Table 2.

Reports of the adverse effects of rosiglitazone on the cardiovascular system in pre-clinical and clinical studies

Model	Dose of rosiglitazone	Major findings	Interpretation	Ref.
Isolated and cultured vascular smooth muscle cells	1-10 μmol/L; incubated for 24 h	Induced cell death in a concentration-dependent manner	Rosiglitazone induced apoptotic cell death through an ERK1/2-independent pathway	[17]
		Increased caspase 3 activity and the cytoplasmic histone-associated DNA fragmentation
		PD98059 (MAPKK inhibitor) did not abolish rosiglitazone induced ERK1/2 activation (proapoptotic effects)
Rats with I/R injury	3 mg/kg per day po; pretreated for 14 d prior to I/R	Did not reduce left ventricular infarct size or hypertrophy	Rosiglitazone did not prevent left ventricular remodeling, but was associated with increased mortality after myocardial infarction	[21]
		Increased mortality rate
		Improved ejection fraction and prevented an increase left ventricular end diastolic pressure
Swine with I/R injury	3 mg/kg per day po; pretreated for 8 d prior to I/R	Increased expression of PPARγ	Rosiglitazone had no cardioprotective effects in a swine model of myocardial I/R injury	[25]
		Had no effect on myocardial contractile function
		Did not alter substrate uptake and proinflammatory cytokines expression
PPARγ-knockout (CM-PGKO) mouse	10 mg/kg per day po; 4 wk	Increased phosphorylation of p38 mitogen-activated protein kinase	Rosiglitazone caused cardiac hypertrophy at least partially independent of PPARγ in cardiomyocytes	[15]
		Induced phosphorylation of extracellular signal-related kinase 1/2
		Did not affect phosphorylation of c-Jun N-terminal kinases
		Induced cardiac hypertrophy
Wild type and PPARγ overexpression mice	10 mg/kg per day po; 15 d	Increased lipid accumulation	Rosiglitazone and PPARγ overexpression could be harmful to cardiac function	[24]
		Increased size of the heart
		Decreased fractional shortening
		Increased CD36 expression
Swine with I/R injury	0.1, 1.0 10 mg/kg iv; pretreated for 60 min	Attenuated MAP shortening during ischemia by blocking cardiac KATP channels	Rosiglitazone promoted onset of ventricular fibrillation during cardiac ischemia	[20]
		Increased propensity for ventricular fibrillation during myocardial ischemia
Sprague-Dawley rats	15 mg/kg per day po; 21 d	Induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin	Rosiglitazone induced cardiac hypertrophy via the mTOR pathway	[16]
		Reduced heart rate and increased stroke volume
		Increased heart glycogen content, myofibrillar protein content and turnover
		Reduced glycogen phosphorylase expression and activity
Meta-analysis in T2DM (n = 15 565, control = 12 282)	Received rosiglitazone more than 24 wk	Increased the risk of myocardial infarction	Rosiglitazone increased in the risk of myocardial infarction and borderline increased in risk of cardiovascular death	[11]
		Increased cardiovascular death incidence
RECORD study (n = 4447)	Received rosiglitazone with mean follow-up time of 3.75 yr	Increased the risk of heart failure	Rosiglitazone increased risk of heart failure, but did not increase the risk of cardiovascular death or all cause mortality	[18]
RECORD study (n = 4447)	Received rosiglitazone with mean follow-up time of 5.5 yr	Increased the risk of heart failure	Rosiglitazone increased risk of heart failure	[65]
			Suggestion of contraindication for rosiglitazone to be used in patients developing symptomatic heart failure
Case-control analysis of a retrospective cohort study (n = 159 026)	Treated with TZDs at least 1 yr	Increased risk of heart failure	Rosiglitazone was associated with risk of heart failure, acute myocardial infarction, and mortality	[19]
		Increased mortality
		Increased risk of acute myocardial infarction
Retrospective, double-blind, randomized clinical studies with rosiglitazone (n = 14 237)	Received rosiglitazone 24-52 wk	Increased heart failure incidence	Rosiglitazone increased the risk of heart failure and myocardial infarction	[13]
		Increased events of myocardial ischemia
A meta-analysis of randomized controlled trials (n = 6421, control = 7870)	Received rosiglitazone at least 12 mo	Increased risk of myocardial infarction and heart failure	Rosiglitazone increased risk of myocardial infarction and heart failure, without increased risk of cardiovascular mortality	[23]
		No increased risk of cardiovascular mortality

I/R: Ischemia/reperfusion; PPAR: Peroxisome proliferator-activated receptor; T2DM: Type 2 diabetes mellitus; RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; ERK: Extracellular signal-regulated kinase; TZD: Thiazolidinedione; mTOR: Mammalian Target of Rapamycin pathway