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박재형,Margaret M. Park,Samar Farha,Jacqueline Sharp,Erika Lundgrin,Suzy Comhair,Wai Hong Tang,Serpil C. Erzurum,James D. Thomas 한국심초음파학회 2015 Journal of Cardiovascular Imaging (J Cardiovasc Im Vol.23 No.2
Background: New 2-dimensional strain echocardiography enables quantification of right ventricular (RV) mechanics byassessing global longitudinal strain of RV (GLSRV) in patients with pulmonary arterial hypertension (PAH). However, theprognostic significance of impaired GLSRV is unclear in these patients. Methods: Comprehensive echocardiography was performed in 51 consecutive PAH patients without atrial fibrillation (40females, 48 ± 14 years old) with long-term follow-up. GLSRV was measured with off-line with velocity vector imaging (VVI,Siemens Medical System, Mountain View, CA, USA). Results: GLSRV showed significant correlation with RV fractional area change (r = -0.606, p < 0.001), tricuspid annular planesystolic excursion (r = -0.579, p < 0.001), and RV Tei index (r = 0.590, p < 0.001). It showed significant correlations with pulmonaryvascular resistance (r = 0.469, p = 0.001) and B-natriuretic peptide concentration (r = 0.351, p = 0.012). During a clinical followuptime (45 ± 15 months), 20 patients experienced one or more adverse events (12 death, 2 lung transplantation, and 15 heartfailure hospitalization). After multivariate analysis, age [hazard ratio (HR) = 2.343, p = 0.040] and GLSRV (HR = 2.122, p =0.040) were associated with adverse clinical events. Age (HR = 3.200, p = 0.016) and GLSRV (HR = 2.090, p = 0.042) were alsosignificant predictors of death. Impaired GLSRV (≥ -15.5%) was associated with lower event-free survival (HR = 4.906, p = 0.001)and increased mortality (HR = 8.842, p = 0.005). Conclusion: GLSRV by VVI showed significant correlations with conventional echocardiographic parameters indicating RVsystolic function. Lower GLSRV (≥ -15.5%) was significantly associated with presence of adverse clinical events and deaths inPAH patients.
Kim, Jongmin,Hwangbo, Cheol,Hu, Xiaoyue,Kang, Yujung,Papangeli, Irinna,Mehrotra, Devi,Park, Hyekyung,Ju, Hyekyung,McLean, Danielle L.,Comhair, Suzy A.,Erzurum, Serpil C.,Chun, Hyung J. American Heart Association, Inc. 2015 CIRCULATION - Vol.131 No.2
<P><B>Background—</B></P><P>Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary arterioles, characterized by increased pulmonary arterial pressure and right ventricular failure. The cause of PAH is complex, but aberrant proliferation of the pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells is thought to play an important role in its pathogenesis. Understanding the mechanisms of transcriptional gene regulation involved in pulmonary vascular homeostasis can provide key insights into potential therapeutic strategies.</P><P><B>Methods and Results—</B></P><P>We demonstrate that the activity of the transcription factor myocyte enhancer factor 2 (MEF2) is significantly impaired in the PAECs derived from subjects with PAH. We identified MEF2 as the key cis-acting factor that regulates expression of a number of transcriptional targets involved in pulmonary vascular homeostasis, including microRNAs 424 and 503, connexins 37, and 40, and Krűppel Like Factors 2 and 4, which were found to be significantly decreased in PAH PAECs. The impaired MEF2 activity in PAH PAECs was mediated by excess nuclear accumulation of 2 class IIa histone deacetylases (HDACs) that inhibit its function, namely HDAC4 and HDAC5. Selective, pharmacological inhibition of class IIa HDACs led to restoration of MEF2 activity in PAECs, as demonstrated by increased expression of its transcriptional targets, decreased cell migration and proliferation, and rescue of experimental pulmonary hypertension models.</P><P><B>Conclusions—</B></P><P>Our results demonstrate that strategies to augment MEF2 activity hold potential therapeutic value in PAH. Moreover, we identify selective HDAC IIa inhibition as a viable alternative approach to avoid the potential adverse effects of broad spectrum HDAC inhibition in PAH.</P>