ASSOCIATED FACTORS OF EJECTION FRACTION IN INSULIN-TREATED PATIENTS WITH TYPE 2 DIABETES

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1 Rev. Med. Chir. Soc. Med. Nat., Iaşi 204 vol. 8, no. 4 INTERNAL MEDICINE - PEDIATRICS ORIGINAL PAPERS ASSOCIATED FACTORS OF EJECTION FRACTION IN INSULIN-TREATED PATIENTS WITH TYPE 2 DIABETES Gina Botnariu *, A. O. Petriş, O. R. Petriş 2, Alina D. Popa 2, Irina Iuliana Costache University of Medicine and Pharmacy Grigore T. Popa - Iași Faculty of Medicine. Department of Medical Specialties (I) 2. Department of Preventive Medicine and Interdisciplinarity *Corresponding author. ASSOCIATED FACTORS OF EJECTION FRACTION IN INSULIN-TREATED PA- TIENTS WITH TYPE 2 DIABETES (Abstract). Aim of the study: to evaluate the relation between ejection fraction (EF), diabetes characteristics and cardiovascular risk factors. Material and methods: We carried out a cross-sectional study in 7 patients with insulintreated type 2 diabetes hospitalized at the Sf. Spiridon Emergency Clinical Hospital, Iasi. All patients were evaluated for asymptomatic organ damage and cardiovascular risk factors of hypertension and diabetes metabolic control. Global ejection fraction (EF) was evaluated through 2-D echocardiography. Results and discussion: In the studied group the ejection fraction had significant negative correlations with the duration of the disease (p=0.007) and the presence of microalbuminuria (p=0.00). There were some differences between the categories realized by grouping the patients according to the presence of hypertension and/or previous myocardial infarction. In patients without personal history of cardiovasc ular disease EF was correlated only with LDLc levels. In the hypertensive patients without myoca r- dial infarction it was correlated with diabetes duration, Hb Ac and LDLc. In those patients with both conditions, EF had significant correlations with Hb Ac and microalbuminuria. Conclusions: These results emphasized that the determinants associated with heart failure in patients with type 2, insulin-treated diabetes, differ according to the presence of high blood pressure and myocardial infarction. Keywords: ARTERIAL ESSENTIAL HYPERTEN- SION, DIABETES MELLITUS, HEART FAILURE Metabolic syndrome is a frequent association in hypertensive patients because insulin resistance is the main trigger of metabolic abnormalities and is related to lifestyle characteristics (). High blood pressure is associated with primary lifestyle risk factors, and induces a large range of injuries in cardiovascular and renal system since the earliest stages (, 2, 3, 4). Metabolic syndrome is acknowledged as the clustering of risk factors (obesity, insulin resistance, dyslipidemia and hypertension) associated with the subsequent development of cardiovascular disease and type 2 diabetes (8, 9, 0,, 2). The metabolic syndrome is a known risk factor for cardiovascular morbidity and mortality (, 2); moreover, some of the antihypertensive drugs, such as beta-blockers and diuretics, have metabolic side effects that could inter- 946

2 Associated factors of ejection fraction in insulin-treated patients with type 2 diabetes fere and worsen the preexistent anomalies (5, 6, 7). Diabetes mellitus (DM) and congestive heart failure (HF) are frequently associated. The presence of DM in HF patients determines an increased number of adverse events compared with patients without DM. Recent guidelines regarding glycemic control emphasized the importance of the individualization of therapy and targets depending of patient diseases and the risks associated with hypoglycemia. This balance in establishing therapeutic targets may be particularly relevant in patients with DM and HF (8). The aim of the study was to evaluate the relation between ejection fraction (EF), diabetes characteristics and cardiovascular risk factors. MATERIAL AND METHODS During January 202 and December 203, we carried out a cross-sectional study in 7 patients hospitalized at the Sf. Spiridon Emergency Clinical Hospital, in Iasi. The inclusion criteria were the presence of insulin-treated type 2 diabetes. The exclusion criteria were type diabetes, type 2 diabetes treated with non-insulinic agents, patients refusal. The information obtained from patients was directly registered in a well-structured questionnaire filled in as part of direct interview. The questions here comprised referred to the following aspects: demographic data, previous myocardial infarction, history of high blood pressure and duration of diabetes. The diagnosis of arterial hypertension was assessed in the presence of values higher than 40/85 mmhg, or normal ones in treated patients for high BP. All patients underwent physical examination, laboratory investigations and diagnostic tests having as aim to search for asymptomatic organ damage and cardiovascular risk factors. A complete 2 lead ECG was registered to identify patients with previous asymptomatic myocardial infarction (MI). Global ejection fraction (EF) was evaluated through 2-D echocardiography. We examined the relation between EF, diabetes characteristics and cardiovascular risk factors. Continuous data was expressed as medium and standard deviation. The Shapiro- Wilk test was used to evaluate the normal distribution of the analyzed data. The chisquare test was used to determine significant differences between various categories formed out of the frequency data. Association between variables was estimated by Pearson correlation coefficient. Stepwise multiple regressions were used to identify the variables with a predictive role in ejection fraction. The study was conducted after obtaining written informed consent in accordance with the Declaration of Helsinki. We paid full respect to the confidentiality and intimacy terms when maneuvering the data and records keeping of the participating subjects to the study. RESULTS We conducted a cross-sectional study on a sample of 7 patients with insulintreated type 2 diabetes. The mean duration of the disease was 9.56 years and almost three quarters had a poor glycemic control. The criteria associated to metabolic control which were analyzed were: LDLc, HDLc, Hb Ac, microalbuminuria and blood pressure. Most of the patients had abnormal levels of these parameters, indicating a poor metabolic control (tab. I). 947

3 Gina Botnariu et al. 82.5% of the patients had high blood pressure (BP) and 24.6% had had myocardial infarction in their medical history. All normotensive patients had not had a previous myocardial infarction, while 42 (29.8%) of hypertensive ones experienced it (p<0.00). The ejection fraction (EF) was also evaluated by 2-D Echocardiography, having a mean value of 54.82%. However a high proportion of the participants had cardiac failure (35.%) (tab. I). In the sample studied the ejection fraction had significant negative correlations with the duration of the disease (p=0.007) and the microalbuminuria (p=0.00)(fig. ). However, there were noticed some differences between the categories realized by grouping the patients according to the presence and/or the association of hypertension and previous myocardial infarction (tab. II). In patients without personal history of cardiovascular disease, EF was related only with LDLc levels. In the hypertensive patients without myocardial infarction it was related with diabetes duration, Hb Ac and LDLc, while in those with both conditions, EF had significant correlations with Hb Ac and microalbuminuria (tab. II). In the multivariate analysis, we included as potential predictors of EF the following parameters: diabetes duration, microalbuminuria, HDLc, LDLc, HbAc. When analyzing the entire sample, the predictors of EF were only diabetes duration and microalbuminuria (R=0.33, R 2 = 0.). Age (mean ± SD) TABLE I. Background characteristics Mean Gender males (N, %) 84 (49,) Smokers (N, %) 2 (2,3) Diabetes duration (mean ± SD) ±.052 y.o. 9.56±6.52 years High BP (N, %) 4 (82,5) Myocardial infarcts (N, %) 42 (24,6) Ejection fraction (mean ± SD) 54,82±2,50 Hb Ac %(mean ± SD) ±2.46 LDLc mg/dl (mean ± SD) 56.64±53.99 HDLc mg/dl (mean ± SD) 38.68±0.93 Microalbuminuria mg/dl(mean ± SD) 63.43±36.87 Polineuropathie (N, %) 23 (7,9) Cardiac failure (N, %) 60 (35,) HbAc>7% (N, %) 26 (73,7) LDLc>00 mg/dl (N, %) 35 (78,9) HipoHDLc (N, %) 47 (87) 948

4 Associated factors of ejection fraction in insulin-treated patients with type 2 diabetes Fig.. Association between ejection fraction and microalbuminuria TABLE II Significant correlations between the ejection fractions and characteristics of diabetes Diabetes Micro Ejection fraction Age Hb Ac LDLc HDLc duration albuminuria r ** ** Total sample p Patients without high BP and MI (N=30) Patients with high BP and without MI (N=99) Patients with high BP and with MI (N=42) r ** p r ** * -.28 * p r ** * p However, we identified different predictors of EF, when analyzing on the subgroups determined by the presence of high BP and previous myocardial infarction. In diabetics without cardiovascular diseases, only one predictor was identified: LDLc (R=0.47, R 2 =0.22). Hypertensive diabetics with MI had as predictors of EF, diabetes duration and microalbuminuria (R=0.30, R 2 =0.09). The participants with high blood pressure, but without MI had as predictors of EF both LDLc and Hb Ac (R=0.65, R 2 =0.42) (tab. III). 949

5 Gina Botnariu et al TABLE III Multiple linear regression coefficients and associated p-values for ejection and specific characteristics Standardized Coefficients p. 95% Confidence Interval for B Beta Lower Bound Upper Bound Total sample (Constant) microalbuminuria (Constant) microalbuminuria diabetes duration Patients without high BP and MI (N=30) (Constant) LDL Patients with high BP and with MI (N=42) (Constant) microalbuminuria (Constant) microalbuminuria diabetes duration Patients with high BP and without MI (N=99) (Constant) Hb Ac (Constant) Hb Ac LDL DISCUSSION Diabetes is currently among the most challenging threats to public health. It is estimated that 382 million people worldwide have diabetes and the majority will likely die from cardiovascular disease (9). In patients with type 2 diabetes, HbAc is used to evaluate the long term glycemic control and represents an indicator of development of micro vascular and macrovascular complications. Even if the improvement of glucose control significantly reduces the risk of micro vascular complications, most of the trials failed to show if there is also a decrease of risk for atherosclerotic diseases. Despite this, the value of HbAc is still used as a surrogate measure of anti diabetic drugs potential to lower cardiovascular risk. Some authors considered that this assumption is no longer acceptable (0). Cardiovascular diseases are the main causes of death and disability among people with type 2 diabetes. It is estimated that 65% of diabetics would die due to heart disease or stroke. Also, they are two to four times more likely to have atherosclerotic cardiovascular diseases than adults without diabetes (). In our sample, 24.6% had myocardial infarction in their medical history. However a higher proportion of the participants had cardiac failure (35.%). The incidence of HF in patients with ischemic heart disease was 35.7% in non diabetic patients, and 45.7% in diabetic patients (2). Several studies have suggested that diabetics, with or without previous cardiovascular disease, 950

6 Associated factors of ejection fraction in insulin-treated patients with type 2 diabetes have up to five-fold increased risk of heart failure (3). At least 3 mechanisms are involved in inducing HF in diabetic patients: associated diaseases or favoring coronary atherosclerosis or through diabetic cardiomyopathy (4). In the sample we studied, the ejection fraction had significant negative correlations with the duration of the disease and the levels of microalbuminuria and the predictors of EF were only diabetes duration and microalbuminuria. Other studies, such as UK Prospective Diabetes Study (UKPDS), demonstrated a strong association between the incidence of HF and HbAc levels in diabetic patients (5). A large trial, conducted in 48,858 diabetic patients, showed that the increase of Hb Ac with % was associated with a 2% increased risk of hospitalization for the same patients (6). In our study, Hb Ac was significantly associated with EF in patients with high blood pressure even if myocardial infarction was present or not. In normotensive patients, there were no correlations between Hb Ac and EF. However, in these patients diabetes duration was a significant predictor of left ventricular systolic function. Other studies demonstrated that the onset of HF may be better correlated with the duration of the disease. It is considered that the development of HF may be more closely related to the duration of DM than to glycemic control (4). In patients without personal history of cardiovascular disease or high blood pressure, EF was correlated only with LDLc levels. In the hypertensive patients without myocardial infarction it was correlated with Hb Ac and microalbuminuria, while in those with both conditions, EF had significant correlations with diabetes duration, Hb Ac and LDLc. In another study, performed in a well characterized population of patients with anterior MI and mild residual left ventricular dysfunction or preserved ejection fraction, diabetes is associated with worse functional class and a greater risk of developing congestive heart failure in the following year (3). In our study, the predictors of EF in patients with previous MI were: diabetes duration, microalbuminuria, HDLc, LDLc, HbAc. CONCLUSIONS The results of our study suggested that there would be some differences between determinants associated to heart failure in type 2 insulin-treated diabetics, according to the presence of high blood pressure and myocardial infarction. Future research will clarify the extent of this association and its relevance for clinical practice. REFERENCES. Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part : Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 998; 5: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 200; 285:

7 Gina Botnariu et al. 3. Balkau B, Charles MA: Commalet on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR).Diabet Med 999; 6: Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: Findings from the Third National Health and Nutrition Examination Survey. JAMA 2002; 287: Ferrannini E, Natali A, Capaldo B, Lehtovirta M, Jacob S, Yki-Jarvinen H: Insulin resistance, hyperinsulinemia, and blood pressure: Role of age and obesity. European Group for the Study of Insulin Resistance (EGIR). Hypertension 997; 30: Kaplan MN: Primary hypertension: Pathogenesis. In: Kaplan s Clinical Hypertension, 8 th Ed., Lippincott Williams & Wilkins, Philadelphia, USA, 2002, Cuspidi C, Meani S, Fusi V, Severgnini B, Valerio C, Catini E, Leonetti G, Magrini F, Zanchetti A: Metabolic syndrome and target organ damage in untreated essential hypertensives. J Hypertens 2004; 22: Nasir S., Aquilar D. Congestive heart failure and diabetes mellitus: balancing glycemic control with heart failure improvement.am J Cardiol. 202; 0(9 Suppl): 50B-57B. 9. Fonarow GC. Diabetes Medications and Heart Failure: Recognizing the Risk. Circulation. 204 Sep McMurray JJ, Gerstein HC2, Holman RR3, Pfeffer MA4. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol 204; 2(0): Disease-Diabetes_UCM_33865_Article.jsp 2. Tenenbaum A, Motro M, Fisman EZ, Leor J, Boyko V, Mandelzweig L, Behar S: Status of glucose metabolism in patients with heart failure secondary to coronary artery disease. Am J Cardiol 2002; 90: Manes C., Greaves S., Pfeffer M.A, Rutherford J.D., Rouleau JL., Hennekens C., Solomon S.D.. Influence of diabetes mellitus on development of heart failure following anterior myocardial infarction Cardiovascular Medicine 204; 7(6): Bauters C, Lamblin N, Mc Fadden EP, Van Belle E, Millaire A, de Groote P. Influence of diabetes mellitus on heart failure risk and outcome. Cardiovascular Diabetology 2003; 2():. 5. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 32: Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV: Glycemic control and heart failure among adult patients with diabetes. Circulation 200; 03:

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