Tachycardia-Induced Heart Failure Does Not Alter Myocardial P-glycoprotein Expression

J. Jason Sims, Pharm.D.; Brien L. Neudeck, Pharm.D.; Jennifer M. Loeb, B.S.; Nicholas A. Wiegert, B.S.


Pharmacotherapy. 2004;24(1) 

In This Article

Abstract and Introduction

Study Objective: To determine the effects of tachycardia-induced heart failure on myocardial P-glycoprotein (P-gp) expression.
Design: Nonblinded, parallel, sham-controlled, animal model study.
Setting: University laboratory.
Animals: Thirty mongrel dogs.
Intervention: Heart failure was induced by rapid ventricular pacing over 4 weeks; sham procedures were performed for the control group.
Measurements and Main Results: Myocardial biopsies were taken from the left ventricular lateral wall and prepared for P-gp quantification by laser-induced fluorescence. The relative amount of P-gp messenger RNA (mRNA) was assessed by reverse transcriptase polymerase chain reaction. Rapid ventricular pacing produced heart failure and reduced the area ejection fraction from 48% ± 6% to 21% ± 6% (p<0.05 vs baseline). However, heart failure did not alter the quantity of myocardial P-gp (0.20 ± 0.02 µg/ml for the control group vs 0.23 ± 0.02 µg/ml for the intervention group, p=0.4). Furthermore, heart failure did not alter P-gp expression significantly.
Conclusion: Myocardial P-gp does not change in response to tachycardia-induced heart failure. Thus, there is a low likelihood for P-gp–related drug resistance during a syndrome similar to tachycardia-induced heart failure.

Heart failure afflicts approximately 5 million people in the United States; over 500,000 new cases are diagnosed every year.[1] The annual cost for heart failure medical care is more than $20 billion.[2,3] Mortality from heart failure remains high even in the presence of aggressive and appropriate pharmacotherapy.[4] Thus, the need to improve treatment of heart failure is clear.

Although the reasons heart failure continues to progress in patients receiving appropriate therapy are not known, one explanation may be the development of myocardial drug resistance. This drug resistance, however, cannot be fully explained by disease progression alone. Thus, other mechanisms may contribute. One possible and unexplored mechanism of drug resistance in patients with heart failure is altered myocardial expression of the multidrug efflux protein, P-glycoprotein (P-gp).

P-glycoprotein is a 170-kD protein encoded by the human MDR1 gene and is a member of the adenosine 5'-triphosphate–binding cassette family of transporters.[5] P-glycoprotein is best known for the efflux of chemotherapeutic agents leading to drug resistance and therapeutic failure. However, P-gp has been identified in many organs, such as the heart.[6–9] Although the exact physiologic role of P-gp is not known, this protein appears to be involved primarily in cellular protection against potentially toxic compounds, such as drugs.[10] Of importance, many drugs commonly administered in patients with heart failure are P-gp substrates, inhibitors and/or inducers, such as amiodarone, atorvastatin, carvedilol, digoxin, and losartan.[11–15]

Since the role of P-gp is to protect cells from potentially harmful substances, it probably is involved in the cellular response against stress. In fact, numerous stress-inducing stimuli alter P-gp gene expression.[16–21] Moreover, other proteins that share signal transduction pathways similar to that of P-gp have increased during the stress of heart failure.[22–25] Thus, we would expect myocardial P-gp to serve as a barrier between the blood and cardiac myocytes during heart failure to protect against potentially harmful substances such as catecholamines, aldosterone, and cardioactive or vasoactive peptides.[26–28] It is important to recognize that if P-gp is increased with heart failure, it also may decrease myocardial concentrations of drugs that are substrates.

Thus, we hypothesized that heart failure would increase expression of myocardial P-gp. In our study, we tested the hypothesis that tachycardia-induced heart failure increases myocardial P-gp in a canine model.