Abstract
Most studies have confirmed the beneficial effects of autologous bone marrow mononuclear cell (BMMC) transplantation on angina, myocardial perfusion, regional wall motion, and LV ejection fraction (LVEF). Cardiac resynchronization therapy (CRT) has also shown a beneficial effect in patients with heart failure (HF) and electrical/mechanical dyssynchrony. However, the relative contribution of BMMC and CRT in patients with ischemic HF and electromechanical dyssynchrony has never been investigated. The aim of this study was to evaluate the benefit of combining BMMC transplantation with CRT in patients with severe ischemic HF, left bundle branch block (LBBB), and mechanical dyssynchrony. Patients with ischemic HF, LVEF < 35%, LBBB, and mechanical dyssynchrony underwent intramyocardial transplantation of BMMC and CRTD system implantation. This randomized, single-blind, crossover study compared clinical and echocardiographic parameters during two follow-up periods: 6 months of active CRT (BMMC + CRTact) and 6 months of inactive CRT (BMMC + CRTinact). Physical performance was assessed by means of a 6-min walking test. Myocardial perfusion was evaluated by SPECT. Quality of Life (QoL) was assessed through the Minnesota Living with HF Questionnaire (MLwHFQ). Twenty-six patients (64 ± 7 years) were enrolled in the study. The distance covered by the patients during the 6-min walking test significantly increased in the BMMC + CRTinact phase (BMMC therapy only) in comparison with the baseline (269 ± 68 vs 206 ± 51; p = 0.007) and in the BMMC + CRTact phase (BMMC therapy + CRT) in comparison with the BMMC + CRTinact (378 ± 59 vs 269 ± 68; p < 0.001). The summed rest and stress score (SPECT) decreased significantly in the BMMC + CRTact and BMMC + CRTinact phases in comparison with the baseline (p ≤ 0.03). Both phases showed equivalent myocardial perfusion in the segments into which BMMC had been injected. QoL score was significantly lower in the BMMC + CRTinact phase than at the baseline (44.1 ± 14 vs 64.8 ± 19; p < 0.001), and in the BMMC + CRTact phase than in the BMMC + CRTinact phase (26.4 ± 12 vs 44.1 ± 14; p = 0.004). BMMC and CRT seem to act independently on myocardial perfusion and electromechanical dyssynchrony, respectively. Combining these two complementary therapies can significantly improve LV performance in patients with severe HF and electromechanical dyssynchrony.
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Tse, H. F., Kwong, Y. L., Chan, J. K., Lo, G., Ho, C. L., & Lau, C. P. (2003). Angiogenesis in ischemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet, 361, 47–49.
Fuchs, S., Satler, L. F., Kornowski, R., Okubagzi, P., Weisz, G., Baffour, R., et al. (2003). Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease. Journal of the American College of Cardiology, 41, 1721–1724.
Perin, E. C., Dohmann, H. F., Borojevic, R., Silva, S. A., Sousa, A. L., Mesquita, C. T., et al. (2003). Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation, 107, 2294–2302.
Perin, E. C., Dohmann, H. F., Borojevic, R., Silva, S. A., Sousa, A. L., Silva, G. V., et al. (2004). Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation, 110(suppl II), II-213–II-218.
Beeres, S., Bax, J., Dibbets, P., Stokkel, M., Zeppenfeld, K., Fibbe, W., et al. (2006). Effect of intramyocardial injection of autologous bone marrow–derived mononuclear cells on perfusion, function, and viability in patients with drug-refractory chronic ischemia. Journal of Nuclear Medicine, 47, 574–580.
Pokushalov, E., Romanov, A., Chernyavsky, A., Larionov, P., Terekhov, I., Artyomenko, S., et al. (2010). Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: A randomized study. Journal of Cardiovascular Translational Research, 3, 160–168.
Chang, S. A., Kim, H. K., Lee, H. Y., & Kim, Y. J. (2006). Restoration of synchronicity of the left ventricular myocardial contraction with stem cell therapy: new insights into the therapeutic implication of stem cell therapy in myocardial infarction. Circulation, 114(Suppl II), II567.
Ramshorst, J., Atsma, D., Beeres, S., Mollema, S., Marsan, N., Holman, E., et al. (2009). The effect of intramyocardial bone marrow cell injection on left ventricular dyssynchrony and global strain. Heart, 95(2), 98–99.
Hunt, S. A., Abraham, W. T., Chin, M. H., Feldman, A. M., Francis, G. S., Ganiats, T. G., et al. (2005). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (writing committee to update the 2001 guidelines for the evaluation and management of heart failure). Circulation, 112, e154–e235.
Vardas, P. E., Auricchio, A., Blanc, J. J., Daubert, J. C., Drexler, H., Ector, H., et al. (2007). Guidelines for cardiac pacing and cardiac resynchronization therapy. the task force for cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. European Heart Journal, 28, 2256–2295.
Perin, E. C., Silva, G. V., Sarmento-Leite, R., Sousa, A. L., Howell, M., Muthupillai, R., et al. (2002). Assessing myocardial viability and infarct transmurality with left ventricular electromechanical mapping in patients with stable coronary artery disease: validation by delayed-enhancement magnetic resonance imaging. Circulation, 106, 957–961.
Wrobleski, D., Houghtaling, C., Josephson, M. E., Ruskin, J. N., & Reddy, V. Y. (2003). Use of electrogram characteristics during sinus rhythm to delineate the endocardial scar in a porcine model of healed myocardial infarction. Journal of Cardiovascular Electrophysiology, 14, 524–529.
Marchlinski, F. E., Callans, D. J., Gottlieb, C. D., & Zado, E. (2000). Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation, 101, 1288–1296.
Ben-Haim, S. A., Osadchy, D., Schuster, I., Gepstein, L., Hayam, G., & Josephson, M. (1996). Nonfluoroscopic, in vivo navigation and mapping technology. Natural Medicines, 2, 1393–1395.
Gepstein, L., Hayam, G., & Ben-Haim, S. A. (1997). A novel method for nonfluoroscopic catheterbased electroanatomical mapping of the heart. In vitro and in vivo accuracy results. Circulation, 95, 1611–1622.
Van de Veire, N. R., Bleeker, G. B., De Sutter, J., Ypenburg, C., Holman, E. R., van der Wal, E. E., et al. (2007). Tissue synchronisation imaging accurately measures left ventricular dyssynchrony and predicts response to cardiac resynchronisation therapy. Heart, 93, 1034–1039.
Bax, J., Abraham, T., Barold, S., Breithardt, O., Fung, J., Garrigue, S., et al. (2005). Cardiac resynchronization therapy: Part 1-issues before device implantation. Journal of the American College of Cardiology, 46(12), 2153–2167.
Bax, J. J., Bleeker, G. B., Marwick, T. H., Molhoek, S. G., Boersma, E., Steendijk, P., et al. (2004). Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. Journal of the American College of Cardiology, 44, 1834–1840.
Henzlova, M. J., Cerqueira, M. D., Mahmarian, J. J., & Yao, S. S. (2006). Quality Assurance Committee of the American Society of Nuclear Cardiology Stress protocols and tracers. Journal of Nuclear Cardiology, 13, e80–e90.
Berman, D. S., Hachamovitch, R., Kiat, H., Cohen, I., Cabico, J. A., Wang, F. P., et al. (1995). Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. Journal of the American College of Cardiology, 26, 639–647.
Chen, S. L., Fang, W. W., Ye, F., Liu, Y. H., Qian, J., Shan, S. J., et al. (2004). Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. The American Journal of Cardiology, 94, 92–95.
Strauer, B. E., Brehm, M., Zeus, T., Kostering, M., Hernandez, A., Sorg, R. V., et al. (2002). Repair of infracted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation, 106, 1913–1918.
Schächinger, V., Assmus, B., Britten, M., Honold, J., Lehmann, R., Teupe, C., et al. (2004). Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final results of the TOPCARE-AMI trial. Journal of the American College of Cardiology, 44, 1690–1699.
Cassidy, D. M., Vassallo, J. A., Marchlinski, F. E., Buxton, A. E., Untereker, W. J., & Josephson, M. E. (1984). Endocardial mapping in humans in sinus rhythm with normal left ventricles: activation patterns and characteristics of electrograms. Circulation, 70(1), 37–42.
Klemm, H., Krause, K., Ventura, R., Schneider, C., Aydin, M., Johnsen, C., et al. (2010). Slow wall motion rather than electrical conduction delay underlies mechanical dyssynchrony in postinfarction patients with narrow QRS complex. Journal of Cardiovascular Electrophysiology, 21, 70–78.
Hawkins, N., Petrie, M., MacDonald, M., Hogg, K., & McMurray, J. (2006). Selecting patients for cardiac resynchronization therapy: electrical or mechanical dyssynchrony? European Heart Journal, 27, 1270–1281.
Zwanenburg, J. J., Gotte, M. J., Marcus, J. T., Kuijer, J. P., Knaapen, P., Heethaar, R. M., et al. (2005). Propagation of onset and peak time of myocardial shortening in time of myocardial shortening in ischemic versus nonischemic cardiomyopathy: Assessment by magnetic resonance imaging myocardial tagging. Journal of the American College of Cardiology, 46(12), 2215–2222.
Liu, L., Tockman, B., Girouard, S., Pastore, J., Walcott, G., Kenknight, B., et al. (2002). Left ventricular resynchronization therapy in a canine model of left bundle branch block. American Journal of Physiology. Heart and Circulatory Physiology, 282, 2238–2244.
Abbasi, A. S., Eber, L. M., MacAlpin, R. N., & Kattus, A. A. (1974). Paradoxical motion of interventricular septum in left bundle branch block. Circulation, 49, 423–427.
Dillon, J. C., Chang, S., & Feigenbaum, H. (1974). Echocardiographic manifestations of left bundle branch block. Circulation, 49, 876–880.
McDonald, I. G. (1973). Echocardiographic demonstration of abnormal motion of the interventricular septum in left bundle branch block. Circulation, 48, 272–279.
Ozdemir, K., Altunkeser, B. B., Danis, G., Uluca, Y., Tokac, M., Telli, H. H., et al. (2001). Effect of isolated left bundle branch block on systolic and diastolic functions of the left ventricle. Journal of the American Society of Echocardiography, 14, 1075–1079.
Gianfranchi, L., Bettiol, K., Sassone, B., Verlato, R., Corbucci, G., & Alboni, P. (2008). Fusion beat in patients with heart failure treated with left ventricular pacing: may ECG morphology relate to mechanical synchrony? a pilot study. Cardiovascular Ultrasound, 6, 1–9.
Assmus, B., Fischer-Rasokat, U., Honold, J., Seeger, F., Fichtlscherer, S., Tonn, T., et al. (2007). Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure results of the TOPCARE-CHD registry. Circulation Research, 100, 1234–1241.
Cleland, J. G., Daubert, J. C., Erdmann, E., Freemantle, N., Gras, D., Kappenberger, L., et al. (2005). The effect of cardiac resynchronization on morbidity and mortality in heart failure. The New England Journal of Medicine, 352, 1539–1549.
Beshai, J. F., Grimm, R. A., Nagueh, S. F., Baker, J. H., 2nd, Beau, S. L., Greenberg, S. M., et al. (2007). Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. The New England Journal of Medicine, 357(24), 2461–2471.
Sutton, M. G., Plappert, T., Hilpisch, K. E., Abraham, W. T., Hayes, D. L., & Chinchoy, E. (2006). Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation, 113(2), 266–272.
Bleeker, G. B., Mollema, S. A., Holman, E. R., Van de Veire, N., Ypenburg, C., Boersma, E., et al. (2007). Left ventricular resynchronization is mandatory for response to cardiac resynchronization therapy: analysis in patients with echocardiographic evidence of left ventricular dyssynchrony at baseline. Circulation, 116(13), 1440–1448.
Disclosures
Giorgio Corbucci is an employee of Medtronic. Other co-authors have no conflict of interests to disclose.
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Pokushalov, E., Romanov, A., Corbucci, G. et al. Cardiac Resynchronization Therapy and Bone Marrow Cell Transplantation in Patients with Ischemic Heart Failure and Electromechanical Dyssynchrony: A Randomized Pilot Study. J. of Cardiovasc. Trans. Res. 4, 767–778 (2011). https://doi.org/10.1007/s12265-011-9283-1
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DOI: https://doi.org/10.1007/s12265-011-9283-1