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Although drug-eluting stents are still the default interventional treatment of coronary artery disease, drug-coated balloons (DCBs) represent a novel alternative therapeutic strategy in certain anatomic conditions. The effect of DCBs is based on the fast and homogenous transfer of antiproliferative drugs into the vessel wall during single balloon inflation by means of a lipophilic matrix without the use of permanent implants. Although their use is established for in-stent restenosis of both bare-metal and drug-eluting stents, recent randomized clinical data demonstrate a good efficacy and safety profile in de novo small-vessel disease and high bleeding risk. In addition, there are other emerging indications (e.g., bifurcation lesions, large-vessel disease, diabetes mellitus, acute coronary syndromes). Because the interaction among the different delivery balloon designs, doses, formulations, and release kinetics of the drugs used is important, there seems to be no "class effect" of DCBs. On the basis of the amount of recently published data, the International DCB Consensus Group provides this update of previous recommendations summarizing the historical background, technical considerations such as choice of device and implantation technique, possible indications, and future perspectives. • DES still have some limitations in certain clinical and anatomic conditions. • DCBs are a novel therapeutic strategy for coronary artery disease. • Besides ISR, new data show possible indications for native coronary artery disease. • Future research will focus on alternative drug coatings and other possible indications. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to test the feasibility of contrast pulse sequence (CPS) ultrasound imaging for high-resolution perfusion imaging after gene transfer (GT) for therapeutic angiogenesis. Background: Imaging modalities capable of accurate and feasible perfusion measurement are essential for the preclinical and clinical development of therapeutic angiogenesis. However, current methods suffer from compromises between spatial and temporal resolution and sensitivity. Contrast pulse sequence ultrasound is a recently developed real-time perfusion imaging method that generates high-contrast agent-to-tissue specificity and spatial resolution. Methods: Contrast pulse sequence ultrasound was used to noninvasively assess parameters of blood flow 6 days after adenoviral vascular endothelial growth factor (AdVEGF) GT in rabbit and mouse hind limbs with bolus intravenous injection of a microbubble contrast medium. Blood volume, mean transit time, perfusion, and time to the arrival of the contrast bolus were calculated with the gamma variate function. Contrast-enhanced power Doppler ultrasound (CEU), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), and histological capillary measurements were used as reference methods. Results: Blood volume and perfusion increased over 40- and 20-fold, respectively, 6 days after AdVEGF GT in rabbit skeletal muscles. Perfusion values measured with CPS correlated well with those obtained with CEU (r = 0.975) and DCE-MRI (r = 0.854). However, CPS provided superior spatial and temporal resolution showing blood flow in vessels of only 10 to 20 μm in diameter. Contrast pulse sequence ultrasound was also feasible for imaging of therapeutic angiogenesis in mouse hind limbs both at the arterial and capillary levels. The CPS ultrasound revealed that AdVEGF mainly induces angiogenesis in adipose tissue rather than in the skeletal muscle of mouse hind limbs. Conclusions: Contrast pulse sequence ultrasound is an efficient and accurate noninvasive real-time perfusion imaging modality in small laboratory animals and also offers a means for the assessment of muscle perfusion in future clinical trials of therapeutic angiogenesis. [Copyright &y& Elsevier]

Gene transfer for the therapeutic modulation of cardiovascular diseases is an expanding area of gene therapy. During the last decade several approaches have been designed for the treatment of hyperlipidemias, post-angioplasty restenosis, hypertension, and heart failure, and for protection of vascular by-pass grafts and promotion of therapeutic angiogenesis. Adenoviruses (Ads) and adeno-associated viruses (AAVs) are currently the most efficient vectors for delivering therapeutic genes into the cardiovascular system. Gene transfer using local gene delivery techniques have been shown to be superior to less-targeted intra-arterial or intra-venous applications. To date, no gene therapy drugs have been approved for clinical use in cardiovascular applications. In preclinical studies of therapeutic angiogenesis, various growth factors such as vascular endothelial growth factors (VEGFs) and fibroblast growth factors (FGFs), have shown positive results. Gene therapy also appears to have potential clinical applications in improving the patency of vascular grafts and in treating heart failure. Post-angioplasty restenosis, hypertension, and hyperlipidemias (excluding homozygotic familial hypercholesterolemia) can usually be managed satisfactorily by conventional approaches, and are therefore less favored areas for gene therapy. The development of technologies that can ensure long-term, targeted, and regulated gene transfer, and a careful selection of target patient populations, will be very important for the progress of cardiovascular gene therapy in clinical applications.Molecular Therapy (2007) 15 7, 1233–1247. doi:10.1038/sj.mt.6300175 [ABSTRACT FROM AUTHOR]

Members of the vascular endothelial growth factor (VEGF) family are among the most powerful modulators of vascular biology. They regulate vasculogenesis, angiogenesis, and vascular maintenance during embryogenesis and in adults. Because of their profound effects on blood vessels, VEGFs have received much attention regarding their potential therapeutic use in cardiovascular medicine, especially for therapeutic vascular growth in myocardial and peripheral ischemia. However, completed randomized controlled VEGF trials have not provided convincing evidence of clinical efficacy. On the other hand, recent preclinical proangiogenic VEGF studies have given insight, and anti-VEGF studies have shown that the disturbance of vascular homeostasis by blocking VEGF-A may lead to endothelial dysfunction and adverse vascular effects. Excess VEGF-A may contribute to neovascularization of atherosclerotic lesions but, currently, there is no evidence that transient overexpression by gene transfer could lead to plaque destabilization. Here, we review the biology and effects of VEGFs as well as the current status of clinical applications and future perspectives of the therapeutic use of VEGFs in cardiovascular medicine. [Copyright &y& Elsevier]

Critical lower limb ischemia is a common cause for amputation. To develop new therapeutic strategies, more information is needed about molecular mechanisms of tissue responses to ischemic stress and factors inducing angiogenesis. Using a DNA array of 8400 genes, gene expression patterns in human skeletal muscle samples collected from lower limbs amputated due to acute-on-chronic or chronic critical lower limb ischemia, were compared with the control samples collected from the same limb. The results were confirmed by RT-PCR and immunohistochemistry. In acute-on-chronic ischemia, 291 genes were significantly upregulated and 174 genes were downregulated (change in 5.5% of all genes) as compared to control samples. Significant induction of the hypoxia-inducible angiogenic pathway involving hypoxia-inducible factor-1α (HIF-1α), HIF-2α, vascular endothelial growth factor (VEGF) and its angiogenic receptor VEGFR-2, as well as tumor necrosis factor-α (TNF-α) with its downstream signaling machinery promoting inflammation and cell death, were found in acute-on-chronic ischemia. In chronic critical ischemia, gene expression changes were much less striking than in acute-on-chronic ischemia, with 74 genes significantly upregulated and 34 genes downregulated (change in 1.3% of all genes). In the chronic situation, the anabolic and survival factors, insulin-like growth factor-1 (IGF-1) and IGF-2, were upregulated in atrophic and regenerating myocytes together with attenuated HIF, VEGF, and VEGFR-2 expression in the same cells. In conclusion, acute-on-chronic and chronic human skeletal muscle ischemia result in distinct gene expression patterns. These findings may be of importance in the design of novel therapies, such as therapeutic vascular growth, for patients suffering from lower limb ischemia. [Copyright &y& Elsevier]

Stimulation of angiogenesis, arteriogenesis, and lymphangiogenesis (i.e., therapeutic vascular growth) is a new concept for the treatment of ischemic cardiovascular diseases. A wealth of information is already available about the mechanisms and mediators of angiogenesis and arteriogenesis, which has led to the first randomized, controlled, phase II/III trials with recombinant growth factors or their genes. Even though end points predefined in the study protocols have been positive in several trials, it is still evident that the trials have not produced any clearly meaningful clinical benefits for the patients. This review addresses same questions and concepts related to the gene therapy-based applications of therapeutic vascular growth. [Copyright &y& Elsevier]

Background: Drug-coated balloons (DCBs) are accepted treatment strategies for coronary in-stent restenosis and are under clinical investigation for lesions without prior stent implantation. A recently published meta-analysis suggested an increased risk of death associated with the use of paclitaxel-coated devices in the superficial femoral artery. The reasons are incompletely understood as potential underlying pathomechanisms remain elusive, and no relationship to the administered dose has been documented.Objectives: The purpose of this analysis was to investigate the available data on survival after coronary intervention with paclitaxel-coated balloons from randomized controlled trials (RCTs).Methods: PubMed, Web of science, and the Cochrane library database were searched, and a meta-analysis from RCT was performed comparing DCB with non-DCB devices (such as conventional balloon angioplasty, bare-metal stents, or drug-eluting stents) for the treatment of coronary in-stent restenosis or de novo lesions. The primary outcome was all-cause death. The number of patients lost to follow-up was observed at different time points. Risk estimates are reported as risk ratios (RRs) with 95% confidence intervals (CIs).Results: A total of 4,590 patients enrolled in 26 RCTs published between 2006 and 2019 were analyzed. At follow-up of 6 to 12 months, no significant difference in all-cause mortality was found, however, with numerically lower rates after DCB treatment (RR: 0.74; 95% CI: 0.51 to 1.08; p = 0.116). Risk of death at 2 years (n = 1,477, 8 RCTs) was similar between the 2 groups (RR: 0.84; 95% CI: 0.51 to 1.37; p = 0.478). After 3 years of follow-up (n = 1,775, 9 RCTs), all-cause mortality was significantly lower in the DCB group when compared with control treatment (RR: 0.73; 95% CI: 0.53 to 1.00; p = 0.047) with a number needed to treat of 36 to prevent 1 death. A similar reduction was seen in cardiac mortality (RR: 0.53; 95% CI: 0.33 to 0.85; p = 0.009).Conclusions: In this meta-analysis, the use of paclitaxel DCBs for treatment of coronary artery disease was not associated with increased mortality, as has been suggested for peripheral arteries. On the contrary, use of coronary paclitaxel-coated balloons was associated with a trend toward lower mortality when compared with control treatments. [ABSTRACT FROM AUTHOR]

A better understanding of atherogenesis at the level of gene expression could lead to the identification of new therapeutic strategies for vascular diseases. With DNA array technology, it is possible to identify multiple, simultaneous changes in gene expression in small tissue samples from atherosclerotic arteries. We analyzed gene expression in normal arteries and in immunohistologically characterized human advanced atherosclerotic lesions using an array of 18 376 cDNA fragments. The array method was first validated by detecting a group of genes (n=17) that were already known to be connected to atherogenesis. These genes included e.g. Apolipoprotein E, CD68, TIMP and phospholipase D. Next we detected 75 differentially expressed genes that were previously not connected to atherogenesis. A subgroup of genes involved in cell signaling and proliferation was selected for further analyzes with in situ hybridization and RT-PCR which confirmed array results by showing induction in advanced lesions of Janus kinase 1 (JAK-1) which is an important signaling molecule in activated macrophages; VEGF receptor-2 which mediates angiogenic and vasculoprotective effects of VEGF; and an unknown gene, which mapped on chromosome 19. It is concluded that DNA array technology enables fast screening of gene expression in small samples of atherosclerotic lesions. The technique will be useful for the identification of new factors, such as JAK-1 and VEGF receptor-2, which may play an important role in atherogenesis. [Copyright &y& Elsevier]

Therapeutic angiogenesis in ischemic tissues with vascular endothelial growth factors (VEGF) is a promising application of gene therapy. The transient nature of non-integrating vectors such as adenoviruses does not yield permanent therapeutic effect. On the other hand, prolonged VEGF expression by integrating vectors includes the risk of insertional mutagenesis. One way to overcome these obstacles could be combination therapy using two different transient vectors.Dose-response study was performed to evaluate baculovirus tolerance in New Zealand White rabbit skeletal muscle. Secondly, we show the first evidence that baculoviral VEGF-DDNDC gene transfer in healthy skeletal muscle results in statistically significant capillary enlargement compared to both baculovirus and adenovirus b-galactosidase (lacZ) control gene transfers. We also show improved transduction efficiency of baculovirus vector after different modifications of viral genome.In conclusion, both our in vitro and in vivo results suggest baculovirus as potential gene transfer vector. The efficacy of the baculovirus vectors may not reach the adenovirus level but is however sufficient to gain biologically efficient results. This opens promising possibilities regarding combination gene therapy, and should be studied in the future.Molecular Therapy (2006) 13, S63–S63; doi: 10.1016/j.ymthe.2006.08.186 [ABSTRACT FROM AUTHOR]