Oxidative stress and pathological changes after coronary artery interventions

Oxidative stress greatly influences the pathogenesis of various cardiovascular disorders. Coronary interventions, including balloon angioplasty and coronary stent implantation, are associated with increased vascular levels of reactive oxygen species in conjunction with altered endothelial cell and smooth muscle cell function. These alterations potentially lead to restenosis, thrombosis, or endothelial dysfunction in the treated artery. Therefore, the understanding of the pathophysiological role of reactive oxygen species (ROS) generated during or after coronary interventions, or both, is essential to improve the success rate of these procedures. Superoxide O2 ·- anions, whether derived from uncoupled endothelial nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, or mitochondria, are among the most harmful ROS. O2 ·- can scavenge nitric oxide, modify proteins and nucleotides, and induce proinflammatory signaling, which may lead to greater ROS production. Current innovations in stent technologies, including biodegradable stents, nitric oxide donor-coated stents, and a new generation of drug-eluting stents, therefore address persistent oxidative stress and reduced nitric oxide bioavailability after percutaneous coronary interventions. This review discusses the molecular mechanisms of ROS generation after coronary interventions, the related pathological events - including restenosis, endothelial dysfunction, and stent thrombosis - and possible therapeutic ways forward

Oxidative Stress and Pathological Changes After Coronary Artery Interventions

Oxidative stress greatly influences the pathogenesis of various cardiovascular disorders. Coronary interventions, including balloon angioplasty and coronary stent implantation, are associated with increased vascular levels of reactive oxygen species in conjunction with altered endothelial cell and smooth muscle cell function. These alterations potentially lead to restenosis, thrombosis, or endothelial dysfunction in the treated artery. Therefore, the understanding of the pathophysiological role of reactive oxygen species (ROS) generated during or after coronary interventions, or both, is essential to improve the success rate of these procedures. Superoxide O2·− anions, whether derived from uncoupled endothelial nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, or mitochondria, are among the most harmful ROS. O2·− can scavenge nitric oxide, modify proteins and nucleotides, and induce proinflammatory signaling, which may lead to greater ROS production. Current innovations in stent technologies, including biodegradable stents, nitric oxide donor-coated stents, and a new generation of drug-eluting stents, therefore address persistent oxidative stress and reduced nitric oxide bioavailability after percutaneous coronary interventions. This review discusses the molecular mechanisms of ROS generation after coronary interventions, the related pathological events—including restenosis, endothelial dysfunction, and stent thrombosis—and possible therapeutic ways forward

Sox7 controls arterial specification in conjunction with hey2 and efnb2 function

SoxF family members have been linked to arterio-venous specification events and human pathological conditions, but in contrast to Sox17 and Sox18, a detailed in vivo analysis of a Sox7 mutant model is still lacking. In this study we generated zebrafish sox7 mutants to understand the role of Sox7 during vascular development. By in vivo imaging of transgenic zebrafish lines we show that sox7 mutants display a short circulatory loop around the heart as a result of aberrant connections between the lateral dorsal aorta (LDA) and either the venous primary head sinus (PHS) or the common cardinal vein (CCV). In situ hybridization and live observations in flt4:mCitrine transgenic embryos revealed increased expression levels of flt4 in arterial endothelial cells at the exact location of the aberrant vascular connections in sox7 mutants. An identical circulatory short loop could also be observed in newly generated mutants for hey2 and efnb2. By genetically modulating levels of sox7, hey2 and efnb2 we demonstrate a genetic interaction of sox7 with hey2 and efnb2. The specific spatially confined effect of loss of Sox7 function can be rescued by overexpressing the Notch intracellular domain (NICD) in arterial cells of sox7 mutants, placing Sox7 upstream of Notch in this aspect of arterial development. Hence, sox7 levels are crucial in arterial specification in conjunction with hey2 and efnb2 function, with mutants in all three genes displaying shunt formation and an arterial block

Cardiac function in a long-term follow-up study of moderate and severe porcine model of chronic myocardial infarction

Background. Novel therapies need to be evaluated in a relevant large animal model that mimics the clinical course and treatment in a reasonable time frame. To reliably assess therapeutic efficacy, knowledge regarding the translational model and the course of disease is needed. Methods. Landrace pigs were subjected to a transient occlusion of the proximal left circumflex artery (LCx) (n=6) or mid-left anterior descending artery (LAD) (n=6) for 150 min. Cardiac function was evaluated before by 2D echocardiography or 3D echocardiography and pressure-volume loop analysis. At 12 weeks of follow-up the heart was excised for histological analysis and infarct size calculations. Results. Directly following AMI, LVEF was severely reduced compared to baseline in the LAD group -17.1±1.6%, P=0.009 compared to only a moderate reduction in the LCx group -5.9±1.5%, P=0.02 and this effect remained unchanged during 12 weeks of follow-up. Conclusion. Two models of chronic MI, representative for different patient groups, can reproducibly be created through clinically relevant ischemia-reperfusion of the mid-LAD and proximal LCx

Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial.

peer reviewedAIMS: The SEISMIC study was an open-label, prospective, randomised study to assess the safety and feasibility of percutaneous myoblast implantation in heart failure patients with implanted cardioverter-defibrillators (ICD). METHODS AND RESULTS: Patients were randomised 2:1 to autologous skeletal myoblast therapy vs. optimal medical treatment. The primary safety end-point was defined as the incidence of procedural and device related serious adverse events, whereas the efficacy endpoints were defined as the change in global LVEF by MUGA scan, change in NYHA classification of heart failure and in the distance achieved during a six-minute walk test (6MW) at 6-month follow-up. Forty subjects were randomised to the treatment arm (n=26), or to the control arm (n=14). There were 12 sustained arrhythmic events and one death after episodes of ventricular tachycardia (VT) in the treatment group and 14 events in the control group (P=ns). At 6-month follow-up, 6MW distance improved by 60.3+/-54.1?meters in the treated group as compared to no improvement in the control group (0.4+/-185.7?meters; P=ns). In the control group, 28.6% experienced worsening of heart failure status (4/14), while 14.3% experienced an improvement in NYHA classification (2/14). In the myoblast-treatment arm, one patient experienced a deterioration in NYHA classification (8.0%), whereas five patients improved one or two classes (20.0%; P=0.06). However, therapy did not improve global LVEF measured by MUGA at 6-month follow-up. CONCLUSIONS: These data indicate that implantation of myoblasts in patients with HF is feasible, appears to be safe and may provide symptomatic relief, though no significant effect was detected on global LVEF

Accelerated vascular repair following percutaneous coronary intervention by capture of endothelial progenitor cells promotes regression of neointimal growth at long term follow-up: final results of the Healing II trial using an endothelial progenitor cell capturing stent (Genous R stent)

Aims: The study sought to define the long-term angiographic and clinical outcome of a bio-engineered stent, able to sequester endothelial progenitor cells (EPC) to the stent to promote the post-stenting vascular repair response.Methods and results: The HEALING-II was a multicentre, prospective registry, including 63 patients treated with the implantation of a Genous EPC capture stent. Serial quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) analysis was performed at 6 and 18 month. The 18 month composite MACE rate was 7.9%, whereas 6.3% clinically justified target lesion revascularisations were observed. Although patients received one month of clopidogrel, no (sub)acute or late angiographic stent thrombosis occurred. At 6 month follow-up, in-stent late luminal loss was 0.78+/-0.39 mm and percent in-stent volume obstruction was 22.9+/-13.7% (mean+/-sd). Serial angiographic and IVUS analyses were available in 30 event-free patients at post-procedure, 6 months and 18 months. From 6 months to 18 months follow-up, a significant late regression of neointimal hyperplasia was observed on QCA (late luminal loss 0.59+/-0.31, 24.4% reduction or 16.9% by matched serial analysis) and IVUS (percent in-stent volume obstruction 20.3+/-14.3%, 11.4% reduction or 9.6% by matched serial analysis). The relative increase in circulating EPC titers at long-term follow-up correlated with neointimal compaction in individual patients, suggestive of an EPC-mediated vascular repair response.Conclusions: The HEALING II study suggests that the EPC capture stent, aimed to stimulate the coronary vascular repair response, significantly promotes late regression of neointimal hyperplasia up to 18 months after stent implantatio