What are the causes of Takotsubo (stress) cardiomyopathy?

Causes of Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy is primarily caused by catecholamine surge following emotional or physical stressors, particularly in postmenopausal women, with pathophysiological mechanisms including β2-adrenergic receptor signaling changes and microvascular dysfunction. 1

Primary Triggering Factors

• Emotional stressors are common precipitating events, including grief, fear, extreme anger, or sudden surprise 1
• Physical stressors such as acute medical illness, surgery, respiratory failure, or sepsis can trigger the syndrome 1
• Postmenopausal status is a significant risk factor, with 96% of cases occurring in women ≥50 years of age and a mean age of 65 years 2, 1
• Iatrogenic causes including medication administration (particularly exogenous catecholamines) and various medical procedures 3

Pathophysiological Mechanisms

• Catecholamine surge is the primary proposed mechanism, with documented supraphysiological elevations of plasma catecholamines during acute episodes 2, 1
• β2-adrenergic receptor signaling switch from Gs to Gi protein signaling occurs with high circulating epinephrine levels, causing negative inotropy but protecting against apoptosis 2
• Regional differences in adrenergic receptor density explain the characteristic apical involvement, as the ventricular apex has increased β2-adrenergic receptor density 2, 1
• Microvascular vasospasm contributes to the pathophysiology by causing regional myocardial hypoperfusion 1
• Impaired fatty acid metabolism has been implicated in the development of the syndrome 2
• Transient left ventricular outflow tract obstruction can occur and contribute to the clinical presentation 2
• Base-to-apex perfusion gradient differences in myocardial blood flow have been postulated as contributing factors 2

Specific Triggers

Emotional Triggers

• Grief, fear, extreme anger, panic, or sudden surprise 1
• Pre-existing psychiatric disorders such as anxiety and depression may increase susceptibility 1

Physical/Medical Triggers

• Acute medical illness including neurological conditions 1
• Surgical procedures and other invasive medical interventions 1
• Respiratory failure requiring mechanical ventilation 1
• Sepsis and other severe infections 1

Pharmacological Triggers

• Direct administration of catecholamines (epinephrine, norepinephrine) 3
• Medications that increase catecholamine levels or sensitivity 1
• Chemotherapy agents that can affect cardiovascular function 1
• Flecainide and other antiarrhythmic medications have been reported as triggers 4

Endocrine Triggers

• Thyroid dysfunction which can alter cardiovascular response to catecholamines 1
• Other endocrine disorders affecting catecholamine metabolism 1

Clinical Characteristics and Risk Factors

• Female predominance is observed, with approximately 90% of cases occurring in women 1
• Postmenopausal status is the most significant demographic risk factor 2
• Absence of significant coronary artery disease is characteristic, though some patients may have incidental coronary atherosclerosis 1
• Circadian variation may be present, with many episodes occurring in the early morning 2

Variant Forms

• Apical ballooning is the classic presentation, affecting the mid and apical segments of the left ventricle 2
• Mid-ventricular variant with sparing of the apex and base 1
• Basal variant (inverse takotsubo) with hyperkinesis of the apex 1
• Right ventricular involvement is common in many cases 2

Complications and Outcomes

• Life-threatening ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, or ventricular fibrillation occur in 3.0–8.6% of cases 2
• QT interval prolongation occurs in up to half of patients and is associated with increased risk of arrhythmias 2
• Recurrence occurs in approximately 5% of cases, typically 3 weeks to 3.8 years after the first event 2
• In-hospital mortality is approximately 5%, though prognosis is generally favorable with complete recovery in most cases 5