Combination TMR and gene therapy.

Transmyocardial laser revascularization is a promising surgical technique that relieves angina and improves subendocardial perfusion in patients with chronic ischemic heart disease refractory to medical management and not amenable to conventional revascularization techniques. We detail our laboratory experience at the Brigham and Women's Hospital with transmyocardial laser revascularization and discuss the potential clinical applications of this work.

Dynamic aortomyoplasty: clinical experience and thoracoscopic surgery feasibility study.

BACKGROUND: Surgical procedures using the latissimus dorsi (LD) muscle to assist chronic heart failure inflict major trauma on severely sick patients. A less invasive approach may prove beneficial. The aim of this article is to review our clinical and experimental approaches of dynamic aortomyoplasty (AMP) and emphasize the necessity to reorient surgical technique towards new directions and a less invasive thoracoscopic approach. MATERIALS AND METHODS: A clinical pilot study on dynamic descending AMP started in June 1995 and included four patients. Two of them could benefit from LD counterpulsation, surviving 6 months and 18 months. Following this clinical experience, we investigated, on an animal model, minimally invasive thoracoscopic surgery for this procedure. Twelve goats underwent endoscopic LD harvest and video-assisted aortic wrap, and were studied after surgical recovery from an anatomical and functional standpoint. RESULTS: Clinical AMP using open techniques provided extraaortic counterpulsation in NYHA Class IV patients contraindicated for other surgical therapies. However, surgical technique and strategy needed improvements for optimal cardiac assistance and better patient outcome. Minimally invasive thoracoscopic surgery was feasible and reproducible in goats, achieving improved anatomy and physiology as compared to the open technique in humans. When appropriate the wrapping technique and stimulation protocol were used, an optimal counterpulsation was demonstrated. We concluded that thoracoscopic AMP may provide a minimally invasive approach to cardiac assistance and thus, a new surgical option for patients presenting with chronic heart failure.

Central role for CD40/CD40 ligand (CD154) interactions in transplant rejection.

Major advances have been made in understanding the expression and function of CD40 and its ligand CD154. It is now clear that CD40/CD154 interactions are critical in many aspects of the immune response, including T cell activation, T cell-dependent macrophage activation, T cell-B cell interactions and endothelial activation. Moreover, increasing evidence supports a central role for CD40/CD154 interactions in the immune processes of allograft rejection. Functional studies using blocking monoclonal antibodies have revealed beneficial effects of interupting CD40/CD154 co-stimulation in animal models of transplantation, particularly in association with interuption of the CD28/B7 pathway. A next step is to develop new therapeutic approaches to interrupting this pathway in humans, either through the development of receptor antagonists or through the understanding of intracellular signaling pathways utilized by these molecules.

Innovative techniques in skeletal muscle cardiac assistance: first experimental study on minimally invasive aortomyoplasty and cardiomyoplasty.

Skeletal muscle cardiac assistance as a treatment modality for heart failure is considered a high-risk procedure subject to strict patient selection. The aim here is to develop minimally invasive techniques to improve surgical outcomes and increase clinical indications. Ten goats (45-55 kg) were studied. In six, the latissimus dorsi muscle (LDM) was harvested via an open technique on one side vs a minimally invasive technique on the other using video assistance through two 3 cm incisions. Surgical maneuvers and length of procedures were noted. Animals were recovered, observed daily for local complications, and killed after 1 week for comparative anatomic and histopathologic studies. In four other goats, minimally invasive aortomyoplasty or cardiomyoplasty was performed using video assistance (2 aortomyoplasty, 2 cardiomyoplasty). In this experimental series, there were no surgical complications. The minimally invasive LDM harvest required a mean of 81 min (range 55-116 mn) with no gross evidence of muscle damage. The technique of LDM harvesting was standardized and is reproducible. Aortic and cardiac wraping were also achieved through three ports and a left minithoracotomy of 4 cm, using the right or left LDM. A scarf technique for the descending aortomyoplasty using the left LDM, and an anterior wrapping for cardiomyoplasty using the left or right LDM was technically feasible with video assistance. This study suggests future clinical applicability.

Mitral valve reconstruction for mitral insufficiency.

Mitral valve reconstruction is now the procedure of choice for many mitral regurgitant lesions. Early enthusiasm and technical advances in plastic reconstruction of the mitral valve were overshadowed by the development of prosthetic and bioprosthetic valves. With long-term follow-up studies came the realization that the complication rates of prosthetic mitral valves and the durability of bioprostheses were less than ideal. The use of annuloplasty rings and standardization of mitral repair techniques have made these procedures more universally reliable and the excellent results reproducible. Due to the pathological diversity of mitral regurgitation, many different techniques are used to correct the various lesions. Many centers are reporting hospital mortality, survival, freedom from thromboembolism, freedom from reoperation, freedom from infective endocarditis, and freedom from valve-related complications results that compare favorably with those following mitral valve replacement. The preservation of the papillary muscles and chordae tendinea during mitral reconstruction, as well as a lack of foreign materials, contribute to the enhanced systolic function with improved survival and lower complication rates following mitral repair compared with replacement. With improved results and technical advances, the indications for mitral repair have expanded to encompass a broader diversity of lesions and earlier operative intervention.

CD40 and CD40 ligand (CD154) are coexpressed on microvessels in vivo in human cardiac allograft rejection.

BACKGROUND: CD40 is expressed by a wide variety of cells in the immune system, including endothelial cells. It binds to CD40 ligand ([CD40L] CD154), which was originally reported to be restricted in its expression to early-activated T cells. We report here the expression of CD40 and CD40L in human cardiac allografts. METHODS: A total of 123 consecutive biopsies from 11 human cardiac allograft recipients were analyzed by immunohistochemistry for the expression of CD40 and CD40L. The expression of CD40L was also examined in vitro in homogeneous cultures of umbilical vein endothelial cells by reverse transcriptase-polymerase chain reaction and by flow cytometry. RESULTS: CD40 was expressed at low levels, and CD40L was minimal or absent in histologically normal biopsies in the absence of CD3+ T-cell infiltrates. In rejection, the expression of CD40 increased on vascular endothelial cells and on graft-infiltrating leukocytes throughout biopsy specimens. Induced expression of CD40 was strongly associated with the presence of CD3+ T-cell infiltrates, acute rejection, and ischemic injury (P<0.05). CD40L was expressed in biopsies with rejection and was prominent on a subset of infiltrating leukocytes as well as on microvascular endothelial cells. In contrast to CD40, staining of endothelial CD40L was focal in most biopsies. Overall, the expression of CD40L correlated with the presence of CD3+ T-cell infiltrates and rejection (P<0.05), but not ischemic injury (P=0.9). To confirm that the endothelium can synthesize CD40L, we also evaluated the expression of endothelial CD40L in vitro. Cultured endothelial cells were found to express little constitutive CD40L that markedly increased after 24 hr of treatment with supernatants from phytohemagglutinin-activated peripheral blood mononuclear cells or by the cytokines tumor necrosis factor-alpha, interleukin-1a, interleukin-4, or interferon-gamma. CONCLUSION: Both CD40 and CD40L are expressed in vivo on infiltrating leukocytes and on microvascular endothelium in human cardiac allograft rejection. We suggest that endothelial cell CD40 and CD40L play a role in human cell-mediated immune responses such as cardiac allograft rejection.

Aortic valve replacement in patients 80 years and older. Operative risks and long-term results.

BACKGROUND: Forty percent of 7.4 million Americans aged 80 years and older have symptomatic heart disease. Controversy exists as to whether the health care resources allotted to this patient subset represent a cost-effective approach to attaining a meaningful quality of life. Although aortic valve surgery carries greater risks in older than in younger patients, published studies reveal that the elderly should not be denied this procedure. METHODS AND RESULTS: To determine the results of aortic valve replacement (AVR) in an elderly population, we retrospectively analyzed 171 consecutive patients aged 80 to 91 years (mean, 82.6 years; 86 men and 85 women) who underwent AVR at the Texas Heart Institute between 1975 and 1991. Seventy-seven patients had AVR only, and 94 patients had concomitant surgical procedures (coronary artery bypass graft surgery, 75 patients; mitral valve replacement, mitral valve repair, aneurysm repair, 19 patients). The overall 30-day early mortality was 17.5%. The early mortality was 5.2% for patients with AVR only and 27.7% for those with concomitant surgical procedures. Statistical analysis of 17 perioperative variables revealed that left ventricular ejection fraction of less than 45%, hypertension, congestive heart failure, angina, and concomitant surgical procedures were significant univariate predictors of early mortality. Multivariate analysis revealed that left ventricular ejection fraction of less than 45%, hypertension, and concomitant surgical procedures were independent predictors of operative mortality. Mean follow-up of survivors was 39 months. The overall actuarial survival at 1, 3, and 5 years was 90.8%, 84.2%, and 76.0%, respectively. CONCLUSIONS: These results show that AVR can be performed with acceptable operative risks in the elderly. This study further shows that isolated AVR can be done with low operative mortality and that the performance of concomitant surgical procedures exposes elderly patients to higher operative risks.