Master of Science
Physiology and Biophysics
Antonio Abbate MD PhD
Stefano Toldo PhD
THE EFFECTS OF AN INFLAMMASOME INHIBITOR OLT1177 ON THE DEVELOPMENT OF ISCHEMIC HEART FAILURE
By Joseph S. Aliaga, BS
A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University.
Virginia Commonwealth University, 2020
Background: Evidence suggests that prolonged and enhanced pro-inflammatory signaling, modulated by the NLRP3 inflammasome, plays a crucial role in the pathophysiology of several different types of cardiovascular diseases such as acute myocardial infarction (AMI), adverse ventricular remodeling, and heart failure (HF). Consequently, we hypothesize that attenuating the enhanced inflammatory response using a pharmacological NLRP3 inflammasome inhibitor would decrease cell death, improve cardiac function, limit adverse cardiac remodeling, and overall reduce the risk of developing ischemic heart failure. We investigated the role of the NLRP3 inflammasome after a nonreperfused AMI, by studying the effects of inhibiting the NLRP3 inflammasome.
Methods: In this study we used a mouse model of acute myocardial infarction (AMI) due to permanent coronary artery ligation. We assessed cardiac function in mice using transthoracic echocardiography 3 days after inducing a large nonreperfused AMI, via permanent ligation of the LAD coronary artery, and select mice with large nonreperfused anterior infarct (> 4 akinetic segments involving the anterior wall) as well as an enlarged ventricle (left ventricular end-diastolic diameter [LVEDD] > 4.4 mm) and systolic dysfunction (left ventricular ejection fraction [LVEF] < 40%). The mice were then randomly assigned to one of four groups.
Group 1 (n=8) consisted of mice with an AMI and were fed OLT1177, a NLRP3 inflammasome inhibitor admixed with the chow in the diet (3.75 gr/kg) for 10 weeks. Group 2 (n=7) consisted of mice with an AMI and were fed OLT1177, a NLRP3 inflammasome inhibitor admixed with the chow in the diet (7.5 gr/kg) for 10 weeks. Group 3 (n=7) consisted of mice with AMI that were fed a standard diet (without OLT1177) for 10 weeks. Group 4 (n=6) consisted of mice that underwent a sham operation and had no AMI and were fed a standard diet for 10 weeks. We repeated transthoracic echocardiography assessments 4-weeks and 10-weeks after coronary artery ligation surgery with an assessment of changes in LVEF, along with isoproterenol challenge in order to measure contractile reserve, a surrogate for cardiorespiratory fitness. The surviving mice underwent LV catheterization, a terminal procedure, in order to evaluate left ventricular diastolic function in vivo by measuring left ventricular end-diastolic pressure.
Results: At the end of 10 weeks, 2 of 10 mice (20%) had died in OLT 3.75 gr/kg group, as compared with 2 of 9 (22%) in the OLT 7.50 gr/kg group, 3 of 10 mice (30%) in the control diet group, and 0 of 6 mice (0%) in the sham-operated group. Treatment with OLT 3.75 gr/kg or 7.50 gr/kg led to preservation of contractile reserve (percent increase in LVEF after isoproterenol challenge [+33±11% or +40±6% vs +9±7 % in standard diet; P
Conclusions/implications: The results presented in this study show that NLRP3 inhibition with OLT1177 can preserve ß-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in large nonreperfused anterior AMI thereby reducing the risk of developing post-infarct heart failure.
Keywords: Acute myocardial infarction, cardiac remodeling, heart failure, NLRP3 inflammasome, NLRP3 inflammasome inhibitor, OLT1177
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Available for download on Saturday, May 22, 2021