Faculty Bibliography

INTRODUCTION/BACKGROUND:Limited data are available on contemporary percutaneous coronary intervention (PCI) practice patterns and outcomes in elderly patients. The objective of this study was to evaluate "real-world" PCI in elderly and nonelderly patients during the first year of availability of drug-eluting stents (DES) in the United States market (May 1, 2003-April 30, 2004). METHODS:One thousand one hundred sixty-six consecutive patients (272 elderly [age > or =75 years] and 894 nonelderly [age <75 years]) having PCI for de novo coronary artery disease (CAD) at Dartmouth-Hitchcock Medical Center were included in this study. Primary outcome measures of this study were in-hospital major adverse cardiac events (MACE-death, new MI, urgent revascularization). Secondary end points included acute renal failure, respiratory failure, and vascular complications. RESULTS:Elderly patients had higher MACE (8.5% vs 1.5%, P < or = 0.001), unadjusted in-hospital mortality (7.4% vs 0.8%, P < or = 0.001), in-hospital cardiac arrest (1.5% vs 0.3%, P = 0.03), requirements for assisted blood pressure support (13.2% vs 7.0%, P = 0.0001), respiratory failure (2.2% vs 0.9%, P = 0.08), acute renal failure (2.9% vs 0.8%, P = 0.005), and vascular complications (10.3% vs 5.5%, P = 0.005) than their nonelderly counterparts. Higher MACE rates persisted in the elderly despite correction for baseline differences using multivariate regression modeling. CONCLUSIONS:Advanced age remains a predictor of adverse outcomes attending PCI even in the contemporary era in which DES are available. This study highlights the need for further progress and investigation to optimize outcomes of PCI in the elderly.

OBJECTIVES/OBJECTIVE:The purpose of this study is to provide insights into percutaneous coronary intervention (PCI) performed in women in the United States by evaluating gender-based PCI-practice patterns and outcomes. BACKGROUND:Limited "real world" contemporary data exist on how the introduction of DES has impacted PCI in women. METHODS AND RESULTS/RESULTS:Patients (359 women, 807 men) with de novo coronary artery disease having PCI (1,166) were evaluated during the first year, since the introduction of DES in the United States market (May 1, 2003 to April 30, 2004). Women were more likely to be older, hypertensive, obese, diabetic, and have heart failure. Men were more likely to be smokers and have more vessels with obstructive coronary artery disease. PCI procedural success rates, number of vessels attempted, percentage DES utilization, and in-hospital major adverse cardiac events (MACE; death, new myocardial infarction, urgent revascularization) were similar for both genders. However, women had significantly higher unadjusted mortality (3.9% versus 1.6%, P = 0.01), cumulative vascular complications (12.0% versus 4.2%, P < 0.0001), and renal failure (2.5% versus 0.7%, P = 0.01). After adjustment for confounding variables, mortality was similar between genders, but a significant association with vascular complications and trend toward higher rates of renal failure persisted in women. CONCLUSIONS:In this study of the modern era of PCI with DES utilization, in-hospital MACE is similar between men and women. However, the differences in baseline comorbidities and the proclivity for vascular and renal complications highlight the need for further investigation and improvements to optimize outcomes of PCI in women.

Limited published data exist about how the introduction of drug-eluting stents (DESs) has affected the technical aspects of percutaneous coronary intervention and in-hospital patient outcomes in clinical practice. A total of 2,215 consecutive patients who underwent percutaneous coronary intervention for de novo coronary artery disease were divided into 2 cohorts: the pre-DES era (May 1, 2002 to April 30, 2003) and the DES era (May 1, 2003 to April 30, 2004). The procedural success rates (94.9% vs 96.4%, respectively; p = 0.075) and the in-hospital major adverse events (6.4% vs 5.7%, respectively; p = 0.53) were similar between the pre-DES and DES eras. The DES percentage of use increased from 49.5% in the first quarter to 84.1% in the final quarter of the first year after the introduction of this technology (p <0.0001). The results of our study have shown that despite more complex percutaneous coronary intervention procedures with tendencies for more complete lesion coverage and anatomic revascularization, the procedural success and in-hospital outcomes have been comparable since the introduction of DESs.

BACKGROUND:The potential for cellular cardiomyoplasty to provide functional left ventricular recovery in the chronically injured heart remains unclear. METHODS:Yorkshire swine (n = 10; 35-50 kg) had anterolateral myocardial infarction (MI) induced by coil embolization of the left anterior descending artery. Approximately 5 weeks post-MI, a composite, intravascular ultrasound-guided catheter system (TransAccess) was used to deliver an autologous, labeled, bone marrow-derived cell sub-population (approximately 3 x 10(8) cells) or saline control (approximately 50 injections/arm) through coronary veins directly into infarct and peri-infarct myocardium. Two months post-transplant, the animals had blinded endocardial and epicardial left ventricular electrical scar mapping and biventricular electrical stimulation. Coronary angiography and quantitative biplane ventriculography were performed at baseline, transplant, and sacrifice time-points. RESULTS:Robust, viable, predominantly desmin-negative cell grafts were demonstrated post-mortem in all treatment animals. Baseline and pre-transplant global and regional wall motion was similar between groups. The cell treatment group demonstrated functional recovery with a left ventricular ejection fraction of 38.1% at the time of transplant increasing to 48.5% (p = 0.005) at sacrifice, whereas the control arm was unchanged (38.0% vs 34.3%, respectively; p = NS). The regional improvement corresponded with a reduction in percentage of hypokinetic (52.1%-42.9%, p = 0.002) and percentage of akinetic (24.8%-17.7%, p = 0.04) segments in the cell-treated animals. Epicardial scar area was not different (37 cm2 vs 23 cm2, p = 0.37) between groups. CONCLUSIONS:Percutaneous, transvascular, direct intramyocardial bone marrow cell transplantation is safe and feasible in chronically infarcted tissue. In this pilot study, cell therapy improved overall left ventricular systolic function by recruiting previously hypokinetic or akinetic myocardial tissue.

Local delivery of therapeutic agents into the myocardium is limited by suboptimal imaging. We evaluated the feasibility and accuracy of live 3D echo to guide left ventricular endomyocardial injection. An intramyocardial injection catheter was positioned in the left ventricle in five healthy Yorkshire pigs using fluoroscopy. All other catheter manipulations were performed with live biplane and 3D echo guidance. In each animal, a total of 12 endomyocardial injections (volume, 50-100 microl) of echo contrast mixed with blue tissue dye were performed. Four injections, 10 mm apart, were directed to three myocardial target zones: the anterior septum at the mitral valve level (zone 1); the posterolateral wall between the heads of the papillary muscles (zone 2); and the apex (zone 3). The injections were aimed to form a transverse line in zones 1 and 2 and an inverted triangular pyramid in zone 3. The animals were sacrificed, the hearts were inspected and the left ventricular endocardium was examined to create a map of injection marks. Success, defined as a visible injection of tissue dye, was 95%, and accuracy, defined as an injection into the target zone, was 83%. There was no significant difference in accuracy between the zones. Live 3D echo can successfully guide endomyocardial injections by accurately targeting specific myocardial zones, verifying catheter apposition and, when combined with echo contrast, providing real-time visualization of injectate deposition.

Bone marrow cells (BMC) labeled with iron particles can be injected into the heart and detected with MRI. Improvement in conspicuity of labelled cells would be advantageous. This study examined if double contrast with iron oxide and Gd-DTPA enhances cell MRI after transvascular transplantation in myocardial infarction. Ten pigs with week-old myocardial infarction had transvascular peri-infarct delivery of microspheres alone (Group I, n = 3) or mixed with iron-labeled BMCs (Group II, n = 7). Gradient-echo MRI before and 1 min after systemic Gd-DTPA administration produced regions of interest with hypoenhancement that were compared to contralateral regions for contrast-to-noise (CNR) and signal-to-noise (SNR) ratios. All hearts were harvested for gross and microscopic analysis. Areas of focal hypoenhancement corresponding to the BMCs were detected in the myocardium in Group II. Early after administration of Gd-DTPA CNR increased from 17.58 +/- 8.5 to 27.25 +/- 15.8 (P < 0.05) and SNR from 24.87 +/- 9.6 to 35.08 +/- 15.5 (P < 0.05). There was no hypoenhancement in Group I. Tissue examination confirmed presence of iron-containing cells and microspheres in corresponding segments of the heart. The distribution of microspheres was similar between the groups. Double contrast with cellular iron and Gd-DTPA in surrounding myocardium resulted in improved cell localization by MRI.

OBJECTIVES/OBJECTIVE:The study evaluated a nonsurgical means of intramyocardial cell introduction using the coronary venous system for direct myocardial access and cell delivery. BACKGROUND:Direct myocardial cell repopulation has been proposed as a potential method to treat heart failure. METHODS:We harvested bone marrow from Yorkshire swine (n = 6; 50 to 60 kg), selected culture-flask adherent cells, labeled them with the gene for green fluorescence protein, expanded them in culture, and resuspended them in a collagen hydrogel. Working through the coronary sinus, a specialized catheter system was easily delivered to the anterior interventricular coronary vein. The composite catheter system (TransAccess) incorporates a phased-array ultrasound tip for guidance and a sheathed, extendable nitinol needle for transvascular myocardial access. A microinfusion (IntraLume) catheter was advanced through the needle, deep into remote myocardium, and the autologous cell-hydrogel suspension was injected into normal heart. Animals were sacrificed at days 0 (n = 2), 14 (n = 1, + 1 control/collagen biogel only), and 28 (n = 2), and the hearts were excised and examined. RESULTS:We gained widespread intramyocardial access to the anterior, lateral, septal, apical, and inferior walls from the anterior interventicular coronary vein. No death, cardiac tamponade, ventricular arrhythmia, or other procedural complications occurred. Gross inspection demonstrated no evidence of myocardial perforation, and biogel/black tissue dye was well localized to sites corresponding to fluoroscopic landmarks for delivery. Histologic analysis demonstrated needle and microcatheter tracts and accurate cell-biogel delivery. CONCLUSIONS:Percutaneous intramyocardial access is safe and feasible by a transvenous approach through the coronary venous system. The swine offers an opportunity to refine approaches used for cellular cardiomyoplasty.

Optimization of cell seeding and culturing is an important step for the successful tissue engineering of vascular conduits. We evaluated the effectiveness of using a hybridization oven for rotational seeding and culturing of ovine vascular myofibroblasts onto biodegradable polymer scaffolds suitable for replacement of small- and large-diameter blood vessels. Large tubes (12 mm internal diameter and 60 mm length, n = 4) and small tubes (5 mm internal diameter and 20 mm length, n = 4) were made from a combination of polyglycolic acid/poly-4-hydroxybutyrate and coated with collagen solution. Tubes were then placed in culture vessels containing a vascular myofibroblast suspension (10(6) cells/cm(2)) and rotated at 5 rpm in a hybridization oven at 37 degrees C. Light and scanning electron microscopy analyses were performed after 5, 7, and 10 days. Myofibroblasts had formed confluent layers over the outer and inner surfaces of both large and small tubular scaffolds by day 5. Cells had aligned in the direction of flow by day 7. Multiple spindle-shaped cells were observed infiltrating the polymer mesh. Cell density increased between day 5 and day 10. All conduits maintained their tubular shape throughout the experiment. We conclude that dynamic rotational seeding and culturing in a hybridization oven is an easy, effective, and reliable method to deliver and culture vascular myofibroblasts onto tubular polymer scaffolds.

Exposure of vascular cell-seeded, tubular, biodegradable polymers to pulsatile flow conditions has been proposed as a method to develop tissue-engineered blood vessels by "maturing" structural integrity, and increasing collagen content, suture retention, burst pressure, and tissue formation. These in vitro tissue-engineered arteries demonstrate contractile responses to pharmacologic agents and express markers of vascular differentiation. Current methods to induce pulsatile flow in a bioreactor system are limited by the creation of nonphysiologic pressure waveforms and noncompliant reservoirs to house the tissue-engineered vascular constructs. We have developed a novel method for the in vitro development of tubular vascular structures by using a mechanical ventilator to induce pulsatile, laminar flow into a fluid column, resulting in pressurized waveforms similar to mammalian physiology. The vascular constructs are housed in semicompliant tubing to facilitate an additional variable of circumferential stretch as a potential signaling mechanism. This approach more closely approximates mammalian physiology and we hypothesize that it will facilitate mechanical signaling necessary for the development of tissue-engineered vessels for clinical applications.