Takotsubo cardiomyopathy

An example case helps explain this clinical syndrome that mimics acute myocardial infarction.


Case presentation

A 57-year-old woman with a history of hypertension, type 2 diabetes, and hyperlipidemia presented to the ED with chest pain that had begun abruptly one hour earlier. The pain was retrosternal, non-radiating, described as “heaviness,” and associated with diaphoresis and shortness of breath. The patient did not report associated abdominal pain, nausea, orthopnea, paroxysmal nocturnal dyspnea, or prior similar problems. She was visiting from out of town to attend the funeral of her beloved friend.

Initial vitals were blood pressure of 150/70 mm Hg, heart rate of 98 beats/min, and respiratory rate of 16 breaths/min, with an oxygen saturation of 98% on room air. The patient appeared anxious. Cardiovascular findings and the rest of the physical examination were normal.

Initial electrocardiogram (EKG) showed ST-segment elevations in leads V1 to V4. An urgent cardiac catheterization revealed normal coronaries and apical ballooning of the left ventricle with an ejection fraction of 40%.

Background

Takotsubo cardiomyopathy is a clinical syndrome that mimics acute myocardial infarction characterized by transient left ventricular dysfunction in the absence of obstructive coronary artery disease. The term “Tako-tsubo” in Japanese means “fishing pot for trapping octopus,” and the name is based on the shape of the left ventricle in this specific type of cardiomyopathy. It was first described by Japanese researchers in the 1990s (11. Sato TH, Uchida T, Dote K, et al. Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm. In: Kodama K, Haze K, Hori M, eds. Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure. Tokyo, Japan: Kagakuhyoronsha Publishing Co; 1990:56-64.) and is known by several other names, including stress cardiomyopathy, apical ballooning syndrome, and broken heart syndrome.

Etiology and pathophysiology

Despite extensive research, the etiology of this condition is not clearly understood. Sympathetic hyperactivity, increased release of catecholamines leading to myocardial toxicity, and coronary vessel spasms are some of the pathophysiologies described in the literature (22. Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of Takotsubo syndrome. Circulation. 2017;135:2426-41. [PMID: 28606950]). Most patients with this condition report various physical and emotional stressors before the onset of symptoms. These induce a stress response that is mediated by various anatomical structures of the central and autonomic nervous system (22. Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of Takotsubo syndrome. Circulation. 2017;135:2426-41. [PMID: 28606950]).

Acute stress has been shown to activate the brain and hypothalamus-pituitary-adrenal axis, thereby increasing the bioavailability of cortisol, epinephrine, and norepinephrine (33. Steptoe A, Kivimäki M. Stress and cardiovascular disease. Nat Rev Cardiol. 2012;9:360-70. [PMID: 22473079]). Also, the sympathetic fibers that travel along the epicardial vessels and myocardium end up in nerve terminals and release norepinephrine into the synaptic cleft, activating alpha and beta postsynaptic adrenoceptors (44. Lymperopoulos A, Rengo G, Koch WJ. Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation. Trends Mol Med. 2007;13:503-11. [PMID: 17981507]).

Several studies have shown that serum and myocardial catecholamine levels are increased during the acute phases of Takotsubo cardiomyopathy (55. Akashi YJ, Nakazawa K, Sakakibara M, et al. 123I-MIBG myocardial scintigraphy in patients with “Takotsubo” cardiomyopathy. J Nucl Med. 2004;45:1121-7. [PMID: 15235057], 66. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352:539-48. [PMID: 15703419]). This surge in catecholamines increases the heart rate and workload, creating an oxygen demand-and-supply mismatch that results in myocellular hypoxia (77. Zhang X, Szeto C, Gao E, et al. Cardiotoxic and cardioprotective features of chronic β-adrenergic signaling. Circ Res. 2013;112:498-509. [PMID: 23104882]). This is further exacerbated by metabolic derangements and generation of free radicals leading to myocyte dysfunction (88. Y-Hassan S. Acute cardiac sympathetic disruption in the pathogenesis of the takotsubo syndrome: a systematic review of the literature to date. Cardiovasc Revasc Med. 2014;15:35-42. [PMID: 24140050], 99. Okonko DO, Shah AM. Heart failure: mitochondrial dysfunction and oxidative stress in CHF. Nat Rev Cardiol. 2015;12:6-8. [PMID: 25421167]). Additionally, increased release of catecholamines from cardiac sympathetic nerve terminals decrease the myocyte viability, resulting in “contraction-band” necrosis, which is one of the pathological hallmarks of Takotsubo cardiomyopathy (1010. Basso C, Thiene G. The pathophysiology of myocardial reperfusion: a pathologist's perspective. Heart. 2006;92:1559-62. [PMID: 16547203]).

Some studies have also demonstrated a reversal of perfusion defects during left ventricular dysfunction, suggesting a pathogenic role of coronary microvascular spasm (1111. Galiuto L, De Caterina AR, Porfidia A, et al. Reversible coronary microvascular dysfunction: a common pathogenetic mechanism in apical ballooning or Tako-Tsubo syndrome. Eur Heart J. 2010;31:1319-27. [PMID: 20215125]). A few studies have suggested that the endothelial dysfunction represents a key link between stress and myocardial dysfunction in patients with Takotsubo cardiomyopathy (1212. Naegele M, Flammer AJ, Enseleit F, et al. Endothelial function and sympathetic nervous system activity in patients with Takotsubo syndrome. Int J Cardiol. 2016;224:226-30. [PMID: 27661411]). Estrogen deficiency has also been implicated in endothelial dysfunction (1313. Vitale C, Mendelsohn ME, Rosano GM. Gender differences in the cardiovascular effect of sex hormones. Nat Rev Cardiol. 2009;6:532-42. [PMID: 19564884]).

Clinical presentation

Takotsubo cardiomyopathy is more common among elderly women. Symptoms at presentation are typical of acute coronary syndrome. Most patients present with sudden onset of chest pain and shortness of breath. Syncope, generalized weakness, and cough have also been reported. A subset of patients also develop heart failure, pulmonary edema, cardiogenic shock, stroke, arrhythmias, and even cardiac arrest (22. Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of Takotsubo syndrome. Circulation. 2017;135:2426-41. [PMID: 28606950]). Symptoms are typically preceded by stressors, either emotional, like the unexpected death of a family member, or physical, like strenuous activity. However, about 20% of cases do not have any identified triggering event. This type of cardiomyopathy can also be reported after a positive lifetime event and hence is also referred to as “happy heart” syndrome (88. Y-Hassan S. Acute cardiac sympathetic disruption in the pathogenesis of the takotsubo syndrome: a systematic review of the literature to date. Cardiovasc Revasc Med. 2014;15:35-42. [PMID: 24140050]).

ST-segment elevation in the anterior leads is the most common EKG finding. However, reciprocal ST changes and abnormal Q waves are often absent (22. Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of Takotsubo syndrome. Circulation. 2017;135:2426-41. [PMID: 28606950]). A diagnosis of ST-elevation myocardial infarction cannot be ruled out on EKG findings alone, so coronary angiography should be performed without delay. ST-segment depressions, diffuse T-wave inversions, and prolonged QTc interval may also be seen on EKG. A mild to modest increase in cardiac enzymes is also seen. Elevated levels of brain natriuretic peptide (BNP) can also be observed and are attributed to ventricular stretching.

Cardiac catheterization typically reveals normal coronaries or a nonobstructive pattern of coronary artery disease (CAD). However, obstructive CAD can also be seen in nearly 15% of cases (1414. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373:929-38. [PMID: 26332547]). The wall-motion abnormalities do not follow any particular coronary artery territory. In patients with obstructive CAD, the area of left ventricular dysfunction typically extends beyond the territory of the obstructed coronary artery and is reversible (22. Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of Takotsubo syndrome. Circulation. 2017;135:2426-41. [PMID: 28606950], 1515. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155:408-17. [PMID: 18294473]).

Takotsubo cardiomyopathy is named based on the shape of the left ventricle which resembles a Japanese fishing pot for trapping octopus MKSAP 18 image  American College of Physicians
Takotsubo cardiomyopathy is named based on the shape of the left ventricle, which resembles a Japanese fishing pot for trapping octopus. MKSAP 18 image © American College of Physicians

Angiography and echocardiography will demonstrate left ventricular dysfunction. Of interest, the degree of left ventricular dysfunction seen on echocardiogram is usually out of proportion to the level of cardiac enzymes (22. Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of Takotsubo syndrome. Circulation. 2017;135:2426-41. [PMID: 28606950]). Several variants of left ventricular dysfunction have been described. Apical dyskinesia or ballooning with basal hypercontraction is the most common form. It is believed that this apical pattern of left ventricular dysfunction is due to regional distribution of the sympathetic nerve endings releasing catecholamines that act on adrenoreceptors of the myocardium. Other variants, including midventricular, inverted, and regional wall-motion abnormalities, have also been reported (1616. Kurowski V, Kaiser A, von Hof K, et al. Apical and midventricular transient left ventricular dysfunction syndrome (Tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest. 2007;132:809-16. [PMID: 17573507]).

Several diagnostic criteria have been proposed since 2003. In 2018, an international expert consensus developed the InterTAK diagnostic criteria for the diagnosis of Takotsubo cardiomyopathy. For diagnosis, patients should have transient left ventricular wall-motion abnormalities, new EKG abnormalities (ST-segment elevation or depression, T-wave inversions and QTc prolongation), moderately elevated cardiac biomarkers, absence of infectious myocarditis, and postmenopausal status (in women). An emotional, physical, or combined trigger is included in the criteria but not required; pheochromocytoma and neurological disorders like stroke and subarachnoid hemorrhage are also accepted as triggers (1717. Ghadri JR, Wittstein IS, Prasad A, et al. International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology. Eur Heart J. 2018;39:2032-46. [PMID: 29850871]).

Complications

Acute systolic heart failure is the most common complication associated with Takotsubo cardiomyopathy, occurring in 12% to 45% of cases (1818. Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18:8-27. [PMID: 26548803]). A dynamic intraventricular pressure gradient can develop in acute phases due to myocardial stunning of the apical region and hypercontraction of the basal segments, leading to left ventricular outflow tract obstruction (LVOTO). Cardiogenic shock is seen in 4% to 20% of cases, primarily due to the acute left ventricular dysfunction and exacerbated by LVOTO and atrial fibrillation (1818. Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18:8-27. [PMID: 26548803]). Atrial fibrillation and ventricular arrhythmias have been reported in 5% to 15% and 4% to 9% of cases, respectively (1818. Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18:8-27. [PMID: 26548803]). Left ventricular apical thrombus in the akinetic segment has been seen in a small number of patients. Occasionally ventricular rupture and cardiac arrest have also been reported in the literature.

Management

Evidence for the treatment of Takotsubo cardiomyopathy is limited. As there are no randomized controlled trials, the recommendations are based mainly on expert consensus.

Inpatient treatment is largely supportive and directed toward stabilization and management of such complications as acute heart failure, cardiogenic shock, arrhythmias, LVOTO, and ventricular thrombus. During the acute phases of Takotsubo cardiomyopathy, close observation is needed for patients at high risk of complications. Presence of physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and ejection fraction of less than 45% on admission were found to be independent predictors for in-hospital complications in a case series (1414. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373:929-38. [PMID: 26332547]).

Unstable patients who require continuous monitoring of hemodynamics should be admitted to the ICU. Mechanical ventilation may be needed in patients presenting with acute respiratory distress and pulmonary edema. Sympathomimetic agents like beta2-agonists should be discontinued. Patients in cardiogenic shock may need a left ventricular assist device, an intra-aortic balloon pump (IABP), or extracorporeal membrane oxygenation. However, use of IABP is controversial as it is believed to worsen LVOTO (1818. Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18:8-27. [PMID: 26548803]). Inotropic agents like norepinephrine, dopamine, dobutamine, milrinone, or isoproterenol are generally avoided as they might worsen the clinical status and prognosis of patients in a state of sympathetic hyperactivity (1818. Lyon AR, Bossone E, Schneider B, et al. Current state of knowledge on Takotsubo syndrome: a position statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2016;18:8-27. [PMID: 26548803]).

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) and beta-blockers are used to treat left ventricular dysfunction in stable patients. The use of ACE inhibitors and ARBs has been associated with improved survival, but this was not the case with beta-blockers (1414. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373:929-38. [PMID: 26332547]). Anticoagulation must be started and continued if a left ventricular thrombus is detected. In most cases, left ventricular function recovers within weeks to months and sometimes in days. Repeat echocardiography is recommended in three to six months to assess recovery from left ventricular dysfunction.

Prognosis

Historically, Takotsubo cardiomyopathy was believed to have benign clinical outcomes, but recent studies have found risk of death in the short term (about 4% to 5% during the acute phase in hospitalized patients) and long term (22. Pelliccia F, Kaski JC, Crea F, et al. Pathophysiology of Takotsubo syndrome. Circulation. 2017;135:2426-41. [PMID: 28606950], 1919. Tornvall P, Collste O, Ehrenborg E, et al. A case-control study of risk markers and mortality in Takotsubo stress cardiomyopathy. J Am Coll Cardiol. 2016;67:1931-6. [PMID: 27102508]). A case series of patients diagnosed with Takotsubo cardiomyopathy reported a 30-day mortality rate of 5.9%, a long-term death rate of 5.6% per patient-year, and a rate of stroke or transient ischemic attack of 1.7% per patient-year (1414. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373:929-38. [PMID: 26332547]). This increased risk for death compared to the general population persisted after discharge despite the return of left ventricular function and normal or nonobstructive coronary arteries.

Back to the patient

The patient in this case was started on a daily regimen of lisinopril, 5 mg, and metoprolol succinate, 25 mg, and was discharged. A follow-up echocardiogram at her cardiology clinic three months later showed a normal left ventricle with an ejection fraction of 60% and no evidence of wall-motion abnormalities.