Lynn Bailey

Geometric Distortions of the Mitral Valvular-Ventricular Complex in Chronic Ischemic Mitral Regurgitation

Background—Better understanding of the precise 3-dimensional geometric changes of the mitral valvular-ventricular complex in chronic ischemic mitral regurgitation (CIMR) is needed in order to devise better surgical repair techniques. We hypothesized that changes after inferior myocardial infarction would be different in hearts that developed CIMR compared with those that did not. Methods and Results—Twenty-four sheep underwent coronary snare and marker placement (annulus, papillary muscles, and anterior and posterior leaflets). After 8 days, cinefluoroscopy provided 3-dimensional marker data, and snare occlusion of obtuse marginal branches created inferior myocardial infarction, including the posterior papillary muscle. After 7 weeks, the 16 surviving animals were studied again and grouped by mitral regurgitation grade (≥ 2+, n=10 versus ≤ 1+, n=6). End-systolic mitral annulus dimensions, components of papillary muscle and leaflet displacement, were calculated. After inferior myocardial infarction, total displacement of the posterior papillary muscle from the midseptal annulus (“saddle horn”) was greater in CIMR(+) animals: 6.5±3.2 versus 3.1±2.7 (P =0.02), with the posterior papillary muscle moving more laterally (6.8±3.4 versus 2.5±3.5 mm, P =0.01). Increase in mitral annular septal-lateral diameter was greater in animals with CIMR (4.9±2.7 versus 2.3±2.0, P =0.02), and apical displacement of the posterior leaflet (PL) margin was also greater in the CIMR(+) group (1.7±1.0 versus 0.3±0.5, P =0.01). Conclusions—The CIMR(+) group had greater septal-lateral annular dilatation, lateral posterior papillary muscle displacement, and apical PL restriction, indicating that these associated geometric alterations may be important in the pathogenesis of CIMR. Treatment of CIMR should address both annular septal-lateral dilatation and lateral displacement of the posterior papillary muscle.

Alterations in Left Ventricular Torsion and Diastolic Recoil After Myocardial Infarction With and Without Chronic Ischemic Mitral Regurgitation

Background—Chronic ischemic mitral regurgitation (CIMR) is associated with heart failure that continues unabated whether the valve is repaired, replaced, or ignored. Altered left ventricular (LV) torsion dynamics, with deleterious effects on transmural gradients of oxygen consumption and diastolic filling, may play a role in the cycle of the failing myocardium. We hypothesized that LV dilatation and perturbations in torsion would be greater in animals in which CIMR developed after inferior myocardial infarction (MI) than in those that it did not. Methods—8±2 days after marker placement in sheep, 3-dimensional fluoroscopic marker data (baseline) were obtained before creating inferior MI by snare occlusion. After 7±1 weeks, the animals were restudied (chronic). Inferior MI resulted in CIMR in 11 animals but not in 9 (non-CIMR). End-diastolic septal-lateral and anterior-posterior LV diameters, maximal torsional deformation (&phgr;max, rotation of the LV apex with respect to the base), and torsional recoil in early diastole (&phgr;5%, first 5% of filling) for each LV free wall region (anterior, lateral, posterior) were measured. Results—Both CIMR and non-CIMR animals demonstrated derangement of LV torsion after inferior MI. In contrast to non-CIMR, CIMR animals exhibited greater LV dilation and significant reductions in posterior maximal torsion (6.1±4.3° to 3.9±1.9°* versus 4.4±2.5° to 2.8±2.0°; mean±SD, baseline to chronic, *P<0.05) and anterior torsional recoil (−1.4±1.1° to −0.2±1.0° versus −1.2±1.0° to −1.3±1.6°). Conclusion—MI associated with CIMR resulted in greater perturbations in torsion and recoil than inferior MI without CIMR. These perturbations may be linked to more LV dilation in CIMR, which possibly reduced the effectiveness of fiber shortening on torsion generation. Altered torsion and recoil may contribute to the “ventricular disease” component of CIMR, with increased gradients of myocardial oxygen consumption and impaired diastolic filling. These abnormalities in regional torsion and recoil may, in part, underlie the “ventricular disease” of CIMR, which may persist despite restoration of mitral competence.

Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug.

Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-powder electrostatic process. The AC-SES demonstrated enhanced drug stability under simulated use conditions and consistent drug delivery balanced with coating erosion in a porcine coronary implant model. The initial drug burst was eliminated and drug release was sustained after implantation. The coating was absorbed within 90 days. Following implantation into porcine coronary arteries the AC-SES coating is distributed in the surrounding intimal tissue over the course of several weeks. Computational modeling of drug delivery characteristics demonstrates how distributed coating optimizes the load of drug immediately around each stent strut and extends drug delivery between stent struts. The result was a highly efficient arterial uptake of drug with superior performance to a clinical bare metal stent (BMS). Neointimal thickness (0.17±0.07 mm vs. 0.28±0.11 mm) and area percent stenosis (22±9% vs. 35±12%) were significantly reduced (p<0.05) by the AC-SES compared to the BMS 30 days after stent implantation in an overlap configuration in porcine coronary arteries. Inflammation was significantly reduced in the AC-SES compared to the BMS at both 30 and 90 days after implantation. Biocompatible, rapidly absorbable stent coatings enable the matching of drug release with coating erosion and provide for the controlled migration of coating material into tissue to reduce vicissitudes in drug tissue levels, optimizing efficacy and reducing potential toxicity.

The effects of uncontrolled hyperglycemia on thrombosis and formation of neointima after coronary stent placement in a novel diabetic porcine model of restenosis.

BackgroundResults of recent clinical studies suggest that patients with diabetes mellitus have a higher than normal rate of restenosis after percutaneous transluminal coronary angioplasty or coronary stenting. The mechanism for this exaggerated neointimal response is not known. ObjectivesTo determine the technical feasibility of a model of in-stent restenosis in swine with streptozotocin-induced hyperglycemia and to compare the late arterial responses to injury induced by placement of oversized coronary stents in diabetic and nondiabetic animals. MethodsEighteen 25–40 kg castrated male or intact female Yucatan miniature swine aged 6 months were obtained from a commercial supplier. Twelve of the miniature swine were randomly selected for intravenous treatment with 125 mg/kg streptozotocin to induce a hyperglycemic state. Twelve weeks after treatment, all animals underwent placement of oversized balloon-expandable stainless steel stents in the coronary arteries. After 28 days, histomorphometric analysis of the stented coronary arteries to determine the neointimal responses for the diabetic and nondiabetic animals was completed. ResultsSudden death due to stent thrombosis occurred for five of 11 (45%) of the diabetic animals and none of the age-matched nondiabetic control animals (P  = 0.05). For histology after 28 days, the neointimal response was correlated to the extent of arterial injury for the diabetic (r  = 0.79, P  < 0.0001) and nondiabetic (r  = 0.86, P  < 0.0001) animals. The surviving diabetic animals had areas of neointimal (1.67 ± 0.74 mm2) and percentages of in-stent stenosis (28 ± 14) similar to those of the nondiabetic swine (1.36 ± 0.40 mm2, P  = 0.26; 22 ± 6, P  = 0.17). Multiple regression analysis also demonstrated that arterial injury (P  < 0.0001) alone, not hyperglycemia (P  = 0.237), was independently correlated to formation of neointima. ConclusionsUncontrolled hyperglycemia results in greater than normal thrombosis after coronary-stent placement in swine with streptozotocin-induced diabetes. These data suggest that greater than normal early formation of thrombus rather than proliferation of smooth muscle cells contributes to restenosis after coronary stenting in patients with diabetes mellitus.

Experimental evaluation of a short transitional edge protection balloon for intracoronary stent deployment

The purpose of this study was to determine if balloon injury to the adjacent arterial wall during intracoronary stent deployment influences late in‐stent neointimal formation. Stent design and deployment techniques are considered important factors in determining acute and long‐term success with intracoronary stenting. Experimental and clinical studies support that the extent of neointimal formation and the probability for restenosis are influenced by the magnitude of arterial trauma induced with stenting. Nineteen 18‐mm‐long balloon‐expandable stainless steel stents (MULTI‐LINK Duet) were implanted at a 1:1 stent‐to‐artery ratio in the coronary arteries of swine with a conventional noncompliant balloon (n = 10) or a novel noncompliant balloon with short tapered shoulders to prevent edge dissection (n = 9). Quantitative coronary angiography and histology were used to evaluate balloon and artery interactions and the chronic vascular responses to the stents. Nineteen stents were implanted in the coronary arteries of seven swines at an inflation pressure of 14 atm using a standard noncompliant (n = 10) or a unique short transitional edge protection (n = 9) balloon. Histologic analysis at 28 days demonstrated balloon‐associated barotrauma in 13 of 20 (65%) of adjacent nonstented arterial segments with the conventional balloon and only 3 of 18 (17%) of the adjacent nonstented arterial segments with the short transition edge protection balloon (P = 0.022). In‐stent neointimal area and % stenosis correlated with the severity of peristent arterial injury (r = 0.43, P = 0.01). In‐stent vessel injury scores were similar for stents with peristent injury (1.0 ± 0.3) versus stents without peristent injury (1.0 ± 0.03, P = 0.73). In‐stent neointimal area and % stenosis were greater for stents with peristent injury (2.36 ± 0.74 mm2, 32% ± 9%) as compared to stents without peristent injury (1.39 ± 0.70 mm2, 20% ± 10%, P = 0.01). Arterial wall injury adjacent to a stent after high‐pressure deployment contributes to late in‐stent neointimal hyperplasia in this model. These experimental data suggest that further study is warranted to refine stent implantation techniques and that modifications of balloon shape or material may be useful to optimize stent deployment and reduce arterial trauma. Cathet. Cardiovasc. Intervent. 51:112–119, 2000.

Safety and Pharmacokinetics of Sirolimus-eluting Stents in the Canine Cerebral Vasculature: 180 Day Assessment

OBJECTIVE:We evaluated local and systemic pharmacokinetics and pharmacodynamics of sirolimus-eluting stents (SES) in canine cerebral vessels. METHODS:SES (1.5 × 8 mm, 79 &mgr;g/479 &mgr;g sirolimus) and control stents (1.5 × 8 mm stainless steel with or without polymer) were implanted in canine basilar and ventral spinal arteries. Animals were sacrificed for local pharmacokinetic (36 animals at 1, 3, 8, 30, 90, 180 days) and pharmacodynamic (60 animals at 3, 30, 90, 180 days) assessment. RESULTS:Postrecovery adverse clinical events were not serious, requiring no unscheduled treatment. Histologically, brain and spinal cord sections revealed scattered microinfarcts and minimal gliosis consistent with postprocedure changes in all four stent-treatment groups. All stented vessels at all time points demonstrated good luminal patency with low injury and inflammation scores and no thrombosis of either stented or branch arteries. Endothelialization was complete in all stent groups by 30 days. Intimal smooth muscle cell scores were reduced in both SES groups at 30, 90, and 180 days. Systemic sirolimus levels peaked between 1 and 7 hours postimplant (maximum concentration, 1.2 ± 1.47, 79 &mgr;g; 4.5 ± 1.23 ng/ml, 479 &mgr;g), then declined rapidly to 1 ng/ml or less by 96 hours. Peak local tissue sirolimus levels were 41.5 ng/mg (79 &mgr;g) and 65 ng/mg (479 &mgr;g). CONCLUSION:SES in canine cerebral vessels were associated with good luminal patency to 180 days, with complete endothelialization and no evidence of acute thrombosis. This model has shown that SES deployed within the brain do not cause neurotoxicity during a 180-day time course, even when exaggerated doses are used. The findings support the contention that SES are safe to use and maintain patency in cerebral vessels.

Evaluation of high‐pressure retrograde coronary venous delivery of FGF‐2 protein

Delivery of angiogenic factors to ischemic myocardium remains a practical challenge. We evaluated the efficiency and efficacy of delivery of fibroblast growth factor‐2 (FGF‐2) protein via high‐pressure retrograde injection into the anterior interventricular vein (AIV) in a porcine model of chronic myocardial ischemia. Labeled FGF‐2 protein was delivered to the myocardium of three pigs via the AIV and the left anterior descending (LAD) coronary artery in three others. At 1 hr, the amount of protein in the left ventricle and the LAD region was quantified. Copper stents were implanted in the LAD of 25 pigs, resulting in chronic myocardial ischemia. At 4 weeks, microsphere‐derived myocardial blood flow was assessed at rest and during pacing. In eight pigs (AIV FGF), FGF‐2 protein (6 μg/kg) was delivered via high‐pressure retrograde injection into the AIV. Six pigs (intracoronary FGF) received the same amount of FGF‐2 by intracoronary delivery. Five pigs (AIV saline) received a placebo injection into the AIV and six pigs (control) served as controls. Four weeks later, myocardial blood flow was reassessed. At 1 hr, significantly more FGF remained in the left ventricle (1.3 vs. 0.82 μg; P < 0.04) and in the LAD region (1.2 vs. 0.64 μg; P = 0.03) after AIV compared to intracoronary delivery. Four weeks after treatment, resting LAD blood flow (normalized to right ventricular flow) improved slightly in the AIV FGF and intracoronary FGF arms (1.32–1.37 for both; P = 0.11), while it decreased significantly in the AIV saline (1.32–1.23; P = 0.02) and the control arms (1.32–1.19; P = 0.0004). Pacing LAD blood flow decreased significantly in the control arm (1.30–1.23; P < 0.05), but did not change significantly in the other three arms. High‐pressure retrograde injection into the AIV may represent an efficient and effective means for delivering angiogenic factors to ischemic myocardium. Catheter Cardiovasc Interv 2004;61:422–428.

Dose and dose rate effects of beta-particle emitting radioactive stents in a porcine model of restenosis

BACKGROUND Radioactive stents have been proposed as a means to prevent in-stent restenosis by inhibiting intimal proliferation with continuous low-dose irradiation. OBJECTIVES The purpose of this study is to determine the effects of cumulative dose and dose-rate delivery on neointimal formation using 32P and 90Y beta-particle emitting radioactive stents in a porcine coronary model of restenosis. METHODS AND MATERIALS We compared the late histologic results of 0.25 to 32.0 microCi 90Y (half-life 64 hours) (n = 64 stents) and 0.1 to 57.6 microCi 32P (half-life 14.3 days) (n = 55 stents) Beta-particle emitting radioactive stents with non-radioactive (n = 40) stents in a porcine coronary model of restenosis. A computer-based dosimetry modeling program was used to determine the 28 day cumulative dose and dose-rate delivery for the beta-particle emitting radioactive stents at a distance of 0.1 mm from the stent surface. RESULTS Continuous low dose-rate (1 to 5 cGy/hr) radiation delivery for > 2 weeks via a 0.1 to 0.5 microCi 32P radioactive stent effectively reduced in-stent neointimal hyperplasia at 90 days. Cumulative doses of > 55 Gy induced severe adventitial fibrosis, microvascular damage and promoted the formation of a matrix-rich neointima. Delayed vascular repair was evident at focal regions within the body of radioactive stents that delivered cumulative doses of > or = 140 Gy at 28 days and cumulative doses of 1,100 Gy at 90 days. CONCLUSIONS These data may be useful in predicting safe and effective dose and dose rate delivery for beta-particle emitting radioactive stents.

1139-49 Sirolimus-eluting stents: Pharmacokinetics in blood, vessel, and myocardium in a porcine coronary model

Background: Our objective was to evaluate the range of programmable parameters of the Conor Medsystems MedStentTM loaded with lipophilic paclitaxel (PXL) in an in vitro elution experiment. We examined: 1) spatial homogeneity, 2) the breadth of multiple temporal and directional kinetic profiles, and 3) simultaneous combination of PXL with water soluble 2-chlorodeoxyadenosine (CDA), a potent macrophage inhibitor. Methods: Stents (9 formulations of 4 stents each) were immersed in aliquots of agitated N, N-diethylnicotinamide, and released drug was measured by HPLC for up to 30 days. Results: Spatial homogeneity for PXL varied by <3.5%. Graph A shows cumulative release curves for 100% of the loaded PXL over 5-30 days. Seven unique first and zero order temporal profiles were achieved with doses from 10-30 μg released either at the vessel wall or at the wall and lumen. Graph B shows cumulative simultaneous release from stents containing PXL and CDA. Conclusions: This stent’s layered multi-drug/polymer inlay technology permits precise control of spatial and temporal first and zero order pharmacokinetic elution profiles. A novel feature is the ability to simultaneously deliver water soluble and lipid soluble combination chemotherapy from a simple polymer carrier structure. These capabilities are undergoing further investigation in animal and human clinical trials.

Ultra-hydrophilic stent platforms promote early vascular healing and minimise late tissue response: a potential alternative to second-generation drug-eluting stents

AIMS Simple surface modifications can enhance coronary stent performance. Ultra-hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS. METHODS AND RESULTS UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimal hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p<0.04). Endothelialisation was similar on UHS-treated BMS and untreated BMS, both in swine and rabbit models, and lower on DES. Elevation in thrombotic indices was infrequent (never observed with UHS, rare with BMS, most often with DES), but, when present, correlated with reduced endothelialisation (p<0.01). CONCLUSIONS Ultra-hydrophilic surface treatment of contemporary stents conferred good healing while moderating neointimal and thrombotic responses. Such surfaces may offer safe alternatives to DES, particularly when rapid healing and short dual antiplatelet therapy (DAPT) are crucial.