Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology?

OBJECTIVES: To develop and test a new concept of the degradation kinetics of newly developed coronary stents consisting of magnesium alloys. METHODS: Design of a coronary stent prototype consisting of the non-commercial magnesium based alloy AE21 (containing 2% aluminium and 1% rare earths) with an expected 50% loss of mass within six months. Eleven domestic pigs underwent coronary implantation of 20 stents (overstretch injury). RESULTS: No stent caused major problems during implantation or showed signs of initial breakage in the histological evaluation. There were no thromboembolic events. Quantitative angiography at follow up showed a significant (p < 0.01) 40% loss of perfused lumen diameter between days 10 and 35, corresponding to neointima formation seen on histological analysis, and a 25% re-enlargement (p < 0.05) between days 35 and 56 caused by vascular remodelling (based on intravascular ultrasound) resulting from the loss of mechanical integrity of the stent. Inflammation (p < 0.001) and neointimal plaque area (p < 0.05) depended significantly on injury score. Planimetric degradation correlated with time (r = 0.67, p < 0.01). CONCLUSION: Vascular implants consisting of magnesium alloy degradable by biocorrosion seem to be a realistic alternative to permanent implants.

Polymerized degradable hyaluronan--a platform for stent coating with inherent inhibitory effects on neointimal formation in a porcine coronary model.

Biodegradable hyaluronan (hyaluronic acid, HA) made insoluble by self-cross-linking in the presence of N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide (EDC) has been used to cover stents. The maximum polymer-mass on a 16-mm stainless steel stent is approximately 2 mg. During manual crimping and simulated application, the loss of polymerized HA is negligible. The insoluble HA coating has an advantageous inherent antiproliferative effect regarding neointimal formation after local vessel wall injury (overstretch model) and leads to a reduced inflammatory response compared to uncoated stainless-steel stents, used as control, in undiseased pig coronary arteries, over a follow-up period of four weeks. Thus, cross-linked HA stent coating warrants further research as an interactive degradable biomaterial with an inherent inhibitory effect on neointimal formation as a possible biomatrix for local drug delivery to reduce restenosis rate.

Impact of vascular branching sites on focal progression of allograft vasculopathy in transplanted hearts.

BACKGROUND: Cardiac allograft vascular disease (CAVD) represents one of the most accelerated progressing coronary syndromes in the human heart. A variety of risk factors have been identified over recent years; however, little is known about the influence of physical forces. As a model for differences in focal blood flow dynamics, we analyzed progression of intimal hyperplasia at vascular bifurcational sites using intravascular ultrasound (IVUS). METHODS: The most diseased vascular sites ("worst sites") in 59 coronary arteries were assessed (30 MHz, motorized pull back) in 25 consecutive heart transplant recipients at baseline (52.8+/-15.3 days postoperatively) and after 1 year of follow up (360.5+/-24.9 days). Progression of intimal hyperplasia was compared between branching and non-branching lesions as well as in focal relation to the position of the flow divider. RESULTS: A total of 41 (69.5%) worst sites were identified at branching locations. Progression of intimal hyperplasia was found to be significantly more severe at bifurcational sites with an increase in plaque area by 1.5+/-1.8 mm(2) in branching versus 0.4+/-0.6 mm(2) in non-branching lesions (P=0.015). The highest rate in focal progression was found at the opposite site of the flow divider with an increase in maximal intimal thickness by 0.3+/-0.23 mm (180 degrees ) as compared to 0.11+/-0.15 mm (90 degrees, P<0.001) and 0.15+/-0.15 mm (P=0.014) at 270 degrees. CONCLUSIONS: Using serial intravascular ultrasound examinations, vascular branching sites could be identified to be predisposing locations not only for a donor related arteriosclerosis, but also for progression of intimal hyperplasia within transplanted hearts. The highest regional increase in intimal thickness was found at the outer wall of the flow divider, suggesting focal shear or wall stress to be involved in pathogenesis.

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.

Systemic inflammatory response in cardiac allograft vasculopathy: high-sensitive C-reactive protein is associated with progressive luminal obstruction.

BACKGROUND: Response to immunologic and nonimmunologic injury has been reported to initiate the development of cardiac allograft vasculopathy (CAVD). Although histopathologic examinations reveal signs of focal inflammation, little is known about the systemic inflammatory response in this accelerated coronary syndrome. METHODS AND RESULTS: Therefore, we investigated high-sensitive C-reactive protein (CRP) in a large cohort of heart transplant (HTX) recipients (n=102, 90 male, mean age 45.2+/-11.5 years, 6.1+/-3.3 years after HTX) in correlation with a progression of luminal obstruction as assessed by serial coronary angiography (defined as an increase of focal stenosis >/=30% or detection of a new lesion) after a mean interval of 1.8+/-1.0 years. Patients with signs of an acute rejection or infection were excluded. In the entire group, CRP levels ranged from 0.2 to 12.7 mg/L (mean 2.6+/-2.7 mg/L). Patients with progressive CAVD (n=35) presented with significantly higher levels of CRP (4.1+/-3.3 mg/L) than did those with a nonprogressive course (n=67) (1.8+/-1.9 mg/L, P:=0.001). These observations were independent of the initial indication for HTX (atherosclerotic disorder versus cardiomyopathy, P:=0.18) and the severity of CAVD at baseline examination (P:=0.12). CONCLUSIONS: Progressive cardiac allograft vasculopathy is accompanied by a systemic inflammatory reaction, which gives further insight into the pathogenesis of this coronary syndrome and may well serve as an indicator for patients at risk.

Progression of cardiac allograft vascular disease as assessed by serial intravascular ultrasound: correlation to immunological and non-immunological risk factors.

OBJECTIVE: To characterise the severity and progression of cardiac allograft vascular disease (CAVD) in a large patient cohort, and to evaluate possible immunological and non-immunological risk factors for progression. DESIGN: A prospective observational study using intravascular ultrasound. SETTING: Two university hospitals. PATIENTS AND MAIN OUTCOME MEASURES: Changes in focal plaque, lumen, and total vessel area (worst site method) were assessed at baseline and after 12.1 (2.8) months (mean (SD)) of follow up in a cohort of 96 patients (79 male, 17 female; mean age 48.7 (9.6) years; time post-transplant 26.0 (32.4) months). RESULTS: Overall, the mean (SD) intimal index of worst sites increased by 6.7 (8.8)%. The increase in the first 12 months was 7.5 (9.4)%, v 5.9 (8.0)% after the first year (NS). Analysing immunological and non-immunological risk factors (age, underlying disease, sex, donor age, immunosuppression, cytomegalovirus, rejection episodes, cholesterol), low density lipoprotein (LDL) cholesterol was found to be the most important predictor of severe progression (as defined by an increase in intimal index of >/= 15% (p = 0.01). CONCLUSIONS: Progression of CAVD is characterised by a continuing increase in intimal hyperplasia, especially within the first year after heart transplantation. LDL cholesterol is an important predictor of major progression.

Immediate stent implantation versus conventional techniques for the treatment of abrupt vessel closure or symptomatic dissections after coronary balloon angioplasty.

BACKGROUND: Coronary stenting was initially designed to treat a bailout scenario. Prospective randomized trials comparing stent implantation with standard techniques, including emergency coronary artery bypass grafting, are lacking. The aim of this trial was to test the superiority of immediate stent implantation compared with standard techniques for the treatment of abrupt or threatening closure after coronary balloon angioplasty. METHODS: In a prospective trial, 100 patients with abrupt vessel closure or symptomatic dissections causing objective signs of ischemia were randomly assigned to treatment with immediate placement of stents (n = 51) versus standard techniques such as prolonged dilatation or emergency bypass surgery (n = 49). The primary end point was the achievement of successful stabilization not requiring crossover to the other study group. Secondary end points included event-free survival and restenosis. RESULTS: Successful stabilization was achieved in 94% of patients in the stent group compared with 78% of patients in the standard treatment group (P =.038). Two patients died in each group, and there was a trend toward a higher incidence of myocardial infarction (16% vs 8%; P =.163) and a significantly increased creatine phosphokinase level (245 IU/L [95% confidence interval, 217-265 IU/L] vs 179 IU/L [confidence interval 140-212 IU/L]; P =.0002) in the standard treatment group. Event-free survival after 250 days was 72% in the stent group compared with 29% in the standard treatment group (P =.001). The angiographic restenosis rate was 30% in the stent group versus 59% in the standard treatment group (P =.01). CONCLUSIONS: Immediate stenting, if technically feasible, shows superior short- and long-term results compared with standard treatment options.

Impact of chronic infection with chlamydia pneumoniae on incidence of cardiac allograft vasculopathy.

Chronic infection with Chlamydia pneumoniae (CP) is associated with development of coronary disease. However, little information exists concerning CP infection and impact on posttransplant cardiac allograft vasculopathy (CAV). A total of 202 patients were investigated 5.5+/-3.1 years after cardiac transplantation (46.5+/-11.0 years; 169 male, 33 female). Assessment of CAV was performed by annual coronary angiograms. Chlamydia serology (IgG/IgA) was performed using micro-immunofluorescence. Statistics comprised analysis of variance and Kaplan-Meier analysis. A total of 152 patients were CAV positive. Elevated titers were present in 45% (IgG) and 72.8% (IgA) of patients. Generally, serostatus was not associated with development of CAV when evaluated over the total postoperative interval. However, after month 14 there was a significant trend toward lower actuarial freedom from CAV in patients with elevated IgA titers. CP seems not to play a significant role in the development of CAV early after heart transplantation but might be a predicting risk factor after the first postoperative year.

Cardiac allograft vascular disease after orthotopic heart transplantation: methylenetetrahydrofolate reductase gene polymorphism C677T does not account for rapidly progressive forms.

BACKGROUND: Recently, homocysteine (HCY) levels have been suggested to be a risk factor in cardiac allograft vascular disease (CAVD). As plasma levels are partially under genetic control, we investigated the influence of the methylenetetrahydrofolate reductase (MTHFR) polymorphism on HCY levels and development of CAVD in heart transplant (HTX) recipients. METHODS: Genotyping and assessment of fasting HCY levels were performed in a cohort of 146 HTX recipients and correlated to the onset and progression of CAVD, assessed by serial angiography. RESULTS: Actuarial freedom from CAVD did not differ significantly between the genotypes. However, patients positive for CAVD presented with higher HCY levels than CAVD-negative individuals (21.0+/-9.4 vs. 18.2+/-6.6 micromol/L, P=0.046). CONCLUSIONS: There is some evidence that plasma HCY might be involved in development of CAVD. However, polymorphism of the MTHFR gene could not be shown to be related to severity of allograft vascular disease.

Vascular remodeling in cardiac allograft vasculopathy.

Growing evidence suggests that vascular remodeling processes contribute significantly to the amount of luminal obstruction in coronary artery disease. Recently changes in vascular geometry in the form of positive (compensatory enlargement) as well as negative remodeling (constrictive changes) could be demonstrated in transplanted hearts as well. For further characterization intravascular ultrasound provides an excellent insight into time-related changes (by serial follow-up examinations) and into longitudinal spatial relationships within vessels (motorized pullback with 3-D reconstruction). Focused on time-related changes a decrease in total vessel volume within the first year after transplantation as compared to a slight compensatory enlargement in patients 'late' after HTX could be demonstrated. Regarding focal luminal obstruction, local constrictive changes (negative remodeling) were identified to be the most important predictor of severity of stenosis. It is concluded that changes in vascular geometry are of major importance in focal stenosis as well as in a general luminal loss of coronary arteries within transplanted human hearts. These observations might be of special interest regarding pathophysiology and potential therapeutic interventions in this unique form of an accelerated coronary syndrome.

Cardiac allograft vasculopathy--coronary interventions and surgical options.

Despite improved results early after heart transplantation (HTX) obstructive allograft vasculopathy still remains the leading cause of death late after HTX. Studies in the past, focused on angioplasty (PTCA), presented with disappointing results. Using intravascular ultrasound an extensive early recoil could be shown to be the major cause for re/rest-stenosis in dilated lesions. Stimulated by these observations, stent implantation was recently shown to be an effective therapeutical alternative in focal luminal obstruction in graft coronary arteries. Treatment of 41 patients in a single center experience (75 lesions, 85 stents) resulted in a success rate of 98%; no acute or subacute stent thromboses were observed (protocol with ASS and Ticlopidine). Control angiography revealed a 6-month restenosis rate of 14.1% defining stent implantation as the method of choice for relief of focal luminal obstruction. Only limited experience is available regarding the surgical approach with coronary artery bypass grafting. In selected patients (focal obstruction not suitable for interventional therapy, adequate peripheral vessels) it might represent a therapeutical alternative.

[Coronary vasculopathy after heart transplantation--effect of temporal onset, severity and progression on long-term prognosis]. / Koronare Vaskulopathie nach Herztransplantation--Einfluss von zeitlichem Auftreten, Schweregrad und Progredienz auf die Prognose im Langzeitverlauf.

Despite considerable progress in the knowledge about pathophysiology of cardiac allograft vascular disease (CAVD), only few systematic studies are available, characterizing the natural course during long-term follow-up after heart transplantation (HTX). Therefore, we analyzed in 354 heart transplant recipients (305 male, 45.9 +/- 11.2 years, mean observation period 5.8 +/- 3.0 years, range 0.9-12.4 years) the results of 1129 coronary angiograms under the aspects of development, severity, localization, and progression of disease related to the prognosis of patients. As expected an increasing prevalence was found over time with a luminal obstruction > or = 30% in 83% of all patients more than 10 years after HTX. Coronary artery stenosis (> or = 50%) at initial diagnosis was predominantly localized in the LAD (46%) followed by RCX (31%) and RCA (23%). Angiographic risk profiles with an impaired prognosis could be identified in the form of an early development (< 4 years post HTX) of disease (p = 0.03), luminal obstruction > 50% (p = 0.001), and multivessel appearance at first diagnosis (p = 0.02) as well as in progressive forms of CAVD (p = 0.001). Summarizing, CAVD is a frequent finding in HTX recipients. Especially in patients with early onset, progressive, and advanced stages of disease it represents a prognostically limiting complication following HTX. Identification of the natural course is of major importance defining the need and efficacy of future palliative therapeutical approaches.

[Hybrid technique for myocardial revascularization: value of combined minimal invasive bypass technique (MIDCAB) with interventional therapy (PTCA)]. / Hybrid-Verfahren zur Myokardrevaskularisation: Stellenwert der Kombination von minimal-invasiver Bypasstechnik (MIDCAB) mit interventioneller Therapie (PTCA).

BACKGROUND: Minimally invasive direct coronary artery bypass (MIDCAB) grafting without cardiopulmonary bypass (CPB) through an anterolateral minithoracotomy has become a promising therapeutical option especially in multimorbid, elderly and reoperative patients with single vessel disease. However, this procedure precludes complete revascularization in multivessel disease because the minithoracotomy limits the surgical access either to anterior or lateral or posterior vessels of the beating heart. To expand the benefits of the MIDCAB concept to patients with multivessel disease, new interdisciplinary approaches have recently been introduced. METHODS: Since December 1996, 26 patients (21 male, 5 female, mean age 56.6 +/- 18.8 years) underwent a "hybrid" revascularization performed as a primary MIDCAB procedure for grafting of the left anterior descending artery (LAD) with the left internal mammary artery (LIMA) followed by staged angioplasty and stenting of additional coronary lesions. RESULTS: After MIDCAB grafting, the postoperative course was uneventful in all patients. Coronary re-angiography after a median of 7 days revealed patent and functioning LIMA grafts in all patients. Applying subsequent percutaneous transluminal coronary angioplasty (PTCA) and occasional stenting (n = 8), a total of 31 lesions were treated successfully. Procedure related complications did not occur. All patients remained angina-free and no stress electrocardiographic changes were recorded. CONCLUSION: Our preliminary results of a "hybrid" approach to myocardial revascularization suggest that this concept is a safe and effective approach of complete revascularization for selected patients with multivessel involvement. Especially elderly and reoperative patients with significant comorbidity may benefit from hybrid procedures avoiding cardiopulmonary bypass and midsternotomy.

Volumetric remodeling of the proximal left coronary artery: early versus late after heart transplantation.

OBJECTIVES: The aim of this study was to characterize progression of cardiac allograft vasculopathy (CAV) with special respect to coronary artery geometry. BACKGROUND: As previously shown by intravascular ultrasound (IVUS), CAV is characterized by a multifocal intimal hyperplasia. Little is known, however, about vascular remodeling processes influencing vessel geometry and luminal narrowing. METHODS: In 30 heart transplant recipients serial IVUS studies were performed at baseline (BL) and after a mean follow-up period of 12.5+/-2.5 months. Changes in plaque, lumen and vessel volume were assessed in the proximal left anterior descending artery. Pattern of remodeling was analyzed in patients "early" (n = 15, BL study 1.4+/-0.7 months after heart transplantation [HTX]) compared with "late" after HTX (n = 15, BL 46.1+/-29.1 months). RESULTS: Plaque volume was found to increase by a mean of 23.8+/-25.9 mm3, not significantly different within and beyond the 1st year after HTX. Significant differences, however, were observed in changes in vessel volume with a mean decrease of -52.8+/-70.9 mm3 in the early group, whereas late follow-up group presented with an enlargement of 32.3+/-46.0 mm3. Based on these changes, lumen volume decreased by -73.2+/-69.8 mm3 early, in contrast to a slight increase of 5.2+/-32.6 mm3 in the late group. CONCLUSIONS: Progression of CAV is a complex process, modified by changes in the vascular geometry. Especially within the 1st year after HTX, luminal loss is influenced not only by an increase in plaque area but by a decrease in total vessel volume as well.

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.

Mechanism of luminal narrowing in cardiac allograft vasculopathy: inadequate vascular remodeling rather than intimal hyperplasia is the major predictor of coronary artery stenosis. Working Group on Cardiac Allograft Vasculopathy.

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).