Pediatr Cardiol 12:69-73, 1991

Pediatric Cardiology 9 Springer-Verlag New York Inc. 1991

Original Articles Reduced Left Ventricular Afterload and Increased Contractility in Children with Insulin-Dependent Diabetes Mellitus: An M-Mode and Doppler-Echocardiographic Evaluation of Left Ventricular Diastolic and Systolic F u n c t i o n Ole G C t z s c h e , j K e l d Scwensen, j B i r t h e M c l n t y r e , 2 a n d P e r H e n n i n g s e n ~ ~University Department of Cardiology, Skejby Sygehus: and 2University Department of Pediatrics, Aarhus Kommunehospital, A,rhus C, Denmark S U M M A R Y . Twenty-three children with d i a b e t e s meUitus, t h e i r ages r a n g i n g f r o m 0 . 2 - 9 . 8 years, but with no sign of diabetic microvascular disease were investigated by M - m o d e a n d Doppler echocardiography, a l o n g with a comparable group of control subjects. In the d i a b e t i c s , the fractional shortening and the mean velocity of fractional shortening were 14 a n d 18% higher, respectively, whereas the left venlricular e n d - s y s t o l i c wall stress, an i n d i c a t o r o f left ventricular afterload, was markedly reduced (22%). Assuming an unchanged p r e l o a d in t h e t w o groups, this indicates a reduced a f t e r l o a d in these children. Systolic a n d d i a s t o l i c t i m e i n t e r v a l s , heart rate, and blood pressure were s i m i l a r in d i a b e t i c s a n d c o n t r o l s . D o p p l e r - d e r i v e d l r a n s m i tral left v e n t r i c u l a r filling indices were also s i m i l a r . T h u s , in t h e s e d i a b e t i c children no signs of left v e n t r i c u l a r diastolic abnormality were detected. The state of hypercontractility of the left v e n t r i c l e is c o n s i d e r e d to he due to a r e d u c e d a f t e r i o a d in early insulin-dependent diabetes.

KEY WORDS: Diabetes mellitus - - Left ventricular function - - Afterioad - - Doppler echocardiography

T h e e x i s t e n c e o f d i a b e t i c h e a r t d i s e a s e , u n r e l a t e d to c o r o n a r y a t h e r o s c l e r o s i s , has b e e n r e p o r t e d in rec e n t y e a r s [8, 18]. In a d u l t d i a b e t i c s w i t h o u t c o r o n a r y a t h e r o s c l e r o s i s , an e l e v a t e d e n d - d i a s t o l i c p r e s s u r e a n d d e c r e a s e d c o m p l i a n c e o f the left v e n t r i c l e h a v e b e e n o b s e r v e d [7, 22]. S u c h c h a n g e s c o u l d be d u e to the i n c r e a s e d m y o c a r d i a l fibrosis a n d diabetic a n g i o p a t h y o b s e r v e d in the m y o c a r d i u m a f t e r s e v e r a l y e a r s o f d i a b e t i c life [17]. N o n i n v a s i v e s t u d ies h a v e f o c u s e d on a b n o r m a l s y s t o l i c t i m e i n t e r v a l s a n d a b n o r m a l d i a s t o l i c f u n c t i o n o f the left v e n t r i c l e as j u d g e d by e c h o c a r d i o g r a p h y [1, 24]. H o w e v e r , m o s t o f t h e s e s t u d i e s w e r e p e r f o r m e d in a d u l t patients w h e r e the c o n t r i b u t i o n to the a b n o r m a l i t i e s by c o r o n a r y a t h e r o s c l e r o s i s w a s u n k n o w n . The purpose of the present echocardiographic s t u d y w a s to e v a l u a t e left v e n t r i c u l a r s y s t o l i c a n d

Address offprint requests to: Ole GCtzsche, University Depart-

ment of Cardiology, Skejby Sygehus, DK-8200 A,rhus N, Denmark.

d i a s t o l i c f u n c t i o n in d i a b e t i c c h i l d r e n w i t h o u t signs o f m i c r o v a s c u l a r c o m p l i c a t i o n s in e y e s o r k i d n e y s . S e l e c t i n g this a g e g r o u p w o u l d t h u s e l i m i n a t e a n y possible influence of coronary atherosclerosis.

Materials and Methods Twenty-three children with insulin-dependent diabetes mellitus and 14 healthy subjects were investigated. The control subjects were selected by asking the patients to bring along, if possible, a nondiabetic friend of comparable age and size. Clinical data are listed in Table 1. In the diabetic children no signs of retinopathy (background or proliferative) were observed, and repeated urinary examinations were consistently Albustix negative. Serum Hb Alc and the mean value of three blood glucose measurements obtained on the day preceding echocardiography served as indicators of recent and actual metabolic status, respectively. The echocardiographic examination was performed at 8:30 a.m., 2 h after the injection of the morning insulin. All of the diabetic children received a prolonged-action insulin preparation, while 13 of the 23 children in addition received a fast-acting insulin preparation.

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Pediatric Cardiology Vol. 12, No. 2, 1991

Table 1. Clinical data for the two groups Diabetes (n - 23) Age (years) Height (cm) Weight (kg) Heart rate Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

11.7 + 150 + 41.4 _+ 82.0-+ 106.3 +

Controls (n - 14) 2.5 (7-16) 16 (126-177) 11.9 (23.4-62.4) 9.6(67-97) 10 (90-130)

71.0 + 10 (60-95)

11.6_+ 150 -+ 40.5 _+ 80.1 _+ 106.9 +

2.0 (9-15) 12 (132-170) 11.6 (26-59.5) 11.8(65-106) 15 (85-125)

71).0 _+ I I (50-85)

Data are given as the m e a n + SD with the range in p a r e n t h e s e s .

Echocardiography The e x a m i n a t i o n s were performed and analyzed by O.G. and K . S . , w h o were u n a w a r e of w h e t h e r the child e x a m i n e d was a diabetic or control. E c h o c a r d i o g r a p h y was performed with the subject in a left lateral r e c u m b e n t position. M - M o d e registrations were p e r f o r m e d with a 3 . 5 - M H z t r a n s d u c e r , w h e r e a s flow recordings were m a d e with a 2.4-MHz transducer. Guided by two-dimensional e c h o c a r d i o g r a p h y , standard Mm o d e recordings of the aortic and mitral valves, as well as the left ventricle were obtained from the parasternal long-axis view. S i m u l t a n e o u s aortic and mitral valve m o v e m e n t s were recorded by dual M - m o d e e c h o c a r d i o g r a p h y . Registrations were made on photographic paper m o v i n g at 50 m m / s . Transmitral pulsed Doppler inflow recordings were obtained from the apical f o u r - c h a m b e r view with the sample volu m e positioned at the mitral anulus with the c u r s o r line positioned through a line traversing the left ventricle from the apex to the mitral valve anulus. Paper speed was 100 m m / s . A single E C G lead was recorded s i m u l t a n e o u s l y on the echocardiograms. After the examination, blood p r e s s u r e was m e a s u r e d by the cuff method.

Measurements F r o m the M - m o d e tracings the following p a r a m e t e r s were measured, as s h o w n in Fig. 1. Systolic time intervals were as follows: (a) preejection period (PEP), (b) c o n d u c t i o n time (CT), (c) isovolumic contraction time (IVC), and (d) left ventricular ejection time (LVET). To correct for RR interval variation, the PEP index and the L V E T index were calculated according to Weissler [26]. Diastolic time intervals were as follows: (a) isovolumic relaxation time (IVR) and (b) mitral valve-opening time (MO). The left ventricular fractional shortening [(LVIDd LVIDs) x 100/LVIDd], as well as the m e a n velocity of fractional shortening Vfc ( F S / L V E T ) were calculated from the left ventricular internal d i a m e t e r s in systole and diastole (LV1Ds, LVIDd) and the ejection time. Left ventricular end-systolic meridional wall stress (ESWS) was calculated as (0.334 x BPs x L V I D s / L P W T s x 1 + L P W T s / L V I D s ) where BPs is systolic blood pressure and L P W T s the left ventricular posterior wall thickness in systole [11]. Left ventricutar wall m a s s was evaluated as average poste-

Fig. 1. Dual M - m o d e recording of mitral (upper panel) and aorta valves (lower panel). T h e following points were digitized: start of Q wave in E C G to closure of mitral valve for conduction time (CT), closure o f mitral valve to opening of aortic valve for isovolumic contraction time (IVC) [preejection period (PEP) = CT + IVC], opening to closure of aortic valve for left ventricular ejection time (LVET), closure of aortic valve to opening of mitral valve for isovolumic relaxation time (IVR), and opening to closure of mitral valve for mitral valve-opening time (MO).

rior plus septal t h i c k n e s s in diastole, divided by left ventricular internal diameter in diastole (T/r). F r o m the Doppler tracings the following left ventricular filling indices were obtained (Fig. 2): peak early filling o f the ventricle (PEFV) and peak late filling of the ventricle (PLFV). The acceleration and deceleration of P E F V was calculated as the slope of a straight line, drawn between the P E F V and a point at half-peak velocity on the ascending and d e s c e n d i n g side o f the envelope, respectively [15].

GCtzsche et al.: Myocardial Function in Diabetic Children

Table 2. M - m o d e m e a s u r e m e n t s and calculations

PEFV

! DC 600 -'~"

Ii

71

PLFV

Fig. 2.

Pulsed Doppler tracing of left ventricular filling. Digitized points for estimation of peak early filling of left ventricle (PEFV), peak late filling o f left ventricle (PLFV), and acceleration (AC) and deceleration (DC) of early ventricular filling are indicated. The electrocardiogram is s u p e r i m p o s e d .

All photographic strips were coded and read blind. Ten consecutive cycles of technically suitable quality were digitized and the mean value used for data evaluation.

Statistics Values are given as the m e a n _+ SD. S t u d e n t ' s t test with a level of significance of 5% was used for testing differences between groups. Correlations were tested by standard linear regression analysis.

Results

No significant differences in age, sex, weight, or height appeared between the groups. Mean duration of diabetes was 4.6 years (range, 0.2-9.8 years). The mean serum Hb A l c was 9.1 + 2.2% (range, 5.1-14.2) and the mean blood glucose 11.1 -+ 3.1 mmol/L (range, 5.5-18.1). Blood pressure and heart rate did not differ between the groups (Table 1). M-Mode measurements and calculations are given in Table 2. A significant lower LVIDs (14%, p < 0.01) was noted in diabetic children, while the difference (6%) in L V I D d did not quite reach significance (p = 0.06). Consequently, higher fractional shortening (FS, 14%, p < 0.05) and Vcf (18%, p < 0.05) were found in diabetics. Also, a significant reduction (22%, p < 0.01) in ESWS was observed in the diabetic children. The relation between systolic wall stress and FS in the two groups is seen in Fig. 3, where the regression line -+ SD for this relation in the control group is also shown. An estimate of left

L V I D s (mm) LVIDd(mm) STd (mm) L P W T d (mm) L P W T s (mm) T/r FS (%) VCF(circ/s) E S W S (g/cm 2) PEPi (ms) C T (ms) IVC (ms) L V E T i (ms) PEPi/LVETi IVR (ms) M O (ms)

Diabetes

Controls

p

23.1 -+ 3.8 38.5 _+ 3.9 6.9 _+ 1.3 7.2 _+ 1.0 12.2 -+ 1.4 0.181-+ 0.029 40.4 -+ 6.4 0.99 -+ 0.16 53.2 -+ 14.9 1t4 --+ 21 38 _+ 16 48 +- 12 416 +- 26 0.28 -+ 0.06 31 _+ 12 382 _+ 79

26.9 -+ 2.4 41.1 _+ 3.5 7.2 -+ 0.7 7.5 -+ 1.2 11.6 + 1.8 0 . 1 9 0 -+- 0.032 35.3 -+ 6.1 0.84 + 0.16 68.2 _+ 14.2 115 _+ 14 41 -+ 23 42 _+ 20 419 _+ 13 0.28 -+ 0.04 34 + 14 390 -+ 78

0.003 NS NS NS NS NS 0.03 0.03 0.01 NS NS NS NS NS NS NS

CT, c o n d u c t i o n time; E S W S , end-systolic wall stress; FS, fractional shortening; IVC, isovolumic c o n d u c t i o n time; 1VR, isovolumic relaxation time; L P W T d , left ventricular posterior wall in diastole. L P W T s , left ventricular posterior wall t h i c k n e s s in systole; L V E T i , left ventricular ejection time index; LVIDd, left ventricular internal diameter in diastole; L V I D s , left ventricular internal diameter in systole; MO, mitral valve-opening time; PEPi, preejection period index; STd, septal t h i c k n e s s in diastole; T/r, average posterior plus septal wall t h i c k n e s s divided by left ventricular internal diameter in diastole; Vcf, m e a n velocity of circumferential shortening; NS, not significant.

ventricular mass showed no sign of left ventricular h y p e r t r o p h y in diabetes. Correction for individual surface area did not change the results. Considering the left ventricular systolic and diastolic time intervals, no significant differences were o b s e r v e d between the groups (Table 2). Similarly, left ventricular filling characteristics, described by Doppler flowmetry of the mitral valve, showed no significant differences between diabetic children and controls (Table 3). N o n e of the echocardiographic parameters correlated with the indices of metabolic control, age, or diabetes duration.

Discussion

The present results demonstrate that indices of left ventricular contraction (FS, Vcf) were increased short-term in diabetic children with no sign of diabetic angiography in kidney and eyes. Wall stress was estimated using the peak BPs. Assuming no differential fall in pressure between the groups toward the end o f systole, this p a r a m e t e r was used for the estimation of ESWS. Given that preload is unchanged, E S W S is a valid noninvasive indicator of

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Pediatric Cardiology Vol. 12, No. 2, 1991

FS%

Table 3. Doppler echocardiographic +SD

left ventricular

filling

indices

6(

PEFV(cm/s) AC (cm/s-') DC (cm/sZ) PLFV(cm/s) PEFV/PLFV

Diabetes

Controls

p

73.7 647 504 42.7 1.78

75.0 613 521 41.5 1.88

NS NS NS NS NS

+ 18.9 • 223 + 141 4- 10.4 _+ 0.40

-+ 10.9 • 117 • 117 -+ 6.7 + 0.43

AC, acceleration of peak early filling; DC, deceleration of peak early filling; PEFV, peak early filling of left ventricle; P L F V . peak late filling of left ventricle: NS. not significant.

40

8O

ESWS g/cm 2

Fig. 3. Relation b e t w e e n fractional shortening (FS) and end-systolic wall stress (ESWS). Regression line • SD for the control group are indicated. M e a n • SD are s h o w n for diabetics (*) and for controls ( 9

left ventricular afterload [3]. Noninvasive studies have also shown that an increase in the inotropic state by dobutamine infusion increases FS leaving the wall stress unchanged [3, 5]. The relation between wall stress and FS in the present subjects favors the possibility that the reason for the increased contractility is a reduced afterload in diabetic children. Moreover, the observed reduction in ESWS could at least partially reflect the hyperperfusion of the kidney [21], the retina [16], and the subcutaneous tissue [12] seen during early stages of insulin-dependent diabetes mellitus. Thuesen et al. found the left ventricular FS, as well as heart rate increased in young adults with insulin-dependent diabetes mellitus [25]. Improving the metabolic control led to reduction of the FS, indicating that left ventricular hypercontractility is a reversible and probably metabolically induced phenomenon. Others have reported an increased cardiac output during poor metabolic control in young adults with diabetes [10, 20]. No measurement of cardiac output was performed in the present study, but the smaller diameter of the left ventricle in systole and in diastole (although not significant) makes it unlikely that the increased FS reflects an increased cardiac output in these diabetic children. In diabetic children, Friedman et al. observed

an increased systolic diameter of the left ventricle and reduced velocity of circumferential shortening [9]. Whether a considerably higher Hb Alc level in that series could lead to a decreased contractility is speculative, but would indicate that in diabetics with moderate hyperglycemia an increased myocardial contractility is seen, while more extreme metabolic derangement leads to impairment of myocardial function. Such an inverse relationship between FS and the Hb A lc level, averaged over the preceeding 2 years, has in fact been recently reported in diabetic children [14]. Insulin in high doses is known to have positive inotropic and chronotropic effects [19], but this cannot explain the finding since optimizing the metabolic control in diabetic youths leads to a decrease in shortening fraction [25]. Moreover, the therapeutic serum concentration of this hormone is not at a level to explain the phenomenon [2]. An increased serum catecholamine level has been described in insulin-dependent diabetes, but only in patients with considerable metabolic derangement [4]. It is also unknown whether such circulating hormones affect the heart at the cellular level where adrenoceptor modification may have taken place, as described in animals with experimental diabetes [13]. If an increased sympathetic drive were to play a role, one might have expected a concomitant increase in heart rate in these children, but this was not observed. In diabetics, abnormal left ventricular diastolic function has been reported in echocardiographic studies focusing on mitral valve movement and its relation to septal wall motion. The patients studied were young adults with long-term diabetes and vascular complications [23]. The same abnormality has recently been described in children with a mean age of 16.7 years, while younger children had normal diastolic function as judged by this time interval [14]. In the present study pulsed Doppler cardiogra-

GCtzsche et al.: Myocardial Function in Diabetic Children

phy was used to characterize the transmitral flow profile. This method is suitable to detect early diastolic abnormalities in the left ventricle [15], but no impairment was seen in the present children with a mean age of 11.7 years. Even a mild degree of hypertension has been suggested as a cause of early diastolic dysfunction in diabetes [6]; the fact that the present children had a normal blood pressure could mean that an abnormal transmitral flow pattern was not to be expected. In conclusion, diabetic children had hypercontraction of the left ventricle, possibly due to a reduced afterload. Diastolic impairment is likely to appear in diabetic heart disease, but apparently only in adults and conceivably not until hypertension or long-term complications are present in other organs. There is no indication that the state of hypercontraction is directly related to diabetic heart disease. However, it would be of considerable interest to discover whether the children with the most marked afterload reduction will be at risk of developing diabetic angiopathy in other organs.

Acknowledgments. The study was supported by The Danish Heart Association.

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