Xavier Pillois

Reverse Remodeling of the Left Cardiac Chambers After Catheter Ablation After 1 Year in a Series of Patients With Isolated Atrial Fibrillation

Background— Isolated atrial fibrillation (AF) is associated with mild enlargement of the left atrium (LA) and left ventricular (LV) diastolic dysfunction. The impact of ablation of isolated AF on left chamber size and function is unclear, and whether diastolic dysfunction is the cause or the consequence of AF remains unknown. The objective of this prospective study was to evaluate the impact of sinus rhythm restoration by catheter ablation on LV diastolic dysfunction, LA morphology, and mechanical function. Methods and Results— Forty-eight patients with isolated AF were studied by serial echocardiographic studies at baseline and at 1-, 3-, 6-, 9-, and 12-month intervals after radiofrequency ablation. LA dimensions and mechanical function and LV systolic and diastolic functions were evaluated at each time interval. Diastolic function was assessed with conventional Doppler parameters and new indexes such as tissue Doppler imaging, mitral flow propagation velocity, and combined criteria. LV diastolic dysfunction was present in paroxysmal and chronic AF patients with a reduction of tissue Doppler imaging lateral early diastolic peak velocity in 37% (P<0.001) and 48% (P<0.01), respectively, compared with healthy control subjects. At the end of the follow-up, LA area decreased significantly by 18% (P<0.001) in paroxysmal and 23% (P<0.05) in chronic AF patients. Diastolic function improved significantly with an increase in lateral early diastolic peak velocity of 29% (P<0.001) in paroxysmal AF and 46% (P<0.05) in chronic AF patients. A significant increase in LV ejection fraction was also noted for both groups: 7.7% and 18.8%, respectively. Conclusions— This study demonstrates reverse morphological remodeling of the LA and improvement of LV diastolic and systolic functions after restoration of sinus rhythm by ablation for isolated AF. Because patients with isolated AF have none of the traditional causes of LV diastolic dysfunction, our findings suggest that AF may be partly the cause rather than the consequence of diastolic dysfunction.

Experimental Validation of Circumferential, Longitudinal, and Radial 2-Dimensional Strain During Dobutamine Stress Echocardiography in Ischemic Conditions

OBJECTIVES The aim of this study was to assess and validate 2-dimensional (2D) strain for the detection of ischemia during dobutamine stress echocardiography (DSE). BACKGROUND Evaluation of abnormalities of left ventricular (LV) function from wall thickening during DSE is unsatisfactory and requires a high level of expertise. METHODS In 10 open-chest anesthetized pigs, myocardial deformation was studied before and during dobutamine infusion, under control and ischemic conditions produced by various degrees of coronary artery constriction: 2 of nonflow-limiting stenoses (NFLS) of increasing severity reducing left anterior descending artery hyperemic flow by 40% and 70% and 2 flow-limiting stenoses (FLS) reducing resting coronary flow by 25% and 50%. Agreement between 2D strain echocardiography and sonomicrometry (reference method) was evaluated by linear regression and Bland-Altman analysis. RESULTS Good correlation and agreement were observed between 2-dimensional strain and sonomicrometry at rest and during dobutamine infusion; longitudinal strain: r = 0.77, p < 0.001 and r = 0.80, p < 0.001; radial strain: r = 0.57, p < 0.05 and r = 0.63, p < 0.05; and circumferential strain: r = 0.74, p < 0.001 and r = 0.58, p < 0.001. Circumferential and longitudinal strains in the risk area were significantly decreased at rest in the presence of FLS and during dobutamine infusion in the presence of NFLS. By contrast, radial strain was significantly decreased in the presence of severe FLS only during dobutamine infusion. CONCLUSIONS The 2D strain provides accurate assessment of LV regional function. Evaluation of circumferential and longitudinal strains during DSE has real potential for quantitative evaluation of LV deformation in the routine assessment of ischemia.

Fibrinolysis of mechanical prosthetic valve thrombosis: a single-center study of 127 cases.

OBJECTIVES This study was designed to analyze the results of fibrinolytic treatment (FT) in a large single-center group of patients with prosthetic heart valve thrombosis (PHVT). BACKGROUND Fibrinolytic treatment of PHVT represents an alternative to surgery, but is still controversial because of the risk of embolism. METHODS A total of 110 consecutive patients presenting with 127 instances of PHVT received FT between 1978 and 2001. The diagnosis of PHVT was established mainly by fluoroscopy and/or echocardiography. The first fibrinolytic agent used was streptokinase (SK) in 49 cases, urokinase (UK) in 41 cases, and recombinant tissue-type plasminogen activator (rtPA) in 37 cases. A second FT was consecutively infused in 38 patients (30%) and a third FT in 11 others. The efficacy of FT was assessed from hemodynamic parameters derived from echographic examinations as well as on clinical grounds. RESULTS Complete resolution of hemodynamic abnormalities was seen in 90/127 patients, partial resolution in 22/127 patients, and no change in 15/127 patients after one or more consecutive fibrinolytic regimens. When SK or rtPA were used as the first fibrinolytic agent, they appeared significantly superior to UK in terms of valve reopening. Fifteen patients died. Severe hemorrhagic complications were observed in six patients. Nineteen documented embolic events occurred during FT. Finally, PHVT recurred in 24 patients, 17 of whom were retreated with lytic agents. CONCLUSIONS These results indicate that FT is effective in most cases of PHVT, regardless of prosthesis or site involved. However, embolism, hemorrhage, and death were not uncommon after lytic therapy of left-sided PHVT, limiting its application to patients at high risk with alternative treatment.

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetype-inherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, αIIbβ3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for β3 has a wide tissue distribution when present as αvβ3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of β3-deficiency or nonfunction are being increasingly described.

Evaluation of Global Left Ventricular Systolic Function Using Three-Dimensional Echocardiography Speckle-Tracking Strain Parameters

BACKGROUND The aim of this study was to evaluate the capacity and reproducibility of three-dimensional echocardiographic (3DE) strain parameters in the assessment of global left ventricular (LV) systolic function. METHODS A total of 128 subjects with differing LV ejection fractions were investigated using two-dimensional echocardiographic (2DE) and 3DE strains. Three-dimensional echocardiographic strain allows obtaining longitudinal, circumferential, radial, and area strains. First, values of global longitudinal strain (GLS) by 2DE and 3DE speckle-tracking analyses were compared. Thereafter, 3DE strain parameters were correlated with LV ejection fraction and indexed output. Last, the variability of 3DE versus 2DE strain measurements as well as recorded time of analysis were assessed. RESULTS After excluding 21 patients for insufficient image quality, four for arrhythmia, two for severe valvular disease, and one for severe dyspnea, the final population consisted of 100 patients. Comparison between 2DE and 3DE GLS revealed high correspondence (r = 0.91, y = 1.04x - 0.71) and mean error measurement of -1.3% (95% confidence interval, -5.7 to 3.2). Among strain parameters, global area strain exhibited the highest correlation with LV ejection fraction (y = -1.65 + 10.4, r = -0.92, P < .001). Intraobserver measurement variability proved acceptable: 8% for GLS (vs 6% on 2DE analysis), 7% for circumferential strain (vs 15% on 2DE analysis), 7% for radial strain (vs 33% on 2DE analysis), and 5% for global area strain. The mean error between two measurements was lower with 3DE than 2DE analysis for circumferential and radial strains but similar for GLS. The mean time of analysis was of 117 ± 16 sec for 3DE analysis, which was 25% less than for 2DE analysis (P < .001). CONCLUSIONS Of all strain parameters, new 3DE area strain correlated best with common LV systolic function parameters and is thus the most promising approach, while all 3DE strain markers exhibited good reproducibility.

NUCLEOTIDE RECEPTOR P2U PARTIALLY MEDIATES ATP-INDUCED CELL CYCLE PROGRESSION OF AORTIC SMOOTH MUSCLE CELLS

mRNA of the P2u purinoceptor (or nucleotide receptor) is detected both by polymerase chain reaction or Northern blot analyses in cultured aortic smooth muscle cells. When added to the culture medium of these cells, UTP, a specific ligand of the P2u receptor, induces an increased expression of both immediate‐early and delayed‐early cell cycle‐dependent genes. This induction demonstrates similar features (kinetics, concentration dependence) to those obtained after stimulation of aortic smooth cells by exogenous ATP, a common ligand for most P2 purinoceptors. In contrast, 2‐methylthioATP, a preferential ligand for P2γ purinoceptors, induces only a significant increase of immediate‐early genes but not of delayed‐early genes. Moreover, the 2‐methylthioATP‐induced responses (c‐fos mRNA increase, free intracellular calcium transient) are lower than those induced by ATP or UTP and are complementary to those of UTP. These results demonstrate that functional P2u receptors are present on cultured aortic smooth muscle cells and suggest that the bulk of responses induced by extracellular ATP on cell cycle progression are mediated via P2u purinoceptors, a hypothesis confirmed by cytofluorometric studies. Since some ATP‐or UTP‐induced genes code for chemotactic proteins (monocyte chemoattractant protein‐1 and osteopontin), this study suggests that these nucleotides may contribute to vascular or blood cell migration and proliferation and consequently to the genesis of arterial diseases.

Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders.

BackgroundHeritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases.MethodsWe report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes.ResultsWe show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician.ConclusionsThese findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.

The –308 G/A Tumor Necrosis Factor-α Gene Dimorphism: A Risk Factor for Unstable Angina

Abstract Since the inflammatory cytokine tumor necrosis factorα (TNF-α) may play a major role in the pathophysiology of acute coronary syndromes, 299 consecutive male patients hospitalized for coronary artery disease (i.e., lumen lost ≥50%) were genotyped for the functional −308G/A TNF-α polymorphism using restriction fragment length polymorphism method, in order to evaluate its potential association with the risk of unstable angina and/or myocardial infarction. A higher frequency of carriers of the A allele was observed in patients with unstable angina (n = 58) when compared to control patients with stable angina (n = 95) (39.66% vs. 23.16% respectively, p = 0.029, odds ratio = 2.2) but not in patients with myocardial infarction (n = 146) (23.97% vs. 23.16%, p = NS). Furthermore, we evidenced an interaction of the polymorphism studied with body mass index in patients with unstable angina. Thus, when stratified analysis was performed, results in patients with a body mass index ≤ 27 showed a more striking association between A allele carriage frequency and unstable angina (p = 0.012, odds ratio = 3.0). These results suggest the crucial role of TNF-α in the mechanisms responsible for unstable angina in accordance with the concept of vulnerable plaque. On the other hand, mechanisms controlling myocardial infarction appear more complex and heterogeneous.

Diagnostic value of isoproterenol testing in arrhythmogenic right ventricular cardiomyopathy.

Background—Although the Task Force Criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) have recently been updated, the diagnosis remains challenging in the early stages. The aim of this study was to evaluate the diagnostic value of &bgr;-adrenergic stimulation in ARVC. Methods and Results—We evaluated 412 consecutive patients (213 men, age 41.5±16 years) referred for premature ventricular contractions evaluation or suspected ARVC. Isoproterenol testing was performed with continuous infusion of isoproterenol (45 &mgr;g/min) for 3 minutes. It was considered positive if there were either (1) polymorphic premature ventricular contractions with ≥1 couplet or (2) sustained or nonsustained ventricular tachycardia with left bundle branch block excluding right ventricular outflow tract ventricular tachycardia. ARVC was diagnosed in 35 patients at initial evaluation (23 men, aged 42±15 years). Isoproterenol testing was positive in 32 of 35 (91.4%) patients with ARVC and in 42 of 377 (11.1%) patients without ARVC (P<0.0001). Sensitivity, specificity, positive, and negative predictive values of isoproterenol testing to diagnose ARVC were 91.4%, 88.9%, 43.2%, and 99.1%, respectively. During a mean follow-up period of 5.6±4.4 years, 6 additional patients met diagnostic criteria for ARVC. Importantly, initial isoproterenol testing was positive in 6 of 6 (100%) of these patients. Survival free from ARVC diagnosis was significantly lower in the positive isoproterenol group than in the negative isoproterenol group (P<0.0001, exact log-rank test). Conclusions—Ventricular arrhythmogenicity during isoproterenol testing is highly sensitive (sensitivity, 91.4%) for the diagnosis of ARVC, particularly in its early stages.

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real‐time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440‐13_c.1440‐1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.