Clinical, epidemiologic, and pathologic data

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1 AJH 2000;13: ORIGINAL CONTRIBUTIONS Effect of Blood Glucose on Left Ventricular Mass in Patients With Hypertension and Type 2 Diabetes Mellitus João S. Felicio, Sandra R.G. Ferreira, Frida L. Plavnik, Valdir Moisés, Oswaldo Kohlmann, Jr, Artur B. Ribeiro, and Maria-Teresa Zanella The aim of our prospective study was to evaluate the influence of blood glucose (BG) on left ventricular mass and diastolic function in patients with hypertension and type 2 diabetes mellitus (DM). Fifty-six hypertensive patients with type 2 DM and 26 healthy controls were investigated. They were submitted to echocardiography (ECHO) with Doppler and we calculated the mean of their fasting BG values, office blood pressure (OBP), cholesterol and fractions, and triglycerides during the previous 4 years. The diabetic patients were then followed-up for 1 year with OBP, fasting BG, and lipids measured every 2 months. After this period, the patients were again submitted to ECHO and in 22 patients (group I [GI]), reductions greater than 10% in left ventricular mass index (LVMI) were observed ( v g/m 2, P <.01), whereas increases greater than 10% (group II [GII], n 17) (94 18 v g/m 2, P <.01) or no changes (group III [GIII], n 17) (98 16 v g/m 2, NS) in LVMI were detected in the remaining patients. The OBP values did not change during the follow-up. In GI the reduction of LVMI was associated with a BG fall from to mg/dl (P <.01) and a correlation was observed between BG and LVMI percent variations ( ) (r 0.48, P <.01). No important changes in left ventricular diastolic function were observed during the follow-up. We concluded that the improvement in glycemic control may contribute to LVH regression in hypertensive patients with type 2 DM. Am J Hypertens 2000; 13: American Journal of Hypertension, Ltd. KEY WORDS: Left ventricular hypertrophy, type 2 diabetes mellitus, hypertension, diastolic filling, glycemic control. Clinical, epidemiologic, and pathologic data support the occurrence of a specific cardiomyopathy related to diabetes mellitus (DM). 1 5 Proposed causes of this cardiomyopathy include metabolic abnormalities (hyperglycemia and changes in myocardial lipid metabolism), Received February 25, Accepted April 4, From the Nephrology and Endocrinology Divisions, UNIFESP, São Paulo, Brazil. Address correspondence and reprint requests to Maria-Teresa Zanella, MD, Hospital do Rim e Hipertensão, Rua Borges Lagoa 960, Vila Clementino, São Paulo, Brasil hypertension, and autonomic neuropathy Preclinical cardiac abnormalities such as left ventricular hypertrophy (LVH) and cardiac diastolic dysfunction have been found with higher frequency in hypertensives with type 2 DM when compared with essential hypertensives. 11,12 However, little is known about the effect of an improved glycemic control on left ventricular mass and cardiac diastolic function in patients with type 2 DM It has also been suggested that diabetic patients with long-term good glycemic control have a better survival rate than subjects with higher average values of fasting blood glucose (FBG). 16 Furthermore, the 2000 by the American Journal of Hypertension, Ltd /00/$20.00 Published by Elsevier Science, Inc. PII S (00)

2 1150 FELICIO ET AL AJH NOVEMBER 2000 VOL. 13, NO. 11 epidemiologic analyses of the United Kingdom Prospective Diabetes Study (UKPDS) data have shown an association between intensive blood glucose control and the risk of diabetic complications. 17,18 Nevertheless, these studies have not evaluated the role of satisfactory blood glucose control in the reversal of left ventricular structural and functional abnormalities. The purpose of this prospective study was to investigate the influence of blood glucose (BG) control on left ventricular mass and cardiac diastolic function in hypertensives with type 2 DM. METHODS Patients Fifty-six patients (40 women and 16 men) with hypertension and type 2 DM were evaluated at the beginning of the study period. All patients were submitted to M-mode, two-dimensional echocardiography (ECHO) with cardiac Doppler to assess left ventricular mass (LVM) and diastolic function. The following parameters were calculated: the mean of the FBG values, total cholesterol (TC) and fractions (highdensity lipoprotein [HDL], low-density lipoprotein [LDL] and very low-density lipoprotein [VLDL]), triglycerides (TG), and office blood pressure (OBP) levels during a previous mean period of 4 years; these values were considered as basal indices of OBP, blood lipid profile, and glucose control. Patients were then followed for a period of 1 year with OBP, FBG, TC and fractions, and TG measured every 2 months. The mean of these values were called follow-up values. After this 1-year period, patients were again submitted to ECHO. All patients had normal levels of serum creatinine and 24-h urinary protein excretion ( 150 mg/24 h). Patients with clinical or echocardiographic evidence of ischemic or valvular heart disease were not included in this study, nor were those with congestive heart failure, alcoholism, or secondary or severe hypertension. 19 Criteria for established hypertension were systolic and diastolic blood pressure 140/90 mm Hg on repeated measurements. 19 Diabetes was diagnosed according to the National Diabetes Data Group Criteria. 20 Type 2 DM were identified as those with disease onset at the age of 30 years or after with no need of insulin treatment. All diabetic patients received general information on DM and dietary instructions consisting of a reduction in the intake of total energy, total fat, and dietary cholesterol. They were treated only with diet or diet plus oral antidiabetic agents (sulphonylureas, metformin, or acarbose) and antihypertensive drugs. None of them was treated with insulin before the beginning of the study or during follow-up. They returned to the clinic every 2 months with the aim of improving glycemic and blood pressure control in relation to the previous 4 years. A group of 26 healthy control subjects (15 women and 11 men) was compared at baseline with the group of our diabetic patients. This study was approved by the Institutional Ethics Committee. Echocardiography M-mode, two-dimensional echocardiographic and cardiac Doppler studies were performed using a commercially available echo-doppler unit (Esaote Biomédica, Florence, Italy; model SIM 5000) equipped with a 2.5-MHz mechanical transducer. It was performed with the patients in the partial left lateral supine position. M-mode measurements were performed according to the recommendations of the American Society of Echocardiography. 21 LVM was calculated as previously recommended by Deveraux et al. 22 The left ventricular mass index (LVMI) was calculated by dividing LVM by the body surface area. LVH was present if LVMI was 134 g/m 2 in men and 110 g/m 2 in women. 22,23 The width of the 95% confidence interval for a single replicate measurement of LVM is approximately 59 g. 24 It exceeds average decreases in LVM noted in echocardiographic studies of LVM regression with antihypertensive drugs. 25 However, the width of a population confidence interval decreases proportionally with the inverse of the square root of the sample size. Hence, in 56 patients it would be 59 g/square root of 56 or 7.9 g. Patients were divided according to the changes in left ventricular mass index during the study period (Table 1). We considered a variation 10% in LVMI to separate the groups. It exceeded the limit of 7.9 g in LVM in all patients studied. All examinations were analyzed blindly by one independent echocardiographer. Transmitral blood flow signals were obtained and the following measurements were made on consecutive cardiac cycles: (1) peak flow velocity of early left ventricular (LV) filling (peak E), (2) peak flow velocity of late (atrial) LV filling (peak A), (3) deceleration time (DT), (4) isovolumetric-relaxation period (IVR), and (5) the ratio between heights of early and late diastolic flow velocity peaks (E/A ratio) (normal values 50 cm/s; 80 cm/s; 240 ms; 110 ms, and 1, respectively). 26,27 Other Measurements To create a measure of the previous long-term glycemic control, the average of all FBG values available before the study was calculated (mean period of 4 years and mean of 3.7 values of FBG/patient/year). If several FBG values were recorded during a month, only the first value of the month was used. 16 The same procedure was used to calculated previous indexes of OBP, TC and fractions, and TG. These indices were referred to as the basal average of FBG, OBP, TC and fractions, and TG values. Statistical Analysis All normally distributed values are given as mean SD and all other values are given

3 AJH NOVEMBER 2000 VOL. 13, NO. 11 LVH IN TYPE 2 DIABETES MELLITUS 1151 TABLE 1. CLINICAL, LABORATORY, AND ECHOCARDIOGRAPHIC PARAMETERS BEFORE AND AFTER 1 YEAR OF FOLLOW-UP Reductions in LVMI > 10% Increases in LVMI > 10% No Variation in LVMI Subgroups (n) GI (22) GII (17) GIII (17) Age (years) Weight (kg) Systolic office blood pressure (mm Hg) Basal Follow-up Diastolic office blood pressure (mm Hg) Basal Follow-up Echocardiographic data LVMI (g/m 2 ) Basal Follow-up 89 23* * DT (ms) Basal Follow-up Peak E (cm/s) Basal Follow-up Peak A (cm/s) Basal Follow-up E/A ratio Basal 0.9 ( ) 1.0 ( ) 0.9 ( ) Follow-up 0.8 ( ) 0.8 ( ) 0.8 ( ) IVR (ms) Basal Follow-up Laboratory data Fasting blood glucose (mg/dl) Basal Follow-up * Total cholesterol (mg/dl) Basal Follow-up HDL-cholesterol (mg/dl) Basal Follow-up * LDL-cholesterol (mg/dl) Basal Follow-up * VLDL-cholesterol (mg/dl) Basal Follow-up Triglycerides (mg/dl) Basal Follow-up LVMI left ventricular mass index; GI, GII, GIII group I, group II, group III; DT deceleration time; IVR isovolumetric relaxation period; HDL high-density lipoprotein; LDL low-density lipoprotein; VLDL very low-density lipoprotein. *P.01 v basal; P.05 v basal. as median (range). In comparisons of the nonnormally distributed variables, the Kruskal-Wallis test of variance was used to test for differences between the three groups. If differences were found, the Mann-Whitney test was used for comparisons between two groups. For all normally distributed variables, analysis of vari-

4 1152 FELICIO ET AL AJH NOVEMBER 2000 VOL. 13, NO. 11 ance was performed to test the differences among the three groups. If differences were found, the Student s t test was used for comparison between two groups. For longitudinal analysis, two variables of the same group were compared using paired t test or Wilcoxon test. For correlation analysis, correlation coefficients (Pearson or Spearman) were calculated. The relative changes ( ) during the follow-up in LVMI, OBP, and the average of FBG, TC and fractions, and TRIG were calculated ([follow-up baseline)/baseline]100). A P value (two-tailed) less than.05 was considered statistically significant. All calculations were made with a commercially available program, SigmaStat 1.0 (Jandel Scientific Corporation, Chicago, Illinois). RESULTS At baseline patients with hypertension and type 2 DM did not differ in age (57 8 v 55 8 years), body mass index (BMI) (27 5 v 29 5 kg/m 2 ), or gender when compared with the control group. Diabetic patients, when compared with nondiabetic hypertensive patients, showed increased LVMI ( v 82 14, P.01) and abnormalities in diastolic function (E/A Ratio 0.9 [ ] v 1.2 [ ], P.01; DT v ms, P.05; IVR v ms, P.01), respectively. In 22 patients (group I [GI]) reductions in LVMI 10% were observed, whereas in 17 patients (group II [GII]) an increase in LVMI 10% was detected. No changes in LVMI occurred in the remaining 17 patients (group III [GIII]). At the beginning, the three subgroups did not differ in age, weight, OBP, TC and fractions, or TG, as shown in Table 1. The values of OBP, weight, TC, and TG did not change during the follow-up. In addition, the antihypertensive and oral antidiabetic agents used during the follow-up did not differ in the three subgroups studied. In GI, the reduction of LVMI was associated with a decrease in the average FBG values from to mg/dl during the study (P.01). In contrast, no statistically significant changes in FBG were detected in the other two groups (GII to mg/dl, NS; GIII to mg/dl, NS) (Table 1). When all 56 patients were evaluated, a correlation was observed between FBG and LVMI percent variations ( ) (r 0.48; P.01). No correlation was observed between LVMI, OBP, and TC and fractions percent variations (Fig. 1). A more detailed analysis of GI subgroup showed that 11 of 13 patients who had LVH had their LVMI reduced to normal values during the follow-up period. This subgroup also showed a reduction in the average of FBG from to mg/dl during the study (P.01) whereas no changes in the average of OBP were observed. FIG. 1. Blood glucose and left ventricular mass changes in type 2 diabetes patients: 1-year follow-up. FBG fasting blood glucose; LVMI left ventricular mass index. DISCUSSION The present prospective study showed that improvements in glycemic control contribute to the regression of LVH in patients with hypertension and type 2 DM. These changes in left ventricular mass index occurred independently of any marked variation in either blood pressure or lipids levels. In our study, the diastolic function was not affected by blood glucose control variations in all groups. This result suggests that left ventricular diastolic dysfunction, after it is initiated, become unaffected directly by improvement in glycemic control or, alternatively, that a longer period of good glycemic control is needed to reverse this abnormality. These findings, however, are in agreement with the concept that abnormalities of diastolic function are largely irreversible. 8,9 Nevertheless, the contribution of better glycemic control to the regression of LVH may contribute indirectly to an improvement in left ventricular diastolic function. Prospective follow-up data on cardiac function and dimension in type 2 DM are scarce. 9,13 15 Vanninen et al 13 and Uusitupa et al 14 have described in newly diagnosed type 2 DM an improvement in diastolic and systolic function with the reduction of hyperglycemia, respectively. However, the role of duration of DM in the improvement of diastolic function remains to be elucidated. In the 38 patients studied by Vanninen and coworkers, no changes in LVMI were detected. Because it has been demonstrated that interstitial connective tissue increased in alloxan-induced diabetic dogs within 1 year, it is possible that patients with newly diagnosed type 2 DM are not the best group to evaluate the effect of the reduction of hyperglicemia on LVM. Furthermore, our patients had a satisfactory blood pressure control before starting the study. It might have minimized the blood pressure

5 AJH NOVEMBER 2000 VOL. 13, NO. 11 LVH IN TYPE 2 DIABETES MELLITUS 1153 effect on LVMI and maximized the visibility of the effect of better blood glucose control on regression of LVH. It was reported before that values of LVMI correlate significantly with values of FBG in hypertensive patients with DM. 6,11 Resnick and others have described in diabetics and in hypertensive patients elevated levels of cytosolic free calcium (Ca i ) In addition, it was observed that both glucose and insulin have primary cellular ionic effects on Ca i levels in isolated heart cells. 31 In vitro glucose levels around 180 mg/dl can elevate Ca i concentration in heart muscle. 31 Recently, Barbagallo et al have suggested that glucoserelated excess Ca i is a fundamental lesion in diabetes that contributes to the elevated blood pressure and cardiac mass in this disease. 6 Our results provide clinical support to this hypothesis. In the present study a significant positive correlation was found between changes in blood glucose values and changes in LVMI. This may suggest that the increases in blood glucose contribute to LVH. The fact that no changes in blood pressure were detected during the follow-up reinforces this hypothesis. The most important observation in this study, however, is the fact that patients who had high blood glucose values showed reductions in LVMI associated with an improvement in glycemic control. The coexistence of LVH and possible ischemic heart disease is a well-known phenomenon in the general population. 32 It has been suggested that ischemic heart disease is a consequence rather than a cause of LVH. 33 In addition, the findings of Ghali et al 34 and Fujita et al 35 suggest that the contribution from ischemia to enlargement of LVM is rather small. We have not excluded silent ischemia, a condition claimed to be frequently present in type 2 DM. Nevertheless, this claim is based on noninvasive methods revealing a prevalence of ischemia in 36% 36 and 31% 37 of patients with type 2 DM. In contrast, coronary angiography only revealed a prevalence of significant coronary artery disease in 8% and 11% of the diabetic patients included in the two above-mentioned studies, respectively. Therefore, ischemic heart disease does not seem to be an important contributor to the LVH in our patients. Other variables, such as insulin resistance 38 and free fatty acids, 39 which might be involved in the regression of LVH in our patients, were not evaluated in this study. Patients with type 2 DM are more stable in blood glucose control than patients with type 1 DM 40 and FBG has been commonly used to monitor glycemic control in type 2 diabetic patients treated with diet alone or oral hypoglycemic agents. 41 In both crosssectional and prospective 45 studies a good correlation was shown between FBG and HbA1. 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