Stem cells improve right ventricular functional recovery after acute pressure overload and ischemia reperfusion injury.
BACKGROUND
In many clinical scenarios, a relatively untrained right ventricle may be subjected to acute elevations in pulmonary artery and right ventricular pressures. The right and left heart are distinctly different in this regard and there is currently no in vivo model to study right ventricular ischemia in the setting of acute pressure overload. In acute injury, cardiomyocytes produce tumor necrosis factor, which mediates a proinflammatory pathway, eventually leading to myocardial dysfunction. Stem cells have been shown to reduce the production of proinflammatory mediators by the ischemic myocardium and protect the myocardium. Pretreatment with stem cells has been shown to protect the left ventricle. The effect of acute pressure overload to the untrained right ventricle is still not well understood. Furthermore, it is unclear whether pretreatment with stem cells would protect the right ventricle when it is subjected to acute pressure overload and concomitant ischemia reperfusion injury. The purpose of this study was (1) to create a simple model of acute pressure overload for the study of concomitant right ventricular ischemia and reperfusion, and (2) to evaluate the effect of pretreatment with stem cells prior to ischemia reperfusion injury.


METHODS
Isolated rat hearts were perfused with the modified Langendorff technique with the latex balloon in the right ventricle instead of the left, with a pressure-transduced balloon being used to create an acute elevation in right ventricular pressure before ischemia. In the first of a two-series experiment, there were two experimental groups (N = 8 per group): one with right ventricular balloon end-diastolic pressure (EDP) of 5 mmHg (physiological), and the other with an EDP of 40 mmHg (pathologic). In the second series, the hearts with the higher balloon pressure (EDP 40 mmHg) were divided into two experimental groups (N = 5 per group). The control group was not pretreated. One group was pretreated with human mesenchymal stem cells 5 min immediately prior to ischemia reperfusion injury. Right ventricular developed pressure (RVDP), contractility (+dP/dt), and compliance (-dP/dt) were continuously assessed. Additionally, mesenchymal stem cells (MSCs) in culture were stressed by hypoxia and activation was determined by measuring vascular endothelial growth factor-A (VEGF) and hepatocyte growth factor (HGF) production by enzyme-linked immunosorbent assay.


RESULTS
Recovery of RVDP, +dP/dt, and -dP/dt was significantly higher (P < 0.001) in the group with lower EDP compared to the group with the higher EDP [RVDP: 79.53 +/- 6.34 versus 54.28 +/- 10.76%; +dP/dt: 76.54 +/- 8.79 versus 38.75 +/- 19.74%; -dP/dt: 72.29 +/- 7.02 versus 30.54 +/- 12.44%]. In the higher EDP groups, pretreatment with human mesenchymal stem cells significantly improved myocardial function recovery (P < 0.01) when compared to controls [RVDP: 75.76 +/- 7.97 versus 59.10 +/- 11.18%; +dP/dt: 71.78 +/- 10.36 versus 54.93 +/- 12.64%; -dP/dt: 77.38 +/- 11.09 versus 59.30 +/- 15.20%]. Further, hypoxic MSCs demonstrated significantly greater VEGF and HGF release than controls.


CONCLUSIONS
This compounded injury model allowed the study of right ventricular dysfunction in the setting of acute pressure overload and ischemia. Additionally, we have also demonstrated that pretreatment with stem cells of an acutely pressure overloaded right ventricle prior to ischemia reperfusion injury improves functional recovery. This is the first report of a modified Langendorff technique to study right ventricular function in the setting of acute pressure overload and ischemia and the effect of pretreatment with stem cells.
Wairiuko
George M
GM
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Crisostomo
Paul R
PR
Wang
Meijing
M
Morrell
Eric D
ED
Meldrum
Kirstan K
KK
Lillemoe
Keith D
KD
Meldrum
Daniel R
DR
D000818:Animals; D001794:Blood Pressure; D015687:Cell Hypoxia; D003971:Diastole; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor