Mehrdad Rezaee

Inhibition of δ-Protein Kinase C Protects Against Reperfusion Injury of the Ischemic Heart In Vivo

Background—Current treatment for acute myocardial infarction (AMI) focuses on reestablishing blood flow (reperfusion). Paradoxically, reperfusion itself may cause additional injury to the heart. We previously found that &dgr;-protein kinase C (&dgr;PKC) inhibition during simulated ischemia/reperfusion in isolated rat hearts is cardioprotective. We focus here on the role for &dgr;PKC during reperfusion only, using an in vivo porcine model of AMI. Methods and Results—An intracoronary application of a selective &dgr;PKC inhibitor to the heart at the time of reperfusion reduced infarct size, improved cardiac function, inhibited troponin T release, and reduced apoptosis. Using 31P NMR in isolated perfused mouse hearts, we found a faster recovery of ATP levels in hearts treated with the &dgr;PKC inhibitor during reperfusion only. Conclusions—Reperfusion injury after cardiac ischemia is mediated, at least in part, by &dgr;PKC activation. This study suggests that including a &dgr;PKC inhibitor at reperfusion may improve the outcome for patients with AMI.

Adjunctive Platelet Glycoprotein IIb/IIIa Receptor Inhibition With Tirofiban Before Primary Angioplasty Improves Angiographic Outcomes

Background—Previous work has suggested that platelet glycoprotein IIb/IIIa receptor blockade may confer benefit in the treatment of acute myocardial infarction. The TIGER-PA pilot trial was a single-center randomized study to evaluate the safety, feasibility, and utility of early tirofiban administration before planned primary angioplasty in patients presenting with acute myocardial infarction. Methods and Results—A total of 100 patients presenting with acute myocardial infarction were randomized to either early administration of tirofiban in the emergency room or later administration in the catheterization laboratory. The primary outcome measures were initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion (“blush”). Thirty-day major adverse cardiac events were also assessed. Angiographic outcomes demonstrate a significant improvement in initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion when patients are given tirofiban in the emergency room before primary angioplasty. The rate of 30-day major adverse cardiac events suggests that early administration may be beneficial. Conclusions—This pilot study suggests that early administration of tirofiban improves angiographic outcomes and is safe and feasible in patients undergoing primary angioplasty for acute myocardial infarction.

Simultaneous Assessment of Fractional and Coronary Flow Reserves in Cardiac Transplant Recipients Physiologic Investigation for Transplant Arteriopathy (PITA Study)

Background—The utility of measuring fractional flow reserve (FFR) to assess cardiac transplant arteriopathy has not been evaluated. Measuring coronary flow reserve (CFR) as well as FFR could add information about the microcirculation, but until recently, this has required two coronary wires. We evaluated a new method for simultaneously measuring FFR and CFR with a single wire to investigate transplant arteriopathy. Methods and Results—In 53 cases of asymptomatic cardiac transplant recipients without angiographically significant coronary disease, FFR and thermodilution-derived CFR (CFR thermo) were measured simultaneously with the same coronary pressure wire in the left anterior descending artery and compared with volumetric intravascular ultrasound (IVUS) imaging. The average FFR was 0.88±0.07; in 75% of cases, the FFR was less than the normal threshold of 0.94; and in 15% of cases, the FFR was ≤0.80, the upper boundary of the gray zone of the ischemic threshold. There was a significant inverse correlation between FFR and IVUS-derived measures of plaque burden, including percent plaque volume (r =0.55, P <0.0001). The average CFR thermo was 2.5±1.2; in 47% of cases, CFR thermo was ≤2.0. In 14%, the FFR was normal (≥0.94) and the CFR was abnormal (<2.0), suggesting predominant microcirculatory dysfunction. Conclusions—FFR correlates with IVUS findings and is abnormal in a significant proportion of asymptomatic cardiac transplant patients with normal angiograms. Simultaneous measurement of CFR with the same pressure wire, with the use of a novel coronary thermodilution technique, is feasible and adds information to the physiological evaluation of these patients.

Selective regional myocardial infiltration by the percutaneous coronary venous route: A novel technique for local drug delivery

Recent advances in the treatment of heart disease, in particular cardiovascular gene therapy and therapeutic angiogenesis, highlight the need for efficient and practical local delivery methods for the heart. We assessed the feasibility of percutaneous selective coronary venous cannulation and injection as a novel approach to local myocardial drug delivery. In anesthetized swine, the coronary sinus was cannulated percutaneously and a balloon‐tipped catheter advanced to the anterior interventricular vein (AIV) or middle cardiac vein (MCV). During balloon occlusion, venous injection of radiographic contrast caused regional infiltration of targeted myocardial regions. Complete AIV occlusion had no impact on LAD flow parameters. Videodensitometric analysis following venous injection showed that radiographic contrast persisted for at least 30 min. Selective regional myocardial infiltration is feasible by this approach, targeting selected myocardial beds, including the apex, anterior wall, septum, and inferoposterior wall. This novel technique has potential application for local myocardial drug or growth factor delivery. Cathet. Cardiovasc. Intervent. 51:358–363, 2000.

Novel percutaneous adventitial drug delivery system for regional vascular treatment

A novel intracoronary microsyringe system (MicroSyringe) was developed for regulated drug injection into the adventitial space. In this report, the feasibility, safety, and distribution pattern of vascular treatment with this modality were tested in 17 swine by delivering Oregon green‐labeled paclitaxel (OGP) and tacrolimus. Coronaries were harvested 0.5–96 hr postinjection and analyzed for drug by fluorescence histochemistry (OGP) and liquid chromatography‐mass spectrometry (tacrolimus). Histopathological analysis was subsequently performed. The microsyringe deliveries were performed safely in all cases. In the OGP‐injected group, within 2 hr postprocedure there was intense staining of the adventitia, media, and endothelium around the injection site, and by 23 hr staining extended distally by 27.5 mm. With tacrolimus, similar longitudinal drug distribution was seen; furthermore, by 48 hr there was detectable drug over 40 mm proximal and distal to the injection site. Significant levels of tacrolimus were detectable in coronaries at 96 hr. Percutaneous adventitial delivery is safe, feasible, and provides consistent dosing for complete treatment of a vascular territory. Catheter Cardiovasc Interv 2004;63:222–230.

Evaluation of high‐pressure retrograde coronary venous delivery of FGF‐2 protein

Delivery of angiogenic factors to ischemic myocardium remains a practical challenge. We evaluated the efficiency and efficacy of delivery of fibroblast growth factor‐2 (FGF‐2) protein via high‐pressure retrograde injection into the anterior interventricular vein (AIV) in a porcine model of chronic myocardial ischemia. Labeled FGF‐2 protein was delivered to the myocardium of three pigs via the AIV and the left anterior descending (LAD) coronary artery in three others. At 1 hr, the amount of protein in the left ventricle and the LAD region was quantified. Copper stents were implanted in the LAD of 25 pigs, resulting in chronic myocardial ischemia. At 4 weeks, microsphere‐derived myocardial blood flow was assessed at rest and during pacing. In eight pigs (AIV FGF), FGF‐2 protein (6 μg/kg) was delivered via high‐pressure retrograde injection into the AIV. Six pigs (intracoronary FGF) received the same amount of FGF‐2 by intracoronary delivery. Five pigs (AIV saline) received a placebo injection into the AIV and six pigs (control) served as controls. Four weeks later, myocardial blood flow was reassessed. At 1 hr, significantly more FGF remained in the left ventricle (1.3 vs. 0.82 μg; P < 0.04) and in the LAD region (1.2 vs. 0.64 μg; P = 0.03) after AIV compared to intracoronary delivery. Four weeks after treatment, resting LAD blood flow (normalized to right ventricular flow) improved slightly in the AIV FGF and intracoronary FGF arms (1.32–1.37 for both; P = 0.11), while it decreased significantly in the AIV saline (1.32–1.23; P = 0.02) and the control arms (1.32–1.19; P = 0.0004). Pacing LAD blood flow decreased significantly in the control arm (1.30–1.23; P < 0.05), but did not change significantly in the other three arms. High‐pressure retrograde injection into the AIV may represent an efficient and effective means for delivering angiogenic factors to ischemic myocardium. Catheter Cardiovasc Interv 2004;61:422–428.

Long-Term Histopathologic and IVUS Evaluations of a Novel Coiled Sheet Stent in Porcine Carotid Arteries

Carotid angioplasty with stent placement has been proposed as an alternative method for revascularization of carotid artery stenosis. A novel stent with a laser-cut, rolled sheet of Nitinol (EndoTex Interventional Systems, Inc., Cupertino, CA) has been developed to customize treatment of stenotic lesions in carotid arteries utilizing a single stent, designed to adapt to multiple diameters and to tapered or nontapered configurations. The purpose of this study is to evaluate the conformability and vascular response to a novel stent in a chronic porcine carotid model using serial three-dimensional intravascular ultrasound (IVUS) analysis as well as histological examination. Ten Yucatan pigs underwent stent implantation in both normal carotid arteries with adjunctive balloon angioplasty. Three-dimensional IVUS analysis was performed before stent implantation, after adjunctive balloon angioplasty, and at follow-up [1 month (n = 6), 3 months (n = 6), or 6 months (n = 8)]. Histological examination (injury score, percent plaque obstruction, and qualitative analysis) was also performed. All stents were successfully deployed and well apposed in different sized vessels (lumen area range: 19–30 mm2). Volumetric IVUS analysis showed no significant difference between the lumen areas before stent implantation and after adjunctive balloon angioplasty and no stent area change at each follow-up point compared to immediately postprocedure. Histological examination revealed minimal injury and neointimal hyperplasia at each follow-up point. In the chronic porcine carotid model, the novel stent system demonstrated good conformability, resulting in minimal vessel injury and neointimal formation.

Early Experience with a Novel Plaque Excision System for the Treatment of Complex Coronary Lesions

The use of directional coronary atherectomy (DCA) in current practice has been limited. The SilverHawk System is a newly developed plaque excision device that aims to overcome the drawbacks of prior DCA platforms. The device was evaluated in a porcine coronary model and in a series of patients. Procedural variables along with outcomes were reviewed. Quantitative angiography (QCA) was performed and excised tissue fragments were weighed and examined histologically. In porcine cases, pretreatment MLD increased from 0.51 ± 0.26 to 2.36 ± 0.59 mm postdebulking and 19.9 ± 7.6 mg of tissue was retrieved. In human cases, pretreatment MLD increased from 0.8 ± 0.4 to 2.2 ± 0.5 mm postdebulking and 15.2 ± 7.8 mg of tissue was retrieved without complications. These data show that the SilverHawk System may offer significant utility in treating a wide variety of complex coronary lesions. Catheter Cardiovasc Interv 2004;61:35–43.

Percutaneous Endocardial Versus Selective Coronary Venous Cellular Delivery: Comparisons of Transplant Efficiency, Distribution, and Efficacy in Reducing Infarct Size and Improving Myocardial Function

1176-174 Citation: Supplement to Journal of the American College of Cardiology, March 19, 2003, Vol. 41, Issue 6, Suppl. A Percutaneous Endocardial Versus Selective Coronary Venous Cellular Delivery: Comparisons of Transplant Efficiency, Distribution, and Efficacy in Reducing Infarct Size and Improving Myocardial Function Erik T. Price, Fumiaki Ikeno, Ralph C. Fenn, Pauline Chu, Jennifer K. Lyons, Peter J. Fitzgerald, Alan C. Yeung, Paul G. Yock, Mehrdad Rezaee Stanford University Medical Center, Stanford, CA Background: Cellular transplantation is an emerging option for the treatment of ischemic cardiomyopathy. Percutaneous endocardial delivery (PED) and percutaneous coronary venous delivery (PCVD) offer potential advantages in safety, transplant efficiency, and targeted distribution for preservation of myocardium. Methods: A total of 22 swine were studied: 6 PED and 4 PCVD for acute feasibility arm; and 4 PED, 4 PCVD, and 4 combined controls for chronic efficacy arm (LAD infarct by balloon occlusion). Porcine fibroblasts labeled with iron nano-particles were used for transplantation. Between 2-2.5x106cells were injected into the infarct area either by PED using a BioCardia(tm) helical infusion catheter, or by PCVD using a single high-pressure (100-200 mmHg) injection through a balloon-tipped catheter in the anterior interventricular vein (AIV). Ejection fraction (EF) was measured at infarct induction (day 0), cell delivery (day 7), and sacrifice (day 28). Horizontal cross-sections of the left ventricle were stained with tetrazolium for infarct size, then with H&E and Prussian Blue for cell identification. A linear computational model was used to estimate transplant efficiency. Results: Acute studies demonstrated safe, targeted transplantation using both modalities. In infarcted animals, PED and PCVD resulted in 17.3 ± 24.3% and 15.7 ± 11.6% of fibroblasts identified after 21 days. PED resulted in 98.4% of cells in the anteroseptal walls, with 95.8% localized to the endocardial half, at an average depth of 3.4 ± 3.9 mm. PCVD resulted in 97.6% of cells in the anteroseptal walls, a radial 21.8 ± 7.9 mm from the AIV, with 60.1% localized to the endocardial half. With both modalities >96.0% of cells were within 5 mm of the infarct zone. Both PED and PCVD trended in reduced infarct size compared to the controls (3.9 ± 1.6 and 7.9 ± 6.0, vs. 13.9 ± 10.8, p=0.12 and p=0.37 respectively), and improved EF (26.0 ± 3.2 and 26.8 ± 12.6 vs. 17.0 ± 9.8, p=0.13 and p=0.27 respectively). Conclusions: PED and PCVD provide comparable efficiency and targeted distribution. As anticipated, PCVD provides regional delivery, and PED a more local distribution. Studies are underway to further establish the efficacy of both modalities.

Initial experience with the novel 6 Fr-compatible system for debulking de novo coronary arterial lesions

The purpose of this study was to determine the efficacy of a novel system for debulking of de novo native coronary arterial lesions. The Helixciser De Novo system is a novel 6 Fr‐compatible catheter with a cutter encased in a slotted‐orifice housing to excise atheromatous plaque. The cutter rotates at 15,000 rpm, debulking the plaque as it tracks through the lesion over a straight wire or a self‐expanding nitinol helical‐shaped wire. The tissue is aspirated via an Archimedes screw pump to vacuum collection chamber. The device was evaluated in a porcine toxic coronary stent model of chronic occlusion and in five patients with focal de novo native coronary arterial lesions. Procedural variables along with outcomes were reviewed. Quantitative angiography (QCA) and volumetric intravascular ultrasound (IVUS) analysis were performed. In a porcine model of chronic occlusion, QCA demonstrated pretreatment minimal lumen diameter (MLD) increased from 0.77 ± 0.59 to 1.88 ± 0.25 mm postdebulking. IVUS analysis demonstrated pretreatment lumen volume (LV) increased from 15.8 ± 22.2 to 46.4 ± 28.9 mm3 postdebulking. In human clinical feasibility cases, QCA demonstrated pretreatment MLD increased from 0.96 ± 0.40 to 2.04 ± 0.19 mm postdebulking. IVUS analysis demonstrated pretreatment LV increased from 38.40 ± 12.78 to 52.05 ± 15.68 mm3 postdebulking. Preliminary results document the feasibility of Helixcision De Novo for treatment of focal de novo native coronary arterial lesions. Quantitative angiographic and IVUS analysis indicate that this system can effectively debulk plaque from selected noncalcified atherosclerotic lesions and thus may represent an alternative treatment strategy for coronary artery disease. Catheter Cardiovasc Interv 2004;62:308–317.