Contrast induced nephropathy (CIN) remains a clinical problem associated with significant morbidity and mortality. Some clinical trials suggest a protective effect of the antioxidant agent N-Acetylcysteine (NAC). We hypothesize that NAC added to a radiographic contrast agent can provide cardiac and renal protection. A preliminary study was performed that demonstrated that NAC significantly ameliorates CIN and reduces myocardial infarct (MI) size in a pig model of myocardial ischemia and reperfusion. However this study was small in size and NAC protection was provided during both ischemia and reperfusion. This proposal is directed at exploring the cardiorenal protective effect of NAC more extensively in a setting that simulates clinical practice. The primary goal of this study is to demonstrate the safety of this approach. Furthermore this proposal is directed at quantifying the cardiac efficacy of NAC by studying cardiac function and detailed MI analysis. In addition we aim to analyze the protective effects on renal function and tubular injury. Myocardial infarctions (MI) will be induced in minipigs by a one hour ligation of the mid left anterior descending artery. At the time of reperfusion all animals will received the same volume of intracoronary Iopamidol contrast (200mL) to induce CIN. Half the animals will receive NAC. The following parameters will be analyzed: myocardial function analysis (magnetic resonance imaging), myocardium-at-risk for infarction (Evans-Blue perfusion stain, fluoroscopic microspheres), myocardial infarction size (TTC stain), cardiac and renal apoptosis (TUNEL stain), renal function (Creatinine), renal tubular markers of kidney injury and an arrhythmia evaluation (ECG telemetry, electrophysiological testing). Confirmation of this conceptual approach of antioxidant-enhanced-contrast agents would lay the foundation for a clinical trial and at the same time provide opportunities to study the molecular mechanisms that mediate the renal and cardioprotective effects.

Public Health Relevance

The detection of coronary heart disease or the treatment of heart attacks requires the use of contrast agents. Unfortunately, these contrast agents are toxic to the kidneys and some patients will develop kidney failure. We are investigating if the antioxidant N-Acetylcysteine added to a contrast agent can reduce kidney toxicity and protect the heart at the same time.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL094807-01A1
Application #
7787295
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2010-01-04
Project End
2011-11-30
Budget Start
2010-01-04
Budget End
2010-11-30
Support Year
1
Fiscal Year
2010
Total Cost
$188,125
Indirect Cost
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Meyer, Markus; McEntee, Rachel K; Nyotowidjojo, Iwan et al. (2015) Relationship of exercise capacity and left ventricular dimensions in patients with a normal ejection fraction. An exploratory study. PLoS One 10:e0119432
Meyer, Markus; Bell, Stephen P; Chen, Zengyi et al. (2013) High dose intracoronary N-acetylcysteine in a porcine model of ST-elevation myocardial infarction. J Thromb Thrombolysis 36:433-41
LeWinter, Martin M; Meyer, Markus (2013) Mechanisms of diastolic dysfunction in heart failure with a preserved ejection fraction: If it's not one thing it's another. Circ Heart Fail 6:1112-5