Alexander N. Kharlamov

Progress in treatment by percutaneous coronary intervention: The stent of the future

First generation drug-eluting stents have considerably reduced in-stent restenosis and broadened the applications of percutaneous coronary interventions for the treatment of coronary artery disease. The polymer is an integral part of drug-eluting stents in that, it controls the release of an antiproliferative drug. The main safety concern of first generation drug-eluting stents with permanent polymers--stent thrombosis--has been caused by local hypersensitivity, delayed vessel healing, and endothelial dysfunction. This has prompted the development of newer generation drug-eluting stents with biodegradable polymers or even polymer-free drug-eluting stents. Recent clinical trials have shown the safety and efficacy of drug-eluting stents with biodegradable polymer, with proven reductions in very late stent thrombosis as compared to first generation drug-eluting stents. However, the concept of using a permanent metallic prosthesis implies major drawbacks, such as the presence of a foreign material within the native coronary artery that causes vascular inflammation and neoatherosclerosis, and also impedes the restoration of the vasomotor function of the stented segment. Bioresorbable scaffolds have been introduced to overcome these limitations, since they provide temporary scaffolding and then disappear, liberating the treated vessel from its cage. This update article presents the current status of these new technologies and highlights their future perspectives in interventional cardiology.

Emerging technologies: Polymer-free phospholipid encapsulated sirolimus nanocarriers for the controlled release of drug from a stent-plus-balloon or a stand-alone balloon catheter

Drug-eluting stents have proven to be effective in reducing the risk of late restenosis. In order to achieve a controlled and prolonged release of the antiproliferative agent, current drug-eluting stents utilise various biodegradable as well as non-erodible polymeric blends to coat the stent surface and to serve as drug carriers. The utilisation of polymeric compounds in current drug-eluting stents may eventually limit their performance as well as their clinical applicability due to the potential induction of undesirable local reactions. The development of alternative, polymer-free drug carriers has the potential to overcome some of the limitations of current drug-eluting stent formulations. Moreover, improvements in drug carriers may also result in an expansion of the technological possibilities for other intravascular drug delivery systems, such as metal-free or even implant-free solutions. This article describes the structure and the preclinical validation profile of a novel phospholipid encapsulated sirolimus nanocarrier, used as a coating in two formulations: a coronary stent-plus-balloon system and a stand-alone balloon catheter. The nanoparticles provided a stable, even and homogenous coating to the devices in both formulations. Dose-finding studies allowed the most appropriate identification of the best nanoparticle structure associated with an extremely efficient transfer of drug to all layers of the vessel wall, achieving high tissue concentrations that persisted days after the application, with low systemic drug leaks.

Plasmonic photothermic and stem cell therapy of atherosclerotic plaque as a novel nanotool for angioplasty and artery remodeling.

BACKGROUND Some modern angioplasty techniques drastically affect the geometry of the plaque and the lumen, but have some inherent clinical and technical limitations. METHODS A total of 101 Yucatan miniature swine were allocated to the three following groups (34 pigs into 60/15- to 70/40-nm silica-gold nanoparticles (NPs), 34 swine into ferromagnetic group with iron-bearing NPs and delivery in hand of magnetic fields, and 33 in a sirolimus stenting control). Animals in the nanogroup were subdivided further into four subsets according to the delivery approach: (1) Intracoronary infused circulating stem progenitor cells (SPCs), including SP(+) (side population) cells, (2) intracoronary infused, ultrasound-mediated, albumin-coated, gas-filled microbubbles, (3) CD73(+)105(+) SPCs in the composition of a bioengineered on-artery patch (cardiac surgery), (4) CD73(+)CD105(+) SPCs engrafted by manual subadventitial injection (cardiac surgery). NPs were detonated with a microwatt near-infrared (NIR) laser (821 nm, 35-44 W/cm(2) for 7 min of exposure). RESULTS Changes of the total atheroma volume (TAV; mm(3)) immediately after the laser irradiation at month 6 in the nanoshell, ferromagnetic, and control groups were -7.54%/-22.92%, -9.7%/-16.84%, and -10.5%/-7.06% (p<0.01), respectively, and in the subsets reached -2.79%/-21.92%, -6.26%/-15.24%, -4.6%/-31.21%, -16.5%/-23.3% (p<0.05), respectively. Some cases of atherothrombosis and distal embolism (23.5%) were documented only in the microbubbles subset. The impact of the therapy on the nonorganic part of the plaque-antiinflammative and antiapoptotic effects, signs of neovascularization, and restoration of artery function-were predominant in the observed subsets with SPCs (p<0.01). CONCLUSION Nanoburning, especially in combination with stem cell technologies, is a very challenging technique for altering advanced plaque and holds the promise of revolutionizing state-of-the-art interventional cardiology, assuring destruction of plaque and functional restoration of the vessel wall. It could potentially become the current mechanical and pharmacological treatment.

Freeing the vessel from metallic cage: What can we achieve with bioresorbable vascular scaffolds?

After the era of balloon angioplasty and bare-metal stents, drug eluting stents were introduced to solve the problem of in-stent restenosis [1]. The follow-up of the first 45 patients implanted with the sirolimus eluting Bx velocity stent (Cordis, Johnson & Johnson, Warren, NJ, USA) was found to have negligible neointimal hyperplasia [2, 3]. This was confirmed in the randomized RAVEL study [4, 5]. The introduction of drug eluting stents was thus dubbed the third revolution in interventional cardiology. Both large scale randomised trials and all-comer registries showed excellent results in terms of the need for repeat revascularisation. However, these new devices created again a new enemy: by interfering profoundly with the healing process, lack of endothelialization and late persistent or acquired malapposition of the permanent metallic implant became the nidus of late and very late stent thrombosis, without mentioning the hypersensitive reaction mediated by eosinophils which sometimes triggered these catastrophic events [6–8]. Vasomotion testing demonstrated abnormal vasoconstriction responses to acetylcholine distal to the deployed stent, suggesting that the structure and function of the endothelium remained abnormal [9, 10]. Fully bioresorbable scaffolds (BRS) are a novel approach that provides transient vessel support with drug delivery capability without the long-term limitations of metallic drugeluting stents, such as permanent caging with or without malapposition. By liberating the coronary artery from the metallic caging, the vessel recovers pulsatility and becames responsive to the shear stress and physiological cyclic strain. The technology has a potential to overcome many of the safety concerns associated with metallic drug-eluting stents, and possibly even convey more clinical benefits.

Plasmonic photothermal therapy for atheroregression below Glagov threshold

The advent of nanomedicine allowed for the development and design of tools that enhance detailed diagnosis and target treatment of atherosclerosis. Given the rapid progress in nanoagent synthesis and utility, clinical application of these technologies can be anticipated in the near future. This review article focuses on the development of these technologies in interventional cardiology, with the main goal of achieving atheroregression below a Glagov threshold of 40%. Special attention is given to plasmonic photothermal therapy. Vascular remodeling maintains the lumen dimension as long as the external elastic membrane can accommodate an increase in plaque burden that does not surpass a certain threshold. We propose that this threshold becomes the target for the development of strategies that reverse atherosclerosis, especially for the generation of devices and tools of nanomedicine.

Phenomenon of elongated struts: Is optical coherence tomography accurate enough to analyze scaffold area?

A team of Prof. Serruys during 2009–2012[1–10] published some results of multi-modality imaging studies within ABSORB (a bioabsorbable everolimus-eluting coronary stent system for patients with single de novo coronary artery lesions) trial. The first two publications[1,2] of the first generation Absorb BVS (bioresorbable vascular scaffold) reported few observations made at 6and 24month follow-ups using different imaging modalities: 1) complete bioresorption; 2) physiologically or pharmacologically induced vasomotion, and 3) between 6 and 24 months, late lumen enlargement with plaque media regression without pathological remodeling has been established. The second generation of Absorb BVS [4] (n = 101 with two subgroups: B1 — clinical and imaging follow-up at 6 and 24 months, n = 45, and B2 — follow-up at 12 and 36 months, n = 56; NCT00856856), with changes in the design platform and manufacturing process, fully remediated this mechanical deficiency so that the scaffold area (SA) was found to be unchanged at 6 and 12 months by 1-mm analysis of optical coherence tomography (OCT) [6–8]. Struts that were recognizable on OCT at 24 months showed signs of bioresorption accompanied by unexplained increase in mean scaffold area (see Fig. 1) compared with baseline (0.54 ± 1.09 mm on intravascular ultrasound, p = 0.003; 0.77 ± 1.33 mm in OCT, p = 0.016) [2,8]. An accuracy of OCT for assessment of SA requires further studies. Three years post-procedure after Absorb BVS implantation, biodegrading struts become more pliable and soft causing deformation with smoothing and elongation of struts in remodeling artery wall with accumulation of proteoglycan, and extracellular matrix as well as cellular recomposition of the tissue environment [3,9,10]. The essential mechanisms of the elongated strut phenomenon remain unknown, taking into account increase in scaffold area and signs of biodegradation [9]. Particularly, percentage of the hyperechogenicity area [5], a more sensitive parameter to measure degradation of polymeric material, decreased from a baseline value of 25.3% to 20.4% at 6 months and to 13.8% at 24 months. By our courtesy, there are four probable scenarios to explain a phenomenon of elongated struts (see Fig. 1):

Cardiovascular burden and percutaneous interventions in Russian Federation: systematic epidemiological update

The situation with cardiovascular (CV) burden in Russian population is alerting, and becomes of interest due to high CV mortality, and shorter lifespan if compare with the Western society amid the absence of the established monitoring or screening system for major CV risk factors. The purpose of this systematic epidemiological update was to explore CV burden in Russia. The study represents pooled results with a systematic epidemiological review of the national mass screening, selected randomized clinical trials and statistical datasets of the national public health CV institutions exploring the trends of the CV burden in all 83 regions of Russia. We overviewed data from a number of the available Russian-speaking national data sources of 2001-2014, and NANOM-FIM trial (NCT01270139) as the only available real-world population study. The CV diseases in Russia accounted for 54.9% of all deaths in 2011-2014. The death rate was 13.3 per 1,000 citizens with CV mortality of 653.9 per 100,000. The life expectancy achieves 64.3 years for male and 76.1 years for female. The mean age of pts in trial was 51.6 years (77.2% males). A total of 175 Russian PCI centers implemented 205,902 angio a year, and 75,378 PCI achieving 531 PCI per 1,000,000 with placement of 101,451 stents (1.37 stents per PCI; 48,057 DES). The smoking (17.3% of screened with a 2,786 cigarettes a year; 70.6% in trial), excessive alcohol consumption (1.8% of screened with a 11.6 L per year; 50.6% in trial), unhealthy Russian diet (abundance of carbohydrates/sugar, saturated and trans fats in 24.3% of screened), psychosocial factors (20%) and physical inactivity (19.6% of screened) remain the major modifiable risk factors. They, in turn, affect such risk factors as dyslipidemia (86.7% in trial), obesity (16.7% of screened; BMI in trial was 28.4), and hypertension (40.8% suffered; 86.1% in trial). CV mortality was not directly associated with a level of poverty (r=0.26, P=0.02) or socio-economic development (P>0.05) in regions. The documented 27% 10-year decline of CV mortality was interpreted as a success of the national policy. Mortality statistics show the stark reality of a high CV burden in Russia. New national program and aggressive emerging efforts are required to tackle CV diseases in Russia.

Bioresorbable Scaffolds for Atheroregression: Understanding of Transient Scaffolding.

This review focuses on the clinical and biological features of the bioresorbable scaffolds in interventional cardiology highlighting scientific achievements and challenges of the transient scaffolding with Absorb BVS. Special attention is granted to the vascular biology pathways which, involved in the resorption of scaffold, artery remodeling and mechanisms of Glagovian atheroregression setting the stage for subsequent clinical applications. Twenty five years ago Glagov described the phenomenon of limited external elastic membrane enlargement in response to an increase in plaque burden. We believe this threshold becomes the target for development of strategies that reverse atherosclerosis, and particularly transient scaffolding has a potential to be a tool to ultimately conquer atherosclerosis.This review focuses on the clinical and biological features of the bioresorbable scaffolds in interventional cardiology highlighting scientific achievements and challenges of the transient scaffolding with Absorb BVS. Special attention is granted to the vascular biology pathways which, involved in the resorption of scaffold, artery remodeling and mechanisms of Glagovian atheroregression setting the stage for subsequent clinical applications. Twenty five years ago Glagov described the phenomenon of limited external elastic membrane enlargement in response to an increase in plaque burden. We believe this threshold becomes the target for development of strategies that reverse atherosclerosis, and particularly transient scaffolding has a potential to be a tool to ultimately conquer atherosclerosis.

Plasmonics for treatment of atherosclerosis: Results of NANOM-FIM trial

Background: Atheroregression becomes an attractive target for cardiovascular treatment. Some clinical trials have demonstrated that intensive therapy with rosuvastatin or recombinant ApoA-I Milano can partially reduce the total atheroma volume (TAV) up to 6.38 mm 3 or 14.1 mm 3 respectively. Our previous bench studies of selected nanotechnologies documented TAV reduction up to unprecedented 79.4 mm 3 . Methods: The completed observational three arms (n=180) first-in-man trial (the NANOM FIM trial) assessed (NCT01270139) the safety and feasibility of two delivery techniques for nanoparticles (NP), and plasmonic photothermal therapy (PPTT). Patients were assigned to receive either (1) nano-intervention with delivery of silica-gold NP in bioengineered on-artery patch (n=60), or (2) nano-intervention with delivery of silica-gold iron-bearing NP with targeted micro-bubbles or stem cells using magnetic navigation system (n=60) versus (3) stent implantation (n=60). The primary outcome was TAV at 12 months. Results: The mean TAV reduction at 12 months in nano group was 60.3 mm 3 (SD 39.5; min 41.9 mm 3 , max 94.2 mm 3 ; p<0.05) up to mean 37.8% (95% CI: 31.1%, 51.7%; p<0.05) plaque burden. The analysis of the event free survival of the ongoing clinical follow-up shows the significantly lower risk of cardiovascular death in nano group when compared with others (91.7% vs 81.7% and 80% respectively; p<0.05) with no cases of the target lesion-related complications. Conslusions: PPTT using silica-gold NP associated with significant regression of coronary atherosclerosis.

Can we adapt histological injury score for optical coherence tomography of coronaries

Coronary angioplasty and stenting invariably produces iatrogeniccoronary artery injury; the extent of which is exuberant neointimalformation [1]. Different injury scores have been described during last20 years to quantify the severity of deep injury for the artery wall withfurther late arterial response after stent deployment, but in the case ofhistologic analysis in animal studies only. Two commonly used injuryscores are Schwartz score