Epidemiology
Stress cardiomyopathy is still rarely diagnosed. Over the last few years, however, the number of published reports of patients presenting with this syndrome has steadily increased. Serial case studies coming from Japan reveal a prevalence of 1.2-2.0% among patients with acute coronary syndrome. [26] In a recent US study, stress cardiomyopathy was diagnosed in about 2.2% of patients admitted with suspected acute coronary syndrome. A German series reported an incidence of 0.1-2.3%; a study from France investigating this syndrome in a large urban population showed a prevalence of 0.9% and, the incidence of stress cardiomyopathy in an Italian investigation was 2%. [27-31] It is likely that prior to our current understanding, these patients were diagnosed as ‘acute myocardial infarction with normal coronaries’ secondary to coronary arterial spasm.
Classification
1. Stress cardiomyopathy can involve any segment of the left ventricular wall. There are now four different types, based on anatomic location, described in the literature. [32]
2. Classic type, which is the most commonly reported, is described as apical ballooning or Tako-tsubo type.
3. The second type is the reverse type; with hyperdynamic apex and akinesia of the base of the left ventricular wall (reverse Takotsubo or reverse apical ballooning type). This type is rarely described in the literature. [7,33-36]
4. The third type involves the mid left ventricular wall, sparing the base and the apex. It is called the "mid ventricular type."[9,11,37]
5. The fourth type is localized wall motion abnormality affecting a segment of the left ventricular wall, usually the anterior wall. [10,12,14,34,38]
Theories behind Stress Cardiomyopathy
Several mechanisms have been proposed for stress cardiomyopathy
Epicardial Coronary Vasospasm
In all documented patients presenting with stress cardiomyopathy, relevant coronary artery obstruction has been excluded and coronary vasospasm is unlikely since the region of wall motion abnormalities does not correspond to the perfusion territory of a single coronary artery. Many studies have evaluated the presence of either spontaneous or provoked multivessel epicardial spasm during angiography. In a systematic review only a few patients experienced spontaneous multivessel epicardial spasm (1.4%). Using provocative tests such as infusion of ergonovine or acetylcholine, nearly 28% experienced multivessel spasm. However, results varied widely in different series. Taken together, epicardial vasospasm seems to be an unlikely mechanism as a cause of stress cardiomyopathy but may account for a few cases of elevated cardiac enzymes with normal coronary arteries. [39]
Microvascular Dysfunction
Investigators have reported that patients with stress cardiomyopathy have impaired coronary microcirculation since, using a Doppler guide wire, diminished coronary flow reserve (CFR) was observed. [40] These results were confirmed by other groups suggesting that microvascular dysfunction contributes substantially to the development of this syndrome. Recently, reduced coronary flow velocity in the absence of coronary artery stenosis was noted immediately after the onset of stress cardiomyopathy. Additionally, myocardial contrast echocardiographic studies revealed perfusion defects in the left ventricular apex which normalize after a follow up of 4 weeks, suggesting that microvascular dysfunction might have been responsible for the reversible contractile impairment. [4] However, it is unclear whether coronary microvascular dysfunction is the primary mechanism involved in the pathogenesis of the syndrome or whether it is simply an associated secondary phenomenon. Furthermore, the underlying cause of the potential microvascular dysfunction is unknown.
Catecholamine Induced Myocyte Injury
The most widely proposed hypothesis for stress cardiomyopathy relates to the role of stress. In the majority of cases, triggering conditions that preceded onset were said to involve exposure to endogenous (emotional) or exogenous stresses (trauma, surgical procedure, exacerbation of a pre-existing condition). This suggests that increased sympathetic activity plays a major role in the origin of this syndrome. One group of investigators described notably elevated norepinephrine concentrations in patients with stress cardiomyopathy. [41] This was confirmed by others who demonstrated significantly increased catecholamine concentrations in comparison to patients with Killip class III myocardial infarction. Increased serum concentrations of catecholamines have been shown to generate direct myocyte injury. Oxidation of catecholamines results in the formation of highly toxic substances and free radicals causing intracellular calcium overload and myocardial cell damage. The typical histological signs of catecholamine toxicity, described as focal, mononuclear, inflammatory areas of fibrotic response and characteristic contraction bands, are also reported to be present in patients with stress cardiomyopthy. [5,42] Contraction bands have been reported in several clinical settings of extensive catecholamine production such as phaeochromocytoma or subarachnoid haemorrhage, showing that catecholamines may be an important link between emotional stress and cardiac injury. [5] The distinctive contractile pattern of stress cardiomyopathy may be explained by an enhanced responsiveness of apical myocardium to sympathetic stimulation. Alternatively, a base-to-apex perfusion gradient could result in regional differences in myocardial blood flow in the setting of catecholamine-mediated epicardial or microvascular vasoconstriction. [5] Interestingly, the wall motion abnormalities observed in stress cardiomyopathy are not the same as those found with subarachnoid haemorrhage or intracranial haemorrhage, in which only the basal segments of the left ventricle are affected. [43]
Obstruction of Left Ventricular Outflow Tract
Left ventricular outflow tract (LVOT) obstruction was observed in a report of three patients with tako-tsubo cardiomyopathy. [44] Other groups confirmed these abnormal findings, especially in women in the presence of abnormal myocardial functional architecture, such as localized mid-ventricular septal thickening. [3] It was hypothesized that in the presence of increased concentrations of catecholamines caused by emotional stress, this mid-ventricular septal thickening could lead to the development of severe transient left ventricular mid-cavity obstruction, resulting in subendocardial ischaemia unrelated to a specific coronary artery territory. However, it remains unclear whether the observed intraventricular gradient is a consequence rather than a cause of stress cardiomyopathy.
Diagnosis
The diagnosis of stress-induced stress cardiomyopathy is based on the following criteria:
(a) Transient akinesis or dyskinesis of the left ventricular wall (ballooning) seen on echocardiography (or any other imaging modality) accompanied by chest discomfort; commonly, but not universally, apically located;
(b) New electrocardiographic changes (either ST elevation or T wave inversion);
(c) No significant obstructive epicardial coronary artery disease;
(d) Absence of recent significant head trauma, phaeochromocytoma, myocarditis or hypertrophic cardiomyopathy.
Stress cardiomyopathy can present with the following changes on the ECG (Table 3)
• Diffuse symmetric T-wave inversion
• Pronounced prolongation of the QT interval
• Loss of R wave progression
• Prolonged PR interval
• Pathologic Q waves in leads V1, V2, V3 and aVL
Table 3. ECG findings & cardiac markers
|
Characteristics ST Elevation |
(%) (N ) 87.5 (136) |
|
T wave inversion |
75 (104) |
|
Q Waves |
50 (22) |
|
Positive cardiac markers |
85.5 (117) |
N = number of cases data was reported
Echocardiography findings in stress cardiomyoapthy are as follows:
• Transient, regional akinesis or dyskinesis, usually involving the entire LV (and RV) apex;
• A unique variant is "reverse stress cardiomyopthy" in which the apex is spared and only the basal portion of the LV myocardium is dysfunctional;
• Regardless of the location of regional dysfunction, the most important echo feature to distinguish this disease from an acute MI is a regional wall motion abnormality in multiple coronary artery territories rather than a single coronary artery zone, as well as involvement of the adjacent RV wall;
• Reduced left ( and often right) ventricular ejection fraction and systolic dysfunction;
• Apical- ‘ballooning’ with abnormal wall motion of the mid and distal ( and/or mid) left ventricle;
• Restoration of normal global and regional myocardial function with serial exams over time.
Electrocardiography
ST elevation (<2 mm) or T wave inversion in the anterior leads (V1-V6) have been the most commonly recorded findings mimicking acute MI. [5] In comparison to patients with anterior infarct, these ST elevations are less prominent. Electrocardiographic changes may be present for several hours followed by normalization and development of T wave inversion. Furthermore, in several cases transient prolongation of the QT interval was observed with a subsequent normalization within some weeks. [2] Even though QT interval prolongation is present in stress cardiomyopathy, rate adaptation of ventricular repolarization is not significantly altered in comparison to acute ST elevation myocardial infarction, suggesting a different effect of autonomic nervous activity on the ventricular myocardium. [45]
Laboratory Investigation
Blood values of myocardial creatine kinase (CK), CK-MB, and troponin are often only slightly elevated. There are also reports of increased concentrations of B-type natriuretic peptide (BNP) in stress cardiomyopathy patients. [46] Recently, serum concentrations of the N-terminal fragment of BNP (NT-proBNP) were shown to be a valuable marker for assessment of myocardial deterioration and recovery. [47] Moreover, low NT-proBNP values on admission were shown to be a reliable indicator of a favorable prognosis for patients presenting with stress cardiomyopathy.
Echocardiography
In the apical four-chamber view, typical akinesia of the left ventricular apex and/or the mid-portion of the left ventricle as well as a hypercontractile base are typically found. Interestingly, the wall motion abnormalities exceed the area assigned to one coronary vessel. In a few cases, LVOT obstruction with an end-systolic pressure gradient of up to 60 mm Hg was observed. [3] After normalization of myocardial function the pressure gradient disappeared. These findings of mid-cavity dynamic obstruction in the acute phase of stress cardiomyopathy correlate with localized mid-ventricular septal thickening when cardiac function returns to normal. Stress cardiomyopathy, can be reasonably suspected using careful evaluation of the initial echocardiography examination in conjunction with ECG, laboratory, and clinical data. Wall motion analysis should reveal an apical ballooning appearance involving many coronary territories with mild elevation of cardiac enzyme levels or ECG changes. Furthermore, the additional presence of right ventricular apical akinesia during echocardiography examination makes the diagnosis of this syndrome very likely. [8]
Coronary Angiography and Ventriculography
In all reported cases of stress cardiomyopathy, coronary angiography excluded relevant coronary artery obstruction in patients presenting with stress cardiomyopathy. Ventriculography usually displays typical apical ballooning and hypercontraction of the basal segments. In some cases, mid-ventricular ballooning sparing the basal and apical segments can be present. [9]
Cardiovascular Magnetic Resonance Imaging
Cardiovascular MRI provides morphologic and precise functional information of the left ventricle. More recently published data also documented regional wall motion abnormalities of the right ventricle in the acute phase of this syndrome.[48] Sporadically, focal signal increases in different left ventricular segments was detectable in the T2-weighted turbo-spin echo sequences, indicating myocardial edema. First-pass perfusion imaging did not show any evidence of focal perfusion abnormalities, corresponding to a specific vascular territory. So far, in all cases, the observed endocardial delayed hyperenhancement was small in comparison to the extent of the wall motion abnormalities.[49,50] In view of the fact that in myocarditis areas of hyperenhancement originate from the epicardium, late MRI enhancement sequences can assist in the differential diagnosis of stress cardiomyopathy.
Myocardial Single Photon Emission Computed Tomography
Several reports describe thallium-201 (201Tl) perfusion patterns with a perfusion defect in the apical LV region in the acute phase of stress cardiomyopathy despite normal coronary arteries. [51] These defects decrease with recovery. Investigators have reported a diminished accumulation of iodine-123 [123] metaiodobenzylguanidine (MIBG) in the hypokinetic region. [46] Investigators have also demonstrated impaired myocardial fatty acid metabolism rather than disturbed myocardial perfusion during the early phase.[52] In stress cardiomyopathy, technetium-99 m (99mTc)-tetrofosmin myocardial single photon emission computed tomography (SPECT) showed that myocardial perfusion in the apical region was impaired immediately after hospitalization with recovery after 3-5 days. [53]
Myocardial Biopsy
Several groups have investigated endomyocardial biopsies from both the right and left ventricle, revealing myocyte injury and a slight increase in connective tissue. From a systematic analysis it is known that stress cardiomyopathy is accompanied by severe cellular morphological alterations, with many vacuoles of different sizes contributing to cellular deterioration. The content of myocardial contractile material is reduced and detected in the border area of the cells. Contraction bands are sporadically present. Clusters of mitochondria with abnormalities in size and shape can be observed. The myocyte nuclei typically appear rounded or oval either in the middle or in the border area of the cells. Cell swelling associated with damage to the basal lamina or damaged mitochondria with flocculent densities are typical signs of oncotic cell death and are absent. Additionally, apoptotic and autophagic cell death can be excluded by electron microscopy and immunohistochemistry. Moreover, the interstitial space is widened and contains fibrotic material, including collagen fibrils, formations of cell debris, macrophages, and an increased number of fibroblasts. Most noteworthy, these alterations are transient and almost completely reversible after functional recovery. [42]
Management
The management of stress cardiomyopathy consists of supportive and symptomatic treatment. Initially patients are managed as if they had a myocardial infarction, including urgent coronary angiography with a view to performing a primary coronary intervention.
These patients should be treated with aspirin, low molecular weight heparin, and angiotensin-converting enzyme (ACE) inhibitors; B-blockers and diuretics may also be administered. Beyond the standard care for congestive heart failure with diuretics and vasodilators, the treatment of stress cardiomyopathy largely remains unclear and involves only symptomatic management. With good initial medical support, patients with stress cardiomyopathy show good clinical and echocardiographic improvement in left ventricular function. [54] These patients also have an excellent short and long-term prognosis. Complications, such as cardiogenic shock, pulmonary edema or malignant arrhythmias, should be treated according to the usual management strategies (Table 4). However, the overall prognosis of patients presenting with this syndrome is favorable; the reported in-hospital mortality rates range from 0-8%. [55] Vasoactive agents should be used very carefully since they may further worsen the delicate situation. In cases of severe circulatory dysfunction, intra-aortic balloon counterpulsation should be considered. In a stable clinical setting, administration of anxiolytic agents is preferred. Data from an animal model of stress cardiomyopathy suggest that its development seems to be diminished after a- and B-blockade.[56] Thus, B-blockers should be given in the acute and chronic phases and may possibly help to prevent recurrences, which have been described as occurring in 2.7-8% of patients.[39] In order to prevent acute left ventricular thrombus formation, which has been observed in patients presenting with TTC, the administration of low molecular weight heparin is warranted. After restitution of contractile function, further anticoagulation with warfarin is not required. In the event of life threatening arrhythmias such as torsade de pointes tachycardia and ventricular fibrillation, the implantation of a cardioverter-defibrillator has to be considered.
Table 4. Complications and outcome
|
Complication Total patients with a complication |
N(%) 35 (18.9) |
|
Shock |
12 (6.5) |
|
Thrombus |
7 (3.8) |
|
CHF |
7 (3.8) |
|
CVA |
3 (1.6) |
|
Ventricular tachycardia |
3 (1.6) |
|
Atrial fibrillation |
2 (1.1) |
|
LV rupture |
1 (0.5) |
|
Pneumothorax |
1 (0.5) |
|
Ventricular fibrillation |
1 (0.5) |
|
Ventricular septal defect |
1 (0.5) |
|
Death |
6 (3.2) |
Prognosis
Almost all patients with stress cardiomyopathy with left ventricular impairment demonstrate normal function within a few weeks. There is no data on frequency of patients with residual long term left ventricular impairment.[54] Rarely, this syndrome can be complicated by left ventricular rupture, thus making stress cardiomyopathy a newly recognized cause of sudden death in up to 3% of patients.[13] However, the overall prognosis of patients presenting with this syndrome is favorable; the reported in-hospital mortality rates range from 0-8%. [55] In the majority of patients, left ventricular function returns to normal in 6±3 days. This syndrome may recur in up to 10% of patients, making it difficult to know how long to continue medical treatment.
Sex-Related Differences
In a study of transient left ventricular apical ballooning involving 185 cases, it was confirmed that most cases involved older women. [13] Many unanswered questions regarding stress cardiomyopathy remain. Among these the most puzzling one is the apparent increased incidence in females, who comprise over 90% of reported cases. Sex-related differences in the response of the adrenal medulla to sudden high-intensity sympathetic discharge and differing pharmacokinetics of epinephrine release could explain the increased rate in women. Of interest, basal plasma epinephrine levels are lower in women than in men.[6] This difference could reflect reduced synthesis, increased degradation or reduced basal release with more potential stores for sudden release. Estrogen has cardioprotective effects against acute injury through a variety of complex mechanisms.[57,58] Stress activates early gene expression in both the central nervous system and the ventricular myocardium in rodent models,56 the myocardial changes in gene expression being mediated by activation of both ct-adrenoceptors and P-adrenoceptors. Estrogen reduces these changes in gene expression, protecting against the apical ventricular dysfunction observed in this rodent model of stress cardiomyopathy (conscious immobilization).[56] Chronic (but not acute) exposure of the rat ventricular myocardium to estrogen reduces the catecholamine and ischemia/reperfusion enhanced expression of Pi adrenoceptors. [59] Oophorectomy increases the expression of Pi adrenoceptors, an effect that is reversed by estrogen supplementation. [60] Beyond the myocardium, greater vascular P2 adrenoceptor-mediated sensitivity has been demonstrated in women than in men. [61] Estrogens could, therefore, influence the Pi adrenoceptor: P2 adrenoceptor signaling ratio in women in favor of the protective effects of P2 adrenoceptors-Gi protein signaling following surges in catecholamine levels. This protection would occur at the mechanical cost of negative inotropism in regions with the highest density of P-adrenoceptors, namely the apical myocardium. Recently, Ueyama et al [56] suggested that estrogen supplementation partially prevents emotional stress-induced cardiovascular responses, both by an indirect action on the nervous system and by direct action on the heart. Thus, a reduction in estrogen levels following menopause might augment vascular reactivity to stress resulting in a high incidence of stress cardiomyopathy in post-menopausal women.
