Rationale The effects of c-kitPOS cardiac progenitor cells (CPCs) (and adult cell therapy in general) on left ventricular (LV) function have been regarded as modest or inconsistent. Objective To determine whether three CPC infusions have greater efficacy than one infusion. Methods and Results Rats with a 30-day-old myocardial infarction received one or three CPC infusions into the LV cavity, 35 days apart. Compared with vehicle-treated rats, the single-dose group exhibited improved LV function after the 1st infusion (consisting of CPCs) but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group regional and global LV function improved by a similar degree after each CPC infusion, resulting in greater cumulative effects. For example, the total increase in LV ejection fraction was approximately triple in the multiple-dose group vs. the single-dose group (P<0.01). The multiple-dose group also exhibited more viable tissue and less scar, less collagen in the risk and noninfarcted regions, and greater myocyte density in the risk region. Conclusions This is the first demonstration that repeated CPC administrations are markedly more effective than a single administration. The concept that the full effects of CPCs require repeated doses has significant implications for both preclinical and clinical studies; it suggests that the benefits of cell therapy may be underestimated or even overlooked if they are measured after a single dose, and that repeated administrations are necessary to properly evaluate the effectiveness of a cell product. In addition, we describe a new method that enables studies of repeated cell administrations in rodents.

Background Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. Methods This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency–to–high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. Results Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was – 0.57 and – 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. Conclusions This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442.

SummaryWhen pulmonary embolism (PE) develops, circulatory collapse and hypoxia are caused at the same time. The rapid and proper use of extracorporeal life support (ECLS) can improve the mortality rate of patients with collapsed massive PE. No study has examined the influence of treatment that involved adding catheter based-intervention to ECLS with massive collapsed PE. Thirty-five patients with massive PE were examined, and 10 of these patients were placed on ECLS. Eight of the 10 patients placed on ECLS for massive PE were female, and the median age was 61 years. Seven patients had in-hospital onset PE and 3 patients out-of-hospital onset PE. Their underlying conditions were a cerebral infarction (3 patients), coronary artery disease (5 patients), collagen disease (one patient), postoperative state (3 patients), and lung disease (2 patients). Pulmonary angiographic findings showed that a filling defect or complete occlusion was observed in all 10 patients in the proximal lobular arteries, 6 of which had large thrombi stretching to the main pulmonary arteries. All patients underwent thrombolysis. Percutaneous catheter embolus fragmentation and/or thrombectomy were undertaken in 7 patients. All patients required red blood cell transfusion for cannulation site bleeding. The mean duration of ECLS bypass was 48 ± 44 hours. The 30 day mortality rate was 30%. The current study clarified the characteristics of patients with massive PE requiring ECLS. These patients have extensive pulmonary thromboemboli, thus, the aggressive use of catheter-based intervention appears to have beneficial effects for massive PE requiring ECLS. (Int Heart J 2012; 53: 370-374)

Background Although c-kitpos cardiac stem cells (CSCs) preserve left ventricular (LV) function and structure after myocardial infarction (MI), CSC doses have been chosen arbitrarily and the dose-effect relationship is unknown. Methods and Results Rats underwent a 90-min coronary occlusion followed by 35 days of reperfusion. Vehicle or CSCs at 5 escalating doses (0.3 ×106, 0.75 ×106, 1.5 ×106, 3.0 ×106, and 6.0 ×106 cells/heart) were given intracoronarily 4 h after reperfusion. The lowest dose (0.3 ×106) had no effect on LV function and morphology, whereas 0.75, 1.5, and 3.0 ×106 significantly improved regional and global LV function (echocardiography and hemodynamic studies). These three doses had similar effects on echocardiographic parameters (infarct wall thickening fraction, LV end-systolic and end-diastolic volumes, LV ejection fraction) and hemodynamic variables (LV end-diastolic pressure, LV dP/dtmax, preload adjusted maximal power, end-systolic elastance, preload recruitable stroke work), and produced similar reductions in apoptosis, scar size, infarct wall thinning, and LV expansion index and similar increases in viable myocardium in the risk region (morphometry). Infusion of 6.0 ×106 CSCs markedly increased post-procedural mortality. GFP and BrdU staining indicated that persistence of donor cells and formation of new myocytes were negligible with all doses. Conclusions Surprisingly, in this rat model of acute MI, the dose-response relationship for intracoronary CSCs is flat. A minimal dose between 0.3 and 0.75 ×106 is necessary for efficacy; above this threshold, a four-fold increase in cell number does not produce greater improvement in LV function or structure. Further increases in cell dose are harmful.