Catherine Sportouch-Dukhan

Low-Flow, Low-Gradient Severe Aortic Stenosis Despite Normal Ejection Fraction Is Associated With Severe Left Ventricular Dysfunction as Assessed by Speckle-Tracking Echocardiography: A Multicenter Study

Background— Low-flow low-gradient (LFLG) is sometimes observed in severe aortic stenosis (AS) despite normal ejection fraction, but its frequency and mechanisms are still debated. We aimed to describe the characteristics of patients with LFLG AS and assess the presence of longitudinal left ventricular dysfunction in these patients. Methods and Results— In a multicenter prospective study, 340 consecutive patients with severe AS and normal ejection fraction were studied. Longitudinal left ventricular function was assessed by 2D-strain and global afterload by valvulo-arterial impedance. Patients were classified according to flow and gradient: low flow was defined as a stroke volume index ⩽35 mL/m2, low gradient as a mean gradient ⩽40 mm Hg. Most patients (n=258, 75.9%) presented with high-gradient AS, and 82 patients (24.1%) with low-gradient AS. Among the latter, 52 (15.3%) presented with normal flow and low gradient and 30 (8.8%) with LFLG. As compared with normal flow and low gradient, patients with LFLG had more severe AS (aortic valve area=0.7±0.12 cm2 versus 0.86±0.14 cm2), higher valvulo-arterial impedance (5.5±1.1 versus 4±0.8 mm Hg/mL/m2), and worse longitudinal left ventricular function (basal longitudinal strain=−11.6±3.4 versus −14.8±3%; P<0.001 for all). Conclusions— LFLG AS is observed in 9% of patients with severe AS and normal ejection fraction and is associated with high global afterload and reduced longitudinal systolic function. Patients with normal-flow low-gradient AS are more frequent and present with less severe AS, normal afterload, and less severe longitudinal dysfunction. Severe left ventricular longitudinal dysfunction is a new explanation to the concept of LFLG AS.

Delayed Postconditioning in the Mouse Heart In Vivo

Background— Reperfusion during acute myocardial infarction remains the best treatment for reducing infarct size. Postconditioning, applied at the onset of reperfusion, reduces myocardial infarction both in animals and humans. The objective of this study was to identify the time delay to apply postconditioning at reperfusion, allowing preservation of cardioprotection in the mouse myocardium. This is a major issue in the management of acute myocardial infarction patients. Methods and Results— Mice were subjected to 40 minutes of ischemia and 60 minutes of reperfusion (IR60′). Postconditioning protocols corresponding to repetitive ischemia (3 cycles of 1 minute of ischemia and 1 minute of reperfusion) were applied during early reperfusion at various time durations (&Dgr;t) after reopening of the coronary artery (&Dgr;t=10 seconds, 1, 5, 10, 15, 20, 30, and 45 minutes; PostC&Dgr;t). Infarct size/area at risk was reduced by 71% in PostC&Dgr;1 compared with IR60′ mice (P=5×10−6). There was a linear correlation (r2=0.91) between infarct size and &Dgr;t, indicating that the cardioprotective effect of delayed postconditioning was progressively attenuated when &Dgr;t time increased. The protective effect of PostC&Dgr;1 and PostC&Dgr;15 was still effective when the duration of reperfusion was prolonged to 24 hours (IR24 hours; PostC&Dgr;1 and PostC&Dgr;15 versus IR24 hours, P=0.001). Similar results were obtained for internucleosomal DNA fragmentation and lactate dehydrogenase release. Conclusions— This study in our in vivo mouse model of myocardial IR shows for the first time that delaying the intervention of postconditioning to 30 minutes does not abrogate the cardioprotective effect of postconditioning. This finding provides evidence that the time window of protection afforded by postconditioning may be larger than initially reported.

Association between cardiovascular vs. non‐cardiovascular co‐morbidities and outcomes in heart failure with preserved ejection fraction

The prevalence of cardiovascular and non‐cardiovascular co‐morbidities and their relative importance for outcomes in heart failure with preserved ejection fraction (HFPEF) remain poorly characterized. This study aimed to investigate this.

Myocardial Expression of a Dominant-Negative Form of Daxx Decreases Infarct Size and Attenuates Apoptosis in an In Vivo Mouse Model of Ischemia/Reperfusion Injury

Background— Apoptosis has been described extensively in acute myocardial infarction and chronic heart failure. Because Daxx (death-associated protein) appears to be essential for stress-induced cell death and acts as an antisurvival molecule, we tested the hypothesis that Daxx is involved in myocardial ischemia/reperfusion–induced cell death in vivo. Methods and Results— Transgenic mice overexpressing a dominant-negative form of Daxx (Daxx-DN) under the control of the &bgr;-actin promoter and control wild-type mice underwent an ischemia/reperfusion protocol: 40 minutes of left coronary artery occlusion and 60 minutes of reperfusion. Area at risk and infarct size were measured after dual staining by triphenyltetrazolium chloride and phthalocyanine blue dye. Apoptosis was measured in the ischemic versus the nonischemic part of the left ventricle by terminal deoxynucleotidyl transferase–mediated dUTP biotin nick end labeling staining, enzyme-linked immunosorbent assay, and Western blotting of caspase-3, caspase-8, and poly(ADP-ribose) polymerase. The mitogen-activated protein kinase status was investigated by Western blot analysis. Comparison between groups was assessed by ANOVA or Student t test (statistical significance: P<0.05). Left ventricle tissues from transgenic mice expressed Daxx-DN at the protein level. Area at risk/left ventricle values were comparable among groups. Infarct size/area at risk was 45% reduced in Daxx-DN versus wild-type mice (P<0.001). This cardioprotection was maintained for a 4-hour reperfusion. Ischemia/reperfusion-induced apoptosis was significantly decreased and ERK1/2 prosurvival pathway was activated in ischemic Daxx-DN hearts. Conclusions— Our study clearly indicates that Daxx participates in myocardial ischemia/reperfusion proapoptotic signaling in vivo.

Down-regulation of the transcription factor ZAC1 upon pre- and postconditioning protects against I/R injury in the mouse myocardium

AIMS Myocardial infarction leads to heart failure and death. Ischaemic preconditioning (PreC) and postconditioning (PostC) reduce infarct size in animal models and human. Zac1 was identified as the only gene related to apoptosis and jointly down-regulated upon PreC and PostC. The aim of our study was to investigate the role of Zac1 down-regulation during ischaemia-reperfusion (I/R) in vivo. METHODS AND RESULTS C57BL/6 mice were submitted to myocardial I/R injury, PreC, or PostC protocols. QPCR and immunochemistry showed that Zac1 expression was down-regulated both at the transcriptional and the protein levels upon PreC and PostC. Zac1(-/-) Knockout mice (n = 7) developed smaller infarcts (54%) than Zac1(+/+) littermates (n = 8) and decreased apoptosis (61.7%) in the ischaemic part of the left ventricle during I/R (Zac1(-/-), n = 6 vs. Zac1(+/+), n = 7; P = 0.0012). Mutants showed under control conditions a decrease of 53.9% in mRNA of Daxx, a pro-apoptotic protein playing a key role in I/R injuries (4.81 ± 0.77, n = 4 Zac1(-/-) mice vs. 10.44 ± 3.5, n = 7 Zac1(+/+) mice; P = 0.0121). CONCLUSION Our study shows for the first time that Zac1 is down-regulated both at the transcriptional and protein levels upon PreC and PostC in wild-type mice. Moreover, inactivation of Zac1 in vivo is associated with a decreased amount of Daxx transcripts and, upon I/R injury, decreased infarct size and apoptosis. Altogether, our results show that Zac1 down-regulation plays a key role during cardioprotection against I/R injury and support the concept that cardioprotection regulates a network of interacting pro-apoptotic genes including Zac1 and Daxx.

New Insights in Research About Acute Ischemic Myocardial Injury and Inflammation

Recognition that inflammation may contribute to the pathogenesis of various cardiac diseases has naturally led to the evaluation of the therapeutic potential of a range of anti-inflammatory approaches. Unfortunately, results in most settings have been disappointing. The majority of novel approaches fail despite promising preclinical data, partly attributable to off-target effects. The purpose of this review, focused on inflammation following acute myocardial ischemia, is to give a brief overview of the new insights regarding research on pro-inflammatory signaling cascades that could be targeted for cardioprotective therapeutic developments.

0009: Cardiac involvement in hypereosinophilic syndrome: role of multimodality imaging

Cardiac disease occurs in more than 50% of patients with idiopathic hypereosinophilic syndrome; it is the major cause of morbidity and mortality in patients with this syndrome. The overall mortality is high if untreated. We aim to rapport recent experience in these cardiac diseases, especiall echographic features and the contribution of multimodalities imaging. This retrospective, descriptive and multicenter study reports the findings of patients in cardiac centers of Marseille, Montpellier and Rennes between September 2008 and March 2014. Echographic, MRI cardiac, coronarographic, PET CT, biology and histologic findings are reported. Seven patients have been reported. Echocardiography is the reference diagnostic method. Classical findings are progressive endomyocardial thickening, apical obliteration of one or both ventricles by echogenic material suggestive of fibrosis or thrombus formation, posterior mitral leaflet involvement and papillary dysfunction resulting in severe mitral regurgitation. These features are involved in embolic events or heart failure. MRI helps refine the diagnosis. The characteristic irreversible stage shows a circumferential thickened fibrotic sub endocardium with wall thrombi. The CT identifies non ischemic thrombus excluding coronary artery disease by coronary imaging. Coronary angiography may reveal fibrosis by the smoothed appearance of the ventricular walls and apical filling. PET CT shows general signs of myocarditis, such as myocyte necrosis, in the first stage of the disease. Symptomatic treatment can lead to cardiac surgery (mitral valve replacement, resection of endomyocardial fibrosis). Each imaging technique plays a role in each of the three stages of the disease and the typical features of myocarditis, thrombus or fibrosis must be identified. Only seven cases of this rare disease have been identified in three french cardiac centers since 2008; this too small sample does not allow us to draw statistical conclusions. Download : Download high-res image (84KB) Download : Download full-size image Abstract 0009 - Figure: endomyocardial thickening and mitral involvement

090 - Could heart rate predict duration of hospitalizations for patients admitted for acute pericarditis?

Purpose Acute pericarditis is rather frequent. Annual incidence is estimated to 27.7 new cases per 100,000 inhabitants in Europe. About 5% of all non-ischemic chest pains admitted at emergencies could be pericarditis. Most of the patients are young patients, with a significant cost to society, particularly as regards hospitalizations. Indeed, pericarditis represents 1% of all hospitalizations in department of cardiology. It could be very interesting if clinical presentation and especially heart rate could help predict duration of hospitalizations. Methods Between March 2007 and February 2010, we conducted a retrospective study concerning all patients admitted in our center for acute pericarditis. Diagnosis criteria included 2 among the 4 following: typical chest pain, friction rub, pericardial effusion on echocardiography, or typical ECG findings. We evaluated hospital events (heart failure, acute pains, death) and biology during hospitalization (CRP on admission, on days 1, 2, 3, and especially peak). At one month, clinical events were recorded through phone calls when not noticed in clinical settings. Results We included 73 patients. Mean age was 41.0 y (CI 95% 37.2-44.8) and mean hospitalization duration was 3.5 d (2.5-4.5). Heart rate on admission was 88 bpm (83.6-92.4) and 71.8 bpm (68.9-74.7) on discharge. CRP peak was strongly correlated with heart rate (r=0.54; p Conclusion In acute pericarditis, cardiac frequency at admission is correlated with hospitalization duration, and could be a new prognostic marker. This point deserves to be explored, in order to reduce hospitalization duration. Download : Download full-size image

Response to Letter Regarding Article, “Low-Flow, Low-Gradient Severe Aortic Stenosis Despite Normal Ejection Fraction Is Associated With Severe Left Ventricular Dysfunction as Assessed by Speckle-Tracking Echocardiography: A Multicenter Study”

Response: We read the comments of Dr Ozkan and would like to answer his questions and remarks. Concerning left ventricular midwall fractional shortening, it is known for a long time that it is impaired in severe aortic stenosis (AS). Midwall fractional shortening has been shown to be particularly reduced in low-flow, low-gradient AS, as shown by Hachicha et al1 and confirmed in our study.2 In both studies, midwall fractional shortening was particularly low in the group of low-flow AS, although the difference was not significant in our study ( P =0.07), probably related to the small sample size in each subgroup. Dr Ozkan underlines that values of basal strain as low as −13.9% have been reported in normal individuals,3,4 meaning that the low basal strain observed in patients with AS in our study does not systematically represent left ventricular dysfunction. However, a …