The Role of Pioglitazone in Vascular Transcriptional Remodeling in Individuals Undergoing Coronary Artery Bypass Grafting
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- HDL-S1P change
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 70 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Pioglitazone
Research participants will be randomized to receive pioglitazone hydrochloride 45mg/day for 5 days prior to coronary artery bypass surgery.
干预措施: Pioglitazone 45 mg (Drug)
结局指标
主要结局
HDL-S1P change
时间窗: Five days
Change in S1P content of isolated HDL between baseline and after treatment with pioglitazone hydrochloride 45 mg/day
次要结局
- SPHK1 - atrial appendage(Five days)
- SPHK1 - internal thoracic artery(Five days)
- S1PR1 - saphenous vein(Five days)
- SPHK1 - aortic artery(Five days)
研究者
Andrei Carvalho Sposito
Professor of cardiology
University of Campinas, Brazil