RICERCA ITALIANA     

Effects of Rosiglitazone and Metformin on the Development and Progression of Chronic Heart Failure in a model of insulin-resistance and heart failure

Università degli Studi di Napoli "Federico II"

Abstract

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone represent a relatively new class of insulin-sensitizing agents, recommended for the treatment of type 2 diabetes. TZDs have been extensively investigated with regard to their metabolic effects, but to a lesser extent as to their interaction with heart structure and function. Understanding of this interaction is particularly relevant for several reasons: 1) type 2 diabetes is marked by increased incidence of cardiovascular complications, including myocardial infarction, heart failure, and stroke, and these events account for more than 70% of mortality in diabetic patients; 2) TZDs use has been even associated with first appearance of symptoms of heart failure. Consequently, it is recommended to use TZDs cautiously in patients with CHF. Data from large cohorts of patients with type 2 diabetes have shown that TZD therapy is associated with significantly lower incidence of heart failure as compared with insulin therapy and that the association of TZD and metformin results in lower mortality in patients discharged after hospitalization for acute myocardial infarction. As with TZDs, the current contraindication to metformin use in diabetes associated with CHF causes some frustration to clinicians who want to exploit the many beneficial effects of the drug in their diabetic patients. Again, the real question is whether the postulated risks of metformin use in CHF are greater than or even outweighed by the benefits. The main objective of this study is to explore the effect of rosiglitazone as monotherapy and the combination of rosiglitazone and metformin on progressive cardiac remodelling and dysfunction, and subsequent CHF in an animal model of insulin resistance and metabolic syndrome. The model employed will allow us to get insights into the cellular and molecular mechanisms underlying the cardiac interaction of rosiglitazone and metformin. In particular, the study will generate data regarding the effect of the drugs on myocardial structure and ventricular geometry (cell size, interstitial fibrosis, and capillary density) and the expression of regulatory proteins of contractility and cardiomyocyte survival (SERCA2, cytokines, apoptosis, etc). Experiments will be performed in spontaneously hypertensive, obese, heart failure-prone (SHHF) rats, which represent a congenital model of hypertension and insulin resistance. These animals develop compensatory cardiac hypertrophy between 6-8 months, with preserved contractile performace. Thereafter, LV remodeling occurs, progressing to dilated cardiomyopathy, severe contractile dysfunction and decompensated heart failure. SHHF animals will be purchased from Charles River at age 8 months and housed in an environment at a constant 22° C, with a fixed 12:12-h artificial light-dark cycle. After a two-week acclimatization, they will be randomly assigned to three experimental groups: untreated (UN), rosiglitazone (RO), and rosiglitazone plus metformin (RM). Twenty rats will be allocated to each group. Animals will be fed either Purina 5008 chow or chow to which rosiglitazone (2 mg/day) or metformin (250 mg/day) or the two drugs were added.
To assess in vivo left ventricular (LV) morphology and function, echocardiography will be performed at baseline (before treatment) and every two months thereafter, until the age of 15 months (end of study). To assess LV hemodynamics and contractility at the end of the study, rats will be anesthetized and catheters will be inserted into the LV. In a subgroup of rats, hemodynamic parameters will be evaluated in the isolated, perfused heart. Myocardial tissue will be excised and appropriately handled for histological examination and molecular studies. Blood samples will be taken at the end of the study period for the determination of markers of inflammation (TNF-alpha, IL-6) and LV remodeling (ANF, BNP, ACE, Aldosterone, Nor-Epinephrine). <<<

Principal Investigator

Luigi Saccà Università degli Studi di NAPOLI "Federico II"

Research Objectives

The main objective of this study is to explore the effect of rosiglitazone as monotherapy and the combination of rosiglitazone and metformin on progressive cardiac remodelling and dysfunction, and subsequent CHF in an animal model of insulin resistance and metabolic syndrome. The model employed will allow us to get insights into the cellular and molecular mechanisms underlying the cardiac interaction of rosiglitazone and metformin. In particular, the study will generate data regarding the effect of the drugs on myocardial structure and ventricular geometry (cell size, interstitial fibrosis, and capillary density) and the expression of regulatory proteins of contractility and cardiomyocyte survival (SERCA2, cytokines, apoptosis, etc)

Significance of the Project
The effects of TZDs on the heart have been the object of several studies. Most of them suffer from the limitation inherent in acute experiments carried out in the isolated perfused heart or in the ischemia-reperfusion model. Clearly, in these conditions TZDs have a reduced potential to fully exert their effects, given the impossibility for TZDs to affect the metabolic environment as they do in the clinical reality.
On the other hand, little attention has focused on the effects of TZDs on progressing heart failure and even less on the crucial question whether TZDs impact on the biology of CHF in diabetic or severe insulin resistant models. The current approach has the potential to provide new data regarding the role of TDZs in CHF. These data are very likely to bear clinical relevance in relation to the current debate of TDZs use in diabetics with CHF. Appraisal of the effect on CHF of the combination therapy with TDZs and metformin is another aspect that the current approach might help elucidate. This is particularly important in view of the increasing use of this combined therapeutic approach and the lack of human data on its effect on the progression of CHF. <<<

Timescale

12 months

National and international background

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone represent a relatively new class of insulin-sensitizing agents, largely recommended for the treatment of type 2 diabetes. TZDs have been extensively investigated with regard to their metabolic effects, but to a lesser extent as to their interaction with heart structure and function. Full understanding of this interaction is particularly relevant for several reasons: 1) type 2 diabetes is marked by increased incidence of cardiovascular complications, including myocardial infarction, heart failure, and stroke, and these events account for more than 70% of mortality in diabetic patients; 2) TZDs use in patients with diabetes associated with chronic heart failure (CHF) may exacerbate heart disease, and this is more likely to occur when TZDs are administered in combination with insulin (1); 3) in some patients, TZDs use has been even associated with first appearance of symptoms of heart failure (2). Consequently, it is recommended to use TZDs cautiously in patients with class I or II NYHA, whereas in patients with class III or IV NYHA, TZDs should not be used at all (1).
The current guidelines pose a major clinical dilemma, given the rising prevalence of the association between diabetes and CHF. The matters are further complicated by the fact that also metformin, another key agent in the treatment of type 2 diabetes, has received warning against prescription in patients with CHF that requires pharmacological treatment (3).
The distinct role of TZDs in the worsening of CHF and the underlying mechanisms are still unclear. On a clinical ground, TZDs may cause weight gain, fluid retention, increased plasma volume, and edema, each of which exerts negative effects on the failing heart (4,5). In clinical trials using TZDs, CHF was not frequently present, which makes it difficult to draw conclusions regarding the effects of TZDs on incident CHF. However, one thing is clear and that is when TDZs are added to insulin therapy, the incidence of CHF is definitely increased (1).
Against this background, retrospective analyses of data from large cohorts of patients with type 2 diabetes have shown that TZD therapy is associated with significantly lower incidence of heart failure as compared with insulin therapy and that the association of TZD and metformin results in lower mortality in patients discharged after hospitalization for acute myocardial infarction (6,7). Furthermore, an observational study in a cohort of patients with diabetes and CHF derived from the National Heart Care Project revealed that use of TZD or metformin was independently associated with a significantly lower risk of all-cause-mortality as compared with that observed in the patients receiving neither insulin-sensitizing drug (8). Another important observation is that the echocardiographic indices of myocardial function do not appear to deteriorate during TZDs therapy in type 2 diabetic patients (9). Conversely, TZDs may even improve cardiac performance and, overall, exert a favourable influence on cardiovascular risk factors (10).
Clearly, these studies cast serious doubts on the current recommendations against the use of insulin-sensitizers in patients with CHF. On the other hand, the question whether the potential benefits of TZDs use in patients with contraindications due to CHF counterbalance, or even outweigh, the risk of worsening heart disease remains a crucial yet unresolved issue.
Nor is the question answered by the many studies that have examined the cardiac effects of TZDs in experimental models. The evidence available from these studies in general supports a beneficial impact of TZDs on cardiac function. Indeed, TZDs have been shown to be cardioprotective in several animal models, particularly in the ischemia-reperfusion model of myocardial injury (11-15).
The main effects of TZDs can be summarized as follows: 1) reduction of the tissue necrosis (infarct size) associated with acute myocardial infarction; 2) improvement of functional contractile recovery from myocardial ischemia; 3) improvement of PCr and ATP recovery from ischemia; 4) improvement of endothelial dysfunction and decrease of peripheral vascular resistance; 5) prevention of NFkB activation and attenuated transcription of such genes as TNF-alpha, IL-6, ICAM-1, P-selectin, and MCP-1 that exert multiple deleterious effects on the recovery from ischemia. Ultimately, TDZs, besides the anticipated favourable effects on metabolism and energetics, also act in the heart as anti-inflammatory and anti-apoptotic factors, growth suppressors, and inotropic and lusitropic agents.
Of interest is also the finding that if rosiglitazone is given for only 2 days there are no changes in insulin sensitivity (14), yet rosiglitazone reduces the infarct size and apoptosis in the ischemia-reperfusion rat model, indicating that its cardiac protective effect is partially independent of insulin sensitization.
Unfortunately, the majority of the experimental studies on the cardiac effect of TZDs are either acute in vivo experiments or have been performed in the isolated perfused heart. While these experimental studies are crucial to our understanding of basic mechanisms of TDZs and heart interaction, they have little relevance in the setting of chronic heart failure. One experimental study has looked at the effect of rosiglitazone on the progression of heart failure secondary to myocardial infarction in nondiabetic rats. Contrary to the beneficial effects largely documented in the immediate recovery from ischemia-reperfusion, rosiglitazone was unable to prevent ventricular remodelling and this was associated with increased post-myocardial infarction mortality (16).
Although this finding was obtained in normal animals, it supports the cautionary suggestion against TDZs prescription in patients with CHF. On the other hand, one may also speculate that when TDZs are used in patients with CHF and diabetes, the insulin-sensitizing action might activate metabolic mechanisms that benefit the diabetic failing heart.
In the light of this controversy, it would be desirable to further investigate the relationship between TZDs and cardiac growth and function both in the context of heart failure development as well as its progression. In other words, the idea is to test the ability of TZDs to: 1) delay the onset of heart failure in an animal model prone to develop CV complications because of insulin-resistance/metabolic syndrome (prevention study); and 2) attenuate the progression of CHF once this has developed (therapeutic study).
The following specific questions appear particularly timely:
1) How do TZDs interfere with the mechanisms that lead to the development of heart failure?
2) What is the impact of TZDs on the signalling activated by heart failure and governing the growth response and ultimately the contractile dysfunction?
3) Are TZDs capable of affecting the progression of heart failure?

As with TZDs, the current contraindication to metformin use in diabetes associated with CHF causes some frustration to clinicians who want to exploit the many beneficial effects of the drug in their diabetic patients. Again, the real question is whether the postulated risks of metformin use in CHF (essentially lactic acidosis) are greater than or even outweighed by the benefits. There is a diffuse feeling that the recommendation to avoid metformin in CHF patients is not fully evidence-based (17).
In real practice, metformin is sometimes used even in the presence of contraindications, based on the fact that lactic acidosis is an extremely rare event. In addition, possible advantages of metformin in reducing cardiovascular events have emerged from prospective studies (18) and has more recently been inferred from large retrospective analyses (8). In view of these data and the complementary mechanism of action, the combination therapy with TDZs and metformin has recently added to the antidiabetic therapeutic options. However, the way the association of the two insulin-sensitizers acts in the context of diabetes and developing or established CHF is largely unknown. Thus, the current project is also intended to address the additional question:

4) Is the effect of TZDs on cardiac dysfunction and CHF progression affected by concomitant treatment with the insulin-sensitizing agent metformin? <<<