doi: 10.1161/01.CIR.0000054675.30348.9A
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;107:1350.)
© 2003 American Heart Association, Inc.
Clinician Update |
Glitazones and Heart Failure
Critical Appraisal for the Clinician
From the Division of Cardiac Surgery (C.W., R.D.W., P.W.M.F., S.V.) and the Division of Cardiology (P.L.), Toronto General Hospital, University of Toronto, Toronto, Canada.
Correspondence to Subodh Verma, MD, PhD, Division of Cardiac Surgery, Toronto General Hospital, EN 14-217, 200 Elizabeth St, Toronto, ON, Canada, M5G 2C4. E-mail subodh.verma{at}sympatico.ca
Key Words: heart failure • pharmacology • vasculatures
Mr S. is a 46-year-old East-Indian male with typical manifestations of the cardiovascular dysmetabolic syndrome of insulin resistance (type II diabetes, obesity, dyslipidemia, hypertension, and elevated levels of high-sensitivity C-reactive protein). His medications include ramipril, simvastatin, enteric-coated aspirin, metformin, and glyburide. He has no symptoms of cardiac ischemia or congestive heart failure and has preserved left ventricular function. Over the past few months his glycemic control has been inadequate, and a decision to initiate an insulin sensitizer (glitazone) is made. Treatment is initiated with rosiglitazone 4 mg twice daily, with marked improvement in glycemic control and other components of the cardiovascular dysmetabolic syndrome. Approximately 6 months after initiation of therapy, your junior resident receives a phone call from Mr S, who is extremely anxious and distraught about the possibility of developing heart failure on glitazone therapy. The resident and the patient request your expert opinion about the effects of glitazones on cardiac function and associated hemodynamics.
Insulin resistance has been increasingly recognized as a central metabolic disturbance predisposing a patient to hypertension, hyperlipidemia, premature atherosclerosis, left ventricular hypertrophy, and endothelial dysfunction.1 In addition to being a powerful risk marker for the development of cardiovascular disease, insulin resistance is also closely related to cardiac dysfunction and heart failure.2 Thiazolidinediones (TZD; glitazones) are peroxisome proliferator-activated receptor (PPAR) agonists that specifically augment insulin sensitivity and counter insulin resistance in patients with the cardiovascular dysmetabolic syndrome. Currently, there are 2 commercially available glitazones, rosiglitazone and pioglitazone. Troglitazone was withdrawn from the market because of hepatic side effects. The PPAR family is composed of 3 subtypes. TZDs bind with high affinity to the PPAR
isoform. The PPAR isoform is found in the heart,3–6 endothelium, vascular smooth muscle (including atherosclerotic lesions and neointima formed after angioplasty), liver, skeletal muscle, monocytes/macrophages, and many other tissues and cell types.7 Specifically by decreasing insulin resistance, TZDs improve global cardiovascular and metabolic health by improving glucose homeostasis, decreasing plasma insulin levels, improving endothelial function, decreasing vascular inflammation and C-reactive protein levels, and correcting lipid abnormalities.8–12 The ability of TZDs to counter the metabolic syndrome has led to widespread use of these drugs in patients with insulin resistance and diabetes.
There has been increasing discussion about whether TZDs affect cardiac function, with evidence suggesting both negative and positive effects on myocardial performance. Consequently, the practicing cardiologist is often faced with a difficult decision about whether to initiate therapy because a large proportion of patients with diabetes often have coexisting ischemic and nonischemic cardiomyopathy. In this article we summarize the available data on glitazones and cardiac function in an attempt to facilitate the decision-making process for a busy clinician.
Hemodynamic Effects of Glitazones as They Relate to Cardiac Function
Effects on Vascular Resistance and Afterload
There is accumulating evidence to suggest that insulin stimulates endothelium-dependent nitric oxide-mediated vasodilatation, and that this effect is closely associated with the overall effects of insulin on glucose disposal.13,14 Importantly, insulin-mediated vasorelaxation is blunted in patients with insulin resistance (also known as vascular insulin resistance).13,15 In addition to decreased NO-mediated vasorelaxation, patients with insulin resistance often have coexistent hyperinsulinemia, which is a stimulus for enhanced endothelin production, thereby further impairing endothelial function and increasing vascular tone.13 Improving insulin sensitivity with glitazones may counter vascular insulin resistance and reduce hyperinsulinemia-induced endothelin-1 production, resulting in improved tonic vasodilator response to insulin and reduction in peripheral vascular resistance and blood pressure. By reducing plasma insulin levels, these agents may reduce the blood-pressure-raising actions of insulin such as renal sodium retention and increased sympathetic activity.16
The aforementioned vascular effects of glitazones may offer an advantage to patients with heart failure by decreasing afterload and peripheral vascular resistance. Indeed, in troglitazone-treated patients, decreased peripheral resistance produced an increase in stroke volume and cardiac output.17 Earlier studies with troglitazone demonstrated a significant reduction in diastolic blood pressure by 6.5 mm Hg (8%).17 Likewise, rosiglitazone (4 mg twice a day over 52 weeks) is associated with a significant decrease in systolic blood pressure (3.5 mm Hg) and diastolic pressure (2.7 mm Hg). Although reductions in afterload and blood pressure would theoretically be beneficial to diabetic patients with heart failure, this remains to be carefully evaluated.
Effects on Left Ventricular Mass and Contractility
Left ventricular hypertrophy is an important risk factor for coronary heart disease and cardiac-related mortality. The growth factor actions of insulin, acting via insulin-like growth factors, may lead to an exaggerated hypertrophic response of the left ventricle in response to arterial hypertension. In fact, the potent effects of angiotensin-converting enzyme inhibitors on regression of left ventricular hypertrophy are related, in part, to their ability to improve insulin sensitivity.18 Yamamoto et al5 demonstrate that PPAR activators inhibit cardiac hypertrophy in cardiac myocytes and regulate cardiomyocyte hypertrophy, mediated in part through the nuclear factor-
B pathway. Asakawa et al3 report that the PPAR-dependent pathway plays a critical role in the inhibition of cardiac hypertrophy in response to in vitro and in vivo physiological and pharmacological stimulation.
Experimental studies suggest that glitazones may exert inotropic effects, but the exact nature of this response remains unclear.19 Studies with troglitazone suggest that the response is transient and that the main hemodynamic effect of long-term treatment with glitazone treatment is vasodilation, not inotropy. Indeed, troglitazone treatment results in increased myocardial blood flow, which in turn may lead to an increase in myocardial performance. However, clinical and echocardiographic studies with glitazones in patients with type-2 diabetes show a neutral effect on cardiac structure and function.12,20
Effects on Neurohumoral Regulation
Insulin and insulin resistance have complex and inter-related effects on components of the neurohumoral cascade activated in patients with heart failure. It is well accepted that increased sympathetic tone can induce insulin resistance, and conversely, hyperinsulinemia and insulin resistance promote increased sympathetic discharge.2 The renin-angiotensin system is activated progressively as cardiac function deteriorates, and inhibition of angiotensin-converting enzyme favorably remodels the myocardium in patients with heart failure.21 A growing body of evidence suggests that glitazones counter angiotensin activation, thus having a beneficial effect on ventricular remodeling in diabetic patients with heart failure.22–24 Evidence suggests that glitazones significantly reduce the production of tumor necrosis factor-
(TNF-), a key factor in the development and progression of heart failure.25 PPAR activators inhibit the cardiac expression of TNF- in part through attenuating nuclear factor-B activation.4 In chronic heart failure, plasma levels of endothelin are increased and are of prognostic value.26 Preliminary studies indicate that glitazones may reduce endothelin-1 production, which in turn may benefit diabetic patients with heart failure.9,27
Effects on Ischemia and Reperfusion-Induced Cardiac Dysfunction
Accumulating evidence suggests that glitazones may exert beneficial effects in experimental models of ischemia and reperfusion injury. Yue et al6 demonstrated that rosiglitazone reduced the extent of myocardial infarction and improved contractile performance after ischemia and reperfusion injury. Likewise, Wayman et al28 demonstrated an effect of PPAR agonists in reducing myocardial infarct size. This effect may be mediated through an effect of glitazones to inhibit the Jun NH2-terminal kinase/activating protein-1 in the heart.29
Effects on Myocardial Metabolism
Insulin resistance adversely affects myocardial metabolism and bioenergetics. Because glucose uptake and metabolism are dependent on insulin, resistance to its effects is particularly detrimental in the failing heart. Improving insulin sensitivity prevents the heart’s reliance on free fatty acids as the primary source of energy production by improving myocardial glucose use.30 Glucose provides a greater amount of ATP for a given rate of oxygen consumption, and hence correcting myocardial insulin resistance has important implications for myocardial metabolic function.31
Do Glitazones Precipitate Heart Failure?
It is unclear whether glitazones have a direct detrimental effect on cardiac function. The majority of mechanistic and experimental studies would suggest that glitazones might favorably influence cardiac hemodynamics in heart failure. However, large-scale clinical trials have reported fluid retention and increase in plasma volume (6% to 7%) with glitazone therapy, with an increased incidence of peripheral edema occurring in 2% to 5% patients.12 Although the mechanistic basis remains elusive, some evidence suggests that this effect may be related to increased endothelial cell permeability induced by glitazone therapy.32 Others report that glitazones may interfere with renal hemodynamics.33 Glitazone-induced peripheral edema and fluid retention seem to be refractory to diuretics but promptly respond to withdrawal of therapy. An increase in preload with resultant pulmonary edema may contribute to worsening cardiac function in patients with brittle heart failure, and hence these agents are contraindicated in the setting of New York Heart Association class III and IV functional status. The Canadian Adverse Reaction Monitoring Program (CADRMP) received 8 reports of heart failure related to rosiglitazone between March 2000 and February 2001, and 2 similar reports for pioglitazone between August 2000 and August 2001.34 Previously reported cases of glitazone-related pulmonary edema occurred 4 to 13 months after starting therapy,33,35 although pulmonary edema has been reported as early as 3 days after treatment.34 Scattered reports indicate that glitazone-induced pulmonary edema may occur in patients with normal left ventricular systolic function after remarkable increase of body weight, although this seems to be an isolated observation.35
Concluding Remarks
You ask your junior resident to discuss the following issues with Mr S. Insulin resistance affects a large number of North Americans and consists of a cluster of cardiovascular and metabolic risks that include diabetes, hypertension, obesity, dyslipidemia, and atherosclerotic cardiovascular disease. Countering insulin resistance with glitazones holds promise for cardiovascular risk reduction in patients with the metabolic syndrome. However, because a large number of diabetic patients develop heart failure, there has been increasing discussion about the role of these agents in modulating cardiac function. Insulin resistance may play an important role in the development of adverse cardiac remodeling and facilitate the expression of heart failure. This may be caused directly by the effect of insulin resistance on myocardial angiotensin regulation, cytokine production, sympathetic nervous system activity, and altered myocardial metabolism. In addition, insulin resistance adversely affects vascular hemodynamics, and resistance to the vascular actions of insulin may serve to augment peripheral and coronary vascular tone and to raise blood pressure. From this standpoint, glitazone therapy may afford protection against the development and progression of heart failure if initiated early in the course of the disease (Table and Figure). On the other hand, glitazone therapy is associated in 2% to 5% of patients with increases in fluid retention, increased plasma volume, and pulmonary edema and may predicate heart failure in patients with poor ventricular function. It is possible that early intervention with glitazones in patients with the metabolic syndrome and preserved heart function may delay the development of heart failure. However, in patients with established heart failure, the beneficial effects of glitazones may be offset by an increase in fluid volume and pulmonary edema. In such patients, glitazone therapy should be initiated with caution and promptly withdrawn with worsening heart failure.
|
|
You inform the resident that because Mr S has no evidence of ischemic cardiomyopathy and has preserved left ventricular function, treatment with a glitazone is safe and not likely to precipitate heart failure. Furthermore, early and aggressive intervention with a glitazone in patients with the metabolic syndrome may delay the onset of heart failure in this patient and offer benefits in terms of cardiovascular risk reduction. Lastly, you remind the resident that PPAR agonists (glitazones) have pleiotropic anti-atherogenic and antiinflammatory effects36 that may contribute to improved systemic vascular homeostasis in patients with diabetes.
Note Added in Proof
During the review process, an important paper by Shiomi et al37 was published evaluating the effects of glitazones on left ventricular remodeling and failure after a myocardial infarction. The authors report that pioglitazone improved left ventricular remodeling and function in mice with postinfarction heart failure, in part, via attenuated expression of inflammatory cytokines and chemokines, and hence may hold promise as preventative strategies, in heart failure.
Acknowledgments
Supported by the Heart and Stroke Foundation of Ontario (R.D.W., S.V., P.P.L.).
References
1. Reaven G. Metabolic syndrome: pathophysiology and implications for management of cardiovascular disease. Circulation. 2002; 106: 286–288.
2. Coats AJ, Anker SD, Anker S. Insulin resistance in chronic heart failure. J Cardiovasc Pharmacol. 2000; 35: S9–S14.[CrossRef][Medline] [Order article via Infotrieve]
3. Asakawa M, Takano H, Nagai T, et al. Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo. Circulation. 2002; 105: 1240–1246.
4. Takano H, Nagai T, Asakawa M, et al. Peroxisome proliferator-activated receptor activators inhibit lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal rat cardiac myocytes. Circ Res. 2000; 87: 596–602.
5. Yamamoto K, Ohki R, Lee RT, et al. Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes. Circulation. 2001; 104: 1670–1675.
6. Yue Tl TL, Chen J, Bao W, et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation. 2001; 104: 2588–2594.
7. Bishop-Bailey D. Peroxisome proliferator-activated receptors in the cardiovascular system. Br J Pharmacol. 2000; 129: 823–834.[CrossRef][Medline] [Order article via Infotrieve]
8. Diep QN, El Mabrouk M, Cohn JS, et al. Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-gamma. Circulation. 2002; 105: 2296–2302.
9. Fukunaga Y, Itoh H, Doi K, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis. 2001; 158: 113–119.[CrossRef][Medline] [Order article via Infotrieve]
10. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002; 106: 679–684.
11. Pasceri V, Wu HD, Willerson JT, et al. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation. 2000; 101: 235–238.
12. Mudaliar S, Henry RR. New oral therapies for type 2 diabetes mellitus: the glitazones or insulin sensitizers. Annu Rev Med. 2001; 52: 239–257.[CrossRef][Medline] [Order article via Infotrieve]
13. Mather K, Anderson TJ, Verma S. Insulin action in the vasculature: physiology and pathophysiology. J Vasc Res. 2001; 38: 415–422.[CrossRef][Medline] [Order article via Infotrieve]
14. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001; 37: 1344–1350.
15. Baron AD. Insulin resistance and vascular function. J Diabetes Complications. 2002; 16: 92–102.[CrossRef][Medline] [Order article via Infotrieve]
16. Anderson EA, Balon TW, Hoffman RP, et al. Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension. 1992; 19: 621–627.
17. Ghazzi MN, Perez JE, Antonucci TK, et al. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes. 1997; 46: 433–439.[Abstract]
18. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens. 1992; 5: 95–110.[Medline] [Order article via Infotrieve]
19. Shimoyama M, Ogino K, Tanaka Y, et al. Hemodynamic basis for the acute cardiac effects of troglitazone in isolated perfused rat hearts. Diabetes. 1999; 48: 609–615.[Abstract]
20. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2000.
21. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991; 325: 293–302.[Abstract]
22. Sugawara A, Takeuchi K, Uruno A, et al. Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes. Hypertens Res. 2001; 24: 229–233.[CrossRef][Medline] [Order article via Infotrieve]
23. Sugawara A, Takeuchi K, Uruno A, et al. Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells. Endocrinology. 2001; 142: 3125–3134.
24. Hattori Y, Akimoto K, Kasai K. The effects of thiazolidinediones on vascular smooth muscle cell activation by angiotensin II. Biochem Biophys Res Commun. 2000; 273: 1144–1149.[CrossRef][Medline] [Order article via Infotrieve]
25. Bryant D, Becker L, Richardson J, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation. 1998; 97: 1375–1381.
26. Cheng TO. Endothelin receptor blockade in congestive heart failure. Circulation. 2001; 104: e96.[Medline] [Order article via Infotrieve]
27. Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochem Pharmacol. 2000; 60: 1245–1250.[CrossRef][Medline] [Order article via Infotrieve]
28. Wayman NS, Hattori Y, McDonald MC, et al. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J. 2002; 16: 1027–1040.
29. Khandoudi N, Delerive P, Berrebi-Bertrand I, et al. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma, inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. Diabetes. 2002; 51: 1507–1514.
30. Rodrigues B, Cam MC, McNeill JH. Metabolic disturbances in diabetic cardiomyopathy. Mol Cell Biochem. 1998; 180: 53–57.[CrossRef][Medline] [Order article via Infotrieve]
31. Stanley WC, Lopaschuk GD, Hall JL, et al. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions: potential for pharmacological interventions. Cardiovasc Res. 1997; 33: 243–257.
32. Niemeyer NV, Janney LM. Thiazolidinedione-induced edema. Pharmacotherapy. 2002; 22: 924–929.[CrossRef][Medline] [Order article via Infotrieve]
33. Thomas ML, Lloyd SJ. Pulmonary edema associated with rosiglitazone and troglitazone. Ann Pharmacother. 2001; 35: 123–124.[CrossRef][Medline] [Order article via Infotrieve]
34. Wooltorton E, Rosiglitazone (Avandia), and pioglitazone (Actos), and heart failure. CMAJ. 2002; 166: 219.
35. Hirsch IB, Kelly J, Cooper S. Pulmonary edema associated with troglitazone therapy. Arch Intern Med. 1999; 159: 1811.
36. Barbier O, Torra IP, Duguay Y, et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol. 2002; 22: 717–726.
This article has been cited by other articles:
 |
|
 |
|
  M. Kindermann and M. Bohm Sweet hearts die earlier--lessons from CHARM Eur. Heart J., June 1, 2008; 29(11): 1342 - 1343. [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Lincoff, K. Wolski, S. J. Nicholls, and S. E. Nissen Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Trials JAMA, September 12, 2007; 298(10): 1180 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Granberry, J. B. Hawkins, and A. M. Franks Thiazolidinediones in patients with type 2 diabetes mellitus and heart failure Am. J. Health Syst. Pharm., May 1, 2007; 64(9): 931 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-H. Cho, Y. J. Choi, S. A. Jo, J. Ryou, J. Y. Kim, J. Chung, and I. Jo Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition Am J Physiol Cell Physiol, August 1, 2006; 291(2): C317 - C326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gomez-Garre, M. Herraiz, M. L. Gonzalez-Rubio, R. Bernal, P. Aragoncillo, A. Carbonell, J. J. Rufilanchas, and A. Fernandez-Cruz Activation of peroxisome proliferator-activated receptor-{alpha} and -{gamma} in auricular tissue from heart failure patients Eur J Heart Fail, March 1, 2006; 8(2): 154 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Cekmen, M. Cesur, R. Cetinbas, P. Bedel, and O. Erdemli Acute Pulmonary Edema Due to Rosiglitazone Use in a Patient With Diabetes Mellitus J Intensive Care Med, January 1, 2006; 21(1): 47 - 50. [Abstract] [PDF]
|
|
|
|
 |
|
 W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk Myocardial Substrate Metabolism in the Normal and Failing Heart Physiol Rev, July 1, 2005; 85(3): 1093 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Cariou, J.-C. Fruchart, and B. Staels Review: Vascular protective effects of peroxisome proliferator-activated receptor agonists The British Journal of Diabetes & Vascular Disease, May 1, 2005; 5(3): 126 - 132. [Abstract] [PDF]
|
|
|
|
 |
|
 E. L. Schiffrin Peroxisome proliferator-activated receptors and cardiovascular remodeling Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1037 - H1043. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Verma, M. A. Kuliszewski, S.-H. Li, P. E. Szmitko, L. Zucco, C.-H. Wang, M. V. Badiwala, D. A.G. Mickle, R. D. Weisel, P. W.M. Fedak, et al. C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function: Further Evidence of a Mechanistic Link Between C-Reactive Protein and Cardiovascular Disease Circulation, May 4, 2004; 109(17): 2058 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Wang, N. Ciliberti, S.-H. Li, P. E. Szmitko, R. D. Weisel, P. W.M. Fedak, M. Al-Omran, W.-J. Cherng, R.-K. Li, W. L. Stanford, et al. Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage: A New Paradigm in Glitazone Pleiotropy Circulation, March 23, 2004; 109(11): 1392 - 1400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Singh Rosiglitazone and Heart Failure: Long-Term Vigilance Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1): 21 - 25. [Abstract] [PDF]
|
|
|
|
 |
|
 E. L. Schiffrin, F. Amiri, K. Benkirane, M. Iglarz, and Q. N. Diep Peroxisome Proliferator-Activated Receptors: Vascular and Cardiac Effects in Hypertension Hypertension, October 1, 2003; 42(4): 664 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. P. Kennedy Do Thiazolidinediones Cause Congestive Heart Failure? Mayo Clin. Proc., September 1, 2003; 78(9): 1076 - 1077. [PDF]
|
|
|
|
|
|
J. B. Buse Glitazones and Heart Failure: Critical Appraisal for the Clinician Circulation, August 26, 2003; 108 (8): e57 - e57. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||