Alain Lalande

Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus

We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA) and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocalization of wild-type and mutant rod proteins in SMC, in conjunction with differences in their coimmunoprecipitation capacities, strongly suggest a dominant-negative effect. Human MYH11 gene mutations provide the first example of a direct change in a specific SMC protein leading to an inherited arterial disease.

Major prognostic impact of persistent microvascular obstruction as assessed by contrast-enhanced cardiac magnetic resonance in reperfused acute myocardial infarction

The aim of this study was to compare the prognostic significance of microvascular obstruction (MO) and persistent microvascular obstruction (PMO) as assessed by cardiac magnetic resonance (CMR) in patients with acute myocardial infarction (AMI). CMR was performed in 184 patients within the week following successfully reperfused first AMI. First-pass images were performed to evaluate extent of MO and late gadolinium-enhanced images to assess PMO and infarct size (IS). Major adverse cardiac events (MACE) were collected at 1-year follow-up. MO and PMO were found in 127 (69%) and 87 (47%) patients, respectively. By using univariate logistic regression analysis, high Global Registry of Acute Coronary Events (GRACE) risk score (odds ratio [OR] 95% confidence interval [CI]: 3.6 [1.8–7.4], p < 0.001), IS greater than 10% (OR [95% CI]: 2.7 [1.1–6.9], p = 0.036), left ventricular ejection fraction less than 40% (OR [95% CI]: 2.4 [1.1–5.2], p = 0.027), presence of MO (OR [95% CI]: 3.1 [1.3–7.3], p = 0.004) and presence of PMO (OR [95% CI]:10 [4.1–23.9], p < 0.001) were shown to be significantly associated with the outcome. By using multivariate analysis, presence of MO (OR [95% CI]: 2.5 [1.0–6.2], p = 0.045) or of PMO (OR [95% CI]: 8.7 [3.6–21.1], p < 0.001), associated with GRACE score, were predictors of MACE. Presence of microvascular obstruction and persistent microvascular obstruction is very common in AMI patients even after successful reperfusion and is associated with a dramatically higher risk of subsequent cardiovascular events, beyond established prognostic markers. Moreover, our data suggest that the prognostic impact of PMO might be superior to MO.

Mapping of Familial Thoracic Aortic Aneurysm/Dissection With Patent Ductus Arteriosus to 16p12.2–p13.13

Background—Three loci have been shown to be responsible for nonsyndromic familial thoracic aortic aneurysms (TAAs) and aortic dissections (ADs). We recently described a large family in which TAA/AD associates with patent ductus arteriosus (PDA) and provided genetic arguments for a unique pathophysiological entity. Methods and Results—Genome-wide scan was performed in 40 subjects belonging to 3 generations in this large pedigree. Using the 7 TAA/AD cases as affected, we observed positive 2-point LOD scores on adjacent markers at chromosome 16p, with a maximum LOD score value of 2.73 at &thgr;=0, a value that increased to 3.56 when 5 PDA cases were included. Multipoint linkage analysis yielded a maximum LOD score of 4.14 in the vicinity of marker D16S3103. Fine mapping allowed the observation of recombinant haplotypes that delimited a critical 20-cM interval at 16p12.2-p13.13. Automatic determination of aortic compliance with cine MRI showed that all subjects bearing the disease haplotype, even asymptomatic, displayed a very low level of aortic compliance and distensibility. Aortic stiffness was strongly associated with disease haplotype with a marked effect of age, indicating subclinical and early manifestation of the disease. Conclusions—Genetic analysis of this family identified a unique locus responsible for both TAA/AD and PDA at chromosome 16p12.2-p13.13 with aortic stiffness as an early hallmark of the disease. TAA/AD with PDA is a new monogenic entity among the genetically heterogeneous group of TAA/AD disease.

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

Thoracic aortic aneurysm and aortic dissection (TAA and AD) are an important cause of sudden death. Familial cases could account for 20% of all cases. A genetic heterogeneity with two identified genes (FBN1 and COL3A1) and three loci (3p24–25 or MFS2/TAAD2, 5q13–q14 and 11q23.2–24) has been shown previously. Study of a single family composed of 179 members with an abnormally high occurrence of TAA/AD disease. A total of 40 subjects from three generations were investigated. In addition to five cases of stroke and three cases of sudden death, there were four cases of AD and four cases of TAA in adults. In all, 11 cases of patent ductus arteriosus (PDA) were observed, two of which were associated with TAA and one with AD. Segregation analysis showed that the distribution of these vascular abnormalities was more likely compatible with a single genetic defect with an autosomal dominant pattern of inheritance. There were no clinical signs of Marfan, Elhers–Danlos vascular type or Char syndromes. Genetic linkage analysis was performed for seven genes or loci implicated in familial TAA/AD disease (COL3A1, FBN1, 3p24–25 or MFS2/TAAD2, 5q13–q14 and 11q23.2–q24), Char syndrome (TFAP2B) or autosomal recessive PDA (12q24). Using different genetic models, linkage with these seven loci was excluded. Familial TAA/AD with PDA is likely to be a particular heritable vascular disorder, with an as yet undiscovered Mendelian genetic basis.

Time course of NAA T2 and ADCw in ischaemic stroke patients: 1H MRS imaging and diffusion-weighted MRI

BACKGROUND AND PURPOSE Proton spectroscopy and quantitative diffusion-weighted imaging (DWI) were used to investigate the pertinence of N-acetyl aspartate (NAA) as a reliable marker of neuronal density in human stroke. METHODS The time courses of tissue water apparent diffusion coefficient (ADC(w)) and metabolite T2 were investigated on a plane corresponding to the largest area of cerebral infarction, within and outside the site of infarction in 71 patients with a large cortical middle cerebral artery territory infarction. RESULTS Significant reductions are seen in NAA T2 deep within the infarction during the period comprised between 5 and 20 days postinfarction; the relaxation times appearing to normalise several months after stroke. After an acute reduction in ADC(w), the pseudonormalisation of ADC(w) occurs at 8-12 days after the ischaemic insult. The minimum in N-acetyl aspartate T2 relaxation times and the pseudonormalisation of ADC(w) appear to coincide. CONCLUSIONS The data suggest that modifications in the behaviour of the observed proton metabolites occur during the period when the vasogenic oedema is formed and cell membrane integrity is lost. For this reason, NAA may not be a reliable marker of neuronal density during this period.

Automatic detection of left ventricular contours from cardiac cine magnetic resonance imaging using fuzzy logic.

RATIONALE AND OBJECTIVES Gated cardiac cine magnetic resonance imaging provides accurate dynamic data of the left ventricular function. However, the manual extraction of important physiologic parameters such as myocardium wall thickness and left ventricular volumes is invariably time consuming and subjective. To reduce the variability and time constraints inherent in observer contour tracing, the authors developed an automatic left ventricle contour-detection method. METHODS The purpose was to apply fuzzy logic-based automatic contour detection to identification of endocardial and epicardial borders in short-axis magnetic resonance images. The automatic contouring was compared with manual tracing using the calculated ejection fraction as the comparison criterion. RESULTS A good correlation was found between the two approaches (r2 = 0.98). CONCLUSIONS The ejection fraction can be obtained using this automatic contouring method.

Influence of age and sex on aortic distensibility assessed by MRI in healthy subjects

Magnetic resonance imaging (MRI) is particularly well adapted to the evaluation of aortic distensibility. The calculation of this parameter, based on the change in vessel cross-sectional area per unit change in blood pressure, requires precise delineation of the aortic wall on a series of cine-MR images. Firstly, the study consisted in validating a new automatic method to assess aortic elasticity. Secondly, aortic distensibility was studied for the ascending and descending thoracic aortas in 26 healthy subjects. Two homogeneous groups were available to evaluate the influence of sex and age (with an age limit value of 35 years). The automatic postprocessing method proved to be robust and reliable enough to automatically determine aortic distensibility, even on artefacted images. In the 26 healthy volunteers, a marked decrease in distensibility appears with age, although this decrease is only significant for the ascending aorta (8.97+/-2.69 10(-3) mmHg(-1) vs. 5.97+/-2.02 10(-3) mmHg(-1)). Women have a higher aortic distensibility than men but only significantly at the level of the descending aorta (7.20+/-1.61 10(-3) mmHg(-1) vs. 5.05+/-2.40 10(-3) mmHg(-1)). Through our automatic contouring method, the aortic distensibility from routine cine-MRI has been studied on a healthy subject population providing reference values of aortic stiffness. The aortic distensibility calculation shows that age and sex are causes of aortic stiffness variations in healthy subjects.

Visual estimation of the global myocardial extent of hyperenhancement on delayed contrast-enhanced MRI

MRI with paramagnetic contrast agent allows the assessment of the extent of myocardial tissue injury after infarction. Visual segmental scoring has been widely used to define the transmural extent of myocardial infarction, but no attempt has been made to use visual scores in order to assess the percentage of the whole myocardium infarcted. By summing all the segmental scores using a 17-segment model, a global index of the size of the infarcted myocardium is easily obtained. The entire left ventricle of 60 patients with a recent myocardial infarction was scanned using an ECG-gated gradient echo sequence after injection of gadolinium contrast agent. The global score was defined as the sum of the scores on each segment, and expressed as a percentage of the maximum possible score. This index was compared with a planimetric evaluation of hyperenhancement, expressed as a percentage of the left ventricle myocardial volume. There is a good correlation between the two methods (r=0.91; y=1.06x+0.20), and the Bland-Altman plot shows a high concordance between the two approaches (mean of the differences =1.45%). A visual approach based on a 17-segment model can be used to evaluate the global myocardial extent of the hyperenhancement with similar results to planimetry.

The extent of myocardial damage assessed by contrast‐enhanced MRI is a major determinant of N‐BNP concentration after myocardial infarction

To evaluate the relationship between N‐terminal Pro‐Brain Natriuretic Peptide (N‐BNP) level and contrast‐enhanced MRI in patients after acute myocardial infarction (MI).

3D segmentation of abdominal aorta from CT-scan and MR images

We designed a generic method for segmenting the aneurismal sac of an abdominal aortic aneurysm (AAA) both from multi-slice MR and CT-scan examinations. It is a semi-automatic method requiring little human intervention and based on graph cut theory to segment the lumen interface and the aortic wall of AAAs. Our segmentation method works independently on MRI and CT-scan volumes and has been tested on a 44 patient dataset and 10 synthetic images. Segmentation and maximum diameter estimation were compared to manual tracing from 4 experts. An inter-observer study was performed in order to measure the variability range of a human observer. Based on three metrics (the maximum aortic diameter, the volume overlap and the Hausdorff distance) the variability of the results obtained by our method is shown to be similar to that of a human operator, both for the lumen interface and the aortic wall. As will be shown, the average distance obtained with our method is less than one standard deviation away from each expert, both for healthy subjects and for patients with AAA. Our semi-automatic method provides reliable contours of the abdominal aorta from CT-scan or MRI, allowing rapid and reproducible evaluations of AAA.