Original Article
Altered Platelet Calcium Metabolism as an Early Predictor of Increased Peripheral Vascular Resistance and Preeclampsia in Urban Black Women
N Engl J Med 1990; 323:434-438August 16, 1990
- Abstract
- Abstract
Background.
Although preeclampsia is an important and relatively common medical problem, its pathophysiology remains unresolved and the search for a biochemical marker that precedes the hemodynamic abnormalities of preeclampsia continues. We designed a study to investigate the hemodynamic changes that characterize preeclampsia and to evaluate the metabolism of platelet intracellular calcium as a possible predictor of the development of preeclampsia.
Methods.
Hemodynamic measurements and spectrofluorometric determinations of the levels of intracellular calcium in platelets in the basal state and after stimulation with an agonist were performed in 48 nulliparous black women during each trimester of pregnancy. The data on the 14 women (29 percent) in whom preeclampsia developed were then compared with the data on the other 34, who served as normotensive controls.
Results.
There was no significant difference between the two groups in the basal levels of intracellular calcium at any time. In contrast, the levels measured after arginine vasopressin was administered during the first trimester indicated an exaggerated response in the group with preeclampsia as compared with the control group (1494±388 [±SEM] percent vs. 545±55 percent of base line; P<0.0002), which was sustained through the second and third trimesters. All but three of the women with preeclampsia had responses higher than the highest response among the controls. Platelet intracellular calcium responses to arginine vasopressin during the first trimester were a sensitive predictor of the subsequent development of preeclampsia (P<0.00009). Although vascular resistance was similar in the two groups during the first trimester, it subsequently decreased in the control group (P<0.02) but not in the group with preeclampsia.
Conclusions.
Our findings indicate that preeclampsia is characterized by the absence of the normal pregnancy-related decrease in vascular resistance, which is preceded in most instances by an exaggerated response of platelet intracellular calcium to arginine vasopressin early in pregnancy. We therefore propose that an increase in the sensitivity of platelet calcium to arginine vasopressin can be used as an early predictor of subsequent preeclampsia. (N Engl J Med 1990; 323:434–8.)
Media in This Article
Figure 1
Distribution of the Responses of Platelet Intracellular Calcium to Arginine Vasopressin (Expressed as a Percentage of Base-Line Values) in the First Trimester in 14 Women in Whom Preeclampsia Later Developed and 34 Who Had Normal Pregnancies.Table 1
Characteristics of the Study Groups.*Article Activity
- Article
PREECLAMPSIA affects at least 5 to 6 percent of nulliparous pregnant women and up to 20 percent of indigent inner-city pregnant women, causing substantial increases in both maternal and fetal—neonatal morbidity and mortality. However, the pathophysiology of preeclampsia is poorly understood; proposed primary abnormalities have included alterations in systemic hemodynamics, renal hemodynamics, cellular cation metabolism, prostaglandin metabolism, endocrine function, and uteroplacental function.1 2 3 4 5 6 7 Early biochemical abnormalities that precede and predict the development of preeclampsia have long been looked for but have remained elusive.1 , 2
Normal pregnancy is characterized by both increased cardiac output and reduced peripheral vascular resistance,2 , 4 , 8 as well as by blunted responsiveness of vascular tissue to the pressor effects of angiotensin II.9 , 10 Accordingly, it has been proposed that preeclampsia may result from the absence of an appropriate decrease in vascular resistance and pressor responses to vasoactive stimuli.4
Alternatively, increased cardiac output has been proposed as the fundamental hemodynamic defect in preeclampsia.2 , 3 A number of investigators have examined the relation between cardiac output and ppregnancy-induced hypertension2 , 11 12 13 14 15 16; their data collectively indicate no clear relation, with reports of increased, decreased, and unchanged cardiac output. Despite these observations, Easterling and Benedetti2 recently suggested that the fundamental hemodynamic change in preeclampsia is an elevation of cardiac output early in pregnancy, well before the onset of severe disease, with compensatory vasodilatation that maintains normotension. To account for the finding of increased peripheral vascular resistance in patients with preeclampsia,4 , 11 they propose that a change in the hemodynamic pattern of preeclampsia occurs late in the disease, with a "crossover" from a state of high cardiac output to one of high resistance.2 However, longitudinal studies of cardiac output and vascular resistance during normal pregnancies and pregnancies with preeclampsia have not yet been reported. Nonetheless, the observations that women with preeclampsia do not have the decline in vasopressor response that is characteristic of normal pregnancy and that this hemodynamic abnormality is evident early in pregnancy10 suggest that preeclampsia is more likely to be characterized as a state of enhanced vascular reactivity occurring early in the course of the disease.
The level of free intracellular calcium is a major determinant of vascular smooth-muscle tone and, consequently, of peripheral vascular resistance.17 , 18 A number of studies, recently reviewed,19 have implicated abnormalities in the cellular handling of intracellular calcium in hypertensive states. Furthermore, we have recently reported that preeclampsia is associated with a significant increase in intracellular calcium,3 although the differences in peripheral vascular resistance between healthy nonpregnant women and pregnant women have not been associated with differences in intracellular calcium levels.8 Thus, an increase in platelet intracellular calcium may contribute to the increase in peripheral vascular resistance in preeclampsia, and a decrease in intracellular calcium may contribute to the decrease in vascular resistance characteristic of normal pregnancy. We conducted the present study to compare longitudinal changes in peripheral vascular resistance and cardiac output in normal pregnancy and pregnancy with preeclampsia and to determine their relation to changes in the metabolism of platelet intracellular calcium. We used platelets in evaluating intracellular calcium metabolism because they are accessible and have anatomical and functional properties that make them plausible surrogates for vascular smooth-muscle cells.7 8 9
Methods
Subjects
Forty-eight nulliparous young black women were enrolled in the study at the end of their first trimester of pregnancy. All were normotensive, with no history of hypertension, were not taking any medications, and had no history of substance abuse; their characteristics are shown in Table 1Table 1
Characteristics of the Study Groups.*. They were recruited from the obstetrical—gynecological clinics of the Detroit Medical Center—Wayne State University, and all gave informed consent to participation. This study was approved by the Human Investigation Committee of Wayne State University.All subjects were studied at enrollment and near the end of the second trimester (25 weeks) and the third trimester (34 to 36 weeks). On completion of the study, 14 subjects were found to have preeclampsia; the data on this group were consequently separated from and compared with the data on the other 34 subjects. The diagnosis of preeclampsia was made on the basis of the criteria of the American College of Obstetrics and Gynecology (blood pressure, > 140/90 mm Hg and proteinuria [>0.3 g of urinary protein per day] or edema or both).20 All measurements were obtained by personnel unaware of the clinical status of each subject.
Hemodynamic Function
All hemodynamic measurements were made while the subjects were recumbent on their left side for 20 minutes, so that the uterus would not interfere with venous return through the vena cava and the associated reduction in cardiac output would be avoided. Blood pressure was determined in the right arm with a standard mercury-column sphygmomanometer; the values reported here represent the mean of three readings taken one minute apart. Blood flow and vascular resistance in the forearm and cardiac output were measured by electrical-impedance plethysmography (IPG 102, RJL Systems, Detroit). This method, although challenged,21 has been shown to be a valid technique for measuring cardiac output in both pregnant22 , 23 and nonpregnant24 25 26 subjects. It is based on the detection of changes in electrical resistance in any region of the body, which reflect changes in pulsatile blood volume during the cardiac cycle.24 , 25 , 27 To determine blood flow in the forearm, two detecting electrodes were placed 10 cm apart and centered in the right forearm, and two signal-introduction electrodes were placed approximately 20 cm proximal and distal to the area to be measured. Blood flow was then calculated from the resulting tracing according to the backslope-projection method of Nyboer.24 In our laboratory, the coefficient of variation for blood flow calculated with this method is 2 to 4 percent. Vascular resistance in the forearm was calculated by dividing the mean arterial pressure by blood flow in the forearm. Stroke volume was similarly determined by impedance plethysmography,8 , 25 and cardiac output was calculated by multiplying the stroke volume by the heart rate as determined from simultaneously obtained electrocardiographic readings. Data on cardiac output were normalized for body-surface area and are reported as the cardiac index.
Platelet Calcium
Blood samples (≈15 ml each) were collected in EDTA-treated Vacutainer tubes and centrifuged at 200×g for 15 minutes at 21°C for the determination of platelet intracellular ionized calcium levels. The platelet-rich plasma was incubated in 3 μmol of fura-2-acetoxymethyl ester (fura-2) per liter at 37°C for 30 minutes and centrifuged at 650×g for 10 minutes at 21°C; the plasma and extracellular fura-2 was removed by aspiration. The platelet pellet was then suspended in a calcium-free HEPES (10 mM) buffer (pH 7.4) and centrifuged at 650×g; the platelets were suspended at a concentration of 1×107 cells per milliliter in HEPES (10 mM) containing calcium (1.5 mM). We have previously found that this method of preparing platelets by differential centrifugation yields results indistinguishable from those obtained in platelets purified by gel filtration.28 Intracellular calcium was measured in a SPEX 1680 dual-excitation monochromator spectrofluorometer (SPEX Industries, Edison, N.J.) with excitation wavelengths of 340 and 380 nm, an emission wavelength of 505 nm, and entry and exit slits set at 3 nm. The response of intracellular calcium levels to arginine vasopressin and thrombin was determined by measuring the peak response to 9μmol of arginine vasopressin per liter and to thrombin at a concentration of 0.3 U per milliliter, after a stable base-line value for calcium had been established before each agonist was added. The response to each agonist is expressed as the percent increase over the base-line calcium level. All measurements were made in a water-jacketed cuvette at 37°C, with continuous stirring. The intracellular calcium level was calculated from the ratio of fluorescence at 340 nm to that at 380 nm, as described by Grynkiewicz et al.29; the maximal ratio was obtained with 0.7 percent Triton X-100, and the minimal ratio with 5 mM EGTA-TRIS (pH 8.6).29
Statistical Analysis
Data were evaluated by two-way analysis of variance (time × group) with a repeated-measures component after it was verified that the data were normally distributed. The predictive value of the level of platelet intracellular calcium in prospectively identifying women in whom preeclampsia developed was assessed by discriminant analysis.30 These data were further evaluated with a stepwise Cox proportional-hazards model31 to determine the relative risk associated with changes in platelet calcium values. Statistical analyses were performed with the software SPSS/PC+ (SPSS, Chicago) and BMDP (University of California, Berkeley). All values are expressed as means ±SEM.
Results
There were no significant differences between the group with preeclampsia and the control group in age, height, weight, or blood pressure at entry into the study (Table 1). The control group had a significant increase in forearm blood flow (P<0.03) that resulted in a significant decrease in vascular resistance from the first to the second trimester (P<0.05), which was sustained into the third trimester (Table 2Table 2
Mean (±SEM) Forearm Vascular Resistance and Cardiac Index in the Study Groups.). In contrast, the group with preeclampsia had no significant decrease in vascular resistance between the first and third trimesters (Table 2). The cardiac index did not differ significantly between the two groups at the end of the first trimester and remained comparable in them during the second and third trimesters, although it exhibited a progressive, significant increase in both groups during the later trimesters (P<0.03) (Table 2).There were no significant changes in basal levels of intracellular calcium in either group during the course of pregnancy, and there were no significant differences between the groups (Table 3Table 3
Mean (±SEM) Responses of Platelet Intracellular Calcium Levels to Arginine Vasopressin (AVP) and Thrombin.). In contrast, there was a significant decrease in the response of intracellular calcium to arginine vasopressin from the first to the second trimester, which was sustained through the third trimester (P<0.05) (Table 3). Furthermore, there was a significant increase in the response of intracellular calcium to arginine vasopressin during the first trimester in the group with preeclampsia as compared with that in the control group (P<0.0002) (Fig. 1Figure 1Distribution of the Responses of Platelet Intracellular Calcium to Arginine Vasopressin (Expressed as a Percentage of Base-Line Values) in the First Trimester in 14 Women in Whom Preeclampsia Later Developed and 34 Who Had Normal Pregnancies. and Table 3); this difference was sustained through the third trimester. There was no significant change in either group in the response of intracellular calcium to thrombin during the course of pregnancy, and there were no differences between the groups in this response, although values tended to be higher in the group with preeclampsia.Discriminant analysis indicated that the platelet intracellular calcium response to arginine vasopressin during the first trimester was a significant predictor of the subsequent development of preeclampsia (chi-square = 30.3; P<0.00009). When the response of intracellular calcium to arginine vasopressin, the base-line level of intracellular calcium, and mean arterial pressure were included in the discriminant function, the group status of 88 percent of the patients in the group with preeclampsia and 96 percent of those in the control group was correctly identified. Similarly, when the Cox proportional-hazards model was applied, the response of intracellular calcium to arginine vasopressin was found to be a significant risk factor for the development of preeclampsia (P<0.0009): an increase of 1 SD (864 percent) in the response was associated with a relative risk of 3.08 (95 percent confidence interval, 3.18 to 4.63). After the risk associated with this variable in this model was accounted for, increased mean arterial pressure remained as a risk factor: an increase of 1 SD (6.6 mm Hg) in mean arterial pressure was associated with a relative risk of 2.04 (95 percent confidence interval, 1.67 to 2.50).
Discussion
This study demonstrates an early intrinsic biochemical marker for the subsequent development of preeclampsia in an otherwise normal group of women studied prospectively — namely, a marked increase in the sensitivity of platelet intracellular calcium to arginine vasopressin during the first trimester of pregnancy. The usefulness of this biochemical predictor is enhanced by the accessibility of platelets for study and the availability of sensitive indicators for the measurement of intracellular calcium.
Several recent studies have demonstrated increased intracellular calcium in platelets in hypertensive states (reviewed by Sowers et al.19), although this difference is not evident in neutrophils.32 Abnormal metabolism of platelet intracellular calcium in persons with hypertension is further evidenced by impaired activation of membrane calcium—adenosine triphosphatase in the platelets of such persons33 and by the significant correlations between blood pressure and both platelet-free intracellular calcium34 and platelet-membrane–bound calcium.35 In contrast, in the present study basal intracellular calcium levels did not differ between the group with preeclampsia and the control group at any time during pregnancy, and the significant decrease in peripheral vascular resistance over the course of normal pregnancy was not accompanied by a comparable decrease in intracellular calcium levels. Thus, changes in vascular tone are not necessarily reflected by comparable changes in platelet intracellular calcium values, suggesting that changes in basal platelet intracellular calcium levels may not reflect comparable changes in vascular smooth muscle. Similarly, recent data8 , 36 indicate that over the course of normal pregnancy there is no change in the platelet intracellular calcium level despite the significant decrease in peripheral vascular resistance that accompanies pregnancy.4 , 8 9 10 , 37 Haller et al.,36 however, in a cross-sectional study of women in the third trimester, reported that basal platelet intracellular calcium increased in their subjects with preeclampsia as compared with their controls; we did not observe such a difference in the present study. The reason for this discrepancy is not clear; however, Haller et al. used quin-2 (quin-2-tetraacetoxymethyl ester) for measuring intracellular calcium, whereas we used the more sensitive fura-2; their basal platelet intracellular calcium values were approximately twice ours. Thus, the discrepancy may be partly the result of such methodologic differences.29
The striking increase in the sensitivity of platelet intracellular calcium levels to arginine vasopressin noted by the end of the first trimester in the group with preeclampsia (Fig. 1) occurred well before any signs of preeclampsia were evident. This increase parallels the increase in vascular sensitivity to a pressor agent (angiotensin II) found early in pregnancy in women with preeclampsia.10 Since platelets express angiotensin II receptors, although in very low density 38 , 39 we investigated this parallel further by evaluating the peak responses of platelet calcium to angiotensin II; however, the platelets consistently showed no response to any of the concentrations of angiotensin II used (data not shown). Haller et al.36 found that platelets from women with preeclampsia showed increased sensitivity to angiotensin II; this was similar to the increased sensitivity to arginine vasopressin that we observed in the present study. However, these patients all had established preeclampsia at the time of study, as indicated by severe hypertension and marked proteinuria (> 1.0 g of urinary protein per day), whereas our patients had the exaggerated response of platelet calcium to arginine vasopressin early in pregnancy, before the development of significant differences in blood pressure between the women who eventually had preeclampsia and those who did not.
The data from this study do not support the notion that preeclampsia represents a hyperdynamic state characterized by an early increase in cardiac output, with compensatory vasodilatation to maintain normotension, since there was no significant difference between the two groups in cardiac index at any time during the study. Previous studies have evaluated the relation between cardiac output, systemic vascular resistance, and preeclampsia4 , 11 12 13 14 15 16 , 24 , 40 41 42 43 44 and have reported increases, decreases, and no difference in pregnancies with preeclampsia as compared with normal pregnancies, although these studies have been of a cross-sectional nature and many have not limited their subjects to patients with uncomplicated preeclampsia before treatment. When these criteria have been met,4 , 41 , 43 reduced rather than increased cardiac output has characterized the preeclamptic state. Wallenburg45 recently reported that patients with untreated preeclampsia had uniformly low cardiac output and elevated systemic vascular resistance, whereas those who were evaluated during treatment had no uniform pattern. Although we did not observe a similar decrease in cardiac output in the present study, both our data and data from previous studies4 , 41 , 43 , 45 indicate that cardiac output is not increased in preeclampsia, and are consistent with the classic notion that the primary hemodynamic abnormality in preeclampsia is an increase in peripheral vascular resistance, in agreement with earlier reports of increased vascular reactivity to angiotensin II early in preeclampsia.9 , 10
Supported by a grant (HD-24497) from the National Institute of Child Health and Human Development.
Source Information
From the Division of Endocrinology and Hypertension (M.B.Z., P.C.Z., G.N., P.R.S., M.F.W., J.R.S.), the Department of Nutrition and Food Science (M.B.Z., J.R.S.), and the Department of Obstetrics and Gynecology (S.B., G.N., C.K., R.J.S.), Wayne State University, Detroit. Address reprint requests to Dr. Sowers at the Division of Endocrinology and Hypertension, Wayne State University School of Medicine, 4H-UHC, 4201 St. Antoine, Detroit, MI 48201.
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