Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity.

Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy.

Apical left ventricular myocardial dysfunction is an early feature of cardiac involvement in myotonic dystrophy type 1.

INTRODUCTION: Left ventricular (LV) dysfunction is a major prognostic determinant in myotonic dystrophy type 1 (DM1). Therefore, markers of early-stage LV impairment may be useful. The aim of this study was to evaluate 2D echocardiographic LV strain in a cohort of DM1 patients with preserved left ventricular ejection fraction (LVEF) and to compare the results with matched controls. METHODS: This prospective single-center study included 33 consecutive DM1 patients between February 2014 and February 2015. Mean age was 38.2±12.9 years, and 17 (52%) were males. Exclusion criteria were LVEF <55%, QRS >120 milliseconds, history of atrial fibrillation, and presence of a pacemaker with ventricular pacing. DM1 patients were matched to healthy controls according to sex and age. RESULTS: DM1 patients showed significant impairment of global longitudinal strain (GLS) as compared to controls (-18.0±1.9 vs -19.1±2.4; P=.03), characterized by a marked alteration at the apex (-20.0±3.3 vs -22.7±3.1; P<.001). DM1 patients had also global radial strain impairment (20.0±9.8 vs 27.5±14.9; P=.024) compared to controls while global circumferential strain was not statistically different between groups (P=.94). Intra- and inter-observer analysis showed good reproducibility of GLS. CONCLUSION: Despite preserved LVEF, DM1 patients exhibited significantly altered LV GLS, particularly at the apex, as compared with controls. The detection of impaired myocardial deformation at early stages of the disease might help to screen high-risk patients who need closer follow-up.

Unmasked Brugada pattern by ajmaline challenge in patients with myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) generates missplicing of the SCN5A gene, encoding the cardiac sodium channel (Nav 1.5). Brugada syndrome, which partly results from Nav 1.5 dysfunction and causes increased VF occurrence, can be unmasked by ajmaline. We aimed to investigate the response to ajmaline challenge in DM1 patients and its potential impact on their sudden cardiac death risk stratification. METHODS: Among 36 adult DM1 patients referred to our institution, electrophysiological study and ajmaline challenge were performed in 12 patients fulfilling the following criteria: (1) PR interval >200 ms or QRS duration >100 ms; (2) absence of complete left bundle branch block; (3) absence of permanent ventricular pacing; (4) absence of implantable cardioverter-defibrillator (ICD); (5) preserved left-ventricular ejection fraction >50%; and (6) absence of severe muscular impairment. Of note, DM1 patients with ajmaline-induced Brugada pattern (BrP) were screened for SCN5A. RESULTS: In all the 12 patients studied, the HV interval was <70 ms. A BrP was unmasked in three patients but none carried an SCN5A mutation. Ajmaline-induced sustained ventricular tachycardia occurred in one patient with BrP, who finally received an ICD. The other patients did not present any cardiac event during the entire follow-up (15 ± 4 months). CONCLUSION: Our study is the first to describe a high prevalence of ajmaline-induced BrP in DM1 patients. The indications, the safety, and the implications of ajmaline challenge in this particular setting need to be determined by larger prospective studies.

Left ventricular non-compaction and idiopathic dilated cardiomyopathy: the significant diagnostic value of longitudinal strain.

Left ventricular non-compaction (LV NC) is characterized by abnormal trabeculations that are mainly at the LV apex. Distinction between LV NC and non-specific dilated cardiomyopathies (DCMs) remains often challenging. We sought to find additive tools comparing the longitudinal strain characteristics of LVNC versus idiopathic DCM in a cohort of patients. 48 cases of LVNC (derivation cohort) were compared with 45 cases of DCM. Global and regional multi-layer (sub-endocardial, mid-wall, and sub-epicardial) LV longitudinal strain analysis was performed. Results were compared to define the best tool for distinguishing LVNC from DCM. A validation cohort (41 LVNC patients) was then used to assess the performance of the proposed diagnostic tools. In the derivation cohort, longitudinal deformation (strain) was greater in LVNC than in DCM patients. Longitudinal shortening was greater in the non-compacted segments than in the compacted ones. A mid-wall strain base-apex gradient had 88.4 % sensitivity and 66.7 % specificity in distinguishing LVNC from DCM (AUC = 0.83; cut-off of -23 or |0.23|%). In a multivariable model, the base-apex mid-wall gradient in an apical 4-chamber view was the only independent echocardiographic criteria (OR = 0.76, CI 95 % [0.66; 0.90], p = 0.0010) allowing the distinction between LVNC and DCM. In the validation cohort, the base-apex mid-wall gradient of strain had 88.4 % sensitivity, 85.7 % negative predictive values for the diagnosis of LVNC. Longitudinal strain, especially the base-apex longitudinal gradient of strain, appears as an additive valuable tool for distinguishing LVNC from DCM.

Quantitative regional analysis of left atrial function by Doppler tissue imaging-derived parameters discriminates patients with posterior and anterior myocardial infarction.

BACKGROUND: Doppler tissue imaging can now be used for the assessment of left atrial (LA) function. LA function was evaluated by this technique in a group of patients hospitalized for acute myocardial infarction and in a control population. METHODS: Patients were all prospectively imaged with a scanner. To study the LA, a region of interest was located in the proximal part of the lateral and septal LA walls. Doppler tissue imaging, tissue tracking, strain, and delays were recorded. RESULTS: In all, 12 patients with posterior (age 54 +/- 9 years) and 13 with anterior (age 64 +/- 16 years) acute myocardial infarction, along with 16 control patients (age 54 +/- 9 years), were analyzed. Early diastolic septal velocity was found to be the best parameter for discriminating among the 3 groups. Peak strain was also relevant and did not correlate with left ventricular function. CONCLUSIONS: LA is accessible to Doppler tissue imaging analysis. Strain can quantify LA function relatively independently of left ventricular function, and may provide new insights on LA function.

Tissue Doppler echocardiographic quantification. Comparison to coronary angiography results in Acute Coronary Syndrome patients.

BACKGROUND: Multiples indices have been described using tissue Doppler imaging (DTI) capabilities. The aim of this study was to assess the capability of one or several regional DTI parameters in separating control from ischemic myocardium. METHODS: Twenty-eight patients with acute myocardial infarction were imaged within 24-hour following an emergent coronary angioplasty. Seventeen controls without any coronary artery or myocardial disease were also explored. Global and regional left ventricular functions were assessed. High frame rate color DTI cineloop recordings were made in apical 4 and 2-chamber for subsequent analysis. Peak velocity during isovolumic contraction time (IVC), ejection time, isovolumic relaxation (IVR) and filling time were measured at the mitral annulus and the basal, mid and apical segments of each of the walls studied as well as peak systolic displacement and peak of strain. RESULTS: DTI-analysis enabled us to discriminate between the 3 populations (controls, inferior and anterior AMI). Even in non-ischemic segments, velocities and displacements were reduced in the 2 AMI populations. Peak systolic displacement was the best parameter to discriminate controls from AMI groups (wall by wall, p was systematically < 0.01). The combination IVC + and IVR< 1 discriminated ischemic from non-ischemic segments with 82% sensitivity and 85% specificity. CONCLUSION: DTI-analysis appears to be valuable in ischemic heart disease assessment. Its clinical impact remains to be established. However this simple index might really help in intensive care unit routine practice.

2-D left ventricular flow estimation by combining speckle tracking with Navier-Stokes-based regularization: an in silico, in vitro and in vivo study.

Despite the availability of multiple ultrasound approaches to left ventricular (LV) flow characterization in two dimensions, this technique remains in its childhood and further developments seem warranted. This article describes a new methodology for tracking the 2-D LV flow field based on ultrasound data. Hereto, a standard speckle tracking algorithm was modified by using a dynamic kernel embedding Navier-Stokes-based regularization in an iterative manner. The performance of the proposed approach was first quantified in synthetic ultrasound data based on a computational fluid dynamics model of LV flow. Next, an experimental flow phantom setup mimicking the normal human heart was used for experimental validation by employing simultaneous optical particle image velocimetry as a standard reference technique. Finally, the applicability of the approach was tested in a clinical setting. On the basis of the simulated data, pointwise evaluation of the estimated velocity vectors correlated well (mean r = 0.84) with the computational fluid dynamics measurement. During the filling period of the left ventricle, the properties of the main vortex obtained from the proposed method were also measured, and their correlations with the reference measurement were also calculated (radius, r = 0.96; circulation, r = 0.85; weighted center, r = 0.81). In vitro results at 60 bpm during one cardiac cycle confirmed that the algorithm properly measures typical characteristics of the vortex (radius, r = 0.60; circulation, r = 0.81; weighted center, r = 0.92). Preliminary qualitative results on clinical data revealed physiologic flow fields.

Anatomic M-mode, a pertinent tool for the daily practice of transthoracic echocardiography.

OBJECTIVES: We sought to compare anatomic M-mode (AMM), a new echocardiographic postprocessing option, and conventional M-mode (CMM) using fundamental imaging and tissue harmonic imaging. METHODS: Transthoracic echocardiography was performed in 15 selected patients to analyze the reproducibility of AMM and in 47 patients to assess its clinical value versus CMM. Acquisitions were performed successively: CMM fundamental imaging; CMM tissue harmonic imaging; tissue harmonic imaging cineloops for AMM; and fundamental imaging cineloops for AMM. Quantitative analysis was performed offline. The angle alpha between the CMM line and the septal endocardial interface was calculated and the expected percentage of error in measuring left ventricular diameter was derived. RESULTS: AMM analysis was reproducible. Optimal AMM full echocardiographic definition was obtainable in 77% of the population, whereas CMM was optimal for 49% because of scan line misalignment, causing a measurement overestimation exceeding 5%. CONCLUSION: The ability with AMM to reduce the alpha angle to 0 degrees and, thus, avoid overestimation of left ventricular dimensions might improve follow-up in several pathologic conditions.

Determination of the optimal region for interaliasing distance measurement for flow regurgitant rate calculation: a fluid simulation study.

BACKGROUND: Color Doppler imaging of the convergent region is promising for quantifying valvular regurgitation. Nevertheless, proximal isovelocity surface area method has limitations. We sought to determine the optimal localization to measure the most precise flow rate using a new approach: the interaliasing distance. METHODS: A finite volume-based program was used to perform simulations in unsteady flow conditions. Different instantaneous flow rates, leaflet angles, and orifice sizes were tested reproducing physiologic conditions. Relative difference between actual and interaliasing distance flow rate was calculated for each configuration. RESULTS: The relationship between the relative error and the aliasing velocity location was described by a third-order polynomial equation. The magnitude of relative error is a function of the flow rate, orifice size, and leaflet angle. CONCLUSION: The optimal distance from the orifice to measure the interaliasing distance was when the closer aliasing was between 4 and 8 mm from the orifice.

Quantitative assessment of regurgitant flow with total digital three-dimensional reconstruction of color Doppler flow in the convergent region: in vitro validation.

BACKGROUND: This study was designed to develop and test a total digital 3-dimensional (3D) color flow map reconstruction for proximal isovelocity surface area (PISA) measurement in the convergent region. METHODS: Asymmetric flow convergent velocity field was created in an in vitro pulsatile model of mitral regurgitation. Image files stored in the echocardiographic scanner memory were digitally transferred to a computer workstation, and custom software decoded the file format, extracted velocity information, and generated 3D flow images automatically. PISA and volume flow rate were calculated without geometric assumption. For comparison, regurgitant volume was also calculated, using continuous wave Doppler, 2-dimensional (2D), and M-mode color flow Doppler with the hemispheric approach. RESULTS: Flows from 3D digital velocity profiles showed a closed, excellent relation with actual flow rates, especially for instantaneous flow rate. Regurgitant volume calculated with the 3D method underestimated the actual flow rate by 2.6%, whereas 2D and the M-mode method show greater underestimation (44.2% and 32.1%, respectively). CONCLUSION: Our 3D reconstruction of color flow Doppler images gives more exact information of the flow convergent zone, especially in complex geometric flow fields. Its total digital velocity process allows accurate measurement of convergent surface area and improves quantitation of valvular regurgitation.

Experimental study of laminar blood flow through an artery treated by a stent implantation: characterisation of intra-stent wall shear stress.

The stimulation of endothelial cells by arterial wall shear stress (WSS) plays a central role in restenosis. The fluid-structure interaction between stent wire and blood flow alters the WSS, particularly between stent struts. We have designed an in vitro model of struts of an intra-vascular prosthesis to study blood flow through a 'stented' section. The experimental artery consisted of a transparent square section test vein, which reproduced the strut design (100x magnifying power). A programmable pump was used to maintain a steady blood flow. Particle image velocimetry method was used to measure the flow between and over the stent branches, and to quantify WSS. Several prosthesis patterns that were representative of the total stent strut geometry were studied in a greater detail. We obtained WSS values of between -1.5 and 1.5Pa in a weak SS area which provided a source of endothelial stimulation propitious to restenosis. We also compared two similar patterns located in two different flow areas (one at the entry of the stent and one further downstream). We only detected a slight difference between the weakest SS levels at these two sites. As the endothelial proliferation is greatly influenced by the SS, knowledge of the SS modification induced by the stent implantation could be of importance for intra-vascular prostheses design optimisation and thus can help to reduce the restenosis incidence rate.

Computational approach to estimating the effects of blood properties on changes in intra-stent flow.

In this study various blood rheological assumptions are numerically investigated for the hemodynamic properties of intra-stent flow. Non-newtonian blood properties have never been implemented in blood coronary stented flow investigation, although its effects appear essential for a correct estimation and distribution of wall shear stress (WSS) exerted by the fluid on the internal vessel surface. Our numerical model is based on a full 3D stent mesh. Rigid wall and stationary inflow conditions are applied. Newtonian behavior, non-newtonian model based on Carreau-Yasuda relation and a characteristic newtonian value defined with flow representative parameters are introduced in this research. Non-newtonian flow generates an alteration of near wall viscosity norms compared to newtonian. Maximal WSS values are located in the center part of stent pattern structure and minimal values are focused on the proximal stent wire surface. A flow rate increase emphasizes fluid perturbations, and generates a WSS rise except for interstrut area. Nevertheless, a local quantitative analysis discloses an underestimation of WSS for modelisation using a newtonian blood flow, with clinical consequence of overestimate restenosis risk area. Characteristic viscosity introduction appears to present a useful option compared to rheological modelisation based on experimental data, with computer time gain and relevant results for quantitative and qualitative WSS determination.

DECOPI (DEsobstruction COronaire en Post-Infarctus): a randomized multi-centre trial of occluded artery angioplasty after acute myocardial infarction.

AIM: To determine whether late recanalization of an occluded infarct artery after acute myocardial infarction is beneficial. METHODS AND RESULTS: Two hundred and twelve patients with a first Q-wave myocardial infarction (MI) and an occluded infarct vessel were enrolled. After coronary and left ventricular contrast angiography, patients were randomized to percutaneous revascularization (PTCA, n=109), carried out 2-15 days after symptom onset or medical therapy (n=103). The primary endpoint was a composite of cardiac death, non-fatal MI, or ventricular tachyarrhythmia. The majority had single-vessel disease and less than one-third had involvement of the left anterior descending artery. The use of pharmacological therapy was high in both groups. At six months, left ventricular ejection fraction was 5% higher in the invasive compared with the medical group (P=0.013) and more patients had a patent artery (82.8% vs 34.2%, P<0.0001). Restenosis was seen in 49.4% of patients in the PTCA group. At a mean of 34 months of follow-up, the occurrence of the primary endpoint was similar in the medical and PTCA groups (8.7% vs 7.3% respectively, P=0.68), but the overall costs were higher for PTCA. The secondary endpoint combining the primary endpoint with admission for heart failure was also similar between groups (12.6% vs 10.1% in the medical and PTCA groups, respectively, P=0.56). CONCLUSIONS: Systematic late PTCA of the infarct vessel was associated with a higher left ventricular ejection fraction at six months, no difference in clinical outcomes, and higher costs than medical therapy. These results must be interpreted with caution given the small size and low risk of the population.