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.

SUMMARYCoronary microvascular hyperplasia is a cause of microvessel angina, although the underlying cellular mechanisms remain unclear. We examined how mononuclear cells expressing β-actin (β-MNCs), which were identified in coronary vessels, induce coronary microvascular hyperplasia.The presence of β-MNCs in coronary hyperplastic arterial (HAM) and venous microvessels (HVM) was examined by endomyocardial biopsy in 25 patients with suspected microvessel angina. β-MNCs were identified in 14 HAMs obtained from 11 patients. Basic fibroblast growth factor and heparin sulfate were injected into the infarcted myocardium to induce HAM and HVM in 28 beagles, and then we examined the role of β-MNCs in the onset of HAM and HVM. The following changes were observed after infarction induction in beagles: (a) migration of β-MNCs from the existing microvessels into the interstitial space at 1-2 weeks; (b) those traversing the adventitia into the media, but not intima, of microvessels; (c) their transformation to smooth muscle cells (SMCs) and/or connective tissues (collagen and elastin fibers); (d) and medial hyperplasia without intimal hyperplasia. Medial hyperplasia was classified into SMC-proliferative and both SMC-and connective tissue-proliferative types. β-MNCs expressed CD 34 but did not express other major vessel-related cell markers.β-MNCs are a vascular progenitor, and migrate out of the adventitia into media, and participate in the etiology of coronary microvascular medial hyperplasia. (Int Heart J 2012; 53: 43-53) Key words: β-MNC migration, Coronary microvessels, Medial hyperplasia, Microvessel angina C hest pain accompanied by ischemic electrocardiographic changes, but without demonstrable angiographic coronary changes, is called "microvessel angina". 1-4)Anatomical and functional abnormalities of coronary microvessels are considered the cause of this phenomenon, including microvascular spasm due to endothelial dysfunction, [5][6][7] coronary capillary swelling, 8) and microvascular luminal narrowing by swollen endothelium. 9)In addition to these endothelium-related changes, arteriolar and small arterial medial hyperplasia have been observed in endomyocardial biopsy specimens. 10,11) The exact cellular mechanisms of medial hyperplasia are, however, not known.In an earlier study, histological examination of coronary microvessels in patients with microvessel angina revealed mononuclear cells expressing β-actin (β-MNCs) in the media and adventitia of the hyperplastic coronary microvessels. We also found β-MNCs in animals. 12,13) In this study, we performed more detailed examinations of the role of β-MNCs in hyperplastic coronary microvessels in patients with microvessel angina and in animals treated with basic fibroblast growth factor (bFGF) and heparin sulfate after induction of myocardial infarction. 14,15) MethodsSubjects: A total of 25 consecutive patients with chest pain with depression of the ST segment on electrocardiography (during spontaneous angina or treadmill-induced), but without demonstrable angiogra...