James Yeh

Initial Experience of a Second-Generation Self-Expanding Transcatheter Aortic Valve: The UK & Ireland Evolut R Implanters’ Registry

OBJECTIVES The authors present the UK and Irish real-world learning curve experience of the Evolut R transcatheter heart valve. BACKGROUND The Evolut R is a self-expanding, repositionable, and fully recapturable second-generation transcatheter heart valve with several novel design features to improve outcomes and reduce complications. METHODS Clinical, procedural, and 30-day outcome data were prospectively collected for the first 264 patients to receive the Evolut R valve in the United Kingdom and Ireland. RESULTS A total of 264 consecutive Evolut R implantations were performed across 9 centers. The mean age was 81.1 ± 7.8 years, and the mean logistic European System for Cardiac Operative Risk Evaluation score was 19.9 ± 13.7%. Procedural indications included aortic stenosis (72.0%), mixed aortic valve disease (17.4%), and failing aortic valve bioprostheses (10.6%). Conscious sedation was used in 39.8% of patients and transfemoral access in 93.6%. The procedural success rate was 91.3%, and paravalvular leak immediately after implantation was mild or less in 92.3%. Major complications were rare: cardiac tamponade in 0.4%, conversion to sternotomy in 0.8%, annular rupture in 0.0%, coronary occlusion in 0.8%, major vascular in 5.3%, acute kidney injury in 6.1%, new permanent pacemaker implantation in 14.7%, and procedure-related death in 0.0%. At 30-day follow-up, survival was 97.7%, paravalvular leak was mild or less in 92.3%, and the stroke rate was 3.8%. CONCLUSIONS This registry represents the largest published real-world experience of the Evolut R valve. The procedural success rate was high and safety was excellent, comparable with previous studies of the Evolut R valve and other second-generation devices. The low rate of complications represents an improvement on first-generation devices.

Thoracic endovascular aortic repair (TEVAR) in proximal (type A) aortic dissection: Ready for a broader application?

Objective: Thoracic endovascular aortic repair (TEVAR) has demonstrated encouraging results and is gaining increasing acceptance as a treatment option for aortic aneurysms and dissections. Yet, its role in managing proximal aortic pathologies is unknown—this is important because in proximal (Stanford type A) aortic dissections, 10% to 30% are not accepted for surgery and 30% to 50% are technically amenable for TEVAR. We describe our case series of type A aortic dissections treated by using TEVAR. Methods: Between year 2009 and 2016, 12 patients with acute, subacute, or chronic type A aortic dissection with the proximal entry tear located between the coronaries and brachiocephalic artery were treated with TEVAR at 3 centers. Various stent‐graft configurations were used to seal the proximal entry tear in the ascending aorta under rapid pacing. Results: A total of 12 patients (9 male, 3 female), mean age 81 ± 7 years, EuroSCORE II 9.1 ± 4.5, underwent TEVAR for the treatment of type A aortic dissection. Procedural success was achieved in 11 of 12 patients (91.7%). There was 1 minor stroke and 1 intraprocedural death. No additional deaths were reported at 30 days. At 36 months, there were 4 further deaths (all from nonaortic causes). The mean survival of these 4 deceased was 23 months (range 15‐36 months). Follow‐up computed tomography demonstrated favorable aortic remodeling. Conclusions: TEVAR is feasible and reveals promising early results in selected patients with type A aortic dissection who are poor candidates for surgical repair. The current iteration of stent‐graft technology, however, needs to be adapted to features specific to the ascending aorta.

Evaluation of Methods for Sizing and Counting of Ultrasound Contrast Agents

A precise, accurate and well documented method for the sizing and counting of microbubbles is essential for all aspects of quantitative microbubble-enhanced ultrasound imaging. The efficacy of (a) electro-impedance volumetric zone sensing (ES) also called a Coulter counter/multisizer; (b) optical microscopy (OM); and (c) laser diffraction (LD), for the sizing and counting of microbubbles was assessed. Microspheres with certified mean diameter and number concentration were used to assess sizing and counting reproducibility (precision) and reliability (accuracy) of ES, OM and LD. SonoVue™ was repeatedly (n = 3) sized and counted to validate ES, OM and LD sizing and counting efficacy. Statistical analyses of intra-method variability for the SonoVue™ mean diameter showed that the best microbubble sizing reproducibility was obtained using OM with a mean diameter sizing variability of 1.1%, compared with a variability of 4.3% for ES and 7.1% for LD. The best microbubble counting reproducibility was obtained using ES with a number concentration variability of 8.3%, compared with a variability of 22.4% for OM and 32% for LD. This study showed that no method is fully suited to both sizing and counting of microbubbles.

A Targeting Microbubble for Ultrasound Molecular Imaging

Rationale Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld. Objective To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging. Methods and Results Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab’)2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification. Conclusions Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)–(iii) desired for clinical applications.

Quantitative Ultrasound Molecular Imaging

Ultrasound molecular imaging using targeting microbubbles is predominantly a semi-quantitative tool, thus limiting its potential diagnostic power and clinical applications. In the work described here, we developed a novel method for acoustic quantification of molecular expression. E-Selectin expression in the mouse heart was induced by lipopolysaccharide. Real-time ultrasound imaging of E-selectin expression in the heart was performed using E-selectin-targeting microbubbles and a clinical ultrasound scanner in contrast pulse sequencing mode at 14 MHz, with a mechanical index of 0.22-0.26. The level of E-selectin expression was quantified using a novel time-signal intensity curve analytical method based on bubble elimination, which consisted of curve-fitting the bi-exponential equation [Formula: see text] to the elimination phase of the myocardial time-signal intensity curve. Ar and Af represent the maximum signal intensities of the retained and freely circulating bubbles in the myocardium, respectively; λr and λf represent the elimination rate constants of the retained and freely circulating bubbles in the myocardium, respectively. Ar correlated strongly with the level of E-selectin expression (|r|>0.8), determined using reverse transcriptase real-time quantitative polymerase chain reaction, and the duration of post-lipopolysaccharide treatment-both linearly related to cell surface E-selectin protein (actual bubble target) concentration in the expression range imaged. Compared with a conventional acoustic quantification method (which used retained bubble signal intensity at 20 min post-bubble injection), this new approach exhibited greater dynamic range and sensitivity and was able to simultaneously quantify other useful characteristics (e.g., the microbubble half-life). In conclusion, quantitative determination of the level of molecular expression is feasible acoustically using a time-signal intensity curve analytical method based on bubble elimination.

Novel reconstruction of a vascular aneurysm in Marfan syndrome

A 46-year-old lady with genetically confirmed Marfan syndrome presented with a recent onset of pulsatile sensation in the left supraclavicular fossa. She had previously undergone a Crawford II repaired for descending aortic dissection in 2005, and a valve-sparing aortic root replacement for ascending aortic dissection in 2008. She had bilateral mastectomy for breast cancer in 2007. Computed tomography (CT) angiogram showed a newly developed circumscribed aneurysm (4.1 × 3.3 cm) of her left subclavian …

Molecular Imaging of Inflammation Using Echocardiography. Advances with the Use of Microbubbles

Ultrasound molecular imaging uses microbubbles conjugated with targeting ligands. When administered intravenously these ‘targeting bubbles’ attach to areas expressing the molecule of interest for ultrasound detection. The migration of this technology to human application has been limited by uncertainties regarding its safety and efficacy, including: (i) the lack of targeting bubbles that do not contain immunogenic (strept)avidin for ligand conjugation; (ii) the traditional use of high power ultrasound causing ‘instantaneous’ bubble destruction, raising concerns about biosafety and rendering it not a real-time imaging technique (limiting bedside interpretation); (iii) the absence of robust molecular quantification methods, diminishing its potential diagnostic power. Progress has been made in all three areas recently. An example is molecular imaging of E-selectin expression for detecting endothelial activation or inflammation in the heart. Inflammation underlies important cardiovascular diseases, such as coronary atheromatous heart disease, myocarditis and heart transplant rejection. Endothelial activation occurs early in inflammation and E-selectin is classically expressed only on activated endothelial cells. E-selectin targeting bubbles, based on maleimide-thiol conjugation chemistry, were successfully engineered. They allowed high resolution real-time and quantitative ultrasound molecular imaging of the heart in mice. Future directions in the field includes establishing 3-D ultrasound molecular imaging, and therapies using targeting bubbles as vehicles for targeted delivery of therapeutic agents such as drugs or genetic materials. All these help gather the financial and research momentum required to establish the technology in humans.

Efficacy and safety of vorapaxar for the prevention of adverse cardiac events in patients with coronary artery disease: a meta-analysis

BACKGROUND Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Vorapaxar, a protease-activated receptor-1 (PAR-1) antagonist, is a novel antiplatelet agent that may provide us a new way in antithrombotic therapy. Several studies had been conducted to evaluate the efficacy of vorapaxar in the treatment of CAD, but the results were inconsistent. Here a meta-analysis was made to assess the efficacy and safety of vorapaxar in reducing adverse cardiac events in patients with CAD. METHODS A comprehensive literature search was conducted. The primary efficacy endpoint was the major adverse cardiac events, which was defined as a composite of cardiovascular death, myocardial infarction (MI), stroke, urgent coronary revascularization, or recurrent ischemia with rehospitalization. The primary safety endpoint was the composite of major or minor bleeding events. Pooled effects were measured by odds ratios (ORs) with 95% confidence intervals (CIs). A random-effect or fixed model was used in this meta-analysis. RESULTS Totally, 31,388 patients from four randomized controlled trials (RCTs) were included in this meta-analysis. Patients who took vorapaxar combined with standard dual anti-platelet therapy (aspirin and thienopyridine) showed a lower incidence in major adverse cardiac events (OR, 0.86, 95% CI: 0.75-0.99, P=0.03), MI (OR, 0.79, 95% CI: 0.67-0.95, P=0.01) and ischemic stroke (OR, 0.72, 95% CI: 0.58-0.89, P=0.003) than those who only took placebo instead. But there was no significant reduction in cardiovascular death (OR, 0.95, 95% CI: 0.82-1.09, P=0.45). Nevertheless, the vorapaxar group were associated with a higher risk of bleeding events (P<0.001). CONCLUSIONS The result of this meta-analysis indicated that adding vorapaxar to the standard dual anti-platelet therapy may be efficient in reducing the incidence of major adverse cardiac events at the cost of increasing risk of bleeding events.

EFFECT OF TRIPTOLIDE ON PROLIFERATION AND APOPTOSIS OF ANGIOTENSIN II-INDUCED CARDIAC FIBROBLASTS IN VITRO: A PRELIMINARY STUDY

Background: The effect of triptolide (TPL) on cardiac fibroblasts (CFbs) and cardiac fibrosis remain unknown till now. This study was conducted to explore the effects of TPL on proliferation and apoptosis of angiotensin II (Ang II)-induced CFbs. Materials and Methods: Ang II was used to promote proliferation of CFbs. Two dosages of TPL (10ng/ml and 100ng/ml) were chosen. MTT assay was used to detect cell survival rate in vitro. Flow cytometer was performed to analyze apoptosis of CFbs. Hydroxyproline concentration was detected with hydroxyproline assay kit. Quantitative real-time PCR was used to detect the expression of TGF-β1 and Smad3 mRNA. Results: Ang II promoted CFbs proliferation significantly. Compared to Ang II group, TPL markedly reduced the viability of CFbs and its Hydroxyproline concentration (P<0.05). Besides, TPL can significantly promote apoptosis of CFbs (P<0.05). Furthermore, TPL reduced the expressions of TGF-βΙ and Smad3 mRNA in Ang II-induced CFbs (P<0.05). Conclusion: TPL can inhibit the proliferation of CFbs in rats by down-regulating TGF-β1/Smad3 signaling pathway. TPL might be a promising therapeutic drug for myocardial fibrosis.