Neurodegeneration and Unfolded-Protein Response in Mice Expressing a Membrane-Tethered Flexible Tail of PrP

The cellular prion protein (PrP^C) consists of a flexible N-terminal tail (FT, aa 23–128) hinged to a membrane-anchored globular domain (GD, aa 129–231). Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrP_Δ141–225, or “FTgpi”). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.     

Left ventricular markers of global dyssynchrony predict limited exercise capacity in heart failure, but not in patients with preserved ejection fraction

ABSTRACT: BACKGROUND: The aim of this study was to prospectively examine echocardiographic parameters that correlate and predict functional capacity assessed by 6 min walk test (6-MWT) in patients with heart failure (HF), irrespective of ejection fraction (EF). METHODS: In 147 HF patients (mean age 61 +/- 11 years, 50.3% male), a 6-MWT and an echo-Doppler study were performed in the same day. Global LV dyssynchrony was indirectly assessed by total isovolumic time - t-IVT [in s/min; calculated as: 60 -- (total ejection time + total filling time)], and Tei index (t-IVT/ejection time). Patients were divided into two groups based on the 6-MWT distance (Group I: <=300 m and Group II: >300 m), and also in two groups according to EF (Group A: LVEF >= 45% and Group B: LVEF < 45%). RESULTS: In the cohort of patients as a whole, the 6-MWT correlated with t-IVT (r = -0.49, p < 0.001) and Tei index (r = -0.43, p < 0.001) but not with any of the other clinical or echocardiographic parameters. Group I had lower hemoglobin level (p = 0.02), lower EF (p = 0.003), larger left atrium (p = 0.02), thicker interventricular septum (p = 0.02), lower A wave (p = 0.01) and lateral wall late diastolic myocardial velocity a' (p = 0.047), longer isovolumic relaxation time (r = 0.003) and longer t-IVT (p = 0.03), compared with Group II. In the patients cohort as a whole, only t-IVT ratio [1.257 (1.071-1.476), p = 0.005], LV EF [0.947 (0.903-0.993), p = 0.02], and E/A ratio [0.553 (0.315-0.972), p = 0.04] independently predicted poor 6-MWT performance (<300 m) in multivariate analysis. None of the echocardiographic measurements predicted exercise tolerance in HFpEF. CONCLUSION: In patients with HF, the limited exercise capacity, assessed by 6-MWT, is related mostly to severity of global LV dyssynchrony, more than EF or raised filling pressures. The lack of exercise predictors in HFpEF reflects its multifactorial pathophysiology.     

Different determinants of exercise capacity in HFpEF compared to HFrEF

Background

Quality of life is as important as survival in heart failure (HF) patients. Controversies exist with regards to echocardiographic determinants of exercise capacity in HF, particularly in patients with preserved ejection fraction (HFpEF). The aim of this study was to prospectively examine echocardiographic parameters that correlate and predict functional exercise capacity assessed by 6 min walk test (6-MWT) in patients with HFpEF.

Methods

In 111 HF patients (mean age 63?±?10 years, 47% female), an echo-Doppler study and a 6-MWT were performed in the same day. Patients were divided into two groups based on the 6-MWT distance (Group I: ≤ 300 m and Group II: >300 m).

Results

Group I were older (p?=?0.008), had higher prevalence of diabetes (p?=?0.027), higher baseline heart rate (p?=?0.004), larger left atrium - LA (p?=?0.001), longer LV filling time - FT (p?=?0.019), shorter isovolumic relaxation time (p?=?0.037), shorter pulmonary artery acceleration time - PA acceleration time (p?=?0.006), lower left atrial lateral wall myocardial velocity (a’) (p?=?0.018) and lower septal systolic myocardial velocity (s’) (p?=?0.023), compared with Group II.Patients with HF and reduced EF (HFrEF) had lower hemoglobin (p?=?0.007), higher baseline heart rate (p?=?0.005), higher NT-ProBNP (p?=?0.001), larger LA (p?=?0.004), lower septal s’, e’, a’ waves, and septal mitral annular plane systolic excursion (MAPSE), shorter PA acceleration time (p?<?0.001 for all), lower lateral MAPSE, higher E/A & E/e’, and shorter LVFT (p?=?0.001 for all), lower lateral e’ (p?=?0.009), s’ (p?=?0.006), right ventricular e’ and LA emptying fraction (p?=?0.012 for both), compared with HFpEF patients.In multivariate analysis, only LA diameter [2.676 (1.242–5.766), p?=?0.012], and diabetes [0.274 (0.084–0.898), p?=?0.033] independently predicted poor 6-MWT performance in the group as a whole. In HFrEF, age [1.073 (1.012–1.137), p?=?0.018] and LA diameter [3.685 (1.348–10.071), p?=?0.011], but in HFpEF, lateral s’ [0.295 (0.099–0.882), p?=?0.029], and hemoglobin level [0.497 (0.248–0.998), p?=?0.049] independently predicted poor 6-MWT performance.

Conclusions

In HF patients determinants of exercise capacity differ according to severity of overall LV systolic function, with left atrial enlargement in HFrEF and longitudinal systolic shortening in HFpEF as the the main determinants.