|Year : 2016 | Volume
| Issue : 1 | Page : 17-22
Prognostic significance of glycosylated hemoglobin in nondiabetic patients in acute coronary syndrome
Sushil Singh, Manish Bansal, Khushboo Rani, Varun Gupta
Postgraduate Department of Medicine, SN Medical College, Agra, Uttar Pradesh, India
|Date of Web Publication||4-Mar-2016|
Room No 5, Hari Krishna Bhawan, In Front of Noori Gate, S. N. Medical College, Agra - 282 001, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: The role of glycosylated hemoglobin (HbA1c) in predicting the outcome of acute coronary syndrome (ACS) remains largely controversial. Much lesser is known of its importance in nondiabetics. Herein, we conducted a study to seek the association between the levels of HbA1c and the clinical outcome in nondiabetic patients who presented with ACS. Objective: The objective was to determine the impact of HbA1c levels on the severity and complications of ACS in nondiabetics. Materials and Methods: This observational cross-sectional study included 100 patients without diabetes mellitus who were admitted to the coronary care unit with symptoms suggestive of ACS. The diagnosis of ACS was made on the basis of troponin T value, electrocardiogram (ECG), and echocardiograph. Patients were stratified according to their HbA1c into two groups: Group 1 HbA1c <5.6 (36, 36%), Group 2 HbA1c between 5.7 and 6.4 (64, 64%). Main outcome measures were ECG changes (ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction), troponin T value, regional wall motion abnormalities and left ventricular ejection fraction on echo, along with the complications such as heart failure and arrhythmias. Data were analyzed separately using multiple regression analysis. Results: The mean age of patients was 58.67 years out of which 69% were males and 31% females. Of the total, 28% were smokers, 33% were known to be hypertensive, 32% had dyslipidemia, and body mass index was ≥25 kg/m2 in 9% of the subjects. The findings of this study found that increased levels of HbA1c were in general, associated with poorer outcomes in the nondiabetics. Conclusion: HbA1c is a predictor of major adverse outcomes in ACS in patients even when they are nondiabetics. Measurement of HbA1c levels may improve risk assessment in such patients when presenting with ACS.
Keywords: Acute coronary syndrome, glycosylated hemoglobin, nondiabetics
|How to cite this article:|
Singh S, Bansal M, Rani K, Gupta V. Prognostic significance of glycosylated hemoglobin in nondiabetic patients in acute coronary syndrome. Heart India 2016;4:17-22
|How to cite this URL:|
Singh S, Bansal M, Rani K, Gupta V. Prognostic significance of glycosylated hemoglobin in nondiabetic patients in acute coronary syndrome. Heart India [serial online] 2016 [cited 2021 Dec 2];4:17-22. Available from: https://www.heartindia.net/text.asp?2016/4/1/17/178123
| Introduction|| |
In recent years, much attention has been paid to the glycometabolism in patients with coronary artery disease (CAD). Numerous prior studies have shown that elevated glycosylated hemoglobin (HbA1c) increases the risk of death and in-hospital complications in patients with the acute coronary syndrome (ACS) and in patients undergoing coronary revascularization.,,,, Epidemiological evidence now suggests that HbA1c level is an independent risk factor for cardiovascular events in primary and secondary populations.,,, However, the prognostic value of HbA1c level in patients with the coronary atherosclerotic disease has not been well characterized, and the studies that examined this relationship have reported conflicting results.,,,,,,,,,,,, Diabetes is considered a highly “vascular disease” with both microvascular and macrovascular complications. Macrovascular complications start taking place long before the patient develops overt diabetes. This could reflect blood testing being performed during the hospitalization in patients with previously unrecognized diabetes. In addition, the stress of myocardial infarction (MI) unmasks or worsens the tendency toward hyperglycemia. Hyperglycemia is an independent risk factor for cardiovascular disease (CVD). Mechanisms of increased risk include endothelial dysfunction, platelet activation, coagulation abnormalities, and abnormal plaque composition. Diabetes may predispose to coronary thrombosis through increased primary and secondary platelet aggregation and increased platelet activation. In addition to platelet activation, diabetes is associated with an increase in plasma fibrinogen, which is a cardiovascular risk factor. Elevated plasma fibrinogen is also associated with other cardiovascular risk factors including older age, increased body mass, smoking, total cholesterol, and triglycerides. Fibrinolytic activity is reduced, tissue plasminogen activator activity is decreased because of increased plasma concentrations of and enhanced binding to its inhibitor, plasminogen activator inhibitor. Coronary tissue from diabetics contained a greater amount of lipid-rich atheroma and more macrophage infiltration, both of which are associated with a greater risk of plaque rupture, and a higher incidence of coronary heart disease. Hyperglycemia accelerates the process of atherosclerosis by the formation of glycated proteins and advanced glycation end products, which act by increasing the endothelial dysfunction. Recent data indicated a high prevalence of abnormal glucose metabolism in patients with no history of diabetes mellitus (DM) at the time of acute MI. In patients with ACS, up to 40% have impaired blood glucose levels on admission. This has been associated with increased mortality, irrespective of diabetic status. In nondiabetic patients, the at-admission plasma glucose level predicts both long-term morbidity (for example, re-infarction, hospitalization with heart failure, adverse ventricular remodeling) and mortality. Recent evidence has shown that chronic glucose dysregulation, assessed by HbA1c levels, is also of prognostic value with regard to future CVD and congestive heart failure. Stress hyperglycemia even in nondiabetics, is associated with many abnormalities like increased activation of stress-responsive kinases  and induction of apoptosis and myocyte necrosis, which in turn leads to systolic and diastolic dysfunction. HbA1c is an easy marker of long-term glucose regulation; it also unmasks minor glycometabolic disease, such as impaired glucose tolerance, impaired fasting glucose or metabolic syndrome. To comprehensively analyze these data, we performed a systematic review to examine whether an association exists between elevated HbA1c and all-cause mortality in patients hospitalized with ACS.
| Materials and Methods|| |
This is a cross-sectional study conducted at S. N. Medical College, Agra, during the period (May 2012-December 2013). A total of 100 patients who were admitted to the Coronary Care Unit with ACS were selected; with a mean age of 58.67 years. Patients' data of age, sex, body mass index (BMI), history of DM, hypertension, smoking, and hyperlipidemia were obtained. Serum levels of the following parameters were tabulated: HbA1c, fasting total serum cholesterol, low-density lipoprotein, cholesterol, and high-density lipoprotein. Patients were excluded if they had history of fasting blood sugar ≥126 (7 mmol/L), postprandial blood sugar ≥200 (11.1 mmol/L) after a 75 g oral glucose, HbA1c level >6, chronic kidney disease on maintenance dialysis and uremia, CLD, sepsis, hypothyroidism, those who donated blood recently or acute and chronic blood loss, gestational DM, excessive alcohol intake, hemoglobinopathy (sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase deficiency), treatment of anemia with iron or erythropoietin, autoimmune hemolytic anemia. Patients were stratified according to their HbA1c level into two groups: Group 1: <5.6 (n = 36) and Group 2: 5.7-6.4 (n = 64).
Left ventricular ejection fraction was measured by Simpson's method using two-dimensional echocardiography (ECHO). BMI was measured as weight (kg)/height (m 2) and obesity was defined as BMI ≥30 kg/m 2.
By using Statistical Package for Social Sciences software, all data of different variables were entered and analyzed with appropriate statistical tests and procedures.
Chi-square (χ2) was used for categorical variables, Student's t- test for continuous variables and to compare means. Bivariate Pearson's correlation coefficient was calculated to evaluate the associations among different variables. Partial correlation regression and multivariate analysis were used to determine the association between HbA1C levels and ejection fraction (EF) with control over other variables. In all statistical analysis, level of significance (P value) was set at P ≤ 0.05.
| Results|| |
In this study, 100 ACS patients were enrolled with a mean age of 58.67 years. The number of male patients was 69 as compared to 31 females with a sex ratio of approximately 2:1. Most of the patients were in the age group of 40-60 years [Table 1].
In our study, 64 out of 100 patients were of high normal HbA1c, and 36 belonged to normal HbA1c. The mean value of HbA1c in patients with normal HbA1c was 5.3 ± 0.14 and in patients with high normal HbA1c were 6.10 ± 0.16 [Table 2].
There were 76.57% (49 out of 64 patients) cases of ST-segment elevation MI in high normal HbA1c level patients as compared to 69.45% (25 out of 36 patients) in normal HbA1c level patients [Table 3].
In all 100 patients, troponin T values were estimated. Patients with high normal HbA1c levels had mean troponin T value 2179.3 ± 252.1 as compared to patients with normal HbA1c level with mean troponin T value 1915.9 ± 244.7 with P< 0.0001 which is statistically significant, which means these two groups are significantly different [Table 4].
In our study, 81 cases out of 100 were positive for the presence of regional wall motion abnormalities (RWMA) on ECHO. Of these, 54 (66.66%) patients had high normal HAb1C and 27 (33.33%) patients had normal HAb1C [Table 5].
In all 100 patients, left ventricular ejection fraction (LVEF) was estimated by ECHO and mean LVEF was 42.64%. Patients with high normal HbA1c level had lower LVEF with mean EF of 38.22 ± 11.54 as compared to patients with normal HbA1c level with mean 47.64 ± 8.32 with P< 0.0001 [Table 6].
Patients were assessed clinically for signs of heart failure and were then grouped according to their HbA1c levels. It was found that the percentage of heart failure in high normal HbA1c level patients were 68.75% (11 out of 16 patients) as compared to 31.25% (5 out of 16 patients) in normal HbA1c level patients [Table 7].
Electrocardiogram was obtained in all the patients included in this study, and the patients were divided on the basis of arrhythmia on presentation. The percentage of arrhythmia in high normal HbA1c level patients was 69.23% (9 out of 13 patients) as compared to 30.77% (4 out of 13 patients) in normal HbA1c level [Table 8].
| Discussion|| |
The objective of this endeavor was to study the prognostic value of HbA1c in nondiabetic patients presenting with ACS. Totally, 100 patients (diagnosed as per clinical symptoms, electrocardiogram [ECG] changes, troponin T values), who were above 30 years of age and gave consent were enrolled in this study. Different metabolic parameters, ECG, ECHO criteria were evaluated in them. The results were analyzed in terms of demographic profile (age and sex), metabolic parameters (blood sugar both fasting and postprandial, HbA1c, lipid profile, troponin T, BMI), ECG and ECHO criteria, severity (troponin T quantitative levels, EF, RWMA, ECG), and complications (left ventricular filling [LVF], arrhythmia). In the current study, we found a relation between HbA1c and poor outcome among patients of ACS without known diabetes. Elevated HbA1c level was a strong and independent predictor of severity and complication in ACS patients even in nondiabetics. Selvin et al. and Khaw et al. showed that an elevated HbA1c is associated with increased cardiovascular risk in patients with and without diabetes. Malmberg et al. found an association between elevated HbA1c and mortality after MI, relative risk (95% confidence interval) 1.07 (1.01-1.21); however, Timmer et al. and Cao et al. did not confirm this, (1.63 [0.99-2.79] and 1.08 [0.31-3.23]), respectively., Increasing HbA1c levels were clearly associated with adverse baseline characteristics such as a higher cardiovascular risk profile, explaining in part the poorer outcome of ACS [Table 9]. In a systematic review of 15 studies (1966-1998) on AMI, the association of hyperglycemia with increased in-hospital mortality was stronger in nondiabetic patients than in diabetic patients. In a study conducted in Asian Indians with normal glucose tolerance (NGT), a strong correlation of HbA1c and cardiovascular risk factors were found. NGT subjects with three or more metabolic abnormalities had the highest HbA1c levels and an HbA1c cut off point of ≥6.5% was found to have the highest accuracy in predicting both metabolic syndrome and CAD. Elevated glucose is not only a feature of glucose dysregulation, but also of stress and a more high-risk patient population. Stress hyperglycemia is a common occurrence in patients admitted to the intensive care units with ACS. Hence, elevated HbA1c levels can be predictive for CVD and mortality in patients without DM, regardless of fasting glucose levels, a finding that was suggested in a recent cohort study. In addition to the effect of associated insulin resistance, excess glucose may be directly detrimental during ACS, offering a target for treatment. The molecular mechanisms for this adverse effect include the promotion of oxidative stress, nonenzymatic glycation of platelet glycoproteins with abrupt changes in aggregability, amplification of inflammation, and suppression of immunity. In fact, some studies have shown even higher cardiovascular mortality and morbidity in patients with hyperglycemia in previously undiagnosed diabetes than in patients with known diabetes or normoglycemic subjects. It has been shown that higher HbA1c is associated with a larger infarct size, a lower ventricular function, and a higher Killip class. In addition, part of the association between long-term abnormalities in glucose control and outcome is due to the same complex mechanisms responsible for the adverse association between overt DM and cardiovascular outcome.
In our study, [Table 2] 76 out of 100 patients had ST segment elevation on ECG. Among these 76 patients, who had ST segment elevation on ECG, 49 patients belonged to high normal HbA1c group and 27 patients in normal HbA1c group. 24 patients showed no ST segment elevation on ECG, of these patients, 15 were in high normal HbA1c group, and 9 were in the normal HbA1c group. Hence, we found that the ST segment elevated ACS is more common in high normal HbA1c group as compared to the normal HbA1c group.
Furthermore, we found that most of the patients with high normal HbA1c have higher troponin T values as compared to most of the patients with normal HbA1c.
In our study, RWMA was assessed by ECHO, which showed 81 patients out of 100 having RWMA. Among these 81 patients, 54 (66.66%) belonged to high normal HbA1c group, and 27 (33.33%) patients were in the normal HbA1c group. 19 patients out of 100 had no RWMA, of these 10 (52.63%) belonged to high normal HbA1c group and 9 (47.36%) to the normal HbA1c group. Thus, RWMA on ECHO was more common in high normal HbA1c group (66.66%) as compared to normal HbA1c group (33.33%).
In our study, we found that most of the patients having high normal HbA1c had lower LVEF (mean 38.22% ± 11.54%) as compared to most of the patients with normal HbA1c, who had higher LVEF (47.64% ± 8.32%). This is also supported by the study given below.
Razzaq et al., showed that the mean EF was significantly lower in group HbA1c 6.5-8.5 and in group HbA1c >8.5 as compared with that group <6.5. A linear decrease in EF was found with rising HbA1c levels in patients with unstable angina (P = 0.0043), with ST-segment elevation myocardial infarction (P = 0.0290) and nonsegment elevation myocardial infarction (P = 0.0015). Heart failure was seen in 16 patients out of 100. Totally, 11 (68.75%) patients with heart failure were in high normal HbA1c group and 5 (31.25%) were in the normal HbA1c group. It is also supported by the study given below.
The study by Mani and John , in which 27.0% patients of heart failure were in low HbA1c group (<7%) and 73% patients with heart failure were in high HbA1c group (>7%). There is a correlation between HbA1c and heart failure, as the increase in value of HbA1c increases the chance of heart failure in both the studies.
Arrhythmia was present in 13 patients out of 100. 9 (69.23%) patients of arrhythmia were in high normal HbA1c group and 4 (30.76%) were in the normal HbA1c group. Study by Vinita Elizabeth Mani and John , in which 47.1% patients of arrhythmia were in low HbA1c group (<7%) and 52.9% patients of Arrhythmia were in high HbA1c group (>7%) also supports this.
| Conclusion|| |
This study shows that ACS patients without known DM are associated with poorer outcomes if they have higher levels of HbA1c. High normal HbA1c is associated with more complications such as LVF and arrhythmia. High normal HbA1c is also associated with more severe ACS in terms of higher levels of troponin T, lower EF, presence of RWMA on ECHO, Presence of ST elevation on ECG as compared to normal HbA1c patients. In this study, we also found, that there is more prevalence of ACS in patients who have a high normal level of HbA1c. HbA1c may be used to assess cardiovascular risk in a nondiabetic population with ACS. Elevated HbA1c level is an independent risk factor for morbidity and mortality in ACS patients without known DM.
| References|| |
American Diabetes Association. Standards of medical care in diabetes-2010. Diabetes Care 2010;33 Suppl 1:S11-61.
Sato KK, Hayashi T, Harita N, Yoneda T, Nakamura Y, Endo G, et al.
Combined measurement of fasting plasma glucose and A1C is effective for the prediction of type 2 diabetes: The Kansai Healthcare Study. Diabetes Care 2009;32:644-6.
Edelman D, Olsen MK, Dudley TK, Harris AC, Oddone EZ. Utility of hemoglobin A1c in predicting diabetes risk. J Gen Intern Med 2004;19:1175-80.
Laakso M. Dyslipidemia, morbidity, and mortality in non-insulin-dependent diabetes mellitus. Lipoproteins and coronary heart disease in non-insulin-dependent diabetes mellitus. J Diabetes Complications 1997;11:137-41.
Clarkson P, Celermajer DS, Donald AE, Sampson M, Sorensen KE, Adams M, et al
. Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol 1996;28:573-9.
Shechter M, Merz CN, Paul-Labrador MJ, Kaul S. Blood glucose and platelet-dependent thrombosis in patients with coronary artery disease. J Am Coll Cardiol 2000;35:300-7.
Cubbon RM, Wheatcroft SB, Grant PJ, Gale CP, Barth JH, Sapsford RJ, et al.
Temporal trends in mortality of patients with diabetes mellitus suffering acute myocardial infarction: A comparison of over 3000 patients between 1995 and 2003. Eur Heart J 2007;28:540-5.
Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendíc S, Rydén L, et al.
Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: A prospective study. Lancet 2002;359:2140-4.
Foo K, Cooper J, Deaner A, Knight C, Suliman A, Ranjadayalan K, et al.
A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes. Heart 2003;89:512-6.
Hadjadj S, Coisne D, Mauco G, Ragot S, Duengler F, Sosner P, et al.
Prognostic value of admission plasma glucose and HbA in acute myocardial infarction. Diabet Med 2004;21:305-10.
Bauters C, Ennezat PV, Tricot O, Lauwerier B, Lallemant R, Saadouni H, et al.
Stress hyperglycaemia is an independent predictor of left ventricular remodelling after first anterior myocardial infarction in non-diabetic patients. Eur Heart J 2007;28:546-52.
O'Sullivan CJ, Hynes N, Mahendran B, Andrews EJ, Avalos G, Tawfik S, et al.
Haemoglobin A1c (HbA1C) in non-diabetic and diabetic vascular patients. Is HbA1C an independent risk factor and predictor of adverse outcome? Eur J Vasc Endovasc Surg 2006;32:188-97.
Hadjadj S, Coisne D, Mauco G, Ragot S, Duengler F, Sosner P, et al.
Prognostic value of admission plasma glucose and HbA in acute myocardial infarction. Diabet Med 2004;21:305-10.
Rasoul S, Ottervanger JP, Bilo HJ, Timmer JR, van 't Hof AW, Dambrink JH, et al.
Glucose dysregulation in nondiabetic patients with ST-elevation myocardial infarction: Acute and chronic glucose dysregulation in STEMI. Neth J Med 2007;65:95-100.
Cakmak M, Cakmak N, Cetemen S, Tanriverdi H, Enc Y, Teskin O, et al.
The value of admission glycosylated hemoglobin level in patients with acute myocardial infarction. Can J Cardiol 2008;24:375-8.
Razzaq MK, Rasheed JI, Mohmmad HS. The value of admission glucose and glycosylated hemoglobin in patients with acute coronary syndrome. Iraqi Postgrad Med J 2013;12.
Timmer JR, Hoekstra M, Nijsten MW, van der Horst IC, Ottervanger JP, Slingerland RJ, et al
. Prognostic value of admission glycosylated hemoglobin and glucose in nondiabetic patients with ST-segment-elevation myocardial infarction treated with percutaneous coronary intervention. Circulation 2011;124:704-11.
Liu Y, Yang YM, Zhu J, Tan HQ, Liang Y, Li JD. Prognostic significance of hemoglobin A1c level in patients hospitalized with coronary artery disease. A systematic review and meta-analysis. Cardiovasc Diabetol 2011;10:98.
Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al.
Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421-31.
Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: The European prospective investigation into cancer in Norfolk. Ann Intern Med 2004;141:413-20.
Malmberg K, Norhammar A, Wedel H, Rydén L. Glycometabolic state at admission: Important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: Long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999;99:2626-32.
Timmer JR, Bilo HJ, Ottervanger JP, Dambrink JH, Miedema K, Hoorntje JC, et al.
Dysglycemia in suspected acute coronary syndromes. Eur J Intern Med 2005;16:29-33.
Cao JJ, Hudson M, Jankowski M, Whitehouse F, Weaver WD. Relation of chronic and acute glycemic control on mortality in acute myocardial infarction with diabetes mellitus. Am J Cardiol 2005;96:183-6.
Gerstein HC, Swedberg K, Carlsson J, McMurray JJ, Michelson EL, Olofsson B, et al.
The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: An analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Arch Intern Med 2008;168:1699-704.
Goode KM, John J, Rigby AS, Kilpatrick ES, Atkin SL, Bragadeesh T, et al
. Elevated glycated haemoglobin is a strong predictor of mortality in patients with left ventricular systolic dysfunction who are not receiving treatment for diabetes mellitus. Heart 2009;95:917-23.
Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al
. Glycemic control and heart failure among adult patients with diabetes. Circulation 2001;103:2668-73.
Pazin-Filho A, Kottgen A, Bertoni AG, Russell SD, Selvin E, Rosamond WD, et al
. HbA 1c as a risk factor for heart failure in persons with diabetes: The Atherosclerosis Risk in Communities (ARIC) study. Diabetologia 2008;51:2197-204.
Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes: An update. Diabetes Care 2004;27:1879-84.
Menon V, Greene T, Pereira AA, Wang X, Beck GJ, Kusek JW, et al
. Glycosylated hemoglobin and mortality in patients with nondiabetic chronic kidney disease. J Am Soc Nephrol 2005;16:3411-7.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]