John D. Sparkes

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.

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.

Collagenase Plaque Digestion for Facilitating Guide Wire Crossing in Chronic Total Occlusions

Background—Chronic total occlusions (CTOs) are associated with significant angina, impaired left ventricular function, and worse long-term outcomes. Percutaneous coronary interventions in CTO are unsuccessful in up to 50% of cases, primarily because of inability to cross the lesion with a guide wire. Collagen is the predominant component of the atherosclerotic plaque. The objective of this study was to determine the efficacy and toxicity of local delivery of a collagen-degrading enzyme to facilitate guide wire crossing in CTO. Methods and Results—Type IA collagenase (100 or 450 &mgr;g) or placebo was locally administered to 45 CTOs in a rabbit femoral artery model. Mean occlusion duration was 16±5 weeks. Attempts to cross the CTO (mean length, 28±9 mm) with conventional guide wires were assessed at 72 hours after treatment. An additional 3 arteries per group were assessed for collagenase effects at 24 hours after treatment. Successful guide wire crossings were significantly higher in collagenase-treated arteries (13 of 21, 62%) than in placebo-treated arteries (7 of 24, 29%) (P =0.028). No adverse effects on arterial structure were observed in collagenase-treated arteries. At 24 hours, collagenase-treated arteries demonstrated increased collagenase protein, gelatinase activity, and collagen fragments. Conclusions—Local delivery of collagenase can safely facilitate guide wire crossing of CTO. This novel approach could lead to higher percutaneous coronary intervention success rates in CTO.

Thrombin-activatable fibrinolysis inhibitor (TAFI): a novel predictor of angiographic coronary restenosis

The fibrinolytic system is closely related to several processes that are involved in restenosis. We previously showed that low PAI-1 plasma levels predicted restenosis. Recently, a different fibrinolytic inhibitor, TAFI, has been described. The aims of this study were to evaluate the relationship between pre-procedural plasma levels of TAFI and late angiographic restenosis and the interaction between TAFI and PAI-1.We prospectively studied 159 patients with stable angina who underwent successful elective angioplasty or stenting of de novo native coronary artery lesions. TAFI and PAI-1 antigen levels were measured in plasma samples drawn before the procedure. Follow-up coronary angiography was performed in 92% of patients. There was a significant correlation between pre-procedural TAFI levels and 6-month % diameter stenosis (DS) (r = 0.21; p = 0.013). The overall angiographic restenosis rate (DS>50%) was 31%. Pre-procedural TAFI levels were significantly higher in patients with restenosis (108 +/- 33% versus 94+/-30%, p = 0.011). Restenosis rates for patients in the upper tertile of TAFI levels were 2-fold higher than for those in the lowest tertile (45% versus 22%; p = 0.016). A combination of high TAFI and low PAI-1 levels identified patients at the highest risk of restenosis (53%) compared to 14% in patients with low TAFI and high PAI-1 levels; p = 0.027. In conclusion, pre-procedural plasma TAFI antigen levels identify patients at increased risk for restenosis after PCI.

The role of oxidized phospholipids, lipoprotein (a) and biomarkers of oxidized lipoproteins in chronically occluded coronary arteries in sudden cardiac death and following successful percutaneous revascularization

AIMS OxPL are pro-inflammatory and may mediate atherogenesis, thrombosis and endothelial dysfunction. We studied the histological presence and temporal increases in oxidized phospholipids on apolipoprotein B-100 particles (OxPL/apoB), lipoprotein (a) [Lp(a)] and biomarkers of oxidized lipoproteins in subjects with chronic total coronary occlusions (CTO) with sudden cardiac death (SCD) and following percutaneous coronary intervention (PCI). METHODS Eight subjects with SCD and CTO and 33 patients with successful PCI of CTO were included. Blood samples were drawn before PCI, immediately post-PCI, at 6 and 24 h, at 3 days and at 1 week. Plasma levels of OxPL/apoB, Lp(a), IgG and IgM autoantibodies to malondialdehyde (MDA) low-density lipoprotein and apoB-immune complexes were measured in all samples and compared with previous data from 141 patients undergoing PCI of non-CTO vessels. RESULTS Immunohistochemistry of coronary CTOs revealed OxPL and MDA-like epitopes, particularly in areas of recanalized and organized thrombus and neovascularization. Following PCI, OxPL/apoB and Lp(a) levels, expressed as percent change from baseline levels before PCI, rose gradually and progressively over the next 7 days. In contrast, levels of OxPL/apoB and Lp(a) in non-CTO vessels rose immediately post PCI and then dropped rapidly to baseline within 24 h. CONCLUSIONS CTOs contain immunohistological evidence of OxPL and MDA-like epitopes. Successful PCI of CTOs results in a slower increase in OxPL/apoB and Lp(a) but higher increase in IgM immune complexes compared to non-CTO vessels. Pro-inflammatory oxidation-specific epitopes may impact development of CTOs and affect outcomes following PCI that can be evaluated in larger clinical trials.

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 &mgr;g. 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.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: . Unique identifier: [NCT01271335][1]. # Clinical Perspective {#article-title-25} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01271335&atom=%2Fcirculationaha%2F125%2F3%2F522.atom

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.

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.

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.