C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A.

A GGGGCC hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense repeat-containing transcripts undergo repeat-associated non-AUG-initiated translation to produce five dipeptide proteins (DPRs). The polyGR and polyPR DPRs are extremely toxic when expressed in Drosophila neurons. To determine the mechanism that mediates this toxicity, we purified DPRs from the Drosophila brain and used mass spectrometry to identify the in vivo neuronal DPR interactome. PolyGR and polyPR interact with ribosomal proteins, and inhibit translation in both human iPSC-derived motor neurons, and adult Drosophila neurons. We next performed a screen of 81 translation-associated proteins in GGGGCC repeat-expressing Drosophila to determine whether this translational repression can be overcome and if this impacts neurodegeneration. Expression of the translation initiation factor eIF1A uniquely rescued DPR-induced toxicity in vivo, indicating that restoring translation is a potential therapeutic strategy. These data directly implicate translational repression in C9orf72 repeat-induced neurodegeneration and identify eIF1A as a novel modifier of C9orf72 repeat toxicity

Comparison of the Effects of Ramipril Versus Telmisartan on High-Sensitivity C-Reactive Protein and Endothelial Progenitor Cells After Acute Coronary Syndrome

To compare the anti-inflammatory and endothelial progenitor cell mobilizing effects of ramipril and telmisartan in patients presenting with acute coronary syndrome (ACS), 42 patients with ACS were randomized after successful percutaneous coronary intervention to ramipril 5 mg/day (22 patients) or telmisartan 80 mg/day (20 patients). Peripheral blood samples were drawn at baseline and at 20 days to measure high-sensitivity C-reactive protein and to assess 4 populations of progenitor cells by flow cytometry, namely CD34(+)/ KDR(+), CD34(+)/CD133(+), CD34(+)/CD133(+)/CD45(-), and CD34(+)/KDR(+)/CD45(-) cells. High-sensitivity C-reactive protein levels, similar in the 2 groups at baseline, were significantly more decreased by telmisartan than by ramipril at follow up (p = 0.013 for time-by-drug interaction). The main effect for time was also significant (p <0.001). CD34(+)/KDR(+) and CD34(+)/CD133(+) cells were similar at baseline and did not change over time (p = 0.2 and p = 0.1, respectively). In contrast, for CD34(+)/KDR(+)/CD45(-) and CD34(+)/CD133(+)/CD45(-) cells, a significant increase with time was seen (p = 0.02 and p = 0.002, respectively) and no differential effect of either drug was seen. In conclusion, telmisartan shows a more potent anti-inflammatory effect than ramipril after an ACS. The 2 drugs do not show a differential effect on endothelial progenitor cell mobilization. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;103:1500-1505

Left ventricular end-diastolic pressure predicts in-hospital outcomes in takotsubo syndrome

Aims: Takotsubo syndrome (TTS) is associated to serious adverse in-hospital complications. We evaluated the role of invasively assessed left ventricular end-diastolic pressure (LVEDP) for predicting in-hospital complications in TTS patients compared to the most widely used echocardiographic parameters of ventricular function. Methods and results: We prospectively enrolled 130 patients (mean age 71.2 ± 11.3 years, 114 [87.7%] female) with TTS. Invasive measurement of LVEDP was performed at the time of cardiac catheterization. The rate of in-hospital complications (composite of acute heart failure, life-threatening arrhythmias and all-cause death) was examined. In-hospital complications occurred in 37 (28.5%) patients. Patients who experienced in-hospital complications had a higher prevalence of neurological trigger and lower prevalence of emotional trigger, higher LVEDP and mean E/e' ratio and lower LV ejection fraction (LVEF) values compared to those who did not experience in-hospital complications. At multivariate logistic regression, higher LVEDP [odds ratio (OR) 1.12, 95% confidence interval (CI) [1.05-1.20], P < 0.001] and lower LVEF (OR 0.95, 95% CI [0.91-0.99], P = 0.011) remained independently predictors of in-hospital complications, while emotional trigger was associated to a lower risk (OR 0.24, 95% CI [0.06-0.96], P = 0.044). The area under the curve (AUC) for LEVDP in the prediction of in-hospital events was 0.776 (95% CI [0.69-0.86], P <0.001, with a sensitivity and specificity of 95% and 58% using a LVEDP cut-off value of 22.5 mmHg). The AUC was significantly higher for LVEDP than for E/e' ratio (P = 0.037). Conclusions: LVEDP measured at the time of catheterization may help in identifying TTS patients at higher risk of cardiovascular deterioration with relevant therapeutic implications

Recurrence of angina after ST-segment elevation myocardial infarction: the role of coronary microvascular obstruction

Background: The recurrence of angina after percutaneous coronary intervention affects 20-35% of patients with stable coronary artery disease; however, few data are available in the setting of ST-segment elevation myocardial infarction. We evaluated the relation between coronary microvascular obstruction and the recurrence of angina at follow-up.Methods: We prospectively enrolled patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Microvascular obstruction was defined as thrombolysis in myocardial infarction flow less than 3 or 3 with myocardial blush grade less than 2. The primary endpoint was the recurrence of angina at follow-up. Moreover, angina status was evaluated by the Seattle angina questionnaire summary score (SAQSS). Therapy at follow-up and the occurrence of major adverse cardiovascular events were also collected.Results: We enrolled 200 patients. Microvascular obstruction occurred in 52 (26%) of them. Follow-up (mean time 25.17 +/- 9.28 months) was performed in all patients. Recurrent angina occurred in 31 (15.5%) patients, with a higher prevalence in patients with microvascular obstruction compared with patients without microvascular obstruction (13 (25.0%) vs. 18 (12.2%), P=0.008). Accordingly, SAQSS was lower and the need for two or more anti-anginal drugs was higher in patients with microvascular obstruction compared with patients without microvascular obstruction. At multiple linear regression analysis a history of previous acute coronary syndrome and the occurrence of microvascular obstruction were the only independent predictors of a worse SAQSS. Finally, the occurrence of major adverse cardiovascular events was higher in patients with microvascular obstruction compared with patients without microvascular obstruction.Conclusions: The recurrence of angina in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention is an important clinical issue. The occurrence of microvascular obstruction portends a worse angina status and is associated with the use of more anti-anginal drugs