CoreValve Prosthesis Depth: What is the Optimal Measurement Target?

BACKGROUND AND AIM OF THE STUDY: A major drawback of the transcatheter aortic valve replacement (TAVR) procedure using the self-expandable Medtronic CoreValve (MCV) prosthesis is the high incidence of conduction disturbances and the need for postprocedural permanent pacemaker (PPM) implantation. The depth of prosthesis implantation may be an important contributing factor. The study aim was to determine the relationship between angiographic measurements of the MCV prosthesis depth and the occurrence of new conduction disturbances and need for PPM after TAVR. METHODS: A retrospective analysis was conducted of 157 consecutive patients who had undergone TAVR procedures with the MCV between 2009 and 2013. Patients with pre-existing pacemakers (n = 27) were excluded. Prosthesis depth was defined as the angiographic distance from the lowest part of the prosthesis to the base of the non-coronary cusp (NCcD) and the base of the left coronary cusp (LCcD). RESULTS: A 26 mm MCV was implanted in 50% of patients, and a 29 mm MCV in 38%. The rate of new ≥2nd degree atrioventricular block (AVB) after TAVR was 5%, and the incidence of new left ventricular bundle branch block (LBBB) was 23%. PPMs were implanted in 13 patients (10%) within 30 days after the procedure. Freedom from new ≥2nd degree AVB, LBBB and the need for PPM after TAVR was significantly higher among patients with NCcD <6 mm or LCcD <8 mm (90% and 89%, respectively) compared to patients with NCcD ≥6 mm or LCcD ≥8 mm (53% and 54%, respectively) (p <0.0001). CONCLUSIONS: Prosthesis depth, measured relative to either the NCcD or LCcD, strongly predicted the occurrence of conduction disturbances and the need for PPM following TAVR with the MCV prosthesis.

Long-term Follow-up of Coronary Artery Bypass Patients With Preoperative and New Postoperative Native Coronary Artery Chronic Total Occlusion.

BACKGROUND: Chronic total occlusions (CTOs) of native coronary arteries are a frequent finding among patients who are referred for surgical revascularization with coronary artery bypass grafting (CABG). The long-term clinical significance of native coronary artery CTO identified at baseline and 1 year after CABG is unknown. METHODS: All patients who underwent 1-year follow-up angiography as part of the multicentre Radial Artery Patency Study (RAPS) were assessed for late clinical events. RESULTS: At a mean follow-up of 7.3 ± 2.9 years, the study group of 388 patients had the following outcomes: 39 (10%) deaths, 6 (1.5%) cases of nonfatal myocardial infarction, and 19 (4.9%) cases of percutaneous coronary intervention (PCI). CTO of ≥ 1 native coronary artery in the baseline preoperative coronary angiogram was demonstrated in 240 (61.9%) patients. The composite of all-cause death, nonfatal myocardial infarction, and PCI occurred significantly more often in patients with at least 1 preoperative CTO than in patients without a preoperative CTO (20% vs 11%; P = 0.048). A new native coronary artery CTO 1 year after surgery occurred in 169 (43.6%) patients. The composite of all-cause death, nonfatal myocardial infarction, and PCI occurred significantly more often in patients with a new CTO 1 year after CABG compared with those without a new CTO (21.3% vs 12.8%; P = 0.028). CONCLUSIONS: In patients undergoing CABG, both preoperative CTOs and new CTOs that develop 1 year after surgery are associated with adverse long-term clinical outcomes.

Gender differences in the prevalence and treatment of coronary chronic total occlusions.

BACKGROUND: Gender differences exist in the presentation and outcomes of patients with coronary artery disease (CAD). Our study objective was to compare gender differences in prevalence, co-morbidities, and revascularization treatment in CAD patients with chronic total occlusions (CTOs). METHODS: A retrospective analysis using the Canadian Multicenter CTO Registry, which included 1,690 consecutive CTO patients identified at coronary angiography and a control group of 7,682 non-CTO patients. RESULTS: The prevalence of women in the CTO group was significantly lower compared to the control group (19% vs. 30%, P < 0.001). Within the overall CTO group, women were significantly older than men (70 ± 12 vs. 66 ± 11 years, P < 0.001) with more comorbidities, including hypertension and heart failure. Rates of PCI in the CTO group were similar between gender (10%), however, women with CTO were treated significantly less by CABG compared to men (19% vs. 27%, P = 0.003). Moreover, compared to male patients, significantly fewer women undergoing CABG had revascularization of the CTO artery (84% vs. 93%, P = 0.03). Multivariable analysis indicated that female gender (along with age, chronic renal failure, prior MI and cerebro-vascular disease) were independent predictors for not receiving CABG treatment for CTO. CONCLUSIONS: Female gender differences exist in CTO patients with both lower prevalence of CTOs at angiography and lower revascularization rates of CTOs by CABG. © 2015 Wiley Periodicals, Inc.

Native coronary artery patency after coronary artery bypass surgery.

OBJECTIVES: The aim of the study was to determine native coronary artery patency 1 year after coronary artery bypass grafting and to identify clinical and angiographic predictors for the development of a chronic total occlusion (CTO). BACKGROUND: In contrast to the large body of information regarding graft patency, data regarding atherosclerosis progression and vessel patency in surgically bypassed native coronary arteries are less clear. METHODS: Of the 440 patients who underwent 1-year follow-up angiography as part of the multicenter RAPS (Radial Artery Patency Study), included in our study were 388 patients (88%) for whom angiograms were available for review. Angiograms were reviewed for native coronary artery patency in an independent blinded manner. RESULTS: On the pre-operative angiogram, CTO of at least 1 native coronary vessel was demonstrated in 240 patients (61.9%) having 305 occluded vessels. At 1 year after coronary artery bypass grafting, at least 1 new native coronary artery CTO occurred in 169 patients (43.6%). In 7.5% of patients, the native artery and the graft supplying that territory were both occluded. A new CTO was almost 5 times more likely to occur in coronary vessels with a pre-operative proximal stenosis >90% compared with vessels with proximal stenosis <90% (45.5% vs. 9.5%, respectively, p < 0.001). Patients with a new CTO had significantly more baseline Canadian Cardiovascular Society class 4 angina compared with patients without a new CTO. A new CTO was less likely to occur in the left anterior descending artery (18.4%), supplied by the left internal thoracic artery. When comparing radial artery and saphenous vein grafts, neither the type of graft nor graft patency had any association with native coronary artery occlusion. CONCLUSIONS: CTO of surgically bypassed coronary arteries 1 year after coronary artery bypass grafting is extremely common.

Comparison of the frequencies of myocardial edema determined by cardiac magnetic resonance in diabetic versus nondiabetic patients having percutaneous coronary intervention for ST elevation myocardial infarction.

The specific mechanisms by which diabetes may affect the myocardial tissue response to ischemia are unclear. Our objective was to prospectively quantify the degree of myocardial edema in diabetics versus nondiabetics with ST elevation myocardial infarction using cardiac magnetic resonance. Fifty-two patients (16 diabetics and 36 nondiabetics) were enrolled after primary percutaneous coronary intervention and underwent cardiac magnetic resonance on a 1.5-T scanner at 48 hours and 6 months. Myocardial edema was quantified using a T2 mapping technique, and infarct size and microvascular obstruction size were assessed by way of a contrast-enhanced T1-weighted inversion recovery gradient-echo sequence. The infarct segment T2 was elevated in diabetics compared with nondiabetics (59.0 ± 8.0 vs 50.8 ± 3.1 ms, p <0.001) at 48 hours. Multivariate analysis demonstrated that diabetes (p <0.001) and symptom-to-balloon time (p = 0.04) were independent predictors of the degree of acute myocardial edema. Infarct size was nonsignificantly higher in the diabetic group at 48 hours (26.9 ± 9.4% vs 20.1 ± 10.1% of myocardium, p = 0.07) and 6 months (17.1 ± 6.3% vs 13.4 ± 6.1% of myocardium, p = 0.09). Microvascular obstruction size was equivalent in both groups, and there was a trend toward lower myocardial salvage index in diabetics (34.2 ± 11.8 vs 49.6 ± 13.4, p = 0.08). In conclusion, diabetes is associated with increased myocardial edema in the acute phase after primary percutaneous coronary intervention. Our results offer insight into the complex processes that characterize myocardial tissue response to injury in diabetic patients.

Therapeutic angiogenesis with VEGF164 for facilitation of guidewire crossing in experimental arterial chronic total occlusions.

AIMS: Percutaneous revascularisation of chronic total occlusions (CTO) is limited by failure of guidewire crossing. Neovascularisation within the proximal CTO segment may be important for guidewire crossing and dramatically declines in CTO beyond six weeks of age. The aims of the current study were to determine whether local delivery of a pro-angiogenic growth factor increases neovascularisation in mature CTO and facilitates guidewire crossings. METHODS AND RESULTS: CTO (n=51) were created in the femoral arteries of 44 New Zealand white rabbits using the thrombin injection model. At 12 weeks, CTO were treated with poly-lactic-glycolic-acid (PLGA) microspheres containing either bovine serum albumin (BSA) (n=15) or recombinant mouse VEGF164 (n=14), or received no intervention (controls, n=12). Contrast-enhanced magnetic resonance angiography (CEMRA) was performed prior to treatment and at three weeks post treatment. Animals were sacrificed at three weeks post treatment and arterial samples were excised for micro-computed tomography imaging (µCT) and histologic morphometric analysis. Guidewire crossing was assessed at three weeks post treatment in an additional 10 VEGF164-treated CTO. In comparison to BSA-treated and control non-intervened CTO, VEGF164-treated CTO showed a significant increase in relative blood volume index in the proximal segment of the CTO lesion as determined by CEMRA and by µCT. Histologic measurements of microvessel area were also higher in VEGF164-treated CTO. Guidewire crossing across the proximal fibrous cap was successful in eight out of 10 VEGF164-treated CTO. CONCLUSIONS: Angiogenic therapy appears to be a promising strategy to improve neovascularisation and guidewire crossing rates in CTO.

Characterizing myocardial edema and hemorrhage using quantitative T2 and T2* mapping at multiple time intervals post ST-segment elevation myocardial infarction.

BACKGROUND: Accurate characterization of the longitudinal trends of myocardial edema and hemorrhage has been previously limited by subjective qualitative methods. We aimed to prospectively characterize the evolution of myocardial edema and hemorrhage post acute myocardial infarction using quantitative measures. METHODS AND RESULTS: Sixty-two patients were enrolled post primary percutaneous coronary intervention and underwent cardiovascular magnetic resonance on a 1.5-T scanner at 48 hours, 3 weeks, and 6 months. Myocardial edema and hemorrhage were assessed by T2 and T2* mapping, respectively, in both infarct segment (IS) and remote segment (RS). At 48 hours, T2 is higher in IS compared with RS (56.7 ms versus 43.4 ms; P<0.01). At 3 weeks T2 remains higher in IS compared with RS (51.8 ms versus 39.5 ms; P<0.01), and subsequently equalizes by 6 months (39.8 ms versus 39.5 ms; P=nonsignificant). T2 is also increased in RS at day 2 versus 3 weeks (43.4 ms versus 39.5 ms; P<0.01). At 48 hours T2* was reduced in IS compared with RS (32.4 ms versus 37.4 ms; P<0.01). At 3 weeks (IS, 37.7 ms versus RS, 38.4 ms; P=nonsignificant) and 6 months (IS, 37.3 ms versus RS, 38.2 ms; P=nonsignificant), T2* values were equal in both segments. CONCLUSIONS: Quantification of myocardial edema and hemorrhage by T2 and T2* mapping is feasible post acute myocardial infarction and demonstrates that hemorrhage resolves faster than edema. Noninfarcted segments can also demonstrate edema in the acute phase possibly due to global hyperemia.

Statin therapy prevents expansive remodeling in venous bypass grafts.

BACKGROUND: Venous grafts (VG) have high failure rates by 10 years in aortocoronary bypass surgery. We have previously shown that expansive remodeling followed by increased LDL retention are early atherosclerotic changes in experimental VG placed in the arterial circulation. The objective of this study was to determine whether statin therapy prevents these expansive remodeling changes. METHODS AND RESULTS: Reversed jugular vein-to-common carotid artery interposition graft was constructed in 27 cholesterol-fed (0.5%) rabbits. Rabbits were randomized either to control or atorvastatin (5 mg/kg/day) groups, starting two weeks prior to vein graft implantation and continuing until sacrifice at 1 or 12 weeks post-surgery. Ultrasound measurements of arterial luminal cross-sectional area (CSA) were done at day 3 and at 4, 8 and 12 weeks post-surgery. Histomorphometric measurements were performed following sacrifice at 12 weeks. Atorvastatin treatment significantly decreased total plasma cholesterol levels at 4, 8 and 12 weeks (12 weeks: 6.7 ± 4.2 mmol/L versus control 38.7 ± 10.6 mmol/L, p<0.0002). Atorvastatin significantly reduced expansive remodeling at 4, 8 and 12 weeks (lumen CSA: 44.6 ± 6.6 mm(2) versus control 77.6 ± 10.7 mm(2), p<0.0001). Intimal CSA by histomorphometry was also significantly reduced by atorvastatin at 12 weeks (5.59 ± 2.19 mm(2) versus control 9.57 ± 2.43 mm(2), p<0.01). VG macrophage infiltration, MMP-2 activity and metalloelastase activity were reduced in the atorvastatin treated group. CONCLUSION: Atorvastatin inhibits both expansive remodeling and intimal hyperplasia in arterialized VG, likely through inhibition of macrophage infiltration and reduction of tissue proteolytic activity. The mechanism proposed above may be important for preventing VG atherosclerosis and late VG failure.

Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry.

OBJECTIVES: The purpose of this study was to determine the prevalence, clinical characteristics, and management of coronary chronic total occlusions (CTOs) in current practice. BACKGROUND: There is little evidence in contemporary literature concerning the prevalence, clinical characteristics, and treatment decisions regarding patients who have coronary CTOs identified during coronary angiography. METHODS: Consecutive patients undergoing nonurgent coronary angiography with CTO were prospectively identified at 3 Canadian sites from April 2008 to July 2009. Patients with previous coronary artery bypass graft surgery or presenting with acute ST-segment elevation myocardial infarction were excluded. Detailed baseline clinical, angiographic, electrocardiographic, and revascularization data were collected. RESULTS: Chronic total occlusions were identified in 1,697 (18.4%) patients with significant coronary artery disease (>50% stenosis in ≥1 coronary artery) who were undergoing nonemergent angiography. Previous history of myocardial infarction was documented in 40% of study patients, with electrocardiographic evidence of Q waves corresponding to the CTO artery territory in only 26% of cases. Left ventricular function was normal in >50% of patients with CTO. Half the CTOs were located in the right coronary artery. Almost half the patients with CTO were treated medically, and 25% underwent coronary artery bypass graft surgery (CTO bypassed in 88%). Percutaneous coronary intervention was done in 30% of patients, although CTO lesions were attempted in only 10% (with 70% success rate). CONCLUSIONS: Chronic total occlusions are common in contemporary catheterization laboratory practice. Prospective studies are needed to ascertain the benefits of treatment strategies of these complex patients.

Collagenase Total Occlusion-1 (CTO-1) trial: a phase I, dose-escalation, safety study.

BACKGROUND: Percutaneous interventions for chronic total occlusions have low success rates, primarily because of failure of guide wire crossing. Collagen-rich matrix constitutes the main barrier to chronic total occlusion crossing. In preclinical studies, local delivery of a bacterial collagenase formulation improved guide wire crossing. The Collagenase Total Occlusion-1 (CTO-1) Trial is a phase I, dose-escalation trial to assess the safety and efficacy of collagenase therapy to facilitate guide wire crossing in coronary artery chronic occlusions. METHODS AND RESULTS: Twenty subjects with ≥1 previous failure of chronic total occlusion guide wire crossing were enrolled at 2 sites. Subjects were treated in 4 distinct cohorts of 5 patients, with escalation of collagenase dose in each cohort from 300 to 1200 µg. Collagenase was locally delivered into the occlusions with either an over-the-wire balloon system (n=8) or a fine-cross microcatheter (n=12) for a period of 30 minutes. Subjects were brought back to the catheterization laboratory for guide wire crossing and angioplasty the next day. Guide wire crossing was successfully achieved in 15 subjects (75%). A soft-tip guide wire (Whisper, Pilot-50, Fielder XT) was either the sole or predominant guide wire used in 75% of successful crossings. Non-ST-segment-elevation myocardial infarctions occurred in 3 patients as a result of side-branch ischemia during stenting. Computed tomographic angiography at 3 months showed no late complications and patent stents in successfully treated chronic total occlusion. Anginal improvement occurred with a reduction in Canadian Cardiovascular Society class from baseline to 3 months (2.5±0.6 versus 0.9±0.9; P<0.001). CONCLUSION: Local delivery of collagenase into coronary chronic total occlusion is feasible and safe with encouraging guide wire crossing results in previously failed cases. Larger clinical trials are required to determine efficacy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01271335.

Inhibition of intimal hyperplasia after stenting by over-expression of p15: a member of the INK4 family of cyclin-dependent kinase inhibitors.

We evaluated the role of p15(Ink4), a member of the INK4 family of CDK inhibitors on vascular smooth muscle cells (VSMCs) proliferation, cell cycle progression and intimal hyperplasia after stenting. Aortic VSMCs transduced with either adenovirus encoding for p15(Ink4) or ß-galactosidase were assessed for DNA synthesis, cell cycle progression, and pRb phosphorylation. Rabbit carotid arteries were stented and treated with peri-adventitial delivery of saline or adenovirus encoding for p15(Ink4) or ß-galactosidase. p15(Ink4) transgene and protein expression were evaluated at 24 h and 72 h, respectively. In-stent cell proliferation was evaluated by BrdU at day 7. Histomorphometric analysis of in-stent intimal hyperplasia was performed at 10 weeks. Human p15(Ink4) DNA was detected in transduced VSMCs at 24h. p15(Ink4) over-expression reduced VSMCs DNA synthesis by 60%. Cell cycle progression was inhibited, with a 30% increase in G1 population accompanied by inhibition of pRb phosphorylation. Human p15(Ink4) transgene was identified in transduced stented arteries but not in control arteries. p15(Ink4) immunostaining was increased and cell proliferation significantly reduced by 50% in p15(Ink4) transduced arteries. Intimal cross-sectional area (CSA) of p15(Ink4)-treated group was significantly lower than the ß-gal treated and non-transduced groups (p=0.008). There were no differences in the intimal or medial inflammatory response between groups. p15(Ink4) over-expression blocks cell cycle progression leading to inhibition of VSMCs proliferation. Peri-adventitial delivery of p15(Ink4) significantly inhibits in-stent intimal hyperplasia.

Intravascular and extravascular microvessel formation in chronic total occlusions a micro-CT imaging study.

OBJECTIVES: The purpose of this study was to characterize the 3-dimensional structure of intravascular and extravascular microvessels during chronic total occlusion (CTO) maturation in a rabbit model. BACKGROUND: Intravascular microchannels are an important component of a CTO and may predict guidewire crossability. However, temporal changes in the structure and geographic localization of these microvessels are poorly understood. METHODS: A total of 39 occlusions were created in a rabbit femoral artery thrombin model. Animals were sacrificed at 2, 6, 12, and 24 weeks (n > or =8 occlusions per time point). The arteries were filled with a low viscosity radio-opaque polymer compound (Microfil) at 150 mm Hg pressure. Samples were scanned in a micro-computed tomography system to obtain high-resolution volumetric images. Analysis was performed in an image processing package that allowed for labeling of multiple materials. RESULTS: Two distinct types of microvessels were observed: circumferentially oriented "extravascular" and longitudinally oriented "intravascular" microvessels. Extravascular microvessels were evident along the entire CTO length and maximal at the 2-week time point. There was a gradual and progressive reduction in extravascular microvessels over time, with very minimal microvessels evident beyond 12 weeks. In contrast, intravascular microvessel formation was delayed, with peak vascular volume at 6 weeks, followed by modest reductions at later time points. Intravascular microvessel formation was more prominent in the body compared with that in the proximal and distal ends of the CTO. Sharply angulated connections between the intravascular and extravascular microvessels were present at all time points, but most prominent at 6 weeks. At later time points, the individual intravascular microvessels became finer and more tortuous, although the continuity of these microvessels remained constant beyond 2 weeks. CONCLUSIONS: Differences are present in the temporal and geographic patterns of intravascular and extravascular microvessel formation during CTO maturation.

Effects of distal embolization on the timing of platelet and inflammatory cell activation in interventional coronary no-reflow.

INTRODUCTION: Myocardial hypoperfusion following percutaneous coronary intervention, termed "no-reflow", may be initiated by distal coronary embolization. This study examined the effects of distal embolization on the extent and timing of inflammation and platelet activation in an experimental model of coronary no-reflow. MATERIAL AND METHODS: A no-reflow model was established in 9 Yorkshire pigs by injecting incremental doses of biologically inert polystyrene microspheres into the left anterior descending artery every 20 minutes via a transit catheter. A control group included 3 pigs that received corresponding intra-coronary boluses of normal saline. At predefined time points, coronary sinus blood samples were drawn and immediately analyzed by flow cytometry analysis for a panel of white blood cell and platelet activation markers, and the inflammatory cytokine TNFalpha. RESULTS: No-reflow was achieved after delivery of 1,169,000+/-303,000 (range: 680,000 to 2,600,000) microspheres. In the distal embolization group, there were significant increases above baseline values in polymorphonuclear-platelet aggregates (146%-218%), in monocyte-platelet aggregates (51%-94%) and in TNFalpha levels (54%-84%) at multiple time points prior to no- reflow (15% cumulative dose and higher). For Annexin A5, there was a significant increase at 52% of cumulative dose (177% above baseline). Controls only showed one significant increase above baseline value for polymorphonuclear-platelet aggregates at the time of the last injection. CONCLUSIONS: Widespread activation of interacting inflammatory and coagulation pathways following microsphere embolization occurred prior to the onset of angiographic no-reflow. This activation pattern cannot be attributed to prolonged coronary sinus instrumentation. Interactions between white blood cells (polymorphonuclears and monocytes) and platelets likely play an important role in the pathogenesis of no-reflow following distal embolization and may represent important therapeutic targets.

Visible angiographic complications predict short and long-term outcomes in patients with post-procedural creatine-phosphokinase elevation.

OBJECTIVES: To assess whether visible angiographic complication is related to outcome in patients with elevated creatine phosphokinase (CK-MB) following percutaneous coronary intervention (PCI). BACKGROUND: Elevated biomarkers following PCI are associated with increased incidence of adverse events but the absolute risk of such events is low. A more specific marker of risk is needed. METHODS: Consecutive patients with elevated post-PCI CK-MB were divided into two groups according to presence (n = 115, 43%) or absence (n = 150, 57%) of an angiographic complication. A control group (n = 250) was randomly chosen from 2,403 patients undergoing PCI during the same period without CK-MB elevation. Major adverse cardiac events (MACE) were assessed at 30 days and 1 year. RESULTS: Patients with an identifiable angiographic complication and elevated postprocedural CK-MB had significantly worse outcomes at 30 days and 1 year compared with biomarker positive patients without an identifiable complication and control patients (30 day MACE rate: 8% vs 0% vs 0.4%, respectively, p < 0.001; 1 year MACE rate: 26% vs 11% vs 11%, respectively, p = 0.002, all p-values for angiographic complication vs no angiographic complication and for angiographic complication vs control). Biomarker positive patients without identifiable angiographic complication had an excellent short and long term outcome, which was no different from biomarker negative patients (1 year MACE rate: 11% vs 11%, p = 0.53). CONCLUSION: Post-PCI patients without visible angiographic complications have an excellent short and long term outcome. These findings call into question the need for routine CK-MB monitoring after PCI in the absence of clinical symptoms or angiographic complication.

Natural history of experimental arterial chronic total occlusions.

OBJECTIVES: We sought to perform the first systematic study of the natural history of chronic total arterial occlusions (CTOs) in an experimental model. BACKGROUND: Angioplasty of CTOs has low success rates. The structural and perfusion changes during CTO maturation, which may adversely affect angioplasty outcome, have not been systematically studied. METHODS: Occlusions were created in 63 rabbit femoral arteries by thrombin injection. Histology, contrast-enhanced magnetic resonance imaging, relative blood volume (RBV) index, and micro-computed tomography imaging were analyzed at 2, 6, 12, and 18 to 24 weeks. RESULTS: Early changes were characterized by an acute inflammatory response and negative arterial remodeling, with >70% reduction of arterial cross-sectional area (CSA) from 2 to 6 weeks. Intraluminal neovascularization of the CTO occurred with a 2-fold increase in total (media + intima) microvessel CSA from 2 to 6 weeks (0.014 +/- 0.002 mm2 to 0.023 +/- 0.005 mm2, p = 0.0008) and a 3-fold increase in RBV index (5.1 +/- 1.9% to 16.9 +/- 2.7%, p = 0.0008). However at later time periods, there were significant reductions in both RBV (3.5 +/- 1.1%, p < 0.0001) and total microvessel CSA (0.017 +/- 0.002 mm2, p = 0.011). Micro-computed tomography imaging demonstrated a corkscrew-like recanalization channel at the proximal end at 6 weeks that regressed at later time points. These vascular changes were accompanied by a marked decrease in proteoglycans and accumulation of a collagen-enriched extracellular matrix, particularly at the entrance ("proximal fibrous cap"). CONCLUSIONS: This study is the first to systematically analyze compositional changes occurring during CTO maturation, which may underlie angioplasty failure. Negative remodeling, regression of intraluminal channels, and CTO perfusion, together with the accumulation of dense collagen, may represent important targets for novel therapeutic interventions.

Expansive remodeling in venous bypass grafts: novel implications for vein graft disease.

OBJECTIVE: To date, intimal hyperplasia has been regarded as the principle mechanism responsible for subsequent vein graft disease. Lumen remodeling has not been previously considered as an additional mechanism. The objectives of this study were to determine changes in lumen remodeling in arterialized vein grafts, the accompanying cellular and extracellular matrix events contributing to remodeling, and the effects of a high cholesterol diet. METHODS AND RESULTS: Reversed jugular vein-to-common carotid artery interposition grafts were constructed in 70 normocholesterolemic and 11 hypercholesterolemic male New Zealand white rabbits. The lumen area initially remained unchanged between 1 and 4 weeks but significantly increased by 40% at 12 weeks. This phase of expansive positive remodeling was accompanied by significantly increased cell apoptosis, collagen synthesis (1.7-fold), collagen content (3.7-fold), gelatinase (MMP-2 and MMP-9) levels and decreased tissue inhibitor of metalloproteinase (TIMP) levels. Expansive remodeling temporally corresponded to high macrophage infiltration and increased low density lipoprotein (LDL) retention (fourfold) in the vein grafts. A high cholesterol diet stimulated early macrophage infiltration and increased MMP-12 (metalloelastase) levels, which was associated with earlier onset of expansive remodeling. CONCLUSION: Expansive lumenal remodeling is a novel mechanism of vein graft response to the arterial circulation, which is accelerated by a high cholesterol diet.

Low-energy gamma-emitting stents inhibit intimal hyperplasia with minimal "edge effects" in a pig coronary artery model.

PURPOSE: The objective of this study was to determine the effects of different doses of gamma-emitting radioactive stents on intimal hyperplasia in a porcine coronary stent model at 28 days. METHODS: Sixty-four bare stents and those coated with palladium-103 [activities of 0 (control), 0.5, 1.0, 2.0, and 4.0 mCi] were implanted in the coronary arteries of 32 pigs. Stented segments were evaluated by histomorphometry at 28 days. RESULTS: There was significantly more intima in the 0.5- and 1-mCi stents than in controls (4.27+/-0.52 and 4.71+/-1.13 vs. 1.71+/-0.61 mm(2); P<.0001). Neointimal formation in 2-mCi stents was similar to that in controls, while that in 4-mCi stents was reduced compared to that in controls (2.34+/-1.61 and 0.82+/-0.25 vs. 1.71+/-0.61 mm(2); P=NS and P<.05, respectively). Stent margin neointimal response was representative of that within the stent body, with nonsignficant modest increases in intimal area at adjacent nonstented segments in radioactive stent groups. There was a dose-dependent increase in inflammation scores. Radioactive stents had lower intimal smooth muscle and higher fibrin scores. There was an increase in adventitial fibrosis in 1- and 2-mCi stents versus controls (1.26+/-0.99, and 2.25+/-1.27 vs. 0.21+/-0.31; P<.001). CONCLUSION: Dose-response inhibition of in-stent hyperplasia with minimal "edge effects" occurs with low-energy gamma-emitting stents. An increased inflammatory response at higher doses in palladium-103 stents indicates that later follow-up studies are necessary.

High prevalence of thrombophilia among young patients with myocardial infarction and few conventional risk factors.

BACKGROUND: Thrombophilia refers to series of acquired and inherited conditions that confer a tendency to thrombus formation. The exact relationship between thrombophilia and MI is not well established. OBJECTIVES: To determine the prevalence of thrombophilia in young patients with their first MI and few conventional risk factors. METHODS: We evaluated the baseline characteristics and the thrombophilia profile, including anti-cardiolipin antibodies, activated protein C resistance (APCR) with the factor V Leiden mutation, prothrombin G20210A mutation, protein C, protein S, and antithrombin-III levels, among 85 consecutive patients (<50 year old) who were admitted to CCU with their first MI. Patients were divided into two groups: group A-patients with < or =1 risk factor and group B-patients with > or =2 risk factors. RESULTS: 92% were male and 55% with anterior wall MI. Overall, the risk factor profile was: smoking in 60%, hyperlipidemia in 42%, positive family history in 29%, hypertension in 18%, diabetes mellitus in 13%, and obesity in 8%. Forty-seven percent of patients had < or =1 risk factor (n=40, group A) and 53% had > or =2 risk factors (n=45, group B). The prevalence of the prothrombin mutation was 15% in group A compared to 7% in group B (p=0.12). APCR secondary to a heterozygous genotype of factor V Leiden mutation was found in 20% in group A compared to 2% in group B (p<0.01). Anti-cardiolipin antibodies were found in 16% in group A compared to 22% in group B (p=ns). Finally, we have found that the likelihood of identifying at least one thrombophilia marker was 50% in group A compared to 29% in group B (p=0.046). CONCLUSIONS: The likelihood to detect at least one thrombophilia marker in young patients with MI and few conventional risk factors is significantly high. Thrombophilia may contribute to the development of MI in this specific group of young patients.

Thr325Ile polymorphism of the TAFI gene is related to TAFI antigen plasma levels and angiographic restenosis after percutaneous coronary interventions.

BACKGROUND: The fibrinolytic system is closely related to several processes that are involved in restenosis. We have previously shown that high pre-procedural plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) antigen predicted angiographic restenosis. The aims of this study were to evaluate the relationship between Thr325Ile polymorphisms, plasma levels of TAFI antigen, and late angiographic restenosis after percutaneous coronary intervention (PCI). METHODS: We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty or stenting of de novo native coronary artery lesions. Blood samples were drawn before the procedure. TAFI antigen levels were measured, as well as the presence of TAFI Ile325Thr genetic variation. Follow-up coronary angiography was performed in 90% of patients. RESULTS: The genotypes based on Ile325Thr substitution had significantly different TAFI antigen levels: genotype C/C>C/T>T/T (111+/-29%, 87+/-24%, and 59+/-22%, respectively, p<0.006). T/T genotype was associated with lower rates of restenosis compared to C/T and C/C genotypes (25% versus 37% and 33%, respectively, p<0.05). CONCLUSIONS: These data suggest that plasma TAFI antigen levels are genetically controlled. The T/T Thr325Ile polymorphism of the TAFI gene is associated with lower plasma levels of TAFI antigen and lower restenosis rates after PCI.

Pre-procedural plasma levels of C-reactive protein and interleukin-6 do not predict late coronary angiographic restenosis after elective stenting.

AIMS: Inflammatory markers may serve as an important prognostic predictor in patients with coronary heart diseases. In patients undergoing coronary interventions, it has been shown that baseline C-reactive protein (CRP) could predict late clinical restenosis. Only a few small studies have examined the possible relationship with angiographic restenosis. In patients with stable angina pectoris,we examined whether baseline CRP and IL-6 predict late coronary angiographic restenosis after stenting. METHODS AND RESULTS: Pre-procedural plasma levels of CRP and IL-6 were measured in 216 patients with stable angina pectoris undergoing elective coronary stenting. Angiographic follow-up was performed in all patients at 6 months. Baseline CRP levels were 6.15 +/- 0.78 mg/L versus 5.24 +/- 1.17 mg/L in the patent and restenosis groups, respectively (P=0.64). IL-6 levels were 0.46 +/- 0.03 ng/L versus 0.40 +/- 0.07 ng/L in the patent and restenosis groups, respectively (P=0.50). CRP levels were obtained again at the time of angiographic follow-up and were found to be similar in both groups (2.89 +/- 0.29 mg/L versus 2.61 +/- 0.63 mg/L, P=0.72). Moreover, in a sub-group of 43 patients, serial blood samples were obtained at several time points after the procedure up to 6 months. Both CRP and IL-6 plasma levels increased significantly in response to the procedure. CRP levels peaked at 3 days (11.27 +/- 1.53 mg/L versus 4.26 +/- 0.72 mg/L at baseline, P<0.0001). IL-6 levels reached maximum values after 24 h (1.08 +/- 0.14 ng/L versus 0.53 +/- 0.08 ng/L at baseline, P<0.0001). However, in this sub-group of patients, neither peak CRP nor IL-6 levels were found to predict late angiographic restenosis. CONCLUSIONS: Coronary stenting is associated with transient increases in both CRP and IL-6 levels. However, pre-procedural CRP and IL-6 levels do not predict late coronary angiographic restenosis.