The Role of Pioglitazone in Vascular Transcriptional Remodeling (PREVALENT)

The Role of Pioglitazone in Vascular Transcriptional Remodeling in Individuals Undergoing Coronary Artery Bypass Grafting

Acute myocardial infarction (AMI) remains the leading cause of death worldwide. In this scenario, early coronary reperfusion is the main therapeutic strategy as it substantially reduces mortality. Paradoxically, however, reperfusion triggers additional tissue damage that accounts for about 50% of the infarcted heart mass, i.e., ischemia and reperfusion injury (IRL). In this context, sphingosine-1-phosphate (S1P) is a sphingolipid synthesized by sphingosine kinases (Sphk), carried in plasma bound to high-density lipoprotein (HDL) and released after cellular damage such as LIR. Particularly, in animal models of AMI, therapies targeting downstream S1P receptor signaling triggered by HDL/S1P are able to promote endothelial barrier functions and attenuate secondary damage to LIR. Thus, the molecular control of sphingosine kinase 1 (Sphk1) transcription during LIR in vivo or during hypoxia/reoxygenation (H/R) in vitro may represent an important mechanism for maintaining endothelial homeostasis since it promotes the generation of S1P and this may promote subsequent HDL enrichment. Thus, the role of pioglitazone hydrochloride 45mg/day for five days in volunteers undergoing coronary artery bypass grafting (BVR) will be investigated in order to verify the vascular expression of SPhk1, transcriptome and vascular proteome remodeling, as well as S1P content in HDL.

Study Overview

• Status: Recruiting
• Conditions: Myocardial Reperfusion Injury
• Intervention / Treatment: Drug: Pioglitazone 45 mg

Detailed Description

This will be a prospective, randomized and open clinical study. From a sample of patients hospitalized for myocardial revascularization surgery, followed at the cardiac surgery outpatient clinic, 20 research participants, male, aged over 40 years, non-diabetic or diabetic with disease duration of less than 10 years, glycated hemoglobin <8% and non-user of NPH insulin, body mass index (BMI) between 20 and 34.9kg/m2 and glomerular filtration rate above 45mL/min who will be monitored at the Hospital de Clínicas/UNICAMP and randomized to receive pioglitazone hydrochloride 45mg/day for 5 days before surgery. The amount of S1P in HDL at baseline (before surgery) will be assessed. This same measurement will be repeated on day 5 (coinciding with the day of surgery) after using pioglitazone hydrochloride 45mg/day. In addition, on the day of surgery, a saphenous vein fragment of approximately 2 cm and an internal thoracic artery fragment of approximately 1 cm will be collected, which will not impair the quality of the graft nor the extent of the material to be used as a graft, because in this case the vascular material is abundant. An aortic artery button and an atrial appendage button will also be collected, which will be discarded. In addition, the results of serum troponin levels in the first 24h post-SVR (6, 12, 24h) will be evaluated to estimate the extent of troponin release. Postoperative examination.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Andrei Sposito, Professor; Phone Number: +551935218788; Email: sposito@unicamp.br
• Study Contact Backup: Name: Isabella Bonilha, biomedical; Phone Number: +551935217959; Email: ibonilha@unicamp.br

Study Locations

• Brazil
  • SP
    • Campinas, SP, Brazil, 13083-887
      • Recruiting
      • University of Campinas
      • Principal Investigator: Andrei C Sposito, MD, PhD
      • Contact: Andrei C Sposito, MD, PhD; Phone Number: +551935218788; Email: sposito@unicamp.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male individuals
• Individuals undergoing CABG surgery for coronary artery disease
• Be over 40 years of age
• BMI between 20 and 34.9kg/m2
• Non-diabetic or if diabetic, disease duration < 10 years, Hba1c < 8%, non-user of NPH insulin
• Ejection fraction > 40%
• Glomerular filtration rate > 45 mL/min

Exclusion Criteria:

• BMI greater than 35 kg/m2, steatohepatitis, chronic kidney disease, systemic vasculitis, conditions that induce systemic inflammation such as psoriasis and systemic lupus erythematosus
• contraindications to the use of pioglitazone hydrochloride (heart failure, liver failure - AST or ALT > 2.5x upper normal limit, history of bladder cancer or macroscopic hematuria without investigation)
• moderate or severe valve disease
• need for concomitant use of other hypoglycemic therapies during hospitalization, particularly insulin
• peripheral edema
• recent hospitalization
• known allergy to any study drug
• polyuria, polydipsia, weight loss, or other clinical signs of volume depletion or diabetes, difficult-to-control systemic arterial hypertension, defined as individuals taking 4 or more drugs
• those who withdraw the Informed Consent Form (TCLE), or who, for some reason, are not able to sign or understand the TCLE
• history of gastrointestinal disorders that may interfere with study drug absorption
• research participant who is participating in other clinical trials or whose participation ended less than six months ago
• Research participant who has left ventricular dysfunction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pioglitazone; Research participants will be randomized to receive pioglitazone hydrochloride 45mg/day for 5 days prior to coronary artery bypass surgery.	Drug: Pioglitazone 45 mg; We investigated the role of pioglitazone hydrochloride 45mg/day for five days in patients admitted for coronary artery bypass grafting (CABG) in order to investigate vascular SPhk1 expression, vascular transcriptome and proteome remodeling, as well as S1P content in HDL; Other Names: pioglitazone hydrochloride
No Intervention: Placebo; Research participants will be randomized to not receive intervention in the days prior to coronary artery bypass graft surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HDL-S1P change	Change in S1P content of isolated HDL between baseline and after treatment with pioglitazone hydrochloride 45 mg/day	Five days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SPHK1 - internal thoracic artery	Difference in SPHK1 expression in the internal thoracic artery cells determined by western blot between groups	Five days
S1PR1 - saphenous vein	Difference in S1P receptor (S1PR1) expression in saphenous vein endothelial cells determined by western blot between groups	Five days
SPHK1 - aortic artery	Difference in SPHK1 expression in the aortic artery cells determined by western blot between groups;	Five days
SPHK1 - atrial appendage	Difference in SPHK1 expression in the atrial appendage cells determined by western blot between groups;	Five days

Collaborators and Investigators

• Sponsor: University of Campinas, Brazil
• Investigators: Principal Investigator: Andrei Sposito, Professor, University of Campinas, Brazil

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2023
• Primary Completion (Estimated): June 28, 2024
• Study Completion (Estimated): December 22, 2024

Study Registration Dates

• First Submitted: March 7, 2023
• First Submitted That Met QC Criteria: March 17, 2023
• First Posted (Actual): March 20, 2023

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Cardiomyopathies; Reperfusion Injury; Myocardial Reperfusion Injury; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: PREVALENT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No