AV nodal conduction time and prolongs AV nodal refractory period, which may convert supraventricular tachycardia or slow the rate in atrial fibrillation. It also has vasodilator activity but may be less potent than other agents. Total peripheral resistance, systemic blood pressure, and afterload are decreased.

Calcium channel blockers provide control of hypertension associated with less impairment of function of the ischemic kidney. They may have beneficial long-term effects, but this remains uncertain.

Amlodipine (Norvasc)

Amlodipine is generally regarded as a dihydropyridine, although experimental evidence suggests that it also may bind to the nondihydropyridine binding sites. The drug is appropriate for the prophylaxis of variant angina.

Amlodipine has antianginal and antihypertensive effects. It blocks the postexcitation release of calcium ions into cardiac and vascular smooth muscle, thereby inhibiting the activation of adenosine triphosphatase (ATPase) on myofibril contraction. The overall effect is reduced intracellular calcium levels in cardiac and smooth muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries.

Amlodipine also increases myocardial oxygen delivery in patients with vasospastic angina. In addition, it may potentiate ACE inhibitor effects. During depolarization, amlodipine inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.

The drug benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias and can be used during pregnancy if clinically indicated. Amlodipine has a substantially longer half-life than nifedipine and diltiazem and is administered daily.