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Improved myocardial function using a Na+/H+ exchanger inhibitor during cardioplegic arrest and cardiopulmonary bypass
Charles S Cox1, Steven J Allen, Henning Sauer
1Department of Surgery, Center for Microvascular and Lymphatic Studies at the University of Texas-Houston, Medical School, Houston, TX, USA. Charles.S.Cox@uth.tmc.edu
Insights
Sodium-hydrogen exchanger inhibition improved systolic function after cardiopulmonary bypass (CPB)/cardioplegic arrest (CPA) but did not reduce myocardial edema. This suggests a potential therapeutic target for post-CPB/CPA myocardial dysfunction.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Physiology
Background:
- Myocardial dysfunction after cardiopulmonary bypass (CPB) and cardioplegic arrest (CPA) is partly due to myocardial edema.
- Ischemia/reperfusion during CPB/CPA activates the Na(+)/H(+) exchanger, leading to intracellular Na(+) and water accumulation.
- Selective Na(+)/H(+) exchanger inhibition was hypothesized to reduce edema and improve cardiac performance post-CPB/CPA.
Purpose of the Study:
- To investigate the effect of Na(+)/H(+) exchanger inhibition on myocardial edema and function after CPB/CPA.
- To determine if EMD 87580, a selective Na(+)/H(+) exchanger inhibitor, mitigates CPB/CPA-induced myocardial dysfunction.
Main Methods:
- Anesthetized dogs underwent instrumentation for myocardial function assessment (ultrasonic crystals, LV micromanometer) and myocardial water content (MWC) measurement.
- Animals received either EMD 87580 (treatment group, n=5) or saline vehicle (control group, n=9) prior to and during CPB/CPA.
- Myocardial function and MWC were evaluated at baseline, after 2 hours of hypothermic CPB/CPA, and 45 minutes of reperfusion/rewarming.
Main Results:
- Preload recruitable stroke work remained stable in the EMD 87580 group and was significantly higher post-CPB compared to controls.
- Maximal rate of rise of LV pressure (dp/dtMAX) was preserved in the EMD 87580 group but decreased significantly in controls.
- Myocardial water content increased in both groups with no significant difference observed between treated and control animals.
Conclusions:
- Na(+)/H(+) exchanger inhibition with EMD 87580 improves systolic function following CPB/CPA.
- The observed functional improvement is not attributed to a reduction in myocardial edema.
- This suggests that Na(+)/H(+) exchanger inhibition may offer a therapeutic benefit for systolic dysfunction post-CPB/CPA through mechanisms other than edema reduction.
Introduction:
We have demonstrated that a component of post-cardiopulmonary bypass (CPB)/cardioplegic arrest (CPA) myocardial dysfunction is related to myocardial edema. Myocardial ischemia/reperfusion that occurs with CPB/CPA activates the Na(+)/H(+) exchanger to normalize intracellular pH, with intracellular Na(+) (and water) accumulation. We hypothesized that Na(+)/H(+) exchanger inhibition with a selective inhibitor (EMD 87580) would decrease myocardial edema and improve myocardial performance after CPB/CPA.
Methods:
Anesthetized dogs (n = 14) were instrumented with myocardial ultrasonic crystals, and left ventricular (LV) micromanometer, to study myocardial function. Myocardial tissue water (MWC) was determined using microgravimetry. Treated animals (n = 5) received EMD 87580 (5 mg/kg IV pretreatment and 10 mol/L cardioplegia); control animals (n = 9) received a saline vehicle. After baseline, hypothermic CPB/CPA was initiated for 2 h, followed by reperfusion/rewarming for 45 min and separation from CPB. Myocardial function parameters and MWC were measured at 30 min, 60 min, and 120 min after CPB.
Results:
Preload recruitable stroke work did not decrease from baseline in EMD 87580-treated animals, and was significantly greater in EMD 87580-treated animals than control animals at 120 min after CPB. At a similar LV end-diastolic volume, the maximal rate of rise of LV pressure (dp/dtMAX) was significantly decreased from baseline at all time points in control animals, and unchanged in EMD 87580-treated animals. MWC increased with CPB/CPA in both groups, with no difference between groups. There was no difference in - dp/dtMAX or slope of the end-diastolic pressure-volume relationship.
Conclusion:
Na(+)/H(+) exchanger inhibition improves systolic but not diastolic function after CPB/CPA. This is not due to a reduction in MWC.