Takotsubo Syndrome: Pathophysiology and Clinical Implications

Epidemiology

Takotsubo syndrome is increasing in incidence, which may reflect the rising prevalence of modern life stressors and the greater awareness and detection of the condition by the clinical cardiology community, as well.^[5,9] Takotsubo syndrome accounts for ≈2% to 3% of all patients and 5% to 6% of female patients presenting with acute coronary syndrome,^[9,14,15] although it may be underappreciated and underdiagnosed especially in patients who have coexisting coronary artery disease.^[16]

Whereas the condition can occur in any age group, it characteristically affects women in the sixth decade of life, although patients <50 years of age account for ≈10% of cases.^[17] Younger patients are more likely to be male, or have atypical takotsubo, fewer comorbidities, and acute neurological or psychiatric disorders, and to develop in-hospital complications.^[17]

Although increasing age may be a risk factor for developing takotsubo syndrome,^[15] the underlying mechanism remains unknown, but can be explained in part by the influences of age and sex on the sympathetic nervous system. Sympathetic nervous system activity increases with age, particularly in women, and cardiac sympathetic stimulation is augmented because of an imbalance in neuronal norepinephrine homeostasis.^[18,19] With age, there is a decrease in vagal tone and baroreflex sensitivity with a concomitant increase in sympathetic activation,^[18] potentially rendering the myocardium more susceptible to enhanced levels of catecholamines. Although increasing age may be a risk factor for developing takotsubo syndrome, it is not an independent risk factor for in-hospital mortality which contrasts with the well-recognized age-related mortality seen in patients with acute coronary syndrome.^[9]

Although most patients (80%–90%) who develop takotsubo syndrome are women,^[15,20] the mechanism underlying this large sex disparity is unknown. Several hypotheses have been proposed and centered on estrogen deprivation occurring postmenopause and its role in regulating sympathetic drive and microvascular blood flow through endothelium-dependent and -independent mechanisms.

Familial takotsubo syndrome has been described,^[21] although multigenerational Mendelian inheritance does not occur, suggesting that a genetic predisposition may interact with environmental factors or have a polygenic cause. Polymorphisms of the β₁- and β₂-adrenoreceptor genes have been associated with reduced left ventricular function in patients with takotsubo syndrome, but results are conflicting and inconclusive.^[22,23] Larger studies are currently underway to explore potential genetic associations (GENETIC [Is There a Genetic Predisposition for Acute Stress-induced {Takotsubo}Cardiomyopathy], NCT04513054).

Table 1. Differential Diagnosis in Takotsubo Syndrome
	Takotsubo syndrome	Myocardial infarction with nonobstructive coronary arteries	Type 2 myocardial infarction	Type 1 myocardial infarction
Characteristic clinical features	Acute chest pain or dyspnea Preceding stressor* Can be associated in the context of other illness Preexisting psychiatric illness	Acute chest pain Varies depending on underlying pathology Requires clinical evidence of myocardial infarction	Acute chest pain Supply or demand imbalance Tachycardia or hypotension Concomitant illness Usually have comorbidities	Acute chest pain Traditional cardiovascular risk factors
Investigations
ECG	Widespread ST-segment or T-wave abnormality QTc prolongation (late)	New ischemic changes	New ischemic changes Tachycardia	Territorial ST-segment or T-wave abnormality
Blood test results	Moderate cardiac troponin elevation Marked B-type natriuretic peptide, and C-reactive protein elevation	Elevated troponin >99th centile	Elevated troponin >99th centile	Marked cardiac troponin elevation Moderate B-type natriuretic peptide, and C-reactive protein elevation
Echocardiography	Temporary left ventricular dysfunction regional wall motion abnormality depending on subtype of takotsubo (apical, basal, focal)	Normal or persistent left ventricular impairment Regional wall motion abnormality	Normal or persistent left ventricular impairment May have regional wall motion abnormality	Normal or persistent left ventricular impairment regional wall motion abnormality
Coronary angiography	Normal or nonobstructive coronary artery disease Apical ballooning on left ventriculogram	Normal or nonobstructive coronary artery disease Evidence of acute plaque rupture on intravascular ultrasound or optical coherence tomography	Normal, nonobstructive or obstructive coronary artery disease	Obstructive disease
MRI	No persistent late gadolinium enhancement Elevated native T1/T2	Late gadolinium enhancement Regional wall motion abnormality	Normal or late gadolinium enhancement May have regional wall motion abnormality	Late gadolinium enhancement-infarct pattern Elevated native T1/T2 Regional wall motion abnormality

MRI indicates magnetic resonance imaging.
*Not always present.

Table 2. Management Pathway in Patients With Takotsubo Syndrome
Management
Acute complications
Heart failure/pulmonary edema	Diuretics, nitroglycerin (if no left ventricular outflow obstruction)
Left ventricular outflow obstruction	Consider: intravenous fluids, β-blocker (if no heart failure), left ventricular assist device Avoid: diuretics, nitroglycerin, intra-aortic balloon pump
Shock/pump failure	Consider: left ventricular assist device, venous to arterial extracorporeal membrane oxygenation Avoid: inotropes such as epinephrine, norepinephrine, dobutamine, milrinone, and isoprenaline
Arrhythmias	Ventricular arrhythmias: β-blocker, magnesium, direct current cardioversion Avoid: QT prolonging drugs
	High-degree atrioventricular block: temporary pacing Avoid: β-blockers, permanent devices
Thromboembolism	Left ventricular thrombus: Anticoagulation for at least 3 mo Consider: Prophylactic anticoagulation in patients with left ventricular ejection fraction <30% and apical ballooning
Predischarge
Bystander coronary disease	Secondary prevention: antiplatelet and statin therapy
Left ventricular dysfunction	Heart failure treatment: β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, diuretics
Tachycardia	β-Blocker, ivabradine (if in sinus and cannot tolerate β-blockers)
Assess for left ventricular thrombus	Cardiac imaging and assessment for anticoagulation
Long term
Recurrence prevention	Continue angiotensin-converting enzyme inhibitors or angiotensin receptor blocker therapy
Address risk factors	Underlying mental health conditions