-Despite its functional importance in various fundamental bioprocesses, the studies of N6-methyladenosine (m6A) in the heart are lacking. Here we show that, fat mass and obesity-associated (FTO), an m6A demethylase, plays a critical role in cardiac contractile function during homeostasis, remodeling and regeneration. -We used clinical human samples, preclinical pig and mouse models and primary cardiomyocyte cell cultures to study the functional role of m6A and FTO in the heart and in cardiomyocytes. We modulated expression of FTO using AAV9 (in vivo), adenovirus (both in vivo and in vitro) and siRNAs (in vitro) to study its function in regulating cardiomyocyte m6A, calcium dynamics and contractility and cardiac function post-ischemia. We performed methylated (m6A) RNA immunoprecipitation sequencing (MeRIP-seq) to map transcriptome-wide m6A, and MeRIP qPCR assays to map and validate m6A in individual transcripts, in healthy and failing hearts and myocytes. -We discovered that FTO has decreased expression in failing mammalian hearts and hypoxic cardiomyocytes, thereby increasing m6A in RNA and decreasing cardiomyocyte contractile function. Improving expression of FTO in failing mouse hearts attenuated the ischemia-induced increase in m6A and decrease in cardiac contractile function. This is carried out by the demethylation activity of FTO, which selectively demethylates cardiac contractile transcripts, thus preventing their degradation and improving their protein expression under ischemia. Additionally, we demonstrate that FTO overexpression in mouse models of MI decreased fibrosis and enhanced angiogenesis. -Collectively, our study demonstrates the functional importance of FTO-dependent cardiac m6A methylome in cardiac contraction during heart failure and provides a novel mechanistic insight into the therapeutic mechanisms of FTO.

Objective: To evaluate the prevalence and significance of khat chewing in patients with acute coronary syndrome (ACS). From January 29, 2007, through July 29, 2007 consecutive patients presenting with ACS were enrolled in a prospective, multicenter study from 6 adjacent Middle Eastern countries. Patients and MethOds:Results: Of the 8176 study patients, 7242 (88.6%) were nonkhat chewers, and 934 (11.4%) were khat chewers, mainly of Yemeni origin. Khat chewers were older (57 vs 56 years; p=.01) and more likely to be men (85.7% vs 74.5%) compared with non-khat chewers. Non-khat chewers were more likely to have diabetes mellitus, hypertension, dyslipidemia, obesity, and prior history of coronary artery disease and revascularization. Cigarette smoking was more prevalent in khat chewers, and they were more likely to present greater than 12 hours after onset of symptoms compared with non-khat chewers. At admission, khat chewers had higher heart rate, Killip class, and Global Registry of Acute Coronary Events risk scores. Khat chewers had a significantly higher risk of cardiogenic shock, stroke, and mortality. After adjustment of baseline variables, khat chewing was an independent risk factor for in-hospital mortality (odds ratio, 1.9; 95% confidence interval, 1.3-2.7; p<.001) and stroke (odds ratio, 2.7; 95% confidence interval, 1.3-5.9; p=.01).cOnclusiOn: In this large cohort of patients with ACS, khat chewing was prevalent and was associated with increased risk of stroke and death. In the context of increasing global migration, a greater awareness of potential widespread practices is essential. Mayo

Background: The purpose of this study was to report the prevalence and the significance of clinically recognized chronic obstructive pulmonary disease (COPD) during acute coronary syndrome (ACS). Hypothesis: COPD in patients with ACS is associated with worse outcome. Methods: Data were derived from a prospective, multicenter, multinationalstudy of 8167 consecutive patients hospitalized with ACS from February to June 2007 in 6 Middle Eastern countries. Data were analyzed according to the presence or absence of COPD. Demographic, management, and in-hospital outcomes were compared. Results: The prevalence of COPD was 5.3%. When compared with non-COPD patients, COPD patients were older and more likely to have diabetes, hypertension, and dyslipidemia. Atypical presentations were more common in COPD patients (P = 0.001). COPD patients were less likely to be treated with thrombolytic therapy (P = 0.001), β-blockers (P = 0.001), and glycoprotein IIb/IIIa inhibitors, and more likely to receive angiotensin-converting enzyme (ACE) inhibitors. Although there was no difference in in-hospital mortality between the 2 groups, patients with COPD were more likely to have heart failure (P = 0.001). Despite the fact that COPD patients with ST-segment elevation myocardial infarction were less likely to receive thrombolytic therapy, they suffered more bleeding complications (2.8% vs 1%, P = 0.04), resulting in prolonged hospitalization. COPD was not an independent predictor of increased in-hospital mortality. Conclusions: In this large cohort of patients with ACS, the prevalence of COPD was 5·3%. Atypical presentation is common among COPD patients, and this may result in delayed therapy. ACS in COPD patients was associated with higher risk of heart failure and major bleeding complications without increased risk of in-hospital mortality.

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