Blood-brain barrier disruption after cardiac surgery.

BACKGROUND AND PURPOSE: CNS complications are often seen after heart surgery, and postsurgical disruption of the BBB may play an etiologic role. The objective of this study was to determine the prevalence of MR imaging-detected BBB disruption (HARM) and DWI lesions after cardiac surgery. MATERIALS AND METHODS: All patients had an MRI after cardiac surgery. For half the patients (group 1), we administered gadolinium 24 hours after surgery and obtained high-resolution DWI and FLAIR images 24-48 hours later. We administered gadolinium to the other half (group 2) at the time of the postoperative scan, 2-4 days after surgery. Two stroke neurologists evaluated the images. RESULTS: Of the 19 patients we studied, none had clinical evidence of a stroke or delirium at the time of the gadolinium administration or the scan, but 9 patients (47%) had HARM (67% in group 1; 30% in group 2; P = .18) and 14 patients (74%) had DWI lesions (70% in group 1; 78% in group 2; P = 1.0). Not all patients with DWI lesions had HARM, and not all patients with HARM had DWI lesions (P = .56). CONCLUSIONS: Almost half the patients undergoing cardiac surgery have evidence of HARM, and three-quarters have acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR imaging can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery.

Computer aided minimally invasive cardiac procedures.

Minimally invasive cardiac procedures have been investigated to reduce the risks associated with open heart surgery. With the assistance of improvements in engineering technologies such as medical imaging, surgical navigation, and robotic devices, more cardiac surgeries can be performed in a minimally invasive fashion. We have surveyed these state-of-the-art engineering technologies and the minimally invasive cardiac procedures that are benefited from these technologies.

Rapamycin promotes the enrichment of CD4(+)CD25(hi)FoxP3(+) T regulatory cells from naïve CD4(+) T cells of baboon that suppress antiporcine xenogenic response in vitro.

The CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells play an important role in regulating the immune response. These Treg cells are present in peripheral blood and lymphoid organs and have a high potential for immunotherapy in clinics. Adoptive cell transfer therapy using CD4(+)CD25(+) cells has been shown to prevent autoimmune diseases and has also induced transplant tolerance in mice. Treg cells low frequency in peripheral blood will necessitate its ex vivo expansion to enable adaptive immunotherapy. Recently, it has been reported that rapamycin, an immunosuppressive agent, inhibits T-cell proliferation while selectively increasing the number of Treg cells. Based on this additional mode of action, rapamycin can be used to expand Treg cells for ex vivo cellular therapy in T-cell-mediated diseases and in transplantation. We have reported the ex vivo expansion of baboon Treg cells, using irradiated pig peripheral blood mononuclear cell (PBMC) and interleukin (IL)-2, and have demonstrated the suppression of autologus CD4(+)CD25(neg) T-cell proliferation in response to pig PBMCs. In the present study, we have expanded baboon CD4(+) T cells in the presence or absence of rapamycin (0.1-10 nmol/L) using irradiated pig PBMCs and IL-2 to enrich the regulatory T cells. CD4(+)CD25(+)FoxP3(+) Treg cells were increased up to 2 times in the presence of rapamycin versus without rapamycin in vitro. However, a higher dose of rapamycin (> or = 10 nmol/L) considerably decreases the number of Treg cells. Furthermore, purified CD4(+)CD25(+) Treg cells enriched from CD4(+) cells in the presence of rapamycin were able to suppress the baboon anti-porcine xenogeneic immune responses in vitro up to 93% at a 1:1 ratio (Treg cells:T effector cells) and suppression ability exists even at a 1:256 ratio, whereas freshly isolated natural Treg cells suppress only 70% at 1:1 and lose their suppressive ability (>50%) at 1:16. Our results demonstrate that the addition of rapamycin to the culture enriches the Treg phenotype and induces functional regulatory T cells. This method may allow the production of large numbers of regulatory cells for the preclinical testing of Treg cell therapy in a non-human primate model.

Sustained angina relief 5 years after transmyocardial laser revascularization with a CO(2) laser.

BACKGROUND: Although transmyocardial laser revascularization (TMR) has provided symptomatic relief of angina over the short term, the long-term efficacy of the procedure is unknown. Angina symptoms as assessed independently by angina class and the Seattle Angina Questionnaire (SAQ) were prospectively collected up to 7 years after TMR. METHODS: Seventy-eight patients with severe angina not amenable to conventional revascularization were treated with a CO(2) laser. Their mean age was 61+/-10 years at the time of treatment. Preoperatively, 66% had unstable angina, 73% had had >/=1 myocardial infarction, 93% had undergone >/=1 CABG, 42% had >/=1 PTCA, 76% were in angina class IV, and 24% were in angina class III. Their average pre-TMR angina class was 3.7+/-0.4. RESULTS: After an average of 5 years (and up to 7 years) of follow-up, the average angina class was significantly improved to 1.6+/-1 (P=0.0001). This was unchanged from the 1.5+/-1 average angina class at 1 year postoperatively (P=NS). There was a marked redistribution according to angina class, with 81% of the patients in class II or better, and 17% of the patients had no angina 5 years after TMR. A decrease of >/=2 angina classes was considered significant, and by this criterion, 68% of the patients had successful long-term angina relief. The angina class results were further confirmed with the SAQ; 5-year SAQ scores revealed an average improvement of 170% over the baseline results. CONCLUSIONS: The long-term efficacy of TMR persists for >/=5 years. TMR with CO(2) laser as sole therapy for severe disabling angina provides significant long-term angina relief.

Functional comparison of transmyocardial revascularization by mechanical and laser means.

BACKGROUND: As a result of the clinical benefit observed in angina patients treated by transmyocardial revascularization (TMR) with a laser, interest in mechanical TMR has been renewed. Although the injury induced by mechanical TMR is similar to laser TMR, the resultant impact on myocardial contractility is unknown. The purpose of this study was to determine whether mechanical TMR improves ventricular function as compared with laser TMR in chronically ischemic myocardium. METHODS: After establishing an area of chronic myocardial ischemia, 25 domestic pigs were randomized to treatment by: excimer laser (group I), a hot needle (50 degrees C) (group II), a normothermic needle (group III), an ultrasonic needle (40 KHz) (group IV), or no treatment (group V). All devices create a transmural channel of the same diameter; 22 +/- 1 transmural channels were created in each animal. Regional myocardial contractility was assessed by measuring ventricular wall thickening at rest and with dobutamine stress echocardiography. Six weeks after revascularization, the animals were restudied at rest and with stress. Postsacrifice and histologic analysis of angiogenesis and TMR effects was then assessed. RESULTS: Laser TMR provided significant recovery of ischemic myocardial function. This improvement in contractility after laser TMR was a 75% increase over the baseline function of the ischemic zone (p < 0.01). Mechanical TMR provided no significant improvement in function posttreatment. In fact, TMR achieved with an ultrasonic needle demonstrated a 40% worsening of the contractility versus the pretreatment baseline (p < 0.05). Histologic analysis demonstrated a significant increase in new blood vessels in the ischemic zone after laser TMR, which was not demonstrated for any of the other groups (p < 0.05). Additionally, evaluation of the mechanical TMR channels demonstrated significant scarring, which correlated with the functional results. CONCLUSIONS: Using devices to create an injury analogous to the laser, mechanical TMR failed to improve the function of chronically ischemic myocardium. Only laser TMR significantly improved myocardial function.

Postoperative troponin I values: insult or injury?

BACKGROUND: Troponin I (TnI) is increasingly employed as a highly specific marker of acute myocardial ischemia. The value of this marker after cardiac surgery is unclear. HYPOTHESIS: The purpose of this study was to measure serum TnI levels prospectively at 1, 6, and 72 h after elective cardiac operations. In addition, TnI levels were measured from the shed mediastinal blood at 1 and 6 h postoperatively. Serum values were correlated with cross clamp time, type of operation, incidence of perioperative myocardial infarction, as assessed by postoperative electrocardiograms (ECG) and regional wall motion, as documented by intraoperative transesophageal echocardiography (TEE). METHODS: Sixty patients underwent the following types of surgery: coronary artery bypass graft (CABG) (n = 45), valve repair/replacement (n = 10), and combination valve and coronary surgery (n = 5). Myocardial protection consisted of moderate systemic hypothermia (30-32 degrees C), cold blood cardioplegia, and topical cooling for all patients. RESULTS: Of 60 patients, 57 (95%) had elevated TnI levels, consistent with myocardial injury, 1 h postoperatively. This incidence increased to 98% (59/60) at 6 h postoperatively. There was a positive correlation between the length of cross clamp time and initial postoperative serum TnI (r = 0.70). There was no difference in the serum TnI values whether or not surgery was for ischemic heart disease (CABG or CABG + valve versus valve). There were no postoperative myocardial infarctions as assessed by serial ECGs. There was no evidence of diminished regional wall motion by TEE. Levels of TnI in the mediastinal shed blood were greater than assay in 58% (35/60) of the patients at 1 h and in 88% (53/60) at 6 h postoperatively. Patients who received an autotransfusion of mediastinal shed blood (n = 22) had on average a 10-fold postoperative increase in serum TnI levels between 1 and 6 h. Patients who did not receive autotransfusion average less than doubled their TnI levels over the same interval. At 72 h, TnI levels were below the initial postoperative levels but still indicative of myocardial injury. CONCLUSION: Postoperative TnI levels are elevated after all types of cardiac surgery. There is a strong correlation between intraoperative ischemic time and postoperative TnI level. Further elevation of TnI is significantly enhanced by reinfusion of mediastinal shed blood. Despite these postoperative increases in TnI, there was no evidence of myocardial infarction by ECG or TEE. The postoperative TnI value is even less meaningful after autotransfusion of shed mediastinal blood.

Results of clinical trials of transmyocardial laser revascularization versus medical management for end-stage coronary disease.

BACKGROUND DATA: Over 5,000 patients worldwide have undergone transmyocardial laser revascularization (TMR) since 1990 for the treatment of myocardial ischemia due to end-stage coronary artery disease. Recently, four prospective randomized controlled clinical trials have reported their results in comparing TMR to maximal medical therapy. The purpose of this review is to provide an update and comparison of the results of these trials. METHODS: Patients with severe angina were randomized to treatment by laser TMR (carbon dioxide or holmium YAG) or continuing on maximum medical therapy. All patients were followed for a year and had reassessment of angina class and quality of life at that time. RESULTS: All of the trials demonstrated that TMR provided significant relief of angina when compared to medical management. Additional objective data in the form of exercise tolerance and myocardial perfusion scanning was used to support the symptomatic improvement. CONCLUSION: Symptomatic improvement is seen for patients with severe diffuse coronary artery disease treated by TMR.

Transmyocardial laser revascularization in the treatment of myocardial ischemia.

Since 1990, over five thousand patients worldwide have undergone transmyocardial laser revascularization (TMR) for the treatment of myocardial ischemia due to end-stage coronary artery disease. Recently four prospective randomized controlled clinical trials have reported their results in comparing TMR to maximal medical therapy. All of the trials demonstrated that TMR provided notable relief of angina when compared to medical management. Additional objective data in the form of exercise tolerance and myocardial perfusion scanning are used to support the symptomatic improvement. Although the trials are similar, they are not identical, and this review provides an update and comparison of their results.

Transmyocardial laser revascularization in the patient with unmanageable unstable angina.

BACKGROUND: Transmyocardial laser revascularization (TMR) provides relief for patients with chronic angina, nonamenable to direct coronary revascularization. Unmanageable, unstable angina (UUA) defines a subset of patients with refractory angina who are at high risk for myocardial infarction and death. Patients were classified in the UUA group when they had been admitted to the critical care unit with unstable angina for 7 days with three failed attempts at weaning them off intravenous antianginal medications. METHODS: Seventy-six treated patients were analyzed to determine if TMR is a viable option for patients with unmanageable unstable angina. These patients were compared with 91 routine protocol patients (protocol group [PG]) undergoing TMR for chronic angina not amenable to standard revascularization. The procedure was performed through a left thoracotomy without cardiopulmonary bypass. These patients were followed for 12 months after the TMR procedure. Both unmanageable and chronic angina patients had a high incidence of at least one prior surgical revascularization (87% and 91%, respectively). RESULTS: Perioperative mortality (< or = 30 days post-TMR) was higher in the UUAG versus PG (16% vs 3%, p = 0.005). Late mortality, up to 1 year of follow-up, was similar (13% vs 11%, UUAG vs PG; p = 0.83). A majority of the adverse events in the UUAG occurred within the first 3 months post-TMR, and patients surviving this interval did well, with reduced angina of at least two classes occurring in 69%, 82%, and 82% of patients at 3, 6, and 12 months, respectively. The percent improvement in angina class from baseline was statistically significant at 3, 6, and 12 months. A comparable improvement in angina was found in the protocol group of patients. CONCLUSIONS: TMR carried a significantly higher risk in unmanageable, unstable angina than in patients with chronic angina. In the later follow-up intervals, however, both groups demonstrated similar and persistent improvement in their angina up to 12 months after the procedure. TMR may be considered in the therapy of patients with unmanageable, unstable angina who otherwise have no recourse to effective therapy in the control of their disabling angina.

Up-regulation of vascular endothelial growth factor mRNA and angiogenesis after transmyocardial laser revascularization.

BACKGROUND: Angiogenesis has been proposed as a potential mechanism whereby transmyocardial laser revascularization (TMLR) has provided clinical relief of angina. Experimental work has found histologic evidence supporting this, as well as an improved response when angiogenic growth factors have been added to TMLR. The purpose of this study was to demonstrate that the molecular response to TMLR was an increase in the production of endogenous vascular endothelial growth factor to promote angiogenesis. METHODS: Ameroid constrictors were placed on the proximal circumflex artery in 12 domestic pigs. After a chronic ischemic zone was established the animals were randomly divided into two groups. In the TMLR group the ischemic zone was treated with carbon dioxide laser. In the control group the ischemic zone was untreated. Six weeks later the animals were sacrificed, and sections from the ischemic zone and the nonischemic zone were submitted for immunohistochemical, histologic, and molecular analysis. Messenger RNA was obtained from northern blot analysis after being probed with vascular endothelial growth factor. RESULTS: There was a twofold increase in the vascular endothelial growth factor messenger RNA in the ischemic zone of the TMLR group compared with the control group. Additionally, there was a threefold increase in the number of new blood vessels in the ischemic zone of the TMLR group compared with the control group. CONCLUSIONS: Transmyocardial laser revascularization promotes angiogenesis by upregulation of vascular endothelial growth factor. The resulting angiogenesis could be the principle mechanism for the clinical efficacy of TMLR.

Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease.

BACKGROUND: The construction of subendocardial channels to perfuse ischemic areas of the myocardium has been investigated since the 1950s. We assessed the safety and efficacy of transmyocardial revascularization with a carbon dioxide laser in patients with refractory angina and left ventricular free-wall ischemia that was not amenable to direct coronary revascularization. METHODS: In a prospective, controlled, multicenter trial, we randomly assigned 91 patients to undergo transmyocardial revascularization and 101 patients to receive continued medical treatment. The severity of angina (according to the Canadian Cardiovascular Society [CCS] classification), quality of life, and cardiac perfusion (as assessed by thallium-201 scanning) were evaluated at base line and 3, 6, and 12 months after randomization. RESULTS: At 12 months, angina had improved by at least two CCS classes in 72 percent of the patients assigned to transmyocardial revascularization, as compared with 13 percent of the patients assigned to medical treatment who continued medical treatment (P<0.001). Patients in the transmyocardial-revascularization group also had a significantly improved quality of life as compared with the medical-treatment group. Myocardial perfusion improved by 20 percent in the transmyocardial-revascularization group and worsened by 27 percent in the medical-treatment group (P=0.002). In the first year of follow-up, 2 percent of patients assigned to undergo transmyocardial revascularization were hospitalized because of unstable angina, as compared with 69 percent of patients assigned to medical treatment (P<0.001). The perioperative mortality rate associated with transmyocardial revascularization was 3 percent. The rate of survival at 12 months was 85 percent in the transmyocardial-revascularization group and 79 percent in the medical-treatment group (P=0.50). CONCLUSIONS: In patients with angina refractory to medical treatment and coronary artery disease that precluded coronary-artery bypass surgery or percutaneous transluminal coronary angioplasty, transmyocardial revascularization improved cardiac perfusion and clinical status over a 12-month period.

Left ventricular functional improvement after transmyocardial laser revascularization.

BACKGROUND: Transmyocardial laser revascularization has been used to treat patients with end-stage coronary artery disease that is not amenable to standard revascularization. Although there is evidence of angina relief and quality of life enhancement, there is little information concerning improvement in myocardial contractility. The purpose of this study was to determine whether transmyocardial laser revascularization improves myocardial function in chronically ischemic myocardium. METHODS: In a model of chronic ischemia by Ameroid occlusion of the circumflex artery, domestic pigs (n = 8) were treated with transmyocardial laser revascularization. Before laser treatment, segmental contraction was assessed at rest and with dobutamine stress echocardiography. Myocardium subtended by the occlusion was compared with that remote from the occlusion. Six weeks after transmyocardial laser revascularization, the animals were restudied at rest and with stress, and then sacrificed. Sham-treated control animals (n = 4) underwent the same procedures but were not treated with transmyocardial laser revascularization. Control animals did not demonstrate significant recovery of function. RESULTS: Transmyocardial laser revascularization improved resting function in chronically ischemic myocardium by 100%. CONCLUSIONS: Transmyocardial laser revascularization significantly improves the function of chronically ischemic myocardium. These data may help explain the mechanisms by which transmyocardial laser revascularization is clinically effective.

Thoracoscopic transmyocardial laser revascularization.

Transmyocardial laser revascularization has been used to treat patients with end-stage coronary artery disease and severe disabling angina. Typically, the operative approach is through a left anterior thoracotomy. I report a case of transmyocardial laser revascularization performed thoracoscopically.

Thoracoscopic transmyocardial laser revascularization.

BACKGROUND: Transmyocardial laser revascularization is a promising surgical technique used to treat nonreconstructable ischemic heart disease. Recent clinical data show that this technique improves the regional perfusion of ischemic myocardium and reduces angina. Presently, transmyocardial laser revascularization requires an open, lateral thoracotomy. We report here the use of thoracoscopic techniques to perform transmyocardial laser revascularization in a closed chest fashion. METHODS: Five Yorkshire farm pigs underwent left chest thoracoscopic exploration and pericardiotomy. A specialized laser handpiece then was introduced into the chest and thoracoscopic transmyocardial laser revascularization was performed (one channel per square centimeter) using an 800-W CO2 laser. RESULTS: Video analysis and gross pathology revealed that the anatomic area accessible to thoracoscopic transmyocardial laser revascularization included the entire left ventricular free wall distributions of the left anterior descending, left circumflex, and posterior descending arteries, from base to apex. Standard hematoxylin and eosin staining confirmed the creation of complete and patent 1-mm-diameter transmural channels throughout these distributions. CONCLUSION: We have shown that transmyocardial laser revascularization can be performed effectively and safely by thoracoscopy, and that this less invasive technique may reduce morbidity and provide a more cost-effective alternative therapy for nonreconstructable ischemic heart disease.

Transmyocardial laser revascularization: results of a multicenter trial with transmyocardial laser revascularization used as sole therapy for end-stage coronary artery disease.

BACKGROUND: Transmyocardial laser revascularization was used as the sole therapy for patients with ischemic heart disease not amenable to percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. This technique uses a carbon dioxide laser to create transmyocardial channels for direct perfusion of the ischemic heart. METHODS: Since 1992, 200 patients, at eight hospitals in the United States, have undergone transmyocardial laser revascularization. The patients have a combined 1560 months of follow-up for an average of 10 +/- 3 months per patient. Their age was 63 +/- 10 years and their ejection fraction was 47% +/- 12%. Eighty-two percent had at least one previous bypass graft operation and 38% had a prior angioplasty. Preoperatively, the patients underwent nuclear single photon emission computed tomography perfusion scans to identify the extent and severity of their ischemia. These scans were repeated at 3, 6, and 12 months. Angina class, admissions for angina, and medications were recorded. RESULTS: The perioperative mortality was 9%. Angina class decreased significantly from before treatment to 3, 6, and 12 months (p < 0.001). Likewise, there was a significant decrease in the number of perfusion defects in the treated left ventricular free wall. Concomitantly, there was a significant decrease in the number of admissions for angina in the year after the procedure when compared with the year before treatment (2.5 vs 0.5 admissions per patient-year). CONCLUSION: These combined results indicate that transmyocardial laser revascularization provides angina relief, decreases hospital admissions, and improves perfusion in patients with severe coronary artery disease.

Clinical studies of TMR with the CO2 laser.

OBJECTIVE: This paper reviews the current status of transmyocardial laser revascularization by a carbon dioxide laser. SUMMARY: Since 1990 over 3000 patients worldwide have been treated with a carbon dioxide laser. A nonrandomized phase II trial was completed in 1995. A randomized controlled phase III trial has completed enrollment, and analysis of the follow-up is pending. METHODS: In each trial 200 patients with endstage coronary artery disease and severe disabling angina that was not amenable to conventional revascularization were enrolled. Preoperative evaluation included confirmation of angina class and evidence of reversible ischemia based on myocardial perfusion scans. Repeat evaluations were done postoperatively at 3, 6 and 12 months. RESULTS: 80% of the patients showed a significant improvement in angina class status postoperatively and 30% had no angina at one year of follow-up. Concomitant with this there was significantly less ischemia noted on follow-up perfusion scans. CONCLUSIONS: Early results from nonrandomized and randomized controlled trials of transmyocardial laser revascularization by carbon dioxide laser indicate that this technique provides angina relief and improved perfusion in patients with end-stage coronary artery disease.

Transmyocardial laser revascularization: operative techniques and clinical results at two years.

OBJECTIVES: A new technique, transmyocardial laser revascularization, provides direct perfusion of ischemic myocardium via laser-created transmural channels. From 1993 to 1995, we have treated 20 patients (mean age 61 years, four women and 16 men) with transmyocardial laser revascularization. Preoperatively, the average angina class was 3.7. The patients were screened before the operation by a technetium sestamibi perfusion scan to identify the location and extent of their reversible ischemia. METHODS: Operative exposure is gained via a left anterior thoracotomy. With the use of a 850-watt carbon dioxide laser, an average of 21 +/- 4 channels were created in 22 minutes with a total operative time of less than 2 hours. RESULTS: The in-hospital mortality was two of 20 patients. Three additional patients died after discharge. After an accumulated 172 patient-months (mean follow-up 11 +/- 8 months, range 1 to 26 months), the mean angina class is I (p = 0.01). Postoperative sestamibi scans were obtained at 3, 6, and 12 months. Using the septum as a control and comparing the postoperative results with the preoperative baseline, we noted a significant improvement in perfusion particularly in the areas of reversible ischemia. CONCLUSION: These early results indicate that transmyocardial laser revascularization is a simple operative technique that may improve myocardial perfusion and provide angina relief for patients in whom standard methods of revascularization is contraindicated.