MiR-145 expression and rare NOTCH1 variants in bicuspid aortic valve-associated aortopathy

<div><p>MicroRNAs (miRNAs) may serve as elegant tool to improve risk stratification in bicuspid aortic valve (BAV)-associated aortopathy. However, the exact pathogenetic pathway by which miRNAs impact aortopathy progression is unknown. Herewith, we aimed to analyze the association between circulating miRNAs and rare variants of aortopathy-related genes. 63 BAV patients (mean age 47.3±11.3 years, 92% male) with a root dilatation phenotype, who underwent aortic valve+/-proximal aortic surgery at a single institution (mean post-AVR follow-up 10.3±6.9 years) were analyzed. A custom-made HaloPlex HS panel including 20 aortopathy-related genes was used for the genetic testing. miRNAs were extracted from whole blood and miRNA analysis was performed using miRNA-specific assay. Study endpoint was the association between circulating miRNAs and rare genetic variants in the aortopathy gene panel. The study cohort was divided into a subgroup with rare variants vs. a subgroup without rare variants based on the presence of rare variants in the respective genes (i.e., at least one variant present). The genetic analysis yielded n = 6 potentially and likely pathogenic rare variants within the <i>NOTCH1</i> gene as being the most common finding. Univariate analysis between blood miRNAs and <i>NOTCH1</i> variants revealed a significantly lower expression of miR-145 in the subgroup of patients with <i>NOTCH1</i> variants vs. those without <i>NOTCH1</i> variants (i.e., delta Ct 4.95±0.74 vs. delta Ct 5.57±0.78, p = 0.04). Our preliminary data demonstrate a significant association between blood miR-145 expression and the presence of rare <i>NOTCH1</i> variants. This association may be indicative of a specific pathogenetic pathway in the development of genetically-triggered bicuspid aortopathy.</p></div

Demographics and intraoperative variables.

<p>Demographics and intraoperative variables.</p

Expression of miR-145 in patients with and without rare <i>NOTCH1</i> variants.

<p>Expression of miR-145 in patients with and without rare <i>NOTCH1</i> variants.</p

Rare genetic variants within the 20 candidate genes in the aortopathy gene panel [13].

<p>Rare genetic variants within the 20 candidate genes in the aortopathy gene panel [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200205#pone.0200205.ref013" target="_blank">13</a>].</p

Expression of microRNAs in patients with and without potentially/likely pathogenic NOTCH1 variants.

<p>Normalized delta Ct values are shown.</p

Potential mechanistic linkage between NOTCH1 variants, miR-145 expression and bicuspid aortopathy.

<p>Potential mechanistic linkage between NOTCH1 variants, miR-145 expression and bicuspid aortopathy.</p

Correlation of individual microRNAs.

<p>Correlation of individual microRNAs.</p

Coronary Sinus Lead Removal: A Comparison between Active and Passive Fixation Leads

<div><p>Background</p><p>Implantation of coronary sinus (CS) leads may be a difficult procedure due to different vein anatomies and a possible lead dislodgement. The mode of CS lead fixation has changed and developed in recent years.</p><p>Objectives</p><p>We compared the removal procedures of active and passive fixation leads.</p><p>Methods</p><p>Between January 2009 and January 2014, 22 patients at our centre underwent CS lead removal, 6 active and 16 passive fixation leads were attempted using simple traction or lead locking devices with or without laser extraction sheaths. Data on procedural variables and success rates were collected and retrospectively analyzed.</p><p>Results</p><p>The mean patient age was 67.2 ± 9.8 years, and 90.9% were male. The indication for lead removal was infection in all cases. All active fixation leads were Medtronic^® Attain StarFix^™ Model 4195 (Medtronic Inc., Minneapolis, MN, USA). The mean time from implantation for the active and passive fixation leads was 9.9 ± 11.7 months (range 1.0–30.1) and 48.7 ± 33.6 months (range 5.7–106.4), respectively (p = 0.012). Only 3 of 6 StarFix leads were successfully removed (50%) compared to 16 of 16 (100%) of the passive fixation CS leads (p = 0.013). No death or complications occurred during the 30-day follow-up.</p><p>Conclusion</p><p>According to our experience, removal of the Starfix active fixation CS leads had a higher procedural failure rate compared to passive.</p></div

Re-implantation status.

<p>Re-implantation status.</p

Left and right ventricular heart histology in transversal orientation and haematoxylin staining, Caspase-3 staining for evaluation of apoptotic myocyte numbers.

<p>A: Healthy heart of 3-weeks old Lewis rat B: Hypertrophic heart of 4-weeks old Lewis rat, 3 weeks after TAC with thickened myocardium C: Failing heart of 7-weeks old Lewis rat, 6 weeks after TAC with thinned myocardium D-F: Healthy heart (D), hypertrophic heart (E) and failing heart (F) of Lewis rat, after 2 weeks of mechanical unloading. * Caspase-3 staining of the respective image to the left. Representative images.</p