Cellular and Molecular Neurobiology

, Volume 32, Issue 5, pp 847–857

Stress Cardiomyopathy: A Syndrome of Catecholamine-Mediated Myocardial Stunning?


    • Division of Cardiology, Department of MedicineJohns Hopkins University School of Medicine
Original Paper

DOI: 10.1007/s10571-012-9804-8

Cite this article as:
Wittstein, I.S. Cell Mol Neurobiol (2012) 32: 847. doi:10.1007/s10571-012-9804-8


During the past few years, a novel syndrome of heart failure and transient left ventricular systolic dysfunction precipitated by acute emotional or physical stress has been described. While patients with “stress cardiomyopathy” (SCM) typically present with signs and symptoms that resemble an acute coronary syndrome, it has become clear that this syndrome has unique clinical features that can readily be distinguished from acute infarction. In particular, in contrast to the irreversible myocardial injury seen with infarction, the myocardial dysfunction of SCM is completely reversible and occurs in the absence of plaque rupture and coronary thrombosis. There is increasing evidence that exaggerated sympathetic stimulation may play a pathogenic role in the development of SCM. Plasma catecholamine levels have been found to be markedly elevated in some patients with SCM, and the syndrome has been observed in other clinical states of catecholamine excess such as central neurologic injury and pheochromocytoma. Further, intravenous catecholamines can precipitate SCM in humans and can reproduce the syndrome in animal models. The precise mechanism in which excessive sympathetic stimulation may result in transient left ventricular dysfunction remains controversial. Abnormal myocardial blood flow due to sympathetically mediated microvascular dysfunction has been suggested and is supported by decreased coronary flow reserve during the acute phase of this syndrome. An alternative explanation is the direct effect of catecholamines on cardiac myocytes, possibly through cyclic AMP-mediated calcium overload. This manuscript will review the clinical and diagnostic features of SCM and will summarize the evidence supporting a sympathetically mediated pathogenesis. Clinical risk factors that appear to increase susceptibility to SCM, possibly by modulating myocyte and microvascular sensitivity to catecholamines, will also be highlighted.


Stress cardiomyopathyTakotsubo cardiomyopathyApical ballooningCatecholaminesMyocardial stunning


Human beings have always had an intuitive understanding of the close relationship between their emotions and their hearts, and there is now considerable epidemiologic evidence in the modern era supporting the association of acute emotional stress with cardiovascular morbidity and mortality. Large population-based studies have demonstrated increases in sudden death and myocardial infarction following emotionally traumatic events such as earthquakes (Leor et al. 1996), acts of terrorism (Meisel et al. 1991), and even sporting events (Wilbert-Lampen et al. 2008). Well-designed case-crossover studies have shown that acute emotional triggers such as anger more than double the risk of myocardial infarction (Mittleman et al. 1995). There is considerable evidence to suggest that enhanced sympathetic stimulation resulting from these acute emotional triggers can precipitate myocardial infarction and sudden death through a variety of pathophysiologic mechanisms that include coronary vasoconstriction (Yeung et al. 1991), acute plaque rupture (Burke et al. 1999), and electrical instability (Steinberg et al. 2004). Until recently, however, there has been little evidence to support a direct relationship between acute emotional stress and cardiac contractile function.

During the past few years, a novel syndrome of heart failure and transient left ventricular systolic dysfunction precipitated by acute emotional or physical stress has been described. While patients with “stress cardiomyopathy” (SCM) typically present with electrocardiographic (ECG) abnormalities, elevated cardiac enzymes, and cardiac contractile dysfunction, it has become clear that this syndrome has unique clinical features that can readily be distinguished from those of an acute myocardial infarction. In particular, in contrast to the irreversible myocardial injury seen with infarction, the myocardial dysfunction of SCM is transient and completely reversible and occurs in the absence of coronary thrombosis. While the precise mechanism of SCM remains unknown, there is increasing evidence that the “stunned” myocardium characteristic of this unique disorder may be sympathetically mediated. This article will review the clinical features and diagnostic criteria of SCM, and evidence from both human studies and animal models supporting the role of the sympathetic nervous system in the pathogenesis of this disorder will be highlighted. Clinical risk factors that may influence the cardiovascular response to sympathetic stimulation and thus increase individual susceptibility to SCM will also be discussed.


Stress cardiomyopathy is referred to by a variety of names in the medical literature. The syndrome was originally described by Satoh and colleagues in Japan in 1990 and was called takotsubo cardiomyopathy (Satoh et al. 1990), named after the octopus trapping pot with a wide base and narrow neck that they felt resembled the morphologic appearance of the left ventricle in patients with this condition. For the next decade, reports of takotsubo cardiomyopathy appeared exclusively in Japanese medical journals. When Japanese authors finally published their experience with this syndrome in an American medical journal in 2001 (Tsuchihashi et al. 2001), they chose the name transient left ventricular apical ballooning syndrome, a descriptive term they likely felt would be more acceptable to a Western audience. In 2005, SCM received worldwide attention when our group at Johns Hopkins and a second group from the Minneapolis Heart Institute reported the clinical and neurohumoral features of the syndrome in two separate major medical journals (Wittstein et al. 2005; Sharkey et al. 2005). The term stress cardiomyopathy was formally introduced, and the nickname broken heart syndrome was quickly popularized by the media (Wittstein et al. 2005). A year later in 2006, the American Heart Association officially classified SCM as an acquired type of cardiomyopathy.

There is considerable debate regarding the ideal nomenclature for the syndrome. We prefer the name stress cardiomyopathy because it emphasizes the importance of acute stress, whether emotional or physiologic, in the pathogenesis of this disorder. Further, it is now clear that the left ventricle in some patients with SCM can assume morphologic appearances that spare the apex (Hurst et al. 2006; Reuss et al. 2007), making the names takotsubo and transient left ventricular apical ballooning syndrome both confusing and somewhat inaccurate for these subgroups. Until a clear and consistent nomenclature is agreed upon, physicians should be aware that all four names are used interchangeably in the literature to refer to the same clinical condition.


While SCM was considered to be an extremely rare condition just a few years ago, it has become clear from the rapidly expanding medical literature that the syndrome is far more prevalent than what was originally believed. Retrospective series from countries worldwide have demonstrated that SCM accounts for approximately 2% of patients with a suspected acute coronary syndrome (ACS) (Parodi et al. 2007; Eshtehardi et al. 2009). The prevalence is even higher in women presenting with suspected ACS, with rates ranging from 4.7 to 7.5% (Strunk et al. 2006; Wedekind et al. 2006). These series likely underestimate the true prevalence of the disorder, because they report only those patients undergoing coronary angiography and do not include patients in medical, surgical, and neurologic intensive care units where the syndrome is common but often unrecognized.

Patient Demographics and Clinical Presentation

Stress cardiomyopathy has been described in patients with diverse ethnic backgrounds from countries worldwide. A marked age and gender discrepancy has been reported in all of these series, with older post-menopausal women being most commonly affected. In a systematic review of 28 case series, 91% of the reported cases were women, the mean age ranged from 62 to 76 years, and coronary risk factors were common (Pilgrim and Wyss 2008). We have also noticed a racial discrepancy at our institution, with 77% of the patients in our series being Caucasian, 17% being African American, and 6% being from a variety of other ethnic backgrounds. Co-morbidities commonly observed in patients with SCM include thyroid disease, chronic obstructive pulmonary disease, and mood disorders such as anxiety and depression (Mudd et al. 2007; Regnante et al. 2009).

Patients with SCM can present with symptoms indistinguishable from those of an acute myocardial infarction, with chest pain and shortness of breath being the most common (Pilgrim and Wyss 2008). Heart failure and pulmonary edema occur frequently and have been described in 15.9% of the reported cases, with cardiogenic shock and life threatening arrhythmias occurring in 10.3 and 14.6% of the cases, respectively (Pilgrim and Wyss 2008). Cases of apical thrombus formation, cardioembolic stroke, left ventricular free wall rupture, and pericarditis have also been reported.

Diagnostic Criteria

While there are no uniformly accepted diagnostic criteria for SCM, guidelines have been proposed (Kawai et al. 2007; Novo et al. 2008). The most widely cited criteria were introduced by investigators from the Mayo Clinic in 2004 and were modified in 2008 (Prasad et al. 2008). We have used similar diagnostic criteria at our institution with some minor differences (Table 1). While not all of these criteria are uniformly agreed upon, it is our opinion that the following six criteria can be used to make the diagnosis of SCM and to distinguish the syndrome from acute myocardial infarction:
Table 1

Proposed criteria for the diagnosis of stress cardiomyopathy

Modified Mayo Clinic criteria (Prasad et al. 2008)

Johns Hopkins criteria

Transient hypokinesis, akinesis, or dyskinesis of the left ventricular mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; 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 cardiac troponin

Absence of: Pheochromocytoma and myocarditis

Helpful, but not mandatory, criteria

An acute identifiable trigger (either emotional or physical)

Characteristic ECG changes that may include some or all of the following:

 ST-segment elevation at time of admission (often ≤2 mm in magnitude, and usually not associated with reciprocal ST-segment depression)

 Diffuse deep T-wave inversion (may be present on admission or may evolve during the first several hospital days)

 QT interval prolongation (usually maximal by 24–48 h)

Mildly elevated cardiac troponin (often appears disproportionately low given the degree of wall motion abnormality)

Mandatory criteria (all three criteria must be met)

Absence of coronary thrombosis or angiographic evidence of acute plaque rupture

Regional ventricular wall motion abnormalities that extend beyond a single epicardial vascular distribution

Complete recovery of regional wall motion abnormalities (recovery is usually within days to weeks)

An acute trigger: SCM is precipitated by an acute emotional or physical trigger in the majority of cases reported. The most common emotional triggers appear to be grief, often due to the death of a loved one, or fear (e.g., robbed at gunpoint, motor vehicle accident). SCM can also be precipitated by a wide variety of physical stressors including respiratory emergencies (e.g., asthma exacerbation, airway compromise, pneumothorax), surgical procedures, metabolic insults (e.g., hypoglycemia), hemodynamic derangements (e.g., hypotensive gastrointestinal bleeding), and various neurologic insults that include subarachnoid hemorrhage (Otomo et al. 2006) and stroke (Yoshimura et al. 2008). The numerous potential triggers of this syndrome have recently been reported in a large single center series (Sharkey et al. 2010). It is important to remember, however, that an identifiable trigger is not required to make the diagnosis of SCM. In the largest series of SCM reported to date, a stressful precipitant could only be identified in 71% of the cases (Eitel et al. 2011).

Characteristic electrocardiographic features: No ECG findings are absolutely diagnostic of SCM, but certain characteristic findings should raise suspicion for the diagnosis. While the initial ECG of SCM can be nonspecific, up to 21−49% of patients will have ST-segment elevation at the time of presentation, typically in precordial leads (Sharkey et al. 2010). Compared to patients with anterior ST-segment elevation myocardial infarction (STEMI), patients with SCM tend to have a smaller magnitude of ST-segment elevation (Sharkey et al. 2008) and are less likely to have reciprocal inferior ST-segment depression (Ogura et al. 2003). Within 24−48 h of the initial presentation, patients with SCM typically develop marked QT interval prolongation and deep diffuse T-wave inversion in both precordial and limb leads (Wittstein et al. 2005). The T-wave inversion is more commonly observed in patients with apical ballooning than in those with mid-ventricular and basal variants (Hahn et al. 2007) and can take days, weeks, or even months to normalize. Patients with SCM can also present with pathologic Q-waves that are usually seen in precordial leads. These Q-waves are transient in most cases and typically resolve within days to weeks of the initial presentation (Wittstein et al. 2005).

Mild cardiac enzyme elevation: Despite having extensive ventricular wall motion abnormalities, most patients with SCM have only mildly elevated cardiac enzymes at the time of admission. These enzyme levels are significantly lower than those seen in patients with acute myocardial infarction (Parodi et al. 2007; Ogura et al. 2003). In addition, brain natriuretic peptide (BNP) levels in SCM are markedly elevated at the time of admission, but in contrast to acute myocardial infarction, these levels rapidly decline and do not appear to have prognostic importance (Wittstein et al. 2005).

Absence of coronary thrombosis or acute plaque rupture: SCM is characterized by the absence of thrombotic coronary disease. At the time of angiography, patients with SCM have either normal coronary arteries (Pilgrim and Wyss 2008) or non-obstructive coronary atherosclerosis (Hoyt et al. 2010). Because these patients typically present with chest pain, dynamic ECG changes, elevated cardiac enzymes, and focal wall motion abnormalities, coronary angiography should be performed to definitively exclude plaque rupture and coronary thrombosis unless there is an obvious contraindication.

Ventricular “ballooning”: The most defining characteristic of SCM is the unusual left ventricular contractile pattern typically seen with echocardiography or ventriculography at the time of presentation (Fig. 1). In contrast to acute infarction, the left ventricular wall motion abnormalities in SCM extend beyond a single coronary territory. The majority of patients have the well-described “apical ballooning” pattern in which there is akinesis or dense hypokinesis of the apical and midventricular segments with sparing of the base. More recently, variants of this syndrome have been reported in which the apex is not affected (Hurst et al. 2006; Reuss et al. 2007). Patients with “basal” and “midventricular” ballooning patterns tend to be younger and have less heart failure, but otherwise have many of the same clinical features as patients with apical involvement (Hahn et al. 2007). While SCM is characterized primarily by left ventricular dysfunction, approximately one-third of the patients will also have right ventricular involvement (Elesber et al. 2006).
Fig. 1

Left ventriculography during systole of the three different variants of stress cardiomyopathy. On the left is the “apical ballooning” variant with apical and mid-ventricular akinesis with sparing of the base. In the middle is the “mid-ventricular ballooning” variant with akinesis of the mid-ventricle but normal contractility of the apex and base. On the right is the “basal ballooning” pattern with basal and mid-ventricular akinesis and normal apical contractility. Reproduced with kind permission from Springer Science + Business Media (Wittstein 2008, Fig. 1)

Recovery of left ventricular function: Complete recovery of ventricular systolic function is one of the hallmarks of SCM. Despite extensive wall motion abnormalities at the time of initial presentation, follow-up assessment of ventricular function has demonstrated recovery in all series to date. Most patients demonstrate significant improvement in systolic function within a week of the initial presentation, and complete recovery is often observed by the end of the third week. Cases of very slow left ventricular recovery have been published, and some authors have reported a recovery period of up to 1 year (Sharkey et al. 2010). This tends to be the exception, however, and as a general rule, if systolic function in a patient suspected of having SCM has not completely normalized within 12 weeks, alternative diagnoses should be considered.


The treatment of SCM in the acute period is primarily supportive. Hemodynamically stable patients are frequently treated with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and beta blockers. Unless there is a clear contraindication, patients with apical akinesis should be anticoagulated until apical contractility improves in order to reduce the risk of thromboembolic events. For hemodynamically unstable patients, reported treatment has included inotropes, vasopressors, and intra-aortic balloon counterpulsation. There are also limited reports that patients with hypotension and left ventricular outflow tract (LVOT) obstruction may derive hemodynamic and echocardiographic benefit from the administration of intravenous beta blockade (Kyuma et al. 2002). Fortunately, even the most unstable patients typically demonstrate rapid clinical improvement and rarely require hemodynamic support for more than a few days.

There is no consensus regarding the long-term management of SCM. While it is reasonable to treat patients with beta blockers and ACE inhibitors during the period of ventricular recovery, there are currently no data to support that the chronic use of these agents prevents recurrence of SCM or improves survival. It has therefore become our practice to stop these medications once left ventricular function has normalized. Physicians should also be aware that some patients will continue to have episodic chest discomfort for weeks to months after the initial presentation. Nitrates and calcium channel blockers can be effective in relieving symptoms in these individuals.

Prognosis and Recurrence

Patients with SCM have a favorable prognosis and a relatively low risk of recurrence. They have a better long-term survival and fewer major adverse cardiac events compared to patients with acute myocardial infarction (Nunez-Gil et al. 2008). In a systematic review of 28 case series, the recurrence and in-hospital mortality rates of SCM were only 3.1 and 1.7%, respectively (Pilgrim and Wyss 2008). In a large single center retrospective experience from the Mayo Clinic, the recurrence rate of SCM was 11.4% during the 4 years following the initial presentation. Four-year survival was no different than that observed in an age and gender matched population (Elesber et al. 2007). In another large single center series, patients with SCM were found to have reduced survival compared to an age and sex-matched population, but most of the deaths occurred within the first year and were due to non-cardiac causes. The recurrence rate at 4 years in this series was only 5% (Sharkey et al. 2010).

Evidence Supporting the Role of the Sympathetic Nervous System in the Pathogenesis of SCM

While the clinical features of SCM have become increasingly well recognized over the past few years, the precise pathophysiologic mechanism of this disorder remains unknown. Considerable evidence suggests that enhanced sympathetic stimulation may be central to the pathogenesis of SCM:
  1. 1)

    Elevated plasma catecholamines: Patients with SCM due to emotional stress have been shown to have markedly elevated plasma catecholamine levels at the time of admission compared to patients with Killip III myocardial infarction (Wittstein et al. 2005). The marked elevation in dihydroxyphenylalanine, dihydroxyphenylglycol, and norepinephrine observed in these patients during the acute phase of the syndrome suggests enhanced catecholamine synthesis, neuronal reuptake and metabolism, and spillover, respectively. Elevated norepinephrine levels have also been demonstrated with coronary sinus sampling, suggesting increased local myocardial catecholamine release in patients with SCM (Kume et al. 2008).

  2. 2)

    Heart rate variability: Indices of heart rate variability have demonstrated sympathetic predominance and marked depression of cardiac parasympathetic activity during the acute phase of SCM (Ortak et al. 2009). Complete recovery of cardiac autonomic tone is observed within 3 months of the initial presentation.

  3. 3)

    Association of SCM with high catecholamine states: SCM has been associated with catecholamine secreting tumors such as pheochromocytoma and paraganglioma (Takizawa et al. 2007; Wittstein 2007). The syndrome is also commonly seen following various types of central neurologic injury such as subarachnoid hemorrhage and stroke (Otomo et al. 2006; Yoshimura et al. 2008), pathologic states known to be associated with enhanced sympathetic stimulation. Further, SCM has been precipitated in a variety of clinical situations by the intravenous administration of catecholamines and beta agonists (Abraham et al. 2009).

  4. 4)

    Nuclear imaging: Positron emission tomography (PET) imaging has been performed during the acute phase of SCM using the norepinephrine analog 11C hydroxyephedrine and has demonstrated increased sympathetic activity in the regions of ventricular akinesis (Prasad et al. 2009). Myocardial scintigraphy with the norepinephrine analog 123I-metaiodobenzyl-guanidine (MIBG) has also demonstrated decreased uptake in regions of contractile dysfunction with an increased washout rate on delayed imaging (Burgdorf et al. 2008). These findings suggest increased sympathetic stimulation of preganglionic neurons during the acute phase of the syndrome which typically recovers within 6 months of the initial presentation (Moriya et al. 2002).

  5. 5)

    Histopathology: Endomyocardial biopsy samples from patients with SCM have demonstrated contraction band necrosis (CBN) (Wittstein et al. 2005), a unique form of myocyte injury characterized by hypercontracted sarcomeres, dense eosinophilic transverse bands, and an interstitial mononuclear inflammatory response that is distinct from the polymorphonuclear inflammation seen with infarction. CBN has been observed in other states of catecholamine excess such as pheochromocytoma and subarachnoid hemorrhage. In patients who have died acutely following SCM, immunohistochemical studies have revealed intense expression of β1-adrenergic receptors in deep myocardial and subendocardial layers as well as in apoptotic cardiomyocytes, suggesting that enhanced sympathetic stimulation contributes to the myocardial injury seen in this condition (D’Errico et al. 2011).

  6. 6)

    Animal models: Left ventricular apical ballooning has been reproduced in rats subjected to immobilization stress, and this effect can be attenuated with adrenoceptor blockade (Ueyama et al. 2002). SCM has also been induced in monkeys with the infusion of intravenous epinephrine, resulting in increased myocytolysis in the apical portion of the ventricle (Izumi et al. 2009). Administration of the beta-blocker metoprolol decreases epinephrine-mediated myocytolysis and results in improvement in left ventricular ejection fraction.


Possible Pathophysiologic Mechanisms of Sympathetically Mediated Myocardial Dysfunction in Stress Cardiomyoapthy

Precisely how increased sympathetic activity results in transient myocardial dysfunction in SCM remains unknown. Several pathophysiologic mechanisms have been proposed (Fig. 2), and the clinical evidence supporting or refuting these mechanisms will be reviewed.
Fig. 2

Possible mechanistic link between acute stress and the syndrome of stress cardiomyopathy. Increased sympathetic stimulation may mediate myocardial stunning through a variety of possible pathophysiologic effects that include microvascular dysfunction and myocyte calcium overload. Risk factors that may increase individual susceptibility to these pathophysiologic responses are also shown. Modified from Bhattacharyya et al. (2007), copyright © 2007, with permission from Elsevier (Bhattacharyya and Steptoe 2007, Fig. 1)

Plaque rupture: Catecholamine-mediated plaque rupture followed by rapid and complete lysis of thrombus has been proposed as a possible mechanism of SCM. Some authors have reported eccentric atherosclerotic plaque in the mid portion of the left anterior descending (LAD) coronary artery using intravascular ultrasound, but these findings have not been uniformly supported. It has also been suggested that plaque rupture and transient coronary thrombosis must occur in a long wrap-around LAD to explain the apical ballooning pattern (Ibanez et al. 2004). It has been demonstrated, however, that apical ballooning can occur even in the absence of a wrap-around LAD, and the prevalence of this coronary anatomy is no higher in SCM than it is in a control population (Hoyt et al. 2010). Further, plaque rupture and transient thrombosis in a large wrap-around LAD would not explain the basal and mid-ventricular ballooning patterns that have been reported.

Epicardial spasm: Ischemia resulting from catecholamine-mediated coronary spasm could account for the myocardial stunning that characterizes SCM, but this hypothesis is not supported by clinical observations. First, while epicardial spasm has been reported in isolated cases of SCM, it is rarely observed during angiography, even when provocative agents such as ergonovine and acetylcholine are administered (Pilgrim and Wyss 2008; Martinez-Selles et al. 2010). Second, the majority of patients with SCM have no ST-segment elevation on ECG, an observation that seems inconsistent with diffuse epicardial spasm. Finally, the wall motion abnormalities seen with the various “ballooning” patterns do not correlate with epicardial vascular territories, and even multivessel spasm would not account for the unusual patterns of akinesis that have been reported.

Intraventricular obstruction: An intraventricular pressure gradient has been reported in some patients with SCM during the acute presentation (Tsuchihashi et al. 2001; Sharkey et al. 2005). It has been suggested that excessive sympathetic stimulation may lead to mid-cavity obstruction in individuals with smaller ventricles and localized septal thickening. The subsequent pressure gradient between apex and base could result in apical subendocardial ischemia and transient dysfunction. It is likely, however, that the intraventricular gradient observed in some patients with SCM is a consequence rather than the underlying cause of the myocardial dysfunction. Only a small minority of cases in the literature has reported an intraventricular gradient (Pilgrim and Wyss 2008). In addition, an apex to base gradient due to intraventricular obstruction would not account for the basal and mid-ventricular variants that have been reported in this syndrome.

Microvascular dysfunction: There is growing evidence that the transient myocardial dysfunction seen in SCM may be due to sympathetically mediated microcirculatory dysfunction. Significant reductions in coronary flow reserve and velocity during coronary angiography have been observed using a Doppler flow wire (Kume et al. 2005). Doppler transthoracic echocardiography during the acute phase of SCM has also demonstrated abnormal coronary flow reserve following the infusion of adenosine (Meimoun et al. 2008) or dipyridamole (Rigo et al. 2009). Despite the absence of obstructive coronary disease, most patients with SCM undergoing coronary angiography have elevated thrombolysis in myocardial infarction (TIMI) frame counts (Bybee et al. 2004), a well-validated index of coronary blood flow. Irrespective of the ballooning variant, this abnormality in flow is frequently observed in all three epicardial vessels, suggesting a downstream microcirculatory disturbance that may be sympathetically mediated. This idea is supported by a study from Japan in which patients with SCM were found to have elevated plasma catecholamine levels and evidence from left ventricular endomyocardial biopsy of microvascular endothelial cell apoptosis (Uchida et al. 2010).

Direct myocyte effects: Myocardial stunning in SCM may alternatively result from the direct effects of catecholamines on cardiac myocytes. Lyon and colleagues have suggested that high levels of circulating epinephrine may cause a switch from Gs to Gi protein signaling via the β2-adrenergic receptor (Lyon et al. 2008). The resulting negative inotropic effect would be most pronounced at the apex of the heart where the β-receptor density is greatest. While this hypothesis is intriguing, it does not readily explain the non-apical variants of SCM that have been frequently observed. Catecholamines are known to decrease myocyte viability through cyclic adenosine monophosphate-mediated calcium overload (Mann et al. 1992). This results in contraction band necrosis, a histopathologic finding associated with catecholamine excess that has now been well described in SCM (Wittstein et al. 2005). There is evidence that patients with SCM may also have a disturbance in myocyte calcium handling. During the acute phase of the syndrome, there is down-regulation of sarcoplasmic Ca2+ ATPase (SERCA2a) gene expression, increased ventricular expression of sarcolipin, and dephosphorylation of phospholamban (PLN) (Nef et al. 2009), possibly resulting in transient myocardial contractile dysfunction due to decreased calcium affinity. These abnormalities are no longer observed once cardiac contractile function has recovered. Data from animal models also support the hypothesis that catecholamine-mediated abnormalities of calcium handling may be central to the pathogenesis of SCM. In a rat model of SCM, acute beta-adrenergic stimulation results in left ventricular dysfunction and myocyte injury through calcium leakage due to hyperphosphorylation of the ryanodine receptor 2 (RyR2) (Ellison et al. 2007).

Factors that may Increase Susceptibility to SCM

Several risk factors have been identified that may increase individual susceptibility to SCM. These risk factors may affect vulnerability by enhancing the sympathetic response to acute stress or by influencing the myocyte and microvascular responses to catecholamine release. While it is likely that many such risk factors exist, only those that are supported by clinical observations and research will be discussed here.

Hormonal influence: A consistent observation in all series of SCM reported to date is the striking preponderance of post-menopausal women. Female hormones exert important influences on the sympathetic neurohormonal axis as well as on coronary vasoreactivity and myocyte calcium handling. Cardiac vagal tone and baroreflex sensitivity decrease significantly as women age (Lavi et al. 2007), potentially making post-menopausal women more susceptible to the deleterious cardiovascular effects of sympathetic stimulation following an acute stressor. Further, catecholamine-mediated vasoconstriction (Sung et al. 1999) and the sympathetic response to mental stress are attenuated by estrogen in post-menopausal women (Komesaroff et al. 1999). In an animal model of SCM, estrogen supplementation in ovariectomized rats attenuates the negative effect of immobilization stress on left ventricular systolic function (Ueyama et al. 2007). These observations suggest that sex hormones likely have an important influence on stress-related myocardial stunning, but there are currently no clinical data to suggest that estrogen replacement can prevent the occurrence or recurrence of SCM.

Mood disorders and antidepressant use: High-anxiety trait has been identified in patients with SCM (Del Pace et al. 2011), and we have previously reported a high prevalence of mood disorders and antidepressant use in patients with this syndrome (Mudd et al. 2007). This may have pathogenic importance since patients with depressive disorders have decreased vagal tone and an increased adrenomedullary hormonal response to stressful events (Cevik and Nugent 2008), and some patients with depression have very high-noradrenaline spillover (Barton et al. 2007). Further, the increased use of antidepressants such as selective norepinephrine reuptake inhibitors may facilitate myocardial stunning in this population by increasing local catecholamine levels.

Endothelial dysfunction: Available data suggest that patients with SCM may be individuals with inherent endothelial dysfunction and chronic impairment of coronary vasodilatory reserve. Barletta and colleagues performed cold pressor testing (CPT) on subjects who had fully recovered from an episode of SCM (median 688 days from the acute presentation) (Barletta et al. 2009). Compared to an age, sex, and risk factor matched control group, CPT in patients with SCM resulted in significant catecholamine elevation and transient apical and mid-ventricular wall motion abnormalities, and there was no detectable increase in coronary blood flow. Martin and colleagues used peripheral arterial tonometry (PAT) to assess endothelial function in subjects with a prior episode of SCM (Martin et al. 2010). In contrast to a post-menopausal control group, subjects with prior SCM demonstrated increased catecholamine production, impaired vascular vasodilation, and increased vasoconstriction when subjected to mental stress testing. These studies suggest that individuals with SCM may have inherent abnormalities of endothelial function and coronary flow reserve and may thus be particularly susceptible to myocardial stunning during periods of acute stress and catecholamine excess.

Genetic determinants: SCM has been reported in siblings, but the genetic determinants of this syndrome are unknown. Specific polymorphisms of alpha- and beta-adrenergic receptors have been associated with neurogenic stunned myocardium following subarachmoid hemorrhage, a condition that almost certainly shares an overlapping pathophysiology with SCM (Zaroff et al. 2006). While adrenergic receptor polymorphisms have not been identified yet in patients with SCM, patients with this disorder appear to have an increased frequency of the L41Q polymorphism of the G protein coupled receptor kinase 5 (GRK5) compared to a control population (Spinelli et al. 2010). The L41 variant of GRK5 attenuates the β-adrenergic receptor’s response to catecholamine stimulation. In the setting of catecholamine stimulation, ventricular ballooning might result from either a negative inotropic effect due to β-receptor uncoupling or from ischemia resulting from an imbalance between α1-adrenergic coronary vasoconstriction and β-adrenergic vasodilation. While larger genetic studies are warranted, these initial reports suggest the exciting possibility that individual susceptibility to SCM may in part be genetically influenced.

A Proposed Paradigm for the Mechanism Underlying SCM

A proposed paradigm for the mechanism of SCM is illustrated in Fig. 2. Acute emotional or physical stress results in sympathetic stimulation and catecholamine release. Enhanced sympathetic stimulation may lead to a variety of pathophysiologic effects, the most likely being catecholamine-mediated microvascular dysfunction and myocyte calcium overload. Certain individuals may be particularly susceptible to these pathophysiologic effects that ultimately lead to the clinical features of SCM.

The early reports of SCM suggested that the syndrome occurred in response to severe and intense emotional or physiologic stress. It is now clear that some patients with this syndrome present with fairly subtle triggers, and in the largest series reported to date, no trigger at all could be identified in almost 30% of the patients (Eitel et al. 2011). As shown in Fig. 3, the intensity of the trigger required to induce SCM may be dependent on clinical risk factors that increase myocardial and microvascular susceptibility to sympathetic stimulation. Thus, the 20-year-old man who has no clinical risk factors may require massive catecholamine release, such as that seen with neurologic injury or intravenous epinephrine, in order to develop the clinical syndrome of SCM. A moderate amount of sympathetic stimulation may be required to induce SCM in the post-menopausal woman who has no other risk factors. As the number of risk factors in a given individual increases, however, the threshold for developing SCM is lowered, and the clinical syndrome may occur following relatively mild sympathetic stimulation. This model offers a possible explanation for why SCM can be precipitated by such variable triggers, and it is certain that additional risk factors will be identified over the next few years as our experience with this syndrome continues to grow.
Fig. 3

A proposed model to explain how stress cardiomyopathy can be precipitated by triggers of variable intensity. The amount of stress needed to induce the clinical syndrome is dependent on individual risk factors that likely influence myocyte and microvascular sensitivity to sympathetic stimulation (see text). SCM stress cardiomyopathy


In just a few short years, SCM has emerged from relative obscurity and has become a widely recognized and accepted clinical syndrome. There is increasing evidence that enhanced sympathetic stimulation underlies the pathogenesis of SCM, and this syndrome serves as a dramatic example of the profound effects that stress and catecholamines can have on cardiovascular morbidity and mortality. Exciting challenges for the future will include identifying those risk factors that increase individual susceptibility to this unique disorder and elucidating the precise cellular and molecular mechanisms of stress-induced myocardial stunning.

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