Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform

Objectives

The aim of this study was to validate the Lipochip^® genetic diagnostic platform by assessing effectiveness, sensitivity, specificity and costs for the identification of patients with familial hypercholesterolemia (FH) in Spain. This platform includes the use of a DNA micro array, the detection of large gene rearrangements and the complete resequencing of the low-density lipoprotein receptor gene.

Design and methods

DNA samples of patients with clinically diagnosed FH were analyzed for mutations by application of the Lipochip^® platform. Results obtained were confirmed by DNA sequencing and MLPA analysis by two other, independent laboratories.

Results

Of 808 patients tested, Lipochip^® detected a mutation in 66% of the cases and of these 78% were detected by the micro array. A specificity of 99.5% at a sensitivity of 99.8% was reached. A positive test result could be reported within 22 days after start of analysis. The total average screening costs of $ 350 per case were significantly lower compared to other existing screening programs.

Conclusion

Lipochip^® provides a reliable, fast and cheap alternative for the genetic testing of patients with clinically diagnosed FH.     

Ischemic stroke in patients with intermittent claudication: a clinical study of 142 cases

The clinical features, risk factors, neuroimaging findings, and outcome of acute ischemic stroke were assessed in patients with intermittent claudication. Data from 142 patients with ischemic stroke and intermittent claudication were collected from a prospective hospital-based stroke registry in which 2500 consecutive acute stroke patients attended over a 12-year period. Ischemic stroke in patients with intermittent claudication accounted for 7.7% of all ischemic strokes (n = 1840). Ischemic stroke with and without intermittent claudication showed a similar in-hospital mortality rate (16% vs 14%) and absence of functional limitation at hospital discharge (20.5% vs 18.5%). Ischemic stroke patients with intermittent claudication showed a significantly shorter length of stay than patients without symptomatic peripheral arterial disease (14.6 vs 18.8 days, p < 0.05). Ischemic heart disease, transient ischemic attack (TIA), renal dysfunction, and watershed infarct were significant independent predictors of ischemic stroke in patients with intermittent claudication. Although cerebral infarction in patients with intermittent claudication showed a clinical profile suggestive of poor outcome, the prognosis was similar to that of ischemic stroke without intermittent claudication.     

Long-Term Outcomes of the FORMA Transcatheter Tricuspid Valve Repair System for the Treatment of Severe Tricuspid Regurgitation: Insights From the First-in-Human Experience

ObjectivesTo evaluate the long-term (≥2 years) outcomes following transcatheter tricuspid valve repair (TTVr) with the FORMA Transcatheter Tricuspid Valve Repair System (Edwards Lifesciences, Irvine, California).BackgroundScarce data exist on long-term outcomes following TTVr.MethodsThis multicenter experience included patients with severe tricuspid regurgitation (TR) who underwent TTVr with the FORMA system at 4 centers under a compassionate clinical use program. Data were collected at baseline, 30 days, and 1 year, and yearly thereafter.ResultsNineteen patients (76 ± 9 years of age, 74% women, mean EuroSCORE II [European System for Cardiac Operative Risk Evaluation] 9.2 ± 5.6%) with functional TR were included. Procedural success was achieved in 17 (89%) patients and there were no cases of 30-day mortality. At a median follow-up of 32 (interquartile range: 24 to 36) months, 4 (24%) patients had died (3 from terminal heart failure, 1 from sepsis) and 3 (18%) patients required rehospitalization for heart failure. There was 1 device-related thrombosis and 1 pulmonary embolism, both in the setting of subtherapeutic oral anticoagulation. Less than severe TR was observed at echocardiography in 67% of patients at the 2- to 3-year follow-up. Among 15 successfully implanted patients with at least 24-month follow-up, significant improvements in New York Heart Association functional class (p < 0.001), 6-min walk test (+54 m; p = 0.016) and Kansas City Cardiomyopathy Questionnaire score (+16 points; p = 0.016) were observed, compared with baseline.ConclusionsTTVr using the FORMA system showed favorable long-term safety profile in high-surgical-risk patients, with sustained functional improvement and acceptable TR reduction up to 3 years.     

A noncognate aminoacyl-tRNA synthetase that may resolve a missing link in protein evolution

Efforts to delineate the advent of many enzymes essential to protein translation are often limited by the fact that the modern genetic code evolved before divergence of the tree of life. Glutaminyl-tRNA synthetase (GlnRS) is one noteworthy exception to the universality of the translation apparatus. In eukaryotes and some bacteria, this enzyme is essential for the biosynthesis of Gln-tRNAGln, an obligate intermediate in translation. GlnRS is absent, however, in archaea, and most bacteria, organelles, and chloroplasts. Phylogenetic analyses predict that GlnRS arose from glutamyl-tRNA synthetase (GluRS), via gene duplication with subsequent evolution of specificity. A pertinent question to ask is whether, in the advent of GlnRS, a transient GluRS-like intermediate could have been retained in an extant organism. Here, we report the discovery of an essential GluRS-like enzyme (GluRS2), which coexists with another GluRS (GluRS1) in Helicobacter pylori. We show that GluRS2's primary role is to generate Glu-tRNAGln, not Glu-tRNAGlu. Thus, GluRS2 appears to be a transient GluRS-like ancestor of GlnRS and can be defined as a GluGlnRS.     

Imaging for Tricuspid Valve Repair and Replacement

Primary or secondary tricuspid regurgitation (TR) represents an important health care burden and challenge which has often been neglected or undertreated in the past. The expansion and reinforcement of the indications for tricuspid valve (TV) intervention in the 2017 editions of the guidelines as well as the introduction of transcatheter tricuspid valve intervention (TTVI) has considerably increased the attention of the community on the TV and the volume of TV interventions in the past years. Depending on the anatomic target, TTVI can be categorized as the following: 1) direct or indirect tricuspid restrictive annuloplasty; 2) direct (edge-to-edge repair) or indirect (coaptation device) restoration of leaflet coaptation; 3) heterotopic tricuspid valve implantation; and 4) transcatheter tricuspid valve replacement. Multimodality imaging has crucial role for the following: 1) patient selection for TTVI and procedure planning; 2) guiding and monitoring the procedure; and 3) assessing and following over time the results of the procedure. The key points for pre-procedural imaging are: 1) accurate quantitation of TR severity; 2) proper identification of the mechanism(s) responsible for the TR; and 3) quantitation of RV dysfunction and pulmonary arterial hypertension. This imaging work-up is essential to select the right type of intervention for the right patient and TV. Transesophageal echocardiography and fluoroscopy imaging is also key for guiding the TTVI procedures and fusion between these 2 modalities may further enhance the quality of procedure guiding.     

Percutaneous Left Atrial Appendage Closure With the Ultraseal Device: Insights From the Initial Multicenter Experience

Objectives

This study sought to evaluate the feasibility, safety, and efficacy of the Ultraseal device for left atrial appendage closure (LAAC) (Cardia, Eagan, Minnesota) in patients with nonvalvular atrial fibrillation at high bleeding risk.

Transcatheter Tricuspid Valve Replacement for Treating Severe Tricuspid Regurgitation: Initial Experience With the NaviGate Bioprosthesis

Despite the growing evidence with emerging transcatheter tricuspid valve repair therapies, the experience with transcatheter tricuspid valve replacement remains sparse. We describe a case of severe tricuspid regurgitation in a 79-year-old patient deemed unsuitable for isolated tricuspid valve surgery, successfully treated with a 40-mm self-expandable NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA) valved stent via a transatrial approach, with excellent result and hemodynamic performance at 4 months.     

La presión arterial ambulatoria nocturna se asocia al remodelado auricular y la activación neurohormonal en pacientes con fibrilación auricular idiopática

Introduction and objectives

Hypertension is a risk factor for atrial fibrillation. Activation of the renin-angiotensin-system seems to be involved in atrial enlargement, with release of atrial and brain natriuretic peptides. The aim of this study was to evaluate the relationship between ambulatory blood pressure and levels of natriuretic peptides, with left atrial size in normotensives with idiopathic atrial fibrillation.

Methods

This was a cross-sectional study in patients with idiopathic atrial fibrillation. The following measurements were recorded during the course of the study: office and 24-h ambulatory blood pressure, atrial and brain natriuretic peptides, plasma renin, aldosterone, and angiotensin-converting enzyme.

Results

Forty-eight patients (mean age 55 [10] years; 70.6% male) were included in the study. Mean office sitting blood pressure values were 132.49 (14.9)/80.96 (9.2) mmHg. Mean 24-h ambulatory systolic and diastolic blood pressure values were 121.10 (8.3)/72.11 (6.8) mmHg (daytime, 126.8 [9.7]/77.58 [7.9] mmHg; nighttime, 114.56 [11.6]/68.6 [8.8] mmHg). A clear trend towards increased left atrial size with higher ambulatory blood pressure values was noted, which was statistically significant for nighttime values (r=0,34; P=.020 for systolic and r=0,51; P=.0001 for diastolic). A significant correlation between atrial natriuretic peptide and nighttime systolic (r=0,297; P=.047) and diastolic (r=0,312; P=.037) blood pressure was observed. Significant correlations were also observed between left atrial size and atrial natriuretic peptide levels (r=0,577; P<.0001) and brain natriuretic peptide levels (r=0,379; P=.012).

Conclusions

Nighttime blood pressure is associated with left atrial size and the release of natriuretic peptides in normotensive patients with idiopathic atrial fibrillation.Full English text available from:www.revespcardiol.org/en     

Evidence of antiangiogenic and antimetastatic activities of the recombinant disintegrin domain of metargidin

Metargidin, a transmembrane protein of the adamalysin family, and integrins, e.g., alpha5beta1 and alphav, are preferentially expressed on endothelial cells on angiogenesis. Furthermore, metargidin interacts with these integrins via its disintegrin domain. In this study, recombinant human disintegrin domain (RDD) was produced in Escherichia coli by subcloning its cDNA into the pGEX-2T vector, and the effect of purified RDD on different steps of angiogenesis was evaluated. At concentrations of 2-10 micro g/ml, RDD exhibited inhibitory activities in a variety of in vitro functional assays, including endothelial cell proliferation and adhesion on the integrin substrates fibronectin, vitronectin, and fibrinogen. RDD (10 micro g/ml) totally abrogated endothelial cell migration and blocked most capillary formation in a three-dimensional fibrin gel. To test RDD efficacy in vivo, the RDD gene inserted into pBi vector containing a tetracycline-inducible promoter was electrotransferred into nude mouse muscle. RDD was successfully synthesized by muscle cells in vivo as shown by immunolabeling and Western blotting. In addition, 78% less MDA-MB-231 tumor growth, associated with strong inhibition of tumor angiogenesis, was observed in athymic mice bearing electrotransferred RDD. Moreover, in the presence of RDD, 74% fewer B16F10 melanoma lung metastases were found in C57BL/6 mice. Taken together, these results identified this RDD as a potent intrinsic inhibitor of angiogenesis, tumor growth, and metastasis, making it a promising tool for use in anticancer treatment.