br Material and methods br Acknowledgments We are

Material and methods
Acknowledgments We are grateful to D. Trono (Lausanne, Switzerland) for the plasmid pMD2.G and psPAX2. We thank Brigitte Jenewein for her excellent technical assistance with the confocal laser-scanning microscopy and the flow cytometry analysis. This work was supported by funding from the Austrian Academy of Sciences.
Introduction In the last decade, stem cell therapy has been introduced as a novel treatment for acute myocardial infarction (AMI) (Bouchentouf et al., 2010; Silva et al., 2009). Although the benefits to overall systolic function have been confirmed, the effect of stem purchase A-366 on diastolic function has been rarely studied. Experimental studies have suggested that the myocardial transfer of bone-marrow-derived cells (BMCs) may enhance diastolic function after MI (Limbourg and Drexler, 2005; Orlic et al., 2001), but the early- and mid-term clinical effects of intracoronary BMCs have been contradictory. The BOOST trial (Schaefer et al., 2006) concluded that BMC transfer improved diastolic function at 6-month follow up, whereas Herbots et al. (Herbots et al., 2009) did not find a similar improvement in diastolic left ventricular (LV) function at 4months. There is another unanswered question concerning the effect of BMC therapy on exercise capacity. Symptoms of cardiac disease generally manifest during exercise, and it is well known that resting parameters of LV systolic function correlate poorly with exercise capacity (Franciosa et al., 1981). Changes in exercise capacity may be the result of changes in cardiac diastolic function. The BALANCE (Yousef et al., 2009) and ASTAMI (Beitnes et al., 2009) studies could not come to a consistent conclusion regarding the effect of stem cells on exercise capacity. Among research methodologies, meta-analysis is most useful when there is no adequately powered, prospective, randomized study to answer the question at hand. This meta-analysis attempted to determine whether autologous BMCs are beneficial to LV diastolic function and exercise capacity after AMI.
Results
Discussion The findings from the trials are listed as follows: 1) BMC therapy after AMI has been shown to lead to a mild mid-term improvement in diastolic cardiac function, including E/Ea and PVR, compared to the control group; 2) this improvement was accompanied by an improved exercise capacity after 1year of follow up. The E/A ratio, DT and IVRT have a biphasic relationship to LV diastolic properties and filling pressure. Patients with AMI may have pseudo-normal or restrictive mitral flow patterns at baseline due to a high filling pressure. Changes in these parameters should therefore be interpreted with caution. Modern tissue Doppler measurements of LV diastolic function may be more sensitive than traditional echocardiographic methods for risk prediction. E/Ea is a non-invasive, reproducible index, even beyond the usual Doppler parameters. E/Ea has been extensively correlated with invasively measured LV diastolic pressures regardless of LV ejection fraction (Bruch et al., 2005). E/Ea is the strongest predictor of primary cardiac events and represents a simple, effective tool for assessing cardiac risk in a hypertensive population (Sharp et al., 2010) and for assessing heart failure (HF) (Bruch et al., 2007). Therefore, we chose E/Ea as our primary endpoint. Because all diastolic indices have limitations, a comprehensive evaluation was conducted. A further decrease in E/Ea and other tissue Doppler indicators was observed in the BMC group, which probably reflects a decrease in the LV filling pressure during recovery after AMI. Combined with other indices, a decreased PVR corresponded to a decrease in left atrial pressure and LV filling pressures after BMC therapy. These findings suggest that the BMC transfer group recovered from a very mild form of early diastolic dysfunction and may have improved survival after AMI. One may argue that at the long-term follow up (3–5years) for diastolic function, patients in the BMC group did not achieve further benefits compared to the control group. It is well known that diastolic function is related to myocardial relaxation and passive LV properties. After myocardial infarction, improved systolic function was observed in BMC-treated patients (Plewka et al., 2009). Enhanced systolic function could result in increased restorative forces, which would lead to a decreased LV filling pressure, as we found with PVR, and lead to an improvement in early diastolic relaxation and passive myocardial movement. Because systolic function only exhibited mild to moderate improvement in the first few months, it is possible that BMC therapy was not responsible for the long-term beneficial effect on diastolic function. We must be cautious about the current long-term results of BMC transplantation regarding diastolic function because only two trials, with a total of 156 patients, were available at this stage (Beitnes et al., 2011; Schaefer et al., 2010). Furthermore, the long-term results may be influenced by many other uncertainties; years after the cell therapy, any impact of BMCs could become minimal.