Sequencing of NOTCH1 gene in an Italian population with bicuspid aortic valve: Preliminary results from the GISSI OUTLIERS VAR study.

BACKGROUND: Bicuspid aortic valve (BAV) formation is genetically determined, with reduced penetrance and variable expressivity. NOTCH1 is a proven candidate gene and its mutations have been found in familial and sporadic cases of BAV. METHODS: 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. RESULTS: We identified 63 variants, in heterozygous and homozygous states. Fifty-two are common polymorphisms present in almost all patients. Eleven variants are new and never yet reported: two are non-synonymous substitutions, Gly540Asp in exon 10 and Glu851Gln in exon 16; one is in the 3'UTR region and seven in introns, one corresponds to a T allele insertion in intron 27. We selected four statistically noteworthy and seven new variants identified in six BAV patients and correlated them with clinical and demographic variables and with imaging and histological parameters. Preliminary data show that four were BAV patients with isolated stenosis in patients over 60 aged. These variants may correlate with a later need for surgery for the presence of stenosis and not aortic valve regurgitation or ascending aortic aneurysm. CONCLUSIONS: Completing the genotyping of 62 BAV patients we found 11 new variants in the NOTCH1 gene never yet reported. These findings confirm that the identification of new, clinically remarkable biomarkers for BAV requires a deeper genetic understanding of the NOTCH1 gene variants, which could be targeted by future diagnostic and therapeutic strategies.

Intervendor Consistency and Accuracy of Left Ventricular Volume Measurements Using Three-Dimensional Echocardiography.

BACKGROUND: Intervendor consistency of left ventricular (LV) volume measurements using three-dimensional transthoracic echocardiography (3DTTE) has never been reported. Accordingly, we designed a prospective study to (1) compare head-to-head the accuracy of three three-dimensional echocardiography (3DE) systems in measuring LV volumes and ejection fraction (EF) against cardiac magnetic resonance (CMR); (2) assess the intervendor variability of LV volumes and EF; and (3) compare the accuracy of fully automated versus semiautomated (i.e., manually corrected) methods of LV endocardial delineation against CMR. METHODS: We studied 92 patients (64% males, 52 years [95% CI, 20-83]) with a wide range of end-diastolic volumes (from 87 to 446 mL) and EFs (from 16% to 77%) using three different 3DE platforms (iE33; Vivid E9; Acuson SC2000) during the same echo study. CMR was performed within 3 ± 5 hours from the 3DE study in 35 patients. RESULTS: LV volumes provided by the three 3DE systems correlated with CMR volumes: end-diastolic volume (iE33: R2 = 0.93; E9: R2 = 0.94; SC2000: R2 = 0.94), end-systolic volume (iE33: R2 = 0.93; E9: R2 = 0.95; SC2000: R2 = 0.94), and EF (iE33: R2 = 0.79; E9: R2 = 0.80; SC2000: R2 = 0.77). In the 92 patients studied, LV volumes and EFs measured with the three systems were similar. Use of fully automated endocardial border detection algorithms significantly underestimated LV volumes, and the degree of underestimation was higher with larger LV volumes. CONCLUSIONS: LV volumes and EFs measured with the three 3DE systems are consistent. Fully automated algorithms underestimated LV volumes. Our findings may help in the clinical interpretation of LV parameters obtained using different 3DE systems and encourage the clinical use of 3DTTE.

Left bundle branch block: from cardiac mechanics to clinical and diagnostic challenges.

Left bundle branch block (LBBB) results in an altered pattern of left ventricular (LV) activation and subsequent contraction, causing remarkable changes in LV mechanics, perfusion and workload and ultimately leading to pathologic cardiac remodelling. Clinical and diagnostic notions about the LBBB phenomenon had evolved from just an electrocardiographic pattern to a critically important finding affecting diagnostic and clinical management of many patients and adversely influencing their outcomes. Recent advances in imaging techniques significantly improved the assessment of patients with LBBB and provided additional insights into pathophysiological mechanisms of LV remodelling. In the current review we summarized currently available data on the LBBB epidemiology, diagnosis, its impact on clinical management and prognosis, and the role and place of various imaging modalities in assessing cardiac mechanics and perfusion abnormalities, as well as their potential implications for diagnostic and treatment strategies.

Current Clinical Applications of Three-Dimensional Echocardiography: When the Technique Makes the Difference.

Advances in ultrasound, computer, and electronics technology have permitted three-dimensional echocardiography (3DE) to become a clinically viable imaging modality, with significant impact on patient diagnosis, management, and outcome. Thanks to the inception of a fully sampled matrix transducer for transthoracic and transesophageal probes, 3DE now offers much faster and easier data acquisition, immediate display of anatomy, and the possibility of online quantitative analysis of cardiac chambers and heart valves. The clinical use of transthoracic 3DE has been primarily focused, albeit not exclusively, on the assessment of cardiac chamber volumes and function. Transesophageal 3DE has been applied mostly for assessing heart valve anatomy and function. The advantages of using 3DE to measure cardiac chamber volumes derive from the lack of geometric assumptions about their shape and the avoidance of the apical view foreshortening, which are the main shortcomings of volume calculations from two-dimensional echocardiographic views. Moreover, 3DE offers a unique realistic en face display of heart valves, congenital defects, and surrounding structures allowing a better appreciation of the dynamic functional anatomy of cardiac abnormalities in vivo. Offline quantitation of 3DE data sets has made significant contributions to our mechanistic understanding of normal and diseased heart valves, as well as of their alterations induced by surgical or interventional procedures. As reparative cardiac surgery and transcatheter procedures become more and more popular for treating structural heart disease, transesophageal 3DE has expanded its role as the premier technique for procedure planning, intra-procedural guidance, as well as for checking device function and potential complications after the procedure.

Sex- and Method-Specific Reference Values for Right Ventricular Strain by 2-Dimensional Speckle-Tracking Echocardiography.

BACKGROUND: Despite the fact that assessment of right ventricular longitudinal strain (RVLS) carries important implications for patient diagnosis, prognosis, and treatment, its implementation in clinical settings has been hampered by the limited reference values and the lack of uniformity in software, method, and definition used for measuring RVLS. Accordingly, this study was designed to establish (1) the reference values for RVLS by 2-dimensional speckle-tracking echocardiography; and (2) their relationship with demographic, hemodynamic, and cardiac factors. METHODS AND RESULTS: In 276 healthy volunteers (55% women; age, 18-76 years), free wall and septum RVLS (6 segments) and free wall RVLS (3 segments) using both 6- and 3-segment regions of interest were obtained. Feasibility of 6-segment RVLS was 92%. Free wall RVLS from 3- versus 6-segment regions of interest had similar values, yet 6-segment region of interest was more feasible (86% versus 73%; P<0.001) and reproducible. Reference values (lower limits of normality) were as follows: 6-segment RVLS, -24.7±2.6% (-20.0%) for men and -26.7±3.1% (-20.3%) for women; 3-segment RVLS, -29.3±3.4% (-22.5%) for men and -31.6±4.0% (-23.3%) for women (P<0.001). Free wall RVLS was 5±2 strain units (%) larger in magnitude than 6-segment RVLS, 10±4% larger than septal RVLS, and 2±4% larger in women than in men (P<0.001). At multivariable analysis, age, sex, pulmonary systolic pressure, right atrial minimal volume, as well as right atrial and left ventricular longitudinal strain resulted as correlates of RVLS values. CONCLUSIONS: This is the largest study providing sex- and method-specific reference values for RVLS. Our data may foster the implementation of 2-dimensional speckle-tracking echocardiography-derived RV analysis in clinical practice.

New speckle-tracking algorithm for right ventricular volume analysis from three-dimensional echocardiographic data sets: validation with cardiac magnetic resonance and comparison with the previous analysis tool.

AIMS: (i) To validate a new software for right ventricular (RV) analysis by 3D echocardiography (3DE) against cardiac magnetic resonance (CMR); (ii) to assess the accuracy of different measurement approaches; and (iii) to explore any benefits vs. the previous software. METHODS AND RESULTS: We prospectively studied with 3DE and CMR 47 patients (14-82 years, 28 men) having a wide range of RV end-diastolic volumes (EDV 82-354 mL at CMR) and ejection fractions (EF 34-81%). Multi-beat RV 3DE data sets were independently analysed with the new software using both automated and manual editing options, as well as with the previous software. RV volume reproducibility was tested in 15 random patients. RV volumes and EF measurements by the new software had an excellent accuracy (bias ± SD: -15 ± 24 mL for EDV; 1.4 ± 4.9% for EF) and reproducibility compared with CMR, provided that the RV borders automatically tracked by software were systematically edited by operator. The automated analysis option underestimated the EDV, overestimated the ESV, and largely underestimated the EF (bias ± SD: -17 ± 10%). RV volumes measured with the new software using manual editing showed similar accuracy, but lower inter-observer variability and shorter analysis time (3-5') in comparison with the previous software. CONCLUSION: Novel vendor-independent 3DE software enables an accurate, reproducible and faster quantitation of RV volumes and ejection fraction. Rather than optional, systematic verification of border tracking quality and manual editing are mandatory to ensure accurate 3DE measurements. These findings are relevant for echocardiography laboratories aiming to implement 3DE for RV analysis for both research and clinical purposes.

Rationale and design of GISSI OUTLIERS VAR Study in bicuspid aortic valve patients: prospective longitudinal, multicenter study to investigate correlation between surgical, echo distinctive features, histologic and genetic findings in phenotypically homogeneous outlier cases.

BACKGROUND/OBJECTIVES: Bicuspid aortic valve (BAV) is the most common congenital heart disorder, affecting up to 2% of the population. Involvement of aortic root and ascending aorta (aneurysm or, eventually, dissection) is frequent in patients with pathologic or normal functioning BAV. Unfortunately, there are no well-known correlations between valvular and vascular diseases. In VAR protocol, with a new strategy of research, we analysemultiple aspects of BAV disease through correlation between surgical, echo, histologic and genetic findings in phenotypically homogeneous outlier cases. METHODS: VAR protocol is a prospective, longitudinal, multicenter study. It observes 4 homogeneous small groups of BAV surgical patients (15 patients each): isolated aortic regurgitation, isolated ascending aortic aneurysm, aortic regurgitation associated with aortic aneurysm, isolated aortic stenosis in older patients (>60years). Echo analysis is extended to first-degree relatives and, in case of BAV, genetic test is performed. Patients and relatives are enrolled in 10 cardiac surgery/cardiologic centers throughout Italy. CONCLUSIONS: The aim of the study is to identify predictors of favorable or unfavorable evolution of BAV in terms of valvular dysfunction and/or aortic aneurysm. Correlations between different features could help in identification of various BAV risk groups, rationalizing follow-up and treatment.