Digital Theses Archive


Tesi etd-09012022-114147

Type of thesis
Pirfenidone to reduce scar size and prevent adverse ventricular remodeling after myocardial infarction
Scientific disciplinary sector
Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE
relatore Prof. EMDIN, MICHELE
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Exam session start date
Background: An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling, increasing the risk for ventricular arrhythmias and heart failure. Pirfenidone is a drug currently approved for the treatment of idiopathic pulmonary fibrosis, and reduces LV fibrosis in patients with heart failure and preserved ejection fraction. <br><br>Aims: 1) To investigate the molecular pathways involved in cardiac remodeling and modulated by pirfenidone and/or standard therapies for MI, based on prior knowledge, 2) to assess the effect of pirfenidone on top of standard treatment for MI on ventricular remodeling and the expansion of infarct scar in a rat model of reperfused MI, 3) to characterize the different profiles or protein expression in the infarct zone in animals receiving or not receiving pirfenidone. <br><br>Methods: <br>1) We assessed the molecular information and transcriptomic data from a swine model of MI through a bioinformatic analysis. <br>2) Circulating levels of pirfenidone were much lower in pigs compared to human patients, therefore the assessment of pirfenidone in a pig model was not pursued. Male Wistar rats were randomized to: sham procedure (group 1; n=13), reperfused MI induced by surgical ligation of the left anterior descending artery for 45 minutes (group 2; n=17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta-blocker, and also mineralocorticoid receptor antagonist [MRA]) (group 3; n=17), reperfused MI plus pirfenidone alone (group 4; n=17), reperfused MI plus standard therapy and pirfenidone (group 5; n=17). Rats surviving LAD ligation and reperfusion underwent cardiac magnetic resonance (CMR) after 72 hours and 30 days from MI, and were sacrificed the day after the second CMR exam. The primary endpoint was the change in late gadolinium enhancement (LGE) mass as a percentage of LV mass. <br>3) In 4-month-old pigs, MI was induced by occluding the left anterior descending (LAD) artery through an angioplasty balloon for 90 minutes. Pigs surviving MI induction were randomized in a 1:1 fashion to 2 arms: <br>- control group (n=13): MI induction and reperfusion, standard treatment (see below),<br>- colchicine group (n=13): MI induction and reperfusion, standard treatment plus colchicine. <br>The pigs underwent a first cardiovascular magnetic resonance (CMR) 72 hours after MI induction, and another CMR at day 30. The pigs were then sacrificed the day after the second CMR exam. The primary efficacy endpoint was myocardial salvage index (MSI).<br> <br>Results:<br>1) Pirfenidone had a more widespread action than gold-standard drugs, encompassing 6 motives (cardiomyocyte cell death, impaired myocyte contractility, extracellular matrix remodeling and fibrosis, hypertrophy, renin-angiotensin-aldosterone system activation, and inflammation), with prominent effects on p38γ-MAPK12, the TGFβ1-SMAD2/3 pathway and other effector proteins such as matrix metalloproteases 2 and 14, PDGFA/B, and IGF1.<br>2) Forty-six rats survived until the second CMR. Percent changes in LV end-diastolic and end-systolic volume (p=0.370 and 0.423, respectively), ejection fraction (p=0.236) and mass (p=0.815) did not differ significantly between rats on pirfenidone plus standard therapy compared with those receiving standard therapy alone. The decrease in LGE mass was significantly greater in rats on pirfenidone plus standard therapy vs. rats on standard therapy alone: -22.0% (interquartile range [IQR], -37.1 to -5.7, range -51.1 to +37.5) vs. +1.9% (-7.7 to +12.5, range -19.8 to +56.5), p=0.029. <br><br>Conclusions:<br>1) A bioinformatic approach allowed to identify several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodeling, and suggests additional effects over guideline-recommended therapies.<br>2) Pirfenidone had additive effects to standard therapy for MI (including an MRA) in reducing LV fibrosis in a rat model of reperfused MI, while it did not further improve LV function, volumes or mass. <br>