Psychological distress and personality factors in takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TCC) is a transient condition characterised by severe left ventricular dysfunction combined with symptoms and signs mimicking myocardial infarction. Emotional triggers are common, but little is known about the psychological background characteristics of TCC. This study examined whether patients with TTC have higher levels of psychological distress (depressive symptoms, perceived stress, general anxiety), illness-related anxiety and distinct personality factors compared with healthy controls and patients with heart failure. METHODS AND RESULTS: Patients with TCC (N = 18; mean age 68.3 ± 11.7 years, 77.8 % women) and two comparison groups (healthy controls: N = 19, age 60.0 ± 7.6, 68.4 % women and patients with chronic heart failure: N = 19, age 68.8 ± 10.1, 68.4 % women) completed standardised questionnaires to measure depression (PHQ­9), perceived stress (PSS-10), general anxiety (GAD-7), illness-related anxiety (WI-7) and personality factors (NEO-FFI and DS-14). Psychological measures were obtained at 23 ± 18 months following the acute TTC event. Results showed that patients with TCC had higher levels of depressive symptoms (5.2 ± 5.2 vs. 2.5 ± 2.4, p = 0.039) and illness-related anxiety (2.1 ± 1.7 vs. 0.7 ± 1.3, p = 0.005) compared with healthy controls. Patients with TCC did not display significantly elevated perceived stress (p = 0.072) or general anxiety (p = 0.170). Regarding personality factors, levels of openness were lower in TCC compared with healthy controls (34.2 ± 4.3 vs. 38.2 ± 5.6, p = 0.021). No differences between TCC and heart failure patients were found regarding the psychological measures. CONCLUSIONS: TCC is associated with higher levels of depressive symptoms, more illness-related anxiety and less openness compared with healthy controls. These data suggest that TCC is associated with adverse psychological factors that may persist well after the acute episode.

Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons.

Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.

Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1.

Aging of transgenic mice that overexpress the London mutant of amyloid precursor protein (APP/V717I) (Moechars et al., 1999a) was now demonstrated not to affect the normalized levels of alpha- or beta-cleaved secreted APP nor of the beta-C-terminal stubs. This indicated that aging did not markedly disturb either alpha- or beta-secretase cleavage of APP and failed to explain the origin of the massive amounts of amyloid peptides Abeta40 and Abeta42, soluble and precipitated as amyloid plaques in the brain of old APP/V717I transgenic mice. We tested the hypothesis that aging acted on presenilin1 (PS1) to affect gamma-secretase-mediated production of amyloid peptides by comparing aged APP/V717I transgenic mice to double transgenic mice coexpressing human PS1 and APP/V717I. In double transgenic mice with mutant (A246E) but not wild-type human PS1, brain amyloid peptide levels increased and resulted in amyloid plaques when the mice were only 6-9 months old, much earlier than in APP/V717I transgenic mice (12-15 months old). Mutant PS1 increased mainly brain Abeta42 levels, whereas in aged APP/V717I transgenic mice, both Abeta42 and Abeta40 increased. This resulted in a dramatic difference in the Abeta42/Abeta40 ratio of precipitated or plaque-associated amyloid peptides, i.e., 3.11+/-0.22 in double APP/V717I x PS1/A246E transgenic mice compared with 0.43 +/- 0.07 in aged APP/V717I transgenic mice, and demonstrated a clear difference between the effect of aging and the effect of the insertion of a mutant PS1 transgene. In conclusion, we demonstrate that aging did not favor amyloidogenic over nonamyloidogenic processing of APP, nor did it exert a mutant PS1-like effect on gamma-secretase. Therefore, the data are interpreted to suggest that parenchymal and vascular accumulation of amyloid in aging brain resulted from failure to clear the amyloid peptides rather than from increased production.