Xiaoshun Liu

Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice

Background— Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG). Methods and Results— Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes, predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening, and calcium handling in isolated cardiomyocytes and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates. Ten days after myocardial infarction, LV cGMP levels had increased to a greater extent in wild-type mice than in PDE5-TG mice (P<0.05). Ten weeks after myocardial infarction, LV end-systolic and end-diastolic volumes were larger in PDE5-TG than in wild-type mice (57±5 versus 39±4 and 65±6 versus 48±4 &mgr;L, respectively; P<0.01 for both). LV systolic dysfunction and diastolic dysfunction were more marked in PDE5-TG than in wild-type mice, associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium. Conclusions— Increased PDE5 expression predisposes mice to adverse LV remodeling after myocardial infarction. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.

Study of antirestenosis with the BiodivYsio dexamethasone-eluting stent (STRIDE): A first-in-human multicenter pilot trial

The aim of this multicenter pilot study was to evaluate the acute safety and efficacy of the dexamethasone‐eluting stent (0.5 μg/mm2 of stent) implanted in patients with de novo single‐vessel disease. This study included 71 patients, 42% of whom had unstable angina pectoris. An appropriately sized BiodivYsio Matrix Lo stent loaded with a total dexamethasone dose of 0.5 μg/mm2 of stent was used. Technical device success rate was 95%. Six‐month MACE occurred in two patients (3.3%). Binary restenosis rate was 13.3%. Late loss was 0.45. Late loss and percent diameter stenosis were lower in the unstable angina pectoris patients compared to the stable patients (0.32 ± 0.39 vs. 0.60 ± 0.55 mm, P < 0.07, and 26.86 ± 14 vs. 38.40 ± 16%, P < 0.02). This study demonstrated the feasibility and safety of the implantation of a dexamethasone‐eluting stent and its effect on in‐stent neointimal hyperplasia. Catheter Cardiovasc Interv 2003;60:172–178.

Dexamethasone-eluting stent: an anti-inflammatory approach to inhibit coronary restenosis

The long-term efficacy of percutaneous coronary interventions is still hampered by restenosis. Restenosis is the result of a complex pathophysiological process, which is thought to be caused by an exaggerated healing response induced by the vascular injury caused by the percutaneous coronary interventions and the implantation of a foreign body (the stent). There is increasing evidence that inflammation plays an important role in the initiation and development of neointimal hyperplasia and subsequent restenosis. Dexamethasone (Decadron®, Merck Sharpe and Dohme Ltd) is a glucocorticoid with well-known potent anti-inflammatory and antiproliferative properties. Early studies using either systemic or local delivery of dexamethasone have shown limited beneficial effects on restenosis. The dexamethasone-eluting stent (Dexamet™, Abbott Vascular Devices Ltd) is one of the first generation of drug-eluting stents for local drug delivery to prevent restenosis. Preclinical studies demonstrated that implantation of dexamethasone-loaded coronary stents was safe and had a beneficial effect on stent implantation-related inflammation. A pilot trial suggested a beneficial effect on restenosis. Large randomized trials are underway to confirm these findings. This article reviews the potential role of inflammation in the pathogenesis of restenosis and the efficacy of dexamethasone in the prevention of restenosis.

The effect of reduced blood-flow on the coronary wall temperature. Are significant lesions suitable for intravascular thermography?

AIMS The purpose of this study was to investigate the relation between acute coronary flow reduction and arterial wall temperature. METHODS AND RESULTS Five pigs with normal coronary arteries were catheterized. Arterial wall temperature was studied with a thermographic system that uses a 4-thermistor sensor tip. Flow velocity was studied at the same time and place with the temperature measurements, using a Doppler wire. In order to modify the coronary flow, a balloon was gradually inflated proximally to the thermographic sensors. Temperature differences and flow velocities were simultaneously recorded. Flow velocities above an average peak velocity (APV) of 9 cm/s were associated with unaffected temperature measurements. At flow velocities around 4 cm/s, the wall temperature was increased (deltaT=0.015+/-0.005 degrees C, P approximately 0.05), following the heart-rate. When flow velocity dropped further below this value, the local wall temperature was logarithmically increased to a maximum value observed at total vessel occlusion (deltaT=0.188+/-0.023 degrees C, P<0.001). CONCLUSION The reduction of coronary flow has an effect on the arterial wall temperature. This effect however, appears only below a critical threshold of APV and in a logarithmic fashion. Above this threshold, temperature measurements should be unaffected from flow reductions and related to the regional temperature heterogeneity.

Long-term biocompatibility evaluation of a novel polymer-coated stent in a porcine coronary stent model

Background Polymer coatings have been used to modify the surface of stents and to serve as a matrix for local drug delivery. Methods Bare stainless steel stents or poly‐bis‐trifluorethoxy phosphazene (PTFEP) dip‐coated stents (Coroflex, Germany) were randomly implanted into porcine coronary arteries with a balloon‐to‐artery ratio of 1.1‐1.2:1. Scanning electron microscopy (SEM), repeat quantitative coronary angiography (QCA) and histomorphometric analysis were performed at 5 days, 6 weeks and 6 months. Results At 5 days, complete endothelial cell coverage with fibrin strands was detected in both the bare and the coated stents with SEM. Late loss, determined by QCA, of coated and bare stents was identical at all time points. Histomorphometric analysis showed that coated and bare stents elicited a similar tissue response at 5 days. At 6 weeks, the coated stents showed a moderate peri‐strut inflammatory response, resulting in increased neointimal hyperplasia. Compared to the bare stents, however, no significant differences were observed. At 6 months, peri‐strut inflammation was minimal and similar in the coated and the bare stent groups. Neointimal hyperplasia of the coated and bare stent groups was also comparable (1.37 ±0.44 compared with 1.15 ±0.40mm2, P = 0.213) and decreased compared to the 6‐week response. Conclusion This PTFEP stent coating showed a long‐term biocompatibility in a porcine coronary stent model. Because no increased proliferative response was observed up to 6 months, this phosphazene coating may serve as a vehicle for local drug delivery. Coron Artery Dis 14:401‐408 •c 2003 Lippincott Williams & Wilkins.

Methotrexate loaded SAE coated coronary stents reduce neointimal hyperplasia in a porcine coronary model

Objective: To evaluate the effect of stent based methotrexate delivery on neointimal hyperplasia. Methods: Stainless steel coronary stents and biological polymer coated (SAE) stents were randomly implanted in coronary arteries of pigs with a stent to artery ratio of 1.1:1. The pigs were killed after five days (10 stents) or four weeks (20 stents). Second, stainless steel coronary stents were dip coated in a 10 mg/ml methotrexate–SAE polymer solution, resulting in a total load of 150 μg methotrexate/stent. SAE coated stents and methotrexate loaded stents were randomly implanted in porcine coronary arteries with a stent to artery ratio of 1.2:1 and followed up to four weeks. Results: SAE coated stents and bare stents elicited a similar tissue response at five days. At four weeks, neointimal hyperplasia induced by the coated stents was less pronounced than with the bare stents (1.32 (0.66) v 1.73 (0.93) mm2, p > 0.05). In vitro drug release studies showed that 50% of the methotrexate was released in 24 hours, and all drug was released within four weeks. No impact on vascular smooth muscle cell proliferation or viability was observed in in vitro cell cultures. At four weeks the arteries with methotrexate loaded stents had decreased peristrut inflammation and neointimal hyperplasia (1.22 (0.34) v 2.25 (1.28) mm2, p < 0.01). Conclusions: SAE coating had an excellent biocompatibility with vascular tissue. Stent based delivery of methotrexate in the SAE coating effectively reduced neointimal hyperplasia in a porcine coronary stent model, potentially due to reduced peristrut inflammation.

Stent‐based tempamine delivery on neointimal formation in a porcine coronary model

Background: Tempamine is one of new class of antioxidant agents, the nitroxides, which have shown a wide range of biological effects like suppressing free radical driven reactions to maintain cell functions. The objectives of this study were to evaluate the effect of a biodegradable polymer coated stent loaded with tempamine on in‐stent neointimal formation. Methods: Stainless steel stents were dip coated in biodegradable elastomeric poly (ester‐amide) (co‐PEA) or in polymer solution mixed with 50%(wt%) and 100%(wt%) tempamine. One group 100% (wt%) tempamine loaded stents were further dip coated in co‐PEA polymer to form a top layer. Stainless steel bare, polymer‐only, and different doses tempanine coated stents were implanted into porcine coronary arteries with a stent to artery ratio 1.2:1. Histomorphometric analysis was performed at 5 days and 6 weeks respectively Results: Histomorphometric analysis showed that the bare, polymer‐only and tempamine‐coated stents elicited a similar tissue response at 5 days. At 6 weeks, the peri‐strut inflammation and neointimal hyperplasia of polymer‐only stents were comparable to the bare stents. Compared to the bare stents, 50% tempanine coated stents had a trend to decrease the arterial injury (0.62±0.41 versus 0.34±0.18, P = 0.075) and neointimal hyperplasia (1.80±0.77 versus 1.27±0.39 mm2, P = 0.085). However, 100% tempanine coated showed significantly increased inflammatory response and neointimal formation Conclusion: These co‐PEA polymer coatings showed a biocompatible performance. Loaded with 50% tempamine had a trend to decrease neointimal hyperplasia. The 100% tempamine for stent‐based delivery may have potential cytotoxic effects to arterial wall. Using a co‐PEA polymer topcoat could effectively abolish these side effects.

Local methylprednisolone delivery using a BiodivYsio phosphorylcholine-coated drug-delivery stent reduces inflammation and neointimal hyperplasia in a porcine coronary stent model

Phosphorylcholine (PC)-coated stents have shown excellent blood and tissue biocompatibility in porcine coronary arteries. The purpose of this study was to determine the efficacy of local methylprednisolone (MP) delivery using PC-coated stents to inhibit inflammatory response and in-stent neointimal hyperplasia in an overstretched porcine coronary model. BiodivYsio (Biocompatibles, Farnham, Surrey, UK) PC-coated drug delivery (DD) stents and DD stents loaded with a high dose of MP (269 μg) were implanted in the coronary arteries of 20 pigs with a balloon/artery ratio of 1.2 : 1. At five days the peri-strut inflammatory response score and thrombus score of the MP-loaded DD stents were lower than in the control stents. The neointimal hyperplasia of MP-loaded DD stents was significantly reduced (0.80 ± 0.10 versus 0.48 ± 0.10 mm2, p < 0.01). At four-week follow-up, the inflammatory response of MP-loaded stents was lower than the control stents, but without significant difference. The MP-loaded stents showed decreased peri-strut arterial injury and in-stent neointimal hyperplasia (2.42 ± 0.87 versus 1.62 ± 0.71 mm2, p < 0.05). It is concluded that local vascular delivery of a high dose of MP from PC-coated DD stents could effectively decrease inflammatory response and thrombus formation after oversized stent deployment and result in a significant reduction of neointimal hyperplasia. (Int J Cardiovasc Intervent 2003; 5: 166-171)

Placental growth factor increases regional myocardial blood flow and contractile function in chronic myocardial ischemia.

Placental growth factor (PlGF) has a distinct biological phenotype with a predominant proangiogenic role in disease without affecting quiescent vessels in healthy organs. We tested whether systemic administration of recombinant human (rh)PlGF improves regional myocardial blood flow (MBF) and systolic function recovery in a porcine chronic myocardial ischemia model. We implanted a flow-limiting stent in the proximal left anterior descending coronary artery and measured systemic hemodynamics, regional myocardial function using MRI, and blood flow using colored microspheres 4 wk later. Animals were then randomized in a blinded way to receive an infusion of rhPlGF (15 μg·kg(-1)·day(-1), n = 9) or PBS (control; n = 10) for 2 wk. At 8 wk, myocardial perfusion and function were reassessed. Infusion of rhPlGF transiently increased PlGF serum levels >30-fold (1,153 ± 180 vs. 33 ± 18 pg/ml at baseline, P < 0.001) without affecting systemic hemodynamics. From 4 to 8 wk, rhPlGF increased regional MBF from 0.46 ± 0.11 to 0.85 ± 0.16 ml·min(-1)·g(-1), with a concomitant increase in systolic wall thickening from 11 ± 3% to 26 ± 5% in the ischemic area. In control animals, no significant changes from 4 to 8 wk were observed (MBF: 0.45 ± 0.07 to 0.49 ± 0.08 ml·min(-1)·g(-1) and systolic wall thickening: 14 ± 4% to 18 ± 1%). rhPlGF-induced functional improvement was accompanied by increased myocardial neovascularization, enhanced glycogen utilization, and reduced oxidative stress and cardiomyocyte apoptosis in the ischemic zone. In conclusion, systemic rhPlGF infusion significantly enhances regional blood flow and contractile function of the chronic ischemic myocardium without adverse effects. PlGF protein infusion may represent an attractive therapeutic strategy to increase myocardial perfusion and energetics in chronic ischemic cardiomyopathy.

A nonsurgical porcine model of left ventricular dysfunction. Validation of myocardial viability using dobutamine stress echocardiography and positron emission tomography

BACKGROUND: Although several shortterm animal models of stunning and hibernation have been studied extensively, it has been difficult to produce a consistent animal model of chronic hibernation. The aim of the present study was to develop a nonsurgical porcine stent model of coronary stenosis in order to investigate the relationship between chronic dysfunctional myocardium and viability using 2D-echo, dobutamine stress echo (DSE) and positron emission tomography (PET). METHODS AND RESULTS: Focal progressive coronary stenosis was induced by implantation of an oversized stent in the left anterior descending (LAD) and/or circumflex (LCX) coronary artery in a total of 115 pigs, according to various experimental protocols: copper stent in the LAD (group I, n = 5); noncoated stainless steel stent in the LAD combined with balloon overstretch (group II, n = 7); poly(organo)phosphazene-coated stent in the LAD (group III, n = 77); and poly(organo)phosphazene-coated stent in both the LAD and the LCX (group IV, n = 26). Occurrence of left ventricular dysfunction was evaluated weekly by 2D-echo. At the time of left ventricular dysfunction the presence of viable myocardium within the dysfunctional region was investigated with DSE and PET, and confirmed by histology. The degree of coronary artery stenosis was measured by quantitative coronary angiography and morphometry. Severe coronary artery stenosis in the presence of dysfunctional, but viable, myocardium was induced in groups III and IV (47% and 11% of the animals, respectively). CONCLUSIONS: The authors developed a nonsurgical porcine stent model of progressive coronary stenosis using an oversized polymer-coated stent resulting in chronically decreased myocardial function, with residual inotropic reserve and viable myocardium. This condition may arise from repetitive periods of ischemia, or from sustained hypoperfusion, or a combination of these processes eventually leading to myocardial hibernation. (Int J Cardiovasc Intervent 2000; 3: 111-120)