Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications

Trisha Singh, BM; Hilal Khan, MB BCh BAO, MRCP; David T. Gamble, MPharm, MBBS; Caroline Scally, MBChB; David E. Newby, DM, PhD; Dana Dawson, MD, DPhil

Disclosures

Circulation. 2022;145(13):1002-1019.

Long-term Management

As with in-hospital management, no therapeutic interventions have been shown to reduce recurrences or any other major cardiovascular events in patients with takotsubo syndrome. The focus is therefore to ensure the treatment of associated risk factors and concomitant disease.

Concomitant Disease

Patients with concomitant coronary artery disease (bystander disease) should continue to receive preventative therapies including antiplatelet, statin, and angiotensin-converting enzyme inhibitor therapies. Furthermore, those who have dual pathology (concurrent acute myocardial infarction) may require dual antiplatelet therapy, and treatment should be tailored to individual patients (Daghem et al, A tear and a broken heart. 2022). Where patients demonstrate a degree of persistent left ventricular systolic dysfunction, they should be managed and treated for left ventricular systolic dysfunction according to established guidelines.^[63] However, in the vast majority of patients who have normalization of their left ventricular ejection fraction, there is no clear evidence that β-blocker therapy improves long-term survival benefit or reduces the recurrence of takotsubo syndrome.^[9,65,68] Likewise, the evidence for angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy is contradictory and uncertain.^[9,65,69] Randomized controlled trial evidence is urgently needed. In the meantime, each clinician should continue to apply their best judgment, but conservative medical management appears to be the most appropriate approach in the absence of treatable risk factors or comorbidities.

Risk Factors

Psychiatric disorders, usually anxiety or depression, are common in patients with takotsubo syndrome, suggesting that some patients might benefit from a combined psychocardiological rehabilitation. Cognitive-behavioral therapy alongside cardiac rehabilitation can improve mental health and reduce negative thinking compared with cardiac rehabilitation alone.^[70] Studies are currently underway to establish whether structured exercise training and mental well-being programs can improve cardiac energetics and attenuate cardiac limitation on exercise after takotsubo syndrome (PLEASE study [Physical Exercise and Mental Wellbeing Rehabilitation for Acute Stress-induced Takotsubo Cardiomyopathy: The PLEASE Study]; NCT04425785). Whether antidepressant or other psychiatric therapies might provide clinical benefit in such patients is controversial and has not been investigated.

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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