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P-wave duration changes and dispersion in preeclampsia

European Journal of Obstetrics & Gynecology and Reproductive Biology, pages 141 - 145

Abstract

Objective

The purpose of this research was to studyPwave parameters to determine the association between preeclampsia and future cardiovascular risk and to study the possible correlation betweenPwaves and severity of preeclampsia.

Study design

In this case-control study 58 pregnant women with preeclampsia and 30 normal pregnant women were compared by measuring maximum and minimumP-wave durations andP-wave dispersion (Pd) in the late third trimester.

Results

MinimumPwave values were lower and Pd values were higher, both significantly, in the preeclampsia groups than in the control group. In addition, the Pd values of the severe preeclampsia group were higher compared to that of the mild preeclampsia group.

Conclusion

Preeclampsia predisposes the patient to future cardiovascular complications including atrial or ventricular arrhythmias, but validated tools to assess the risks are yet not available.P-wave duration and Pd constitute a recent contribution to the field of noninvasive electrocardiology. Our data clearly demonstrated that minimumPwave and Pd values were significantly altered in preeclamptic pregnant women when compared to the controls. This important association can be used to screen women for increased risk in order to better target counseling regardinglifestyle modifications and to follow up and manage women with a history of preeclampsia more closely.

Keywords: Atrial fibrillation, Electrocardiographic screening, Hypertension, Preeclampsia.

Introduction

A healthy pregnancy is associated with changes in cardiovascular risk factors with high cardiac output, hypercoagulability, increased inflammatory activity, and insulin resistance with dyslipidemia [1] . Considering the metabolic syndrome-like picture presented by pregnant women with preeclampsia (hypertension, proteinuria, exaggerated insulin resistance, and endothelial dysfunction [2] ) and the state of uncontrolled inflammatory response [3] , it is not surprising that preeclampsia predisposes the patient to chronic hypertension, stroke, ischemic heart disease, peripheral arterial disease, venous thromboembolism, and other cardiovascular complications[4], [5], [6], and [7]. Furthermore, early onset or more severe or recurrent preeclampsia and complications such as placental abruption, preterm delivery and poor fetal growth are associated with increased cardiovascular risk in later life[8], [9], and [10].

Despite these clinical and experimental data, confirmed tools to determine future cardiovascular risk in women with a history of preeclampsia are not yet present. Several authors have defined electrocardiographic (ECG) screening as an agreeable tool for risk prediction in hypertensive patients[11] and [12]. Prognostic ECG abnormalities are voltage criteria of left ventricular hypertrophy (LVH) and repolarization abnormalities in hypertensive populations[13] and [14]. Non-specific ECG changes have also been demonstrated to be critical in estimating future cardiovascular disease (CVD) morbidity and mortality[15] and [16].P-wave dispersion (Pd) is defined as the difference between the maximal and minimalP-wave durations recorded from multiple surface ECG leads. Increased Pd values were associated with an increased risk for paroxysmal atrial fibrillation. Cardiovascular risk factors, such as coronary artery disease, obesity, hypertension and valvular disease, have all been suggested as affecting Pd values[17] and [18].

In the present study, our aim was to evaluate the association between preeclampsia and future cardiovascular risk. As such, for the first time in the medical literature, we studiedP-wave parameters not in women with a past history of preeclampsia, but in preeclampsia during pregnancy, and compared their data with that of a group of healthy pregnant women. We also tried to determine whether there was any correlation betweenP-wave characteristics and the severity of preeclampsia.

Materials and methods

Fifty-eight consecutive pregnant women with preeclampsia and 30 healthy age matched pregnant women underwent standard 12-lead ECG between January and July 2014 at Zekai Tahir Burak Women's Health Training and Research Hospital. Women with pre-known any chronic systemic disease (endocrinological, cardiovascular, gastrointestinal, immunological, or oncological) or multiple pregnancies were excluded. The ethics committee of our hospital approved the study, and informed consent was obtained from all pregnant before participation in the study.

The diagnostic criteria of preeclampsia included maternal systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg measured at resting for two times at 4-h intervals after 20 weeks of gestation in a previously normotensive woman, and proteinuria based on either measurement of ≥300 mg per 24-h urine collection or at least one positive dipstick reading. Severe preeclampsia was defined when maternal blood pressure was ≥160/110 mmHg on two occasions at least 4 h apart or one or more of the following conditions were present: renal insufficiency, thrombocytopenia, elevated liver transaminases to twice the normal concentrations, cerebral or visual symptoms, pulmonary edema, and severe right hypochondriac pain [19] . Age, gestational week, body mass index (BMI), resting heart rate, blood pressure, and hemoglobin levels of the participants were recorded.

All cases and controls underwent ECG and additionally echocardiography for excluding present cardiac anomaly. The 12-lead ECG was obtained at a paper speed of 50 mm/s and 1-mV/cm standardization. ECGs were recorded in a silent room, with the subject in the resting position at admission to our unit. All of the patients were in sinus rhythm and none was taking medications such as magnesium,corticosteroids, anti-arrhythmics or any antihypertensives.

ECGs without clearly identifiablePwaves were excluded from the Pd analysis.P-wave duration was evaluated in all 12 leads. Pregnant with measurablePwaves in >10 ECG leads were included in the study. Beginning of theP-wave was defined as the first atrial deflection from the isoelectric line, and the offset was the return of the atrial signal to baseline. Maximum (Pmax) and minimum (Pmin)P-wave durations were defined as the longest and shortest measurableP-wave durations, respectively, in any lead.P-wave dispersion (Pd) was calculated as the maximum minus minimumP-wave duration (Pd = Pmax − Pmin). The principal investigator (O.K.) without the knowledge of the patients or the controls performed measurements ofP-wave duration manually. To improve accuracy, the measurements were performed with calipers and a magnifying lens to define the ECG deflection.

Statistical analysis

The data were analyzed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL) version 12.0. Descriptive statistics were expressed as mean and standard deviation for numerical variables. Comparisons of multiple independent groups were performed with the Kruskal–Wallis test for numerical variables that are not normally distributed. Subgroup comparisons were performed using the Mann–WhitneyUtest with Bonferroni correction. The level of statistical significance was considered asp < 0.05.

Results

Five pregnant women were excluded from the study, because of unclearly identifiablePwaves in two, mild mitral stenosis in one and mitral valvular prolapses in two. Nonspecifically ST segments andTwave abnormalities were detected in 8 women but these changes were considered usual in pregnancies.

The study included a total of 88 pregnant women: 28 in the mild preeclampsia group, 30 in the severe preeclampsia group, and 30 healthy women without any complication of pregnancy. All of the groups were comparable in age, gravidity, BMI, and maternal resting heart rate. The mean gestational ages of the control and mild and severe preeclampsia groups were 38.7 ± 0.9, and 38.0 ± 1.4, and 35 ± 2.7 weeks, respectively, based on ultrasonographic measurements and first day of last menstrual period. The characteristics of the groups are showed in Table 1 .

Table 1 Characteristics of the study population.

Parameters Control (±SD) Mild preeclampsia (±SD) Severe preeclampsia (±SD) P value
Number (n) 30 28 30  
Age (yrs ± SD) 27.2 ± 4.8 28.2 ± 5.5 28.5 ± 5.6 0.593
Gestational week 38.7 ± 0.9 c 38.0 ± 1.4 c 35.3 ± 2.7a and b <0.001
BMI 29.2 ± 2.4 30.3 ± 4.1 28.4 ± 3.8 0.132
Heart rate (min) 79.6 ± 5.5 80.8 ± 7.3 82 ± 5.7 0.318
Systolic BP (mmHg) 110.6 ± 8.2b and c 142.5 ± 8.6a and c 160.6 ± 14.0a and b <0.001
Diastolic BP (mm Hg) 72.5 ± 7.4b and c 88.4 ± 8.2a and c 103.1 ± 8.6a and b <0.001

a Different from the control group.

b Different from the mild preeclampsia group.

c Different from the severe preeclampsia group.

SD: Standard deviation; BMI: body mass index.

Although there were no differences inPmaxvalues among the groups,Pminvalues were significantly lower in the preeclampsia groups than in the control group.Pminvalues were comparable between the mild and severe preeclampsia groups. Pd values were significantly higher in the preeclampsia groups than in the control group; they were also higher in the severe preeclampsia group than in the mild preeclampsia group.P-wave measurements of the groups are presented in Table 2 and Fig. 1 .

Table 2 P-wave measurements of the study population.

Parameter Control group (±SD) Mild preeclampsia (±SD) Severe preeclampsia (±SD) P value
Number (n) 30 28 30  
Pmax (ms) 96.7 ± 21.5 99.9 ± 8.2 97.7 ± 13.3 0.719
Pmin (ms) 53.8 ± 14.4b and c 38.9 ± 10.7 a 36.5 ± 12.3 a <0.001
Pd (ms) 42.1 ± 17b and c 58.0 ± 10.8a and c 60.3 ± 17.7a and b <0.001

a Different from the control group.

b Different from the mild preeclampsia group.

c Different from the severe preeclampsia group.

Pmax: maximumP-wave duration;Pmin: minimumP-wave duration; Pd:P-wave dispersion.

gr1

Fig. 1 The mean values ofP-wave dispersion in pregnant with preeclampsia and controls.

Comments

In 2011, the American Heart Association guidelines acknowledged preeclampsia as an independent gender-specific cardiovascular risk factor [20] . It has been estimated that compared with women without a history of pregnancy-related complications, the calculated ten-year CVD risk based on the Framingham score is 31% greater with preeclampsia history and 27% greater with gestational hypertension [21] .

Present evidences propose that pre-pregnancy risk factors and preeclampsia itself might both contribute to the development of long-term cardiovascular disease risk. Although a direct causative relationship between preeclampsia and cardiovascular disease has not yet been identified [22] , it has been hypothesized that permanent vascular damage continuously during the preeclamptic process due to exaggerated inflammation, increased oxidative stress, hypercoagulability and endothelial injury contribute to the pathogenesis of CVD. Increased levels of both soluble Fms-like tyrosine kinase 1(sFlt1), an endogenous inhibitor of angiogenic growth factors and soluble endoglin, a circulating co-receptor of transforming growth factor-β, have been observed to in preeclampsia when compared with healthy pregnancies[23] and [24].In addition, when these proteins are injected into rodents, the animals develop systemic endothelial dysfunction resulting in a syndrome that resembles maternal preeclampsia [25] . Some animal studies have showed that experimental preeclampsia induces long-term changes in the global plasma protein profile that correlate with alterations associated with CVD [26] .

The Rochester Family Heart Study, with a mean follow up of 27 years, showed that the coronary artery calcium score was higher among patients with a history of preeclampsia (Odds Ratio [OR] 2.4; 95% CI 1.2–4.9) after adjusting for age, blood pressure, and BMI [27] .Interestingly, fetal growth restriction alone, without preeclampsia, is also associated with impaired vascular function in the long term [28] .

P-wave dispersion (Pd) has been reported to be influenced by various cardiovascular risk factors[17] and [18]. Meta-analysis has demonstrated that increased pulse wave velocity (PWV), which supposedly indicates increased vascular stiffness related to endothelial dysfunction, is an important feature of preeclampsia [29] . In a study that assessed women with a history of preeclampsia at a mean of 16 months after delivery, a trend toward increased heart to brachial PWV was observed, suggesting that following a preeclamptic pregnancy, there might be persistent vascular stiffness that mainly affects the smaller arteries [30] . Perhaps studying acute atherosis of the uterine spiral arteries and the molecular interaction between trophoblastic and vascular cells might shed light on the development of atherosclerosis, stenosis, and CVD later in life [31] . Another study calculated the radial augmentation index, which is a marker of arterial stiffness similar to PWV, and reported that women with a history of early onset preeclampsia had increased arterial stiffness [28] .

P-wave parameters have been found to be independently associated with increased risk of atrial fibrillation (AF) and recurrent transient ischemic attacks[32] and [33]. Although rare in pregnancy, AF is the most common form of arrhythmia and causes serious medical complications, as well as early death [34] . Pd has previously been studied by different investigators in the hypertensive population, in acute ischemic stroke [35] , following coronary artery bypass surgery [36] , in association with myocardial ischemia [37] , autonomic tone changes such as the Valsalva maneuver [38] , renal function decline [39] , and during angina episodes [40] . ProlongedPmaxand Pd have been notified to represent an increased risk for paroxysmal AF and are therefore predictor markers in patients with no underlying heart disease [41] . These changes inP-wave parameters are caused by electrophysiological and electromechanical abnormalities resulting from exaggerate systemic inflammation, ischemia, increased oxidative stress, and enhanced sympathetic activity[42] and [43],which are also closely related to preeclampsia[44] and [45].P-wave dispersion was found to be significantly higher in hypertensive individuals who developed AF when compared to hypertensive patients who had no AF episodes during the follow up period. In the multivariate analysis, Pd was an independent predictor of the onset of AF in the hypertensive population (OR 2.81,p < 0.001), even after correcting for age. In the same study, no significant correlation was found between Pd and blood pressure level, left atrial dimension, or left ventricular mass [46] . In another publication, in addition to Pd being a sensitive and specific ECG predictor of paroxysmal lone AF, a reverse relation was reported betweenPminand Pd, implying that Pd, as a marker of atrial depolarization heterogeneity, was indirectly reflecting interatrial conduction defects and atrial size and structure abnormalities [36] .

Our study is unique in that, for the first time, we investigatedP-wave characteristics in groups of pregnant women with and without preeclampsia. Our hypothesis was based on previous data suggesting that pregnancy itself may act as an early natural “stress test” unmasking underlying defects and thereby identifying women at high risk for CVD later in life [47] . The findings of our study were in accord, to some extent, with results reported previously. In a recent study [48] that compared thePwave characteristics of healthy pregnant women in the second trimester with those of non-pregnant women, both thePmaxand the Pd were significantly longer in the pregnant subjects (103.1 ± 5.4 vs. 96.8 ± 7.4 ms,p < 0.001; 50.7 ± 6.8 vs. 41.6 ± 5.5 ms,p < 0.001, respectively). Although a comparison is not feasible because our study did not include non-pregnant individuals, the differences between the basal measurements of the two studies can be at least partially explained by the varying gestational weeks. In another study [49] , Pd was increased in pregnancy due to shortening of the minimumP-wave length, and it reached its longest length in the third trimester. Pregnancy also had no effect onPmax, similar to the changes in our preeclampsia patients. In our study on pregnant women in their late third trimesters,Pminvalues were lower and Pd values were higher, both significantly, in preeclampsia patients than in the control group. Furthermore, even higher Pd values discriminated the severe preeclampsia cases from the mild ones, which can be used as a clinical marker in differential diagnosis.

The major limitations of the present study are the relatively small population size and short-term follow up. Other limitations of our study include manual calculation ofP-wave parameters, using a magnifying lens instead of computer-assistedP-wave calculations, absence of Holter monitoring and strain rate parameters, and lack of electrophysiological evaluation. Furthermore, it has been shown that Pd varies with BMI and age, yet both parameters were similar among all three of our groups. Internal influences such as anxiety might also dramatically alter the results[50] and [51], and as anxiety levels were not measured routinely, statistical standardization could not be performed. Pd might also be influenced by autonomic function [52] ; thus, no standardization could be performed in the current study design. Diurnal variation might also be an intervening factor, as most studies did not elaborate on the time of day during which the ECG measurements were conducted [53] .

Despite these limitations, our study is the first of its kind to investigate the relationship between CVD risk and preeclampsia by measuringP-wave characteristics during pregnancy. This important association can be used to screen for increased risk in order to better target counseling regarding lifestyle modifications and to follow up and manage women with a history of preeclampsia more closely[54] and [55].Our data indicated thatPminand Pd values also correlate with the severity of preeclampsia. We believe that larger studies are needed to reproduce our data, and thus, to clarify the predictive value ofP-wave characteristics to foresee future cardiovascular complications.

Condensation

P-wave dispersion was prolonged in patients with preeclampsia, which may cause an increased risk of atrial fibrillation in this patient group.

Conflict of interest statement

None of the authors has any conflict of interest.

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Footnotes

a Department of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey

b Department of Perinatology, Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey

c Department of Cardiology, Ataturk Education and Research Hospital, Ankara, Turkey

lowast Corresponding author. Tel.: +90 533 646 9213; fax: +90 312 312 4931.