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National Taiwan University College of Medicine, Department of Internal Medicine (T.-M.L.), Cardiology Section, National Taiwan University Hospital, Taipei, Taiwan 10002; and Department of Surgery (T.-F.C.), Municipal Jen-Ai Hospital, Taipei, Taiwan 10002
Address all correspondence and requests for reprints to: Dr. Tsung-Ming Lee, Department of Internal Medicine, Cardiology Section, Chi-Med Medical Center, 901, Chung-Hwa Road, Yang-Kan City, Tainan, 710, Taiwan. E-mail: tsungm.lee{at}msa.hinet.net.
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Abstract |
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Introduction |
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Alternatively, in patients with type 2 diabetes, the use of sulfonylurea drugs may be harmful by preventing endogenous cardioprotective mechanisms. Previous studies have shown that sulfonylurea drugs increased early mortality in diabetic patients after direct angioplasty for acute myocardial infarction (6). The KATP channels of pancreatic ß-cells are critical in the regulation of glucose-regulated insulin secretion (7). Unfortunately, KATP channels also occur in the cardiovascular system, where they are thought to play an important role in ischemic preconditioning (IP). Thus, blockade of these channels by glibenclamide may worsen myocardial ischemia by preventing IP. Differential response of myocardial KATP channels to sulfonylureas was determined by the sulfonylurea receptor (SUR) isoform because multiple regions of SUR contribute to coupling antagonist-occupied site(s) with the inward rectifier K+ channel (KIR)-gating machinery (8). Glimepiride is pharmacologically distinct from glibenclamide because of differences in receptor-binding properties (9), which could result in a reduced binding to cardiomyocyte KATP channels as reflected in the lower KATP channel current inhibition activity (10). We hypothesized that inhibition of KATP channels with these agents may be responsible for the excess cardiovascular mortality associated with diabetes. To date, although the acute effect of sulfonylurea on IP phenomenon has been studied in nondiabetic patients (11), the conclusions from nondiabetic patients are not necessarily relevant to diabetic patients, considering the different response to ischemia at the cellular levels in diabetic heart (3). Furthermore, an acute interaction between sulfonylurea derivatives and myocardial KATP channels may not be relevant to the chronic setting of type 2 diabetes. It remained unclear what would happen in the clinical setting if ischemia occurred in diabetic patients chronically treated with sulfonylureas. Thus, it is important to assess whether diabetes-associated inherent changes in the properties of KATP channels (intrinsic factor) or the acute and chronic use of sulfonylurea drugs (extrinsic factor) plays a role in the impairment of IP response. The goals of the present study were to determine whether diabetes mellitus or the acute and chronic use of sulfonylurea drugs alters myocardial IP responses and to assess whether an exogenous agonist of KATP channels, nicorandil, can mimic the beneficial effects of IP against ischemic response in patients undergoing coronary angioplasty.
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Subjects and Methods |
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The study was conducted prospectively. All patients fulfilled the entry criteria of: 1) history of chronic stable angina pectoris for at least 3 months and a positive standard stress test for myocardial ischemia; 2) neither pathologic Q waves nor bundle branch block on the electrocardiogram (ECG) that could have interfered with the interpretation of ST-segment changes; 3) single proximal or mid artery lesion; and 4) successful balloon angioplasty resulting in residual stenosis less than 30% immediately after the procedure. To make collateral circulation of these study patients homogenous, patients with angiographically visible collateral blood at baseline were excluded. Cardiovascular drugs, including calcium channel and ß-adrenergic blockers and caffeinecontaining beverages, except aspirin (100 mg/d) were withheld for 24 h before the procedure. Any patients who had taken nitroglycerin within 4 h of catheterization were excluded from this study. A total of 55 consecutive patients were enrolled, and 43 successful experiments were randomized into 7 groups (Fig. 1
). Twelve patients had to be excluded: 8 because of multiple vessel lesions and collaterals, 3 because of failed angioplasty, and 1 because of medications. There were 20 nondiabetic and 23 diabetic patients taking different sulfonylurea drugs. A patient was defined as having diabetes if a physician had diagnosed diabetes before. Eligible patients were required to have the same sulfonylureas for at least 3 months. Diabetic patients were divided into two groups on the basis of their use of sulfonylureas at the time of angioplasty, i.e. group glibenclamide or group glimepiride.
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Study protocol
Catheterization procedures. After completion of the diagnostic catheterization, iv heparin was supplemented to maintain activated clotting time at 300–350 sec, and a 6F Judkins guiding catheter was advanced to the ostium of the left or right coronary artery as described previously (14). To assess collateral flow during coronary occlusion, a 0.014-inch Doppler wire (FloWire, Cardiometrics, Inc., Mountain View, CA) was first introduced through a standard angioplasty-type Y-connector attached to the angiographic catheter. Collateral blood flow during balloon inflations was defined as the sum of systolic and diastolic collateral blood flow velocity integral, which has been demonstrated to be a good indicator of monitoring the function of collateral vessels (15). The distal segment of the guide wire was placed 2–3 cm beyond the balloon catheter tip. The external end of the guide wire was connected to the chest lead by a sterile alligator clamp to record intracoronary (ic) ECG. Multiple pairs of perpendicular views (90°) of the left and right coronary arteries were obtained. The precise angle, skew rotation, and table height of each projection were recorded so that the projection could be duplicated. Nonionic contrast medium was used in all patients to prevent a vasodilation effect during coronary angiography (16). Blood pressure and heart rate were continuously monitored during the procedure. Patients were not medicated with sedatives.
Angioplasty procedure. After angiographic collateral assessment and ic ECG monitor, iv administration of nicorandil was given via the guiding catheter. An iv injection of saline was given in the control group. After a 10-min drug-free period, the lesion was crossed with a balloon. After the balloon was positioned across the lesion, the patients underwent two 120-sec balloon inflations separated by 120-sec intervals of reperfusion, with the Doppler guide wire remaining across the lesion at the same site for each successive recording.
Angiography measurements. Digital coronary angiograms were recorded in three orthogonal projections before and after each procedure. For each lesion, the view showing the most severe degree of stenosis was used for analysis. Quantitative measurements of coronary artery dimensions were made using a computer-based edge enhancement technique (DCI System, Philips, Inc., Best, The Netherlands), as previously described (14). All injections and projections throughout a given study were performed by the same operator (T.-M.L.) to minimize variability in angiographic technique.
Assessment of myocardial ischemia. The ic ECG was recorded on-line at a paper speed of 25 mm/sec during the two balloon inflations and at selected times after deflation. Calibration was performed at the beginning of the procedure (1 mV = 5 mm). At all time-points, the ST-segment shift was measured 80 msec after the J point on a minimum of three complexes. ST-segment elevation was evaluated in a blinded manner by two observers (T.-M.L. and T.-F.C.) who viewed the ECGs in random order without knowledge of which patient was being presented. Differences in interpretation were resolved by consensus. Changes in ST-segment levels at baseline were used as the control, and the differences in ST-segment levels between the control and at the ends of the first inflation and the second inflation were compared to evaluate the severity of myocardial ischemia.
To confirm myocardial ischemia during balloon inflations, selective catheterization of the great cardiac vein was successfully attempted. Simultaneous samples of the aortic root and the great cardiac vein were obtained for measurements of lactate contents. The myocardial lactate extraction ratio (MLR) was calculated using the following formula: [(LAO-LCV)/LAO] x 100, where LAO and LCV represent plasma lactate concentrations in the aortic root and in the great cardiac vein, respectively. To determine the confounding roles of glucose and insulin in IP, sinus blood samples reflecting local concentrations for glucose and insulin concentrations were assayed at the end of the study.
Before coronary angioplasty, patients were informed that they might develop chest pain during balloon inflations. Immediately before termination of balloon inflation, patients were asked to quantify the intensity of chest pain by using a visual-analog scale (17) ranging from no pain (0) to the most severe pain (10).
Statistics
The continuous variables are expressed as mean ± SD. Patients were analyzed using ANOVA among the groups. Visual analog scales were analyzed using the Wilcoxon signed rank test. The 
2 analysis was used for categoric variables, and Fisher’s exact test was used for patient numbers less than five. Probability values are two-tailed, and a P value of less than 0.05 is considered statistically significant.
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Results |
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. These groups were comparable in terms of gender, age, lipid profile, heart rate (data not shown), and blood pressure (data not shown). Coronary risk factors for coronary artery disease were evenly distributed among the groups. The number of oral hypoglycemic agents was similar in the diabetic groups, with a mean number of 2.3 in the glibenclamide group and 2.4 in the glimepiride group. Twelve patients received an average of 12.9 ± 4.5 mg/d glibenclamide, and 11 patients received an average of 2.9 ± 1.0 mg/d glimepiride. Glucose concentrations were significantly higher in diabetic patients compared with those in nondiabetics (Table 2). Insulin concentrations were significantly increased in glibenclamide-treated diabetic patients, compared with concentrations in glimepiride-treated diabetic patients (118 ± 23 vs. 68 ± 13 µU/ml; P < 0.0001). The balloon pressure used was similar. During or after the procedure, no patient developed any major complications that might affect myocardial ischemia.
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)No significant changes in mean blood pressure and heart rate among the groups at baseline and the ends of the first and second balloon inflations (data not shown) were found. Rate pressure product, an index of oxygen consumption, was comparable among the seven groups. The quantitative variables for the assessment of the collateral circulation obtained during the first and second balloon inflations indicated the presence of low-grade collaterals and did not differ among the study groups. Coronary stenosis was similarly reduced among the groups.
Myocardial ischemia (Table 3)
Chest pain. Before each inflation, all patients were asymptomatic. In the nondiabetic control group, chest pain during the second inflation was significantly less than during the first inflation, indicating effective IP. However, the severity of chest pain was significantly increased in patients pretreated with glibenclamide at the second inflation compared with that in the control and glimepiride-treated groups.
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Intracoronary ECG.
The ST-segment shift values at the end of the two inflations are reported in Table 3. Before each inflation, there was no ST-segment shift in the ic ECG. In the control patients, the ST-segment shift was significantly greater during the first inflation than during the second inflation, consistent with IP. Conversely, the nondiabetic or diabetic patients administered with glibenclamide developed higher ST-segment shift during the second inflation than that in the control or glimepiride-treated groups alone. In the diabetic glibenclamide-treated group, the reduction in the ST-segment shift afforded by nicorandil in the first inflation (-58% vs. the first inflation in the glibenclamide group alone) was similar to that afforded by preconditioning (-59% during the second vs. the first inflation).
Lactate measurements. The respective baseline values were positive and similar, indicating the absence of significant lactate production in the preangioplasty state. MLR was more negative in the glibenclamide-treated groups than in the control or glimepiride-treated groups at the second inflation, indicating less lactate production from ischemic myocardium. In diabetic patients, nicorandil can significantly improve metabolic parameters in glibenclamide-treated patients, but not in glimepiride-treated patients at the second inflation. In groups treated with glimepiride, the magnitude of attenuated lactate production was less in diabetes than that in nondiabetes at the second inflation (-59 ± 21% vs. -26 ± 16% in nondiabetes; P = 0.007), suggesting that diabetes mellitus per se plays a role in determining lactate production. In diabetic glimepiride-treated patients, lactate production was significantly attenuated in the presence of nicorandil, compared to the glimepiride-treated group alone at the first inflation (-52 ± 14% vs. -153 ± 55%; P = 0.002).
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Discussion |
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Our conclusions are supported by the following observations. 1) Short duration of coronary occlusion was effective in reducing ST-segment levels in nondiabetics treated with or without glimepiride, not with glibenclamide. The acute effect of sulfonylureas was further supported by the observation in the chronic use of sulfonylurea that the lactate production was not further attenuated after nicorandil administration in glimepiride-treated diabetic patients, at the dose which nicorandil can significantly improve metabolic parameters in glibenclamide-treated diabetic patients. The results suggest that either acute or chronic administration of glibenclamide abolishes the cardioprotective effects of IP, but not glimepiride. Our findings were compatible with previous studies, showing that glibenclamide impaired IP response in type 2 diabetic patients (18). 2) Among the patients treated with glimepiride, the magnitude of attenuated lactate production was less than that in nondiabetes at the second inflation, suggesting diabetes mellitus per se is an important factor that reduced the responsiveness of the hearts to agents directly activating myocardial KATP channels. Furthermore, in diabetic glimepiride-treated patients, lactate production was significantly attenuated in the presence of nicorandil, compared to the glimepiride-treated group alone at the first inflation, suggesting that activation of KATP channels also provides cardioprotection in such patients. Thus, IP can be induced, although attenuated, in diabetes mellitus by exogenous agonists of KATP channels. 3) Sulfonylurea- and diabetes-associated mechanisms may share common mediators because the two conditions may act in a synergistic manner as assessed by myocardial ischemia. The above evidence suggests that impaired intrinsic and extrinsic activation of KATP channels is important in the reduced cardioprotection of the diabetic heart to repeated ischemia.
Effect of diabetes on IP
In this study, we demonstrated a lack of IP-induced protection in diabetic hearts. It appears that diabetes mellitus alters functional responses of the myocardium to activation of KATP channels. The mechanisms by which diabetes affects IP remain undefined. However, several factors can be excluded. 1) Hemodynamics and collateral circulation: Diabetes did not exert any hemodynamic effects, nor was it associated with an increase in myocardial collateral blood flow here. 2) Differences in insulin concentrations: Although insulin secretion significantly increases in type 2 diabetic patients treated with glibenclamide compared with glimepiride as shown in this study, the increased insulin levels cannot be a confounding factor of IP. Increased insulin levels have been shown to enhance IP independently of KATP channels (19). Thus, if diabetic patients treated with glibenclamide had induced IP by increasing insulin levels, we should have obtained fewer ECG changes and less pain in diabetic patients at the end of the first inflation. 3) Differences in glucose concentrations: Blood glucose concentrations have been shown to linearly prevent reductions of myocardial infarction by IP (20). Experiment-induced different glucose levels are responsible for different modulation of IP response. However, when nicorandil was administered in diabetic patients, the impairment of IP improved without significant changes in blood glucose levels, suggesting that factors other than glucose may contribute to the pathogenesis of impaired IP in diabetic patients.
The diminished responses in diabetic patients are not due to nonspecific impairment of IP because their responses to an exogenous agonist, nicorandil, were preserved. There may be some mechanisms related to the elevated threshold for inducing IP in diabetic patients. Diabetes has been associated with changes in ion channel activities in cardiomyocytes (3). It is possible that the number or affinity of KATP channels in the myocardium decreases with diabetes mellitus (4). In inside-out patches from rat ventricular myocytes, there was a greater outward single-channel current in diabetics (3). Glycated proteins produce free radicals and hydrogen peroxide in diabetes mellitus (21). A diabetes-associated increase of oxygen free radicals could be one of the mechanisms responsible for an attenuated response of KATP channels (22). Oxygen free radicals may react with various thio-containing proteins, including channel proteins, from the reduced to the oxidized form. Mitochondrial KATP channels, formed by assembly of Kir6.1 and the sulfonylurea receptors, contain thio groups (23). Thus, diabetes-related oxidant damage, especially during stressful conditions such as myocardial ischemia, could be a functional disadvantage in the activation of KATP channels.
Effect of sulfonylurea drugs on IP
Our results reflect different effects of glibenclamide and glimepiride treatment on myocardial ischemia in type 2 diabetic patients undergoing coronary angioplasty. Myocardial ischemia induced by coronary angioplasty is more severe during glibenclamide treatment than during glimepiride treatment of type 2 diabetic patients. The molecular composition of KATP channels differs among tissue types. Glimepiride, the newer sulfonylurea derivative, has been reported to be more specific than glibenclamide for the SUR1 receptor in the pancreatic ß-cells (10). A 3-fold higher concentration of glimepiride is needed to inhibit myocardial KATP channels to the same extent as glibenclamide (10). In our study, the oral doses of glibenclamide (10 mg) and glimepiride (2 mg) result in plasma concentrations of about 500 nmol/liter (24) and 500 nmol/liter (25), respectively. Furthermore, previous studies have shown that glibenclamide inhibits the activity of endogenous ecto-5'-nucleotidase (26) and decreased the adenosine concentrations in the interstitial space of ventricular muscles. In contrast, glimepiride stimulates 5'-nucleotidase from the membrane-bound amphiphilic form into the soluble hydrophilic form (27), which in turn resulted in increased adenosine concentrations. Increased interstitial adenosine levels have been shown to enhance IP response (28). Thus, it is not surprising that glimepiride does not inhibit the protection induced by IP, whereas glibenclamide abolished the protection.
Our results seemed not consistent with the findings of Reimann et al. (29), showing that both glibenclamide and glimepiride inhibited in vitro KATP channels of myocardial sarcolemmal type assessed by patch clamp studies at the same concentration of 100 nmol/liter. Cardiac myocytes contain two distinct KATP channels, with one subtype located in the sarcolemma and the other in the inner membrane of the mitochondria (29). Mitochondrial KATP channels share some pharmacological properties with sarcolemmal KATP channels, while possessing a distinct structure. The pore of sarcolemmal KATP channels is formed from four inwardly rectifying potassium channel subunits (Kir6.1/6.2), and four sulfonylurea subunits (SUR2A), whereas mitochondrial KATP channels consist of Kir6.1 and SUR1 (30). There is an emerging consensus that activation of mitochondrial KATP channels reduces myocardial ischemia (30). Glimepiride at the concentration of 10 µmol/liter has been shown to inhibit SUR2A-associated current, not SUR1-associated current (31). Thus, it is not surprising that glimepiride even at supratherapeutic levels did not worsen myocardial ischemia, which was compatible with our results.
Clinical implications
In type 2 diabetic patients, many factors contribute to increased morbidity and mortality by coronary artery disease. Diabetes mellitus produces morphological and functional alterations of myocardium. The most common cause of death in patients with type 2 diabetes mellitus is coronary artery disease (32). Diabetic hearts are more susceptible to coronary artery disease than nondiabetic hearts (33). Inhospital mortality after myocardial infarction was significantly higher in diabetic patients than in nondiabetic patients after justifying the adverse baseline characteristics associated with diabetes mellitus (34). The finding was compatible with our working hypothesis that the higher mortality after myocardial infarction might be explained, at least in part, by the diabetes-associated impairment of IP.
Our results show that either acute loading or long-term use of sulfonylureas may abolish IP response in humans. Sulfonylureas are commonly used in the treatment of type 2 diabetes mellitus and are generally well tolerated; however, a serious consideration in treating patients with a sulfonylurea drug is the reported high incidence of cardiovascular morbidity and mortality as compared with treatment with diet alone (35, 36). Like ischemic animals, diabetics seem to be much more cardiovascularly sensitive to sulfonylureas than normals (10). Selective blockade of myocardial KATP channels with glibenclamide at therapeutic doses is associated with a significantly impaired cardioprotection of IP and, thereby, contributes to this increase in mortality. Unlike glibenclamide, glimepiride does not block the mitochondrial KATP channels of the myocardium by more selectively binding with SUR1 receptor (10). This result was consistent with the notion that glimepiride can be used safely in patients with type 2 diabetes mellitus (25). This finding is especially important in older persons with diabetes, in whom IP has been shown to be impaired by attenuated activation of KATP channels (14). Thus, although the precise underlying pathophysiological mechanism is not fully known, these data may be important in choosing sulfonylurea drugs for patients with type 2 diabetes.
Conclusions
Both diabetes mellitus and sulfonylureas can act in synergism to inhibit intrinsic and extrinsic properties of KATP channels in patients undergoing coronary angioplasty. Acute or chronic administration of glibenclamide, but not of the pancreas-specific glimepiride, induces potentially harmful cardiovascular effects in both diabetic and nondiabetic patients with coronary artery disease. Glimepiride offers some promise for diabetic therapy while minimizing undesirable side effects in cardiac tissues.
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Acknowledgments |
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Footnotes |
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Received June 10, 2002.
Accepted October 11, 2002.
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