Lakshmana Pendyala

Endothelium-Dependent Vasomotor Dysfunction in Pig Coronary Arteries With Paclitaxel-Eluting Stents Is Associated With Inflammation and Oxidative Stress

OBJECTIVES We sought to evaluate coronary epicardial and intramyocardial resistance, arterial vasomotor function, local inflammatory reaction, and superoxide anion (O(2)(.-)) production after overlapping paclitaxel-eluting stent (PES) implantation in a porcine model. BACKGROUND PES implantation has been shown to elicit coronary vasomotor dysfunction. However, underlying mechanisms remain largely unknown. METHODS Nine pigs received overlapping PES and bare-metal stents (BMS) in the coronary arteries, and 3 sham animals were naïve. At 1 month, inflammatory response at the overlapped region was assessed by histopathology and scanning electron microscopy. Endothelial vasomotor function and O(2)(*-) at nonstented coronary reference segments were measured by angiography and organ chamber tensiometry, and lucigenin luminometry; vasomotor function of distal resistance arteries was measured by myography. RESULTS Paclitaxel-eluting stents showed reduced late lumen loss, but inflammation and luminal inflammatory cell adherence were higher than for BMS (p < 0.001) at overlapped segments. Endothelium-dependent relaxation to substance P was significantly impaired in PES at nonstented coronary reference segments (>or=15 mm proximally and distally) and perfusion bed resistance arteries (p < 0.05). In contrast, endothelium-independent relaxation to nitroglycerin and sodium-nitroprusside was similar between groups. Local O(2)(*-) production at both proximal and distal nonstented coronary reference segments was elevated for PES when compared with O(2)(*-) production in BMS and naïve arteries (p < 0.001). CONCLUSIONS Abnormal endothelium-dependent relaxation at both coronary conduit and resistance arteries was demonstrated after overlapping PES implantation. Profound localized inflammatory reaction, as well as enhanced local oxidative stress, may contribute to vasomotor dysfunction.

Impact of the Definition Utilized on the Rate of Contrast-Induced Nephropathy in Percutaneous Coronary Intervention

Several definitions have been used to assess rates of contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI). Whether the definition influences observed rates of CIN is unclear. The Oxilan Registry was the first-ever prospective analysis of the efficacy and safety of ioxilan (low-osmolar and low-viscosity contrast medium), including rates of CIN assessed by multiple definitions, in PCI. From July 2006 to June 2007, consecutive patients undergoing PCI using ioxilan were enrolled. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were assessed at baseline and 3 to 5 days after PCI. CIN was defined as SCr increase >or=0.5 mg/dl, eGFR decrease >or=25%, SCr increase >or=25%, or the composite. Of 400 patients (age 62 +/- 11 years), 19% were women, 37% were diabetic, 22% were anemic, and 8% had a history of congestive heart failure. Baseline SCr was 1.12 +/- 0.3 mg/dl and 24% had an eGFR <60 ml/min. CIN rates were 3.3% (SCr increase >or=0.5 mg/dl), 7.6% (eGFR decrease >or=25%), 10.2% (SCr increase >or=25%), and 10.5% (composite). Hospitalization was prolonged in 3.4% of patients with CIN and none required dialysis. There were no deaths or severe allergic reactions. Non-ST-elevation myocardial infarction and repeat revascularization each occurred in 0.8%. In conclusion, in this unselected population undergoing PCI, CIN ranged in frequency from 3.3% to 10.5% depending on the definition used and was not associated with in-hospital mortality or substantial morbidity, such as dialysis. The wide variation in CIN and its lack of association with adverse outcomes underscore the need for a standardized, clinically relevant definition.

Ghrelin and cardiovascular diseases.

Ghrelin, a newly discovered bioactive peptide, is a natural endogenous ligand of the growth hormone (GH) secretagogue receptor and initially identified as a strong stimulant for the release of GH. Subsequent research has shown that ghrelin and its various receptors are ubiquitous in many other organs and tissues. Moreover, they participate in the regulation of appetite, energy, bodyweight, metabolism of glucose and fat, as well as modulation of gastrointestinal, cardiovascular, pulmonary, immune functions and cell proliferation/apoptosis. Increasing evidence has demonstrated that ghrelin has a close relationship with cardiovascular system. Ghrelin and its receptors are widely distributed in cardiovascular tissues, and there is no doubt that the effects of ghrelin in the cardiovascular system are mediated not only via its growth-hormone-releasing effect but also by its direct effects on the heart. Exogenous administration of ghrelin can dilate peripheral blood vessels, constrict coronary artery, improve endothelial function, as well as inhibit myocardial cell apoptosis. So, ghrelin may have cardiovascular protective effect, including lowering of blood pressure, regulation of atherosclerosis, and protection from ischemia/reperfusion injury as well as improving the prognosis of myocardial infarction and heart failure. Some of these new functions of ghrelin may provide new potential therapeutic opportunities for ghrelin in cardiovascular medicine. In this paper, we will review the existing evidence for cardiovascular effects of ghrelin, including the cardiovascular function, the variations in ghrelin plasma levels in pathophysiologicalogical conditions, the possible protective mechanisms of ghrelin, as well as its future potential therapeutic roles.

Novel fully bioabsorbable salicylate-based sirolimus- eluting stent

AIMS The concept of fully biodegradable stents has emerged as an attractive alternative to current permanent metallic stents, mainly as a potential solution to avoid late stent thrombotic events. We sought to evaluate a novel, fully bioabsorbable sirolimus-eluting stent (SES) synthesised entirely from a unique salicylic-acid polymer, in a clinically relevant animal model. METHODS AND RESULTS Fully biodegradable balloon-expandable stents (n=45) were implanted in a porcine coronary arteries using quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) to optimise stent apposition. Dose density of sirolimus was 8.3 µg/mm of stent length with in vitro studies demonstrating elution over 30 days and complete stent degradation over 12 months. Animals were terminated at 7, 14, 30, 90, and 180 days for complete histological analysis. Optical coherence tomography (OCT) was also performed for the 90- and 180-days samples. All stents were deployed successfully without notable mechanical difficulties. Angiographic diameter stenosis (DS) was 20±16%, 24±4%, and 23±17%, at one, three, and six months, respectively. In parallel, IVUS showed good stent apposition with DS of 21±9%, 25±7%, and 18±3%; and area stenosis (AS) of 35±13%, 33±7%, and 32±4% at one, three, and six months,respectively. OCT further demonstrated good stent apposition with DS of 28±7% and 20±6%, and AS of 37±10% and 33±13% at three and six months, respectively. OCT showed reduction of stent thickness by 23% from three to six months. Histologic analysis confirmed these in vivo findings and revealed a favourable healing process of absorbable stent incorporation into the arterial wall, without excessive thrombotic or inflammatory reactions. CONCLUSIONS This study shows favourable vascular compatibility and efficacy for a novel fully bioabsorbable salicylate-based SES. This device has good mechanical performance during deployment and stays well-apposed to the vessel wall at long-term follow-up. These initial results are highly encouraging and support progress into more extensive preclinical studies as well as early clinical testing.

Drug-Eluting Stents: Present and Future

In-stent restenosis (ISR) caused by neointimal hyperplasia is the major drawback after percutaneous coronary intervention (PCI) for obstructive coronary disease, occurring in up to 40% of lesions. Recently, one of the most intriguing new therapies developed is drug-eluting stents (DES) that target the central phenomenon of cellular proliferation that causes ISR. The benefits of stent-based drug delivery include maximizing the local tissue levels of therapeutic agents while minimizing systemic toxicity. Numerous DES using different thin-film polymeric drug carrier have been developed and tested, those eluting either antimitotic or antimicrotublar agents such as sirolimus and paclitaxel have been shown effective in clinical trials. Two DES, the J&J Cypher (sirolimus-eluting) and the Boston Scientific Taxus (paclitaxel-eluting) stents, are commercially available in the U.S. after a number of randomized trials demonstrated reductions in late lumen loss, binary restenosis rate, and need for repeat revascularization compared with bare-metal stents (BMS). Because ISR is multifactorial, ideal agents for DES should inhibit thrombus formation, inflammation and cellular proliferation as well as enhance re-endothelialization. The next generation of DES currently undergoing preclinical studies includes new technology, new stent designs and materials, biological polymers, bioabsorbable stents coated with new drugs including stent based gene, as well as cell delivery. The current paper will review and discuss the current and future status of DES.

Abnormal Vasomotor Function of Porcine Coronary Arteries Distal to Sirolimus-Eluting Stents

OBJECTIVES This study sought to determine vasomotor functional responses of conduit coronary artery distal to bare-metal stents (BMS), polymer-only stents (POLY), and sirolimus-eluting stents (SES) in a clinically relevant animal model. BACKGROUND Drug-eluting stents (DES) reduce in-stent restenosis, and also affect neointima formation and vascular remodeling in downstream coronary segments. Whether distal artery vasomotor function is also influenced by DES has not been determined. METHODS Pigs (n = 12) received coronary stent implants, and hearts were harvested at 1 month. Arterial segments >or=15 mm distal to stents were excised and studied in an organ-chamber apparatus. Endothelium-dependent and endothelium-independent relaxation and contraction to classical agonists were measured. RESULTS The SES showed increased lumen area and reduced neointima; abnormal vasomotor function of conduit arteries distal to SES also was observed. Contraction to endothelin-1 was significantly enhanced for SES compared with both BMS and POLY. Endothelium-dependent relaxation to a maximal dose of substance P was attenuated for SES compared with both BMS and POLY (46 +/- 6% vs. 71 +/- 3% and 78 +/- 3%, respectively, p < 0.001). Endothelium-independent relaxation to sodium nitroprusside was potentiated for SES, compared with BMS and POLY (100 +/- 5% vs. 69 +/- 7% and 77 +/- 5%, respectively, p = 0.02). CONCLUSIONS Stent-based local delivery of sirolimus profoundly inhibited neointima formation but caused vasomotor dysfunction in distal conduit vessel segments. These observations suggest that distal coronary vasospasm may be more readily evoked in the presence of DES and contribute to pathophysiological sequela.

High Incidence of Intramural Thrombus After Overlapping Paclitaxel-Eluting Stent Implantation Angioscopic and Histopathologic Analysis in Porcine Coronary Arteries

Background—Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results—Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P=0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS (P<0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P=0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P=0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P=0.34). Conclusions—In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity.Background— Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results— Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P =0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS ( P <0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P =0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P =0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P =0.34). Conclusions— In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity. Received January 30, 2008; accepted April 24, 2008. # CLINICAL PERSPECTIVE {#article-title-2}

Low-dose paclitaxel elution by novel bioerodible sol-gel coating on stents inhibits neointima with low toxicity in porcine coronary arteries

OBJECTIVES The present study was designed to evaluate a novel bioerodible sol-gel film coated paclitaxel-eluting stent (sol-gel-PES, 3 microg per stent) in a porcine coronary artery model. BACKGROUND Although current polymer-based PES decrease restenosis, the permanent polymer and bound drug have raised concerns regarding delayed vessel healing and late stent thrombosis. METHODS Polymer-based PES (poly-PES, n = 8), sol-gel-PES (n = 15), bare metal (BMS, n = 14), and sol-gel film only (sham, n = 12), stents were implanted in 17 juvenile pigs. Animals were terminated 28 days post-implant for angiographic restudy and complete histopathologic and histomorphometric analyses. RESULTS Angiographic late loss was equally reduced for both poly-PES and sol-gel-PES (0.51 +/- 0.64 and 0.61 +/- 0.52 mm, respectively) compared to both BMS and sham (0.98 +/- 0.74 and 1.25 +/- 0.72 mm, p < 0.05). Similarly beneficial results were observed for histomorphometric parameters of neointimal thickness and area, yielding reductions of in-stent stenosis by 43% and 48% for poly-PES, as well as 31% and 37% for sol-gel-PES, vs. BMS and sham, respectively (p < 0.05). Re-endothelialization was complete in all groups. Although the inflammatory cell infiltration and intramural thrombus scores were no different between poly- and sol-gel-PES, medial necrosis was increased for poly-PES (p < 0.05 vs. all others). CONCLUSIONS A novel bioerodible sol-gel film coated with low-dose paclitaxel demonstrates less toxicity to the coronary tunica media, while retaining effective inhibition of neointimal formation at 28 days.

Cellular Cardiomyoplasty and Cardiac Regeneration

Despite of vast improvements in treatment, myocardial infarction often leads to heart failure (HF) which remains the leading cause of death in developed countries. Other than heart transplantation, therapeutic options have a limited role in improving out comes in patients with severe HF. It is therefore no surprise that cardiac cell therapy has raised many hopes as a novel therapeutic approach aimed at cardiac myocyte replacement/regeneration termed “cellular cardiomyoplasty”. However, the ideal source, cell type, critical cell number, and mode of application for optimal therapeutic effect have not been defined thus far. Recent observations of the beneficial effect of cell transplantation in animal experiments have generated tremendous excitement and stimulated clinical studies suggesting that this approach is feasible, safe, and potentially effective in humans. Cell-based myocardial regeneration is currently being explored for a wide range of cardiac disease states, including acute and chronic ischemic myocardial damage, cardiomyopathy and as biological heart pacemakers. The main purpose of this article is to review recent literature on the use of various cells for the examination of their in vitro cardiogenic potential and their in vivo capacity to engraft and improve the functional properties of the infarcted heart.

High Incidence of Intramural Thrombus After Overlapping Paclitaxel-Eluting Stent ImplantationCLINICAL PERSPECTIVE

Background—Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results—Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P=0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS (P<0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P=0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P=0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P=0.34). Conclusions—In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity.Background— Systematic analysis of in vivo angioscopy and postmortem histopathology for paclitaxel-eluting stents (PES) has not been previously reported. We assessed 1-month angioscopic and histopathologic sequelae of overlapping PES in pig coronary arteries. Methods and Results— Overlapping PES and bare-metal stents (BMS; n=9, one pair per pig) were implanted, and animals were euthanized at 1 month. Late lumen loss was reduced in PES compared with BMS (0.46±0.63 mm versus 1.30±0.50 mm; P =0.01). Angioscopically, PES stent struts were clearly visible and accompanied by substantial red material indicating mural thrombi. In contrast, stent struts and mural thrombi were barely visible in BMS ( P <0.001 versus PES). Macroscopically, mural thrombi were abundant but distributed irregularly throughout the PES, with greater concentration in overlapping segments. Only occasional mural thrombi were noted for BMS. Microscopically, neointima of BMS was fibrocellular and mature, whereas only a thin layer of immature neointima was seen in PES. Neointimal thickness was less in PES than BMS (0.11±0.07 mm versus 0.33±0.12 mm; P =0.018). Additionally, extensive para-strut and intramural thrombi, red blood cell debris, and minute luminal thrombi were observed in PES. Despite normal angioscopic appearance of both proximal and distal nonstented reference segments, endothelium-dependent relaxation to substance P was notably diminished (PES, 0±7% versus BMS, 10±6%; P =0.007), whereas nitroglycerin response was preserved (PES, 9±5% versus BMS, 12±7%; P =0.34). Conclusions— In the porcine coronary model, overlapping PES is associated with marked intramural thrombi, which was accurately detected on angioscopy at 1 month. Moreover, despite normal luminal angioscopic appearance, adjacent nonstented reference segments demonstrated impaired endothelium-dependent vasoreactivity. Received January 30, 2008; accepted April 24, 2008. # CLINICAL PERSPECTIVE {#article-title-2}