The Role of Pioglitazone in Vascular Transcriptional Remodeling

NCT ID: NCT05775380

Last Updated: 2024-01-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-15
• Study Completion Date: 2024-12-22

Brief Summary

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.

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.

Conditions

Myocardial Reperfusion Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Pioglitazone

Research participants will be randomized to receive pioglitazone hydrochloride 45mg/day for 5 days prior to coronary artery bypass surgery.

Group Type: ACTIVE_COMPARATOR

Pioglitazone 45 mg

Intervention Type: DRUG

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

Placebo

Research participants will be randomized to not receive intervention in the days prior to coronary artery bypass graft surgery.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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

Intervention Type: DRUG

Other Intervention Names

pioglitazone hydrochloride

Eligibility Criteria

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

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

University of Campinas, Brazil

OTHER

Sponsor Role: lead

Responsible Party

Andrei Carvalho Sposito

Professor of cardiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrei Sposito, Professor

Role: PRINCIPAL_INVESTIGATOR

University of Campinas, Brazil

Locations

University of Campinas

Campinas, São Paulo, Brazil

Site Status: RECRUITING

Countries

Brazil

Central Contacts

Andrei Sposito, Professor

Role: CONTACT

sposito@unicamp.br

+551935218788

Isabella Bonilha, biomedical

Role: CONTACT

ibonilha@unicamp.br

+551935217959

Facility Contacts

Andrei C Sposito, MD, PhD

Role: primary

sposito@unicamp.br

+551935218788

Other Identifiers

PREVALENT

Identifier Type: -

Identifier Source: org_study_id