The Role of Pioglitazone in Vascular Transcriptional Remodeling

Myocardial Reperfusion Injury Clinical Trial

— PREVALENT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05775380
• Other study ID #: PREVALENT
• Status: Recruiting
• Phase: Phase 4
• Start date: June 15, 2023
• Est. completion date: December 22, 2024

Study information

• Verified date: January 2024
• Source: University of Campinas, Brazil
• Contact: Andrei Sposito, Professor
• Phone: +551935218788
• Email: sposito[@]unicamp.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 22, 2024
• Est. primary completion date: June 28, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 40 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Myocardial Reperfusion Injury
• Reperfusion Injury

Intervention

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

Locations

Country	Name	City	State
Brazil	University of Campinas	Campinas	SP

Sponsors (1)

Lead Sponsor	Collaborator
University of Campinas, Brazil

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HDL-S1P change	Change in S1P content of isolated HDL between baseline and after treatment with pioglitazone hydrochloride 45 mg/day	Five days
Secondary	SPHK1 - internal thoracic artery	Difference in SPHK1 expression in the internal thoracic artery cells determined by western blot between groups	Five days
Secondary	S1PR1 - saphenous vein	Difference in S1P receptor (S1PR1) expression in saphenous vein endothelial cells determined by western blot between groups	Five days
Secondary	SPHK1 - aortic artery	Difference in SPHK1 expression in the aortic artery cells determined by western blot between groups;	Five days
Secondary	SPHK1 - atrial appendage	Difference in SPHK1 expression in the atrial appendage cells determined by western blot between groups;	Five days