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J Am Coll Cardiol, 2005; 45:508-514, doi:10.1016/j.jacc.2004.10.054
© 2005 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Impact of diabetes mellitus on myocardial perfusion after primary angioplasty in patients with acute myocardial infarction

Abhiram Prasad, MD, MRCP, FACC*, Gregg W. Stone, MD, FACC{dagger},*, Thomas D. Stuckey, MD, FACC{ddagger}, Costantino O. Costantini, MD{dagger}, Peter J. Zimetbaum, MD, FACC§, Michael McLaughlin, MD§, Roxana Mehran, MD, FACC{dagger}, Eulogio Garcia, MD||, James E. Tcheng, MD, FACC, David A. Cox, MD, FACC#, Cindy L. Grines, MD, FACC**, Alexandra J. Lansky, MD, FACC{dagger} and Bernard J. Gersh, MBChB, DPhil, FACC*

* Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
{dagger} Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York
{ddagger} Moses Cone Heart and Vascular Center, Greensboro, North Carolina
§ Beth Israel Deaconess Medical Center, Boston, Massachusetts
|| Hospital Gregorio Maranon, Madrid, Spain
Duke Clinical Research Institute, Durham, North Carolina
# Mid Carolina Cardiology, Charlotte, North Carolina
** William Beaumont Hospital, Royal Oak, Michigan

Manuscript received September 7, 2004; revised manuscript received October 18, 2004, accepted October 26, 2004.

* Reprint requests and correspondence: Dr. Gregg W. Stone, The Cardiovascular Research Foundation, Columbia University Medical Center, Herbert Irving Pavilion, 5th Floor, 161 Fort Washington Avenue, New York, New York 10032 (Email: gstone{at}crf.org).


   Abstract
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 Abstract
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OBJECTIVES: We investigated the impact of diabetes mellitus on myocardial perfusion after primary percutaneous coronary intervention (PCI) utilizing myocardial blush grade (MBG) and ST-segment elevation resolution (STR).

BACKGROUND: Diabetes is an independent predictor of outcomes after primary PCI for acute myocardial infarction (AMI). Whether the poor prognosis is due to lower rates of myocardial reperfusion is unknown.

METHODS: Reperfusion success in those with and without diabetes mellitus was determined by measuring MBG (n = 1,301) and STR analysis (n = 700) in two substudies of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial among patients undergoing primary PCI for AMI.

RESULTS: There were no differences between those with or without diabetes with regard to postprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 (>95%), distribution of infarct-related artery, and the frequency of stent deployment or abciximab administration. Patients with diabetes mellitus were more likely to have absent myocardial perfusion (MBG 0/1, 56.0% vs. 47.1%, p = 0.01) and absent STR (20.3% vs. 8.1%, p = 0.002). Diabetes mellitus (hazard ratio [HR] 1.63 [95% confidence interval (CI) 1.17 to 2.28], p = 0.004) was an independent predictor of absent myocardial perfusion (MBG 0/1) and absent STR (HR 2.94 [95% CI 1.64 to 5.37], p = 0.005) by multivariate modeling.

CONCLUSIONS: Despite similar high rates of TIMI flow grade 3 after primary PCI in patients with and without diabetes, patients with diabetes are more likely to have abnormal myocardial perfusion as assessed by both incomplete STR and reduced MBG. Diminished microvascular perfusion in diabetics after primary PCI may contribute to adverse outcomes.

Abbreviations and Acronyms
  AMI = acute myocardial infarction
  CADILLAC = Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trial
  CI = confidence interval
  HR = hazard ratio
  MACE = major adverse cardiac events
  MBG = myocardial blush grade
  OR = odds ratio
  PCI = percutaneous coronary intervention
  STR = ST-segment resolution

The major cause of morbidity and mortality in patients with diabetes mellitus is cardiovascular disease (1,2). The presence of diabetes is an independent predictor of early and late mortality after acute myocardial infarction (AMI) (2,3). The higher mortality in AMI patients with versus without diabetes may, in part, be due to more extensive coronary atherosclerosis and concomitant comorbid conditions, reduced cardiac reserve, and excessive delay from symptom onset to presentation (4–6). Treatment of diabetes with sulfonylurea oral hypoglycemic drugs may further diminish the ability of the myocardium to tolerate ischemia (7). Diabetes has also been associated with abnormal coronary endothelial function, diminished coronary flow reserve, and impaired ischemic preconditioning (8–10), all of which may result in abnormal myocardial perfusion.

Recent small studies suggest that acute outcomes in diabetic patients with AMI may be better after reperfusion with primary percutaneous coronary intervention (PCI) than thrombolytic therapy (5,11). However, compared with patients without diabetes, diabetics remain at increased risk for adverse outcomes after primary PCI. Whether this is, in part, due to abnormal myocardial perfusion after PCI in patients with diabetes has not been formally studied. We, therefore, examined the impact of diabetes mellitus on myocardial reperfusion from a large multicenter, prospective study of primary PCI in AMI, utilizing two well-validated measures of myocardial perfusion and reperfusion success, resolution of ST-segment elevation (STR) (12–16) and the myocardial blush grade (MBG) (17–20).


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The details of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial protocol have been published previously (21). In brief, 2,082 patients of any age with AMI within 12 h of symptom onset undergoing primary PCI were enrolled in 76 centers in nine countries between November 1997 and September 1999, and randomized in a 2 x 2 factorial design to primary balloon angioplasty versus stenting, with or without abciximab. The principal exclusion criteria consisted of cardiogenic shock, saphenous vein graft occlusion, and lesions otherwise not amenable to stent implantation. Clinical follow-up continued for one year.

An independent committee blinded to randomization adjudicated all primary end point events. Major adverse cardiac events (MACE) were defined as a composite of death, reinfarction, ischemic-driven target vessel revascularization, or disabling stroke as previously defined (21). Diabetic status was classified by treatment with diet alone, oral hypoglycemic agents, and insulin. The principal clinical results of the CADILLAC trial stratified by diabetes have been previously reported (22). The present analyses are restricted to the impact of diabetes on myocardial perfusion as assessed in formal STR and MBG substudies within the CADILLAC trial.

MBG substudy.   Myocardial blush grade is an angiographic surrogate of myocardial perfusion after PCI, and strongly correlates with survival after reperfusion therapy in AMI (17–20). The details of the CADILLAC myocardial blush substudy have been previously published (23). In brief, myocardial blush in the distribution of the infarct vessel after PCI was analyzed using the methodology of van't Hof et al. (17) at an independent angiographic core laboratory at the Cardiovascular Research Foundation in New York City blinded to clinical outcomes. Based on the maximal densitometric degree of contrast opacification, MBG in 1,301 patients was scored as MBG 0/1 = no or minimal myocardial contrast opacification; MBG 2 = moderate contrast opacification but less than in either an ipsilateral or contralateral noninfarct artery; and MBG 3, normal myocardial blush or contrast opacification, comparable with the other coronary arteries. When myocardial blush persisted ("staining"), MBG-0 was assigned.

STR substudy.   ST-segment monitoring is a well-validated, noninvasive method for assessing the efficacy of myocardial reperfusion therapy in patients with AMI (12–15), and STR has been correlated with the restoration of epicardial and microvascular blood flow and myocyte function (16). The methodology of the CADILLAC STR substudy has also previously been reported (24). In brief, 700 patients who met the following criteria were entered into a formal substudy to examine the impact of electrocardiographic STR after AMI: 1) paired electrocardiograms (ECG) at baseline and within 4 h after PCI (mean 1.8 ± 0.8 h) with >1 mm baseline ST-segment elevation in two contiguous leads in the infarct territory; and 2) absence of conditions on both ECGs confounding interpretation, including left bundle branch block, pacing, preexcitation, ectopy, missing leads, and artifact. ST-segment resolution was measured at an independent core electrocardiographic laboratory (Beth Israel Deaconess Medical Center, Boston, Massachusetts) blinded to clinical outcomes. ST-deviation was measured with digital calipers to the nearest 0.01 mV. The summed level of ST-segment elevation was calculated for anterior myocardial infarction in V1 to V6, I, and aVL, and for inferior myocardial infarction in leads II, III, aVF, V5, and V6. As per Schroder et al. (12), STR was classified as complete (>70%), partial (30% to 70%), or absent (<30%).

Statistical analysis.   Categorical variables were compared with Fisher exact test for paired comparisons and the chi-square test for trend for three-way comparisons. Continuous variables are presented as medians and interquartile ranges, and were compared using the Kruskal-Wallis nonparametric test. Adverse event rates during follow-up were summarized and displayed as Kaplan-Meier estimates and compared using the log-rank test. Stepwise logistic regression analysis was used to identify independent predictors of absent STR (<30%) and absent or minimal blush (MBG 0/1) after PCI. Baseline clinical, angiographic, and procedural variables as seen in Tables 1 and 2 were included in the multivariate models with an entry and exit criteria of p < 0.10. Cox proportional hazard regression was used to identify independent correlates of mortality in diabetics.


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  		Table 1. Baseline Characteristics Stratified by Diabetic Status
 

   Results
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Baseline characteristics.   There were 232 (17.8%) diabetics among the 1,301 patients who were enrolled in the formal MBG substudy, and 118 (16.8%) diabetics among the 700 patients enrolled in the formal STR substudy. The clinical characteristics of patients with and without diabetes for the two substudies are summarized in Table 1. Patients with diabetes were older, more likely to be female and have hypertension and congestive heart failure at presentation, and presented later from the symptom onset, but were less likely to be current smokers. The differences in baseline characteristics are consistent with the diabetic status of the patients and have been observed in previous studies (5); however, we cannot exclude selection bias resulting from a subgroup analysis. As seen in Table 2, diabetic patients were more likely to have multivessel coronary artery disease and preprocedure Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 than nondiabetic patients. There were no differences in the distribution of the infarct-related artery, reference vessel diameter, severity of stenosis, rates of stent implantation or abciximab administration, or postprocedural TIMI flow grade 3 between diabetic and nondiabetic patients.


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  		Table 2. Angiographic and Procedural Data Stratified by Diabetic Status
 
MBG and STR after PCI in diabetes.   There was no difference in the prevalence of diabetes among the patients who were and those who were not included in the MBG and STR subanalyses in the CADILLAC trial (23,24). As seen in Figure 1, absent myocardial perfusion (MBG 0/1) after primary PCI was significantly more common in diabetic compared with nondiabetic patients. By multivariate analysis, diabetes (odds ratio [OR] 1.63 [95% confidence interval (CI) 1.17 to 2.28], p = 0.004), anterior infarction (OR 4.14 [95% CI 3.18 to 5.4], p < 0.0001), and prolonged time from symptom onset to angioplasty (OR 1.07 [95% CI 1.03 to 1.11], p = 0.0008) were independent predictors of absent postprocedural myocardial perfusion.



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  		Figure 1 Myocardial perfusion grade after intervention in patients with and without diabetes.

 
Absent STR was also significantly more frequent in patients with compared to those without diabetes (Fig. 2). By multivariate analysis, diabetes (OR 2.94 [95% CI 1.60 to 5.37], p = 0.0005), anterior infarction (OR 3.98 [95% CI 2.21 to 7.17], p < 0.0001), and prolonged time from symptom onset to angioplasty (OR 1.11 [95% CI 1.04 to 1.19], p = 0.002) were independent predictors of absent STR.



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  		Figure 2 ST-segment resolution after intervention in patients with and without diabetes.

 
Clinical implications of myocardial perfusion after primary PCI in patients with diabetes.   There was an inverse relationship between MBG and mortality in diabetic patients, both at 30 days and 1 year, though this relationship was not statistically significant (Fig. 3). By multivariate analysis, lower creatinine clearance (hazard ratio [HR] 1.06 [95% CI 1.03 to 1.11], p = 0.0003) was the only independent predictor of 30-day mortality in patients with diabetes in this substudy. Absent MBG was not significantly predictive of mortality when forced into this model (HR 1.67 [95% CI 0.33 to 8.44], p = 0.54). Reduced creatinine clearance (HR 1.03 [95% CI 1.01 to 1.04], p = 0.008) and admission Killip class 2/3 (HR 3.63 [95% CI 1.27 to 10.42], p = 0.02) were independent predictors of one-year mortality. In this model the MBG HR for one-year mortality was 3.05 (95% CI 0.86 to 10.84, p = 0.08).



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  		Figure 3 Relationship between myocardial blush grade and 30-day (left) and 1-year (right) mortality in patients with (n = 232) and without diabetes (n = 1,069).

 
As seen in Figure 4, absent STR was a statistically significant univariate predictor of mortality in diabetic patients. By multivariate analysis in this substudy, lower creatinine clearance (HR 1.16 [95% CI 1.03 to 1.29], p = 0.01) was the only independent predictor of 30-day mortality in diabetics. Absent STR was weakly predictive of 30-day mortality when forced into this model (HR 11.04 [0.70 to 165.60], p = 0.08). However, absent STR was a statistically significant independent predictor of one-year mortality in diabetic patients (HR 11.71 [95% CI 1.53 to 89.90], p = 0.02), as was reduced creatinine clearance (HR 1.09 [95% CI 1.03 to 1.14], p = 0.02) and the presence of triple-vessel disease (HR 9.90 [95% CI 1.31 to 75.05], p = 0.03).



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  		Figure 4 Relationship between the ST-segment resolution and 30-day (left) and 1-year (right) mortality in patients with (n = 118) and without diabetes (n = 582).

 

   Discussion
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 Methods
 Results
 Discussion
References
 
The major findings of the present study are: 1) despite similar rates of TIMI flow grade 3 after primary PCI in patients with and without diabetes, patients with diabetes are more likely to have abnormal myocardial perfusion as assessed by both incomplete STR and reduced MBG; and 2) diminished microvascular perfusion in diabetics after primary PCI may contribute to the increased mortality rates in these patients.

Despite the effective restoration of normal epicardial flow rates in >95% of patients with diabetes in this study, complete resolution of ST-segment elevation was observed in only approximately half of the patients. Similarly, only approximately half of patients had normal myocardial perfusion as assessed angiographically by the MBG. By multivariate analysis, the presence of diabetes (as well as anterior AMI and delayed reperfusion) was an independent predictor of both absent STR and a closed microvasculature.

Few prior reports have examined myocardial perfusion in diabetic patients after reperfusion therapy. In a previous study examining pooled data from four TIMI trials, complete STR at 90 min tended to be less often present in patients with diabetes, but only in those without TIMI flow grade 3 (25). A lower likelihood of early STR, defined as ≥50% decrease in ST-segment elevation at 30 min, has been reported from a small study in insulin-requiring diabetics after primary PCI (26). The results of the present multicenter study thus confirm and extend the findings from these studies in demonstrating impaired myocardial perfusion in a relatively large diabetic cohort after primary PCI, independent of epicardial flow rates.

Persistent ST-segment elevation and abnormal myocardial blush in the presence of normal epicardial blood flow are indicative of diminished microvascular blood flow and impaired tissue perfusion, often referred to as the "no-reflow phenomenon" (27,28). Thus, our findings confirm that myocardial microvascular flow is more frequently impaired in diabetes. Impaired myocardial reperfusion as evidenced by diminished STR and abnormal MBG after reperfusion therapy is a powerful predictor of decreased left ventricular functional recovery and greater infarct size (27,29,30), as well as short- and long-term mortality (12,13,15,20,23,24). Thus, abnormal myocardial perfusion may, in part, explain the poor prognosis in patients with, compared to those without, diabetes after primary PCI (31). Our study also confirms the utility of electrocardiographic STR and MBG in predicting mortality in diabetic patients treated with PCI. A negative stepwise relationship between the magnitude of STR and MBG, and 30-day and 1-year mortality was found. In the current study, STR was more useful than MBG in predicting long-term outcomes in diabetics. However, given the fact that the present report was based on different groups of patients in two separate substudies, additional large-scale studies are required to examine the relative prognostic utility of STR and MBG.

While the precise pathophysiologic mechanisms by which diabetes contributes to microvascular injury remain unknown, several potential explanations have been postulated. First, diabetes is associated with a prothrombotic and inflammatory state; microthrombi and leucocyte accumulation in the capillaries of diabetic patients may, thus, lead to coronary microvascular obstruction (32,33). Second, coronary endothelial and smooth muscle dysfunction due to oxidative stress accompanied by reduced nitric oxide bioavailability and increased endothelin release may lead to microvascular spasm and reduce myocardial perfusion after PCI in diabetic patients (33). Third, the acute recruitment of coronary collaterals appears to be impaired in diabetic compared with nondiabetic patients (34). These observations require validation, and further studies are needed to elucidate the mechanisms of microvascular hypoperfusion in diabetics with the aim of developing new therapies.

Study limitations.   The current analyses, as post-hoc analyses of two substudies, are subject to both recognized and unknown biases; STR and MBG were the only markers of myocardial perfusion examined in the present study. Other imaging modalities of microcirculatory function such as contrast echocardiography, positron emission tomographic scanning, and invasive measures of coronary flow reserve (Doppler) may provide additional insights regarding microcirculatory function in the diabetic patient with AMI after reperfusion. An interaction between insulin therapy and myocardial perfusion could not be determined due to the relatively small number of insulin-treated patients included in the analyses. The use of coronary stent has increased significantly since this study was conducted, which may limit the applicability of our findings to current practice. However, recent data suggests that stent deployment does not alter myocardial perfusion (23,24). The present study examined the impact of myocardial perfusion on mortality only; the impact of diabetes and microcirculatory function on myocardial salvage and recovery of left ventricular function was not studied. Finally, while CADILLAC is the largest multicenter trial of primary PCI to date, significantly larger, specifically designed studies are required to comprehensively evaluate all the variables responsible for the adverse prognosis in diabetic patients with AMI.

Conclusions and clinical implications.   With contemporary interventional approaches, the procedural success rate of primary PCI in diabetics with AMI is equivalent to nondiabetic patients. However, a greater proportion of diabetic than nondiabetic patients fail to achieve normal myocardial perfusion, a finding associated with higher mortality in this patient cohort. Additional research is required to develop novel device-based and pharmacologic approaches to enhance microcirculatory function after primary PCI, which may improve the prognosis of patients with diabetes and AMI. In this regard, assessment of STR and MBG after reperfusion are relatively simple, noninvasive methods with prognostic utility beyond TIMI flow grade 3, and, as such, should be included in future studies of reperfusion.


   Footnotes
 
Drs. Lansky and Zimetbaum direct the two core laboratories utilized in the analysis. Dr. Stephen G. Ellis acted as guest editor for this paper.


   References
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 Abstract
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 References
 

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