Abstract
BACKGROUND: Takotsubo cardiomyopathy (TCM) is characterized by systolic ballooning of the left ventricular apex. It is triggered by emotional or physical stress, but the exact mechanism through which stress leads to TCM is not known. HYPOTHESIS: Coronary microvessel apoptosis is the missing link between stress and TCM. METHODS: In 8 female patients with TCM, plasma catecholamines, Thrombolysis in Myocardial Infarction (TIMI) coronary flow grade and myocardial perfusion grade, and apoptosis of the coronary microvessels in the biopsied myocardial specimen by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) were examined. RESULTS: Plasma epinephrine and norepinephrine were increased to 663 +/- 445 and 875 +/- 812 pg/mL (mean +/- SD), respectively. Acetylcholine-induced delayed myocardial perfusion through the ballooning apical segment without flow disturbance in the epicardial coronary arteries (indicating microvessel spasm) and focal myocardial necrosis were observed in all subjects. Apical ballooning disappeared and myocardial perfusion delay was not inducible 1 month later. The number of vessels having apoptotic endothelial cells/10 vessels in arterioles, venules, and capillaries at initial biopsy and repeat biopsy 1 month later were 8.3 +/- 1.4 vs 0.4 +/- 1.1, P < 0.0001; 6.8 +/- 1.8 vs 0.3 +/- 0.7, P < 0.0001; and 7.9 +/- 1.0 vs 0.5 +/- 0.9, P < 0.0001, respectively. CONCLUSIONS: Left ventricular apical ballooning in TCM was considered to be caused by coronary microvessel spasm due to catecholamine-induced endothelial cell apoptosis and myocardial stunning after release of microvessel spasm. Endothelial cell apoptosis of coronary microvessel is therefore considered to be the missing link between stress and TCM.