Assessment of severity in aortic stenosis – Incremental value of endocardial function parameters compared to standard indexes

Several studies have reported that patients (pts) with severe aortic stenosis and similar pressure gradients or even similar aortic valve areas may have quite different symptomatic status and clinical outcomes suggesting that other factors might have a significant impact on the pathophysiology of this disease. Our purpose was to assess the severity of subendocardial wall dysfunction in symptomatic and asymptomatic pts with aortic stenosis using tissue Doppler imaging (TDI), strain rate imaging (SRI) and cyclic variation of integrated backscatter (IB). We studied 68 pts with aortic valvar stenosis and 46 subjects with no signs of heart disease. SRI/IB indexes were calculated in the apical four chambers views at endocardial level. Early diastolic endocardial strain rate showed the best correlation with transvalvar pressure gradients and valve areas. Compared with controls, symptomatic pts showed a more marked decrease in endocardial strain, strain rate and cyclic variation of IB. Receiver operating characteristic (ROC) curves suggested that the thresholds offering an adequate compromise between sensitivity and specificity for the prediction of symptoms were >/=60 mm Hg for the pressure gradient, less than 0.60 cm(2)/m(2) for aortic valve area, less than 20% for strain, less than 2.0 s(-1) for strain rate and less than 3.0 dB for cyclic variation. The combination of pressure gradient, aortic valve area and SRI/IB parameters resulted in an improvement of the overall performance for predicting the symptomatic state. Thus, SRI/IB parameters have an incremental value in differentiating symptomatic and asymptomatic pts with aortic stenosis compared with conventional hemodynamic parameters

Identification of Two DNMT3A Mutations Compromising Protein Stability and Methylation Capacity in Acute Myeloid Leukemia

Somatic mutations of DNMT3A occur in about 20% of acute myeloid leukemia (AML) patients. They mostly consist in heterozygous missense mutations targeting a hotspot site at R882 codon, which exhibit a dominant negative effect and are associated with high myeloblast count, advanced age, and poor prognosis. Other types of mutations such as truncations, insertions, or single-nucleotide deletion also affect the DNMT3A gene, though with lower frequency. The present study aimed to characterize two DNMT3A gene mutations identified by next-generation sequencing (NGS), through analysis of protein stability and DNA methylation status at CpG islands. The first mutation was a single-nucleotide variant of DNMT3A at exon 20 causing a premature STOP codon (c.2385G > A; p.Trp795 17; NM-022552.4). The DNMT3A mutation load increased from 4.5% to 38.2% during guadecitabine treatment, with a dominant negative effect on CpG methylation and on protein expression. The second mutation was a novel insertion of 35 nucleotides in exon 22 of DNMT3A (NM-022552.4) that introduced a STOP codon too, after the amino acid Glu863 caused by a frameshift insertion (c.2586-2587insTCATGAATGAGAAAGAGGACATCTTATGGTGCACT; p. Thr862-Glu863fsins). The mutation, which was associated with reduced DNMT3A expression and CpG methylation, persisted at relapse with minor changes in the methylation profile and at protein level. Our data highlight the need to better understand the consequences of DNMT3A mutations other than R882 substitutions in the leukemogenic process in order to tailor patient treatments, thus avoiding therapeutic resistance and disease relapse

Novel and rare fusion transcripts involving transcription factors and tumor suppressor genes in acute myeloid leukemia

Approximately 18% of acute myeloid leukemia (AML) cases express a fusion transcript. However, few fusions are recurrent across AML and the identification of these rare chimeras is of interest to characterize AML patients. Here, we studied the transcriptome of 8 adult AML patients with poorly described chromosomal translocation(s), with the aim of identifying novel and rare fusion transcripts. We integrated RNA-sequencing data with multiple approaches including computational analysis, Sanger sequencing, fluorescence in situ hybridization and in vitro studies to assess the oncogenic potential of the ZEB2-BCL11B chimera. We detected 7 different fusions with partner genes involving transcription factors (OAZ-MAFK, ZEB2-BCL11B), tumor suppressors (SAV1-GYPB, PUF60-TYW1, CNOT2-WT1) and rearrangements associated with the loss of NF1 (CPD-PXT1, UTP6-CRLF3). Notably, ZEB2-BCL11B rearrangements co-occurred with FLT3 mutations and were associated with a poorly differentiated or mixed phenotype leukemia. Although the fusion alone did not transform murine c-Kit+ bone marrow cells, 45.4% of 14q32 non-rearranged AML cases were also BCL11B-positive, suggesting a more general and complex mechanism of leukemogenesis associated with BCL11B expression. Overall, by combining different approaches, we described rare fusion events contributing to the complexity of AML and we linked the expression of some chimeras to genomic alterations hitting known genes in AML

Assessment of aortic wall mechanics in Marfan syndrome by transesophageal echocardiography and tissue Doppler imaging

Background. It has been described that aortic elastic properties are abnormal in patients with Marfan syndrome irrespective of the aortic diameter. The aim of our study was to investigate the potential value of transesophageal echocardiography combined with tissue Doppler imaging for the assessment of elastic properties of the thoracic aorta in patients with Marfan disease. Methods. Twentyone patients (pts) with Marfan syndrome (Gent criteria) aged 13 to 52 years were studied with multiplane transesophageal echocardiography (TEE). 7/21 pts had surgery for aortic dissection. Sixteen age- and gender-matched healthy subjects who had normal findings at TEE served as controls. The ascending and descending aorta were visualized in a TEE short axis view. Standard formulas and tissue Doppler imaging (TDI, Toshiba corp.) during TEE were used for the quantification of aortic elastic properties. Distensibility, stiffness index, and pulse wave velocity were calculated using M-mode data. TDI tracing displayed accelerated expansion of the aortic wall followed by a slow deceleration, a plateau and then a rapid deceleration into diastole. Acceleration time (AT, msec), maximum wall expansion velocity (Vmax, cm/sec), wall contraction E and A velocities (cm/sec), and peak systolic wall strain (e, %) were determined. Results. Ascending and descending thoracic aorta dilation (>40mm and >30mm) was present in 11/21 and 12/21 pts, respectively. Marfan patients had a lower distensibility and a higher stiffness index both in patients with dilated (p<.001) and normal aortas (p<.05). Highly significant differences were obtained between both groups for Vmax (2.8±1.6 vs 6.7±1.8 cm/sec, p<.0001), AT (68±7 vs 89±5msec, p<.0001) and strain (7.6±1.3% vs 24±2.9%, p<.0001). The indices derived from TDI were significantly decreased compared to controls both in patients with dilated (p<.0001) and normal aortas (p<.001). Significant and independent predictors of aortic dilatation were systolic blood pressure (F=19.2, p<.005), aortic stiffness index (F=21.3, p<.005), Vmax (F=31.2, p<.005), and strain (F=33.6, p<.005). Decreased aortic strain, Vmax and stiffness index were predictive of aortic dissection (Odds ratio = 3.9, p <.0001, 3.5, p <.0001, and 1.5, p<.005, respectively). Conclusion. Our results show that in Marfan syndrome elastic properties of the thoracic aorta are significantly different from normal controls, even in the absence of vessel dilatation. TDI assessment of aortic wall mechanics in Marfan patients is more accurate than standard M-mode measurements and is predictive of aortic dilatation and dissectio

Assessment of aortic elastic properties by transesophageal strain echocardiography after repair of coarctation of the aorta.

Background: Increased arterial stiffness may participate in the genesis of hypertension and persistent increases in left ventricular mass after surgical correction of coarctation of the aorta (CoA). The purpose of the present study was to assess the aortic elastic properties using tissue Doppler imaging (TDI) and strain echocardiography in patients (pts) after coartectomy. Methods: Transesophageal echocardiography with TDI and strain capabilities (Toshiba corp, Tokyo, Japan) was performed in 10 pts aged 12-39 years who had repair of CoA and residual aortic narrowing <30% and who were not hypertensive at rest. 11 age- and sex-matched subjects with no signs of heart disease were selected as normal controls (CTR). Aortic transverse sections were measured at the level of the proximal, distal and coarctation segments. Transverse aortic stiffness was measured by the elastic modulus (Ep) and stiffness index beta () using previously reported formulas. TDI wall velocities during systole (Sw), early relaxation (Ew) and atrial systole (Aw) were measured in transverse views in both groups. Using dedicated software peak systolic strain (ps ) was measured from the resultant deformation curves in the same views. Results: In the coartectomy pts there was a significant increase of Ep (47.66.5 vs 21.82.9 kPa, p<0.001) and (4.112.51 vs 2.280.65, p<0.005) at the level of the proximal and coarctation segments compared with CTR. At the same level Sw velocities were significantly decreased compared with CTR (4.10.8cm/sec vs 6.90.9cm/sec, p<0.001). There was a significant decrease of ps in the coartectomy pts compared with CTR in the proximal and coarctation segments (71.4% vs 232.5%, p<0.0001). Univariate correlations in the coartectomy group showed significant relationships of and Sw velocities (r=-0.66, p<0.01) and and ps (r=-0.78, p<0.001) Conclusion: Thus, pts with CoA have increased proximal aortic stiffness and reduced wall velocities and wall strain even after successful repair

Assessement of viability by strain rate imaging in ischemic cardiomiopathy.

Background. We aimed to determine if strain rate (SR) imaging (ApliQ, Toshiba corp.) during low-dose dobutamine echocardiography (LDDE) provide valuable informations in detecting hibernating but viable myocardium. Methods. LDDE (10 mcg/Kg/min) was performed in 19 pts (age 5813 years) with chronic ischemic left ventricular dysfunction (LVEF 2810%) within 30 days before myocardial revascularization (PTCA 10 pts, CABG 9 pts). Viability by LDDE-2D was defined as an improvement in contractility of 1 grade. Peak strain rate and tissue Doppler were measured at the base, mid and apex in the apical 4 and 2 chamber views (septum, lateral, anterior, inferior). Peak early diastolic (E-SR) and late diastolic (A-SR) myocardial SR was determined at baseline and during dobutamine infusion. Viability by LDDE-SR was defined as an increase in peak SR >15% compared to baseline in > 2 contiguous segments. Results. Mean increase in heart rate during stress tests was 17 +/- 3 beats/min for LDDE-2D and 15 +/- 6 beats/min for LDDE-SR (p=NS). Follow-up echocardiography at rest was repeated 60 days after coronary revascularization. In 97 akinetic segments, contractile reserve was detected in 44 (45%) by LDDE-2D and 54 (56%) by LDDE-SR. At following echocardiography, functional improvement of wall thickening was identified in 57 (59%) segments. The sensitivity and specificity for predicting functional recovery were 87% and 92% for LDDE-2D and 94% and 97% for LDDE-SR. Conclusions. LDDE-SR appears as feasibile as LDDE-DE in predicting recovery of regional ventricular function after coronary revascularization but with the advantage of being automated and quantitative

Assessment of aortic wall mechanics in Marfan syndrome by transesophageal tissue Doppler echocardiography

The aim of this study was to investigate the value of tissue Doppler imaging (TDI) using transesophageal echocardiography (TEE) in assessing the elastic properties of the thoracic aorta in patients with Marfan’s syndrome. Aortic distensibility, stiffness index, and pulse-wave velocity were calculated using M-mode data in a TEE short-axis view in 31 patients with Marfan’s syndrome and 22 normal controls. Acceleration time, maximum wall expansion velocity (Vmax), and wall strain were determined from TDI tracings. Indexes derived from TDI differed at a greater level of significance than M-mode-derived indexes in patients with dilated and normal aortas. Significant predictors of aortic dilation were systolic blood pressure, aortic stiffness index, Vmax, and strain. Decreased aortic strain and Vmax and increased stiffness index were predictive of aortic dissection (odds ratios 4.5, 3.3, and 2.2). In conclusion, the TDI assessment of aortic wall mechanics is complementary to standard M-mode measurements in discriminating normal subjects from patients with Marfan’s syndrome and is accurate in predicting aortic dilation and dissection. Color Doppler myocardial imaging has emerged as a new technique for the assessment of ventricular myocardial velocities and regional ventricular contractility, [1], [2], [3] and [4] and preliminary data suggest its suitability for the evaluation of aortic wall velocities. [5], [6] and [7] This study was performed to assess the potential value of tissue Doppler imaging (TDI) using transesophageal echocardiography (TEE) in evaluating the elastic properties of the ascending and descending thoracic aortas in patients with Marfan’s syndrome and normal controls and in predicting aortic dilation and dissection