25995227

PMC4512882

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.

CDC Public Access

1 UM1 HL-113530/HL/NHLBI NIH HHS/United States
H75 DP424252/DP/NCCDPHP CDC HHS/United States
P01 HL078825/HL/NHLBI NIH HHS/United States
P01-HL78825/HL/NHLBI NIH HHS/United States
R01 HL055757/HL/NHLBI NIH HHS/United States
R01 HL068088/HL/NHLBI NIH HHS/United States
R01 HL074351/HL/NHLBI NIH HHS/United States
R01-HL74351/HL/NHLBI NIH HHS/United States
UM1 HL113530/HL/NHLBI NIH HHS/United States