Gene transfer of cytoprotective and immunomodulatory molecules for prevention of cardiac allograft rejection

Current treatments of heart transplantation are limited by incomplete effectiveness, significant toxicity, and failure to prevent chronic rejection. Genetic manipulation of the donor heart at the time of removal offers the unique opportunity to produce a therapeutic molecule within the graft itself, while minimizing systemic effects. Cytoprotective approaches including gene transfer of heme oxygenase (HO)-1, endothelial nitric oxide synthase, and antisense oligodeoxynucleotides specific for nuclear factor (NF)-κB or intercellular adhesion molecule (ICAM)-1 reduced ischaemia-reperfusion injury and delayed cardiac allograft rejection in small animals. Exogenous overexpression of immunomodulatory cytokines such as interleukin (IL)-4, IL-10 and transforming growth factor-β, as well as gene transfer of inhibitors of pro-inflammatory cytokines also delayed graft rejection. Gene transfer-based blockade of T-cell costimulatory activation with CTLA4-Ig or CD40-Ig resulted in long-lasting graft survival and donor-specific unresponsiveness, as manifested by acceptance of a second graft from the original donor strain but rejection of third-party grafts. Similar results were obtained with donor major histocompatibility complex class I gene transfer into bone marrow cells. Gene therapy approaches to chronic rejection included gene transfer of HO-1, soluble Fas, tissue plasminogen activator and antisense oligodeoxynucleotides specific for the anti-apoptotic mediator Bcl-x or the E2F transcription factor. Despite major experimental advances, however, gene therapy for heart transplantation has not entered the clinical arena yet. Fundamental questions regarding the most suitable vector, the best gene, and safety issues remain unanswered. Well-controlled studies that compare gene therapy with established treatments in non-human primates are needed before clinical trials can be starte

Heart rate never lies: interventional cardiologist and Braude’s quote revised

Background Interventional cardiologists may be immune to stress, allowing them to perform complex percutaneous interventions under pressure.Objectives To assess heart rate (HR) variations as a surrogate marker of stress of interventional cardiologists during percutaneous cardiac procedures and in every-day life.Design This is a single-centre observational study including a total of six male interventional cardiologists performing coronary interventions and pacemaker implantations. Participants were asked to record their HR with the Apple Watch Device during procedures, every-day life and control activities such as outpatient consultations, sport, marital conflicts and sexual intercourse.Results Average daily HR was 88±17 bpm. During work days, HR increased significantly during procedures (90±17 bpm) compared with days outside the cathlab (87±17 bpm, p=0.02). The average HR was higher during a regular week working (88±16 bpm) compared with weekends off (84±18 bpm, p=0.002). Complex cardiac procedures were associated with higher HR up to 122 bpm. Peak HR were higher during physical exertion. Of note, participants complained of hypersexuality and mania after night shifts.Conclusions Work and especially percutaneous cardiac procedures increase HR independently of physical exertion suggesting that interventional cardiologists experience mental stress and emotions

Subsurface ablation of atherosclerotic plaque using ultrafast laser pulses

We perform subsurface ablation of atherosclerotic plaque using ultrafast pulses. Excised mouse aortas containing atherosclerotic plaque were ablated with ultrafast near-infrared (NIR) laser pulses. Optical coherence tomography (OCT) was used to observe the ablation result, while the physical damage was inspected in histological sections. We characterize the effects of incident pulse energy on surface damage, ablation hole size, and filament propagation. We find that it is possible to ablate plaque just below the surface without causing surface damage, which motivates further investigation of ultrafast ablation for subsurface atherosclerotic plaque removal

Ultrafast laser ablation for targeted atherosclerotic plaque removal

Coronary artery disease, the main cause of heart disease, develops as immune cells and lipids accumulate into plaques within the coronary arterial wall. As a plaque grows, the tissue layer (fibrous cap) separating it from the blood flow becomes thinner and increasingly susceptible to rupturing and causing a potentially lethal thrombosis. The stabilization and/or treatment of atherosclerotic plaque is required to prevent rupturing and remains an unsolved medical problem. Here we show for the first time targeted, subsurface ablation of atherosclerotic plaque using ultrafast laser pulses. Excised atherosclerotic mouse aortas were ablated with ultrafast near-infrared (NIR) laser pulses. The physical damage was characterized with histological sections of the ablated atherosclerotic arteries from six different mice. The ultrafast ablation system was integrated with optical coherence tomography (OCT) imaging for plaque-specific targeting and monitoring of the resulting ablation volume. We find that ultrafast ablation of plaque just below the surface is possible without causing damage to the fibrous cap, which indicates the potential use of ultrafast ablation for subsurface atherosclerotic plaque removal. We further demonstrate ex vivo subsurface ablation of a plaque volume through a catheter device with the high-energy ultrafast pulse delivered via hollow-core photonic crystal fiber

Vascular response to everolimus- and biolimus-eluting coronary stents versus everolimus-eluting bioresorbable scaffolds – an optical coherence tomography substudy of the EVERBIO II trial

QUESTIONS UNDER STUDY: Head-to-head optical coherence tomography (OCT) data comparing metallic stents with bioresorbable vascular scaffolds (BVS) are lacking. This study assessed vascular healing at 9-month follow-up after implantation of everolimus- and biolimus-eluting stents (EES BES) and everolimus-eluting BVS.METHODS: OCT was performed in 74 patients enrolled in the EVERBIO II (NCT01711931) trial (23 with EES: 26 lesions, 7 625 struts; 23 with BES: 26 lesions, 6 140 struts; 28 with BVS: 33 lesions, 10 891 struts). OCT images were acquired using the pullback and nonocclusive flushing technique and analysed offline.RESULTS: BVS demonstrated fewer uncovered struts per patient (12 ± 27 [3.8 ± 8.4%] vs 59 ± 55 [21.8 ± 13.7%] in the EES and BES group, p <0.001), and thicker neointimal hyperplasia (BVS 102 ± 44 µm vs EES and BES 66 ± 36 µm, p <0.01). There was no significant difference with regard to malapposed struts (2.1 ± 2.7% in the BVS vs 4.4 ± 8.8% in the EES and BES group, p = 0.41). In a predefined signal intensity scale, quantitative analysis of the “key component” (black) revealed lower intensity in BVS than EES and BES (14 ± 23% vs 13 ± 12%, p = 0.007). Intensity was lower in polylactide-containing stents (BVS and BES) than in EES (15 ± 19% vs 10 ± 10%, p <0.001). CONCLUSIONS: BVS has fewer uncovered struts and presents with a thicker neointimal coverage compared with EES and BES. It is not known whether this improved capping correlates with superior vascular healing. Polylactide-containing stents (BVS and BES) demonstrate lower peristrut intensity compared with EES

Transcutaneous aortic valve implantation using the carotid artery access: Feasibility and clinical outcomes

Background: Transcarotid access is an alternative route for transcutaneous aortic valve implantation (TAVI) in patients with impossible transfemoral access.Aims: We evaluated the safety, effectiveness and early and late clinical outcomes of CoreValve® implantation via the common carotid artery.Methods: Eighteen patients (10 men, 8 women; mean age 84 ± 5 years) at high surgical risk (mean EuroSCORE II 16 ± 13%) with significant peripheral artery disease underwent TAVI via common carotid artery access under general anaesthesia. Mean aortic valve area was 0.64 ± 0.13 cm2 (0.36 ± 0.07 cm2/m2).Results: At a mean follow-up of 605 ± 352 days, two patients (11%) had died in hospital, on days 6 and 20, as a result of sepsis with multiorgan failure (n = 1) or pneumonia (n = 1). There were no perioperative deaths, myocardial infarctions or strokes. Perioperative prosthesis embolization occurred in one patient (6%), requiring implantation of a second valve. In-hospital complications occurred in four patients (23%): blood transfusion for transient significant bleeding at the access site in one patient (6%); permanent pacemaker implantation in two patients (11%); and pericardial drainage in one patient (6%). The rate of event-free in-hospital stay was 66%. Post-procedural echocardiography showed very good haemodynamic performance, with a mean gradient of 8 ± 3 mmHg. Moderate paravalvular leak was present in one patient (6%). Mean intensive care unit stay was 48 ± 31 h; mean in- hospital stay was 7 ± 3 days.Conclusion: TAVI performed by transcarotid access in this small series of severely ill patients was associated with a low incidence of complications, which were associated with the procedure itself rather than the access route

Quantitative angiographic follow-up of the coronary wallstent in native vessels and bypass grafts (European experience - March 1986 to March 1990)

The coronary stent has been investigated as an adjunct to percutaneous transluminal coronary angioplasty to obviate the problems of early occlusion and late restenosis. From March 1986 to March 1990, 265 patients (308 lesions) were implanted with the coronary Wallstent in 6 European centers. For this study, the patients were analyzed accordin