Clinical profile of patients enroled in a cell therapy trial for severe coronary artery disease.

AIMS AND OBJECTIVES: To compare the clinical profile of patients included in a clinical trial of autologous bone marrow cells as an adjunctive therapy to coronary artery bypass grafting with that of patients undergoing routine coronary artery bypass grafting. BACKGROUND: The therapeutic potential of autologous bone marrow cells has been explored in the treatment of severe coronary artery disease. There are few data regarding the clinical and socio-economic profile of patients included in clinical trials using bone marrow cell. DESIGN: Case-control study. METHOD: Sixty-seven patients (61 SD 9) years, 82% men) with multivessel coronary artery disease were divided into two groups: patients in the bone marrow cell group (n = 34) underwent incomplete coronary artery bypass grafting + intramyocardial injection of autologous bone marrow cells (lymphomonocytic fraction -2.0 (SD 0.2 x 10(8)) cells/patient) in the ischaemic, non-revascularised myocardium, whereas patients in the coronary artery bypass grafting group (n = 33) underwent routine bypass surgery. Demographics, socio-economic status, clinical and echocardiographic data were collected. Statistical analysis included the Fisher's exact test (categorical variables) and the Student's t-test (continuous variables). RESULTS: There were no significant differences between groups regarding age, gender, BMI, heart rate, blood pressure and echo data. There was a greater prevalence of obesity (65 vs. 33%; OR = 3.7 [1.3-10.1]), of previous myocardial infarction (68 vs. 39%; OR = 3.2 [1.2-8.8]) and prior revascularisation procedures (59 vs. 24%; OR = 4.5 [1.6-12.7]) in the autologous bone marrow cells group and of smokers in the coronary artery bypass grafting group (51 vs. 23%; OR = 3.5 [1.2-10.4]). CONCLUSIONS: Patients included in this clinical trial of autologous bone marrow cells for severe coronary artery disease presented a greater prevalence of myocardial revascularisation procedures, indicating a more severe clinical presentation of the disease. Fewer smokers in this group could be attributable to life style changes after previous cardiovascular events and/or interventions. RELEVANCE TO CLINICAL PRACTICE: The knowledge of the clinical profile of patients included in cell therapy trials may help researchers in the identification of patients that may be enroled in future clinical trials of this new therapeutic strategy.

Intramyocardial injection of autologous bone marrow cells as an adjunctive therapy to incomplete myocardial revascularization--safety issues.

OBJECTIVES: To determine the safety of intramyocardial injection of autologous bone marrow cells in patients undergoing surgical myocardial revascularization (CABG) for severe coronary artery disease. INTRODUCTION: There is little data available regarding the safety profile of autologous bone marrow cells injected during surgical myocardial revascularization. Potential risks include arrythmias, fibrosis in the injected sites and growth of non-cardiac tissues. METHODS: Ten patients (eight men) were enrolled; they were 59+/-5 years old with limiting angina and were non-optimal candidates for complete CABG. Bone marrow cells (1.3+/-0.3x10(8)) were obtained prior to surgery, and the lymphomonocytic fraction (CD34+ =1.8+/-0.3%) was separated by density gradient centrifugation. During surgery, bone marrow cells were injected in non-grafted areas of ischemic myocardium. During the first year after surgery, the patients underwent laboratory tests, cardiac imaging, and 24-hour ECG monitoring. RESULTS: Injected segments: inferior (n=7), anterior (n=2), septal (n=1), apical (n=1), and lateral (n=1) walls. Except for a transient elevation of C-reactive protein at one month post-surgery (P=0.01), laboratory tests results were within normal ranges; neither complex arrhythmias nor structural abnormalities were detected during follow-up. There was a reduction in functional class of angina from 3.6+/-0.8 (baseline) to 1.2+/-0.4 (one year) (P<0.0001). Also, patients had a significant decrease in the ischemic score assessed by magnetic resonance, not only globally from 0.65+/-0.14 (baseline) to 0.17+/-0.05 (one year) (P=0.002), but also in the injected areas from 1.11+/-0.20 (baseline) to 0.34+/-0.13 (one year) (P=0.0009). CONCLUSIONS: Intramyocardial injection of bone marrow cells combined with CABG appears to be safe. Theoretical concerns with arrhythmias and/or structural abnormalities after cell therapy were not confirmed in this safety trial.

Transmyocardial laser revascularization plus cell therapy for refractory angina.

We report that the use of transmyocardial laser revascularization combined with intramyocardial injection is a therapeutic option for patients with severe ischemic heart disease (IHD) not amenable to conventional myocardial revascularization. Recently, cell therapy with autologous bone marrow cells (BMC) has been tested in clinical trials for severe IHD. We tested the hypothesis that TMLR combined with intramyocardial injection of BMC is safe, and may help increase the functional capacity and myocardial perfusion in patients with refractory angina. We enrolled 8 patients (7 men), 64+/-4 years old, with refractory angina, non-candidates for another procedure. TMLR (8+/-2 laser drills) was performed via a limited thoracotomy. BMC were obtained prior to surgery, and the lymphomonocytic fraction was separated by density gradient centrifugation. During surgery, 5 mL containing approximately 1.6+/-0.2 x 10(8) BMC (CD34+=1.7+/-0.4%) was delivered by multiple injections in the ischemic myocardium. We observed a reduction in the ischemic score as assessed by MRI from 1.56+/-0.09 (B) to 0.93+/-0.10 (6M) (P=0.01), as well as a reduction in functional class of angina from 3.6+/-0.2 (B) to 1.4+/-0.2 (6M) (P<0.0001). We concluded that, in this early experience, the combined strategy of TMLR plus cell therapy appeared to be safe, and may have synergistically acted to reduce myocardial ischemia, with clinically relevant improvement in functional capacity.

Dynamic regulation of MTHFR mRNA expression and C677T genotype modulate mortality in coronary artery disease patients after revascularization.

INTRODUCTION: A large body of evidence links plasma homocysteine (Hcy) concentrations and cardiovascular disease. A common MTHFR polymorphism (C677T) leads to a variant with reduced activity and associated with increased Hcy levels. Coronary surgery precipitates a significant and sustained increase in the blood concentrations of Hcy and elevated levels of plasma Hcy have been associated to saphenous vein (SV) graft disease after CABG. However, the effects of MTHFR genotypes in the incidence of cardiovascular events after CABG have not been investigated prospectively. Here, we investigate whether MTHFR gene variants are associated with an increased cardiovascular risk in individuals submitted to CABG. We also propose a molecular mechanism to explain our findings. METHODS: We performed MTHFR C677T genotypes in 558 patients with two or three vessel-disease and normal left ventricular function prospectively followed in the MASS II Trial, a randomized study to compare treatments for multivessel CAD and preserved left ventricle function. Follow-up time was 5 years. Survival curves were calculated with the Kaplan-Meier method, and evaluated with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, myocardial infarction and refractory angina using a Cox proportional hazards survival model. Finally, using an ex-vivo organ culture we have reproduced the arterialization of SV implants by culturing human SV either under venous hemodynamic condition (flow: 5 mL/min; no pressure) or arterial hemodynamic condition (flow: 50 mL/min; pressure: 80 mm Hg) for 1 day. MTHFR gene expression was quantified by real time RT-PCR in 15 SV from different individuals in both experimental conditions. RESULTS: There were no significant differences among individuals within each genotype group for baseline clinical characteristics. A statistically significant association between the TT genotype, associated with increased serum levels of Hcy, and cardiovascular mortality after 5 years was verified (p=0.007) in individuals submitted to CABG surgery. In addition, MTHFR TT genotype was still significantly associated with a 4.4 fold increased risk in cardiovascular outcomes (p=0.01) even after adjustment of a Cox multivariate model for age, sex, hypertension, diabetes, LDL, HDL, triglycerides, and number of diseased vessels in this population. Finally, a significant reduction in MTHFR gene expression was demonstrated in human SV when submitted to an arterial hemodynamic condition (p=0.02). CONCLUSIONS: There is a dynamic regulation of MTHFR gene expression during the arterialization process of human saphenous vein grafts resulting in lower levels of gene expression when in an arterial hemodynamic condition. In addition, the C677T MTHFR functional variant is associated with a worse outcome in individuals submitted to CABG. Taken together, these data suggest an important role of Hcy metabolism in individuals after CABG.

Clinical judgment and treatment options in stable multivessel coronary artery disease: results from the one-year follow-up of the MASS II (Medicine, Angioplasty, or Surgery Study II).

OBJECTIVES: This study examined the predictive power of clinical judgment in the incidence of cardiovascular end points in a group of individuals with multivessel coronary artery disease (CAD) followed up in the MASS II (Medicine, Angioplasty, or Surgery Study II). BACKGROUND: There is still no consensus on the best treatment for patients with stable multivessel CAD and preserved left ventricular function. METHODS: Preferred treatment allocation was recorded for each of the 611 randomized patients in the MASS II trial before randomization. We have divided our sample according to physician-guided decision and randomization result into two categories: concordant or discordant. The incidence of the points of cardiac death, myocardial infarction, and refractory angina was compared between concordant and discordant patients. RESULTS: The number of concordant individuals was 292 (48.2%), and this number was not different between the three studied treatments (p = 0.11). A significant difference (p = 0.02) was disclosed because of an increased incidence of combined end point events in discordant patients. In the multivariate Cox hazard model, clinical judgment was a powerful predictor of outcome (p = 0.01) even after adjustment for other covariates. The main subgroup explaining this difference was a significant shift toward a worse outcome in the subgroup of discordant patients who underwent percutaneous coronary intervention (PCI) (p = 0.003). CONCLUSIONS: Angiographic variables were more often used in making clinical decisions regarding PCI than clinical variables, and the only independent predictor of concordance status in the PCI group was the number of diseased vessels (p = 0.01). Our data are a reminder that physician judgment remains an important predictor of outcomes.