Increased Coronary Artery Plaque Volume Among Male Marathon Runners.

BACKGROUND: Long-term marathon running improves many cardiovascular risk factors, and is presumed to protect against coronary artery plaque formation. This hypothesis, that long-term marathon running is protective against coronary atherosclerosis, was tested by quantitatively assessing coronary artery plaque using high resolution coronary computed tomographic angiography (CCTA) in veteran marathon runners compared to sedentary control subjects. METHODS: Men in the study completed at least one marathon yearly for 25 consecutive years. All study subjects underwent CCTA, 12-lead electrocardiogram, measurement of blood pressure, heart rate, and lipid panel. A sedentary matched group was derived from a contemporaneous CCTA database of asymptomatic healthy individuals. CCTAs were analyzed using validated plaque characterization software. RESULTS: Male marathon runners (n = 50) as compared with sedentary male controls (n = 23) had increased total plaque volume (200 vs. 126 mm3, p < 0.01), calcified plaque volume (84 vs. 44 mm3, p < 0.0001), and non-calcified plaque volume (116 vs. 82 mm3, p = 0.04). Lesion area and length, number of lesions per subject, and diameter stenosis did not reach statistical significance. CONCLUSION: Long-term male marathon runners may have paradoxically increased coronary artery plaque volume.

Long-Term Marathon Running Is Associated with Low Coronary Plaque Formation in Women.

INTRODUCTION: Marathon running is presumed to improve cardiovascular risk, but health benefits of high volume running are unknown. High-resolution coronary computed tomography angiography and cardiac risk factor assessment were completed in women with long-term marathon running histories to compare to sedentary women with similar risk factors. METHODS: Women who had run at least one marathon per year for 10-25 yr underwent coronary computed tomography angiography, 12-lead ECG, blood pressure and heart rate measurement, lipid panel, and a demographic/health risk factor survey. Sedentary matched controls were derived from a contemporaneous clinical study database. CT scans were analyzed for calcified and noncalcified plaque prevalence, volume, stenosis severity, and calcium score. RESULTS: Women marathon runners (n = 26), age 42-82 yr, with combined 1217 marathons (average 47) exhibited significantly lower coronary plaque prevalence and less calcific plaque volume. The marathon runners also had less risk factors (smoking, hypertension, and hyperlipidemia); significantly lower resting heart rate, body weight, body mass index, and triglyceride levels; and higher high-density lipoprotein cholesterol levels compared with controls (n = 28). The five women runners with coronary plaque had run marathons for more years and were on average 12 yr older (65 vs 53) than the runners without plaque. CONCLUSION: Women marathon runners had minimal coronary artery calcium counts, lower coronary artery plaque prevalence, and less calcified plaque volume compared with sedentary women. Developing coronary artery plaque in long-term women marathon runners appears related to older age and more cardiac risk factors, although the runners with coronary artery plaque had accumulated significantly more years running marathons.

Coronary in-stent restenosis: current status and future strategies.

In-stent restenosis (ISR) is a novel pathobiologic process, histologically distinct from restenosis after balloon angioplasty and comprised largely of neointima formation. As percutaneous coronary intervention increasingly involves the use of stents, ISR is also becoming correspondingly more frequent. In this review, we examine the available studies of the histology and pathogenesis of ISR, with particular reference to porcine and other animal models. An overview of mechanical treatments is then provided, which includes PTCA, directional coronary atherectomy and high speed rotational atherectomy. Radiation-based therapies are discussed, including a summary of current problems associated with this modality of treatment. Finally, novel strategies for the prevention of ISR are addressed, including novel developments in stents and stent coatings, conventional drugs, nucleic acid-based drugs and gene transfer. Until recently, limited pharmacologic and mechanical treatment options have been available for both treatment and prevention of ISR. However, recent advances in gene modification and gene transfer therapies and, more particularly, in local stent-based drug delivery systems make it conceivable that the incidence of ISR will now be seriously challenged.

Percutaneous transvenous cellular cardiomyoplasty. A novel nonsurgical approach for myocardial cell transplantation.

OBJECTIVES: 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.

Do transmyocardial and percutaneous laser revascularization induce silent ischemia? An assessment by exercise testing.

BACKGROUND: Transmyocardial and percutaneous laser revascularization (TMR, PTMR) may reduce angina and increase exercise tolerance in otherwise untreatable angina patients, although the mechanism is unknown and the placebo effect may be significant. One other proposed mechanism is cardiac denervation leading to silent ischemia. METHODS: Electrocardiograms obtained during symptom-limited exercise (ETT, modified Bruce protocol) at baseline and 12 months were analyzed (blinded core laboratory) from 182 patients randomized to TMR (n = 92) or medical therapy alone (MED(TMR), n = 90) and 219 patients randomized to PTMR (n = 109) or medical therapy alone (MED(PTMR), n = 110). RESULTS: Exercise duration increased 1 year after TMR or PTMR relative to medically treated patients (6.8 +/- 3.4 min vs 8.6 +/- 3.5 min for TMR; 7.3 +/- 3.1 min vs 9.1 +/- 3.6 min for PTMR, P <.05). At baseline, 20% of TMR and MED(TMR) subjects had ST depression >1.0 mm, >80% had angina during exercise, but only 3% had ST changes without chest pain (silent ischemia). This did not change after TMR. In the PTMR group, more subjects exercised to >1.0 mm ST depression (from 17% to 34%, P <.05), with no change in MED(PTMR), but the proportion with silent ischemia did not change in either group. CONCLUSION: Exercise tolerance improved after TMR and after PTMR. Relative to PTMR, TMR more effectively suppressed pain during exercise and ischemic ST depression. However, neither TMR nor PTMR induced significant silent ischemia. These results suggest that denervation may not be a significant factor contributing to angina relief after these procedures. The contribution of the placebo effect was not determined by these results.

A novel pulsatile, laminar flow bioreactor for the development of tissue-engineered vascular structures.

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.

Dynamic rotational seeding and cell culture system for vascular tube formation.

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.

Transmyocardial laser revascularization: a review of basic and clinical aspects.

Transmyocardial laser revascularization (TMR or TMLR) is a surgical therapy developed to treat patients with debilitating, medically refractory angina pectoris due to epicardial coronary artery disease that is not amenable to treatment using the traditional methods of percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). This technique can also be applied percutaneously [percutaneous myocardial revascularization (PMR) or direct myocardial revascularization (DMR)]. The original hypotheses which motivated development of TMR were that: (i) oxygenated blood could flow directly from the left ventricle and perfuse the myocardium; and (ii) such artificially created channels would remain patent. However, experimental data have refuted both hypotheses. In the face of early reports of marked clinical benefits in terms of relief of anginal symptoms, alternate hypotheses to explain the mechanism have been pursued, including TMR-associated neoangiogenesis and cardiac denervation. Clinically, numerous reports of reduction in frequency and severity of anginal symptoms, improved exercise tolerance and improved quality of life have appeared from nonblind registry-type studies as well as nonblind randomized clinical trials of TMR or PMR versus continued medical therapy. TMR was not associated with a significant improvement in survival compared with medical therapy alone in randomized trials. For example, the prospective, randomized Angina Treatments-Lasers and Normal Therapies in Comparison (ATLANTIC) trial found a 1-year mortality of 5% in 92 TMR-treated patients and 10% in 90 patients treated with medication only. No proof of improved myocardial blood flow in hearts of treated patients is currently available. The first randomized study of PMR was the Potential Angina Class Improvement From Intramyocardial Channels (PACIFIC) trial which found significantly greater improvements in anginal symptoms and exercise tolerance with PMR plus medical therapy, compared with medical therapy alone. The preliminary results of two double-blind studies with PMR/DMR have been presented but have not yet been published in full. Whereas PMR-treated patients did significantly better than sham-treated control groups after 6 months in the Blinded Evaluation of Laser Intervention Electively For angina pectoris (BELIEF) trial, there was no difference after 1 year between DMR-treated patients and those treated with medication only in the DMR In Regeneration of Endomyocardial Channels Trial (DIRECT). Different devices used for revascularization in these two trials may explain the disparity in the results, and therefore the efficacy and tolerability of each device should be judged upon data collected with that particular device.

Alternatives to traditional coronary bypass surgery.

Over 1 million percutaneous coronary interventions (PCI) and a half million surgical coronary artery bypass grafting procedures (CABG) are performed in the United States annually for treatment of coronary artery disease. With recent advances in anti-restenosis strategies, the number of PCIs is expected to increase dramatically. Still, these therapies treat relatively discrete coronary lesions. However, there is a relatively large number of patients for whom traditional therapies are not optimal, either because there are diffuse coronary artery lesions, because there are chronic total occlusions, or because, in the instance of bypass surgery, creating proximal or distal anastomoses is problematic. We review three strategies in various stages of development aimed at treating patients not optimally served by traditional forms of revascularization: transmyocardial laser revascularization, angiogenic therapies, and direct ventricle-to-coronary artery bypass.

Biointerventional cardiology: the future interface of interventional cardiovascular medicine and bioengineering.

Major advances in cardiovascular intervention for chronic disease are underway. These innovations lie at the interface of minimally invasive catheter-based technologies and biologic approaches for the management of complex cardiovascular diseases. This review highlights key areas where such 'biointerventional' cardiovascular therapies are envisioned to occur: cardiac cell transplantation, myocardial gene therapy, genetic and photodynamic endovascular interventions, and vascular tissue engineering.

Outcomes following percutaneous coronary intervention in patients previously considered "without option": a subgroup analysis of the PACIFIC Trial.

OBJECTIVES: The present study assesses clinical outcomes in patients from the Potential Angina Class Improvement From Intramyocardial Channels (PACIFIC) trial of percutaneous transmyocardial revascularization (PTMR) who had previously been considered "no-option," but who subsequently underwent percutaneous coronary intervention (PCI) for continuing symptoms. BACKGROUND: Patients with advanced symptomatic coronary artery disease who are not candidates for coronary artery bypass grafting (CABG) or PCI comprise an important group, for which no established treatment is currently available. These patients have been described as having "no option," and are currently targeted for various experimental therapies. One such proposed therapy, PTMR, was recently examined in the PACIFIC trial. A subgroup of patients in this trial subsequently underwent PCI, although to initially qualify for the study they had previously been considered as unsuitable for PCI and as having "no option." The therapeutic benefit of PCI for patients of this type is unknown. METHODS: A retrospective analysis was performed on data obtained from all subjects of the PACIFIC study who underwent PCI within the 12-month follow-up period. RESULTS: Ten subjects originally randomized to PTMR and 11 subjects from the medical treatment group underwent PCI. Most had undergone at least one prior PCI and at least one CABG, and there was a high prevalence of cardiovascular risk factors. Despite excellent immediate procedural success, PCI resulted in only modest, statistically nonsignificant increases in mean exercise duration, small improvements in angina status, and no significant improvements in quality of life. CONCLUSIONS: These data suggest that PCI provides only marginal-if any-symptomatic benefit in these patients.

Toward a new blood vessel.

Strategies to treat atherosclerotic coronary artery disease include coronary artery bypass grafting (CABG), in which grafts are used to bypass atherosclerotic vessels and restore blood flow to the ischemic myocardium. The grafts used include healthy arteries or veins harvested from a separate site. Results with arterial grafts have been superior to venous grafts; promoting the practice of total arterial revascularization using only arterial grafts. Suitable arterial grafts, however, are scarce and harvest procedures add to morbidity and cost. Tissue engineering combines the principles of engineering with life sciences for the development of biological substitutes and restore, maintain or improve tissue function. Advances in this field have included the development of tissue-engineered blood vessels, with the potential to serve as arterial grafts, conduits or fistulae. This review describes the history of tissue engineering arteries, the techniques used, and progress to date. The source of cells and the future direction of this field are explored.

Percutaneous mitral valve repair: a feasibility study in an ovine model of acute ischemic mitral regurgitation.

Annuloplasty is the cornerstone of surgical mitral valve repair. A percutaneous transvenous catheter-based approach for mitral valve repair was tested by placing a novel annuloplasty device in the coronary sinus of sheep with acute ischemic mitral regurgitation. Mitral regurgitation was reduced from 3-4+ to 0-1+ in all animals (P < 0.03). The annuloplasty functioned by reducing septal-lateral mitral annular diameter (30 +/- 2.1 mm preinsertion vs. 24 +/- 1.7 mm postinsertion; P < 0.03). These preliminary experiments demonstrate that percutaneous mitral annuloplasty is feasible. Further study is necessary to demonstrate long-term safety and efficacy of this novel approach.

The porcine coronary model of in-stent restenosis: current status in the era of drug-eluting stents.

Drug-eluting stents are revolutionizing interventional cardiology. Sirolimus-eluting stents are in widespread clinical use, associated with well-documented remarkably low restenosis rates, and a number of other agents appear promising in clinical trials. These human studies have been preceded by numerous animal studies, foremost among them the pig coronary model of in-stent restenosis (ISR). The histologic response to porcine coronary stenting was described over a decade ago. Porcine stenting studies now provide examinations not only of histology, but also mechanisms of action, toxicity, and biocompatibility. This review therefore examines the current status of this porcine coronary model of ISR. Contemporary methods of pig coronary stenting are discussed. The morphometric, cellular, and molecular analyses of the responses to stent injury are then described. Finally, recent pig coronary drug-eluting stent studies are examined, with a discussion of their advantages, limitations, and possible future modifications.

Catheter-based coronary bypass: a development update.

Catheter-based coronary bypass has evolved since its origin in 1995. We present a status update of one version of catheter-based bypass, percutaneous in situ coronary venous arterialization (PICVA), its successes and failures, and the many questions and challenges that remain. Initial clinical experience with PICVA demonstrated promising mitigation of angina in no-option patients, but was complicated by a relatively low procedural completion rate and a high incidence of MACE. A great deal was learned in these initial cases. The system of devices is currently undergoing significant modification, and further clinical study is underway.