URL: http://www.clinicaltrials.gov. Unique identifier: NCT00333827.

Background: Cardiovascular diseases are the major cause of death in the world. Current treatments have not been able to reverse this scenario, creating the need for the development of new therapies. Cell therapies have emerged as an alternative for cardiac diseases of distinct causes in experimental animal studies and more recently in clinical trials.

Autoantibodies against muscarinic and adrenergic receptors have been found in the sera of patients with idiopathic dilated cardiomyopathy (IDC) and Chagas disease, but it is still unclear whether they can functionally interact with their respective receptors to modulate cardiac functions. In this study, our goal was to detect the presence of those antibodies in the sera of patients with IDC and characterize their electrophysiological effects on cardiomyocytes from rabbits. By using ELISA immunoassays, we detected high titers of antibodies against muscarinic M2 receptors in the sera of all IDC patients, whereas the detection of antibodies against the beta1-receptor occurred in 50% of them. Electrophysiological experiments using the whole cell configuration of the patch-clamp technique showed that sera from 43% of IDC patients induced a significant decrease (approximately 26%) in isoproterenol-stimulated L-type Ca2+ currents in rabbit ventricular myocytes, whereas the sera from healthy blood donors failed to do so. As expected, IDC sera also decreased the action potential duration (by 10.5%) due to a shortening of the plateau phase. Sera that reduced isoproterenol-stimulated L-type Ca2+ currents did not cause any effect on K+ currents. We conclude that sera from IDC patients have autoantibodies, which interact with muscarinic M2 receptors of rabbit cardiomyocytes, acting in an agonist-like fashion. This action results in changes in electrogenesis, which, as often observed in patients with IDC, could initiate ventricular arrhythmias that lead to sudden death.

No abstract

A forty-one-year-old male with systolic heart failure, FC-III NYHA, clinical stage C due to dilated cardiomyopathy was submitted to an autologous transplant of the mononuclear fraction of bone marrow via coronary artery system through heart catheterism. Two months after the procedure, there was a decrease in plasma BNP and cardiac area reduction at the thorax X-ray and nuclear magnetic resonance. The echocardiogram showed decrease of the secondary regurgitation and mitral ring dilatation. There was a better performance at the ergospirometry, with increase of the maximum oxygen consumption and consequent reduction in drug therapy. The absence of adverse events characterized by clinical/hemodynamic instability, enzymatic alteration or electrocardiogram demonstrate the safety and feasibility of this procedure carried out and described with pioneering spirit in dilated cardiomyopathy.

Given the limited therapeutic options for refractory dilated cardiomyopathy we decided to perform a phase I clinical trial using bone marrow derived mononuclear cells in patients with functional classes II and IV of the NYHA. Inclusion criteria required EF% (Simpson) <35%, VO2 max < 16 kg.ml /min and signed informed consent. After enrollment patients were subject to the following exams at baseline, 2 and 6 months after cell therapy: 12 lead ECG and 24hs holter, echocardiography, chest X-ray, blood biochemistry, BNP, ergoespirometry, MRI and Minnesota Questionnaire. Patients were subject to bone marrow aspiration (80–100 mL) under sedation and local anesthesia and mononuclear cells were obtained after Ficoll gradient centrifugation. A mean of 198 million cells diluted in 20 ml of saline were slowly delivered through catheterization in the coronary arteries (10 ml in LAD, 5 ml in RC, 5 ml in CX). After the procedure patients remained hospitalized for 48hs. We report the results of the first 22 patients that completed the follow-up period. No adverse effects related to the procedure were observed, nor were arrhythmias detected after cell delivery. Four patients died during follow up. For the 18 patients that completed follow up, there was a significant improvement in NYHA functional class and quality of life at 2 and 6 months (p<0.03 and p< 0.007, respectively). There were no statistically significant changes in EF% (18.6%, 18.6% and 19%), EDV (360, 371, 386 ml) or ESV (295, 308, 314 ml) at baseline, 2 and 6 months respectively as measured by MRI. Maximal oxygen consumption showed as significant increase after cell therapy (12.5, 15.3, 16.8 ml/kg.min), and the number of patients with oxygen consumption below the threshold for cardiac transplantation decrease from 75% at baseline to 25% six months after cell therapy. BNP levels were not significantly altered (650, 475, 530 pg/ml). When observed individually, 4 of the 17 patients examined showed an increase in EF% by MRI ≥5%, 7 did not change EF% and 3 decreased EF% by ≥5%. In conclusion, the procedure is safe and feasible but further studies are necessary to test for efficacy.