Abstract
Abstract
In diabetes mellitus, structural and functional alterations of the heart can be already present at the time of first diagnosis. However, how early these alterations may occur has never been fully clarified. The present study aimed at investigating cardiac functional abnormalities in uncomplicated hypertensive or normotensive patients with a recent diagnosis of diabetes mellitus. We studied 40 diabetics (24 normotensives and 16 hypertensives) by means of routine echocardiography plus pulse tissue Doppler analysis. Data were compared with those obtained in healthy age- and sex-matched controls. Left ventricular remodelling was more evident in hypertensive diabetics than in normotensive diabetics vs controls. Diastolic function was altered in diabetic patients only when detected by pulse tissue Doppler analysis and not by conventional transmitral Doppler evaluation. Normotensive patients with type 2 diabetes with little or no evidence at standard echocardiography of alterations in cardiac structure and function, already displayed an alteration in diastolic function when the evaluation was based on the tissue Doppler approach. Patients with type 2 diabetes combined to hypertension showed more evident functional cardiac alterations at echocardiography. These findings support the conclusion that cardiac abnormalities are very early phenomena in type 2 diabetes.
Introduction
Diabetes mellitus is associated with an increased incidence in heart disease and cardiac events (1–3). This is because in the diabetic state the heart frequently undergoes alterations (myocardial hypertrophy, myocardial fibrosis, impairment of systolic and diastolic function, and coronary atherosclerosis), thereby increasing over the years the incidence of clinical events such as coronary artery disease, myocardial infarction, heart failure and sudden death (3–9). Although several studies have shown that in diabetes cardiac functional alterations may be already present at the time of the first diagnosis of this condition in asymptomatic patients (3,10–12), how early they occur has never been fully clarified. Indeed, the possibility exists that these alterations take place earlier than that is currently appreciated because evidence is available that some cardiovascular abnormalities are already detectable in offspring of diabetic patients in absence of any alteration in glucose metabolism (13).
The present study has been aimed at providing more conclusive information on the above-mentioned issue. Diastolic function was assessed by means of a very sensitive technique (pulse tissue Doppler analysis) (11,14,15) in a highly selected diabetic population, i.e. in patients with a recent diagnosis of type 2 diabetes without history of cardiovascular disease and with no evidence of left ventricular hypertrophy and/or systo-diastolic dysfunction at standard echocardiographic evaluation. This selection was made to verify the possible superiority of tissue Doppler in detecting functional alterations, and because of the well-known effect of structural abnormalities on diastolic dysfunction (3–12). The results have been compared with those obtained in diabetic hypertensive patients and in healthy controls.
Methods
Patient recruitment was made in the outpatient clinics of the San Gerardo University Hospital (Monza) and Federico II University Hospital (Naples). We enrolled 40 patients (21 males and 19 females) with an age ranging from 40 to 70 years and a diagnosis of type 2 diabetes mellitus made within the previous 5 years (in the majority of the patients it was made in the previous 2 years) and based on current diagnostic criteria (3). Twenty-four patients were normotensives while the remaining 16 had a history of hypertension and were under drug treatment with an angiotensin-converting enzyme (ACE) inhibitor. No patients had a history of ischaemic heart disease, renal disease, peripheral artery disease or heart failure. Other exclusion criteria were: (i) a fasting blood glucose > 250 mg/dl or a glycated haemoglobin > 8%, (ii) a body mass index > 35 kg/m2, (iii) a thorax conformation preventing collection of good quality echocardiographic data and (iv) the presence of left ventricular anatomic or functional alterations at the standard echocardiographic evaluation (see methods for details).
All patients were under stable antidiabetic oral treatment (mostly metformin) and a few were under additional insulin treatment. Twenty-three healthy volunteers were recruited from the transfusional blood unit of our hospital to serve as controls. All subjects were informed on the purpose of the study at which they agreed to participate. The ethic committees of the institutions involved approved the protocol of the study.
Measurements
Echocardiographic evaluation. M-mode tracings were recorded in the parasternal long axis view, and B-mode evaluation and colour Doppler analysis were performed by SONOS 7500 (HP, Massachusetts) equipped with tissue Doppler analysis software (see below). A 2.5-MHz transducer was used for all measurements. M-mode measurements were performed throughout the cardiac cycle according to the American Society of Echocardiography (ASE) recommendations (16). If the best orientation of left ventricle M-mode recordings could not be obtained, linear dimension measurements were used. Left ventricular mass was calculated according to the ASE formula (0.83 × ((D + T) 3 − D3) + 0.6), D being the left ventricular end-diastolic diameter and T the diastolic thickness of the septum and the posterior wall (16). Patients were recruited only if left ventricular mass (LVM) was less than 125 g/m2 in males and 110 g/m2 in females when indexed to body surface area. The ratio between left ventricular diameter and left ventricular wall thickness (RWT ratio) was considered normal if ≤ 0.42. Recruitment was limited to patients in whom left ventricular systolic and diastolic function at transmitral pulse Doppler was normal, i.e. the left ventricular ejection fraction (as assessed by the modified Simpson rule) was > 50% and the E/A ratio and the deceleration time of early diastolic left ventricular filling (obtained by assessing the blood flow velocities in the apical four chamber view at the top of the mitral leaflets) were > 0.8 and between 180 and 220 ms, respectively.
Pulsed tissue Doppler. Previous studies have shown that pulse tissue Doppler allows the assessment of the speed of myocardial contraction and relaxation directly at tissue level, with thus some potential advantages over standard echocardiographic measurements (11,14,15). Because the left ventricular apex remains relatively still throughout the cardiac cycle, mitral annular motion represents a good surrogate index of the overall longitudinal left ventricular speed of contraction and relaxation. In each patient, the transducer frequencies were about 3.5 MHz, the spectral pulsed Doppler signal filters were adjusted to the limit of 20 cm/s and a minimum optimal gain was used. Images were acquired at a speed of 50 mm/s. In the four-chamber apical view, a 5-mm pulsed Doppler sample volume was placed at the level of the lateral mitral annulus. Sm velocity was measured as a myocardial systolic index that is an index of left ventricular longitudinal systolic function. Em and Am and their ratio (Em/Am) were regarded as myocardial diastolic indexes. We consider values of Em/Am ratio normal if ≥ 1, values of lateral Em ≥ 10 cm/s, septal Em ≥ 8 cm/s and Sm ≥ 8 cm/s (16–20).
Additional data. All patients underwent a thorough medical history and a physical examination. Relevant additional measurements consisted of routine haematochemistry including fasting blood glucose and lipid profile, body mass index that was obtained by dividing weight (kilogram) by the square of height (meters). Blood pressure was measured twice before the echocardiographic examination, using the first and fifth Korotkoff sounds to identify systolic and diastolic values, respectively. Heart rate was obtained by the palpatory method following the blood pressure measurements. All measures were collected in the same day of the echocardiographic study.
Data analysis
Data are shown as means ± standard deviation (SD). The statistical significance of the differences in mean values was assessed by two-way analysis of variance (ANOVA). The two-tailed t-test for unpaired observations was used to locate differences between controls and diabetics. A p < 0.05 was taken as the level of statistical significance. Throughout the text, the symbol “ ± ” refers to the SD of the mean.
Results
Table I shows the demographic, anthropometric and clinical data separately for the control subjects and the diabetic patients with and without a documented history of hypertension. Diabetic normotensive and hypertensive patients were slightly, although not significantly, older than controls. The three groups had similar serum total cholesterol values, whereas serum triglyceride and, as expected, blood glucose values were greater in the two diabetic groups compared with the control one. Body mass index was elevated in the diabetic hypertensive group. Blood pressure was also elevated in this group, the systolic values being somewhat higher also in the normotensive diabetic patients compared with control subjects. Heart rate showed no substantial between-groups difference.
Table I. Demographic, anthropometric and clinical data.
As shown in Figure 1, LVM index, both when calculated by body surface area and by height2.7, showed higher values in hypertensive diabetic patients compared with controls, the values in normotensive diabetic patients being not significantly different from those seen in controls. The RWT (remodelling) ratio was slightly and significantly higher in the two diabetic groups than in the control one, the difference being slightly more evident in the hypertensive patients. The three groups were comparable for systolic and diastolic function as assessed by left ventricular ejection fraction (EF), E/A ratio and deceleration time.
Published online:
27 March 2012Figure 1. Structural and functional characteristics of the left ventricle as derived from standard echocardiography in the three groups of patients of Table I. LVMI, left ventricular mass calculated either via body surface area (BSA) or heigh2.7(ht); RWT, ratio between interventricular septum plus posterior wall and left ventricular end diastolic diameter left ventricle remodelling); LVEF, ejection fraction; E/A, ratio between rapid and atrial left ventricular diastolic filling. C, controls; DN, diabetic normotensives; DH, diabetic hypertensives. Data are means ± SD. *p < 0.05. For other symbols, see methods.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/iblo20/2012/iblo20.v021.i02/08037051.2012.625670/20150517/images/medium/iblo_a_625670_f0001_b.gif"})
Figure 1. Structural and functional characteristics of the left ventricle as derived from standard echocardiography in the three groups of patients of Table I. LVMI, left ventricular mass calculated either via body surface area (BSA) or heigh2.7(ht); RWT, ratio between interventricular septum plus posterior wall and left ventricular end diastolic diameter left ventricle remodelling); LVEF, ejection fraction; E/A, ratio between rapid and atrial left ventricular diastolic filling. C, controls; DN, diabetic normotensives; DH, diabetic hypertensives. Data are means ± SD. *p < 0.05. For other symbols, see methods.
The data obtained by tissue Doppler analysis are shown in Figure 2, upper panels. LSm (i.e. an index of systolic function) was similar in the three groups. In contrast, compared with controls, LEm/Am (i.e. an index of the speed of myocardial tissue relaxation) was reduced to a marked degree in the two diabetic groups. The reduction was slightly but significantly greater for magnitude in the presence of hypertension. The difference was similarly evident when data analysis was confined to subgroups of patients with a normal (≤ 0.42, mean value = 0.36 ± 0.01) RWT ratio and was not related to the duration of diabetes.
Published online:
27 March 2012Figure 2. Systolic and diastolic functional characteristics of the left ventricle as derived from tissue Doppler measurements in patients of Figure 1. The upper panels show data for the three groups of patients of Figure 1 (C, controls; DN, diabetic normotensives; DH, diabetic hypertensives). The lower panels show the data for diabetic patients with a RWT < 0.42. LSm, Systolic wave at tissue Doppler analysis at lateral mitral annulus. Lem/am, ratio between rapid and atrial tissue waves at tissue Doppler analysis at lateral mitral annulus; DM, diabetes mellitus; C, controls; other symbols as in Figure 1.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/iblo20/2012/iblo20.v021.i02/08037051.2012.625670/20150517/images/medium/iblo_a_625670_f0002_b.gif"})
Figure 2. Systolic and diastolic functional characteristics of the left ventricle as derived from tissue Doppler measurements in patients of Figure 1. The upper panels show data for the three groups of patients of Figure 1 (C, controls; DN, diabetic normotensives; DH, diabetic hypertensives). The lower panels show the data for diabetic patients with a RWT < 0.42. LSm, Systolic wave at tissue Doppler analysis at lateral mitral annulus. Lem/am, ratio between rapid and atrial tissue waves at tissue Doppler analysis at lateral mitral annulus; DM, diabetes mellitus; C, controls; other symbols as in Figure 1.
Discussion
Our study shows that normotensive patients with type 2 diabetes who display little or no evidence of alterations in cardiac structure and function at standard echocardiography may have a clear-cut alteration in diastolic function when this variable is assessed by the pulse tissue Doppler approach. This supports the conclusion that cardiac abnormalities are early phenomena in type 2 diabetes. It also indicates that for an early detection of these abnormalities, standard echocardiography may be inadequate and that more sensitive approaches, such as the one used in the present study, should be employed.
Several other results of our study deserve to be mentioned. One, the early cardiac abnormalities detected in our diabetic patients were limited to diastolic function because systolic function was superimposable in the two diabetic and in the control groups even when the sensitive tissue Doppler approach was employed. This is in line with the evidence collected in several studies that diastolic function is more easily altered by a disease process than systolic function (11,12,15,17,18,20,21). An example is arterial hypertension, in which diastolic dysfunction may precede the systolic one (10,17,21–24). Another example is heart failure in which a diastolic dysfunction can be detected even if systolic function is not altered (17–19,24–26).
Two, because of the need to select patients without evident alterations in cardiac structure and function at standard echocardiography, the number of recruited patients was limited. Three, diabetic patients were somewhat older than controls. However, this does not detract from our conclusion because the age difference did not translate into standard diastolic function alterations (measured at mitral leaflets) but only in tissue Doppler measurement differences, documenting once again the superior value of this approach compared with the more traditional one. The same conclusion applies to the finding that in our study hypertensive diabetics, while under the recommended pharmacological treatment with ACE inhibitors, showed blood pressure values higher than those recommended by current guidelines (27) without concomitant alterations in standard diastolic function. We cannot exclude that ACE inhibitor could have produced a favourable effect on cardiac and diastolic function in this group of patients. However, the evidence that normotensive diabetics display a diastolic dysfunction, as measured by pulse wave tissue Doppler, similar to that seen in hypertensives, further supports the major role of diabetes over high blood pressure on cardiac functional abnormalities. Finally, normotensive diabetic patients showed a significant increase in the RWT ratio compared with controls, a finding indicating the presence of an early left ventricular remodelling process (18–20). However, in normotensive diabetic patients, the RWT increase was modest for magnitude, whereas the reduction in Lem/Am compared with the value seen in the control group was quite pronounced.
In conclusion, the present study provides evidence that a subclinical cardiac damage of functional nature is present in diabetes mellitus, even at an early stage of the disease. This may carry important clinical implications, because it is well known that the presence of left ventricular remodelling increases the risk of myocardial infarction, heart failure and cardiac arrhythmias, while the presence of diastolic dysfunction (better detected by tissue Doppler analysis) may lead to diastolic heart failure if not promptly recognised (10,18–20,22,23). Thus the conclusion can be drawn that accurate echocardiographic evaluations, particularly if implemented by tissue Doppler analysis, improve the diagnosis of the early cardiac alterations, allowing the provision of a better estimation of the cardiovascular risk and the implementation of the therapeutic interventions capable to decrease the risk.
| Variable | Normotensive diabetics (n = 24) | Hypertensive diabetics (n = 16) | Normotensive/non-diabetics (n = 23) |
|---|---|---|---|
| Age (years) | 57.7 ± 1.9 | 60.4 ± 1.8 | 54.5 ± 1.9 |
| Males/females | 17/7 | 6/10 | 16/7 |
| BMI (kg/m2) | 26.9 ± 0.6 | 31.0 ± 0.8* | 25.0 ± 0.6 |
| Blood glucose (mg/dl) | 134.0 ± 4.7* | 139.8 ± 9.2* | 88.1 ± 3.7 |
| Systolic BP (mmHg) | 135.1 ± 3.3 | 154.3 ± 3.4* | 127.7 ± 2.0 |
| Diastolic BP (mmHg) | 79.0 ± 1.7 | 89.2 ± 2.8 | 81.1 ± 1.6 |
| Heart rate (beats/minute) | 74.4 ± 2.0 | 78.3 ± 1.5 | 72.4 ± 1.9 |
| Serum triglycerides (mg/dl) | 126.3 ± 14.1* | 129.1 ± 20.5* | 85.7 ± 12.1 |
| Serum t. cholesterol (mg/dl) | 188.2 ± 4.8 | 187.3 ± 9.2 | 204.0 ± 5.8 |
Data are shown as means ± standard error. BMI, body mass index; BP, blood pressure. *p < 0.05 vs normotensive and no diabetics.
Conflict of interest: None.
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