Bernd Heublein

Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, non-randomised multicentre trial

BACKGROUND Coronary stents improve immediate and late results of balloon angioplasty by tacking up dissections and preventing wall recoil. These goals are achieved within weeks after angioplasty, but with current technology stents permanently remain in the artery, with many limitations including the need for long-term antiplatelet treatment to avoid thrombosis. We report a prospective multicentre clinical trial of coronary implantations of absorbable magnesium stents. METHODS We enrolled 63 patients (44 men; mean age 61.3 [SD 9.5 years]) in eight centres with single de novo lesions in a native coronary artery in a multicentre, non-randomised prospective study. Follow-up included coronary angiography and intravascular ultrasound at 4 months and clinical assessment at 6 months and 12 months. The primary endpoint was cardiac death, non-fatal myocardial infarction, or clinically driven target lesion revascularisation at 4 months FINDINGS 71 stents, 10-15 mm in length and 3.0-3.5 mm in diameter, were successfully implanted after pre-dilatation in 63 patients. Diameter stenosis was reduced from 61.5 (SD 13.1%) to 12.6 (5.6%) with an acute gain of 1.41 mm (0.46 mm) and in-stent late loss of 1.08 mm (0.49 mm). The ischaemia-driven target lesion revascularisation rate was 23.8% after 4 months, and the overall target lesion revascularisation rate was 45% after 1 year. No myocardial infarction, subacute or late thrombosis, or death occurred. Angiography at 4 months showed an increased diameter stenosis of 48.4 (17.0%). After serial intravascular ultrasound examinations, only small remnants of the original struts were visible, well embedded into the intima. Neointimal growth and negative remodelling were the main operating mechanisms of restenosis. INTERPRETATION This study shows that biodegradable magnesium stents can achieve an immediate angiographic result similar to the result of other metal stents and can be safely degraded after 4 months. Modifications of stent characteristics with prolonged degradation and drug elution are currently in development.

Coronary-artery stenting compared with balloon angioplasty for restenosis after initial balloon angioplasty. Restenosis Stent Study Group.

BACKGROUND Intracoronary stenting reduces the rate of restenosis after angioplasty in patients with new coronary lesions. We conducted a prospective, randomized, multicenter study to determine whether intracoronary stenting, as compared with standard balloon angioplasty, reduces the recurrence of luminal narrowing in restenotic lesions. METHODS A total of 383 patients who had undergone at least one balloon angioplasty and who had clinical and angiographic evidence of restenosis after the procedure were randomly assigned to undergo standard balloon angioplasty (192 patients) or intracoronary stenting with a Palmaz-Schatz stent (191 patients). The primary end point was angiographic evidence of restenosis (defined as stenosis of more than 50 percent of the luminal diameter) at six months. The secondary end points were death, Q-wave myocardial infarction, bypass surgery, and revascularization of the target vessel. RESULTS The rate of restenosis was significantly higher in the angioplasty group than in the stent group (32 percent as compared with 18 percent, P= 0.03). Revascularization of the target vessel at six months was required in 27 percent of the angioplasty group but in only 10 percent of the stent group (P=0.001). This difference resulted from a smaller mean (+/-SD) minimal luminal diameter in the angioplasty group (1.85+/-0.56 mm) than in the stent group (2.04+/-0.66 mm), with a mean difference of 0.19 mm (P=0.01) at follow-up. Subacute thrombosis occurred in 0.6 percent of the angioplasty group and in 3.9 percent of the stent group. The rate of event-free survival at 250 days was 72 percent in the angioplasty group and 84 percent in the stent group (P=0.04). CONCLUSIONS Elective coronary stenting was effective in the treatment of restenosis after balloon angioplasty. Stenting resulted in a lower rate of recurrent stenosis despite a higher incidence of subacute thrombosis.

Safety and efficacy of bioabsorbable magnesium alloy stents in porcine coronary arteries

Objective: We aimed to determine the safety and efficacy of biobasorbable magnesium alloy stents in porcine coronary arteries. Bioabsorbable magnesium stents carry the potential to overcome the limitations posed by permanent metallic stents such as chronic inflammation, late stent thrombosis, prolonged antiplatelet therapy, and artifacts when imaged by multislice‐computed tomography or magnetic resonance imaging. Methods: Magnesium alloy stents or stainless steel stents were randomly deployed in coronary arteries of domestic or minipigs. Domestic pigs were sacrificed at 3 days (n = 2) or 28 days, and minipigs at 3 months. Results: At 3 days, magnesium alloy stents were intact, but started to show signs of degradation by 28 days. There was no evidence of stent particle embolization, thrombosis, excess inflammation, or fibrin deposition. At 28 days and 3 months, neointimal area was significantly less in magnesium alloy stent segments (2.44 ± 0.88 mm2 and 1.16 ± 0.19 mm2) as compared with the stainless steel stent segments (5.03 ± 1.5 mm2 and 1.72 ± 0.68 mm2, P < 0.001 and 0.02). Quantitative coronary analysis indicates that percentage area stenosis and percentage diameter stenosis in magnesium alloy stent segments improved significantly at 3 months as compared to 28 days. Despite decreased neointimal hyperplasia, lumen area of the magnesium alloy stented vessels did not improve significantly. Conclusion: Magnesium alloy stents are safe and are associated with less neointima formation; however, reduced neointima did not result in larger lumen.

Mechanism of luminal narrowing in cardiac allograft vasculopathy : Inadequate vascular remodeling rather than intimal hyperplasia is the major predictor of coronary artery stenosis

BACKGROUND Despite increasing knowledge about degree and distribution pattern of intimal hyperplasia in cardiac allograft vasculopathy, coronary artery remodeling is only poorly understood in this disease. METHODS To evaluate vascular geometry, intravascular ultrasound was used to characterize 57 advanced lesions in 35 consecutive transplant recipients. Lumen, plaque, and vessel area in these target lesions were compared with proximal and distal reference sites. RESULTS AND CONCLUSIONS Vascular remodeling by compensatory local vessel enlargement (positive remodeling) and circumscript vascular constriction (negative remodeling) could be demonstrated. Plaque area in stenotic lesions was significantly increased compared with the mean reference site (5.6+/-3.0 mm2 versus 2.8+/-1.5 mm2, p < 0.001); however, inadequate compensatory enlargement rather than intimal hyperplasia was shown to be the most important predictor of luminal obstruction (r = 0.77, p < 0.001).

Coronary artery stenting in cardiac allograft vascular disease

Cardiac allograft vascular disease is characterized by diffuse and multifocal heterogeneous myointimal hyperplasia with or without vascular remodeling. Catheter-based interventions are indicated in selected patients. This study documents our experience with percutaneous transluminal coronary angioplasty and coronary stents (n = 48) in a group of 27 patients 5.7 +/- 2.9 years after heart transplantation. Early and intermediate results were controlled by angiography and intravascular ultrasound. Conventional percutaneous transluminal coronary angioplasty resulted in a mild and mostly inadequate gain in luminal dimensions (lumen area: 3.17 +/- 0.92 mm2 to 3.70 +/- 1.21 mm2; minimal lumen diameter: 1.84 +/- 0.23 mm to 2.04 +/- 0.36 mm). Coronary stenting led to a further improvement of luminal gain (lumen area: 3.70 +/- 1.21 mm2 to 5.86 +/- 1.76 mm2; minimal lumen diameter: 2.04 +/- 0.36 mm to 2.53 +/- 0.38 mm). These results were stabilized by application of aspirin and ticlopidine only. There were no stent thromboses or bleeding complications, and early hospital discharge of the patients was possible. At follow-up (mean follow-up period 7.72 +/- 5.45 months (range 0.50 to 23.13 months) all patients were clinically event free. In six of 24 stented vessels (25%) in 16 patients, significant restenosis (>50%) was found by intravascular ultrasound (n = 20) or by angiography (n = 4) 6 months after stent placement. We conclude that in eligible cardiac allograft vascular disease lesions primary stenting may be the method of choice. However, further evaluation of the modalities of stent application and different stent designs with respect to long-term survival is necessary.

Impaired coronary dilator responses to substance P and impaired flow-dependent dilator responses in heart transplant patients with graft vasculopathy☆

OBJECTIVES Because pathologic mechanisms for transplant vasculopathy are still uncertain, we tested the hypothesis that endothelial function, in terms of the release of endothelium-derived relaxing factor (EDRF), is impaired in patients with evidence of angiographic transplant vasculopathy. BACKGROUND The long-term prognosis after heart transplantation is mainly determined by the development of transplant vasculopathy. METHODS The study included 23 patients undergoing diagnostic cardiac catheterization approximately 40 months after heart transplantation. Patients were classified into those with (n = 8) and those without (n = 15) angiographic evidence of transplant vasculopathy. Coronary flow velocity (by intravascular Doppler echocardiography) and epicardial coronary diameter (by quantitative angiography) were determined after intracoronary bolus injections (1 ml) of the endothelium-dependent dilator substance P (20 pmol) and the endothelium-independent dilators nitroglycerin (0.1 mg) and papaverine (8 mg). Substances were injected through the lumen of the Doppler catheter, which was placed into the midportion of the left anterior descending artery. RESULTS Increases in blood flow velocity in response to substance P were significantly less in patients with than in patients without evidence of transplant vasculopathy. In addition, flow-mediated dilation of epicardial coronary arteries in response to papaverine was abolished in patients with such evidence. Vasodilation of epicardial coronary arteries in response to nitroglycerin and increases in flow velocity in response to papaverine were similar in both groups. CONCLUSIONS These results suggest that transplant vasculopathy in heart transplant patients is associated with endothelial dysfunction (that is, impaired EDRF-mediated vasodilation). Furthermore, responsiveness of epicardial arteries to increased flow appears to be abolished in patients with evidence of transplant vasculopathy. These abnormal vascular functions may contribute to the pathogenesis of transplant vasculopathy and its vascular complications.

Mycophenolate mofetil for secondary prevention of cardiac allograft vasculopathy: influence on inflammation and progression of intimal hyperplasia☆

BACKGROUND Cardiac allograft vasculopathy (CAV) remains the single most important complication impairing long-term survival after heart transplantation (HTx). Intimal hyperplasia as a response to immunologic and non-immunologic injury is involved in the pathogenesis. Because improved immunosuppressive properties with mycophenolate mofetil (MMF) have been shown within the first year, beneficial effects on intimal hyperplasia and systemic inflammation might be found late after HTx as well. METHODS After a baseline examination with intravascular ultrasound (IVUS, volumetric assessment) 30 patients (2.0 +/- 1.1 years post-HTx) were prospectively randomized to receive either MMF (2 g/day) or to continue with azathioprine (AZA) as part of a triple immunosuppression protocol with cyclosporine and prednisolone. Markers of systemic inflammation and changes in vascular geometry were evaluated by IVUS after 1 year of follow-up. RESULTS With regard to inflammation, significantly lower values were found for high-sensitive C-reactive protein (CRP) in the MMF group (AZA 1.8 +/- 1.2 mg/liter. vs MMF 1.0 +/- 4.1 mg/liter, p = 0.02). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-6 and transforming growth factor (TGF)-beta did not differ between the groups. IVUS revealed no significant differences between groups. There was a weak trend toward a larger increase in plaque volume (AZA 13 +/- 43 mm(3) vs MMF 27 +/- 41 mm(3), p = 0.33), whereas MMF-treated patients tended to show a small increase in vessel dimensions (AZA +10 +/- 63 mm(3) vs MMF +50 +/- 87 mm(3), p = 0.17). CONCLUSIONS Changing immunosuppression from a standard AZA-based regimen to MMF resulted in a decrease in systemic inflammatory activity as indicated by levels of high-sensitive CRP. However, progression of intimal hyperplasia did not differ significantly, and the weak trend toward vascular enlargement could indicate some influence on vascular geometry.

Preclinical Evaluation of Inducible Nitric Oxide Synthase Lipoplex Gene Therapy for Inhibition of Stent-Induced Vascular Neointimal Lesion Formation

Several reports have established the concept of nitric oxide synthase (NOS) gene transfer for inhibiting smooth muscle cell (SMC) proliferation after vascular injury. To minimize potential risks associated with viral gene transfer, we developed a liposome-based gene transfer approach employing inducible NOS (iNOS) overexpression for inhibition of stent-induced neointimal lesion formation. Therapeutic lipoplexes were transferred to femoral or coronary arteries of Goettingen minipigs, using the Infiltrator local drug delivery device. Efficiency of local iNOS lipoplex transfer was analyzed by iNOS-specific immunohistochemistry. NO-mediated inhibition of stent-induced neointimal lesion formation was analyzed by intravascular ultrasound (IVUS) and computerized morphometry. Gene transfer efficiency increased dose dependently to a maximum of 44.3 +/- 4.2% iNOS-positive vessel area (dose, 2 microg of iNOS lipoplex). Proliferating cell nuclear antigen (PCNA) expression of medial SMCs (immunohistochemistry) was inhibited significantly by transfer of 2 microg of iNOS lipoplexes (111 +/- 27 cells [iNOS] versus 481 +/- 67 cells [control; PCNA-positive medial cells]). IVUS analysis demonstrated that local transfer of iNOS lipoplexes resulted in a significant reduction of femoral in-stent plaque area (control, 40.85 +/- 6.37 mm(2); iNOS, 24.69 +/- 1.8 mm(2); p = 0.03). Coronary in-stent lesion formation was reduced by about 45% as determined by histologic morphometry (control, 4.0 +/- 0.29; iNOS, 2.2 +/- 0.30; p < 0.01). In conclusion, this study demonstrates that local intramural delivery of iNOS lipoplexes can exert therapeutic effects in inhibiting stent-induced neointimal lesion formation. Together with the nonviral character of this gene therapy approach, these findings may have important impact on the transition of NOS-based gene therapy to clinical practice.

ACE-gene polymorphism is associated with the development of allograft vascular disease in heart transplant recipients.

BACKGROUND Cardiac allograft vascular disease is (CAVD) the most important cause of death following heart transplantation (HTX). Although in the past, researchers focused predominantly on mechanisms of endothelial injury, the possible role of recipient-related and genetically determined factors has not been studied in detail. METHODS Stimulated by recent observations in native coronary artery disease, we analyzed the potential impact of angiotensin-converting enzyme (ACE) polymorphism (insertion/deletion [I/D], intron 16) on development and progression of CAVD. We characterized genotype in 146 patients 1 to 12 years after HTX (121 men; mean age, 46.2+/-11.3 years; observation period, 6.1+/-3.8 years) and correlated genotype to the onset and progression of CAVD, defined as luminal obstruction > 50%. RESULTS We found allelic frequencies to be 28.8% (n = 42) for ACE-DD, 49.3% (n = 72) for ACE-DI, and 21.9% (n = 32) for ACE-II. Differences in actuarial freedom from vasculopathy were significant 6 years after transplantation, with 84.6% for ACE-II compared with 54.4% for ACE-DD. We observed intermediate results for ACE-DI genotype (77.3%, p = 0.015). CONCLUSIONS In this large cohort study, we demonstrated a close relationship between the recipient-related ACE-D genotype and development of advanced CAVD. These observations suggest that gene-environment interactions might be clinically important in coronary vasculopathy after HTX.

SILICON CARBIDE-COATED STENTS : CLINICAL EXPERIENCE IN CORONARY LESIONS WITH INCREASED THROMBOTIC RISK

Purpose: To report the results of a prospective, nonrandomized, multicenter study of a semiconductor-coated stent in coronary lesions at high risk for stent thrombosis. Methods: A balloon-expandable tantalum stent was coated with silicon carbide to enhance thromboresistance (Tensum). Patients were enrolled in an observational study that compared coronary stenting with the Tensum stent in patients at low risk for stent thrombosis against those with factors predisposing to local thrombosis (acute myocardial infarction, small vessel diameter, recanalized chronic total occlusion, saphenous vein bypass grafts, and coronary allograft vascular disease). Results: In 294 patients with 364 coronary lesions, 111 patients with 142 lesions were assigned to the high-risk group. Overall, 406 Tensum stents were implanted (94% procedural success) using antiplatelet medication only after the procedure. The stent thrombosis rate (2.7% overall) in the high-risk group (3.6%) was not significantly different from that of the low-risk patients (2.1%). Conclusions: Silicon carbide coating on coronary stents may inhibit acute/subacute stent thrombosis even in patients at high risk. Randomized trials are underway for further evaluation of this promising coated stent.