Azriel B. Osherov

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.

Incidence of early left ventricular thrombus after acute anterior wall myocardial infarction in the primary coronary intervention era

BACKGROUND Rapid reperfusion has been shown to decrease mortality and improve left ventricular (LV) function. Previous studies have reported that LV thrombus (LVT) is a major complication of ST-segment elevation acute anterior wall myocardial infarction (AMI). There are little data on LVT in the current primary percutaneous coronary intervention (PPCI) era. We sought to demonstrate the incidence of LVT after AMI in patients treated with PPCI compared with those treated with thrombolysis or with conservative management. METHODS In a 6-year period, 642 patients with anterior wall AMI and echocardiography were treated with PPCI (n = 297), thrombolysis (n = 128), or conservative treatment (n = 217). Left ventricular thrombus was defined as an echodense mass adjacent to an abnormally contracting myocardial segment. RESULTS The rate of LVT among anterior wall AMI was 6.2%. Predictors for LVT were reduced ejection fraction (adjusted relative risk 0.71, 95% CI 0.52-0.96) and severe mitral regurgitation (adjusted relative risk 2.48, 95% CI 1.0-6.44). There was no statistical difference in LVT rate according to treatment: 21 (7.1%) of 297 patients in the PPCI group, 10 (7.8%) of 128 patients in the thrombolytic group, and 9 (4.1%) of 217 patients in the conservative group (P = .28). Those in the thrombolytic group were characterized by shorter duration from symptom onset and were generally also treated with heparin/low-molecular weight heparin. CONCLUSIONS This is the largest report to evaluate the incidence of LVT formation after AMI. In the current era of rapid reperfusion by PPCI, the rate of thrombus formation is similar to that reported in the past and not different than for patients currently treated conservatively or with thrombolysis.

Proteins mediating collagen biosynthesis and accumulation in arterial repair: novel targets for anti-restenosis therapy

Events contributing to restenosis after coronary interventions include platelet aggregation, inflammatory cell infiltration, growth factor release, and accumulation of smooth muscle cells (SMCs) and extracellular matrix (ECM). The ECM is composed of various collagen subtypes and proteoglycans and over time constitutes the major component of the mature restenotic plaque. The pathophysiology of collagen accumulation in the ECM during arterial restenosis is reviewed. Factors regulating collagen synthesis and degradation, including various cytokines and growth factors involved in the process, may be targets for therapies aimed at prevention of in-stent restenosis.

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.

A perlecan-inducing compound significantly inhibits smooth muscle cell function and in-stent intimal hyperplasia: novel insights into the diverse biological effects of perlecan.

AIMS Perlecan is the major heparan sulfate proteoglycan in the arterial wall. Previous studies have suggested that perlecan is a potent inhibitor of smooth muscle cell (SMC) activity. Therefore, perlecan overexpression may serve as a therapeutic modality to prevent in-stent restenosis (ISR). We have investigated a novel compound (RUS3108), identified in a SMC based screen to induce perlecan synthesis in SMC. The aims of this study were to assess the in vitro effects of RUS3108 and the effects of RUS3108-eluting stents in preventing ISR. METHODS AND RESULTS Rabbit aortic SMC and bovine aortic endothelial cells (EC) were used in this study. Immunohistochemistry showed that RUS3108-treated SMC over-expressed perlecan indicating the drug effects. Furthermore, RUS3108 induced a SMC differentiated phenotype by SMembryonic staining. RUS3108 (1 microM) inhibited 3H-thymidine incorporation by >50%, which was completely reversed by a perlecan antibody. RUS3108 also inhibited SMC migration (Boyden chamber) and MMP-9 activity. In contrast, RUS3108 (100nM) modestly stimulated EC 3H-thymidine incorporation by 22% (p<0.02). In vivo, a total of 30 stents were deployed in rabbit iliac arteries as follows: 1) bare metal stents (n=10), 2) polymer onlycoated stents (n=10), and 3) polymer-coated stents containing RUS3108 (n=10). Rabbits were sacrificed at four weeks and stented segments were subjected to morphometric analysis. Intimal cross sectional area was significantly lower in the RUS3108-eluting stent group (0.31+ or -0.27 mm(2) versus 1.0 + or - 0.31 and 1.25 + or - 0.51 in the bare metal stents and polymer only coated stents groups, respectively, p<0.0001). CONCLUSIONS RUS3108 is a novel perlecan-inducing compound, which is a potent inhibitor of SMC activity and a modest stimulator of EC proliferation. RUS3108-eluting stents may serve as an excellent modality for the prevention of ISR.

Perlecan Heparan Sulfate Proteoglycan Is a Critical Determinant of Angiogenesis in Response to Mouse Hind-Limb Ischemia

BACKGROUND Perlecan is a heparan sulfate proteoglycan (HSPG) constituent of the extracellular matrix with roles in cell growth, differentiation, and angiogenesis. The role of the HS side chains in regulating in vivo angiogenesis after hind-limb ischemia is unknown. METHODS Heparan sulfate (HS)-deficient perlecan (Hspg2(Δ3/Δ3)) mice (n = 35), containing normal perlecan core protein but deficient in HS side chains, and wild-type (n = 33) littermates underwent surgical induction of hind-limb ischemia. Laser Doppler perfusion imaging (LDPI) and contrast-enhanced ultrasonography (CEU) provided serial assessment of hind-limb perfusion. Harvested muscles underwent immunostaining for endothelial cell density (CD31), real-time reverse transcription polymerase chain reaction RT-PCR for vascular endothelial growth factor (VEGF) mRNA expression and western blot analysis for VEGF and fibroblast growth factor (FGF)2 protein expression at days 2 and 28. RESULTS Serial LDPI showed significantly greater perfusion recovery in ischemic limbs of wild-type compared with Hspg2(Δ3/Δ3) mice. CEU showed that normalized microvascular perfusion was increased in wild-type compared with Hspg2(Δ3/Δ3) mice at day 28 (0.67 ± 0.12 vs 0.26 ± 0.08; P = 0.001). CD31-positive cell counts were significantly higher in wild-type compared with Hspg2(Δ3/Δ3) mice on day 28 (122 ± 30 cells vs 84 ± 34 cells per high-power field [HPF]; P < 0.05). Endogenous VEGF mRNA expression (P < 0.05) and VEGF protein expression (P < 0.002) were significantly decreased in the ischemic limbs of Hspg2(Δ3/Δ3) mice compared with wild-type mice at day 2 and day 28, respectively. FGF2 protein expression showed no significant differences. CONCLUSIONS These results suggest that the HS side chains in perlecan are important mediators of the angiogenic response to ischemia through a mechanism that involves upregulation of VEGF expression.

A novel lead attenuator to reduce operator exposure to scattered radiation in transradial coronary procedures.

Introduction The harmful effects of radiation were soon recognised after the discovery of x-rays by Wilhelm Roentgen in 18951. Increased incidences of skin cancer and leukemia confirmed the carcinogenic potential of x-rays in the early twentieth century2. Interventional cardiologists experience frequent radiation exposure through fluoroscopy. Interventional cardiology procedures performed via the radial approach are associated with longer fluoroscopy times and greater cumulative scatter radiation to the operator and staff 3. This approach is gaining popularity and exceeds 90% of cases in dedicated centres4. The cumulative risk associated with a lifetime of exposure could become significant5,6. The lower torso (from the umbilicus and down) acts as a source of scatter radiation to the operator and is not routinely shielded. We developed a uniquely designed, non-disposable lead attenuating material that could shield this region and significantly reduce the radiation scatter exposure to an operator in the catheterisation laboratory.

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.

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 β-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 β-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 β-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.