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Abstract
The link between an emotional or physical stresses and an acute cardiac event was first discovered in Japan. Stress-induced cardiomyopathy is defined as transient left ventricular dysfunction associated with apical and mid ventricular contractile abnormalities and sparing of basal segments that mimics acute myocardial infarction. This article presents an overview of this disorder.
A 64-year-old white female presents to a local emergency room, complaining of substernal chest pain with an onset 2 hours before arrival. She has mild dyspnea; vital signs are normal (heart rate 72 beats per minute, blood pressure 136/72 mm Hg, respirations 20 per minute, temperature 97.9°F, and oxygen saturation 96% on room air). She denies any significant medical history, except that she is postmenopausal and does not take any medications. She walks daily and consumes a balanced diet. Her initial 12-lead electrocardiogram (EKG) shows ST elevation in leads V3-V6. Cardiac enzymes are mildly elevated initially but fail to rise with subsequent measurement (troponin was 3.5 ng/dL and total creatine kinase was 275 µm/L). She is admitted with an acute myocardial infarction (AMI). Echocardiogram reveals further significant abnormalities such as a depressed ejection fraction of 40%, moderate mid ventricle dysfunction, apical akinesis, and preserved basal function. Additional history reveals that this patient received news that her daughter had been severely injured in a car accident several hours before her onset of chest pain. Is there a relationship between this unexpected news and her current presentation?
The link between an emotional or physical stressor and an acute cardiac event was first discovered in Japan.1 It was referred to as "Tako-tsubo," a Japanese term for an octopus trap that resembles alterations to the left ventricle that may be seen on an echocardiogram. Although the name has changed, this same syndrome is now being studied in the United States. These studies will be further discussed throughout this article. More current names include broken heart syndrome, stress-induced cardiomyopathy, transient left ventricular apical ballooning syndrome, and myocardial stunning. For the purpose of this article, it will be referred to as stress-induced cardiomyopathy or stress cardiomyopathy.
Regardless of name, the defining characteristics remain the same. This syndrome is defined as transient left ventricular dysfunction associated with apical and mid ventricular contractile abnormalities and sparing of basal segments that mimics AMI but with minimal release of cardiac enzymes.1 Large areas of focal akinesis are seen throughout the myocardium. Electrocardiogram reveals that distinct changes with no associated coronary artery disease seen are cardiac catheterization. The exact cause remains unknown.
STATISTICS
Postmenopausal women are most at risk for this disease, despite having no previous cardiac history. Patients with this syndrome report a stressful life event occurring within hours of presentation. The prevalence of this syndrome is difficult to determine for several reasons. Stress cardiomyopathy is a relatively new area of interest, with only a small population identified. Japanese literature attributes this disease to as little as 1% of hospital admissions yearly.2 In the United States, Bybee and colleagues reported that stress-induced cardiomyopathy accounted for 2.2% of ST elevation AMIs during the 1-year study.3 Without a thorough history and physical examination, this diagnosis is easily confused with acute coronary syndrome (ACS).
REVIEW OF LITERATURE
Three studies published in the last 2 years in the United States show further evidence that there is, in fact, a link between a stressful event and the cardiac sequelae of events that follow. These research studies attempt to understand the etiology of this disease, which remains unknown to date. The presenting symptoms, diagnostic findings, complications, and treatments are similar among the studies and will be discussed in further detail later. However, each study proposes a different possible explanation to the cause. See Table 1 for a comparison of the current research studies.
 | TABLE 1 Comparison of Research Studies |
One study examined 22 female patients (aged 32-89y) over a 32-month period, who presented to the emergency department with substernal chest pain, ST-segment elevation, systolic dysfunction, absence of coronary artery narrowing, and no previous cardiac disease.2 Each patient experienced a stressful event immediately before the onset of symptoms. Nineteen of the patients experienced a psychological trigger such as a confrontation, an unexpected death of a loved one, or a devastating medical diagnosis. Three other patients experienced a physical stressor such as the exacerbation of a chronic pulmonary disease or seizure. Most patients presented with abrupt onset of severe substernal chest pain. Each patient received a 12-lead EKG, serum troponin, coronary arteriograph, left ventricular angiogram, echocardiogram, and cardiac magnetic resonance imaging (MRI). Most patients showed ST-segment elevation on EKG with T wave abnormalities. Troponin levels were mildly increased, ejection fraction was reduced, and distinct abnormalities were seen on echocardiogram. Patients were managed following the guidelines for ACS. All of the 22 patients survived and previous functional status was restored within 3 to 9 days. This study did not directly investigate the etiology behind this syndrome. However, the researchers proposed cathecholamine-induced cardiotoxicity and microvascular spasm as possible causes.
Wittstein and colleagues in 2005 studied 19 patients, mostly women (95%) with a median age of 63 years, with stress cardioymyopathy to demonstrate features that differentiate this from AMI and to determine its cause.1 News of an unexpected death was the precipitating factor in approximately 50% of the patients. All patients presented with severe chest pain and/or dyspnea within 1 to 5 hours of onset of symptoms. Cardiac catheterization in 95% of the patients revealed normal coronary arteries or only mild luminal narrowing. Several theories are proposed; their conclusions point toward an exaggerated sympathetic response with an increased release of cathecholamines as a probable cause.
Another study reviewed common characteristics and thrombolysis in myocardial infraction scores of 16 women aged 52 to 88 years with transient left ventricular apical ballooning syndrome.3 Abnormal thrombolysis in myocardial infraction scores (attributable to factors such as diabetes, previous cardiac disease, and/or stroke) suggested the impairment of coronary microcirculatory function may contribute to the root cause of this syndrome.
In addition to studies completed in the United States, Japanese researchers continue to investigate this mysterious syndrome to find the true cause. Kurisu and colleagues in 2002 compared this syndrome to an AMI.4 Thirty patients were studied (28 of which were women) with an age range of 55 to 83 years. Their proposition was that multivessel coronary spasm may contribute to the onset. All these studies have several concepts in common. They all acknowledge the link between an emotional stressor and an acute cardiac event. All studies recognize similar presenting symptoms and diagnostic criteria, which will be discussed further in detail. Each group of researchers is unsuccessful in finding a rationale behind this syndrome. Research to date is limited by small sample size (the largest study was 30 patients) and very few men were studied.
PRESENTATION
Patients with stress-induced cardiomyopathy have several common presenting signs and symptoms. The most frequent reason for which patients seek care is moderate to severe substernal chest pain.5 Other signs and symptoms include dyspnea, diaphoresis, nausea, and vomiting. Dyspnea due to pulmonary edema may lead to respiratory distress and the need for mechanical ventilation. Hemodynamic compromise can result in hypotension and eventually cardiogenic shock, requiring the use of an intraaortic balloon pump (4 out of 22 patients in 1 study).2 Syncope and cardiac arrhythmias are more rare presenting symptoms.
Electrocardiogram tracings show a distinct pattern. The most prominent feature initially seen is ST-segment elevation especially in the precordial leads, V3-V6.1-6 As the process continues, deep diffuse T wave inversion, marked prolongation of the QT interval, and new Q waves develop. These changes were sustained even after a complete resolution of the disease.1,4,6 A prolonged PR interval or new bundle branch block are seen less commonly than the above-mentioned changes.
When comparing the initial EKG seen in stress-induced cardiomyopathy and that seen in an AMI, it is hard to distinguish between the 2 based solely on these findings. The ST segment is elevated in both groups and returns to normal within 3 days of onset in stress-induced cardiomyopathy and shortly after reperfusion in an AMI. However, the T wave inversion is deeper and the QT interval is more prolonged in stress-induced cardiomyopathy at 3 days or later.7 The EKG would not be a useful tool early on to distinguish a definite diagnosis.
POSSIBLE CAUSES
The true cause of this phenomenon remains unknown. However, several studies have proposed certain mechanisms. Possibilities include the role of sex hormones, epicardial coronary arterial spasm, microvascular spasm/angina, cathecholamine-induced myocyte injury or vasoconstriction, and ruptured plaque.
Because most patients affected by this syndrome are women, one must question whether or not sex hormones play a role. Sex hormones play an important role in the sympathetic neurohormonal axis and coronary vasoreactivity. Women who have suffered a subarachnoid hemorrhage tend to be more susceptible to sympathetically mediated myocardial stunning and transient left ventricular dysfunction as evidenced by increased cathecholamine production.1 The same may be true in women suffering an emotional stressor.
Several studies suggest that epicardial coronary arterial spasm may be a potential cause for stress cardiomyopathy. Coronary artery spasm may be provoked by intracoronary infusion of acetylcholine.4 Coronary spasm resulted in a luminal narrowing, ST elevation on EKG, which improved after the infusion of nitroglycerin. The authors of this study believe that multivessel coronary spasm may contribute to left ventricular dysfunction. Increased sympathetic tone can cause vasoconstriction resulting in coronary spasm. Coronary artery vasospasm results in ischemia and should be treated with calcium channel blockers. Ischemia leads to alternations of fatty acid unitization, which normally contributes to 70% to 80% of the energy used by myocardial cells during aerobic conditions.9 Arterial spasm ultimately may lead to a stunned myocardium as a result of impaired microcirculation.
Another possible mechanism is microvascular angina/spasm or Syndrome X. This predominately occurs in women who have chest pain during exertion but no evidence of coronary artery disease. Increased sympathetic activity or estrogen deficiency may lead to inappropriate vasoconstriction of microvessels.10 This would result in angina symptoms and may be a possible cause of stress cardiomyopathy.
It has been demonstrated that cathecholamine levels increase dramatically during this syndrome. Several studies suggest that high concentrations of cathecholamines result in myocardial toxicity. Extreme levels of cathecholamines may induce coronary vasoconstriction resulting in hypoxia. This may explain why the left ventricular apex is affected predominantly because this is an area of distal coronary vascularization.11 Cathecholamines also can cause direct injury to the cardiac cells. Cathecholamines are a source of oxygen-derived free radicals, which interfere with sodium and calcium transporters. This results in direct myocyte injury, specifically contraction band necrosis, due to an influx in calcium.1 As a result of a stressful situation, the body releases increased levels of cathecholamines, which are responsible for the "flight or fight" response of the sympathetic nervous system. Cardiac dysfunction would result in the case of excessive cathecholamine release.12 In essence, too much stimulation of the sympathetic nervous system results in a drastic release of cathecholamines, leading to a stunned myocardium.
One final possible explanation is the presence of plaque that ruptures causing a brief interruption of coronary blood supply. This is seen in ACS. It is proposed that the left anterior descending artery alone could supply the akinetic areas of the left ventricle. Using intravascular ultrasound, the researchers were able to find a single ruptured plaque in the left anterior descending artery without any other atherosclerotic disease in the 5 patients studied.13
All of the above hypotheses represent potential causes of stress-induced cardiomyopathy. Similar characteristics have been seen in patients suffering a subarachnoid hemorrhage who have no evidence of coronary artery disease.14 This emphasizes the role of the central nervous system. Only additional research may produce the ultimate answer.
DIAGNOSIS
In addition to the EKG, which has not been shown to be helpful in diagnosing stress-induced cardiomyopathy, there are several diagnostic tests that can be performed that will yield a more definitive diagnosis. These tests include a measurement of cathecholamine and cardiac enzyme levels, cardiac MRI, cardiac catheterization, echocardiography, and myocardial biopsy. Table 2 gives a quick summary of the diagnostic findings and comparison.
 | TABLE 2 Comparison of Stress-induced Cardiomyopathy and Acute Myocardial Infarction |
Plasma levels of catecholamines (specifically epinephrine and norepinephrine) and cardiac enzymes will yield important data in differentiating stress-induced cardiomyopathy and AMI. Catecholamine levels are typically 2 to 3 times higher in patients with stress cardiomyopathy than those with an AMI and 7 to 34 times higher than normal.1 As the disease progresses, these values decrease significantly in both groups but still remain considerably higher in stress cardiomyopathy.
Cardiac enzymes (troponin, creatine kinase, and creatine kinase MB) can be elevated in both stress cardiomyopathy and AMI. However, patients with an AMI will have dramatically increased cardiac enzymes. In stress cardiomyopathy, the enzymes will elevate minimally and peak concentration will be near the initial values.3 In some cases, there is no rise in cardiac enzyme levels.2 Patients diagnosed with an AMI typically show a progressive rise and fall in cardiac enzymes over several hours to days. Cardiac enzyme and cathecholamine levels may be helpful in discriminating between AMI and stress cardiomyopathy; however, the significant differences may not be seen for several days up to a week as the levels rise and fall.
An echocardiogram is a noninvasive painless procedure that may yield some of the most significant findings. Stress cardiomyopathy results in very distinct changes that can be seen on echocardiogram. Stress cardiomyopathy is characterized by systolic dysfunction resulting in akinesia/hypokinesia of the mid and distal left ventricle and a compensatory hypercontractile proximal portion.2 Another finding on echocardiogram is a notably reduced ejection fraction. An initial ejection fraction may be as low as 20%.1 This will, however, rapidly return to near normal levels as this syndrome resolves, usually within 3 to 7 days. In the setting of an AMI, an echocardiogram may show nonspecific regional motion wall abnormalities.8 It would be more useful in excluding the diagnosis of AMI and ruling in a diagnosis of pericarditis, aortic dissection, or pericardial effusion. Echocardiogram is a fast, easy test that will exhibit a true variation from the patient with an AMI.
An MRI is not ordered as a routine test in a patient presenting with ACS. However, it may aid in confirming the diagnosis of stress cardiomyopathy versus AMI. The MRI will confirm the degree and pattern of left ventricular dysfunction.1 With the use of gadolinium contrast enhanced images, additional data can be revealed. A patient with AMI will have delayed gadolinium hyperenhancement, which indicates necrosis, infarction, and decreased viability.1 In comparison, in a patient with stress cardiomyopathy, findings will be consistent with viable myocardium.2 These findings consist of regions that will appear dark and hypoenhanced. Again, this is a relatively easy noninvasive test that will generate important findings. Contraindications (such as a pacemaker) may prevent this test from being completed.
Two additional options, a cardiac catheterization and a cardiac biopsy, are much more invasive. Percutaneous coronary intervention should be performed in all patients with ST-elevation AMI, unless otherwise contraindicated.15 Despite ST elevations on EKG and rise in cardiac enzymes, 2 findings that may miss lead to a diagnosis of AMI, patients with stress cardiomyopathy have normal coronary arteries, without coronary disease, or mild nonobstructive coronary disease.1,6 Patients with any degree of coronary artery disease have less than 50% luminal narrowing.3 In contrast, a patient with an AMI would show significant luminal narrowing and plaque formation.
If a myocardial infarction has been ruled out and the diagnosis still remains unclear, there are several other tests that can be performed to assess for other diagnoses. An endomyocardial biopsy may reveal mild interstitial mononuclear cell infiltrations or slight increase of loose connective tissue.4,10 These findings would be more pronounced with myocarditis, and the patient would usually have a history of a recent upper respiratory infection and fever. This test is not done routinely and would not provide significant results unless myocarditis was suspected.
Several other noninvasive tests can be done to further differentiate a diagnosis if necessary. Serum virus titers for coxsackievirus, cytomegalovirus, influenza, mumps, rubella, adenovirus, and echovirus will not be elevated in stress cardiomyopathy.4 Any elevation could lead to a higher index of suspicion for myocarditis. A chest x-ray may show interstitial pulmonary edema, which may not be present in an AMI unless the AMI results in heart failure.16 Finally, the most important piece of data may come from the patient's history. Any history of an intense emotional or physical stressor occurring within minutes to hours that same day should raise a red flag. Possible stressors include arguments, news of an unexpected death, a catastrophic medical diagnosis, financial losses, fear of medical procedures, or domestic abuse. A thorough history is needed to elicit the circumstances occurring before the onset of signs and symptoms.
Although no formal diagnostic criteria have been developed, Bybee and colleagues in 2003 proposed an algorithm. This algorithm includes 4 criteria, all of which must be met. They include (1) transient akinesis or dyskinesis of the left ventricular apical and mid ventricular segments; (2) absence of obstructive coronary artery disease; (3) new EKG changes, ST elevation, or T wave inversions; and (4)absence of head trauma or bleed, obstructive epicardial coronary artery disease, myocarditis, and hypertrophic cardiomyopathy.6 Patients with subarachnoid hemorrhage may also show regional contractile abnormalities, so this must be ruled out as a cause.14
TREATMENT AND CONTROL
Once the patient is diagnosed with stress cardiomyopathy, management follows guidelines established for ACS and standard supportive care for heart failure. Medical management includes the use of beta-blockers, angiotensin-converting enzyme inhibitors, aspirin, nitrates, and, if needed, intravenous diuretics. Short-term anticoagulation to prevent left ventricular thrombus formation may be added.6 The use of vasopressors is controversial. One study used vasopressors in patients with hypotension to maintain cardiac output, whereas another study recommended against using these agents because of the increased amount of circulating cathecholamines.1,2 Intravenous fluids may be used to maintain systemic blood pressure in the absence of pulmonary edema. In the cases of severe respiratory distress and pulmonary edema, mechanical ventilation may be needed. For severe hemodynamic compromise, an intraaortic balloon counterpulsation may be beneficial when vasopressors or fluid resuscitation is contraindicated.5 Patients who receive medical treatment usually respond well and have rapid clinical improvement. Therapy should continue until left ventricular function improves.6 Specific guidelines regulating the treatment of stress cardiomyopathy have not been developed; current care is directed toward supporting the patient through the acute phase.
THE ROAD TO RECOVERY
Despite the initial severity of this disease, the overall prognosis is very good. Rapid improvement is seen on echocardiogram with ejection fraction doubling within 3 to 7 days.1 At 1-month follow up, complete resolution of regional systolic dysfunction may be seen.17 Functional status is restored to pre-event levels. Hemodynamics are restored and vasoactive medications weaned typically in less than 48 hours.11 Clinical improvement often is seen within days. Complications are rare but can be serious. These complications result from dyskinesis of the apical and mid ventricular segments and hyperdynamic basal segments.6 This, along with a reduced ejection fraction, leads to ineffective left ventricular pumping. Left-sided heart failure with pulmonary edema may result. Transient conduction abnormalities such as heart block and atrial fibrillation, along with ventricular dysrhythmias (ventricular tachycardia and ventricular fibrillation), may also be seen.2,6 Other possible complications are listed in Table 3.
 | TABLE 3 Possible Complications of Stress-induced Cardiomyopathy |
Patients with stress cardiomyopathy follow a similar recovery to patients who suffer an AMI and are usually discharged within a week. Patients are continued on an aspirin, beta-blocker, angiotensin-converting enzyme inhibitor, and a statin for cholesterol control.2,17 Long-term prognosis is favorable. In one study after 4 years, all patients were still alive and none had had a recurrence or decline in left ventricular function.1 Recurrence is rare but does occur despite ongoing medical treatment. In these rare occasions, the patients survived the second illness as well (2 patients in study of 22 patients).2 In both cases, the relapse was triggered by an emotional stressor. Patients are able to regain normal activity levels by the time of discharge and continue at home usually without discomfort. Counseling may be indicated for those patients who are depressed or anxious. Stress management is essential. Death is extremely rare but has been documented as a result of stress cardiomyopathy with in hospital mortality ranging from 0 to 8%.6 Overall, patients with this syndrome have an excellent opportunity to recover without any adverse effects. The use of cardiac rehabilitation and frequency of follow-up is unknown.
This newly recognized cardiomyopathy is most likely underdiagnosed. It can be easily misinterpreted as an AMI. Although presenting signs and symptoms seem similar, further diagnostics can readily distinguish between the 2. Current research studies have discovered the findings consistent with stress cardiomyopathy and appropriate treatment for a favorable outcome. However, the root cause of this syndrome remains undetermined. Most recent studies have provided important data. However, these studies are small; most with populations of 20 to 30 subjects. This disease is relatively rare, and studies with larger numbers may be difficult. However, with better documentation and increased awareness, more cases may be uncovered.
Healthcare providers need first to be familiar with this syndrome in order to recognize it. Once more cases are documented, larger studies may take place, so the cause may be found and possibly prevented. Further research also could lead to the development of standardized diagnosis and treatment criteria. In addition, there is no research stating how long these patients need to remain on medications after resolution. Follow-up at 1 to 3 years in one study showed that the patients were still receiving medications such as an aspirin, statin, beta-blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor, or a combination.2 However, most studies do not mention long-term follow-up and there is no standard of care regarding long-term prevention. More studies are needed to further investigate this.
This newly introduced phenomenon leaves a lot for the medical world to investigate. A detailed history from the patient may prove to be the most important piece of information. Any patient who presents with new onset chest pain and reports an extreme stressor in the hours preceding their symptoms should be considered for stress-induced cardiomyopathy.
References
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